Eficacia y seguridad de las vacunas para la covid‐19
Resumen
Antecedentes
Se han desarrollado distintas formulaciones de vacunas para prevenir el virus SARS‐CoV‐2 y la consiguiente enfermedad de covid‐19. Varias se emplean de forma generalizada en todo el mundo.
Objetivos
Evaluar la eficacia y la seguridad de las vacunas de la covid‐19 (como serie de vacunación primaria completa o como dosis de refuerzo) contra el SARS‐CoV‐2.
Métodos de búsqueda
Se realizaron búsquedas en el Registro Cochrane de Estudios de covid‐19 (Cochrane COVID‐19 Study Register) y en la plataforma COVID‐19 L·OVE (última búsqueda el 5 de noviembre de 2021). Además, se buscó en la Plataforma de registros internacionales de ensayos clínicos de la OMS, en las webs de las autoridades sanitarias y en Retraction Watch.
Criterios de selección
Se incluyeron ensayos controlados aleatorizados (ECA) que compararan las vacunas de la covid‐19 con placebo, ninguna vacuna, otras vacunas activas u otros programas de vacunación.
Obtención y análisis de los datos
Se utilizaron los métodos estándar de Cochrane. Se utilizó el método GRADE para evaluar la certeza de la evidencia de todos los desenlaces, excepto la inmunogenicidad.
Los datos de cada vacuna se resumieron por separado y las estimaciones del efecto resumidas se presentaron con intervalos de confianza (IC) del 95%.
Resultados principales
Se incluyeron y analizaron 41 ECA que evaluaron 12 vacunas distintas, incluyendo programas de vacunas homólogas y heterólogas y el efecto de las dosis de refuerzo. De estos, 32 ensayos fueron multicéntricos y cuatro fueron internacionales. El tamaño muestral de los ECA fue de 60 a 44 325 participantes. Las edades de los participantes fueron: 18 años o más en 36 ECA; 12 años o más en un ECA; 12 a 17 años en dos ECA; y tres a 17 años en dos ECA. Veintinueve ECA proporcionaron resultados para mayores de 60 años, y tres ECA incluyeron pacientes inmunocomprometidos. Ninguno de los ensayos incluyó a embarazadas. Dieciséis ECA tuvieron un seguimiento de hasta 2 meses, 20 ECA de entre 2 y 6 meses, y cinco ECA de entre 6 y 12 meses o menos. Dieciocho informes se basaron en análisis preliminares predefinidos.
El riesgo general de sesgo fue bajo para todos los desenlaces en ocho ECA, mientras que 33 presentaron dudas en al menos un desenlace.
Se identificaron 343 ECA registrados sin resultados disponibles todavía.
Este resumen presenta los resultados de los desenlaces críticos de la covid‐19 sintomática confirmada, la covid‐19 grave y crítica, y los eventos adversos graves solo para las 10 vacunas autorizadas por la OMS. Para el resto de desenlaces y vacunas, léase el texto principal. La evidencia de la mortalidad fue en general escasa y de certeza baja o muy baja para todas las vacunas autorizadas por la OMS, excepto la AD26.COV2.S (Janssen), que probablemente reduce el riesgo de mortalidad por todas las causas (razón de riesgos [RR] 0,25; IC del 95%: 0,09 a 0,67; un ECA, 43 783 participantes; evidencia de certeza alta).
Covid‐19 sintomática confirmada
Evidencia de certeza alta observó que la BNT162b2 (BioNtech/Fosun Pharma/Pfizer), la mRNA‐1273 (ModernaTx), la ChAdOx1 (Oxford/AstraZeneca), la Ad26.COV2.S, la BBIBP‐CorV (Sinopharm‐Beijing) y la BBV152 (Bharat Biotect) reducen la incidencia de covid‐19 sintomática en comparación con el placebo (eficacia de la vacuna [EV]): BNT162b2: 97,84%; IC del 95%: 44,25% a 99,92%; dos ECA, 44 077 participantes; ARNm‐1273: 93,20%; IC del 95%: 91,06% a 94,83%; dos ECA, 31 632 participantes; ChAdOx1: 70,23%; IC del 95%: 62,10% a 76,62%; dos ECA, 43 390 participantes; Ad26.COV2.S: 66,90%; IC del 95%: 59,10% a 73,40%; un ECA, 39 058 participantes; BBIBP‐CorV: 78,10%; IC del 95%: 64,80% a 86,30%; un ECA, 25 463 participantes; BBV152: 77,80%; IC del 95%: 65,20% a 86,40%; un ECA, 16 973 participantes).
Evidencia de certeza moderada observó que NVX‐CoV2373 (Novavax) probablemente reduzca la incidencia de covid‐19 sintomática en comparación con el placebo (EV: 82,91%; IC del 95%: 50,49% a 94,10%; tres ECA, 42 175 participantes).
Existe evidencia de certeza baja de la CoronaVac (Sinovac) para este desenlace (EV: 69,81%; IC del 95%: 12,27% a 89,61%; dos ECA, 19 852 participantes).
Covid‐19 grave o crítica
Evidencia de certeza alta observó que la BNT162b2, la mRNA‐1273, la Ad26.COV2.S, y la BBV152 dan lugar a una gran reducción de la incidencia de la enfermedad grave o crítica por covid‐19 en comparación con el placebo (EV: BNT162b2: 95,70%; IC del 95%: 73,90% a 99,90%; un ECA, 46 077 participantes; mRNA‐1273: 98,20%; IC del 95%: 92,80% a 99,60%; un ECA, 28 451 participantes; AD26.COV2.S: 76,30%; IC del 95%: 57,90% a 87,50%; un ECA, 39 058 participantes; BBV152: 93,40%; IC del 95%: 57,10% a 99,80%; un ECA, 16 976 participantes).
La evidencia de certeza moderada encontró que NVX‐CoV2373 probablemente reduce la incidencia de covid‐19 grave o crítica (EV: 100,00%; IC del 95%: 86,99% a 100,00%; un ECA, 25 452 participantes).
Dos ensayos informaron sobre la alta eficacia de la CoronaVac para la enfermedad grave o crítica con amplios IC, pero estos resultados no pudieron agruparse.
Eventos adversos graves (EAG)
Es probable que la mRNA‐1273, la ChAdOx1 (Oxford‐AstraZeneca)/SII‐ChAdOx1 (Serum Institute of India), la Ad26.COV2.S y la BBV152 den lugar a poca o ninguna diferencia en los EAG en comparación con el placebo (RR: mRNA‐1273: 0,92; IC del 95%: 0,78 a 1,08; dos ECA, 34 072 participantes; ChAdOx1/SII‐ChAdOx1: 0,88; IC del 95%: 0,72 a 1,07; siete ECA, 58 182 participantes; Ad26.COV2.S: 0,92, IC del 95%: 0,69 a 1,22; un ECA, 43 783 participantes); BBV152: 0,65; IC del 95%: 0,43 a 0,97; un ECA, 25 928 participantes). En cada uno de estos casos, la diferencia absoluta en los efectos fue probablemente inferior a 5/1000 participantes.
No está clara la evidencia acerca de los EAG para la BNT162b2, la CoronaVac, la BBIBP‐CorV y la NVX‐CoV2373 en comparación con el placebo (RR: BNT162b2: 1,30; IC del 95%: 0,55 a 3,07; dos ECA, 46 107 participantes; CoronaVac: 0,97; IC del 95%: 0,62 a 1,51; cuatro ECA, 23 139 participantes; BBIBP‐CorV: 0,76; IC del 95%: 0,54 a 1,06; un ECA, 26 924 participantes; NVX‐CoV2373: 0,92; IC del 95%: 0,74 a 1,14; cuatro ECA, 38 802 participantes).
Para obtener información sobre la evaluación de los programas de vacunas heterólogas, las dosis de refuerzo y la eficacia contra las variantes de interés, léase el texto principal de la revisión.
Conclusiones de los autores
En comparación con el placebo, la mayoría de las vacunas reducen, o probablemente reducen, la proporción de participantes con covid‐19 sintomática confirmada, y para algunas de ellas, existe evidencia de certeza alta de que reducen la enfermedad grave o crítica. Es probable que haya poca o ninguna diferencia entre la mayoría de las vacunas y el placebo en cuanto a los efectos adversos graves. Más de 300 ECA registrados están evaluando la eficacia de las vacunas de la covid‐19, y esta revisión se actualiza periódicamente en la plataforma COVID‐NMA (covid-nma.com).
Implicaciones para la práctica
Debido a las exclusiones de los ensayos, estos resultados no pueden extrapolarse a embarazadas, personas con antecedentes de infección por SARS‐CoV‐2 ni personas inmunodeprimidas. La mayoría de los ensayos tuvieron un seguimiento corto y se llevaron a cabo antes de la aparición de variantes preocupantes.
Implicaciones para la investigación
Las investigaciones futuras deberían evaluar el efecto a largo plazo de las vacunas, comparar diferentes vacunas y programas de vacunación, evaluar la eficacia y seguridad de las vacunas en poblaciones específicas e incluir desenlaces como la prevención de la covid‐19 persistente. También es fundamental mantener una evaluación continua de la eficacia y efectividad de las vacunas frente a las nuevas variantes preocupantes.
PICO
Resumen en términos sencillos
¿Cuáles son los beneficios y los riesgos de las vacunas para prevenir la covid‐19?
Mensajes clave
‐ La mayoría de las vacunas reducen, o probablemente reducen, el número de personas que contraen la enfermedad covid‐19 y la enfermedad covid‐19 grave.
‐ Muchas vacunas probablemente aumenten el número de personas que presentan episodios como fiebre o dolor de cabeza en comparación con el placebo (vacuna falsa que no contiene ningún medicamento, pero tiene apariencia idéntica a la vacuna que se está analizando). Es de esperar, ya que estos episodios se deben principalmente a la respuesta del organismo a la vacuna; suelen ser leves y de corta duración.
‐ Muchas vacunas muestran poca o ninguna diferencia en la incidencia de episodios adversos graves en comparación con el placebo.
‐ No hay evidencias suficientes para determinar si hubo una diferencia entre la vacuna y el placebo en términos de mortalidad, porque el número de muertes fue bajo en los ensayos.
‐ La mayoría de los ensayos evaluaron la eficacia de la vacuna durante un corto período de tiempo, y no evaluaron la eficacia para las variantes de interés.
¿Qué es el SARS‐CoV‐2 y la covid‐19?
El SARS‐CoV‐2 (síndrome respiratorio agudo grave por coronavirus 2) es el virus que causa la covid‐19. No todas las personas infectadas por SARS‐CoV‐2 desarrollarán síntomas de covid‐19. Los síntomas pueden ser leves (como fiebre y dolores de cabeza) hasta potencialmente mortales (p. ej., dificultad para respirar) o la muerte.
¿Cómo previenen las vacunas la covid‐19?
Aunque cada vacuna funciona de forma ligeramente distinta, todas ellas preparan el sistema inmunitario del organismo para evitar que las personas se infecten con el SARS‐CoV‐2 o, si se infectan, para prevenir la enfermedad grave.
¿Qué se quería averiguar?
Se quiso averiguar la eficacia de cada vacuna para reducir la infección por SARS‐CoV‐2, la enfermedad por covid‐19 con síntomas, la covid‐19 grave y el número total de muertes (incluyendo cualquier muerte, no solo las relacionadas con la covid‐19).
Se quisieron conocer los episodios adversos graves que pudieran requerir hospitalización, poner en peligro la vida o ambas cosas, los episodios de reactogenia sistémica (reacciones inmediatas a corto plazo a las vacunas debidas principalmente a respuestas inmunológicas; p. ej., fiebre, dolor de cabeza, dolores corporales, cansancio) y cualquier episodio adverso (incluyendo episodios adversos no graves).
¿Qué se hizo?
Se buscaron estudios que examinaran cualquier vacuna de la covid‐19 en comparación con placebo, ninguna vacuna u otra vacuna de la covid‐19.
Solo se seleccionaron ensayos aleatorizados (un diseño de estudio que proporciona las evidencias más sólidas porque evalúan las intervenciones en condiciones ideales entre participantes asignados al azar a uno de dos o más grupos). Se compararon y resumieron los resultados de los estudios y la confianza en la evidencia se evaluó en función de factores como la realización de los estudios.
¿Qué se encontró?
Se encontraron 41 estudios de todo el mundo, en los que participaron 433 838 personas, que evaluaron 12 vacunas diferentes. Treinta y cinco estudios incluyeron solo a personas sanas que nunca habían tenido covid‐19. Treinta y seis estudios incluyeron solo a adultos, dos solo a adolescentes, dos a niños y adolescentes, y uno incluyó a adolescentes y adultos. Tres estudiaron a personas con sistemas inmunitarios debilitados y ninguno a embarazadas.
La mayoría de los casos evaluó los resultados menos de seis meses después de la vacunación primaria. La mayoría recibió cofinanciación de instituciones académicas y compañías farmacéuticas. La mayoría de los estudios comparó la vacuna de la covid‐19 con un placebo. Cinco evaluaron añadir una dosis de refuerzo "mixta".
Resultados principales
A continuación se presentan los resultados de tres desenlaces principales y de 10 vacunas autorizadas por la Organización Mundial de la Salud (OMS) (para el resto de desenlaces y vacunas, véase el texto principal). No hay evidencias suficientes de la diferencia en cuanto a muertes entre las vacunas y el placebo (principalmente porque el número de muertes fue bajo), excepto para la vacuna de Janssen, que probablemente reduce el riesgo de muertes por todas las causas.
Personas con síntomas
Las vacunas de Pfizer, Moderna, AstraZeneca, Sinopharm‐Beijing y Bharat dan lugar a una gran reducción del número de personas con covid‐19 sintomática.
La vacuna de Janssen reduce el número de personas con covid‐19 sintomática.
Es probable que la vacuna Novavax produzca una gran reducción del número de personas con covid‐19 sintomática.
No hay pruebas suficientes para determinar si la vacuna CoronaVac afecta al número de personas con covid‐19 sintomática porque los resultados difirieron entre los dos estudios (uno de ellos solo incluyó a trabajadores sanitarios con un mayor riesgo de exposición).
Enfermedad grave
Las vacunas de Pfizer, Moderna, Janssen y Bharat dan lugar a una gran reducción del número de personas con enfermedad grave.
No hay pruebas suficientes sobre la vacuna CoronaVac y la enfermedad grave, ya que los resultados difirieron entre los dos estudios (uno de ellos solo incluyó a trabajadores sanitarios con un mayor riesgo de exposición).
Episodios adversos graves
Para las vacunas de Pfizer, CoronaVac, Sinopharm‐Beijing y Novavax, no hay pruebas suficientes para determinar si hubo una diferencia entre la vacuna y el placebo, principalmente porque el número de episodios adversos graves fue bajo.
Es probable que las vacunas de Moderna, AstraZeneca, Janssen y Bharat produzcan poca o ninguna diferencia en el número de episodios adversos graves.
¿Cuáles son las limitaciones de la evidencia?
La mayoría de los estudios evaluaron la vacuna durante un corto periodo de tiempo tras la inyección, y no está claro si la protección de la vacuna disminuye con el tiempo ni cómo lo hace. Debido a los criterios de exclusión de los ensayos de vacunas de la covid‐19, los resultados no pueden extrapolarse a embarazadas, personas con antecedentes de infección por SARS‐CoV‐2 ni a personas con sistemas inmunitarios debilitados. Se necesitan más estudios de investigación para comparar las vacunas y los programas de vacunación, así como la eficacia y la seguridad en poblaciones y desenlaces específicos (p. ej., la prevención de la covid‐19 persistente). Además, la mayoría de los estudios se llevaron a cabo antes de la aparición de variantes preocupantes.
¿Cuál es el grado de actualización de esta evidencia?
La evidencia está actualizada hasta noviembre de 2021. Esta es una revisión sistemática continua. Los resultados están disponibles en la plataforma COVID‐NMA (covid‐nma.com) y se actualizan cada dos semanas.
Authors' conclusions
Summary of findings
| Outcomes | Anticipated absolute effects* (95% CI) | Relative effect | № of participants | Certainty of the evidence | Comments | |
|---|---|---|---|---|---|---|
| Risk with placebo | Risk with BNT162b2 | |||||
| Confirmed SARS‐CoV‐2 infection | Outcome not yet measured or reported | |||||
| Confirmed symptomatic COVID‐19b | 3923 per 100,000 | 85 per 100,000 | VE 97.84 (44.25 to 99.92) | 44,077 | ⊕⊕⊕⊕ | — |
| Severe or critical COVID‐19e | 100 per 100,000 | 4 per 100,000 | VE 95.70 | 46,077 | ⊕⊕⊕⊕ | — |
| All‐cause mortalityg | 64 per 100,000 | 68 per 100,000 | RR 1.07 | 43,847 | ⊕⊕⊖⊖ | 2 additional studies (Frenck 2021 (adolescents aged 12–15 years); Walsh 2020 (adults aged 18–85 years)) reported this outcome in 2302 participants (1131 versus 1129 participants and 24 versus 18 participants in the BNT162b2 versus placebo groups, respectively). There were no events in either group and the trials did not contribute to the effect estimate. |
| Systemic reactogenicity events | Outcome not yet measured or reported | |||||
| Any adverse eventi | Outcome not pooled due to considerable heterogeneity (I² = 90%) between included studies: Thomas 2021 (≥ 16 years): RR 2.17, 95% CI 2.09 to 2.26; n = 43,847; Frenck 2021 (12–15 years): RR 1.01, 95% CI 0.73 to 1.41; n = 2260; Walsh 2020 (≥ 18 years): RR 1.50, 95% CI 0.53 to 4.21; n = 42 |
| 46,149 | ⊕⊕⊖⊖ | — | |
| Serious adverse eventsi | 508 per 100,000 | 660 per 100,000 | RR 1.30 | 46,107 | ⊕⊕⊖⊖ | 1 additional trial (Walsh 2020 (adults aged 18–85 years)) reported this outcome in 42 participants (24 BNT162b2 versus 18 placebo). There were no events in either group and the trial did not contribute to the effect estimate. |
| Local reactogenicity events | Outcome not yet measured or reported | |||||
| *The risk in the intervention group (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). COVID‐19: coronavirus disease 2019;CI: confidence interval; RCT: randomized controlled trial; RR: risk ratio; SARS‐CoV‐2: severe acute respiratory syndrome coronavirus 2; VE: vaccine efficacy. | ||||||
| GRADE Working Group grades of evidence | ||||||
| aLast updated: 3 May 2022 | ||||||
| Outcomes | Anticipated absolute effects* (95% CI) | Relative effect | № of participants | Certainty of the evidence | Comments | |
|---|---|---|---|---|---|---|
| Risk with placebo | Risk with mRNA‐1273 | |||||
| Confirmed SARS‐CoV‐2 infectionb | 8957 per 100,000 | 2394 per 100,000 | VE 73.27 | 31,632 | ⨁⨁⨁◯ | Substantial heterogeneity (I² = 66%) between included studies: Ali 2021 (adolescents aged 12–17 years, median 2.3 months' follow‐up): VE 55.7% (95% CI 16.8 to 76.4), n = 3181; El Sahly 2021 (adults aged 18–95 years, 5.3 months' follow‐up): VE 82% (95% CI 79.5 to 84.2), n = 28,451 |
| Confirmed symptomatic COVID‐19 b | 4939 per 100,000 | 336 per 100,000 | VE 93.20 (91.06 to 94.83) | 31,632 | ⨁⨁⨁⨁ | — |
| Severe or critical COVID‐19f | 748 per 100,000 | 13 per 100,000 | VE 98.20 (92.80 to 99.60) | 28,451 | ⨁⨁⨁⨁ | — |
| All‐cause mortalityf | 106 per 100,000 |
112 per 100,000 | RR 1.06 | 30,346 | ⨁⨁◯◯ | 1 additional trial: (Ali 2021 (adolescents aged 12–17 years)) reported on this outcome in 3726 participants (2486 mRNA‐1273 and 1240 placebo). There were no events in either group and the trial did not contribute to the pooled effect estimate |
| Systemic reactogenicity eventsi | 432 per 1000 | 553 per 1000 | RR 1.28 | 34,037 | ⨁⨁⨁⨁ | — |
| Any adverse eventk | Outcome not pooled due to considerable heterogeneity (I² = 100%) between included studies: Ali 2021 (all solicited adverse events, adolescents aged 12–17 years, median 2.8 months' follow‐up): RR 1.47 (95% CI 1.41 to 1.54), n = 3726; El Sahly 2021 (all solicited adverse events, adults aged 18–95 years, 5.3 months' follow‐up): RR 2.15 (95% CI 2.11 to 2.19), n = 29,269 | — | 32,995 | ⨁⨁◯◯ | — | |
| Serious adverse eventsl | 1792 per 100,000 | 1649 per 100,000 | RR 0.92 | 34,072 | ⨁⨁⨁◯ | — |
| Local reactogenicity eventsi | 211 per 1000 | 697 per 1000 | RR 3.30 | 34,037 | ⨁⨁⨁⨁ | — |
| *The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | ||||||
| GRADE Working Group grades of evidence | ||||||
| a. Last updated: 01 March 2023 b. Follow‐up: from 14 days after dose 2 to 2.3 months (median) and 5.3 months c. Moderna TX: Ali 2021 (adolescents aged 12–17 years); El Sahly 2021 (adults aged 18–95 years) d. Despite some concerns with deviations from intervention, not downgraded for risk of bias e. Inconsistency: downgraded one level: I² = 66.37% f. Follow‐up: 5.3 months g. Moderna TX: El Sahly 2021 (adults aged 18–95 years) h. Imprecision downgraded two levels due to small number of events observed and wide CIs that encompass a potential benefit and a potential harm with the intervention i. Follow‐up: seven days j. Despite inconsistency (I² = 61%) not downgraded for inconsistency, as the same direction of effect in both effect estimates k. Follow‐up: 2.8 months (median) and 5.3 months l. Inconsistency: downgraded two levels (I² = 100%) m. Imprecision: downgraded one level due to wide CIs that encompass a potential benefit and a potential harm with the intervention. n. Despite inconsistency (I² = 99%), not downgraded for inconsistency, as the same direction of effect in both effect estimates | ||||||
| Outcomes | Anticipated absolute effects* (95% CI) | Relative effect | № of participants | Certainty of the evidence (GRADE) | Comments | |
|---|---|---|---|---|---|---|
| Risk with placebo | Risk with CVnCOV | |||||
| Confirmed SARS‐CoV‐2 infection | Outcome not yet measured or reported | |||||
| Confirmed symptomatic COVID‐19b | 1187 per 100,000 | 615 per 100,000 | VE 48.20 (31.70 to 60.90) | 25,062 | ⊕⊕⊕⊖ | — |
| Severe or critical COVID‐19f | 82 per 100,000 | 30 per 100,000 | VE 63.80 (0.00 to 91.70) | 25,062 | ⊕⊖⊖⊖ | — |
| All‐cause mortalityh | 30 per 100,000 | 40 per 100,000 | RR 1.33 | 39,529 | ⊕⊖⊖⊖ | — |
| Systemic reactogenicity eventsi | 635 per 1000 | 940 per 1000 | RR 1.48 | 3982 | ⊕⊕⊕⊕ | — |
| Any adverse eventj | 679 per 1000 | 965 per 1000 | RR 1.42 | 3982 | ⊕⊕⊕⊖ | — |
| Serious adverse eventsk | 334 per 100,000 | 414 per 100,000 | RR 1.24 | 39,529 | ⊕⊕⊖⊖ | — |
| Local reactogenicity eventsi | 241 per 1000 | 847 per 1000 | RR 3.51 | 3982 | ⊕⊕⊕⊕ | — |
| *The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). COVID‐19: coronavirus disease 2019CI: confidence interval; RCT: randomized controlled trial; RR: risk ratio; SARS‐CoV‐2: severe acute respiratory syndrome coronavirus 2; VE: vaccine efficacy. | ||||||
| GRADE Working Group grades of evidence | ||||||
| aLast updated: 10 May 2022 | ||||||
| Outcomes | Anticipated absolute effects* (95% CI) | Relative effect | № of participants | Certainty of the evidence | Comments | |
|---|---|---|---|---|---|---|
| Risk with placebo | Risk with ChAdOx1 | |||||
| Confirmed SARS‐CoV‐2 infectionb | 3199 per 100,000 | 1300 per 100,000 | VE 59.35 (48.00 to 68.22) | 43,390 | ⊕⊕⊕⊖ | Substantial heterogeneity (I² = 68%) between included studies: Falsey 2021 (VE 64.35%, 95% CI 56.10% to 71.00%; n = 26,212); Voysey 2021a (VE 54.10%, 95% CI 44.70% to 61.90%; n = 17,178) |
| Confirmed symptomatic COVID‐19b | 2207 per 100,000 | 657 per 100,000 | VE 70.23 (62.10 to 76.62) | 43,390 | ⊕⊕⊕⊕ | — |
| Severe or critical COVID‐19 | Outcome not yet measured or reported | |||||
| All‐cause mortalityf | 52 per 100,000 | 25 per 100,000 | RR 0.48 | 56,727 | ⊕⊕⊖⊖ | 2 additional trials (Asano 2022; Kulkarni 2021) reported this outcome in 1392 participants (192 ChAdOx1 versus 64 placebo and 900 SII‐ChAdOx1 versus 300 placebo, respectively). There were no events in either group in either trial and they did not contribute to the pooled effect estimate. |
| Systemic reactogenicity eventsi | 141 per 1000 | 553 per 1000 | RR 3.93 | 256 | ⊕⊕⊕⊖ | — |
| Any adverse eventl | Outcome not pooled due to considerable heterogeneity (I² = 90%) between included studies: Asano 2022 (RR 2.54, 95% CI 1.73 to 3.74; n = 256); Falsey 2021 (RR 1.37, 95% CI 1.33 to 1.42; n = 32,379); Kulkarni 2021 (RR 1.39, 95% CI 1.12 to 1.74; n = 1200); Voysey 2021a (RR 0.74, 95% CI 0.56 to 0.96; n = 23,745) | — | 57,580 | ⊕⊕⊖⊖ | — | |
| Serious adverse eventso | 794 per 100,000 | 699 per 100,000 | RR 0.88 | 58,182 | ⊕⊕⊕⊖ | — |
| Local reactogenicity eventsi | 94 per 1000 | 604 per 1000 | RR 6.44 | 256 | ⊕⊕⊕⊖ | — |
| *The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). COVID‐19: coronavirus disease 2019CI: confidence interval; RCT: randomized controlled trial; RR: risk ratio; SARS‐CoV‐2: severe acute respiratory syndrome coronavirus 2; VE: vaccine efficacy. | ||||||
| GRADE Working Group grades of evidence | ||||||
| aLast updated: 4 May 2022 | ||||||
| Outcomes | Anticipated absolute effects* (95% CI) | Relative effect | № of participants | Certainty of the evidence | Comments | |
|---|---|---|---|---|---|---|
| Risk with ChAdOx1 | Risk with SII‐ChAdOx1 | |||||
| Confirmed SARS‐CoV‐2 infection | Outcome not yet measured or reported | |||||
| Confirmed symptomatic COVID‐19 | Outcome not yet measured or reported | |||||
| Severe or critical COVID‐19 | Outcome not yet measured or reported | |||||
| All‐cause mortality | — | — | — | — | — | 1 study reported this outcome in 400 participants (Kulkarni 2021). There were no events in either group and no effect estimate could be calculated. |
| Systemic reactogenicity eventsb | 390 per 1000 | 285 per 1000 | RR 0.73 | 400 | ⊕⊕⊕⊖ | — |
| Any adverse evente | 200 per 1000 | 166 per 1000 | RR 0.83 | 400 | ⊕⊕⊖⊖ | — |
| Serious adverse eventsg | 2000 per 100,000 | 1000 per 100,000 | RR 0.50 | 400 | ⊕⊕⊖⊖ | — |
| Local reactogenicity eventsb | 360 per 1000 | 274 per 1000 | RR 0.76 | 400 | ⊕⊕⊖⊖ | — |
| *The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). COVID‐19: coronavirus disease 2019CI: confidence interval; RCT: randomized controlled trial; RR: risk ratio; SARS‐CoV‐2: severe acute respiratory syndrome coronavirus 2. | ||||||
| GRADE Working Group grades of evidence | ||||||
| aLast updated: 10 May 2022 | ||||||
| Outcomes | Anticipated absolute effects* (95% CI) | Relative effect | № of participants | Certainty of the evidence | Comments | |
|---|---|---|---|---|---|---|
| Risk with placebo | Risk with AD26.COV2.S | |||||
| Confirmed SARS‐CoV‐2 infection | Outcome not yet measured or reported | |||||
| Confirmed symptomatic COVID‐19b | 1796 per 100,000 | 594 per 100,000 | VE 66.90 (59.10 to 73.40) | 39,058 | ⊕⊕⊕⊕ | — |
| Severe or critical COVID‐19b | 409 per 100,000 | 97 per 100,000 | VE 76.30 (57.90 to 87.50) | 39,058 | ⊕⊕⊕⊕ | — |
| All‐cause mortalityb | 91 per 100,000 | 23 per 100,000 | RR 0.25 | 43,783 | ⊕⊕⊕⊕ | — |
| Serious adverse eventsb | 448 per 100,000 | 412 per 100,000 | RR 0.92 | 43,783 | ⊕⊕⊕⊖ | — |
| Systemic reactogenicity eventse | 34,575 per 100,000 | 63,273 per 100,000 | RR 1.83 | 7222 | ⊕⊕⊕⊕ | — |
| Any adverse eventh | Outcome not pooled due to considerable heterogeneity (I² = 96%) between included studies: Sadoff 2021a (RR 1.09, 95% CI 0.96 to 1.24; n = 6736); Sadoff 2021b (RR 2.31, 95% CI 1.80 to 2.97; n = 486) | — | 7222 | ⊕⊕⊖⊖ | — | |
| *The risk in the intervention group (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). COVID‐19: coronavirus disease 2019CI: confidence interval; RCT: randomized controlled trial; RR: risk ratio; SARS‐CoV‐2: severe acute respiratory syndrome coronavirus 2; VE: vaccine efficacy. | ||||||
| GRADE Working Group grades of evidence | ||||||
| aLast updated: 4 May 2022 | ||||||
| Outcomes | Anticipated absolute effects* (95% CI) | Relative effect | № of participants | Certainty of the evidence | Comments | |
|---|---|---|---|---|---|---|
| Risk with placebo | Risk with Gam‐COVID‐VAC | |||||
| Confirmed SARS‐CoV‐2 infection | Outcome not yet measured or reported | |||||
| Confirmed symptomatic COVID‐19b | 1022 per 100,000 | 92 per 100,000 | VE 91.10 (83.80 to 95.10) | 18,695 | ⊕⊕⊕⊖ | — |
| Severe or critical COVID‐19b | 408 per 100,000 | 0 per 100,000 | VE 100.00 (94.40 to 100.00) | 19,866 | ⊕⊕⊕⊖ | — |
| All‐cause mortalityf | 18 per 100,000 | 18 per 100,000 | RR 0.99 | 21,862 | ⊕⊖⊖⊖ | — |
| Systemic reactogenicity events | Outcome not yet measured or reported | |||||
| Any adverse event | Outcome not yet measured or reported | |||||
| Serious adverse eventsf | 423 per 100,000 | 275 per 100,000 | RR 0.65 | 21,862 | ⊕⊕⊖⊖ | — |
| Local reactogenicity events | Outcome not yet measured or reported | |||||
| *The risk in the intervention group (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). COVID‐19: coronavirus disease 2019;CI: confidence interval; RCT: randomized controlled trial; RR: risk ratio; SARS‐CoV‐2: severe acute respiratory syndrome coronavirus 2; VE: vaccine efficacy. | ||||||
| GRADE Working Group grades of evidence | ||||||
| aLast updated: 27 May 2022 | ||||||
| Outcomes | Anticipated absolute effects* (95% CI) | Relative effect | № of participants | Certainty of the evidence | Comments | |
|---|---|---|---|---|---|---|
| Risk with placebo | Risk with CoronaVac | |||||
| Confirmed SARS‐CoV‐2 infection | Outcome not yet measured or reported | |||||
| Confirmed symptomatic COVID‐19b | 2398 per 100,000 | 724 per 100,000 | VE 69.81 (12.27 to 89.61) | 19,852 | ⊕⊕⊖⊖ | Considerable heterogeneity (I² = 92%) between included studies: Tanriover 2021 (VE 83.50%, 95% CI 65.40% to 92.10%; n = 10,029); Palacios 2020 (VE 50.70%, 95% CI 35.90 to 62.00%; n = 9823) |
| Severe or critical COVID‐19b | 2 studies report on severe or critical disease due to COVID‐19: Tanriover 2021, with 0/6559 events in the CoronaVac group versus 1/3470 events in the placebo group and a VE of 100%, 95% CI (20.40% to 100.00%); and Palacios 2020, with 0/4953 events in the CoronaVac group and 6/4870 events in the placebo group and a VE of 100%, 95% CI (16.90% to 100.00%). (Note: estimates could not be pooled due to asymmetry in the CIs) | — | 19,852 | ⊕⊕⊖⊖ | — | |
| All‐cause mortalityh | 20 per 100,000 | 10 per 100,000 | RR 0.50 | 22,610 | ⊕⊕⊖⊖ | — |
| Systemic reactogenicity eventsj | 409 per 1000 | 487 per 1000 | RR 1.19 | 23,966 | ⊕⊕⊖⊖ | — |
| Any adverse evento | 531 per 1000 | 579 per 1000 | RR 1.09 | 23,367 | ⊕⊕⊕⊕ | — |
| Serious adverse eventsr | 372 per 100,000 | 361 per 100,000 | RR 0.97 | 23,139 | ⊕⊕⊖⊖ | 2 additional trials (Bueno 2021; Zhang 2021) reported this outcome in 482 participants (270 versus 164 and 24 versus 24 respectively, receiving CoronaVac versus placebo). There were no events in either group and the trials did not contribute to the pooled effect estimate. |
| Local reactogenicity eventsj | 227 per 1000 | 400 per 1000 | RR 1.76 | 23,962 | ⊕⊕⊕⊕ | — |
| *The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). COVID‐19: coronavirus disease 2019CI: confidence interval; RCT: randomized controlled trial; RR: risk ratio; SARS‐CoV‐2: severe acute respiratory syndrome coronavirus 2; VE: vaccine efficacy. | ||||||
| GRADE Working Group grades of evidence | ||||||
| aLast updated: 4 May 2022 | ||||||
| Outcomes | Anticipated absolute effects* (95% CI) | Relative effect | № of participants | Certainty of the evidence | Comments | |
|---|---|---|---|---|---|---|
| Risk with placebo | Risk with WIBP‐CorV | |||||
| Confirmed SARS‐CoV‐2 infectionb | 912 per 100,000 | 328 per 100,000 | VE 64.00 (48.80 to 74.70) | 25,449 | ⊕⊕⊕⊕ | — |
| Confirmed symptomatic COVID‐19b | 746 per 100,000 | 203 per 100,000 | VE 72.80 (58.10 to 82.40) | 25,480 | ⊕⊕⊕⊕ | — |
| Severe or critical COVID‐19 | Outcome not yet measured or reported | |||||
| All‐cause mortality | — | — | — | — | — | 1 trial reported on this outcome in 26,917 participants (13,464 WIBP‐CorV versus 13,453 placebo) (Al Kaabi 2021). There were no events in either group and no effect estimate could be calculated for this outcome. |
| Systemic reactogenicity eventse | 278 per 1000 | 275 per 1000 | RR 0.99 | 27,029 | ⊕⊕⊕⊕ | — |
| Any adverse eventh | 504 per 1000 | 484 per 1000 | RR 0.96 | 27,029 | ⊕⊕⊕⊕ | — |
| Serious adverse eventsi | 579 per 100,000 | 480 per 100,000 | RR 0.83 | 27,029 | ⊕⊕⊖⊖ | — |
| Local reactogenicity eventsk | 290 per 1000 | 255 per 1000 | RR 0.88 | 27,029 | ⊕⊕⊕⊕ | — |
| *The risk in the intervention group (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). COVID‐19: coronavirus disease 2019CI: confidence interval; RCT: randomized controlled trial; RR: risk ratio; SARS‐CoV‐2: severe acute respiratory syndrome coronavirus 2; VE: vaccine efficacy. | ||||||
| GRADE Working Group grades of evidence | ||||||
| aLast updated: 4 May 2022 | ||||||
| Outcomes | Anticipated absolute effects* (95% CI) | Relative effect | № of participants | Certainty of the evidence | Comments | |
|---|---|---|---|---|---|---|
| Risk with placebo | Risk with BBIBP‐CorV | |||||
| Confirmed SARS‐CoV‐2 infectionb | 912 per 100,000 | 242 per 100,000 | VE 73.50 (60.60 to 82.20) | 25,435 | ⊕⊕⊕⊕ | — |
| Confirmed symptomatic COVID‐19b | 746 per 100,000 | 163 per 100,000 | VE 78.10 (64.80 to 86.30) | 25,463 | ⊕⊕⊕⊕ | — |
| Severe or critical COVID‐19 | Outcome not yet measured or reported | |||||
| All‐cause mortality | — | — | — | — | — | 1 study reported this outcome in 26,924 participants (13,471 BBIBP‐CorV versus 13,453 placebo) (Al Kaabi 2021). There were no events in either group and no effect estimate could be calculated for this outcome. |
| Systemic reactogenicity eventse | 274 per 1000 | 288 per 1000 | RR 1.05 | 27,540 | ⊕⊕⊕⊖ | — |
| Any adverse eventh | 3 studies (n = 27,540) reported any adverse event with 1 month or 2.9 months' follow‐up. 2 of the studies reported an effect estimate in favour of BBIBP‐CorV: 1 with RR 0.91, 95% CI 0.89 to 0.94; n = 26,924; and 1 with CIs crossing the line of no effect (RR 0.83, 95% CI 0.36 to 1.95; n = 112). 1 study reported an effect estimate in favour of placebo with CIs not crossing the line of null effect (RR 2.05, 95% CI 1.47 to 2.87; n = 504) | — | 26,924 | ⊕⊕⊖⊖ | — | |
| Serious adverse eventsk | 580 per 100,000 | 441 per 100,000 | RR 0.76 | 26,924 | ⊕⊕⊖⊖ | 1 additional study reported this outcome in 112 participants (84 BBIBP‐CorV versus 28 placebo) (Xia 2020). There were no events in either group and the trial did not contribute to the effect estimate. |
| Local reactogenicity eventse | 3 studies (n = 27,540) reported local adverse events with 7 days' follow‐up. 1 study reported an effect estimate in favour of BBIBP‐CorV: RR 0.71, 95% CI 0.68 to 0.74; n = 26,924. 2 studies reported an effect estimate in favour of placebo with CIs not crossing the line of null effect (RR 10.00, 95% CI 2.36 to 42.34; n = 504 and RR 3.33, 95% CI 0.45 to 24.89; n = 112). | — | 26,924 | ⊕⊕⊖⊖ | — | |
| *The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). COVID‐19: coronavirus disease 2019CI: confidence interval; RCT: randomized controlled trial; RR: risk ratio; SARS‐CoV‐2: severe acute respiratory syndrome coronavirus 2; VE: vaccine efficacy. | ||||||
| GRADE Working Group grades of evidence | ||||||
| aLast updated: 4 May 2022 | ||||||
| Outcomes | Anticipated absolute effects* (95% CI) | Relative effect | № of participants | Certainty of the evidence | Comments | |
|---|---|---|---|---|---|---|
| Risk with placebo | Risk with BBV152 | |||||
| Confirmed SARS‐CoV‐2 infectionb | 1841 per 100,000 | 575 per 100,000 | VE 68.80 (46.70 to 82.50) | 6289 | ⊕⊕⊕⊕ | — |
| Confirmed symptomatic COVID‐19b | 1247 per 100,000 | 277 per 100,000 | VE 77.80 (65.20 to 86.40) | 16,973 | ⊕⊕⊕⊕ | — |
| Severe or critical COVID‐19b | 176 per 100,000 | 12 per 100,000 | VE 93.40 (57.10 to 99.80 | 16,976 | ⊕⊕⊕⊕ | — |
| All‐cause mortalitye | 78 per 100,000 | 39 per 100,000 | RR 0.50 | 25,753 | ⊕⊕⊖⊖ | — |
| Systemic reactogenicity eventsg | 20 per 1000 | 26 per 1000 | RR 1.34 | 25,925 | ⊕⊕⊕⊕ | — |
| Any adverse eventi | 124 per 1000 | 124 per 1000 | RR 1.00 | 25,753 | ⊕⊕⊕⊕ | — |
| Serious adverse eventsi | 463 per 100,000 | 301 per 100,000 | RR 0.65 | 25,928 | ⊕⊕⊕⊕ | 1 additional trial reported this outcome in 175 participants (100 BBV152 versus 75 placebo) (Ella 2021a). There were no events in either group and the trial did not contribute to the pooled effect estimate. |
| Local reactogenicity eventsg | 31 per 1000 | 34 per 1000 | RR 1.08 | 25,750 | ⊕⊕⊕⊕ | — |
| *The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). COVID‐19: coronavirus disease 2019CI: confidence interval; RCT: randomized controlled trial; RR: risk ratio; SARS‐CoV‐2: severe acute respiratory syndrome coronavirus 2; VE: vaccine efficacy. | ||||||
| GRADE Working Group grades of evidence | ||||||
| aLast updated: 4 May 2022 | ||||||
| Outcomes | Anticipated absolute effects* (95% CI) | Relative effect | № of participants | Certainty of the evidence | Comments | |
|---|---|---|---|---|---|---|
| Risk with placebo | Risk with NVX‐CoV2373 | |||||
| Confirmed SARS‐CoV‐2 infection | Outcome not yet measured or reported | |||||
| Confirmed symptomatic COVID‐19b | 1140 per 100,000 | 195 per 100,000 | VE 82.91 (50.49 to 94.10) | 42,175 | ⊕⊕⊕⊖ | Substantial heterogeneity (I² = 65%) between included studies: Dunkle 2021 (VE 90.40%, 95% CI 82.88 to 94.62%; n = 25,452); Heath 2021 (VE 89.70%, 95% CI 80.20% to 94.60%; n = 14,039); Shinde 2021 (VE 49.40%, 95% CI 6.10% to 72.80%; n = 2684) |
| Severe or critical COVID‐19 | 172 per 100,000 | 0 per 100,000 | VE 100.00 | 25,452 | ⊕⊕⊕⊖ | — |
| All‐cause mortalityh | 51 per 100,000 | 46 per 100,000 | RR 0.90 (0.30 to 2.68) | 29,582 | ⊕⊕⊖⊖ | 1 additional study reported on this outcome in 14,039 participants (7020 NVX‐CoV2373 versus 7019 placebo) (Heath 2021). There were no events in either group and the trial did not contribute to the pooled effect estimate. |
| Systemic reactogenicity eventsj | 363 per 1000 | 439 per 1000 | RR 1.21 | 31,063 | ⊕⊕⊕⊕ | — |
| Any adverse eventm | 173 per 1000 | 199 per 1000 | RR 1.15 | 46,231 | ⊕⊕⊕⊖ | Substantial heterogeneity (I² = 57%) between the 5 included studies. |
| Serious adverse eventsm | 777 per 100,000 | 715 per 100,000 | RR 0.92 | 38,802 | ⊕⊕⊖⊖ | 1 additional trial reported on this outcome in 52 participants (29 NVX‐CoV2373 versus 23 placebo) (Keech 2020). There were no events in either group and the trial did not contribute to the pooled effect estimate. |
| Local reactogenicity eventsj | 191 per 1000 | 532 per 1000 | RR 2.78 | 31,063 | ⊕⊕⊕⊕ | — |
| *The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). COVID‐19: coronavirus disease 2019CI: confidence interval; RCT: randomized controlled trial; RR: risk ratio; SARS‐CoV‐2: severe acute respiratory syndrome coronavirus 2; VE: vaccine efficacy. | ||||||
| GRADE Working Group grades of evidence | ||||||
| aLast updated: 2 June 2022 | ||||||
| Outcomes | Anticipated absolute effects* (95% CI) | Relative effect | № of participants | Certainty of the evidence | Comments | |
|---|---|---|---|---|---|---|
| Risk with placebo | Risk with FINLAY‐FR‐2 | |||||
| Confirmed SARS‐CoV‐2 infection | Outcome not yet measured or reported | |||||
| Confirmed symptomatic COVID‐19b | 1084 per 100,000 | 314 per 100,000 | VE 71.00 (58.90 to 79.10) | 28,674 | ⊕⊕⊕⊖ | — |
| Severe or critical COVID‐19 | Outcome not yet measured or reported | |||||
| All‐cause mortalitye | 168 per 100,000 | 62 per 100,000 | RR 0.37 | 28,674 | ⊕⊕⊕⊖ | — |
| Systemic reactogenicity events | Outcome not yet measured or reported | |||||
| Any adverse event | Outcome not yet measured or reported | |||||
| Serious adverse events | Outcome not yet measured or reported | |||||
| Local reactogenicity events | Outcome not yet measured or reported | |||||
| *The risk in the intervention group (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). COVID‐19: coronavirus disease 2019CI: confidence interval; RCT: randomized controlled trial; RR: risk ratio; SARS‐CoV‐2: severe acute respiratory syndrome coronavirus 2; VE: vaccine efficacy. | ||||||
| GRADE Working Group grades of evidence | ||||||
| aLast updated: 6 May 2022 | ||||||
| Outcomes | Anticipated absolute effects* (95% CI) | Relative effect | № of participants | Certainty of the evidence | Comments | |
|---|---|---|---|---|---|---|
| Risk with homologous vaccination scheme | Risk with heterologous vaccination scheme | |||||
| Confirmed SARS‐CoV‐2 infection | Outcome not yet measured or reported | |||||
| Confirmed symptomatic COVID‐19 | Outcome not yet measured or reported | |||||
| Severe or critical COVID‐19 | Outcome not yet measured or reported | |||||
| All‐cause mortality | Outcome not yet measured or reported | |||||
| Systemic reactogenicity eventsb | 60 per 1000 | 118 per 1000 | RR 1.96 | 101 | ⊕⊕⊖⊖ | — |
| Any adverse eventf | 3 studies (n = 564) that compared heterologous versus homologous vaccination schemes reported any adverse event with 1 or 2 months' follow‐up. 2 of the studies reported an effect estimate in favour of homologous scheme but with CIs crossing the line of no effect (RR 1.21, 95% CI 0.87 to 1.68; n = 234; and RR 1.03, 95% CI 0.75 to 1.43; n = 229). 1 study reported an effect estimate in favour of homologous scheme with CIs not crossing the line of null effect (RR 3.19, 95% CI 1.11 to 9.11; n = 101) | — | (3 RCTs)g | ⊕⊖⊖⊖ | — | |
| Serious adverse eventsk | 1 study (Liu 2021: ChAdOx1/BNT162b2 versus ChAdOx1/ChAdOx1) that compared heterologous versus homologous vaccination schemes reported no serious adverse events in the heterologous scheme (0/114) versus 1 serious adverse event (1/115) in the homologous scheme (RR 0.34, 95% CI 0.01 to 8.17). 2 more studies reported the outcome, with 0 events in both groups: Li 2021a: CoronaVac/Ad5 versus CoronaVac/CoronaVac in n = 51 versus n = 50 and Liu 2021: BNT162b2/ChAdOx1 versus BNT162b2/BNT162b2 in n = 115 versus n = 119 respectively, in heterologous versus homologous scheme | — | 229 | ⊕⊖⊖⊖ | — | |
| Local reactogenicity eventsb | 20 per 1000 | 235 per 1000 | RR 11.76 | 101 | ⊕⊕⊖⊖ | — |
| *The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). COVID‐19: coronavirus disease 2019CI: confidence interval; RCT: randomized controlled trial; RR: risk ratio; SARS‐CoV‐2: severe acute respiratory syndrome coronavirus 2. | ||||||
| GRADE Working Group grades of evidence | ||||||
| aLast updated: 4 May 2022 | ||||||
| Outcomes | Anticipated absolute effects* (95% CI) | Relative effect | № of participants | Certainty of the evidence | Comments | |
|---|---|---|---|---|---|---|
| Risk with placebo/no booster | Risk with booster | |||||
| Confirmed SARS‐CoV‐2 infection | Outcome not yet measured or reported | |||||
| Confirmed symptomatic COVID‐19 | Outcome not yet measured or reported | |||||
| Severe or critical COVID‐19 | Outcome not yet measured or reported | |||||
| All‐cause mortalityb | 63 per 100,000 | 80 per 100,000 | RR 1.27 | 28,254 | ⊕⊖⊖⊖ | — |
| Systemic reactogenicity eventsf | 102 per 1000 | 183 per 1000 | RR 1.80 | 119 | ⊕⊕⊖⊖ | — |
| Any adverse event | Outcome not yet measured or reported | |||||
| Serious adverse events | Outcome not yet measured or reported | |||||
| Local reactogenicity eventsf | 119 per 1000 | 766 per 1000 | RR 6.46 | 119 | ⊕⊕⊕⊖ | — |
| *The risk in the intervention group (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). COVID‐19: coronavirus disease 2019CI: confidence interval; RCT: randomized controlled trial; RR: risk ratio; SARS‐CoV‐2: severe acute respiratory syndrome coronavirus 2. | ||||||
| GRADE Working Group grades of evidence | ||||||
| aLast updated: 4 May 2022 | ||||||
Background
Description of the condition
In December 2019, a novel coronavirus, severe acute respiratory syndrome coronavirus‐2 (SARS‐CoV‐2) outbreak began in Wuhan, Hubei Province, China. SARS‐CoV‐2 began to spread worldwide, and on 11 March 2020, the World Health Organization (WHO) declared coronavirus disease 2019 (COVID‐19) a pandemic (WHO 2020a).
In many countries, the number of cases increased exponentially during the first and subsequent waves (Worldometer 2022). The clinical spectrum of COVID‐19 ranges from mild to critical, and approximately 15% to 30% of patients infected with the wild‐type variant of SARS‐CoV‐2 experienced acute respiratory distress syndrome (Attaway 2021). Persons with underlying conditions and weakened immune systems were at higher risk of becoming severely sick (Formica 2021).
Further, genetic variants of SARS‐CoV‐2 have been emerging and circulating at a global level: B.1.1.7 (Alpha), B.1.351 (Beta), P.1 (Gamma), and B.1.617.2 (Delta) variants, and more recently B.1.1.529 (Omicron) (WHO 2022a). Consequently, the WHO has developed a definition of variants of concern for molecular surveillance (WHO 2022a).
Intensive research and development of vaccines is currently underway to curtail the pandemic and prevent disease outbreaks that could overwhelm health systems worldwide (van Riel 2020; WHO 2022b).
Description of the intervention
Vaccines exploit the ability of the immune system to respond to and remember encounters with pathogenic antigens. COVID‐19 vaccine development, aimed at conferring protection against infection, or symptomatic disease, or both, has been accelerated due to priority funding over other diseases.
Different vaccine platform technologies (i.e. technologies that have in common the use of a ‘backbone’ carrier or vector) are being, and have been tested: live attenuated virus vaccines or inactivated virus vaccines (either inactivated whole or altered pathogens); protein‐based vaccines (protein subunits or virus‐like particles); viral vector vaccines (non‐replicating viral vector, replicating viral vector); and nucleic acid‐based vaccines (DNA‐ and RNA‐based vaccines)(Abbasi 2020).
Vaccines may be categorized as either live or non‐live (CDC 2021), distinguishing those vaccines that contain an attenuated (live) form of the pathogen from those that harbour the killed (inactivated, non‐live) version of the pathogen. Non‐live vaccines predominantly induce humoral immunity, whereas live vaccines create a robust cellular and humoral response. The present review includes 12 vaccines within four different non‐live vaccine platform technologies.
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Inactivated virus vaccines
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CoronaVac
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WIBP‐CorV
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BBIBP‐CorV
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BBV152
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Protein subunit vaccines
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NVX‐CoV2373
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FINLAY‐FR‐2
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Viral vector (non‐replicating) vaccines
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ChAdOx1
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Ad26.COV2.S
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Gam‐COVID‐Vac
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Nucleic acid‐based (RNA) vaccines
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BNT162b2
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mRNA‐1273
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CVnCoV
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How the intervention might work
Vaccines aim to generate an immune response that prevents SARS‐CoV‐2 infection or reduces the risk of severe disease or death.
Live attenuated virus vaccines
Live attenuated virus vaccines use a weakened form of the virus and are developed so that in an immunocompetent host, they replicate sufficiently to generate a robust immune response (Pollard 2021). Live attenuated vaccines may potentially replicate in an uncontrolled manner in immunosuppressed individuals, thus rendering them less suitable for use within this population (Rubin 2013).
Inactivated virus vaccines
In contrast, inactivated vaccines contain either inactivated whole or altered pathogens, thus precluding their replication; however, inactivated vaccines do not always induce as strong or long‐lasting an immune response as live attenuated vaccines.
Inactivated virus technologies present multiple viral proteins for immune recognition. They have a stable expression of conformation‐dependent antigenic epitopes (Roper 2009). Pitfalls include their potential to alter viral epitopes, which may adversely affect immunogenicity if the native structure of the viral antigen is not maintained (DeZure 2016). As a result, the administration of multiple doses, booster injections, or adjuvant addition is often needed to elicit protective humoral immune responses(Pollard 2021).
Protein subunit vaccines are composed of fragments of the virus. Akin to inactivated whole‐cell vaccines, protein subunit vaccines do not harbour live components of the pathogen. They are distinguished from inactivated whole‐cell vaccines by containing only the necessary antigenic parts of the pathogen for mounting a protective immune response. As the subunit vaccine only relies on the antigen of interest made using recombinant technology, it is considered a more reliable and safer technique than inactivated vaccines(Dong 2020). Nevertheless, this advantage may be offset by its inability to display the virus's full antigenic complexity. This may cause an unbalanced immune response and lower its protective effect (Enjuanes 2016). Consequently, adjuvants may be required to boost immune responses and increase immunogenicity.
Several other platforms have developed over the past few decades. These include virus‐like particles, viral vectors, nucleic acid‐based RNA and DNA vaccines (Pollard 2021), all of which have been employed in COVID‐19 vaccine development.
Virus‐like particle (VLP) vaccines contain virus‐like particles which closely resemble viruses, but are non‐infectious as they contain no viral genetic material (Oxford Vaccine Group 2020). This platform has been used against hepatitis B and human papillomavirus (HPV), and constitutes another protein‐based vaccine composed of proteins from the viral capsid (Fuenmayor 2017). VLP vaccines consist of self‐assembled viral structural proteins that mimic the conformation of native SARS‐CoV virions (Mortola 2004), making them immunogenic and inducing highly neutralizing‐antibody titres. In light of their non‐replicating and non‐infectious constructs, VLPs may have an enhanced safety profile.
Unlike previous vaccines, viral vectors and nucleic acid‐based RNA and DNA vaccines do not contain antigens, but rather nucleic acid sequences (RNA or DNA) that code for the proteins of interest inside the organism (Pollard 2021).
Viral vector vaccines
They differ from most conventional vaccines because they do not contain antigens (Gavi 2020). They are generally constructed from a carrier virus, such as an adeno‐ or pox‐virus, and are engineered to carry the key target for COVID‐19 vaccines (Dong 2020). Whilst vector vaccines confer the key advantage of including the innate immune responses required for eliciting adaptive immune responses, a potential disadvantage is that the host may already possess immunity against the vector due to prior exposure, thus reducing its effect (Pollard 2021). However, this disadvantage does not exist for all vectors. If the anti‐vector response is likely to interfere with the efficacy induced by adenovirus vectors widely used for SARS‐CoV‐2 vaccines, this is not the case with Pox virus vectors (Dong 2020).
Nucleic acid‐based vaccine – mRNA vaccine
Whilst mRNA vaccines are considered a new type of vaccine (CDC 2021), this platform has garnered interest among researchers for decades. The mechanism of action of mRNA vaccines is to instruct cells how to make a protein that may trigger an immune response (CDC 2021). mRNA translation occurs in the host cell's cytosol, circumventing the risk of integration into the host genome (CDC 2021). Like viral vectors, mRNA vaccines induce dendritic cell sensing – mRNA can stimulate TLR7, thus avoiding the use of adjuvants. Like viral vectors, attenuated vaccines and DNA vaccines, these vaccines can induce a CD8 T cell response. Finally, RNAs rapidly destroy mRNAs in the extracellular medium; these vaccines must be encapsulated.
Nucleic acid‐based vaccine – DNA vaccine
DNA vaccine candidates function by injecting a plasmid containing the DNA sequence encoding a SARS‐CoV‐2 antigen which will stimulate the immune response. Due to the biocompatibility of plasmid DNA, their cost‐efficient production and long shelf life, DNA vaccine‐based immunotherapeutic strategies have been developed for treatment of infections (Hobernik 2018). However, their disadvantage is that the DNA molecules must cross the nuclear membrane to be transcribed, and they generally have low immunogenicity (Dong 2020).
These vaccines are used systemically (usually intramuscular injection), but mucosal SARS‐CoV‐2 vaccines are under development. This type of vaccine is predicted to have a better efficacy against infection. Apart from COVID‐19, only one vaccine used via the nasal route has been approved to date: an attenuated vaccine against the influenza virus.
Why it is important to do this review
Given the importance to global health and the increasing number of vaccine candidates now being tested in phase 2 and phase 3 trials, there is a need to produce and maintain a living synthesis of the efficacy and safety of COVID‐19 vaccines.
This review is part of a larger project: the COVID‐NMA initiative (Boutron 2020a). The COVID‐NMA initiative provides decision‐makers with a complete, high‐quality, and up‐to‐date mapping and synthesis of evidence on interventions for preventing and treating COVID‐19. We developed a master protocol on the effect of all interventions for preventing and treating COVID‐19 (Boutron 2020b), followed by specific protocols for more specific questions. Our results are made available and updated bi‐weekly on the COVID‐NMA platform at covid-nma.com.
We followed the PRISMA guidelines (Page 2021). The protocol is available at doi.org/10.5281/zenodo.6458272 and registered on PROSPERO (www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42021271897). It was peer‐reviewed and processed by Cochrane's Central Editorial Service.
This review will be updated as soon as new evidence changes the conclusions or certainty of the evidence of the review, or at least twice a year if no substantial changes occur.
Objectives
To assess the efficacy and safety of COVID‐19 vaccines (as a full primary vaccination series or as a booster dose) against SARS‐CoV‐2.
Methods
Criteria for considering studies for this review
Types of studies
We included parallel individually or cluster‐randomized controlled trials (RCTs) evaluating COVID‐19 vaccines in humans with no restrictions on language. Single‐arm studies, non‐randomized studies, and modelling studies of interventions for COVID‐19 were not eligible to be included in the review.
Types of participants
We included individuals with no restriction on age and comorbidities, irrespective of their serological status at baseline.
Types of interventions
Eligible interventions included any COVID‐19 vaccines, particularly:
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live attenuated virus vaccine;
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inactivated virus vaccine;
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protein subunit vaccine;
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virus‐like particle (VLP) vaccine;
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non‐replicating viral vector (e.g. recombinant adenovirus) vaccine;
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replicating viral vector vaccine;
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RNA‐based vaccine.
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DNA‐based vaccine;
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Other vaccine types for COVID‐19, if any.
In the analysis, we included only results for vaccine candidates with a selected dose evaluated in phases 2‐3 or phase 3 trials and their corresponding early phases.
Comparators included placebo (placebo could consist of saline placebo, injecting only the vaccine adjuvant or injecting a vaccine protecting against other diseases, such as meningococcal conjugate vaccine), no vaccine, or another COVID‐19 vaccine.
Types of outcome measures
Our outcomes were identified with content experts, considering the outcomes most frequently evaluated in the registered RCTs, and after consulting the main outcomes recommended by the US Food and Drug Administration (FDA) guidance for developing a vaccine (FDA 2020a).
Efficacy outcomes
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Incidence of confirmed SARS‐CoV‐2 infection after complete vaccination (all doses of the primary vaccination schedule)*
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Incidence of confirmed symptomatic COVID‐19 after complete vaccination
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Severe or critical COVID‐19 after complete vaccination, as reported by authors (a table summarising the definitions used in each study can be found in Appendix 1)
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All‐cause mortality
*confirmed by reverse transcription polymerase chain reaction (RT‐PCR), nucleic acid amplification testing (NAAT), or any other validated test.
Safety outcomes
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Incidence of systemic reactogenicity events (i.e. the immediate short‐term reactions of a system to vaccines mainly due to immunological responses, such as fever) reported at day 14 after first dose.
When the number of participants with at least one systemic reactogenicity event is not reported, we used proxy measures as follows.
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For adults: the number of participants with malaise as first choice, headache as second choice, and fever 37.5 °C or greater as third choice;
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For children: irritability as first choice, decreased activity/weakness as second choice, and fever 37.5 °C or greater as third choice.
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Incidence of any adverse event (including non‐serious adverse events). We considered any adverse event reported by authors, prioritizing 'solicited' adverse events. However, when these were not available, we collected 'unsolicited' adverse events.
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Incidence of any serious adverse events (SAEs) as reported by authors (a table reporting the definitions used in each study can be found in Appendix 1).
Immunogenicity outcomes
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Geometric mean titre (GMT) of a specific antibody against SARS‐CoV‐2 (two weeks after the first dose or nearest follow‐up, as mentioned in the manuscript)
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GMT of a neutralizing antibody against SARS‐CoV‐2 (two weeks after second dose or nearest follow‐up, as mentioned in the manuscript)
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Cellular immune responses (i.e. interferon gamma (IFN‐γ) enzyme‐linked immunospot (ELISpot)) (any time point reported by authors)
Specific safety outcomes
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Incidence of local reactogenicity events (i.e. the immediate local short‐term reactions of a system to vaccines mainly due to immunological responses, such as pain and swelling) reported at day seven after first dose.
When the number of participants with at least one local adverse event is not reported, we used as a proxy measure pain as the first choice, local swelling/induration as the second choice, and erythema (redness) as the third choice.
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Incidence of specific safety outcomes
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Cardioembolic events (i.e. pulmonary embolism, stroke, venous thrombosis, cavernous sinus thrombosis, pericarditis, myocardial infarction)
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Haematological events (i.e. thrombocytopenia, haemorrhage, neutropenia, anaemia, lymphadenopathy)
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Neurological events (i.e. nervous system diseases)
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Vaccine‐enhanced disease
Note: as the start of follow‐up (T0) varies (e.g. follow‐up starts "14 days after the last dose" or "21 days after the first dose"), we systematically recorded the T0 considered in the study report. For safety outcomes, we considered T0 = time the first dose is injected when the comparison is vaccine versus placebo/no vaccine; T0 = time after the second dose when the comparison focuses on heterologous vaccination; and T0 = time after the booster or placebo when the comparison assessed the booster dose. We systematically recorded the follow‐up duration for the outcomes considered. When the same outcome was recorded at several time points, we recorded the latest.
For specific antibodies against SARS‐CoV‐2, we considered T0 = 2 weeks after the first dose where available, or the nearest time point.
For neutralizing antibodies against SARS‐CoV‐2, we considered T0 = 2 weeks after the second dose where available, or the nearest time point.
Search methods for identification of studies
We used the search strategies defined in the protocol of the larger COVID‐NMA initiative (covid-nma.com) (Boutron 2020b), and outlined in Appendix 2 to identify randomized trials evaluating vaccines for COVID‐19. The search methods and strategies to identify records for this review are being revised approximately yearly, to ensure that they reflect any terminology changes in the topic area, or in the databases.
Electronic searches
The Epistemonikos L·OVE COVID‐19 platform was searched regularly from 4 September 2020 until 5 November 2021 (Epistemonikos) (app.iloveevidence.com/covid19). This platform is a digital repository built by systematic searches in multiple databases, trial registries and preprint servers. Complete data sources and search methods are available at: app.iloveevidence.com/covid19/methods.
The Cochrane COVID‐19 Study Register has been searched on a regular basis (covid-19.cochrane.org/; last searched 5 November 2021). The Cochrane COVID‐19 Study Register is a specialized register built within the Cochrane Register of Studies (CRS) and is maintained by Cochrane Information Specialists. The register contains study reports from several sources, including:
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daily searches of PubMed;
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daily searches of ClinicalTrials.gov;
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weekly searches of Embase.com;
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weekly searches of the WHO International Clinical Trials Registry Platform (ICTRP);
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weekly searches of medRxiv;
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monthly searches of the Cochrane Central Register of Controlled Trials (CENTRAL).
Complete data sources and search methods for the register are available at: community.cochrane.org/about-covid-19-study-register.
We also searched the Retraction Watch Database for retracted studies (retractionwatch.com/retracted-coronavirus-covid-19-papers/; last searched 5 November 2021).
We also systematically searched for updates or publications of preprints using a preprint tracker, developed in collaboration with a research team from the French National Centre for Scientific Research (CNRS) (Cabanac 2021).
Searching other resources
We searched the following trial registries for unpublished and ongoing studies.
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World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) (trialsearch.who.int/), to identify ongoing and completed clinical trials on COVID‐19 (last searched 3 November 2021). We used the List by Health Topic: 2019‐nCoV / COVID‐19 filter to retrieve all studies identified.
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European Medicines Agency (EMA) clinical data website (clinicaldata.ema.europa.eu/web/cdp/home) to identify trials submitted to the EMA and also for the clinical study report (CSR) of eligible studies (last searched 5 November 2021).
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FDA website (www.fda.gov) to identify FDA approval trials (last searched 5 November 2021).
Data collection and analysis
We search, screen and extract data weekly. The analysis is updated online every 2 weeks (covid-nma.com). The next update will be conducted soon after the publication of this review.
Selection of studies
We searched and screened the citations retrieved and used a spreadsheet to document search dates and citations identified. We identified duplicates in Rayyan (Ouzzani 2016), and then in a spreadsheet to enhance sensitivity. Two review authors (CR, HB) independently screened records and abstracts; a third review author (RA) resolved any disagreements.
We did not check the references of included reports as the living search process identifies COVID‐19 trial records prospectively from the point of trial registration.
Whenever both preprints and subsequent peer‐reviewed publications were available, we favoured the latter as they are the latest documents of trial findings (Boutron 2020b).
We retrieved CSRs for four vaccines (BNT162b2 – BioNtech/Fosun Pharma/Pfizer; mRNA‐123 – ModernaTX; ChAdOx1 – Astra Zeneca+University of Oxford; and AD26.COV2.S – Janssen Pharmaceutical Companies) from the EMA website (www.ema.europa.eu/en). For three vaccines (BNT162b2, mRNA‐123 – ModernaTX and Ad26.COV2.S), we found minor discrepancies when compared to the data reported in the peer‐reviewed publication. Discrepancies were due to different cut‐off dates and follow‐up lengths. We were unable to compare data between the CSR and the peer‐reviewed publication for one vaccine (ChAdOx1) since the publication reports pooled results for four trials (COV001, COV002, COV003, and COV005) and the CSR contains data for only two of them (COV002 and COV003).
Data extraction and management
All data were extracted in duplicate. Two review authors (HB, BB) independently read each preprint, publication, protocol, or other study reports, evaluated the completeness of the data, and assessed the risk of bias. Based on a pilot data extraction form, we designed, evaluated and modified a specific structured data extraction form whenever needed to ensure consistency in the extraction of information. The form was implemented on the COVID‐NMA platform on the extraction module explicitly developed for this purpose (covid-nma.com). All discrepancies automatically identified by the platform data extraction module were discussed by the two review authors to reach a consensus.
Information extracted included study characteristics (such as first author, publication year and journal), number of participants randomized, patient characteristics (age, sex, pre‐existing neutralizing or specific antibodies or participants seropositive, comorbidities), intervention details (type of vaccines, dosing, schedule and route of administration), outcome measures, and risk of bias assessment.
For dichotomous outcomes, we extracted the number of events and number of total participants in each study arm.
For efficacy outcomes, we extracted vaccine efficacy as reported by the authors and 95% confidence interval (CI) for each outcome, when available. Vaccine efficacy measures the percentage reduction in incidence of cases among vaccinated persons compared to unvaccinated persons. It is usually calculated as the incidence rate among unvaccinated – incidence rate among vaccinated / the incidence rate among unvaccinated.
For immunogenicity outcomes, we recorded GMTs and 95% CIs for specific and neutralizing antibodies in the control and intervention. We extracted results related to cellular response as reported by authors.
For safety outcomes, we extracted the data as analyzed by the authors.
We extracted the data as analyzed by the trial authors.
To explore vaccine efficacy on variants of concern, such as Alpha (B.1.1.7), Beta (B.1.351), Gamma (P.1), Delta (B.1.617.2), and Omicron (B.1.1.529), we also took into account that:
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vaccine efficacy on variants of concern is determined by sequencing all available cases where available;
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study authors extrapolated vaccine efficacy on variants of concern
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considering the prevalent variant during the study period
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from other sources: the information was extrapolated from data on the prevalence of the variant in the population during the study period. This information was obtained from outbreak.info or other sources.
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This was done only for critical outcomes of efficacy.
Assessment of risk of bias in included studies
We assessed each study with the Cochrane RoB 2 tool for randomized controlled trials (Sterne 2019). We assessed risk of bias for the critical outcomes of the review. We recorded judgements for each domain using the online data extraction tool we developed. Risk of bias was assessed independently, in duplicate with consensus by researchers with epidemiological training (currently 4 people) or Cochrane Response members (the number of people involved varies). All have been previously trained in clinical epidemiology and systematic reviews. All have participated in a training programme where they had to read the training material and perform data extraction and RoB assessments with a team of experienced researchers. The data quality was assessed by the Cochrane Bias Methods Group, who checked a random sample of 10% of the extracted reports.
The Cochrane RoB 2 tool is structured into five domains: 1) risk of bias arising from the randomisation process; 2) risk of bias due to deviations from intended interventions; 3) risk of bias due to missing outcome data; 4) risk of bias in the measurement of the outcome; and 5) risk of bias in the selection of the reported result. Within each domain, a series of 'signalling questions' elicit information relevant to the risk of bias assessment. The response options to the signalling questions are: "yes"; "probably yes"; "probably no"; "no"; and "no information." A risk of bias judgement for each domain is generated by an algorithm, based on answers to the signalling questions. Judgement can be 'low', ‘some concerns’ or 'high' risk of bias. Overall, risk of bias will be considered as "low risk of bias" if all domains are at 'low risk;' "some concerns" if at least one domain is of ‘some concern’ and no domains are 'high risk of bias;' and "high risk of bias" if there is at least one domain assessed as 'high risk,' or several domains with 'some concerns.' In the context of this review, we are interested in quantifying the effect of assignment to the interventions at baseline, regardless of whether the interventions are received as intended (i.e. the intention‐to‐treat effect).
For cluster‐randomized trials, if any, we planned to rely on the extension of the RoB tool 2 for cluster‐randomized trials. Particularly, we planned to add the domain 1b: risk of bias arising from the timing of identification or recruitment of participants in a cluster‐randomized trial. There were no cluster‐RCTs reported by the date of the last search.
While we relied on the signalling questions to assess each domain and justify our assessment, we did not record the answers of systematic reviewers or how consensus was obtained for the signalling questions; this was done only at the domain level.
The risk of bias assessment was considered part of an evaluation of the certainty of the evidence and sensitivity analysis.
Measures of treatment effect
For dichotomous outcomes, we used vaccine efficacy and risk ratio accompanied by the 95% CI as a measure of effect. For outcomes measured with GMTs, we calculated the geometric mean ratios (GMRs) by taking the anti‐log of the mean difference of the log transformed data between arms.
To date, all trials reported vaccine efficacy. In the future if we identify trials reporting only rate ratio, we will calculate vaccine efficacy using the formula rate ratio = 1 − VE/100.
Unit of analysis issues
We analyzed separately different comparisons from multiple‐arm trials for all pairwise meta‐analyses.
Dealing with missing data
For missing outcome data, we extracted the number of participants who dropped out before the completion of the study, and how the study authors handled missing data. We assessed the appropriateness of any imputation methods used to account for early dropouts in our risk of bias assessments. We conducted sensitivity analysis to assess the potential impact of missing outcome data on the results.
Assessment of heterogeneity
We first generated descriptive statistics for study and population characteristics, and we examined the distribution of important clinical and methodological variables (such as age, immunocompromized status, location etc.). We have considered the variability in point estimates and the overlap in CIs in addition to the I2 statistic to assess the level of statistical heterogeneity (Riley 2011).
Assessment of reporting biases
We assessed the selective non‐reporting or under‐reporting of results in the trials identified according to the framework proposed in Chapter 13 of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2021).
Assessment of risk of bias due to missing results in the included studies
We checked whether the results of all our critical and important outcomes were reported as prespecified in the first version of the trial registry. When more than one version was available and the outcomes were modified, we checked the date of the modification using “history of changes.” Of note, some platforms do not provide information about previous versions of the registers. In these cases, we could not know whether we were assessing the original. When registration was not prospective, we also checked the protocol or statistical analysis plan if available.
We used a matrix indicating the availability of study results as recommended in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2021; Kirkham 2018).
We evaluated whether results were unavailable because of the results' P value, magnitude, or direction. We considered the risk of bias due to missing results if an outcome specified in the registry was missing from the main report.
Due to the small number of trials, we could not assess the potential for reporting bias across studies graphically or statistically.
Data synthesis
We analyzed each type of vaccine separately. We combined trials with comparators as placebo or adjuvant or other control together under the same comparison at the specific vaccine level. We included all eligible RCTs in the primary analysis, whatever the risk of bias assessment. We included early‐phase trials in the analysis only when the selected dose was clearly defined and efficacy outcomes (usually assessed in Phase 3 trials) were available.
We performed a pairwise meta‐analysis and presented summary effect estimates with 95% CIs for each direct comparison, with at least two studies providing data. We used the random‐effects model to incorporate the anticipated clinical and methodological heterogeneity across studies. We presented trials reporting zero events in both arms in the forest plot but did not incorporate these in the analysis.
In the presence of excessive heterogeneity across studies (i.e. diverse forest plots or Tau2 > 75% quartile of empirical distributions, or both) (Turner 2012), we did not synthesize the trial data quantitatively but qualitatively unless we could set up homogeneous subsets of the available trials.
All analyses were undertaken with the statistical software environment R (version 4.0.3) using the packages metafor and meta (Balduzzi 2019; Viechtbauer 2010).
We initially planned to conduct a network meta‐analysis (NMA); however, the network of vaccines appeared very sparse, included mainly comparisons of vaccines against placebo, and only one or two studies informed most of the available comparisons (Figure 1). A network of such structure does not allow proper evaluation of the synthesis assumptions. Additionally, the NMA estimates from this network would not be substantially more precise (and could even be less precise for some comparisons) than the direct ones. We will reassess the feasibility of conducting an NMA regularly as part of the living systematic review process (details of the NMA methods considered for future update versions are available in Appendix 3).
Network graph. The size of the nodes is proportional to the number of participants randomized and the thickness of the lines to the number of studies in each comparison.
Subgroup analysis and investigation of heterogeneity
We had planned to perform subgroup analyses for critical outcomes only (Boutron 2020b). For future updates, we will pursue our prespecified subgroup analyses to explore whether the following population characteristics explain sources of heterogeneity.
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Age:
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children or adolescents (aged less than 18 years);
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adults (aged 18 to 59 years);
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older adults (aged greater than 60 years).
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Specific populations:
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immunocompromized people;
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pregnant women.
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It should be noted that, as the evidence base on COVID‐19/SARS‐CoV‐2 and its variants continues to evolve, we will reassess the feasibility of performing these subgroup analyses in future updates of the review when we could also evaluate the impact of the different SARS‐CoV‐2 variants in a meta‐regression model.
For the current review, we assessed the level of heterogeneity by visual inspection of forest plots, the I2 statistic, the between‐study variance (Tau2), and prediction intervals.
Sensitivity analysis
We performed sensitivity analyses for critical outcomes only. We performed sensitivity analyses by excluding RCTs reported in preprint only and early‐phase trials (1 and 2). We also ran the analyses using the number of participants randomized instead of those analyzed for safety outcomes to assess the potential impact of missing outcome data on the results. For efficacy outcomes, it was not possible to calculate the effect estimate (vaccine efficacy) using the number of participants randomized. We did not perform the planned sensitivity analysis that excluded RCTs with an overall high risk of bias since no RCTs were considered at high risk of bias.
Summary of findings and assessment of the certainty of the evidence
To evaluate the certainty of the evidence in the results of the pairwise comparisons for all outcomes except immunogenetic outcomes, overall certainty of the evidence for each outcome was assessed by one review author (KP) and cross‐checked by another review author (AJ) using the GRADE approach (Schünemann 2021). We used the five GRADE considerations (risk of bias, consistency of effect, imprecision, indirectness, and publication bias) to assess the certainty of the body of evidence. The assessment of imprecision was based on a non‐contextualized approach i.e. rating the certainty that there is any effect (Hultcrantz 2017; Zeng 2021a), with the null effect as the threshold for the critical outcomes of mortality and SAEs (Guyatt 2011). In the description of the results for each outcome, we use different thresholds for the size of the effects.
For outcomes reported as vaccine efficacy, we used a threshold of 30%, based on the WHO guidance document which indicated that the primary efficacy endpoint estimate for a placebo‐controlled trial should be at least 50%, with a statistical success criterion that the lower bound of the confidence interval be more than 30% (WHO 2020b; WHO 2020c). For additional adverse event outcomes (i.e. any adverse event, systemic reactogenicity events, and local reactogenicity events), we considered the thresholds for an effect to be RRs of 0.75 and 1.25 for downgrading imprecision.
For all‐cause mortality and SAEs, we considered the effect was "large" when the absolute difference was greater than 5%; there was a "slight" effect when the absolute difference was from 1% to 5%, and there was "little or no effect" when the absolute difference was less than 1%.
For vaccine efficacy outcomes, when the effect estimate was 70% or greater we considered the vaccine to have a "large effect" (WHO 2020b; WHO 2020c).
For any adverse event, systemic reactogenicity events, and local reactogenicity events, we considered the effect as a "large effect" when the absolute difference was greater than 25%; a "slight effect" when the absolute difference was from 10% to 25%, and "little or no effect" when the absolute difference was less than 10%.
We prepared summary of findings tables to present estimated relative and absolute risks for critical and important outcomes, except for immunogenicity outcomes. We calculated absolute effects with GRADEpro GDT using the pooled baseline risks from the control groups of the included studies. Absolute effects are presented per 1000 for the outcomes 'any adverse event,' 'systemic adverse events,' and 'local adverse events,' and in remaining outcomes with low baseline risk (control group event rates less than 1%) per 100,000. We did not report absolute effect for results with low or very low certainty. For outcomes where vaccine efficacy is presented as the effect measure in the summary of findings tables, we used the corresponding RR to calculate the absolute effect. The rationale for using a footnote for the length of follow‐up was to add the specific time per individual study for each outcome.
Results
Description of studies
The full description of included studies is available at zenodo.org/record/6963352#.YuvhdhzP3RY. Characteristics of excluded studies and unpublished registered studies are summarized in the Characteristics of excluded studies section and in Appendix 4, respectively.
Results of the search
The results of the searches are detailed in Figure 2. On 5 November 2021, after excluding duplicates, we screened 48,047 records: 701 were eligible for full‐text screening; we included 111 reports of 76 studies evaluating vaccine candidates against SARS‐CoV‐2. Thirty early‐phase randomized trials (36 reports) are pending due to uncertainty regarding concentration of the vaccine candidate to be selected for the phase 3 trial or lack of results on efficacy for the selected dose reported in a phase 3 trial (Appendix 5). In seven reports of trials already included in the analysis and in five other reports of trials not included in the analysis, we did not find any outcomes of interest or we were unable to extract the data (i.e. results reported only as figures or in graphs) (Appendix 6). Overall, we included 41 studies in the analyses. These studies assessed four different types of vaccine platforms: RNA‐based vaccines (six studies), non‐replicating viral vector vaccines (10 studies), inactivated virus vaccines (13 studies), and protein subunit vaccines (six studies). They also assessed heterologous vaccine schedules and the effect of booster doses (six studies). Of note, we did not identify any trials reporting the efficacy outcome of interest for the vaccine Ad5‐vectored (non‐replicant viral vector) (Zhu 2021a); however, its efficacy as part of a heterologous scheme is assessed in a trial included in the analysis (Li 2021a).
PRISMA flow diagram of included randomized controlled trials (RCTs) (last search date 5 November 2021). COVID‐NMA is a living systematic review of all trials assessing treatment and preventive interventions for COVID‐19 (Boutron 2020a). This review is a subreview of the COVID‐NMA.
FDA: Food and Drug Administration; ICTRP: World Health Organization (WHO) International Clinical Trials Registry Platform.
Included studies
Source of the data
We identified 41 trials overall. There were 37 primary analyses (Ali 2021; Al Kaabi 2021; Asano 2022; Bonelli 2021; Bueno 2021; Dunkle 2021; Ella 2021a; Ella 2021b; El Sahly 2021; Fadlyana 2021; Falsey 2021; Formica 2021; Frenck 2021; Guo 2021; Hall 2021; Han 2021; Heath 2021; Keech 2020; Kremsner 2021; Kulkarni 2021; Li 2021a; Liu 2021; Logunov 2021; Mok 2021; Palacios 2020; Sablerolles 2021; Sadoff 2021a; Sadoff 2021b; Shinde 2021; Tanriover 2021; Thomas 2021; Toledo‐Romani 2021; Walsh 2020; Wu 2021a; Xia 2020; Xia 2021; Zhang 2021), and Voysey 2021a, which was a combined analysis of four trials ((COV001 (NCT04324606), COV002 (NCT04400838), COV003 (ISRCTN89951424), COV005 (NCT04444674)).
We also identified four articles reporting secondary analyses of the four trials included in Voysey 2021a. Emary 2021 reported results by variants for COV002 (NCT04400838); Clemens 2021 reported results by variants for COV003 (ISRCTN89951424); Madhi 2021b reported results by variants for COV005 (NCT04444674); and Madhi 2021a reported results for participants with HIV included in COV005 (NCT04444674).
The 41 included trials were reported in 63 reports (34 peer‐reviewed publications, 22 reports of preprints, four clinical study reports, and three FDA briefings). Of the 34 peer‐reviewed publications, 17 were published with earlier versions (Appendix 7). Data were initially extracted from these reports and then updated with subsequent publications. Only the latest versions of the reports are referenced. Most of the trials included were performed and results were retrieved before the detection of variants of concern. Overall, 10 trials reported results for a specific SARS‐CoV‐2 variant of concern; four trials presented results on the Alpha variant (B.1.1.7) (Dunkle 2021; Emary 2021; Heath 2021; Kremsner 2021), four on Beta variant (B.1.351) (Madhi 2021b; Sadoff 2021b; Shinde 2021; Thomas 2021), two on Gamma variant (P.1) (Clemens 2021; Kremsner 2021), and one on Delta (B.1.617.2) (Ella 2021b).
Study design
All trials used a parallel‐group individually randomized design. Twenty‐six of the RCTs included in the analysis had two arms (63.4%) and 15 (36.6%) were multiple‐arm trials. There were 13 early‐phase trials: three phase 1 (Ella 2021a; Keech 2020; Walsh 2020), seven phase 1‐2 (Asano 2022; Guo 2021; Han 2021; Sadoff 2021a; Wu 2021a; Xia 2021; Zhang 2021), and three phase 2 (Formica 2021; Liu 2021; Xia 2020). In 40 trials (97.5%) the outcome assessor was blinded. All trials evaluating BNT162b2 (three), mRNA‐1273 (two), CVnCoV RNA (one), Ad26.COV2.S (two), and NVX‐CoV2373 (five) used placebo (normal saline) in the control arm. All trials assessing Gam‐COVID‐Vac (one), CoronaVac (six), WIBP‐CorV (two), BBIBP‐CorV (three), BBV152 (two), and FINLAY‐FR‐2 (one) used adjuvant in the control arm. In the case of ChAdOx1/SII‐ChAdOx1, three trials used placebo (normal saline) in the control arm (Asano 2022; Falsey 2021; Madhi 2021b), three used a non‐COVID‐19 vaccine (MenACWY) (COV001, COV002 and COV003 included in Voysey 2021a), and one used adjuvant (Kulkarni 2021). Two trials assessing heterologous vaccine schedules used regular homologous vaccine schedules as control (Li 2021a; Liu 2021), and four trials compared the effect of different vaccine booster schedules (Bonelli 2021; Li 2021a; Mok 2021; Sablerolles 2021).
Recruitment was completed for 33 trials (80.4%), ongoing for seven trials that reported results of prespecified interim analyses (Frenck 2021; Sadoff 2021a; Sadoff 2021b; Voysey 2021a), and one trial was terminated due to an emergency use authorization for the vaccine candidate (Tanriover 2021). The mean sample size was 10,581 participants with median of 504 (interquartile range (IQR) 180 to 21,977; range: minimum 42 to maximum 44,325).
Study registration
All trial registration records were available; three trials were registered retrospectively (Asano 2022; Shinde 2021; Tanriover 2021).
Settings
Overall, 32 RCTs were multicentre and nine were single‐centre trials (Bonelli 2021; Fadlyana 2021; Hall 2021; Han 2021; Li 2021a; Wu 2021a; Xia 2020; Xia 2021; Zhang 2021). The trials took place in Asia (14 trials, 34.1%), Europe (eight trials, 19.5%), North America (seven trials, 17.0%), worldwide (five trials, 12.1%), South America (four trials, 9.7%), Africa (two trials, 4.8%), and Oceania (one trial, 2.4%).
Characteristics of participants
There were 433,838 participants randomized; 250,200 (57.7%) were assigned to the intervention and 183,638 (42.3%) to the control arm. The number of participants analyzed varied by outcome, from 408 to 418,803 participants. The age range was between three and 100 years; 26 trials included participants 18 years of age or older, seven trials included adults between 18 and 65 years of age, two trials included participants 50 years or older (Liu 2021; Wu 2021a), two trials included participants 12 years old or older (Thomas 2021; Walsh 2020), two trials included only adolescents 12 to 17 years old (Ali 2021; Frenck 2021). Two trials included children and adolescents three to 17 years of age (Han 2021; Xia 2021). Overall, 54.0% of participants were male and the mean age ranged between 14 years (minimum) to 61 years (maximum).
Most trials (n = 35, 85.3%) enrolled healthy or clinically stable participants with no history of SARS‐CoV‐2 infection or COVID‐19 diagnosis, four trials enrolled healthcare workers or individuals considered at substantial risk of exposure to and infection with SARS‐CoV‐2 (Bueno 2021; Dunkle 2021; Palacios 2020; Sablerolles 2021), and two trials included immunocompromized participants in trials assessing booster dose; transplant recipients (Hall 2021) and adults under current rituximab therapy (Bonelli 2021). Thirty‐seven of 41 trials reported that pregnancy was an exclusion criterion. No trials reported data on vaccine efficacy and safety in pregnant women.
Details of the intervention
The included trials reported on four types of vaccine platforms and 12 vaccine candidates: three RNA‐based vaccines (BNT162b2, mRNA‐1273 and CVnCoV), three non‐replicating viral vector vaccines (Ad26.COV2.S, ChAdOx1/SII‐ChAdOx1 and Gam‐COVID‐Vac), four inactivated virus vaccines (CoronaVac, WIBP‐CorV, BBIBP‐CorV and BBV152), and two protein subunit vaccines (NVX‐CoV2373 and FINLAY‐FR‐2). As SII‐ChAdOx1, manufactured in India at Serum Institute of India, is the equivalent of ChAdOx1, we pooled the results for both vaccines in the analysis.
All COVID‐19 vaccine candidates are to be administered through an intramuscular injection. Most of the vaccine candidates full vaccination schedules relied on two doses with a between‐dose time interval varying from 14 to 28 days; however, four trials reported a time interval between doses of less than six weeks to 12 weeks or greater for ChAdOx1 (Voysey 2021a), and one trial one to three months for heterologous compared to a homologous scheme (CoronaVac/Ad5 versus CoronaVac/CoronaVac) (Li 2021a). One vaccine candidate had a two‐dose schedule in adults and three‐dose schedule in children and adolescents (BBIBP‐CorV); one vaccine candidate necessitates a single dose (Ad26.COV2.S), and six studies evaluated the effect of a homologous compared to a heterologous booster dose; the time intervals between complete vaccination and boosters are 28 days (Toledo‐Romani 2021), one month (Bonelli 2021), two months (Hall 2021), three months (Sablerolles 2021), four months (mean) (Mok 2021), and three to six months (Li 2021a). There were no studies on variant‐adapted booster doses.
Outcome measurement
There was some heterogeneity in the way outcomes were assessed.
The definition of 'severe or critical disease' was most often based on the WHO clinical progression scale (Marshall 2020). 'Serious adverse events' were assessed using different grading scales such as ICH and EU Guidelines on Pharmacovigilance for Medicinal Products for Human Use (Sadoff 2021b), Division of AIDS (DAIDS) Table for Grading the Severity of Adult and Pediatric Adverse Events (Kulkarni 2021), and toxicity grading scales adapted from Food and Drug Administration (FDA) grading guidance (Asano 2022). The list of definitions used for both outcomes is in Appendix 1.
Funding and conflict of interest
Trials received mixed (private and public) funding (20 trials, 48.78%), public/non‐profit funding (14 trials, 34.14%), and private funding (seven trials, 17.07%). Overall, 37 trials declared competing interests and four trials declared no competing interests (Fadlyana 2021; Mok 2021; Sablerolles 2021; Tanriover 2021).
Excluded studies
We excluded 590 reports; 579 were RCTs evaluating other interventions and were consequently included in the COVID‐NMA platform (covid-nma.com); 11 reports evaluated vaccines but were not eligible for the review (Baden 2021; Barrett 2021; Ewer 2021; Flaxman 2021; Hsieh 2021; Irfan 2021; Lazarus 2021; Patamatamkul 2021; Ward 2021a; Wu 2021b; Zdanowski 2021). Reasons for exclusion included: not randomized (five reports), secondary analysis (two reports), intervention not relevant to the review (two reports), exploratory analysis (one report), and comment (one report). See Characteristics of excluded studies table.
Ongoing studies
We identified 343 trials from registries; 10 were completed, two were terminated, 172 were not recruiting, 155 were ongoing and four were cancelled (Appendix 4).
RNA‐based vaccine
We identified 73 unpublished trials; 34 were not recruiting (67,412 participants planned) and 39 were ongoing (192 participants planned).
Non‐replicating viral vector
We identified 73 unpublished trials; there was one completed trial without results available (27 participants planned), 39 not recruiting (60,018 participants planned), 32 ongoing (157,387 participants planned), and one cancelled (1210 participants planned).
Replicating viral vector
We identified 10 unpublished trials; one completed trial without results available (90 participants planned), four not recruiting (40,950 participants planned), three ongoing (6434 participants planned), and two terminated (495 participants planned).
Inactivated virus
We identified 61 unpublished trials; four completed trials without results available (19,512 participants planned), 25 not recruiting (146,312 participants planned), and 32 ongoing (122,182 participants planned).
Protein subunit
We identified 91 unpublished trials; two completed trials without results available (173 participants planned), 56 not recruiting (605,200 participants planned), 31 ongoing (260,273 participants planned), and two terminated (no participants).
Live attenuated virus
We identified two studies not recruiting (163 participants planned).
DNA‐based vaccine
We identified 18 unpublished trials; two completed trials without results available (30 participants planned), nine not recruiting (16,238 participants planned), and seven ongoing (997 participants planned).
Virus‐like particles
We identified 12 unpublished trials; two not recruiting (1818 participants planned), nine ongoing (2546 participants planned), and one terminated (997 participants planned).
Any SARS‐CoV‐2 vaccine
We identified three trials; two recruiting (2300 participants planned) and one not recruiting (1314 participants planned).
Risk of bias in included studies
For the overall risk of bias across trials, we judged 34 trials to have 'some concerns' for at least one outcome; eight trials were at low risk of bias for all outcomes (Asano 2022; Hall 2021; Han 2021; Kulkarni 2021; Sadoff 2021a; Walsh 2020; Xia 2020; Xia 2021). Further details of these assessments are available in the risk of bias assessment tables (Appendix 8).
Risk of bias arising from the randomisation process
We judged the risk of bias due to randomization to be appropriate and adequately done in 32 trials. In other trials, the allocation concealment was either unclear (Bueno 2021; Guo 2021; Zhang 2021), or not reported (Bonelli 2021; Formica 2021; Keech 2020; Mok 2021; Sablerolles 2021); we downgraded Toledo‐Romani 2021 due to imbalances in baseline characteristics.
Risk of bias due to deviations from intended interventions
Thirty‐four trials were blinded for participants, outcome assessors or healthcare providers, or both. Participants were blinded in six trials (Liu 2021; Sablerolles 2021; Voysey 2021a (which reported pooled results for four trials)), and blinding was unclear in one (Mok 2021). Nevertheless, no deviations from the intended intervention occurred due to awareness of the intervention received, and we did not downgrade the trials for this reason.
For efficacy outcomes, we judged the risk of bias due to deviation from intended interventions to be low in 13 trials and have 'some concerns' in 28 trials, mainly because analyses used to estimate the effect of assignment to intervention was inappropriate as most analyses were per protocol for efficacy outcomes. Participants were excluded for positive or unknown baseline SARS‐CoV‐2 status, not receiving a scheduled injection, not receiving the correct injection or major protocol deviation. We considered there would be no substantial impact of failure to analyse participants according to their randomized assignment due to the relatively small number of exclusions or a balanced number of exclusions between arms. In contrast, safety outcomes mainly were analyzed using intention‐to‐treat analysis. We considered this method appropriate to estimate the effect of assignment to intervention.
Risk of bias due to missing outcome data
We judged the risk of bias due to missing outcome data as low for all outcomes for 33 trials. There were no missing data or any missing outcome data were reasonably well‐balanced across intervention groups, with similar reasons for missing data across the groups. Additionally, when missingness was related to deviations from the protocol, it was accounted for in the assessment of bias due to deviations from intended interventions and we did not downgrade the trial due to missing outcome data. For eight trials (Bonelli 2021; Bueno 2021; Ella 2021b; Frenck 2021; Hall 2021; Liu 2021; Sablerolles 2021; Shinde 2021), we judged the risk of bias as having 'some concerns' since trialists failed to report data for all or nearly all participants for at least one outcome, and missingness could depend on the true value of the outcome, for instance, unbalanced loss to follow‐up due to adverse events or deceased participants not included in the analysis.
Risk of bias in the measurement of the outcome
We judged the risk of bias as low for all outcomes in 38 trials. We judged three trials as having 'some concerns' due to unclear or not blinded assessment of the safety outcomes whose evaluation can be influenced by knowledge of the intervention assignment (Bonelli 2021; Liu 2021; Mok 2021).
Risk of bias in the selection of the reported results
Thirty‐three trials had prospective registrations or protocols (or both) available with no discrepancies between prespecified and reported outcomes; we judged these trials to be at low risk of bias. Six trials had risk of bias concerns due to reported outcomes that were not prespecified or had discrepancies in time points (Bonelli 2021; Ella 2021a; Fadlyana 2021; Formica 2021; Mok 2021; Wu 2021a).
Bias due to missing results in the synthesis
We present matrices indicating the availability of trial results for critical and important review outcomes in Appendix 9. There was evidence of bias due to missing results in four trials: El Sahly 2021, Dunkle 2021, Sadoff 2021b, and Shinde 2021 planned to assess 'GMTs of neutralizing and specific antibodies' but did not report on them. Toledo‐Romani 2021 reported 'total adverse events', but only reported on 'local and systemic reactogenicity events', in addition to outcomes 'confirmed SARS‐CoV‐2 infection after complete vaccination' and 'GMTs of neutralizing and specific antibodies', which were not reported as well. Kulkarni 2021 did not report on the preplanned analysis for 'GMTs of neutralizing and specific antibodies' as well as 'systemic and local reactogenicity events' when compared to placebo. Tanriover 2021 planned to assess 'GMTs of neutralizing and specific antibodies' and 'confirmed SARS‐CoV‐2 infection after complete vaccination' but did not report on them. Zhang 2021 in phase 2 did not report on the results of 'serious adverse events'. Clemens 2021 did not report on the prespecified outcomes 'systemic and serious adverse events'. Liu 2021 did not report on the prespecified 'local and systemic reactogenicity events'. Hall 2021 and Kremsner 2021 did not report on the prespecified outcome 'confirmed SARS‐CoV‐2 infection after complete vaccination'. Finally, Voysey 2021a reporting on results of four trials did not report on results of 'local adverse events'. Ten registered trials are completed but not yet published (19,832 participants planned); the dates of completion range between 15 January 2021 and 13 October 2021. Publication delay since study completion ranged between 23 days and 295 days.
Overview of the risk of bias assessments by outcome
The outcome 'SARS‐CoV‐2 infection after complete vaccination' was reported in seven trials; in all trials we assessed the overall risk of bias to have 'some concerns'.
The outcome 'confirmed symptomatic COVID‐19 after complete vaccination' was reported in 18 trials; in all trials we assessed the overall risk of bias to have 'some concerns'.
The outcome 'severe or critical COVID‐19 after complete vaccination' was reported in 11 trials. In one of them, we assessed the overall risk of bias for this outcome to be 'low' (Thomas 2021). In 10 trials, we assessed the overall risk of bias for this outcome to have 'some concerns'.
The outcome 'all‐cause mortality' was reported in 22 trials. In 17 trials, we assessed the overall risk of bias for this outcome to be 'low'. In five trials, we assessed the overall risk of bias for this outcome to have 'some concerns'.
The outcome 'serious adverse events' was reported in 32 trials. In 21 of them, we assessed the overall risk of bias for this outcome to be low. In 11 trials, we assessed the overall risk of bias for this outcome to have 'some concerns'.
The outcome 'any adverse event' was reported in 35 trials. In 24 of them, we assessed the overall risk of bias for this outcome to be 'low'. In 11 trials, we assessed the overall risk of bias for this outcome to have 'some concerns'.
The outcome 'systemic adverse events' was reported in 31 trials. In 15 of them, we assessed the overall risk of bias for this outcome to be 'low'. In 16 trials, we assessed the overall risk of bias for this outcome to have 'some concerns'.
Effects of interventions
See: Summary of findings 1 BNT162b2 – Pfizer/BioNTech + Fosun Pharma compared to placebo for vaccination against COVID‐19a ; Summary of findings 2 mRNA‐1273 – ModernaTX compared to placebo for vaccination against COVID‐19a ; Summary of findings 3 CVnCoV – CureVac AG compared to placebo for vaccination against COVID‐19a ; Summary of findings 4 ChAdOx1 – AstraZeneca + University of Oxford compared to placebo for vaccination against COVID‐19a ; Summary of findings 5 SII‐ChAdOx1 – Serum Institute of India/AstraZeneca + University of Oxford compared to ChAdOx1 – University of Oxford for vaccination against COVID‐19a ; Summary of findings 6 AD26.COV2.S – Janssen Pharmaceutical Companies compared to placebo for vaccination against COVID‐19a ; Summary of findings 7 Gam‐COVID‐VAC – Sputnik V compared to placebo for vaccination against COVID‐19a ; Summary of findings 8 CoronaVac – Sinovac compared to placebo for vaccination against COVID‐19a ; Summary of findings 9 WIBP‐CorV – Sinopharm‐Wuhan compared to placebo for vaccination against COVID‐19a ; Summary of findings 10 BBIBP‐CorV – Sinopharm‐Beijing compared to placebo for vaccination against COVID‐19a ; Summary of findings 11 BBV152 – Bharat Biotech compared to placebo for vaccination against COVID‐19a ; Summary of findings 12 NVX‐CoV2373 – Novavax compared to placebo for vaccination against COVID‐19a ; Summary of findings 13 FINLAY‐FR‐2 – Instituto Finlay de Vacunas compared to placebo for vaccination against COVID‐19a ; Summary of findings 14 Heterologous vaccination scheme compared to homologous vaccination scheme for vaccination against COVID‐19a ; Summary of findings 15 Booster compared to placebo/no booster for vaccination against COVID‐19a
We report the network structure, irrespective of the outcomes in Figure 1 and the certainty of evidence for all critical outcomes in the summary of findings tables.
RNA‐based vaccines
BNT162b2 – BioNtech/Fosun Pharma/Pfizer versus placebo (normal saline)
See summary of findings Table 1 and table of results in Appendix 10.
We identified and included three trials in the analysis assessing BNT162b2. The outcomes 'confirmed SARS‐CoV‐2 infection after complete vaccination', 'systemic reactogenicity events', 'GMT of specific antibodies against SARS‐CoV‐2' and 'cellular immune response' were not reported for this comparison.
Critical outcomes
Confirmed symptomatic COVID‐19 after complete vaccination
Two trials reported this outcome (Frenck 2021; Thomas 2021). BNT162b2 results in a large reduction in the incidence of symptomatic COVID‐19 after complete vaccination compared to placebo measured at 1.8 months' and six months' follow‐up (vaccine efficacy (VE) 97.84%, 95% confidence interval (CI) 44.25% to 99.92%; I² = 66%; 2 RCTs, 44,077 participants; high‐certainty evidence; Figure 3).
Analysis 1.1.2: RNA‐based vaccine. Outcome: confirmed symptomatic COVID‐19 after complete vaccination.
Ali 2021 included only participants 3 to 17 years of age. Frenck 2021 included only participants 12 to 15 years of age.
Severe or critical COVID‐19 after complete vaccination
One trial reported severe or critical COVID‐19 (Thomas 2021). BNT162b2 results in a large reduction in the incidence of severe or critical disease due to COVID‐19 compared to placebo measured at six months' follow‐up (VE 95.70%, 95% CI 73.90% to 99.90%; 1 RCT, 46,077 participants; high‐certainty evidence; Figure 4).
Analysis 1.1.3: RNA‐based vaccine. Outcome: severe or critical COVID‐19 after complete vaccination.
*Thomas 2021 reports pooled results including adults' participants from Thomas 2021 and adolescent participants from Frenck 2021.
All‐cause mortality
Two trials reported the outcome in 2302 participants at 1.7 months and 4.7 months' follow‐up (Frenck 2021; Walsh 2020); there were no events and the trials did not contribute to the effect estimate. Only one study contributed to the analysis (Thomas 2021), with a follow‐up of six months. The evidence is uncertain for an effect of BNT162b2 on all‐cause mortality compared to placebo due to very serious imprecision (risk ratio (RR) 1.07, 95% CI 0.52 to 2.22; 1 RCT, 43,847 participants; low‐certainty evidence; Figure 5).
Analysis 1.1.4: RNA‐based vaccine. Outcome: all‐cause mortality.
Ali 2021 included only participants 3 to 17 years of age. Frenck 2021 included only participants 12 to 15 years of age.
Serious adverse events
One trial reported the outcome in 42 participants at 1.7 months' follow‐up (Walsh 2020); there were no events and the trial did not contribute to the effect estimate. Two trials contributed to the analysis at 1.7 months' follow‐up (Frenck 2021; Thomas 2021). The evidence is uncertain for an effect of BNT162b2 on SAEs compared to placebo due to serious inconsistency and serious imprecision (RR 1.30, 95% CI 0.55 to 3.07; I² = 76%; 2 RCTs, 46,107 participants; low‐certainty evidence; Figure 6).
Analysis 1.1.5: RNA‐based vaccine. Outcome: serious adverse events (SAEs).
Ali 2021 included only participants 3 to 17 years of age. Frenck 2021 included only participants 12 to 15 years of age.
Any adverse event
Three RCTs reported the outcome at 1.7 months' follow‐up (Frenck 2021; Thomas 2021; Walsh 2020). We decided not to pool the results due to considerable heterogeneity (I² = 90%) probably caused by studies assessing participants in different age groups; Thomas 2021 included adults while Frenck 2021 included adolescents.
One trial reported results for 43,847 participants 16 years and older (Thomas 2021), the RR for any adverse event was 2.17 (95% CI 2.09 to 2.26). Another trial reported results for 2260 participants between 12 and 15 years of age (Frenck 2021); the RR for any adverse event was 1.01 (95% CI 0.73 to 1.41). A third trial reported results for 42 participants 18 years or older (Walsh 2020); the RR for any adverse event in the study was 1.50 (95% CI 0.53 to 4.21) (Figure 7).
Analysis 1.1.7: RNA‐based vaccine. Outcome: any adverse event (AE).
Ali 2021 included only participants 3 to 17 years of age. Frenck 2021 included only participants 12 to 15 years of age.
Important outcomes
GMTs of a neutralizing antibody against SARS‐COV‐2
Two trials reported GMTs of neutralizing antibodies against SARS‐COV‐2 (Frenck 2021; Walsh 2020). Results are detailed in Appendix 11.
Incidence of specific safety outcomes
Specific safety outcomes were not consistently reported throughout the included trials. Thomas 2021 reported the number of participants with stroke and myocardial infarction, Frenck 2021 reported the number of participants with cavernous sinus thrombosis, venous thrombosis and lymphadenopathy, and Walsh 2020 did not report any specific safety outcome of interest. These outcomes are summarized in detail in Appendix 12.
Vaccine‐enhanced disease
This outcome was reported in a single trial which reported no vaccine‐enhanced disease effect (Thomas 2021).
mRNA‐1273 – ModernaTX versus placebo (normal saline)
See summary of findings Table 2 and table of results in Appendix 13.
We identified and included two trials in the analysis assessing mRNA‐1273. The outcomes 'GMT of specific antibodies against SARS‐CoV‐2', 'GMT of neutralizing antibodies against SARS‐CoV‐2' and 'cellular immune response' were not reported for this comparison.
Critical outcomes
Confirmed SARS‐CoV‐2 infection after complete vaccination
Two trials reported this outcome (Ali 2021; El Sahly 2021). mRNA‐1273 probably results in a large reduction in the incidence of SARS‐CoV‐2 infection compared to placebo at 2.3 months (median) and 5.3 months' follow‐up (VE 73.27%, 95% CI 35.82% to 88.87%; I² = 66%; 2 RCTs, 31,632 participants; moderate‐certainty evidence; Figure 8).
Analysis 1.1.1: RNA‐based vaccine. Outcome: confirmed SARS‐CoV‐2 infection after complete vaccination.
Ali 2021 included only participants 3 to 17 years of age.
Confirmed symptomatic COVID‐19 after complete vaccination
Two trials reported on this outcome (Ali 2021; El Sahly 2021). mRNA‐1273 results in a large reduction in the incidence of confirmed symptomatic COVID‐19 after complete vaccination compared to placebo at 2.3 months (median) and 5.3 months' follow‐up (VE 93.20%, 95% CI 91.06% to 94.83%; I² = 0%; 2 RCTs, 31,632 participants; high‐certainty evidence; Figure 3).
Severe or critical COVID‐19 after complete vaccination
The outcome was reported in one trial (El Sahly 2021). mRNA‐1273 results in a large reduction of the incidence of severe or critical disease due to COVID‐19 compared to placebo at 5.3 months' follow‐up (VE 98.20%, 95% CI 92.80% to 99.60%; 1 RCT, 28,451 participants; high‐certainty evidence; Figure 4).
All‐cause mortality
One study reported the outcome in 3726 participants at 2.3 months (median) follow‐up (Ali 2021); there were no events and the trial did not contribute to the effect estimate. One trial contributed to the analysis with follow‐up of 5.3 months (El Sahly 2021). The evidence is uncertain for an effect of mRNA‐1273 on all‐cause mortality compared to placebo due to very serious imprecision (RR 1.06, 95% CI 0.54 to 2.10; 1 RCT, 30,346 participants; low‐certainty evidence; Figure 5).
Serious adverse events
Two trials reported SAEs (Ali 2021; El Sahly 2021). mRNA‐1273 probably results in no or little difference in the incidence of SAEs compared to placebo at 2.8 months (median) and 5.3 months' follow‐up (RR 0.92, 95% CI 0.78 to 1.08; I² = 0%; 2 RCTs, 34,072 participants; absolute effect: 143 fewer per 100,000 (from 394 fewer to 143 more); moderate‐certainty evidence; Figure 6).
Systemic reactogenicity events
Two trials reported the outcome (Ali 2021; El Sahly 2021). mRNA‐1273 results in a slight increase in the occurrence of any systemic reactogenicity event compared to placebo (RR 1.28, 95% CI 1.22 to 1.34; I² = 61%; 2 RCTs, 34,037 participants; absolute effect: 121 more with systemic reactogenicity events per 1000 (from 95 fewer to 147 more); high‐certainty evidence; Figure 9).
Analysis 1.1.6: RNA‐based vaccine. Outcome: systemic reactogenicity events.
Ali 2021 included only participants 3 to 17 years of age.
Any adverse event
Two RCTs reported the outcome at 2.8 months (median) and 5.3 months' follow‐up (Ali 2021; El Sahly 2021). We decided not to pool the results due to considerable heterogeneity (I² = 100%) probably caused by studies assessing participants in different age groups; Ali 2021 included participants aged three years to 17 years while El Sahly 2021 included adults. One trial reported results for 3726 participants between 12 and 17 years of age (Ali 2021); the risk for any adverse event in the study was 1.47 (95% CI 1.41 to 1.54), the other study reported results for 29,269 participants 18 years and older (El Sahly 2021), the risk for any adverse event in this study was 2.15 (95% CI 2.11 to 2.19) (Figure 7).
Important outcomes
Local reactogenicity events
Two trials reported this outcome (Ali 2021; El Sahly 2021). mRNA‐1273 results in a large increase of local reactogenicity events compared to placebo (RR 3.30, 95% CI 2.02 to 5.40; I² = 99%; 2 RCTs, 34,037 participants; absolute effect: 486 more with local reactogenicity events per 1000 (from 216 more to 930 more); high‐certainty evidence; Figure 10).
Analysis 1.1.8: RNA‐based vaccine. Outcome: local reactogenicity events.
Ali 2021 included only participants 3 to 17 years of age.
Incidence of specific safety outcomes
Specific safety outcomes were not consistently reported throughout the included trials. One trial reported number of participants with pulmonary embolism, pericarditis, venous thrombosis, myocardial infarction, thrombocytopaenia, anaemia and nervous system diseases (El Sahly 2021); the other trial reported number of participants with pericarditis myocardial infarction and lymphadenopathy (Ali 2021). Outcomes were summarized in detail in Appendix 12.
Vaccine‐enhanced disease
One trial reported no vaccine‐enhanced disease effect (El Sahly 2021).
CVnCoV – CureVac AG versus placebo (normal saline)
See summary of findings Table 3 and table of results in Appendix 14.
We identified and included in the analysis one trial assessing CVnCoV. The outcomes 'SARS‐CoV‐2 infection after complete vaccination', 'GMT of specific antibodies against SARS‐CoV‐2', 'GMT of neutralizing antibodies against SARS‐CoV‐2', 'cellular immune response', 'incidence of specific safety outcomes' and 'vaccine‐enhanced disease' were not reported for this comparison.
Critical outcomes
Confirmed symptomatic COVID‐19 after complete vaccination
One trial reported this outcome at 6.2 months' follow‐up (Kremsner 2021). CVnCoV probably results in a small reduction of confirmed symptomatic COVID‐19 after complete vaccination compared to placebo (VE 48.20%, 95% CI 31.70% to 60.90%; 1 RCT, 25,062 participants; moderate‐certainty evidence; Figure 3).
Severe or critical COVID‐19 after complete vaccination
One trial reported the outcome at six months' follow‐up (Kremsner 2021). The evidence is very uncertain for an effect of CVnCoV in reducing severe or critical COVID‐19 compared to placebo due to serious indirectness and very serious imprecision (VE 63.80%, 95% CI 0.00% to 91.70%; 1 RCT, 25,062 participants; very low‐certainty evidence; Figure 4).
All‐cause mortality
One trial reported this outcome at six months' follow‐up (Kremsner 2021). The evidence is very uncertain for an effect of CVnCoV on all‐cause mortality compared to placebo due to serious indirectness and very serious imprecision (RR 1.33, 95% CI 0.46 to 3.83; 1 RCT, 39,529 participants; very low‐certainty evidence; Figure 5).
Serious adverse events
One trial reported this outcome (Kremsner 2021). The evidence is very uncertain for an effect of CVnCoV on SAEs compared to placebo at 1.7 months' follow‐up (RR 1.24, 95% CI 0.90 to 1.71; 1 RCT, 39,529 participants; low‐certainty evidence; Figure 6).
Systemic reactogenicity events
One trial reported this outcome (Kremsner 2021). CVnCoV results in a large increase in the incidence of systemic reactogenicity events compared to placebo at 6.2 months' follow‐up (RR 1.48, 95% CI 1.43 to 1.53; 1 RCT, 3982 participants; absolute effect: 305 more with systemic reactogenicity events per 1000 (from 273 more to 336 more); high‐certainty evidence; Figure 9).
Any adverse event
One trial reported this outcome (Kremsner 2021). CVnCoV probably results in a large increase in the incidence of any adverse event compared to placebo at one‐month follow‐up (RR 1.42, 95% CI 1.38 to 1.47; 1 RCT, 3982 participants; absolute effect: 285 more with any adverse event per 1000 (from 258 more to 319 more); moderate‐certainty evidence; Figure 7).
Important outcomes
Local reactogenicity events
One trial reported this outcome (Kremsner 2021). CVnCoV results in a large increase in the incidence of local reactogenicity events compared to placebo (RR 3.51, 95% CI 3.24 to 3.81; 1 RCT, 3982 participants; absolute effect: 606 more with local reactogenicity events per 1000 (from 541 more to 678 more); high‐certainty evidence; Figure 10).
Non‐replicant viral vector vaccines
ChAdOx1/SII‐ChAdOx1 – AstraZeneca+University of Oxford/Serum Institute of India versus placebo (normal saline/adjuvant/MenACWY)
See summary of findings Table 4 and table of results in Appendix 15.
We identified and included in the analysis seven trials assessing ChAdOx1 – AstraZeneca/University of Oxford and one trial assessing SII‐ChAdOx1, the equivalent of ChAdOx1 manufactured in India at Serum Institute of India (Kulkarni 2021). The latter did not report efficacy outcomes.
The outcomes 'severe or critical COVID‐19 after complete vaccination', 'GMT of neutralizing antibodies against SARS‐CoV‐2' and 'cellular immune response' were not reported for this comparison.
Critical outcomes
Confirmed SARS‐CoV‐2 infection after complete vaccination
This outcome was reported in five RCTs (Falsey 2021; Voysey 2021a (which reported pooled results for four trials)). ChAdOx1 probably reduces SARS‐CoV‐2 infection compared to placebo and MenACWY vaccine at 1.3 months (median) and two months (median) follow‐up (VE 59.35%, 95% CI 48.00% to 68.22%; I² = 68%; 5 RCTs, 43,390 participants; moderate‐certainty evidence; Figure 11).
Analysis 2.1.1: Non‐replicating viral vector vaccine. Outcome: confirmed SARS‐CoV‐2 infection after complete vaccination.
Voysey 2021a: data pooled from four trials.
Confirmed symptomatic COVID‐19 after complete vaccination
Five RCTs reported this outcome (Falsey 2021; Voysey 2021a) (Voysey 2021a (which reported pooled results for four trials)). ChAdOx1 results in a large reduction of the incidence of confirmed symptomatic COVID‐19 after complete vaccination compared to placebo and MenACWY vaccine at 1.3 months (median) and two months (median) follow‐up (VE 70.23%, 95% CI 62.10% to 76.62%; I² = 38%; 5 RCTs, 43,390 participants; high‐certainty evidence; Figure 12).
Analysis 2.1.2: non‐replicating viral vector vaccine. Outcome: confirmed symptomatic COVID‐19 after complete vaccination.
Voysey 2021a: data pooled from four trials.
All‐cause mortality
Two trials reported this outcome in 1456 participants at 2‐month follow‐up (Asano 2022; Kulkarni 2021); there were no events and the trials did not contribute to the effect estimate. Five trials contributed to the analysis with follow‐up from 2.0 months to 4.2 months (Falsey 2021; Madhi 2021a (which reported on HIV‐positive participants who were not included in this pooled analysis); Voysey 2021a (which reported pooled results for four trials)). The evidence is uncertain for an effect of ChAdOx1 on all‐cause mortality compared to placebo and MenACWY vaccine due to very serious imprecision (RR 0.48, 95% CI 0.20 to 1.14; I² = 0%; 5 RCTs, 56,727 participants; low‐certainty evidence; Figure 13).
Analysis 2.1.4: non‐replicating viral vector vaccine. Outcome: all‐cause mortality.
In Kulkarni 2021, the control arm received adjuvant. Voysey 2021a: data pooled from four trials.
Serious adverse events
Seven trials reported this outcome (Asano 2022; Falsey 2021; Kulkarni 2021; Madhi 2021a (which reported on HIV‐positive participants who were not included in this pooled analysis); Voysey 2021a (which reported pooled results for four trials)). ChAdOx1 probably results in no or little increase in the incidence of SAEs compared to placebo and at one month' to 6 months' follow‐up (RR 0.88, 95% CI 0.72 to 1.07; I² = 6%; 7 RCTs, 58,182 participants; absolute effect: 1 fewer with SAEs per 1000 (from 2 fewer to 1 more); moderate‐certainty evidence; Figure 14).
Analysis 2.1.5: non‐replicating viral vector vaccine. Outcome: serious adverse events (SAEs).
In Kulkarni 2021, the control arm received adjuvant. Voysey 2021a: data pooled from four trials.
Systemic reactogenicity events
This outcome was reported in one trial (Asano 2022). ChAdOx1 probably results in a large increase of systemic reactogenicity events compared to placebo (RR 3.93, 95% CI 2.11 to 7.29; 1 RCT, 256 participants; absolute effect: 412 more with systemic reactogenicity events per 1000 (from 156 more to 885 more); moderate‐certainty evidence; Figure 15).
Analysis 2.1.6: non‐replicating viral vector vaccine. Outcome: systemic reactogenicity events.
Any adverse event
Seven trials reported this outcome (Asano 2022; Falsey 2021; Kulkarni 2021; Voysey 2021a (which reported pooled results for four trials). Due to considerable heterogeneity, we decided not to pool the results (I² = 90%). Asano 2022 reported results for 256 participants at 1.2 months' follow‐up; the risk of any adverse event in the study was 2.54 (95% CI 1.73 to 3.74). Falsey 2021 reported results for 32,379 participants at one‐month follow‐up; the risk for any adverse event was 1.37 (95% CI 1.33 to 1.42). Kulkarni 2021 reported results for 1200 participants at 1.9 months' follow‐up; the risk for any adverse event was 1.39 (95% CI 1.12 to 1.74). Lastly, a report pooling four trials presented results for 23,745 participants, the risk for any adverse event was 0.74 (95% CI 0.56 to 0.96) at 3.4 months' follow‐up (Voysey 2021a). Of note, participants in the control arm received different interventions across studies; three trials used normal saline as placebo (Asano 2022; COV005 included in Voysey 2021a; Falsey 2021) and three used MenACWY vaccine (COV001, COV002, COV003 included in Voysey 2021a) and one trial used adjuvant (Kulkarni 2021) (Figure 16).
Analysis 2.1.7: non‐replicating viral vector vaccine. Outcome: any adverse event (AE).
In Kulkarni 2021, the control arm received adjuvant. Voysey 2021a merged results from four different trials where three used quadrivalent meningococcal conjugate vaccine as placebo and one trial used normal saline.
Important outcomes
GMTs of a specific antibody against SARS‐COV‐2
Voysey 2021a reported GMTs of specific antibodies against SARS‐COV‐2. Results are detailed in Appendix 16.
Local reactogenicity events
The outcome was reported in one trial (Asano 2022). ChAdOx1 probably results in a large increase in the number of local reactogenicity events compared to placebo (RR 6.44, 95% CI 2.98 to 13.92; 1 RCT, 256 participants; absolute effect: 510 more with local reactogenicity events per 1000 (from 186 more to 1000 more); moderate‐certainty evidence; Figure 17).
Analysis 2.1.8: non‐replicating viral vector vaccine. Outcome: local reactogenicity events.
Incidence of specific safety outcomes
Specific safety outcomes were not consistently reported throughout the included trials. Madhi 2021a reported number of participants with subsequent nervous system diseases, Falsey 2021 reported number of participants with stroke, cavernous sinus thrombosis, venous thrombosis and nervous system disorders, Voysey 2021a presented results for the number of participants with pulmonary embolism, pericarditis, venous thrombosis, myocardial infarction, anaemia and nervous system diseases, and Asano 2022 and Kulkarni 2021 did not report any specific safety outcome of interest. Outcomes are summarized in detail in Appendix 12.
Vaccine‐enhanced disease
Falsey 2021 reported no vaccine‐enhanced disease effect.
ChAdOx1 – AstraZeneca+University of Oxford versus SII‐ChAdOx1 – Serum Institute of India
See summary of findings Table 5 and table of results in Appendix 17.
Kulkarni 2021 reported results on ChAdOx1 compared to SII‐ChAdOx1 (the equivalent of ChAdOx1 manufactured in India at Serum Institute of India).
Critical outcomes
All‐cause mortality
Kulkarni 2021 reported this outcome at six months' follow‐up. The trial including 400 participants reported zero events for both groups for this outcome (Figure 18).
Analysis 2.2.1: serum Institute of India/Astra Zeneca+University of Oxford – SII‐ChAdOx1 versus University of Oxford – ChAdOx1. Outcome: all‐cause mortality.
Serious adverse events
Kulkarni 2021 reported this outcome at six months' follow‐up. The evidence is uncertain for an effect of SII‐ChAdOx1 on the incidence of SAEs compared to ChAdOx1 due to very serious imprecision (RR 0.50, 95% CI 0.08 to 2.95; 1 RCT, 400 participants; low‐certainty evidence; Figure 19).
Analysis 2.2.2: SII‐ChAdOx1 versus ChAdOx1. Outcome: serious adverse events (SAEs).
Systemic reactogenicity events
Kulkarni 2021 reported this outcome. SII‐ChAdOx1 probably results in a slight decrease in the number of systemic reactogenicity events compared to ChAdOx1 (RR 0.73, 95% CI 0.54 to 0.98; 1 RCT, 400 participants; absolute effect: 105 fewer with systemic reactogenicity events per 1000 (from 179 fewer to 8 fewer); moderate‐certainty evidence; Figure 20).
Analysis 2.2.3: SII‐ChAdOx1 versus ChAdOx1. Outcome: systemic reactogenicity events.
Any adverse event
Kulkarni 2021 reported this outcome at 1.9 months' follow‐up. The evidence is uncertain for an effect of SII‐ChAdOx1 on the incidence of any adverse event compared to ChAdOx1 due to very serious imprecision (RR 0.83, 95% CI 0.52 to 1.33; 1 RCT, 400 participants; low‐certainty evidence; Figure 21).
Analysis 2.2.4: SII‐ChAdOx1 versus ChAdOx1. Outcome: any adverse event (AE).
Important outcomes
Immunogenicity outcomes
Kulkarni 2021 reported that SII‐ChAdOx1 elicited slightly higher levels of specific antibodies against SARS‐COV‐2 (GMR 1.52, 95% CI 1.03 to 2.26) compared to ChAdOx1 (Appendix 16). Results for neutralizing antibodies against SARS‐COV‐2 were not conclusive because of imprecision (GMR 1.23, 95% CI 0.92 to 1.63).
Local reactogenicity events
Kulkarni 2021 reported this outcome. The evidence is uncertain for an effect of SII‐ChAdOx1 on the incidence of local reactogenicity events compared to ChAdOx1 (RR 0.76, 95% CI 0.55 to 1.05; 1 RCT, 400 participants; low‐certainty evidence; Figure 22).
Analysis 2.2.5: SII‐ChAdOx1 versus ChAdOx1. Outcome: local reactogenicity events.
Ad26.COV2.S – Janssen Pharmaceutical Companies versus placebo (normal saline)
See summary of findings Table 6 and table of results in Appendix 18.
We identified and included in the analysis two trials assessing Ad26.COV2.S. The outcomes 'SARS‐CoV‐2 infection after complete vaccination', 'GMT of specific antibodies against SARS‐CoV‐2', and 'cellular immune response' were not reported for this comparison.
Critical outcomes
Confirmed symptomatic COVID‐19 after complete vaccination
This outcome was reported in Sadoff 2021b. Ad26.COV2.S reduces the incidence of confirmed symptomatic COVID‐19 after complete vaccination compared to placebo at 1.9 months (median) follow‐up (VE 66.90%, 95% CI 59.10% to 73.40%; 1 RCT, 39,058 participants; high‐certainty evidence; Figure 12).
Severe or critical COVID‐19 after complete vaccination
This outcome was reported in Sadoff 2021b. Ad26.COV2.S results in a large reduction of severe or critical COVID‐19 compared to placebo at 1.9 months (median) follow‐up (VE 76.30%, 95% CI 57.90% to 87.50%; 1 RCT, 39,058 participants; high‐certainty evidence; Figure 23).
Analysis 2.1.3: non‐replicating viral vector vaccine. Outcome: severe or critical COVID‐19 after complete vaccination.
All‐cause mortality
This outcome was reported in Sadoff 2021b. Ad26.COV2.S probably results in a reduction in all‐cause mortality compared to placebo at 1.9 months (median) follow‐up (RR 0.25, 95% CI 0.09 to 0.67; 1 RCT, 43,783 participants; absolute effect: 69 fewer per 100,000 (from 83 fewer to 30 fewer); high‐certainty evidence; Figure 13).
Serious adverse events
This outcome was reported in Sadoff 2021b. Ad26.COV2.S probably results in little or no difference in the incidence of SAEs at 1.9 months (median) follow‐up (RR 0.92, 95% CI 0.69 to 1.22; 1 RCT, 43,783 participants; absolute effect: 36 fewer per 100,000 (from 139 fewer to 99 more); moderate‐certainty evidence; Figure 14).
Systemic reactogenicity events
Two trials reported this outcome (Sadoff 2021a; Sadoff 2021b). Ad26.COV2.S results in a large increase in systemic reactogenicity events compared to placebo (RR 1.83, 95% CI 1.29 to 2.60; I² = 83%; 2 RCTs, 7222 participants; absolute effect: 28,697 more per 100,000 (from 10,027 more to 55,320 more); high‐certainty evidence; Figure 15).
Any adverse event
The outcome was reported in two trials (Sadoff 2021a; Sadoff 2021b). We decided not to pool the results due to considerable heterogeneity (I² = 96%). Sadoff 2021b reported results for 6736 participants at one‐month follow‐up; the risk for any adverse event was 1.09 (95% CI 0.96 to 1.24). Sadoff 2021a reported results for 486 participants; the risk for adverse events was 2.31 (95% CI 1.80 to 2.97; Figure 16).
Important outcomes
Immunogenicity outcomes
Sadoff 2021a reported GMTs of neutralizing antibodies against SARS‐COV‐2. Results are detailed in Appendix 11.
Local reactogenicity events
Two trials reported this outcome (Sadoff 2021a; Sadoff 2021b). Ad26.COV2.S results in a large increase in local reactogenicity events compared to placebo (RR 3.27, 95% CI 1.91 to 5.62; I² = 84%; 2 RCTs, 7222 participants; absolute effect: 433 more with local reactogenicity events per 1000 (from 174 more to 881 more); high‐certainty evidence; Figure 17).
Incidence of specific safety outcomes
Specific safety outcomes were not consistently reported throughout the included trials: Sadoff 2021b reported the number of participants with pulmonary embolism, cavernous sinus thrombosis, pericarditis and venous thrombosis; Sadoff 2021a did not report any specific safety outcomes of interest. Outcomes are summarized in detail in Appendix 12.
Vaccine‐enhanced disease
Sadoff 2021b reported no vaccine‐enhanced disease effect.
Gam‐COVID‐Vac – Gamaleya Research Institute (Sputnik V) versus placebo (adjuvant)
See summary of findings Table 7 and table of results in Appendix 19.
We identified and included one trial in the analysis assessing Gam‐COVID‐Vac (Logunov 2021).
The outcomes 'SARS‐CoV‐2 infection after complete vaccination', 'incidence of any adverse event', 'systemic reactogenicity events' and 'vaccine‐enhanced disease' were not reported for this comparison.
Some important concerns were raised concerning Logunov 2021: lack of clarity in the definition of the primary outcome; addition of interim analyses; change in outcomes; inadequate reporting with inconsistencies in numbers; and excess of homogeneity of vaccine efficacy across age groups (Bucci 2021). The authors responded to some of these concerns and the manuscript was corrected (Logunov 2021). Nevertheless, uncertainty persists related to the prespecification of the interim analysis and excess of homogeneity of vaccine efficacy across age groups. Consequently, we decided to downgrade the certainty of evidence for these reasons.
Critical outcomes
Confirmed symptomatic COVID‐19 after complete vaccination
This outcome was reported in Logunov 2021. Gam‐COVID‐Vac probably results in a large reduction in the incidence of confirmed symptomatic COVID‐19 after complete vaccination compared to placebo (follow‐up time not reported) (VE 91.10%, 95% CI 83.80% to 95.10%; 1 RCT, 18,695 participants; moderate‐certainty evidence). Of note, vaccine efficacy for this outcome was calculated using RR (Figure 12).
Severe or critical COVID‐19 after complete vaccination
This outcome was reported in Logunov 2021. Gam‐COVID‐Vac probably results in a large reduction in the incidence of severe or critical COVID‐19 compared to placebo (follow‐up time not reported) (VE 100.00%, 95% CI 94.40% to 100.00%; 1 RCT, 19,866 participants; moderate‐certainty evidence; Figure 23).
All‐cause mortality
Logunov 2021 reported this outcome at 1.6 months' follow‐up. The evidence is very uncertain for an effect of Gam‐COVID‐Vac in all‐cause mortality compared to placebo due to serious imprecision (RR 0.99, 95% CI 0.10 to 9.54; 1 RCT, 21,862 participants; very low‐certainty evidence; Figure 13).
Serious adverse events
Logunov 2021 reported this outcome. The evidence is uncertain for an effect of Gam‐COVID‐Vac in the incidence of SAEs compared to placebo at 1.6 months' follow‐up (RR 0.65, 95% CI 0.39 to 1.07; 1 RCT, 21,862 participants; low‐certainty evidence; Figure 14).
Important outcomes
Immunogenicity outcomes
Logunov 2021 reported GMTs of neutralizing and specific antibodies against SARS‐CoV‐2, and cellular immune response. Results are detailed in Appendix 11, Appendix 16, and Appendix 20, respectively.
Incidence of specific safety outcomes
Logunov 2021 reported number of participants with cavernous sinus thrombosis, venous thrombosis, myocardial infarction, lymphadenopathy and nervous system diseases. Details are in Appendix 12.
Inactivated virus vaccines
CoronaVac – Sinovac versus placebo (adjuvant)
See summary of findings Table 8 and table of results in Appendix 21.
We identified and included in the analysis seven trials assessing CoronaVac – Sinovac. The outcome 'SARS‐CoV‐2 infection after complete vaccination' was not reported for this comparison.
Critical outcomes
Confirmed symptomatic COVID‐19 after complete vaccination
This outcome was reported in two trials at 1.4 months (median) to 2 months (median) follow‐up (Palacios 2020; Tanriover 2021). The evidence is uncertain for an effect of CoronaVac on the incidence of confirmed symptomatic COVID‐19 after complete vaccination compared to adjuvant due to serious inconsistency and imprecision (VE 69.81%, 95% CI 12.27% to 89.61%; I² = 92%; 2 RCTs, 19,852 participants; low‐certainty evidence). There was considerable heterogeneity between included studies which could be due to participant’s different level of exposure to the virus across studies (all participants included in Palacios 2020 were healthcare workers compared to a third in Tanriover 2021) (Figure 24).
Analysis 3.1.2: inactivated virus vaccine. Outcome: confirmed symptomatic COVID‐19 after complete vaccination.
Al Kaabi 2021.1 and Al Kaabi N 2021.2 refers to two different comparisons from the same report (Al Kaabi 2021).
Severe or critical COVID‐19 after complete vaccination
Two trials reported this outcome (Palacios 2020; Tanriover 2021). We did not conduct a meta‐analysis for this outcome since the typical normality assumption of the meta‐analysis model would be invalid due to the skewness of the data. This can be seen in the forest plots where the CI is not symmetric around the point estimate. Tanriover 2021, with 0/6559 events in the CoronaVac group versus 1/3470 events in the control group reported a vaccine efficacy of 100.00%, 95% CI 20.40% to 100.00% at 1.4 months (median) follow‐up; and Palacios 2020, with 0/4953 events in the CoronaVac group and 6/4870 events in the control group reported a vaccine efficacy of 100.00%, 95% CI 16.90% to 100.00% at two months (median) follow‐up (Figure 25).
Analysis 3.1.3: inactivated virus vaccine. Outcome: severe or critical COVID‐19 after complete vaccination.
All‐cause mortality
This outcome was reported in two trials at 1.4 months (median) to two months (median) follow‐up (Palacios 2020; Tanriover 2021). The evidence is uncertain for an effect of CoronaVac on all‐cause mortality compared to adjuvant due to very serious imprecision (RR 0.50, 95% CI 0.05 to 5.52; 2 RCTs, 22,610 participants; I² = 32%; low‐certainty evidence; Figure 26).
Analysis 3.1.4: inactivated virus vaccine. Outcome: all‐cause mortality.
Al Kaabi 2021.1 and Al Kaabi N 2021.2 refers to two different comparisons from the same report (Al Kaabi 2021).
Serious adverse events
Two trials reported this outcome in 482 participants at 1.4 months' follow‐up (Bueno 2021; Zhang 2021); there were no events and the trials did not contribute to the effect estimate. Four RCTs contributed to the analysis with follow‐up of two months (median) to four months (Han 2021; Palacios 2020; Tanriover 2021; Wu 2021a). The evidence is uncertain for an effect of CoronaVac on SAEs compared to adjuvant due to very serious imprecision (RR 0.97, 95% CI 0.62 to 1.51; 4 RCTs, 23,139 participants; I² = 0%; low‐certainty evidence; Figure 27).
Analysis 3.1.5: inactivated virus vaccine. Outcome: serious adverse events (SAEs).
Han 2021 included only participants 3 to 17 years of age. Wu 2021a included only participants 60 years of age and older.
Wu 2021a reports data for phase 1 and 2. Al Kaabi 2021.1 and Al Kaabi N 2021.2 refer to two different comparisons from the same report (Al Kaabi 2021).
Systemic reactogenicity events
Six trials reported this outcome (Bueno 2021; Fadlyana 2021; Palacios 2020; Tanriover 2021; Wu 2021a; Zhang 2021). The evidence is uncertain for an effect of CoronaVac on systemic reactogenicity events compared to adjuvant due to serious inconsistency and imprecision (RR 1.19, 95% CI 1.00 to 1.42; 6 RCTs, 23,966 participants; I² = 55%; low‐certainty evidence; Figure 28).
Analysis 3.1.6: inactivated virus vaccine. Outcome: systemic reactogenicity events.
Xia S 2021 included only participants 3 to 17 years of age (Xia 2021). Wu Z 2021 included only participants 60 years of age and older (Wu 2021a).
Wu Z 2021 reports data for phase 2 (Wu 2021a). Al Kaabi 2021.1 and Al Kaabi N 2021.2 refer to two different comparisons from the same report (Al Kaabi 2021). Zhang 2020.1 and Zhang 2020.2 refers to two different comparisons from the same report (Zhang 2021).
Any adverse event
This outcome was reported in five trials at one month' to three months' (median) follow‐up (Han 2021; Palacios 2020; Tanriover 2021; Wu 2021a; Zhang 2021). CoronaVac results in a slight difference in the incidence of any adverse event compared to adjuvant (RR 1.09, 95% CI 1.07 to 1.11; 6 RCTs, 23,367 participants; absolute effect: 48 more with any adverse event per 1000 (from 37 more to 58 more); high‐certainty evidence; Figure 29).
Analysis 3.1.7: inactivated virus vaccine. Outcome: any adverse event (AE).
Han B 2021 and Xia 2021 included only participants 3 to 17 years of age (Han 2021; Xia 2021). Wu Z 2021 included only participants 60 years of age and older (Wu 2021a).
Wu Z 2021 reports data for phase 1 and 2 (Wu 2021a), Al Kaabi 2021.1 and Al Kaabi N 2021.2 refer to two different comparisons from the same report (Al Kaabi 2021). Zhang 2020.1 and Zhang 2020.2 refers to two different comparisons from the same report (Zhang 2021).
Important outcomes
Immunogenicity outcomes
Five trials reported GMTs of neutralizing and specific antibodies against SARS‐COV‐2 (Bueno 2021; Fadlyana 2021; Han 2021; Wu 2021a; Zhang 2021), and one trial reported results for cellular immune response (Zhang 2021). Results are detailed in Appendix 11, Appendix 16, and Appendix 20.
Local reactogenicity events
Six trials reported this outcome (Bueno 2021; Fadlyana 2021; Palacios 2020; Tanriover 2021; Wu 2021a; Zhang 2021) CoronaVac results in a slight increase in the occurrence of local reactogenicity events compared to adjuvant (RR 1.76, 95% CI 1.69 to 1.82; 6 RCTs, 23,962 participants; I² = 0%; absolute effect: 173 more per 1000 (from 157 more to 187 more); high‐certainty evidence; Figure 30).
Analysis 3.1.8: inactivated virus vaccine. Outcome: local reactogenicity events.
Xia S 2021 included only participants 3 to 17 years of age (Xia 2021). Wu Z 2021 included only participants 60 years of age and older (Wu 2021a).
Wu Z 2021 reports data for phase 2 (Wu 2021a). Al Kaabi 2021.1 and Al Kaabi N 2021.2 refer to two different comparisons from the same report (Al Kaabi 2021). Zhang 2020.1 and Zhang 2020.2 refers to two different comparisons from the same report (Zhang 2021).
Incidence of specific safety outcomes
Specific safety outcomes were not consistently reported throughout the included trials: Tanriover 2021 reported number of participants with myocardial infarction and nervous system diseases; Fadlyana 2021 reported the number of participants with venous thrombosis and nervous system diseases; and five trials reported no specific safety outcome of interest (Bueno 2021; Han 2021; Palacios 2020; Wu 2021a; Zhang 2021). Outcomes of interest are summarized in Appendix 12.
Vaccine‐enhanced disease
Palacios 2020 reported no vaccine‐enhanced disease effect.
WIBP‐CorV – Sinopharm‐Wuhan versus placebo (adjuvant)
See summary of findings Table 9 and table of results in Appendix 22.
We identified and included two trials in the analysis assessing WIBP‐CorV. The outcomes 'severe or critical COVID‐19 after complete vaccination', 'cellular immune response' and 'incidence of specific safety outcomes' were not reported for this comparison.
Critical outcomes
Confirmed SARS‐CoV‐2 infection after complete vaccination
This outcome was reported in Al Kaabi 2021. WIBP‐CorV results in a reduction in the incidence of confirmed SARS‐CoV‐2 infection compared to adjuvant at 2.6 months (median) follow‐up (VE 64.00%, 95% CI 48.80% to 74.70%; 1 RCT, 25,449 participants; high‐certainty evidence; Figure 31).
Analysis 3.1.1: inactivated virus vaccine. Outcome: confirmed SARS‐CoV‐2 infection after complete vaccination.
Al Kaabi 2021.1 and Al Kaabi N 2021.2 refer to two different comparisons from the same report (Al Kaabi 2021).
Confirmed symptomatic COVID‐19 after complete vaccination
This outcome was reported in Al Kaabi 2021. WIBP‐CorV results in a large reduction in the incidence of confirmed symptomatic COVID‐19 after complete vaccination compared to adjuvant at 2.6 months (median) follow‐up (VE 72.80%, 95% CI 58.10% to 82.40%; 1 RCT, 25,480 participants; high‐certainty evidence; Figure 24).
All‐cause mortality
This outcome was assessed in one trial (26,917 participants) at 2.6 months (median) follow‐up (Al Kaabi 2021). There were zero events in both groups, therefore no effect estimate could be calculated for this outcome (Figure 26).
Serious adverse events
Two trials assessed this outcome (Guo 2021; Al Kaabi 2021). The evidence is uncertain for an effect of WIBP‐CorV on SAEs compared to adjuvant at 1.6 months (median) and 2.6 months (median) follow‐up due to serious imprecision (RR 0.83, 95% CI 0.60 to 1.15; I² = 0%; 2 RCTs, 27,029 participants; low‐certainty evidence; Figure 27).
Systemic reactogenicity events
Two trials reported this outcome (Guo 2021; Al Kaabi 2021). WIBP‐CorV results in no or little difference in the occurrence of systemic reactogenicity events compared to adjuvant (RR 0.99, 95% CI 0.95 to 1.03; I² = 0%; 2 RCTs, 27,029 participants; absolute effect: 3 fewer with systemic reactogenicity events per 1000 (from 14 fewer to 8 more); high‐certainty evidence; Figure 28).
Any adverse event
Two trials assessed the outcome (Guo 2021; Al Kaabi 2021). WIBP‐CorV results in little difference in the incidence of any adverse event compared to adjuvant at one‐month follow‐up (RR 0.96, 95% CI 0.93 to 0.98; I² = 0%; 2 RCTs, 27,029 participants; absolute effect: 20 fewer with any adverse event per 1000 (from 35 fewer to 10 fewer); high‐certainty evidence; Figure 29).
Important outcomes
Immunogenicity outcomes
Two trials reported GMTs of neutralizing and specific antibodies against SARS‐COV‐2 (Guo 2021; Al Kaabi 2021). Results are reported in Appendix 11 and Appendix 16.
Local reactogenicity events
Two trials reported this outcome (Guo 2021; Al Kaabi 2021). WIBP‐CorV results in little difference in the occurrence of local reactogenicity events compared to adjuvant (RR 0.88, 95% CI 0.85 to 0.92; I² = 0%; 2 RCTs, 27,029 participants; absolute effect: 35 fewer with local reactogenicity events per 1000 (from 44 fewer to 23 fewer); high‐certainty evidence; Figure 30).
Vaccine‐enhanced disease
One trial reported no vaccine‐enhanced disease effect (Al Kaabi 2021).
BBIBP‐CorV – Sinopharm‐Beijing versus placebo (adjuvant)
See summary of findings Table 10 and table of results in Appendix 23.
We identified and included in the analysis three trials assessing BBIBP‐CorV. The outcomes 'severe or critical COVID‐19 after complete vaccination', 'cellular immune response' and 'incidence of specific safety outcomes' were not reported for this comparison.
Critical outcomes
Confirmed SARS‐CoV‐2 infection after complete vaccination
This outcome was reported in one trial (Al Kaabi 2021). BBIBP‐CorV results in a large reduction in SARS‐CoV‐2 infection compared to adjuvant (VE 73.50%, 95% CI 60.60% to 82.20%; 1 RCT, 25,435 participants; high‐certainty evidence; Figure 31).
Confirmed symptomatic COVID‐19 after complete vaccination
This outcome was reported in one trial (Al Kaabi 2021). BBIBP‐CorV results in a large reduction in the incidence of confirmed symptomatic COVID‐19 after complete vaccination compared to placebo (adjuvant) (VE 78.10%, 95% CI 64.80% to 86.30%; 1 RCT, 25,463 participants; high‐certainty evidence; Figure 24).
All‐cause mortality
This outcome was assessed in one trial (26,924 participants) (Al Kaabi 2021). There were zero events in both groups, therefore no effect estimate could be calculated for this outcome (Figure 26).
Serious adverse events
One study assessed this outcome in 112 participants (Xia 2020). There were zero events in both groups and the trial did not contribute to the analysis. One trial contributed to the analysis (Al Kaabi 2021). The evidence is uncertain for an effect of BBIBP‐CorV on SAEs compared to adjuvant at 2.6 months (median) follow‐up (RR 0.76, 95% CI 0.54 to 1.06; 1 RCT, 26,924 participants; low‐certainty evidence; Figure 27).
Systemic reactogenicity events
This outcome was reported in three trials (Al Kaabi 2021; Xia 2020; Xia 2021). BBIBP‐CorV probably results in no or little difference in the occurrence of systemic reactogenicity events compared to adjuvant (RR 1.05, 95% CI 0.86 to 1.28; 3 RCTs, 27,540 participants; absolute effect: 14 more per 1000 (from 38 fewer to 77 more); moderate‐certainty evidence; Figure 28).
Any adverse event
This outcome was reported in three trials (Al Kaabi 2021; Xia 2020; Xia 2021). We decided not to pool the results due to considerable heterogeneity (I² = 90%) probably caused by studies assessing participants in different age groups; reported data for participants aged three years to 17 years old. Xia 2021 reported results for 504 participants at 2.9 months' follow‐up; the risk of any adverse event in the study was 2.05 (95% CI 1.47 to 2.87). Al Kaabi 2021 reported results for 26,941 participants at one‐month follow‐up; the risk for any adverse event was 0.91 (95% CI 0.89 to 0.94). Xia 2020 reported results for 112 participants at one‐month follow‐up; the risk for any adverse event was 0.83 (95% CI 0.36 to 1.94; Figure 29).
Important outcomes
Immunogenicity outcomes
Three trials reported GMTs of neutralizing and specific antibodies against SARS‐COV‐2 (Al Kaabi 2021; Xia 2020; Xia 2021). Results are reported in Appendix 11 and Appendix 16.
Local reactogenicity events
This outcome was reported in three trials (Al Kaabi 2021; Xia 2020; Xia 2021). We decided not to pool the results due to considerable heterogeneity (I² = 90%) probably caused by studies assessing participants in different age groups. Xia 2021 reported results for 504 participants at seven days' follow‐up; the risk of local reactogenicity events in the study was 10.00 (95% CI 2.36 to 42.34). Al Kaabi 2021 reported results for 26,924 participants at seven days' follow‐up; the risk for local reactogenicity events was 0.71 (95% CI 0.68 to 0.74). Xia 2020 reported results for 112 participants at seven days' follow‐up; the risk for local reactogenicity events was 3.33 (95% CI 0.45 to 24.89; Figure 30).
Vaccine‐enhanced disease
One trial reported no vaccine‐enhanced disease effect (Al Kaabi 2021).
BBV152 – Bharat Biotech versus placebo (adjuvant)
See summary of findings Table 11 and table of results in Appendix 24.
We identified and included two trials in the analysis assessing BBV152. The outcome 'vaccine‐enhanced disease' was not reported for this comparison.
Critical outcomes
Confirmed SARS‐CoV‐2 infection after complete vaccination
One trial reported this outcome (Ella 2021b). BBV152 results in a reduction in the incidence of SARS‐CoV‐2 infections compared to adjuvant at 3.3 months (median) follow‐up (VE 68.80%, 95% CI 46.70% to 82.50%; 1 RCT, 6289 participants; high‐certainty evidence; Figure 31).
Confirmed symptomatic COVID‐19 after complete vaccination
This outcome was reported in one trial (Ella 2021b). BBV152 results in a large reduction in the incidence of confirmed symptomatic COVID‐19 after complete vaccination compared to adjuvant at 3.3 months (median) follow‐up (VE 77.80%, 95% CI 65.20% to 86.40%; 1 RCT, 16,973 participants; high‐certainty evidence; Figure 24).
Severe or critical COVID‐19 after complete vaccination
This outcome was reported in one trial at 3.3 months (median) follow‐up (Ella 2021b). BBV152 results in a large reduction of severe or critical COVID‐19 after complete vaccination compared to adjuvant due to very serious imprecision (VE 93.40%, 95% CI 57.10% to 99.80%; 1 RCT, 16,976 participants; high‐certainty evidence; Figure 25).
All‐cause mortality
One trial reported this outcome at 3.3 months (median) follow‐up (Ella 2021b). The evidence is uncertain for an effect of BBV152 on all‐cause mortality compared to adjuvant due to very serious imprecision (RR 0.50, 95% CI 0.17 to 1.46; 1 RCT, 25,753 participants; low‐certainty evidence; Figure 26).
Serious adverse events
This outcome was reported in two trials (Ella 2021a; Ella 2021b); Ella 2021b contributed to the analysis. BBV152 results in little or no difference in the incidence of SAEs compared to adjuvant at 4.9 months (median) follow‐up (RR 0.65, 95% CI 0.43 to 0.97; 1 RCT, 25,928 participants; absolute effect: 162 fewer per 100,000 (from 264 fewer to 14 fewer); high‐certainty evidence; Figure 27).
Systemic reactogenicity events
This outcome was reported in two trials (Ella 2021a; Ella 2021b). BBV152 results in little increase in the occurrence of systemic reactogenicity events compared to adjuvant (RR 1.34, 95% CI 1.15 to 1.58; I² = 0%; 2 RCTs, 25,925 participants; absolute effect: 7 more with systemic reactogenicity events per 1000 (from 3 more to 11 more); high‐certainty evidence; Figure 28).
Any adverse event
This outcome was reported in Ella 2021b. BBV152 results in no or little difference in the occurrence of any adverse event compared to adjuvant at 4.9 months (median) follow‐up (RR 1.00, 95% CI 0.94 to 1.07; 1 RCT, 25,753 participants; absolute effect: 0 fewer with any adverse event per 1000 (from 7 fewer to 9 more); high‐certainty evidence; Figure 29).
Important outcomes
Immunogenicity outcomes
Two trials reported GMTs of neutralizing and specific antibodies against SARS‐COV‐2 (Ella 2021a; Ella 2021b), and Ella 2021a reported results for cellular immune response. Results are detailed in Appendix 11, Appendix 16 and Appendix 20.
Local reactogenicity events
This outcome was reported in two trials (Ella 2021b; Ella 2021a). BBV152 results in no or little difference in the occurrence of local reactogenicity events compared to adjuvant (RR 1.08, 95% CI 0.95 to 1.24; I² = 0%; 2 RCTs, 25,750 participants; absolute effect: 2 more with local reactogenicity events per 1000 (from 2 fewer to 7 more); high‐certainty evidence; Figure 30).
Incidence of specific safety outcomes
Specific safety outcomes were not consistently reported throughout the included trials and are summarized in detail in Appendix 12, rather than pooled in a meta‐analysis.
Protein subunit vaccines
NVX‐CoV2373 – Novavax versus placebo (normal saline)
See summary of findings Table 12 and table of results in Appendix 25.
We identified and included five trials in the analysis assessing NVX‐CoV2373. The outcomes 'SARS‐CoV‐2 infection after complete vaccination', 'severe or critical COVID‐19 after complete vaccination' and 'cellular immune response' were not reported for this comparison.
Low‐certainty evidence for the efficacy outcomes might be explained by the inclusion of results from a trial conducted in South Africa during a period of high prevalence of the Beta variant (Shinde 2021). Vaccine efficacy against this variant was considerably lower than the efficacy reported in the primary analysis or against the Alpha variant.
Critical outcomes
Confirmed symptomatic COVID‐19 after complete vaccination
This outcome was reported in three trials at two months (median) and three months (median) follow‐up (Dunkle 2021; Heath 2021; Shinde 2021). NVX‐CoV2373 probably results in a large reduction of the incidence of confirmed symptomatic COVID‐19 after complete vaccination compared to placebo (VE 82.91%, 95% CI 50.49% to 94.10%; I² = 65%; 3 RCTs, 42,175 participants; moderate‐certainty evidence; Figure 32).
Analysis 4.1.1: protein subunit vaccine. Outcome: confirmed symptomatic COVID‐19 after complete vaccination.
Severe or critical COVID‐19 after complete vaccination
This outcome was reported in one trial at two months (median) follow‐up (Dunkle 2021). NVX‐CoV2373 results in a large reduction of severe or critical COVID‐19 after complete vaccination compared to adjuvant due to very serious imprecision (VE 100.00%, 95% CI 86.99% to 100.00%; 1 RCT, 25,452 participants; moderate‐certainty evidence; Figure 33).
Analysis 4.1.2: protein subunit vaccine. Outcome: severe or critical COVID‐19 after complete vaccination.
All‐cause mortality
One trial reported this outcome in 14,039 participants at three months (median) follow‐up (Heath 2021); there were no events and the trial did not contribute to the effect estimate. Dunkle 2021 contributed to the analysis with follow‐up of two months (median); the evidence is uncertain for an effect of NVX‐CoV2373 on all‐cause mortality compared to placebo due to very serious imprecision (RR 0.90, 95% CI 0.30 to 2.68; 1 RCT, 29,582 participants; low‐certainty evidence; Figure 34).
Analysis 4.1.3: protein subunit vaccine. Outcome: all‐cause mortality.
Serious adverse events
One trial reported the outcome in 52 participants at 1.15 months' follow‐up (Keech 2020); there were no events and the trial did not contribute to the effect estimate. Four trials contributed to the analysis with follow‐up of 1.15 months, two months (median), and three months (Dunkle 2021; Formica 2021; Heath 2021; Shinde 2021). The evidence is uncertain for an effect of NVX‐CoV2373 on SAEs compared to placebo due to very serious imprecision (RR 0.92, 95% CI 0.74 to 1.14, I² = 0%; 4 RCTs, 38,802 participants; low‐certainty evidence; Figure 35).
Analysis 4.1.4: protein subunit vaccine. Outcome: serious adverse events (SAEs).
Systemic reactogenicity events
This outcome was reported in three trials (Dunkle 2021; Formica 2021; Shinde 2021). NVX‐CoV2373 increases slightly the occurrence of systemic reactogenicity events compared to placebo (RR 1.21, 95% CI 1.17 to 1.25, I² = 27%, 3 RCTs, 31,063 participants; absolute effect 76 more per 1000 (from 62 more to 91 more); high‐certainty evidence; Figure 36).
Analysis 4.1.5: protein subunit vaccine. Outcome: systemic reactogenicity events.
Any adverse event
This outcome was reported in five trials (Dunkle 2021; Formica 2021; Heath 2021; Keech 2020; Shinde 2021). NVX‐CoV2373 probably results in little increase in the incidence of any adverse event compared to placebo at 1.15 months (median) to three months (median) follow‐up (RR 1.15, 95% CI 1.05 to 1.26; I² = 57%; 5 RCTs, 46,231 participants; absolute effect: 26 more with any adverse event per 1000 (from 9 more to 45 more); moderate‐certainty evidence; Figure 37).
Analysis 4.1.6: protein subunit vaccine. Outcome: any adverse event (AE).
Important outcomes
Immunogenetic outcomes
Two trials reported GMTs of specific antibodies against SARS‐COV‐2 (Formica 2021; Keech 2020), and Keech 2020 reported GMTs of neutralizing antibodies against SARS‐COV‐2. Results are detailed in Appendix 16 and Appendix 11.
Local reactogenicity events
Three trials reported the outcome (Dunkle 2021; Formica 2021; Shinde 2021). NVX‐CoV2373 results in a large increase in local reactogenicity events compared to placebo (RR 2.78, 95% CI 1.99 to 3.88; I² = 86%; 3 RCTs, 31,063 participants; absolute effect: 340 more with local reactogenicity events per 1000 (from 189 more to 551 more); high‐certainty evidence; Figure 38).
Analysis 4.1.7 Protein subunit vaccine. Outcome: local reactogenicity events
Incidence of specific safety outcomes
Specific safety outcomes were not consistently reported throughout the included trials: Formica 2021 reported number of participants with venous thrombosis, lymphadenopathy and nervous system diseases; Shinde 2021 reported number of participants with anaemia and nervous system diseases; Heath 2021 reported number of participants with myocardial infarction, thrombocytopaenia and nervous system diseases; and Dunkle 2021 reported on the number of events for pulmonary embolism, stroke, venous thrombosis, thrombocytopenia, haemorrhage, neutropenia, anaemia, lymphadenopathy and nervous system diseases. Outcomes are summarized in detail in Appendix 12.
Vaccine‐enhanced disease
One report mentioned this outcome without presenting results (Keech 2020), and two trials reported no vaccine‐enhanced disease effect (Dunkle 2021; Heath 2021).
FINLAY‐FR‐2 – Instituto Finlay de Vacunas versus placebo (adjuvant)
See summary of findings Table 13 and table of results in Appendix 26.
We identified and included in the analysis one trial assessing FINLAY‐FR‐2. The outcomes 'SARS‐CoV‐2 infection after complete vaccination', 'severe or critical COVID‐19 after complete vaccination', 'systemic reactogenicity events', 'incidence of any adverse event', 'incidence of serious adverse events', 'GMT of specific antibodies against SARS‐CoV‐2', 'GMT of neutralizing antibodies against SARS‐CoV‐2', 'cellular immune response', 'incidence of specific safety outcomes' and 'vaccine‐enhanced disease' were not reported for this comparison.
Critical outcomes
Confirmed symptomatic COVID‐19 after complete vaccination
We found one trial reporting this outcome (Toledo‐Romani 2021). FINLAY‐FR‐2 probably results in a large reduction in the incidence of confirmed symptomatic COVID‐19 after complete vaccination compared to adjuvant (VE 71.00%, 95% CI 58.90% to 79.10%; 1 RCT, 28,674 participants; moderate‐certainty evidence; Figure 32).
All‐cause mortality
This outcome was reported in one trial (Toledo‐Romani 2021). FINLAY‐FR‐2 probably results in a reduction of all‐cause mortality compared to adjuvant due to serious risk of bias and imprecision (RR 0.37, 95% CI 0.17 to 0.80; 1 RCT, 28,674 participants; absolute effect: 106 fewer per 100,000 (from 139 fewer to 34 fewer) moderate‐certainty evidence; Figure 34).
Primary series heterologous vaccination scheme versus homologous vaccination scheme
See summary of findings Table 14 and table of results in Appendix 27.
Two publications reported results for three different comparisons involving an RNA‐based vaccine (BNT162b2 – BioNtech/Fosun Pharma/Pfizer), non‐replicating viral vector vaccine (ChAdOx1 – AstraZeneca/University of Oxford), and inactivated virus vaccine (CoronaVac – Sinovac). More specifically the following schemes were compared (vaccine first dose/vaccine second dose): BNT162b2/ChAdOx1 versus BNT162b2/BNT162b2 (Liu 2021), and ChAdOx1/BNT162b2 versus ChAdOx1/ChAdOx1 (Liu 2021), and CoronaVac/Ad5 versus CoronaVac/CoronaVac (Li 2021a).
The outcomes 'SARS‐CoV‐2 infection after complete vaccination', 'symptomatic COVID‐19 after complete vaccination', 'severe or critical COVID‐19', 'all‐cause mortality', 'systemic reactogenicity events' and 'vaccine‐enhanced disease' were not reported for these comparisons.
Critical outcomes
Serious adverse events
One trial reported this outcome in 101 participants at one‐month follow‐up for the comparison CoronaVac/Ad5 versus CoronaVac homologous (Li 2021a), and reported zero events in both groups. Liu 2021 reported the outcome in 234 participants for the comparison BNT162b2/ChAdOx1 versus BNT162b2 homologous and also reported zero events in both groups. The same trial reported the outcome for the comparison ChAdOx1/BNT162b2 versus ChAdOx1 homologous. The evidence is uncertain for an effect of ChAdOx1/BNT162b2 on SAEs compared to ChAdOx1/ChAdOx1 due to serious risk of bias, inconsistency and imprecision (RR 0.34, 95% CI 0.01 to 8.17; 1 RCT, 229 participants; very low‐certainty evidence; Figure 39).
Analysis 5.1.1: heterologous vaccination scheme versus homologous vaccination scheme. Outcome: serious adverse events (SAEs).
Liu X 2021.1 and Liu X 2021.2 are different comparisons for the same report (Liu 2021).
Systemic reactogenicity events
There was one comparison with results for this outcome (Li 2021a). The evidence is uncertain for an effect of CoronaVac/Ad5 on the incidence of systemic reactogenicity events compared to CoronaVac/CoronaVac due to very serious imprecision (RR 1.96, 95% CI 0.52 to 7.41; 1 RCT, 101 participants; low‐certainty evidence; Figure 40).
Analysis 5.1.2: heterologous vaccination scheme versus homologous vaccination scheme. Outcome: systemic reactogenicity events.
Any adverse event
Two trials reported any adverse event on three different comparisons (Li 2021a; Liu 2021). CoronaVac/Ad5 versus CoronaVac homologous at 1‐month follow‐up (RR 3.19, 95% CI 1.11 to 9.11), BNT162b2/ChAdOx1 versus BNT162b2 homologous at two months' follow‐up (RR 1.21, 95% CI 0.87 to 1.68) and ChAdOx1/BNT162b2 versus ChAdOx1 homologous at 2 months' follow‐up (RR 1.03, 95% CI 0.75 to 1.43). The evidence is very uncertain about the effect of heterologous schemes on the incidence of any adverse event compared to homologous schemes due to serious risk of bias, inconsistency and imprecision (Figure 41).
Important outcomes
Immunogenicity outcomes
Li 2021a reported that the heterologous schedule CoronaVac/Ad5 elicited higher levels of specific antibodies against SARS‐COV‐2 (GMR 6.11, 95% CI 3.90 to 9.57) and neutralizing antibodies against SARS‐COV‐2 (GMR 4.25, 95% CI 2.63 to 6.86) compared to the homologous schedule CoronaVac/CoronaVac (Appendix 16 and Appendix 11).
Liu 2021 reported this outcome for two different comparisons. The outcome was measured using IFN‐γ ELISpot 28 days after the administration of the second dose.
The heterologous schedule ChAdOx1/BNT162b2 elicited a larger immune cellular response compared to the homologous schedule ChAdOx1/ChAdOx1 (GMR of number of spot‐forming cells (SFCs) per million peripheral blood mononuclear cell (PBMC)) 3.9 (95% CI 2.9 to 5.3)).
The GMR of SFCs per million PBMCs was 1.2 (95% CI 0.87 to 1.7) for the comparison of the heterologous schedule BNT162b2/ChAdOx to the homologous schedule BNT162b2/BNT162b2 (Appendix 20).
Local reactogenicity events
One trial reported this outcome (Li 2021a). The heterologous schedule (CoronaVac/Ad5) probably results in a large increase in the number of local reactogenicity events compared to the homologous schedule (CoronaVac/CoronaVac) (RR 11.76, 95% CI 1.59 to 87.14; 1 RCT, 101 participants; absolute effect: 215 more with local reactogenicity events per 1000 (from 12 more to 1000 more); low‐certainty evidence; Figure 42).
Analysis 5.1.4: heterologous vaccination scheme versus homologous vaccination scheme. Outcome: local reactogenicity events.
Incidence of specific safety outcomes
Specific safety outcomes were not consistently reported throughout the included trials. Two trials reported on the number of participants with venous thrombosis (Li 2021a; Liu 2021). Outcomes are summarized in detail in Appendix 12.
Boosters
Homologous or heterologous booster versus placebo/no booster
See summary of findings Table 15 and table of results in Appendix 28.
We identified and included two trials in the analysis (Hall 2021; Toledo‐Romani 2021). Hall 2021 included only kidney transplant recipient participants; in our judgement results from this trial are not generally applicable.
mRNA‐1273 booster versus placebo (normal saline)
Hall 2021 compared a booster dose of mRNA‐1273 to placebo after complete vaccination of mRNA‐1273 in kidney transplant recipients. They reported three outcomes of interest.
Systemic reactogenicity events
Follow‐up was seven days, starting after injection of the booster dose. There were 11 systemic reactogenicity events in the intervention arm (60 participants) compared to six in the control arm (59 participants). We assessed the overall risk of bias for the outcome to be low.
The evidence is uncertain for an effect of mRNA‐1273 booster on the incidence of systemic reactogenicity events compared to placebo due to serious imprecision (RR 1.80, 95% CI 0.71 to 4.56; 1 RCT, 119 participants; low‐certainty evidence; Figure 43).
Analysis 6.1.2: booster versus placebo/no booster. Outcome: systemic reactogenicity events.
Immunogenicity outcomes
One trial reported results for cellular immune response (Hall 2021). The outcome was measured using intracellular cytokine staining 28 days after the administration of the booster or placebo. The median CD4+ T cells per million was higher in the booster arm than in the placebo arm (432 versus 67 cells per 100 CD4+ T cells; 95% CI for the between‐group difference, 46 to 986; Appendix 20).
Local reactogenicity events
The follow‐up period was seven days starting after the injection of the booster dose. There were 46 local reactogenicity events in the intervention arm (N = 60) compared to seven in the control arm (N = 59). We assessed the overall risk of bias for the outcome to be low. A‐1273 booster probably results in a large increase in the number of local reactogenicity events compared to placebo (RR 6.46, 95% CI 3.18 to 13.13; 1 RCT, 119 participants; absolute effect: 648 more local adverse event per 1000 (from 259 more to 1000 more); moderate‐certainty evidence; Figure 44).
Analysis 6.1.3: booster versus placebo/no booster. Outcome: local reactogenicity events.
FINLAY‐FR‐1 booster versus no booster dose
All‐cause mortality
Toledo‐Romani 2021 compared a booster dose of FINLAY‐FR‐1 to no booster dose after complete vaccination of FINLAY‐FR‐2 in adults; only all‐cause mortality with a median follow‐up of 1.7 months was reported.
There were 11 deaths in the intervention arm (of 13,883 participants) compared to nine in the control arm (of 14,371 participants). We assessed the overall risk of bias for the outcome to have some concerns due to lack of information about allocation concealment and the use of per‐protocol analysis.
The evidence is very uncertain about the effect of the booster dose of FR‐1 compared to adjuvant due to serious risk of bias and very serious imprecision (RR 1.27, 95% CI 0.52 to 3.05; 1 RCT, 28,254 participants; very low‐certainty evidence; Figure 45).
Analysis 6.1.1: booster versus placebo/no booster. Outcome: all‐cause mortality.
Homologous booster versus heterologous booster
We identified four trials for this comparison (Bonelli 2021; Li 2021a; Mok 2021; Sablerolles 2021). Of note, in all trials specific safety outcomes were not consistently reported; these are summarized in Appendix 9.
BNT162b2 or mRNA‐1273 with homologous booster versus heterologous ChAdOx1 booster
One trial compared a homologous booster dose of BNT162b2 or mRNA‐1273 to a booster dose of ChAdOx1 in immunocompromized adults under current rituximab therapy (Bonelli 2021). They only reported on two outcomes of interest.
Immunogenicity outcomes
Bonelli 2021 reported results for cellular immune response. The outcome was measured using IFN‐γ ELISpot seven days after the administration of the booster dose. The median interquartile range (IQR) number of SFCs per million PBMCs was 459 (133 to 722) in the heterologous booster arm versus 305 (717 to 416) in the homologous booster arm (Appendix 20).
Local reactogenicity events
Follow‐up was two days starting after the injection of the booster dose. There were fewer local reactogenicity events in the ChAdOx1 heterologous booster arm (8/27) compared to the homologous booster arm (16/28) (RR 0.52, 95% CI 0.27 to 1.01). We assessed the overall risk of bias for the outcome to have some concerns due to lack of information about allocation concealment, missingness of outcome data, unclear blinding which could have influenced the measurement of the outcome, and no information on whether the outcome was analyzed as prespecified (Figure 46).
Analysis 6.2.4: homologous booster versus heterologous booster. Outcome: local reactogenicity events.
Bonelli 2021 included only participants under current Rituximab therapy.
Incidence of specific safety outcomes
Bonelli 2021 reported on the number of participants with thrombocytopaenia and nervous system diseases; details are in Appendix 12.
Ad26.COV2.S with homologous booster versus heterologous mRNA‐1273 booster
One trial compared a homologous booster dose of Ad26.COV2.S to a booster dose of mRNA‐1273 in healthcare workers (Sablerolles 2021). They only reported on three outcomes of interest.
Systemic reactogenicity events
Follow‐up was seven days starting after the injection of the booster dose. There were fewer systemic reactogenicity events in the homologous booster arm (62/106) compared to the mRNA‐1273 booster arm (84/111) (RR 0.77, 95% CI 0.64 to 0.94). We assessed the overall risk of bias for the outcome to have some concerns due to lack of information on allocation concealment, use of per‐protocol analysis and missing outcome data (Figure 47).
Analysis 6.2.2: homologous booster versus heterologous booster. Outcome: systemic reactogenicity events.
Immunogenicity outcomes
Sablerolles 2021 reported results for cellular immune response. The proportion of responders was measured using IFN‐y release assay (cut‐off is 0.15 IU/mL) 28 days after the administration of the booster dose. The proportion of responders was lower in the homologous booster arm (32/44; 72.7%) than in the heterologous booster arm (44/48; 91.7%) (RR 0.79, 95% CI 0.64 to 0.96; Appendix 20).
Local reactogenicity events
Follow‐up was seven days starting after the injection of the booster dose. There were fewer local reactogenicity events in the homologous booster arm (73/106) compared to the mRNA‐1273 booster arm (103/111) (RR 0.74, 95% CI 0.65 to 0.85). We assessed the overall risk of bias for the outcome to have some concerns due to lack of information on allocation concealment, use of per‐protocol analysis and missing outcome data (Figure 46).
Ad26.COV2.S with homologous booster versus heterologous BNT162b2 booster
Sablerolles 2021 assessed complete vaccination of Ad26.COV2.S with a homologous booster dose of Ad26.COV2.S versus a heterologous booster dose of BNT162b2 in healthcare workers. They reported on three outcomes of interest.
Systemic reactogenicity events
Follow‐up was seven days starting after the injection of the booster dose. There were 62/106 systemic reactogenicity events in the homologous booster arm compared to 70/111 in the BNT162b2 booster arm (RR 0.93, 95% CI 0.75 to 1.15). We assessed the overall risk of bias for the outcome to have some concerns due to lack of information on allocation concealment, use of per‐protocol analysis and missing outcome data (Figure 47).
Immunogenicity outcomes
Sablerolles 2021 reported results for cellular immune response. The proportion of responders was measured using IFN‐y release assay (cut‐off is 0.15 IU/mL) 28 days after the administration of the booster dose. The response rate was lower in the homologous booster arm (32/44; 72.7%) than in the heterologous booster arm (43/47; 91.5%) (RR 0.79, 95% CI 0.65 to 0.97; Appendix 20).
Local reactogenicity events
Follow‐up was seven days starting after the injection of the booster dose. There were fewer local reactogenicity events in the homologous booster arm (73/106) compared to the BNT162b2 booster arm (97/111) (RR 0.79, 95% CI 0.66 to 0.91). We assessed the overall risk of bias for the outcome to have some concerns due to lack of information on allocation concealment, use of per‐protocol analysis and missing outcome data (Figure 46).
CoronaVac with homologous booster versus heterologous Ad5 booster
One trial compared a complete vaccination of CoronaVac with a homologous booster dose of CoronaVac to a heterologous booster dose of Ad5 in healthy adults (Li 2021a). They reported five outcomes of interest.
Serious adverse events
Zero SAEs were reported in both groups (Figure 48).
Analysis 6.2.1: homologous booster versus heterologous booster. Outcome: serious adverse events.
Systemic reactogenicity events
Follow‐up was one month starting after the injection of the booster dose. There were fewer systemic reactogenicity events in the homologous booster arm (3/102) compared to the Ad5 booster arm (14/96) (RR 0.20, 95% CI 0.06 to 0.68). We assessed the overall risk of bias for the outcome to have some concerns due to the use of per‐protocol analysis (Figure 47).
Any adverse event
Follow‐up was one month starting after the injection of the booster dose. There were fewer adverse events in the homologous booster arm (5/102) compared to the Ad5 booster arm (34/96) (RR 0.14, 95% CI 0.06 to 0.34). We assessed the overall risk of bias for the outcome to have some concerns due to the use of per‐protocol analysis (Figure 49).
Analysis 6.2.3: homologous booster versus heterologous booster. Outcome: any adverse event.
Immunogenicity outcomes
Li 2021a reported that the heterologous booster CoronaVac/Ad5 elicited higher levels of specific antibodies against SARS‐COV‐2 (GMR 8.37, 95% CI 6.52 to 10.75) and neutralizing antibodies against SARS‐COV‐2 (GMR 5.87, 95% CI 4.64 to 7.43) compared to the homologous booster CoronaVac/CoronaVac (Appendix 16; Appendix 11).
Local reactogenicity events
Follow‐up was one month starting after the injection of the booster dose. There were fewer local reactogenicity events in the homologous booster arm (3/102) compared to the Ad5 booster arm (28/96) (RR 0.10, 95% CI 0.03 to 0.32). We assessed the overall risk of bias for the outcome to have some concerns due to the use of per‐protocol analysis (Figure 46).
CoronaVac with a homologous booster versus heterologous BNT162b2 booster
One trial compared complete vaccination of CoronaVac with a homologous booster dose of CoronaVac to a heterologous booster dose of BNT162b2 in adults with low‐immune response against SARS‐CoV‐2 after complete vaccination of CoronaVac (Mok 2021). They reported two outcomes of interest.
Systemic reactogenicity events
Follow‐up was one month starting after the injection of the booster dose. There were fewer systemic reactogenicity events in the homologous booster arm (24/40) compared to the BNT162b2 booster arm (32/40) (RR 0.75, 95% CI 0.56 to 1.01). We assessed the overall risk of bias for the outcome to have some concerns due to lack of information on allocation concealment, unclear blinding which could have influenced the measurement of the outcome, and the outcome not being prespecified (Figure 47).
Local reactogenicity events
Follow‐up was one month starting after the injection of the booster dose. There were fewer local reactogenicity events in the homologous booster arm (12/40) compared to the BNT162b2 booster arm (34/40) (RR 0.35, 95% CI 0.22 to 0.58). We assessed the overall risk of bias for the outcome to have some concerns due to lack of information on allocation concealment, unclear blinding which could have influenced the measurement of the outcome, and the outcome not being prespecified (Figure 46).
Heterologous booster versus heterologous booster
Ad26.COV2.S with mRNA‐1273 booster versus Ad26.COV2.S with BNT162b2 booster
One trial compared mRNA‐1273 booster to BNT162b2 booster in healthcare workers vaccinated with Ad26.COV2.S (Sablerolles 2021). They reported on three outcomes of interest.
Systemic reactogenicity events
Follow‐up was seven days starting after the injection of the booster dose. There were more systemic reactogenicity events in the mRNA‐1273 booster arm (84/111) compared to the BNT162b2 booster arm (70/111) (RR 1.20, 95% CI 1.01 to 1.43). We assessed the overall risk of bias for the outcome to have some concerns due to lack of information on allocation concealment, use of per‐protocol analysis, and missing outcome data (Figure 47).
Immunogenicity outcomes
Sablerolles 2021 reported results for cellular immune response. The proportion of responders was measured using IFN‐y release assay (cut‐off is 0.15 IU/mL) 28 days after the administration of the booster dose. The number of responders was similar in the mRNA‐1273 booster arm (44/48; 91.7%) compared to the BNT162b2 booster arm (43/47; 91.5%) (RR 1.00, 95% CI 0.88 to 1.13; Appendix 20).
Local reactogenicity events
Follow‐up was seven days starting after the injection of the booster dose. There were 103/111 participants with local reactogenicity events in the mRNA‐1273 booster arm compared to 97/111 in the BNT162b2 booster arm (RR 1.06, 95% CI 0.97 to 1.16). We assessed the overall risk of bias for the outcome to have some concerns due to lack of information on allocation concealment, use of per‐protocol analysis, and missing outcome data (Figure 46).
Effects of the intervention on variants of concern
Given that the prevalence of more than one variant in the same population changes and shifts over time, it is to be expected that most of the trials, which collect data over several months, reflect the heterogeneity of COVID‐19 variants in their sample. However, among our included studies, 10 did report vaccine efficacy on confirmed symptomatic COVID‐19 after complete vaccination against four variants of concern: Alpha (Dunkle 2021; Emary 2021; Heath 2021; Kremsner 2021), Beta (Madhi 2021b; Sadoff 2021b; Shinde 2021; Thomas 2021), Gamma (Clemens 2021; Kremsner 2021), and Delta (Ella 2021b). No study had yet reported data regarding the Omicron variant at the time of the data cut‐off (5 November 2021).
We considered the direct evidence when study reports provided evidence on a sequenced sample. When sequencing was not performed, we extrapolated the exposure to variants from the prevalence in the study setting.
Alpha variant (B.1.1.7)
Vaccine efficacy against the Alpha variant was reported in three trials, assessing three different vaccines. All cases of the Alpha variant were detected with genome sequencing. Of note, Emary 2021 includes only participants of the COV002 trial (Voysey 2021a).
Reported vaccine efficacy on confirmed symptomatic COVID‐19 after complete vaccination was 55.10%, 95% CI 23.50% to 73.60% for CVnCoV (Kremsner 2021); 70.40%, 95% CI 43.60% to 84.50% for ChAdOx1 (Emary 2021); and for NVX‐CoV2373 was 86.30%, 95% CI 71.30% to 93.50% (Heath 2021) and 93.60%, 95% CI 81.70% to 97.80% (Dunkle 2021) (Figure 50).
Analysis 7.1.1: variant‐Alpha. Outcome: confirmed symptomatic COVID‐19 after complete vaccination.
Beta variant (B.1.351)
Vaccine efficacy against the Beta variant was reported in four trials, assessing four different vaccines. Results from three trials are based only on genetically sequenced cases (direct evidence) (Madhi 2021b; Shinde 2021; Thomas 2021). In contrast, results in Sadoff 2021b include all cases identified and the prevalence of the Beta variant among participants (94.5%), obtained by sequencing a sample of RT‐PCR positive cases, was extrapolated to the results (indirect evidence). Of note, Madhi 2021b includes only participants of the COV005 trial (Voysey 2021a).
Reported vaccine efficacy on confirmed symptomatic COVID‐19 after complete vaccination was 100.00%, 95% CI 53.50% to 100.00% for BNT16b2 (Thomas 2021); 10.40%, 95% CI 0.00% to 54.80% for ChAdOx1 (Madhi 2021b); 52.00%, 95% CI 30.30% to 67.40% for Ad26.COV2.S (Sadoff 2021b), and 43.00%, 95% CI 0.00% to 70.40% for NVX‐CoV2373 (Shinde 2021) (Figure 51).
Analysis 7.2.1: variant‐Beta. Outcome: confirmed symptomatic COVID‐19 after complete vaccination.
Gamma variant (P.1)
Vaccine efficacy against the Gamma variant was reported in two trials, assessing two different vaccines. All cases of the Gamma variant were detected with genome sequencing. Reported vaccine efficacy on confirmed symptomatic COVID‐19 after complete vaccination was 67.10%, 95% CI 29.80% to 84.60% for CVnCoV (Kremsner 2021), and 63.60%, 95% CI 0.00% to 87.00% for ChAdOx1 (Clemens 2021) (Figure 52).
Analysis 7.3.1: variant‐Gamma. Outcome: confirmed symptomatic COVID‐19 after complete vaccination.
Delta (B.1.617.2)
Vaccine efficacy against the Delta variant was reported in one trial. All cases of the Delta variant were detected with genome sequencing.
Reported vaccine efficacy on confirmed symptomatic COVID‐19 after complete vaccination was 65.20%, 95% CI 33.10% to 83.00% for BBV152 (Ella 2021b) (Figure 53).
Analysis 7.4.1: variant‐Delta. Outcome: confirmed symptomatic COVID‐19 after complete vaccination.
Assessment of vaccine efficacy over time
Out of the 41 included trials, only two studies reported on the change of vaccine efficacy over time for the outcome 'incidence of confirmed symptomatic COVID‐19 after complete vaccination' for comparisons BNT162b2 versus placebo (BioNtech/Fosun Pharma/Pfizer) and mRNA‐1273 versus placebo (ModernaTX) (El Sahly 2021; Thomas 2021).
For the comparison BNT162b2 versus placebo, vaccine efficacy seems to decrease slightly over time. However, the effect remains large: VE 96.20%, 95% CI 93.30% to 98.10% after a median follow‐up less than 2 months and VE 83.70%, 95% CI 74.70% to 89.90% after a median follow‐up of 4 months to 6 months (Figure 54).
Analysis 8.1: follow‐up. RNA‐based vaccine. Outcome: confirmed symptomatic COVID‐19 after complete vaccination.
When comparing mRNA‐1273 with placebo, vaccine efficacy was consistent over time (VE 91.80%, 95% CI 86.90% to 95.10%; median follow‐up less than two months and VE 92.40%, 84.30% to 96.80%; median follow‐up four months or greater) (Figure 54).
Exploration of heterogeneity
Subgroup analysis
We had planned to perform subgroup analysis for different age groups and immunocompromized patients; however due to the low number of studies we could not undertake formal subgroup analyses for each comparison.
Sensitivity analysis
Overall, all results for all outcomes were consistent in every sensitivity analysis as compared with the primary analysis. Small differences were mostly observed due to the increase of uncertainty in the summary estimate when excluding some trials.
RNA‐based vaccines
Overall, results were consistent in all the analyses (Table 1).
| Developer – comparison | Analysesa | Outcomes | ||||||
|---|---|---|---|---|---|---|---|---|
| SARS‐CoV‐2 infection | Symptomatic COVID‐19 | Severe COVID‐19 | All‐cause mortality | SAEs | Systemic reactogenicity events | AEs | ||
| VE (95% CI) No. of trials (No. of participants) | RR (95% CI) No. of trials (No. of participants) | |||||||
| BNT162b2 – Pfizer/BioNTech+Fosun Pharma versus placebo | Main analysis | — | 97.84% (44.25% to 99.92%) 2 RCTs (44,077) | 95.70% (73.90% to 99.90%) 1 RCT (46,077) | 1.07 (0.52 to 2.22) 1 RCT (43,846) | 1.30 (0.55 to 3.07) 2 RCTs (46,107) | — | 1.52 (0.88 to 2.63) 3 RCTs (46,419) |
| Sensitivity 1 | — | — | — | 1.07 (0.52 to 2.22) 1 RCT (44,165) | 1.30 (0.55 to 3.05) 2 RCTs (46,429) | — | 1.52 (0.88 to 2.63) 3 RCTs (46,471) | |
| Sensitivity 2 | — | — | — | — | — | — | — | |
| Sensitivity 3 | — | — | — | —
| —
| — | — | |
| mRNA‐1273 – ModernaTX versus placebo | Main analysis | 73.27% (35.82% to 88.87%) 2 RCTs (31,632) | 93.20% (91.06% to 94.83%) 2 RCTs (31,632) | 98.20% (92.80% to 99.60%) 1 RCT (28,451) | 1.06 (0.54 to 2.10) 1 RCT (30,346) | 0.92 (0.78 to 1.08) 2 RCTs (34,072) | 1.28 (1.22 to 1.34) 2 RCTs (34,037) | 1.19 (0.79 to 1.80) 2 RCTs (34,072) |
| Sensitivity 1 | — | — | — | 1.06 (0.54 to 2.10) 1 RCT (30,415) | 0.92 (0.78 to 1.09) 2 RCTs (34,147) | 1.28 (1.22 to 1.34) 2 RCTs (34,147) | 1.20 (0.79 to 1.80) 2 RCTs (34,147) | |
| Sensitivity 2 | — | — | — | — | — | — | —
| |
| Sensitivity 3 | — | — | — | —
| —
| — | — | |
| CVnCoV – CureVac AG versus placebo | Main analysis | — | 48.20% (31.70% to 60.90%) 1 RCT (25,062) | 63.80% (0.00% to 91.70%) 1 RCT (25,062) | 1.33 (0.46 to 3.83) 1 RCT (39,529) | 1.24 (0.90 to 1.71) 1 RCT (39,529) | 1.48 (1.43 to 1.53) 1 RCT (3982) | 1.42 (1.38 to 1.47) 1 RCT (3982) |
| Sensitivity 1 | — | — | — | — | — | 1.49 (1.39 to 1.60) 1 RCT (39,529)
| 1.43 (1.34 to 1.53) 1 RCT (39,529) | |
| Sensitivity 2 | — | — | — | — | — | — | — | |
| Sensitivity 3 | — | — | — | — | — | — | — | |
| AE: adverse event; CI: confidence interval; COVID‐19: coronavirus disease 2019; RCT: randomized controlled trial; RR: risk ratio; SAE: serious adverse event; SARS‐CoV‐2: severe acute respiratory syndrome coronavirus 2; VE: vaccine efficacy. | ||||||||
aSensitivity 1: participants randomized; Sensitivity 2: early‐phase studies excluded; Sensitivity 3: only published studies.
Non‐replicating viral vector vaccines
Overall, results were consistent in all the analyses (Table 2). An important but not statistically significant reduction in the RR for adverse event was observed, though, when excluding the early‐phase trial.
| Developer – comparison | Analysesa | Outcomes | ||||||
|---|---|---|---|---|---|---|---|---|
| SARS‐CoV‐2 infection | Symptomatic COVID‐19 | Severe COVID‐19 | All‐cause mortality | SAEs | Systemic reactogenicity events | AEs | ||
| VE (95% CI) No. of trials (No. of participants) | RR (95% CI) No. of trials (No. of participants) | |||||||
| ChAdOx1 – AstraZeneca + University of Oxford versus placebo | Main analysis | 59.35% (48.00% to 68.22%) 5 RCTs (43,390) | 70.23% (62.10% to 76.62%) 5 RCTs (43,390) | — | 0.48 (0.20 to 1.14) 5 RCTs (56,726) | 0.88 (0.72 to 1.07) 7 RCTs (58,182) | 3.93 (2.11 to 7.29)
1 RCT (256) | Not pooled |
| Sensitivity 1 | — | — | — | 0.50 (0.20 to 1.21) 5 RCTs (56,873) | 0.86 (0.70 to 1.06) 7 RCTs (58,329) | — | — | |
| Sensitivity 2 | — | — | — | 0.48 (0.20 to 1.14) 5 RCTs (56,623) | 0.88 (0.72 to 1.08) 6 RCTs (57,823) | — | — | |
| Sensitivity 3 | — | — | — | 0.50 (0.20 to 1.21) 5 RCTs (56,623) | 0.86 (0.70 to 1.05) 6 RCTs (56,879) | — | — | |
| Ad26.COV2.S – Janssen Pharmaceutical Companies versus placebo | Main analysis | — | 66.90% (59.10% to 73.40%) 1 RCT (39,058) | 76.30% (57.90% to 87.50%) 1 RCT (39,058) | 0.25 (0.09 to 0.67) 1 RCT (43,783) | 0.92 (0.69 to 1.22) 1 RCT (43,783) | 1.83 (1.29 to 2.60) 2 RCTs (7222) | 1.57 (0.75 to 3.29) 2 RCTs (7222) |
| Sensitivity 1 | — | — | — | 0.25 (0.09 to 0.67) 1 RCT (44,325) | 0.92 (0.69 to 1.22) 1 RCT (44,325) | 1.83 (1.27 to 2.63) 2 RCTs (44,813) | 1.57 (0.74 to 3.32) 2 RCTs (44,813) | |
| Sensitivity 2 | — | — | — | — | — | — | 1.09 (0.96 to 1.24) 1 RCT (6736) | |
| Sensitivity 3 | — | — | — | — | — | — | — | |
| Gam‐COVID‐Vac – Gamaleya Research Institute (Sputnik V) Gam‐COVID‐Vac versus placebo | Main analysis | — | 91.10% (83.80% to 95.10%) 1 RCT (18,695) | 100.00% (94.40% to 100.00%) 1 RCT (19,866) | 0.99 (0.10 to 9.54) 1 RCT (21,862) | 0.65 (0.39 to 1.07) 1 RCT (21,862) | — | — |
| Sensitivity 1 | — | — | — | 1.00 (0.10 to 9.57) 1 RCT (21,977) | 0.65 (0.39 to 1.07) 1 RCT (21,977) | — | — | |
| Sensitivity 2 | — | — | — | — | — | — | — | |
| Sensitivity 3 | — | — | — | — | — | — | — | |
| AE: adverse event; CI: confidence interval; COVID‐19: coronavirus disease 2019; RCT: randomized controlled trial; RR: risk ratio; SAE: serious adverse event; SARS‐CoV‐2: severe acute respiratory syndrome coronavirus 2; VE: vaccine efficacy. | ||||||||
aSensitivity 1: participants randomized; Sensitivity 2: early‐phase studies excluded; Sensitivity 3: only published studies.
Inactivated virus vaccines
Results were consistent, with the exception of an increase in vaccine efficacy against confirmed symptomatic COVID‐19 after complete vaccination for CoronaVac compared to placebo when excluding results reported as preprints (VE 83.5%, 95% CI 65.4% to 92.1%) (Tanriover 2021) (Table 3). Using the participants randomized instead of those analyzed seemed to increase the heterogeneity, whereas excluding early‐phase trials slightly decreased the heterogeneity and increased the precision of the summary estimate.
| Developer – comparison | Analysesa | Outcomes | ||||||
|---|---|---|---|---|---|---|---|---|
| SARS‐CoV‐2 infection | Symptomatic COVID‐19 | Severe COVID‐19 | All‐cause mortality | SAEs | Systemic reactogenicity events | AEs | ||
| VE (95% CI) No. of trials (No. of participants) | RR (95% CI) No. of trials (No. of participants) | |||||||
| CoronaVac – Sinovac versus placebo | Main analysis | — | 69.81% (12.27% to 89.61%) 2 RCTs (19,852) | — | 0.50 (0.05 to 5.52) 1 RCT (12,396) | 0.97 (0.62 to 1.51) 4 RCTs (23,139) | 0.95 (0.55 to 1.62) 7 RCTs (23,956) | 1.09 (1.07 to 1.11) 6 RCTs (23,367) |
| Sensitivity 1 | — | — | — | 0.50 (0.05 to 5.52) 1 RCT (12,408) | 0.99 (0.64 to 1.51) 4 RCTs (23,157) | 1.56 (0.91 to 2.69) 7 RCTs (25,106)
| 1.09 (1.07 to 1.11) 6 RCTs (23,385) | |
| Sensitivity 2 | — | — | — | — | 0.99 (0.63 to 1.55) 2 RCTs (22,610) | 1.21 (0.98 to 1.49) 4 RCTs (23,584) | 1.09 (1.07 to 1.11) 2 RCTs (22,610) | |
| Sensitivity 3 | — | 83.50% (65.40% to 92.10%) 1 RCT (10,029) | — | — | 0.73 (0.24 to 2.21) 4 RCTs (10,894) | 0.94 (0.49 to 1.81) 6 RCTs (11,617) | 1.13 (1.04 to 1.23) 4 RCTs (10,640) | |
| WIBP‐CorV – Sinopharm‐Wuhan versus placebo | Main analysis | 64.00% (48.80% to 74.70%) 1 RCT (25,449) | 72.80% (58.10% to 82.40%) 1 RCT (25,480) | — | — | 0.83 (0.60 to 1.15) 2 RCTs (27,029) | 0.99 (0.95 to 1.03) 2 RCTs (27,029) | 0.96 (0.93 to 0.98) 2 RCTs (27,029) |
| Sensitivity 1 | — | — | — | — | 0.83 (0.60 to 1.15) 2 RCTs (27,053) | 0.99 (0.95 to 1.03) 2 RCTs (27,053) | 0.96 (0.93 to 0.98) 2 RCTs (27,053) | |
| Sensitivity 2 | — | — | — | — | 0.82 (0.59 to 1.14) 1 RCT (26,917) | 0.99 (0.95 to 1.03) 1 RCT (26,917) | 0.96 (0.93 to 0.98) 1 RCT (26,917) | |
| Sensitivity 3 | — | — | — | — | — | — | — | |
| BBIBP‐CorV – Sinopharm‐Beijing | Main analysis | 73.50% (60.60% to 82.20%) 1 RCT (25,463) | 78.10% (64.80% to 86.30%) 1 RCT (25,463) | — | — | 0.76 (0.54 to 1.06) 1 RCT (26,924) | 1.05 (0.86 to 1.28) 3 RCTs (27,540) | Not pooled |
| Sensitivity 1 | — | — | — | — | —
| 1.05 (0.86 to 1.28) 3 RCTs (27,557) | Not pooled | |
| Sensitivity 2 | — | — | — | — | —
| 1.02 (0.98 to 1.06) 1 RCT (26,924) |
| |
| Sensitivity 3 | — | — | — | — | — | — | — | |
| BBV152 – Bharat Biotech | Main analysis | 68.80% (46.70% to 82.50%) 1 RCT (6289) | 77.80% (65.20% to 86.40%) 1 RCT (16,973) | 99.70% (96.79% to 99.79%) 1 RCT (16,976) | 0.50 (0.17 to 1.46) 1 RCT (25,753) | 0.65 (0.43 to 0.97) 1 RCT (25,753) | 1.34 (1.15 to 1.58) 2 RCTs (25,925) | 1.00 (0.94 to 1.07) 1 RCT (25,753) |
| Sensitivity 1 | — | — | — | 0.50 (0.17 to 1.46) 1 RCT (25,778) | 0.65 (0.43 to 0.97) 2 RCTs (25,953) | 1.35 (1.15 to 1.58) 2 RCTs (25,953) | 1.00 (0.94 to 1.07) 1 RCT (25,778) | |
| Sensitivity 2 | — | — | — | — | 0.65 (0.43 to 0.97) 1 RCT (25,753) | 1.34 (1.14 to 1.58) 1 RCT (25,753) | — | |
| Sensitivity 3 | — | — | — | — | — | 1.47 (0.63 to 3.47) 1 RCT (172) | — | |
| AE: adverse event; CI: confidence interval; COVID‐19: coronavirus disease 2019; RCT: randomized controlled trial; RR: risk ratio; SAE: serious adverse event; SARS‐CoV‐2: severe acute respiratory syndrome coronavirus 2; VE: vaccine efficacy. | ||||||||
aSensitivity 1: participants randomized; Sensitivity 2: early‐phase studies excluded; Sensitivity 3: only published studies.
Protein subunit vaccines
Overall, results were consistent in all the analyses (Table 4).
| Developer‐comparison | Analysesa | Outcomes | ||||||
|---|---|---|---|---|---|---|---|---|
| SARS‐CoV‐2 infection | Symptomatic COVID‐19 | Severe COVID‐19 | All‐cause mortality | SAEs | Systemic reactogenicity events | AEs | ||
| VE (95% CI) No. of trials (No. of participants) | RR (95% CI) No. of trials (No. of participants) | |||||||
| NVX‐CoV2373 – Novavax | Main analysis | — | 82.91% (50.49% to 94.10%) 3 RCTs (42,175) | 100.00% (86.99% to 100.00%) 1 RCT (25,452) | 0.90 (0.30 to 2.68) 1 RCT (29,582) | 0.92 (0.74 to 1.14) 4 RCTs (46,202) | 1.21 (1.17 to 1.25) 3 RCTs (31,063) | 1.15 (1.05 to 1.26) 5 RCTs (46,231) |
| Sensitivity 1 | — | — | — | —
| 0.92 (0.74 to 1.14) 4 RCTs (50,111) | 1.21 (1.17 to 1.26) 3 RCTs (34,870)
| 1.16 (1.05 to 1.27) 5 RCTs (50,111) | |
| Sensitivity 2 | — | — | — | — | 0.93 (0.75 to 1.15) 3 RCTs (45,689) | 1.20 (1.17 to 1.24) 2 RCTs (30,550) | 1.14 (1.02 to 1.27) 3 RCTs (45,689) | |
| Sensitivity 3 | — | 77.10% (0.00% to 95.19%) 2 RCTs (16,723) | — | —
| 0.99 (0.65 to 1.51) 3 RCTs (16,620) | 1.24 (1.03 to 1.49) 2 RCTs (1481) | 1.18 (1.03 to 1.35) 4 RCTs (16,672) | |
| FINLAY‐FR‐2 – Instituto Finlay de Vacunas | Main analysis | — | 71.00% (58.90% to 79.10%) 1 RCT (28,674) | — | 0.37 (0.17 to 0.80) 1 RCT (28,674) | — | — | — |
| Sensitivity 1 | — | — | — | —
| — | — | — | |
| Sensitivity 2 | — | — | — | —
| — | — | — | |
| Sensitivity 3 | — | — | — | —
| —
| — | — | |
| AE: adverse event; CI: confidence interval; COVID‐19: coronavirus disease 2019; RCT: randomized controlled trial; RR: risk ratio; SAE: serious adverse event; SARS‐CoV‐2: severe acute respiratory syndrome coronavirus 2; VE: vaccine efficacy. | ||||||||
aSensitivity 1: participants randomized; Sensitivity 2: early‐phase studies excluded; Sensitivity 3: only published studies.
Discussion
Summary of main results
We identified and included 41 RCTs evaluating four different vaccine platforms and 12 vaccine candidates published in 65 reports in the analysis. Six RCTs reported results for three RNA‐based vaccines (BNT162b2 from BioNtech/Fosun Pharma/Pfizer; mRNA‐1273 from ModernaTX; CVnCoV by CureVac AG), and 10 RCTs evaluated three non‐replicating viral vector vaccines (ChAdOx1 by AstraZeneca/University of Oxford and SII‐ChAdOx1; Ad26.COV2.S by Janssen Pharmaceutical Companies; Gam‐COVID‐Vac by Gamaleya Research Institute), 13 RCTs evaluated four inactivated virus vaccines (CoronaVac by Sinovac; WIBP‐CorV by Sinopharm‐Wuhan; BBIBP‐CorV by Sinopharm‐Beijing; BBV152 by Bharat Biotech), and 6 RCTs evaluated two protein subunit vaccines (NVX‐CoV2373 by Novavax; FINLAY‐FR‐2 by Instituto Finlay de Vacunas).
Our review also retrieved two trials comparing heterologous vaccination schemes with homologous vaccination schemes, two trials comparing booster versus placebo/no booster, and four trials comparing homologous and heterologous booster doses. Only 10 studies reported results on vaccine efficacy of six different vaccine candidates against any specific variant, which limits our ability to make any variant‐specific claims.
Efficacy outcomes for vaccines versus placebo
There is moderate‐ to high‐certainty evidence that several vaccine candidates are effective in preventing SARS‐CoV‐2 infection (i.e. mRNA‐1273, ChAdOx1, WIBP‐CorV, BBIBP‐CorV, BBV152); symptomatic COVID‐19 (i.e. BNT162b2, mRNA‐1273, CVnCoV, ChAdOx1, Ad26.COV2.S, Gam‐COVID‐Vac, WIBP‐CorV, BBIBP‐CorV, BBV152, NVX‐CoV2373, FINLAY‐FR‐2), and severe or critical disease compared to placebo (i.e. BNT162b2, mRNA‐1273, Ad26.COV2.S, Gam‐COVID‐Vac, BBV152, NVX‐CoV2373).
There is moderate‐certainty evidence that Ad26.COV2.S and FINLAY‐FR‐2 result in a decrease in all‐cause mortality compared to placebo. Evidence was uncertain and very uncertain for death for all other vaccines because of the low number of events.
Safety outcomes for vaccines versus placebo
Overall, we identified an increase in local reactogenicity events such as pain, redness, swelling, and systemic reactogenicities such as tiredness, headache, muscle pain, chills, fever, and nausea. There is moderate‐ to high‐certainty evidence that most vaccine candidates have an increased risk of systemic reactogenicity events (e.g. fever) compared to placebo (mRNA‐1273, CVnCoV, ChAdOx1, Ad26.COV2.S, WIBP‐CorV, BBIBP‐CorV, BBV152, NVX‐CoV2373). These events were expected.
We did not find evidence of an increase in SAEs. There is moderate‐ to high‐certainty evidence that there is probably little or no difference between mRNA‐1273, ChAdOx1, Ad26.COV2.S and BBV152, and placebo in terms of SAEs. Evidence was uncertain and very uncertain for SAEs for other vaccines because of the low number of events.
We also extracted some specific adverse events, that is, cardioembolic events (pulmonary embolism, stroke, cavernous sinus thrombosis, pericarditis, venous thrombosis, myocardial infarction); haematological events (thrombocytopaenia, haemorrhage, neutropenia, anaemia, lymphadenopathy); and neurological events. The reporting of these events was very inconsistent and the number of events reported was very low.
The outcome 'any adverse event' was reported inconsistently. Some considered only the non‐SAE including local and systemic reactogenicity events. Some also considered SAEs, and frequently it was unclear how these events were classified. Overall, we found moderate‐ to high‐certainty evidence that vaccine increases any adverse event for three vaccines (i.e. CVnCoV, NVX‐CoV2373, CoronaVac) and that vaccine results in no increase in any adverse event for two vaccines (i.e. WIBP‐CorV, BBV152). Evidence was uncertain for other vaccines.
As trials' follow‐up was short and the incidence of SAEs was very low, vaccine safety surveillance systems have been put in place to detect rare adverse events and concerns have been raised related to the occurrence of vaccine‐induced immune thrombocytopaenia and thrombosis (Makris 2021; Ostrowski 2021; Rizk 2021; Sharifian‐Dorche 2021).
Other evidence
We found little evidence regarding the differences between heterologous and homologous vaccination schemes, and the effect of booster vaccines (homologous or heterologous). Outcomes considered were mainly immunogenicity outcomes.
In the two studies (assessing mRNA‐1273 and BNT162b2) for which we have data at different time points, vaccine efficacy at short term was consistent with longer‐term results.
Effects of the interventions on specific subpopulations
Given the sparsity of data, we were unable to explore heterogeneity in the results by conducting subgroup analyses, and therefore decided to present results separately for specific subpopulations. We identified only four clinical trials including children and adolescents, and assessed BNT162b2, mRNA‐1273, CoronaVac and BBIBP‐CorV (Ali 2021; Frenck 2021; Han 2021; Xia 2020). We found more studies focused on, or reporting subgroup data for elderly participants, with single studies reporting different outcomes in elderly participants. However, data were still sparse and should be interpreted with caution. Finally, only three studies reported data for immunocompromized participants, each assessing a different vaccine candidate (ChAdOx1, NVX‐CoV2373, and mRNA‐1273 booster versus placebo). No studies were conducted on pregnant women, and pregnant women were very rarely included in trials although it has been reported that they are at greater risk of severe COVID‐19 disease (Qiao 2020).
Impact of the results on future research
The high efficacy of several vaccine candidates, their marketing authorization and the rapid roll‐out population‐wide, raise the question of the feasibility and ethics of placebo RCTs assessing a new vaccine candidate.
For the ongoing placebo trials, the question is whether participants randomized to the placebo group should be unblinded and offered vaccine. Some argue the need to pursue follow‐up to obtain strong data on long‐term efficacy and safety (WHO Ad Hoc Expert Group 2021); others argue that given the clear evidence of a benefit for important outcomes, it would be unethical not to provide a vaccine to all participants (Dal‐Ré 2021a; Dal‐Ré 2021b).
Assessing vaccine efficacy and safety in randomized trials is also difficult considering the rapid evolution of the disease and the emergence of new variants that could impact vaccine efficacy. Large population‐based observational data provide useful complementary information, although they need to be interpreted carefully because of the risk of bias.
Future research questions should focus on the efficacy and safety of vaccines on specific populations, such as pregnant women, immunosuppressed patients and other vulnerable populations, on variants of concerns, and on how we can overcome the waning of vaccine efficacy over time.
An increasing number of trials consider only immunogenetic outcomes to allow a smaller sample size to generate a more rapid answer. However, there is considerable heterogeneity in assessing these outcomes and a consensus is needed on a core outcome set to enable effective comparison and synthesis of studies. Further, their results must be interpreted with caution.
Overall completeness and applicability of evidence
The evidence identified is incomplete. We identified 344 registered RCTs from registries evaluating the efficacy of COVID‐19, of which 10 were completed but not published (non‐replicating viral vector, replicating viral vector, inactivated virus, protein subunit and DNA‐based platforms). The planned sample size of the completed trials for non‐replicating viral vector vaccines is 27 participants, 90 participants for replicating viral vector vaccines, 19,512 for inactivated virus vaccines, 173 for protein subunit vaccines, and 30 for DNA‐based vaccines, yielding a total planned sample size of 19,832.
The applicability of the results should be interpreted with caution. The trials spanned all geographical regions: seven trials were conducted in North America, 14 in Asia, four in South America, eight in Europe, two in Africa, and one in Oceania. Notwithstanding the worldwide geographical representation of trials, it is noteworthy that the representation is skewed. Inactivated vaccine and protein subunit vaccine trials were mostly limited to India, Cuba, and China. Furthermore, trials for mRNA‐1273 were only conducted in the USA.
Our review also highlights the lack of evidence from RCTs regarding the efficacy of vaccines against specific variants. This is not surprising, given the relatively short period between the dominance of one variant and the next. Future studies might report more consistently on the specific variant predominating in their sample or report results stratified by variant, which would allow for more specific meta‐analyses in the future. It is likely that data on efficacy by variant will mainly come from large population‐based observational studies. The COVID‐NMA initiative identified observational studies evaluating vaccine efficacy on the Delta variant, and provides some results on the platform (covid-nma.com). Given that Omicron has replaced all other variants in most countries, data may not be applicable to the current situation.
We found high‐ or moderate‐certainty evidence for many of the main efficacy results of our review. However, the impact of effect modifiers, such as age or immunocompromized status, could not be explored adequately through subgroup analyses nor by meta‐regression. Specific trials including these specific populations should be conducted. Vaccine efficacy on these subgroups could also be explored through large observational studies using routinely collected data.
Certainty of the evidence
Overall, evidence of the critical outcomes exhibited a certainty of evidence ranging from very low certainty to high certainty. The evidence for outcomes of efficacy against SARS‐CoV‐2 infection, symptomatic COVID‐19, and severe or critical COVID‐19 was most often of moderate or high certainty. In contrast, we frequently downgraded safety outcomes and all‐cause mortality.
The reason for which we downgraded certainty of evidence most often, throughout the results for all vaccine types, was imprecision, referring to wide CIs in our results. This was often the result of a low number of events, and less often due to inconsistencies between the included studies or risk of bias. This explains why so few of the results related to mortality or severe adverse events, which are more rare events, achieved levels of moderate‐ or high‐certainty evidence. We expect higher levels of certainty to be reached as more studies are published, and the body of evidence grows.
In one trial (Logunov 2021), we downgraded the certainty of evidence due to concerns about the trustfulness of the analyses (Bucci 2021). The authors responded to some of these concerns, and the manuscript was corrected (Logunov 2021). Nevertheless, uncertainty persists particularly related to the prespecification of the interim analysis and the excess of homogeneity of vaccine efficacy across age groups.
Potential biases in the review process
We followed the guidance of the Cochrane Handbook for Systematic Reviews of Interventions in order to minimize several potential biases in the review process (Higgins 2021). First, the search strategy was peer reviewed. We initially performed a thorough search in several electronic databases and then considered only high‐quality sources, particularly the L·OVE platform and the Cochrane COVID‐19 Study Register. Second, all data were extracted in duplicate with consensus. Third, to increase our review's informative value, we track all registered trials in a living mapping. Finally, the review is updated continually; each week, we search for new trials and collect data, and bi‐weekly we update the syntheses. All updates of this review are available on the COVID‐NMA platform (covid-nma.com).
Another consideration for this rapidly evolving field is the availability of preprint articles that have not yet undergone peer review. In this review, we also included preprints. However, we are aware of these publications' potentially differing quality and that results could change once the peer‐reviewed journal publications are available (Oikonomidi 2020). To overcome this issue, we developed a preprint tracker to keep us informed of updates, so we can update data collection and data analysis when a preprint is modified or published (Cabanac 2021). We also conducted sensitivity analyses excluding preprints, and found consistent results.
Agreements and disagreements with other studies or reviews
We identified seven systematic reviews reporting on the efficacy of vaccines against COVID‐19 and whose search strategy was run in the second half of 2021 or later. One included only RCTs (Rotshild 2021), three only observational studies (Harder 2021; Kow 2022; Liu 2021), and three a hybrid of RCTs and observational studies (Hayawi 2021; Higdon 2021; Zeng 2021b). We identified one systematic review focused on children and adolescents (Lv 2021). Overall, all the trials included in these reviews were identified in our search and our results are consistent.
There are other living systematic reviews of vaccines for COVID‐19, such as Castagneto Gissey 2021, which includes only RCTs; Harder 2021, which includes, but is not limited to RCTs (the second interim results were published in October 2021). Finally, the Living Vaccine Project, a living systematic review with network meta‐analysis that includes only RCTs recently published their results (Korang 2022). All studies included in their review were included in our review (either the same publication or another with more up‐to‐date data). For the most part, their results are consistent with ours. Concurrently, there are over a dozen protocols of systematic reviews assessing the safety or efficacy of vaccines registered in PROSPERO and listed as ongoing.
Network graph. The size of the nodes is proportional to the number of participants randomized and the thickness of the lines to the number of studies in each comparison.
PRISMA flow diagram of included randomized controlled trials (RCTs) (last search date 5 November 2021). COVID‐NMA is a living systematic review of all trials assessing treatment and preventive interventions for COVID‐19 (Boutron 2020a). This review is a subreview of the COVID‐NMA.
FDA: Food and Drug Administration; ICTRP: World Health Organization (WHO) International Clinical Trials Registry Platform.
Analysis 1.1.2: RNA‐based vaccine. Outcome: confirmed symptomatic COVID‐19 after complete vaccination.
Ali 2021 included only participants 3 to 17 years of age. Frenck 2021 included only participants 12 to 15 years of age.
Analysis 1.1.3: RNA‐based vaccine. Outcome: severe or critical COVID‐19 after complete vaccination.
*Thomas 2021 reports pooled results including adults' participants from Thomas 2021 and adolescent participants from Frenck 2021.
Analysis 1.1.4: RNA‐based vaccine. Outcome: all‐cause mortality.
Ali 2021 included only participants 3 to 17 years of age. Frenck 2021 included only participants 12 to 15 years of age.
Analysis 1.1.5: RNA‐based vaccine. Outcome: serious adverse events (SAEs).
Ali 2021 included only participants 3 to 17 years of age. Frenck 2021 included only participants 12 to 15 years of age.
Analysis 1.1.7: RNA‐based vaccine. Outcome: any adverse event (AE).
Ali 2021 included only participants 3 to 17 years of age. Frenck 2021 included only participants 12 to 15 years of age.
Analysis 1.1.1: RNA‐based vaccine. Outcome: confirmed SARS‐CoV‐2 infection after complete vaccination.
Ali 2021 included only participants 3 to 17 years of age.
Analysis 1.1.6: RNA‐based vaccine. Outcome: systemic reactogenicity events.
Ali 2021 included only participants 3 to 17 years of age.
Analysis 1.1.8: RNA‐based vaccine. Outcome: local reactogenicity events.
Ali 2021 included only participants 3 to 17 years of age.
Analysis 2.1.1: Non‐replicating viral vector vaccine. Outcome: confirmed SARS‐CoV‐2 infection after complete vaccination.
Voysey 2021a: data pooled from four trials.
Analysis 2.1.2: non‐replicating viral vector vaccine. Outcome: confirmed symptomatic COVID‐19 after complete vaccination.
Voysey 2021a: data pooled from four trials.
Analysis 2.1.4: non‐replicating viral vector vaccine. Outcome: all‐cause mortality.
In Kulkarni 2021, the control arm received adjuvant. Voysey 2021a: data pooled from four trials.
Analysis 2.1.5: non‐replicating viral vector vaccine. Outcome: serious adverse events (SAEs).
In Kulkarni 2021, the control arm received adjuvant. Voysey 2021a: data pooled from four trials.
Analysis 2.1.6: non‐replicating viral vector vaccine. Outcome: systemic reactogenicity events.
Analysis 2.1.7: non‐replicating viral vector vaccine. Outcome: any adverse event (AE).
In Kulkarni 2021, the control arm received adjuvant. Voysey 2021a merged results from four different trials where three used quadrivalent meningococcal conjugate vaccine as placebo and one trial used normal saline.
Analysis 2.1.8: non‐replicating viral vector vaccine. Outcome: local reactogenicity events.
Analysis 2.2.1: serum Institute of India/Astra Zeneca+University of Oxford – SII‐ChAdOx1 versus University of Oxford – ChAdOx1. Outcome: all‐cause mortality.
Analysis 2.2.2: SII‐ChAdOx1 versus ChAdOx1. Outcome: serious adverse events (SAEs).
Analysis 2.2.3: SII‐ChAdOx1 versus ChAdOx1. Outcome: systemic reactogenicity events.
Analysis 2.2.4: SII‐ChAdOx1 versus ChAdOx1. Outcome: any adverse event (AE).
Analysis 2.2.5: SII‐ChAdOx1 versus ChAdOx1. Outcome: local reactogenicity events.
Analysis 2.1.3: non‐replicating viral vector vaccine. Outcome: severe or critical COVID‐19 after complete vaccination.
Analysis 3.1.2: inactivated virus vaccine. Outcome: confirmed symptomatic COVID‐19 after complete vaccination.
Al Kaabi 2021.1 and Al Kaabi N 2021.2 refers to two different comparisons from the same report (Al Kaabi 2021).
Analysis 3.1.3: inactivated virus vaccine. Outcome: severe or critical COVID‐19 after complete vaccination.
Analysis 3.1.4: inactivated virus vaccine. Outcome: all‐cause mortality.
Al Kaabi 2021.1 and Al Kaabi N 2021.2 refers to two different comparisons from the same report (Al Kaabi 2021).
Analysis 3.1.5: inactivated virus vaccine. Outcome: serious adverse events (SAEs).
Han 2021 included only participants 3 to 17 years of age. Wu 2021a included only participants 60 years of age and older.
Wu 2021a reports data for phase 1 and 2. Al Kaabi 2021.1 and Al Kaabi N 2021.2 refer to two different comparisons from the same report (Al Kaabi 2021).
Analysis 3.1.6: inactivated virus vaccine. Outcome: systemic reactogenicity events.
Xia S 2021 included only participants 3 to 17 years of age (Xia 2021). Wu Z 2021 included only participants 60 years of age and older (Wu 2021a).
Wu Z 2021 reports data for phase 2 (Wu 2021a). Al Kaabi 2021.1 and Al Kaabi N 2021.2 refer to two different comparisons from the same report (Al Kaabi 2021). Zhang 2020.1 and Zhang 2020.2 refers to two different comparisons from the same report (Zhang 2021).
Analysis 3.1.7: inactivated virus vaccine. Outcome: any adverse event (AE).
Han B 2021 and Xia 2021 included only participants 3 to 17 years of age (Han 2021; Xia 2021). Wu Z 2021 included only participants 60 years of age and older (Wu 2021a).
Wu Z 2021 reports data for phase 1 and 2 (Wu 2021a), Al Kaabi 2021.1 and Al Kaabi N 2021.2 refer to two different comparisons from the same report (Al Kaabi 2021). Zhang 2020.1 and Zhang 2020.2 refers to two different comparisons from the same report (Zhang 2021).
Analysis 3.1.8: inactivated virus vaccine. Outcome: local reactogenicity events.
Xia S 2021 included only participants 3 to 17 years of age (Xia 2021). Wu Z 2021 included only participants 60 years of age and older (Wu 2021a).
Wu Z 2021 reports data for phase 2 (Wu 2021a). Al Kaabi 2021.1 and Al Kaabi N 2021.2 refer to two different comparisons from the same report (Al Kaabi 2021). Zhang 2020.1 and Zhang 2020.2 refers to two different comparisons from the same report (Zhang 2021).
Analysis 3.1.1: inactivated virus vaccine. Outcome: confirmed SARS‐CoV‐2 infection after complete vaccination.
Al Kaabi 2021.1 and Al Kaabi N 2021.2 refer to two different comparisons from the same report (Al Kaabi 2021).
Analysis 4.1.1: protein subunit vaccine. Outcome: confirmed symptomatic COVID‐19 after complete vaccination.
Analysis 4.1.2: protein subunit vaccine. Outcome: severe or critical COVID‐19 after complete vaccination.
Analysis 4.1.3: protein subunit vaccine. Outcome: all‐cause mortality.
Analysis 4.1.4: protein subunit vaccine. Outcome: serious adverse events (SAEs).
Analysis 4.1.5: protein subunit vaccine. Outcome: systemic reactogenicity events.
Analysis 4.1.6: protein subunit vaccine. Outcome: any adverse event (AE).
Analysis 4.1.7 Protein subunit vaccine. Outcome: local reactogenicity events
Analysis 5.1.1: heterologous vaccination scheme versus homologous vaccination scheme. Outcome: serious adverse events (SAEs).
Liu X 2021.1 and Liu X 2021.2 are different comparisons for the same report (Liu 2021).
Analysis 5.1.2: heterologous vaccination scheme versus homologous vaccination scheme. Outcome: systemic reactogenicity events.
Analysis 5.1.4: heterologous vaccination scheme versus homologous vaccination scheme. Outcome: local reactogenicity events.
Analysis 6.1.2: booster versus placebo/no booster. Outcome: systemic reactogenicity events.
Analysis 6.1.3: booster versus placebo/no booster. Outcome: local reactogenicity events.
Analysis 6.1.1: booster versus placebo/no booster. Outcome: all‐cause mortality.
Analysis 6.2.4: homologous booster versus heterologous booster. Outcome: local reactogenicity events.
Bonelli 2021 included only participants under current Rituximab therapy.
Analysis 6.2.2: homologous booster versus heterologous booster. Outcome: systemic reactogenicity events.
Analysis 6.2.1: homologous booster versus heterologous booster. Outcome: serious adverse events.
Analysis 6.2.3: homologous booster versus heterologous booster. Outcome: any adverse event.
Analysis 7.1.1: variant‐Alpha. Outcome: confirmed symptomatic COVID‐19 after complete vaccination.
Analysis 7.2.1: variant‐Beta. Outcome: confirmed symptomatic COVID‐19 after complete vaccination.
Analysis 7.3.1: variant‐Gamma. Outcome: confirmed symptomatic COVID‐19 after complete vaccination.
Analysis 7.4.1: variant‐Delta. Outcome: confirmed symptomatic COVID‐19 after complete vaccination.
Analysis 8.1: follow‐up. RNA‐based vaccine. Outcome: confirmed symptomatic COVID‐19 after complete vaccination.
| Outcomes | Anticipated absolute effects* (95% CI) | Relative effect | № of participants | Certainty of the evidence | Comments | |
|---|---|---|---|---|---|---|
| Risk with placebo | Risk with BNT162b2 | |||||
| Confirmed SARS‐CoV‐2 infection | Outcome not yet measured or reported | |||||
| Confirmed symptomatic COVID‐19b | 3923 per 100,000 | 85 per 100,000 | VE 97.84 (44.25 to 99.92) | 44,077 | ⊕⊕⊕⊕ | — |
| Severe or critical COVID‐19e | 100 per 100,000 | 4 per 100,000 | VE 95.70 | 46,077 | ⊕⊕⊕⊕ | — |
| All‐cause mortalityg | 64 per 100,000 | 68 per 100,000 | RR 1.07 | 43,847 | ⊕⊕⊖⊖ | 2 additional studies (Frenck 2021 (adolescents aged 12–15 years); Walsh 2020 (adults aged 18–85 years)) reported this outcome in 2302 participants (1131 versus 1129 participants and 24 versus 18 participants in the BNT162b2 versus placebo groups, respectively). There were no events in either group and the trials did not contribute to the effect estimate. |
| Systemic reactogenicity events | Outcome not yet measured or reported | |||||
| Any adverse eventi | Outcome not pooled due to considerable heterogeneity (I² = 90%) between included studies: Thomas 2021 (≥ 16 years): RR 2.17, 95% CI 2.09 to 2.26; n = 43,847; Frenck 2021 (12–15 years): RR 1.01, 95% CI 0.73 to 1.41; n = 2260; Walsh 2020 (≥ 18 years): RR 1.50, 95% CI 0.53 to 4.21; n = 42 |
| 46,149 | ⊕⊕⊖⊖ | — | |
| Serious adverse eventsi | 508 per 100,000 | 660 per 100,000 | RR 1.30 | 46,107 | ⊕⊕⊖⊖ | 1 additional trial (Walsh 2020 (adults aged 18–85 years)) reported this outcome in 42 participants (24 BNT162b2 versus 18 placebo). There were no events in either group and the trial did not contribute to the effect estimate. |
| Local reactogenicity events | Outcome not yet measured or reported | |||||
| *The risk in the intervention group (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). COVID‐19: coronavirus disease 2019;CI: confidence interval; RCT: randomized controlled trial; RR: risk ratio; SARS‐CoV‐2: severe acute respiratory syndrome coronavirus 2; VE: vaccine efficacy. | ||||||
| GRADE Working Group grades of evidence | ||||||
| aLast updated: 3 May 2022 | ||||||
| Outcomes | Anticipated absolute effects* (95% CI) | Relative effect | № of participants | Certainty of the evidence | Comments | |
|---|---|---|---|---|---|---|
| Risk with placebo | Risk with mRNA‐1273 | |||||
| Confirmed SARS‐CoV‐2 infectionb | 8957 per 100,000 | 2394 per 100,000 | VE 73.27 | 31,632 | ⨁⨁⨁◯ | Substantial heterogeneity (I² = 66%) between included studies: Ali 2021 (adolescents aged 12–17 years, median 2.3 months' follow‐up): VE 55.7% (95% CI 16.8 to 76.4), n = 3181; El Sahly 2021 (adults aged 18–95 years, 5.3 months' follow‐up): VE 82% (95% CI 79.5 to 84.2), n = 28,451 |
| Confirmed symptomatic COVID‐19 b | 4939 per 100,000 | 336 per 100,000 | VE 93.20 (91.06 to 94.83) | 31,632 | ⨁⨁⨁⨁ | — |
| Severe or critical COVID‐19f | 748 per 100,000 | 13 per 100,000 | VE 98.20 (92.80 to 99.60) | 28,451 | ⨁⨁⨁⨁ | — |
| All‐cause mortalityf | 106 per 100,000 |
112 per 100,000 | RR 1.06 | 30,346 | ⨁⨁◯◯ | 1 additional trial: (Ali 2021 (adolescents aged 12–17 years)) reported on this outcome in 3726 participants (2486 mRNA‐1273 and 1240 placebo). There were no events in either group and the trial did not contribute to the pooled effect estimate |
| Systemic reactogenicity eventsi | 432 per 1000 | 553 per 1000 | RR 1.28 | 34,037 | ⨁⨁⨁⨁ | — |
| Any adverse eventk | Outcome not pooled due to considerable heterogeneity (I² = 100%) between included studies: Ali 2021 (all solicited adverse events, adolescents aged 12–17 years, median 2.8 months' follow‐up): RR 1.47 (95% CI 1.41 to 1.54), n = 3726; El Sahly 2021 (all solicited adverse events, adults aged 18–95 years, 5.3 months' follow‐up): RR 2.15 (95% CI 2.11 to 2.19), n = 29,269 | — | 32,995 | ⨁⨁◯◯ | — | |
| Serious adverse eventsl | 1792 per 100,000 | 1649 per 100,000 | RR 0.92 | 34,072 | ⨁⨁⨁◯ | — |
| Local reactogenicity eventsi | 211 per 1000 | 697 per 1000 | RR 3.30 | 34,037 | ⨁⨁⨁⨁ | — |
| *The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | ||||||
| GRADE Working Group grades of evidence | ||||||
| a. Last updated: 01 March 2023 b. Follow‐up: from 14 days after dose 2 to 2.3 months (median) and 5.3 months c. Moderna TX: Ali 2021 (adolescents aged 12–17 years); El Sahly 2021 (adults aged 18–95 years) d. Despite some concerns with deviations from intervention, not downgraded for risk of bias e. Inconsistency: downgraded one level: I² = 66.37% f. Follow‐up: 5.3 months g. Moderna TX: El Sahly 2021 (adults aged 18–95 years) h. Imprecision downgraded two levels due to small number of events observed and wide CIs that encompass a potential benefit and a potential harm with the intervention i. Follow‐up: seven days j. Despite inconsistency (I² = 61%) not downgraded for inconsistency, as the same direction of effect in both effect estimates k. Follow‐up: 2.8 months (median) and 5.3 months l. Inconsistency: downgraded two levels (I² = 100%) m. Imprecision: downgraded one level due to wide CIs that encompass a potential benefit and a potential harm with the intervention. n. Despite inconsistency (I² = 99%), not downgraded for inconsistency, as the same direction of effect in both effect estimates | ||||||
| Outcomes | Anticipated absolute effects* (95% CI) | Relative effect | № of participants | Certainty of the evidence (GRADE) | Comments | |
|---|---|---|---|---|---|---|
| Risk with placebo | Risk with CVnCOV | |||||
| Confirmed SARS‐CoV‐2 infection | Outcome not yet measured or reported | |||||
| Confirmed symptomatic COVID‐19b | 1187 per 100,000 | 615 per 100,000 | VE 48.20 (31.70 to 60.90) | 25,062 | ⊕⊕⊕⊖ | — |
| Severe or critical COVID‐19f | 82 per 100,000 | 30 per 100,000 | VE 63.80 (0.00 to 91.70) | 25,062 | ⊕⊖⊖⊖ | — |
| All‐cause mortalityh | 30 per 100,000 | 40 per 100,000 | RR 1.33 | 39,529 | ⊕⊖⊖⊖ | — |
| Systemic reactogenicity eventsi | 635 per 1000 | 940 per 1000 | RR 1.48 | 3982 | ⊕⊕⊕⊕ | — |
| Any adverse eventj | 679 per 1000 | 965 per 1000 | RR 1.42 | 3982 | ⊕⊕⊕⊖ | — |
| Serious adverse eventsk | 334 per 100,000 | 414 per 100,000 | RR 1.24 | 39,529 | ⊕⊕⊖⊖ | — |
| Local reactogenicity eventsi | 241 per 1000 | 847 per 1000 | RR 3.51 | 3982 | ⊕⊕⊕⊕ | — |
| *The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). COVID‐19: coronavirus disease 2019CI: confidence interval; RCT: randomized controlled trial; RR: risk ratio; SARS‐CoV‐2: severe acute respiratory syndrome coronavirus 2; VE: vaccine efficacy. | ||||||
| GRADE Working Group grades of evidence | ||||||
| aLast updated: 10 May 2022 | ||||||
| Outcomes | Anticipated absolute effects* (95% CI) | Relative effect | № of participants | Certainty of the evidence | Comments | |
|---|---|---|---|---|---|---|
| Risk with placebo | Risk with ChAdOx1 | |||||
| Confirmed SARS‐CoV‐2 infectionb | 3199 per 100,000 | 1300 per 100,000 | VE 59.35 (48.00 to 68.22) | 43,390 | ⊕⊕⊕⊖ | Substantial heterogeneity (I² = 68%) between included studies: Falsey 2021 (VE 64.35%, 95% CI 56.10% to 71.00%; n = 26,212); Voysey 2021a (VE 54.10%, 95% CI 44.70% to 61.90%; n = 17,178) |
| Confirmed symptomatic COVID‐19b | 2207 per 100,000 | 657 per 100,000 | VE 70.23 (62.10 to 76.62) | 43,390 | ⊕⊕⊕⊕ | — |
| Severe or critical COVID‐19 | Outcome not yet measured or reported | |||||
| All‐cause mortalityf | 52 per 100,000 | 25 per 100,000 | RR 0.48 | 56,727 | ⊕⊕⊖⊖ | 2 additional trials (Asano 2022; Kulkarni 2021) reported this outcome in 1392 participants (192 ChAdOx1 versus 64 placebo and 900 SII‐ChAdOx1 versus 300 placebo, respectively). There were no events in either group in either trial and they did not contribute to the pooled effect estimate. |
| Systemic reactogenicity eventsi | 141 per 1000 | 553 per 1000 | RR 3.93 | 256 | ⊕⊕⊕⊖ | — |
| Any adverse eventl | Outcome not pooled due to considerable heterogeneity (I² = 90%) between included studies: Asano 2022 (RR 2.54, 95% CI 1.73 to 3.74; n = 256); Falsey 2021 (RR 1.37, 95% CI 1.33 to 1.42; n = 32,379); Kulkarni 2021 (RR 1.39, 95% CI 1.12 to 1.74; n = 1200); Voysey 2021a (RR 0.74, 95% CI 0.56 to 0.96; n = 23,745) | — | 57,580 | ⊕⊕⊖⊖ | — | |
| Serious adverse eventso | 794 per 100,000 | 699 per 100,000 | RR 0.88 | 58,182 | ⊕⊕⊕⊖ | — |
| Local reactogenicity eventsi | 94 per 1000 | 604 per 1000 | RR 6.44 | 256 | ⊕⊕⊕⊖ | — |
| *The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). COVID‐19: coronavirus disease 2019CI: confidence interval; RCT: randomized controlled trial; RR: risk ratio; SARS‐CoV‐2: severe acute respiratory syndrome coronavirus 2; VE: vaccine efficacy. | ||||||
| GRADE Working Group grades of evidence | ||||||
| aLast updated: 4 May 2022 | ||||||
| Outcomes | Anticipated absolute effects* (95% CI) | Relative effect | № of participants | Certainty of the evidence | Comments | |
|---|---|---|---|---|---|---|
| Risk with ChAdOx1 | Risk with SII‐ChAdOx1 | |||||
| Confirmed SARS‐CoV‐2 infection | Outcome not yet measured or reported | |||||
| Confirmed symptomatic COVID‐19 | Outcome not yet measured or reported | |||||
| Severe or critical COVID‐19 | Outcome not yet measured or reported | |||||
| All‐cause mortality | — | — | — | — | — | 1 study reported this outcome in 400 participants (Kulkarni 2021). There were no events in either group and no effect estimate could be calculated. |
| Systemic reactogenicity eventsb | 390 per 1000 | 285 per 1000 | RR 0.73 | 400 | ⊕⊕⊕⊖ | — |
| Any adverse evente | 200 per 1000 | 166 per 1000 | RR 0.83 | 400 | ⊕⊕⊖⊖ | — |
| Serious adverse eventsg | 2000 per 100,000 | 1000 per 100,000 | RR 0.50 | 400 | ⊕⊕⊖⊖ | — |
| Local reactogenicity eventsb | 360 per 1000 | 274 per 1000 | RR 0.76 | 400 | ⊕⊕⊖⊖ | — |
| *The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). COVID‐19: coronavirus disease 2019CI: confidence interval; RCT: randomized controlled trial; RR: risk ratio; SARS‐CoV‐2: severe acute respiratory syndrome coronavirus 2. | ||||||
| GRADE Working Group grades of evidence | ||||||
| aLast updated: 10 May 2022 | ||||||
| Outcomes | Anticipated absolute effects* (95% CI) | Relative effect | № of participants | Certainty of the evidence | Comments | |
|---|---|---|---|---|---|---|
| Risk with placebo | Risk with AD26.COV2.S | |||||
| Confirmed SARS‐CoV‐2 infection | Outcome not yet measured or reported | |||||
| Confirmed symptomatic COVID‐19b | 1796 per 100,000 | 594 per 100,000 | VE 66.90 (59.10 to 73.40) | 39,058 | ⊕⊕⊕⊕ | — |
| Severe or critical COVID‐19b | 409 per 100,000 | 97 per 100,000 | VE 76.30 (57.90 to 87.50) | 39,058 | ⊕⊕⊕⊕ | — |
| All‐cause mortalityb | 91 per 100,000 | 23 per 100,000 | RR 0.25 | 43,783 | ⊕⊕⊕⊕ | — |
| Serious adverse eventsb | 448 per 100,000 | 412 per 100,000 | RR 0.92 | 43,783 | ⊕⊕⊕⊖ | — |
| Systemic reactogenicity eventse | 34,575 per 100,000 | 63,273 per 100,000 | RR 1.83 | 7222 | ⊕⊕⊕⊕ | — |
| Any adverse eventh | Outcome not pooled due to considerable heterogeneity (I² = 96%) between included studies: Sadoff 2021a (RR 1.09, 95% CI 0.96 to 1.24; n = 6736); Sadoff 2021b (RR 2.31, 95% CI 1.80 to 2.97; n = 486) | — | 7222 | ⊕⊕⊖⊖ | — | |
| *The risk in the intervention group (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). COVID‐19: coronavirus disease 2019CI: confidence interval; RCT: randomized controlled trial; RR: risk ratio; SARS‐CoV‐2: severe acute respiratory syndrome coronavirus 2; VE: vaccine efficacy. | ||||||
| GRADE Working Group grades of evidence | ||||||
| aLast updated: 4 May 2022 | ||||||
| Outcomes | Anticipated absolute effects* (95% CI) | Relative effect | № of participants | Certainty of the evidence | Comments | |
|---|---|---|---|---|---|---|
| Risk with placebo | Risk with Gam‐COVID‐VAC | |||||
| Confirmed SARS‐CoV‐2 infection | Outcome not yet measured or reported | |||||
| Confirmed symptomatic COVID‐19b | 1022 per 100,000 | 92 per 100,000 | VE 91.10 (83.80 to 95.10) | 18,695 | ⊕⊕⊕⊖ | — |
| Severe or critical COVID‐19b | 408 per 100,000 | 0 per 100,000 | VE 100.00 (94.40 to 100.00) | 19,866 | ⊕⊕⊕⊖ | — |
| All‐cause mortalityf | 18 per 100,000 | 18 per 100,000 | RR 0.99 | 21,862 | ⊕⊖⊖⊖ | — |
| Systemic reactogenicity events | Outcome not yet measured or reported | |||||
| Any adverse event | Outcome not yet measured or reported | |||||
| Serious adverse eventsf | 423 per 100,000 | 275 per 100,000 | RR 0.65 | 21,862 | ⊕⊕⊖⊖ | — |
| Local reactogenicity events | Outcome not yet measured or reported | |||||
| *The risk in the intervention group (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). COVID‐19: coronavirus disease 2019;CI: confidence interval; RCT: randomized controlled trial; RR: risk ratio; SARS‐CoV‐2: severe acute respiratory syndrome coronavirus 2; VE: vaccine efficacy. | ||||||
| GRADE Working Group grades of evidence | ||||||
| aLast updated: 27 May 2022 | ||||||
| Outcomes | Anticipated absolute effects* (95% CI) | Relative effect | № of participants | Certainty of the evidence | Comments | |
|---|---|---|---|---|---|---|
| Risk with placebo | Risk with CoronaVac | |||||
| Confirmed SARS‐CoV‐2 infection | Outcome not yet measured or reported | |||||
| Confirmed symptomatic COVID‐19b | 2398 per 100,000 | 724 per 100,000 | VE 69.81 (12.27 to 89.61) | 19,852 | ⊕⊕⊖⊖ | Considerable heterogeneity (I² = 92%) between included studies: Tanriover 2021 (VE 83.50%, 95% CI 65.40% to 92.10%; n = 10,029); Palacios 2020 (VE 50.70%, 95% CI 35.90 to 62.00%; n = 9823) |
| Severe or critical COVID‐19b | 2 studies report on severe or critical disease due to COVID‐19: Tanriover 2021, with 0/6559 events in the CoronaVac group versus 1/3470 events in the placebo group and a VE of 100%, 95% CI (20.40% to 100.00%); and Palacios 2020, with 0/4953 events in the CoronaVac group and 6/4870 events in the placebo group and a VE of 100%, 95% CI (16.90% to 100.00%). (Note: estimates could not be pooled due to asymmetry in the CIs) | — | 19,852 | ⊕⊕⊖⊖ | — | |
| All‐cause mortalityh | 20 per 100,000 | 10 per 100,000 | RR 0.50 | 22,610 | ⊕⊕⊖⊖ | — |
| Systemic reactogenicity eventsj | 409 per 1000 | 487 per 1000 | RR 1.19 | 23,966 | ⊕⊕⊖⊖ | — |
| Any adverse evento | 531 per 1000 | 579 per 1000 | RR 1.09 | 23,367 | ⊕⊕⊕⊕ | — |
| Serious adverse eventsr | 372 per 100,000 | 361 per 100,000 | RR 0.97 | 23,139 | ⊕⊕⊖⊖ | 2 additional trials (Bueno 2021; Zhang 2021) reported this outcome in 482 participants (270 versus 164 and 24 versus 24 respectively, receiving CoronaVac versus placebo). There were no events in either group and the trials did not contribute to the pooled effect estimate. |
| Local reactogenicity eventsj | 227 per 1000 | 400 per 1000 | RR 1.76 | 23,962 | ⊕⊕⊕⊕ | — |
| *The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). COVID‐19: coronavirus disease 2019CI: confidence interval; RCT: randomized controlled trial; RR: risk ratio; SARS‐CoV‐2: severe acute respiratory syndrome coronavirus 2; VE: vaccine efficacy. | ||||||
| GRADE Working Group grades of evidence | ||||||
| aLast updated: 4 May 2022 | ||||||
| Outcomes | Anticipated absolute effects* (95% CI) | Relative effect | № of participants | Certainty of the evidence | Comments | |
|---|---|---|---|---|---|---|
| Risk with placebo | Risk with WIBP‐CorV | |||||
| Confirmed SARS‐CoV‐2 infectionb | 912 per 100,000 | 328 per 100,000 | VE 64.00 (48.80 to 74.70) | 25,449 | ⊕⊕⊕⊕ | — |
| Confirmed symptomatic COVID‐19b | 746 per 100,000 | 203 per 100,000 | VE 72.80 (58.10 to 82.40) | 25,480 | ⊕⊕⊕⊕ | — |
| Severe or critical COVID‐19 | Outcome not yet measured or reported | |||||
| All‐cause mortality | — | — | — | — | — | 1 trial reported on this outcome in 26,917 participants (13,464 WIBP‐CorV versus 13,453 placebo) (Al Kaabi 2021). There were no events in either group and no effect estimate could be calculated for this outcome. |
| Systemic reactogenicity eventse | 278 per 1000 | 275 per 1000 | RR 0.99 | 27,029 | ⊕⊕⊕⊕ | — |
| Any adverse eventh | 504 per 1000 | 484 per 1000 | RR 0.96 | 27,029 | ⊕⊕⊕⊕ | — |
| Serious adverse eventsi | 579 per 100,000 | 480 per 100,000 | RR 0.83 | 27,029 | ⊕⊕⊖⊖ | — |
| Local reactogenicity eventsk | 290 per 1000 | 255 per 1000 | RR 0.88 | 27,029 | ⊕⊕⊕⊕ | — |
| *The risk in the intervention group (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). COVID‐19: coronavirus disease 2019CI: confidence interval; RCT: randomized controlled trial; RR: risk ratio; SARS‐CoV‐2: severe acute respiratory syndrome coronavirus 2; VE: vaccine efficacy. | ||||||
| GRADE Working Group grades of evidence | ||||||
| aLast updated: 4 May 2022 | ||||||
| Outcomes | Anticipated absolute effects* (95% CI) | Relative effect | № of participants | Certainty of the evidence | Comments | |
|---|---|---|---|---|---|---|
| Risk with placebo | Risk with BBIBP‐CorV | |||||
| Confirmed SARS‐CoV‐2 infectionb | 912 per 100,000 | 242 per 100,000 | VE 73.50 (60.60 to 82.20) | 25,435 | ⊕⊕⊕⊕ | — |
| Confirmed symptomatic COVID‐19b | 746 per 100,000 | 163 per 100,000 | VE 78.10 (64.80 to 86.30) | 25,463 | ⊕⊕⊕⊕ | — |
| Severe or critical COVID‐19 | Outcome not yet measured or reported | |||||
| All‐cause mortality | — | — | — | — | — | 1 study reported this outcome in 26,924 participants (13,471 BBIBP‐CorV versus 13,453 placebo) (Al Kaabi 2021). There were no events in either group and no effect estimate could be calculated for this outcome. |
| Systemic reactogenicity eventse | 274 per 1000 | 288 per 1000 | RR 1.05 | 27,540 | ⊕⊕⊕⊖ | — |
| Any adverse eventh | 3 studies (n = 27,540) reported any adverse event with 1 month or 2.9 months' follow‐up. 2 of the studies reported an effect estimate in favour of BBIBP‐CorV: 1 with RR 0.91, 95% CI 0.89 to 0.94; n = 26,924; and 1 with CIs crossing the line of no effect (RR 0.83, 95% CI 0.36 to 1.95; n = 112). 1 study reported an effect estimate in favour of placebo with CIs not crossing the line of null effect (RR 2.05, 95% CI 1.47 to 2.87; n = 504) | — | 26,924 | ⊕⊕⊖⊖ | — | |
| Serious adverse eventsk | 580 per 100,000 | 441 per 100,000 | RR 0.76 | 26,924 | ⊕⊕⊖⊖ | 1 additional study reported this outcome in 112 participants (84 BBIBP‐CorV versus 28 placebo) (Xia 2020). There were no events in either group and the trial did not contribute to the effect estimate. |
| Local reactogenicity eventse | 3 studies (n = 27,540) reported local adverse events with 7 days' follow‐up. 1 study reported an effect estimate in favour of BBIBP‐CorV: RR 0.71, 95% CI 0.68 to 0.74; n = 26,924. 2 studies reported an effect estimate in favour of placebo with CIs not crossing the line of null effect (RR 10.00, 95% CI 2.36 to 42.34; n = 504 and RR 3.33, 95% CI 0.45 to 24.89; n = 112). | — | 26,924 | ⊕⊕⊖⊖ | — | |
| *The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). COVID‐19: coronavirus disease 2019CI: confidence interval; RCT: randomized controlled trial; RR: risk ratio; SARS‐CoV‐2: severe acute respiratory syndrome coronavirus 2; VE: vaccine efficacy. | ||||||
| GRADE Working Group grades of evidence | ||||||
| aLast updated: 4 May 2022 | ||||||
| Outcomes | Anticipated absolute effects* (95% CI) | Relative effect | № of participants | Certainty of the evidence | Comments | |
|---|---|---|---|---|---|---|
| Risk with placebo | Risk with BBV152 | |||||
| Confirmed SARS‐CoV‐2 infectionb | 1841 per 100,000 | 575 per 100,000 | VE 68.80 (46.70 to 82.50) | 6289 | ⊕⊕⊕⊕ | — |
| Confirmed symptomatic COVID‐19b | 1247 per 100,000 | 277 per 100,000 | VE 77.80 (65.20 to 86.40) | 16,973 | ⊕⊕⊕⊕ | — |
| Severe or critical COVID‐19b | 176 per 100,000 | 12 per 100,000 | VE 93.40 (57.10 to 99.80 | 16,976 | ⊕⊕⊕⊕ | — |
| All‐cause mortalitye | 78 per 100,000 | 39 per 100,000 | RR 0.50 | 25,753 | ⊕⊕⊖⊖ | — |
| Systemic reactogenicity eventsg | 20 per 1000 | 26 per 1000 | RR 1.34 | 25,925 | ⊕⊕⊕⊕ | — |
| Any adverse eventi | 124 per 1000 | 124 per 1000 | RR 1.00 | 25,753 | ⊕⊕⊕⊕ | — |
| Serious adverse eventsi | 463 per 100,000 | 301 per 100,000 | RR 0.65 | 25,928 | ⊕⊕⊕⊕ | 1 additional trial reported this outcome in 175 participants (100 BBV152 versus 75 placebo) (Ella 2021a). There were no events in either group and the trial did not contribute to the pooled effect estimate. |
| Local reactogenicity eventsg | 31 per 1000 | 34 per 1000 | RR 1.08 | 25,750 | ⊕⊕⊕⊕ | — |
| *The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). COVID‐19: coronavirus disease 2019CI: confidence interval; RCT: randomized controlled trial; RR: risk ratio; SARS‐CoV‐2: severe acute respiratory syndrome coronavirus 2; VE: vaccine efficacy. | ||||||
| GRADE Working Group grades of evidence | ||||||
| aLast updated: 4 May 2022 | ||||||
| Outcomes | Anticipated absolute effects* (95% CI) | Relative effect | № of participants | Certainty of the evidence | Comments | |
|---|---|---|---|---|---|---|
| Risk with placebo | Risk with NVX‐CoV2373 | |||||
| Confirmed SARS‐CoV‐2 infection | Outcome not yet measured or reported | |||||
| Confirmed symptomatic COVID‐19b | 1140 per 100,000 | 195 per 100,000 | VE 82.91 (50.49 to 94.10) | 42,175 | ⊕⊕⊕⊖ | Substantial heterogeneity (I² = 65%) between included studies: Dunkle 2021 (VE 90.40%, 95% CI 82.88 to 94.62%; n = 25,452); Heath 2021 (VE 89.70%, 95% CI 80.20% to 94.60%; n = 14,039); Shinde 2021 (VE 49.40%, 95% CI 6.10% to 72.80%; n = 2684) |
| Severe or critical COVID‐19 | 172 per 100,000 | 0 per 100,000 | VE 100.00 | 25,452 | ⊕⊕⊕⊖ | — |
| All‐cause mortalityh | 51 per 100,000 | 46 per 100,000 | RR 0.90 (0.30 to 2.68) | 29,582 | ⊕⊕⊖⊖ | 1 additional study reported on this outcome in 14,039 participants (7020 NVX‐CoV2373 versus 7019 placebo) (Heath 2021). There were no events in either group and the trial did not contribute to the pooled effect estimate. |
| Systemic reactogenicity eventsj | 363 per 1000 | 439 per 1000 | RR 1.21 | 31,063 | ⊕⊕⊕⊕ | — |
| Any adverse eventm | 173 per 1000 | 199 per 1000 | RR 1.15 | 46,231 | ⊕⊕⊕⊖ | Substantial heterogeneity (I² = 57%) between the 5 included studies. |
| Serious adverse eventsm | 777 per 100,000 | 715 per 100,000 | RR 0.92 | 38,802 | ⊕⊕⊖⊖ | 1 additional trial reported on this outcome in 52 participants (29 NVX‐CoV2373 versus 23 placebo) (Keech 2020). There were no events in either group and the trial did not contribute to the pooled effect estimate. |
| Local reactogenicity eventsj | 191 per 1000 | 532 per 1000 | RR 2.78 | 31,063 | ⊕⊕⊕⊕ | — |
| *The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). COVID‐19: coronavirus disease 2019CI: confidence interval; RCT: randomized controlled trial; RR: risk ratio; SARS‐CoV‐2: severe acute respiratory syndrome coronavirus 2; VE: vaccine efficacy. | ||||||
| GRADE Working Group grades of evidence | ||||||
| aLast updated: 2 June 2022 | ||||||
| Outcomes | Anticipated absolute effects* (95% CI) | Relative effect | № of participants | Certainty of the evidence | Comments | |
|---|---|---|---|---|---|---|
| Risk with placebo | Risk with FINLAY‐FR‐2 | |||||
| Confirmed SARS‐CoV‐2 infection | Outcome not yet measured or reported | |||||
| Confirmed symptomatic COVID‐19b | 1084 per 100,000 | 314 per 100,000 | VE 71.00 (58.90 to 79.10) | 28,674 | ⊕⊕⊕⊖ | — |
| Severe or critical COVID‐19 | Outcome not yet measured or reported | |||||
| All‐cause mortalitye | 168 per 100,000 | 62 per 100,000 | RR 0.37 | 28,674 | ⊕⊕⊕⊖ | — |
| Systemic reactogenicity events | Outcome not yet measured or reported | |||||
| Any adverse event | Outcome not yet measured or reported | |||||
| Serious adverse events | Outcome not yet measured or reported | |||||
| Local reactogenicity events | Outcome not yet measured or reported | |||||
| *The risk in the intervention group (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). COVID‐19: coronavirus disease 2019CI: confidence interval; RCT: randomized controlled trial; RR: risk ratio; SARS‐CoV‐2: severe acute respiratory syndrome coronavirus 2; VE: vaccine efficacy. | ||||||
| GRADE Working Group grades of evidence | ||||||
| aLast updated: 6 May 2022 | ||||||
| Outcomes | Anticipated absolute effects* (95% CI) | Relative effect | № of participants | Certainty of the evidence | Comments | |
|---|---|---|---|---|---|---|
| Risk with homologous vaccination scheme | Risk with heterologous vaccination scheme | |||||
| Confirmed SARS‐CoV‐2 infection | Outcome not yet measured or reported | |||||
| Confirmed symptomatic COVID‐19 | Outcome not yet measured or reported | |||||
| Severe or critical COVID‐19 | Outcome not yet measured or reported | |||||
| All‐cause mortality | Outcome not yet measured or reported | |||||
| Systemic reactogenicity eventsb | 60 per 1000 | 118 per 1000 | RR 1.96 | 101 | ⊕⊕⊖⊖ | — |
| Any adverse eventf | 3 studies (n = 564) that compared heterologous versus homologous vaccination schemes reported any adverse event with 1 or 2 months' follow‐up. 2 of the studies reported an effect estimate in favour of homologous scheme but with CIs crossing the line of no effect (RR 1.21, 95% CI 0.87 to 1.68; n = 234; and RR 1.03, 95% CI 0.75 to 1.43; n = 229). 1 study reported an effect estimate in favour of homologous scheme with CIs not crossing the line of null effect (RR 3.19, 95% CI 1.11 to 9.11; n = 101) | — | (3 RCTs)g | ⊕⊖⊖⊖ | — | |
| Serious adverse eventsk | 1 study (Liu 2021: ChAdOx1/BNT162b2 versus ChAdOx1/ChAdOx1) that compared heterologous versus homologous vaccination schemes reported no serious adverse events in the heterologous scheme (0/114) versus 1 serious adverse event (1/115) in the homologous scheme (RR 0.34, 95% CI 0.01 to 8.17). 2 more studies reported the outcome, with 0 events in both groups: Li 2021a: CoronaVac/Ad5 versus CoronaVac/CoronaVac in n = 51 versus n = 50 and Liu 2021: BNT162b2/ChAdOx1 versus BNT162b2/BNT162b2 in n = 115 versus n = 119 respectively, in heterologous versus homologous scheme | — | 229 | ⊕⊖⊖⊖ | — | |
| Local reactogenicity eventsb | 20 per 1000 | 235 per 1000 | RR 11.76 | 101 | ⊕⊕⊖⊖ | — |
| *The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). COVID‐19: coronavirus disease 2019CI: confidence interval; RCT: randomized controlled trial; RR: risk ratio; SARS‐CoV‐2: severe acute respiratory syndrome coronavirus 2. | ||||||
| GRADE Working Group grades of evidence | ||||||
| aLast updated: 4 May 2022 | ||||||
| Outcomes | Anticipated absolute effects* (95% CI) | Relative effect | № of participants | Certainty of the evidence | Comments | |
|---|---|---|---|---|---|---|
| Risk with placebo/no booster | Risk with booster | |||||
| Confirmed SARS‐CoV‐2 infection | Outcome not yet measured or reported | |||||
| Confirmed symptomatic COVID‐19 | Outcome not yet measured or reported | |||||
| Severe or critical COVID‐19 | Outcome not yet measured or reported | |||||
| All‐cause mortalityb | 63 per 100,000 | 80 per 100,000 | RR 1.27 | 28,254 | ⊕⊖⊖⊖ | — |
| Systemic reactogenicity eventsf | 102 per 1000 | 183 per 1000 | RR 1.80 | 119 | ⊕⊕⊖⊖ | — |
| Any adverse event | Outcome not yet measured or reported | |||||
| Serious adverse events | Outcome not yet measured or reported | |||||
| Local reactogenicity eventsf | 119 per 1000 | 766 per 1000 | RR 6.46 | 119 | ⊕⊕⊕⊖ | — |
| *The risk in the intervention group (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). COVID‐19: coronavirus disease 2019CI: confidence interval; RCT: randomized controlled trial; RR: risk ratio; SARS‐CoV‐2: severe acute respiratory syndrome coronavirus 2. | ||||||
| GRADE Working Group grades of evidence | ||||||
| aLast updated: 4 May 2022 | ||||||
| Developer – comparison | Analysesa | Outcomes | ||||||
|---|---|---|---|---|---|---|---|---|
| SARS‐CoV‐2 infection | Symptomatic COVID‐19 | Severe COVID‐19 | All‐cause mortality | SAEs | Systemic reactogenicity events | AEs | ||
| VE (95% CI) No. of trials (No. of participants) | RR (95% CI) No. of trials (No. of participants) | |||||||
| BNT162b2 – Pfizer/BioNTech+Fosun Pharma versus placebo | Main analysis | — | 97.84% (44.25% to 99.92%) 2 RCTs (44,077) | 95.70% (73.90% to 99.90%) 1 RCT (46,077) | 1.07 (0.52 to 2.22) 1 RCT (43,846) | 1.30 (0.55 to 3.07) 2 RCTs (46,107) | — | 1.52 (0.88 to 2.63) 3 RCTs (46,419) |
| Sensitivity 1 | — | — | — | 1.07 (0.52 to 2.22) 1 RCT (44,165) | 1.30 (0.55 to 3.05) 2 RCTs (46,429) | — | 1.52 (0.88 to 2.63) 3 RCTs (46,471) | |
| Sensitivity 2 | — | — | — | — | — | — | — | |
| Sensitivity 3 | — | — | — | —
| —
| — | — | |
| mRNA‐1273 – ModernaTX versus placebo | Main analysis | 73.27% (35.82% to 88.87%) 2 RCTs (31,632) | 93.20% (91.06% to 94.83%) 2 RCTs (31,632) | 98.20% (92.80% to 99.60%) 1 RCT (28,451) | 1.06 (0.54 to 2.10) 1 RCT (30,346) | 0.92 (0.78 to 1.08) 2 RCTs (34,072) | 1.28 (1.22 to 1.34) 2 RCTs (34,037) | 1.19 (0.79 to 1.80) 2 RCTs (34,072) |
| Sensitivity 1 | — | — | — | 1.06 (0.54 to 2.10) 1 RCT (30,415) | 0.92 (0.78 to 1.09) 2 RCTs (34,147) | 1.28 (1.22 to 1.34) 2 RCTs (34,147) | 1.20 (0.79 to 1.80) 2 RCTs (34,147) | |
| Sensitivity 2 | — | — | — | — | — | — | —
| |
| Sensitivity 3 | — | — | — | —
| —
| — | — | |
| CVnCoV – CureVac AG versus placebo | Main analysis | — | 48.20% (31.70% to 60.90%) 1 RCT (25,062) | 63.80% (0.00% to 91.70%) 1 RCT (25,062) | 1.33 (0.46 to 3.83) 1 RCT (39,529) | 1.24 (0.90 to 1.71) 1 RCT (39,529) | 1.48 (1.43 to 1.53) 1 RCT (3982) | 1.42 (1.38 to 1.47) 1 RCT (3982) |
| Sensitivity 1 | — | — | — | — | — | 1.49 (1.39 to 1.60) 1 RCT (39,529)
| 1.43 (1.34 to 1.53) 1 RCT (39,529) | |
| Sensitivity 2 | — | — | — | — | — | — | — | |
| Sensitivity 3 | — | — | — | — | — | — | — | |
| AE: adverse event; CI: confidence interval; COVID‐19: coronavirus disease 2019; RCT: randomized controlled trial; RR: risk ratio; SAE: serious adverse event; SARS‐CoV‐2: severe acute respiratory syndrome coronavirus 2; VE: vaccine efficacy. | ||||||||
| aSensitivity 1: participants randomized; Sensitivity 2: early‐phase studies excluded; Sensitivity 3: only published studies. | ||||||||
| Developer – comparison | Analysesa | Outcomes | ||||||
|---|---|---|---|---|---|---|---|---|
| SARS‐CoV‐2 infection | Symptomatic COVID‐19 | Severe COVID‐19 | All‐cause mortality | SAEs | Systemic reactogenicity events | AEs | ||
| VE (95% CI) No. of trials (No. of participants) | RR (95% CI) No. of trials (No. of participants) | |||||||
| ChAdOx1 – AstraZeneca + University of Oxford versus placebo | Main analysis | 59.35% (48.00% to 68.22%) 5 RCTs (43,390) | 70.23% (62.10% to 76.62%) 5 RCTs (43,390) | — | 0.48 (0.20 to 1.14) 5 RCTs (56,726) | 0.88 (0.72 to 1.07) 7 RCTs (58,182) | 3.93 (2.11 to 7.29)
1 RCT (256) | Not pooled |
| Sensitivity 1 | — | — | — | 0.50 (0.20 to 1.21) 5 RCTs (56,873) | 0.86 (0.70 to 1.06) 7 RCTs (58,329) | — | — | |
| Sensitivity 2 | — | — | — | 0.48 (0.20 to 1.14) 5 RCTs (56,623) | 0.88 (0.72 to 1.08) 6 RCTs (57,823) | — | — | |
| Sensitivity 3 | — | — | — | 0.50 (0.20 to 1.21) 5 RCTs (56,623) | 0.86 (0.70 to 1.05) 6 RCTs (56,879) | — | — | |
| Ad26.COV2.S – Janssen Pharmaceutical Companies versus placebo | Main analysis | — | 66.90% (59.10% to 73.40%) 1 RCT (39,058) | 76.30% (57.90% to 87.50%) 1 RCT (39,058) | 0.25 (0.09 to 0.67) 1 RCT (43,783) | 0.92 (0.69 to 1.22) 1 RCT (43,783) | 1.83 (1.29 to 2.60) 2 RCTs (7222) | 1.57 (0.75 to 3.29) 2 RCTs (7222) |
| Sensitivity 1 | — | — | — | 0.25 (0.09 to 0.67) 1 RCT (44,325) | 0.92 (0.69 to 1.22) 1 RCT (44,325) | 1.83 (1.27 to 2.63) 2 RCTs (44,813) | 1.57 (0.74 to 3.32) 2 RCTs (44,813) | |
| Sensitivity 2 | — | — | — | — | — | — | 1.09 (0.96 to 1.24) 1 RCT (6736) | |
| Sensitivity 3 | — | — | — | — | — | — | — | |
| Gam‐COVID‐Vac – Gamaleya Research Institute (Sputnik V) Gam‐COVID‐Vac versus placebo | Main analysis | — | 91.10% (83.80% to 95.10%) 1 RCT (18,695) | 100.00% (94.40% to 100.00%) 1 RCT (19,866) | 0.99 (0.10 to 9.54) 1 RCT (21,862) | 0.65 (0.39 to 1.07) 1 RCT (21,862) | — | — |
| Sensitivity 1 | — | — | — | 1.00 (0.10 to 9.57) 1 RCT (21,977) | 0.65 (0.39 to 1.07) 1 RCT (21,977) | — | — | |
| Sensitivity 2 | — | — | — | — | — | — | — | |
| Sensitivity 3 | — | — | — | — | — | — | — | |
| AE: adverse event; CI: confidence interval; COVID‐19: coronavirus disease 2019; RCT: randomized controlled trial; RR: risk ratio; SAE: serious adverse event; SARS‐CoV‐2: severe acute respiratory syndrome coronavirus 2; VE: vaccine efficacy. | ||||||||
| aSensitivity 1: participants randomized; Sensitivity 2: early‐phase studies excluded; Sensitivity 3: only published studies. | ||||||||
| Developer – comparison | Analysesa | Outcomes | ||||||
|---|---|---|---|---|---|---|---|---|
| SARS‐CoV‐2 infection | Symptomatic COVID‐19 | Severe COVID‐19 | All‐cause mortality | SAEs | Systemic reactogenicity events | AEs | ||
| VE (95% CI) No. of trials (No. of participants) | RR (95% CI) No. of trials (No. of participants) | |||||||
| CoronaVac – Sinovac versus placebo | Main analysis | — | 69.81% (12.27% to 89.61%) 2 RCTs (19,852) | — | 0.50 (0.05 to 5.52) 1 RCT (12,396) | 0.97 (0.62 to 1.51) 4 RCTs (23,139) | 0.95 (0.55 to 1.62) 7 RCTs (23,956) | 1.09 (1.07 to 1.11) 6 RCTs (23,367) |
| Sensitivity 1 | — | — | — | 0.50 (0.05 to 5.52) 1 RCT (12,408) | 0.99 (0.64 to 1.51) 4 RCTs (23,157) | 1.56 (0.91 to 2.69) 7 RCTs (25,106)
| 1.09 (1.07 to 1.11) 6 RCTs (23,385) | |
| Sensitivity 2 | — | — | — | — | 0.99 (0.63 to 1.55) 2 RCTs (22,610) | 1.21 (0.98 to 1.49) 4 RCTs (23,584) | 1.09 (1.07 to 1.11) 2 RCTs (22,610) | |
| Sensitivity 3 | — | 83.50% (65.40% to 92.10%) 1 RCT (10,029) | — | — | 0.73 (0.24 to 2.21) 4 RCTs (10,894) | 0.94 (0.49 to 1.81) 6 RCTs (11,617) | 1.13 (1.04 to 1.23) 4 RCTs (10,640) | |
| WIBP‐CorV – Sinopharm‐Wuhan versus placebo | Main analysis | 64.00% (48.80% to 74.70%) 1 RCT (25,449) | 72.80% (58.10% to 82.40%) 1 RCT (25,480) | — | — | 0.83 (0.60 to 1.15) 2 RCTs (27,029) | 0.99 (0.95 to 1.03) 2 RCTs (27,029) | 0.96 (0.93 to 0.98) 2 RCTs (27,029) |
| Sensitivity 1 | — | — | — | — | 0.83 (0.60 to 1.15) 2 RCTs (27,053) | 0.99 (0.95 to 1.03) 2 RCTs (27,053) | 0.96 (0.93 to 0.98) 2 RCTs (27,053) | |
| Sensitivity 2 | — | — | — | — | 0.82 (0.59 to 1.14) 1 RCT (26,917) | 0.99 (0.95 to 1.03) 1 RCT (26,917) | 0.96 (0.93 to 0.98) 1 RCT (26,917) | |
| Sensitivity 3 | — | — | — | — | — | — | — | |
| BBIBP‐CorV – Sinopharm‐Beijing | Main analysis | 73.50% (60.60% to 82.20%) 1 RCT (25,463) | 78.10% (64.80% to 86.30%) 1 RCT (25,463) | — | — | 0.76 (0.54 to 1.06) 1 RCT (26,924) | 1.05 (0.86 to 1.28) 3 RCTs (27,540) | Not pooled |
| Sensitivity 1 | — | — | — | — | —
| 1.05 (0.86 to 1.28) 3 RCTs (27,557) | Not pooled | |
| Sensitivity 2 | — | — | — | — | —
| 1.02 (0.98 to 1.06) 1 RCT (26,924) |
| |
| Sensitivity 3 | — | — | — | — | — | — | — | |
| BBV152 – Bharat Biotech | Main analysis | 68.80% (46.70% to 82.50%) 1 RCT (6289) | 77.80% (65.20% to 86.40%) 1 RCT (16,973) | 99.70% (96.79% to 99.79%) 1 RCT (16,976) | 0.50 (0.17 to 1.46) 1 RCT (25,753) | 0.65 (0.43 to 0.97) 1 RCT (25,753) | 1.34 (1.15 to 1.58) 2 RCTs (25,925) | 1.00 (0.94 to 1.07) 1 RCT (25,753) |
| Sensitivity 1 | — | — | — | 0.50 (0.17 to 1.46) 1 RCT (25,778) | 0.65 (0.43 to 0.97) 2 RCTs (25,953) | 1.35 (1.15 to 1.58) 2 RCTs (25,953) | 1.00 (0.94 to 1.07) 1 RCT (25,778) | |
| Sensitivity 2 | — | — | — | — | 0.65 (0.43 to 0.97) 1 RCT (25,753) | 1.34 (1.14 to 1.58) 1 RCT (25,753) | — | |
| Sensitivity 3 | — | — | — | — | — | 1.47 (0.63 to 3.47) 1 RCT (172) | — | |
| AE: adverse event; CI: confidence interval; COVID‐19: coronavirus disease 2019; RCT: randomized controlled trial; RR: risk ratio; SAE: serious adverse event; SARS‐CoV‐2: severe acute respiratory syndrome coronavirus 2; VE: vaccine efficacy. | ||||||||
| aSensitivity 1: participants randomized; Sensitivity 2: early‐phase studies excluded; Sensitivity 3: only published studies. | ||||||||
| Developer‐comparison | Analysesa | Outcomes | ||||||
|---|---|---|---|---|---|---|---|---|
| SARS‐CoV‐2 infection | Symptomatic COVID‐19 | Severe COVID‐19 | All‐cause mortality | SAEs | Systemic reactogenicity events | AEs | ||
| VE (95% CI) No. of trials (No. of participants) | RR (95% CI) No. of trials (No. of participants) | |||||||
| NVX‐CoV2373 – Novavax | Main analysis | — | 82.91% (50.49% to 94.10%) 3 RCTs (42,175) | 100.00% (86.99% to 100.00%) 1 RCT (25,452) | 0.90 (0.30 to 2.68) 1 RCT (29,582) | 0.92 (0.74 to 1.14) 4 RCTs (46,202) | 1.21 (1.17 to 1.25) 3 RCTs (31,063) | 1.15 (1.05 to 1.26) 5 RCTs (46,231) |
| Sensitivity 1 | — | — | — | —
| 0.92 (0.74 to 1.14) 4 RCTs (50,111) | 1.21 (1.17 to 1.26) 3 RCTs (34,870)
| 1.16 (1.05 to 1.27) 5 RCTs (50,111) | |
| Sensitivity 2 | — | — | — | — | 0.93 (0.75 to 1.15) 3 RCTs (45,689) | 1.20 (1.17 to 1.24) 2 RCTs (30,550) | 1.14 (1.02 to 1.27) 3 RCTs (45,689) | |
| Sensitivity 3 | — | 77.10% (0.00% to 95.19%) 2 RCTs (16,723) | — | —
| 0.99 (0.65 to 1.51) 3 RCTs (16,620) | 1.24 (1.03 to 1.49) 2 RCTs (1481) | 1.18 (1.03 to 1.35) 4 RCTs (16,672) | |
| FINLAY‐FR‐2 – Instituto Finlay de Vacunas | Main analysis | — | 71.00% (58.90% to 79.10%) 1 RCT (28,674) | — | 0.37 (0.17 to 0.80) 1 RCT (28,674) | — | — | — |
| Sensitivity 1 | — | — | — | —
| — | — | — | |
| Sensitivity 2 | — | — | — | —
| — | — | — | |
| Sensitivity 3 | — | — | — | —
| —
| — | — | |
| AE: adverse event; CI: confidence interval; COVID‐19: coronavirus disease 2019; RCT: randomized controlled trial; RR: risk ratio; SAE: serious adverse event; SARS‐CoV‐2: severe acute respiratory syndrome coronavirus 2; VE: vaccine efficacy. | ||||||||
| aSensitivity 1: participants randomized; Sensitivity 2: early‐phase studies excluded; Sensitivity 3: only published studies. | ||||||||
