LZV versus placebo

The incidence of the following AEs did not differ significantly between the groups receiving LZV or placebo: 1 or more SAEs (including death), vaccine‐related SAEs, systemic AEs, AEs not related to vaccine, and haematoma at inoculation site.

Participants of the vaccinated group had a higher incidence of vaccine‐related AEs and vaccine‐related systemic AEs beyond AEs at the injection site (erythema, pain, swelling, warmth, pruritus, rash, mass, and varicella‐like rash).

The injection site AEs were erythema, pruritus, swelling, which lasted longer in the LZV group, and duration of rash, which lasted longer in the placebo group.

RZV versus placebo

The incidence of the following AEs did not differ significantly between the groups receiving RZV or placebo: SAEs (including death), SAEs (including death) related to vaccination, and potential immune‐mediated disease.

Systemic AEs (myalgia, fatigue, headache, fever, shivering, and gastrointestinal symptom) as well as local AEs (redness, pain, and swelling) occurred more frequently in the RZV group than in the placebo group.

LZV versus placebo

(Hata 2016; Levin 2018; Mills 2010; Murray 2011; NCT00886613; Oxman 2005; Vermeulen 2012)

The following adverse events did not differ significantly between groups receiving LZV or placebo: death (Hata 2016; Murray 2011; Oxman 2005), 1 or more SAE regardless of type of storage of the vaccine (Murray 2011; Oxman 2005), vaccine‐related serious adverse events (Murray 2011; Oxman 2005), hospitalisation (Oxman 2005), hospitalisation related to HZ (Oxman 2005), systemic adverse events (Hata 2016; Mills 2010; NCT00886613; Oxman 2005; Vermeulen 2012), systemic pruritus (Hata 2016; Vermeulen 2012), general malaise (Hata 2016), headache (NCT00886613), varicella‐like rash not at injection site (from day of vaccination to day 42) (NCT00886613; Oxman 2005; Vermeulen 2012), rash unrelated to HZ (from day of vaccination to day 42) (NCT00886613; Oxman 2005), haematoma at inoculation site (Oxman 2005), and adverse events not related to vaccine (Hata 2016).

Participants in the vaccinated group had a higher incidence of the following: 1 or more adverse events (RR 1.71, 95% CI 1.38 to 2.11; RD 0.23, 95% CI 0.14 to 0.32; NNTH 4.3, 95% CI 3.1 to 7.1) (Analysis 1.2.6) (Hata 2016; Mills 2010; NCT00886613; Oxman 2005; Vermeulen 2012); vaccine‐related adverse events (RR 2.64, 95% CI 1.21 to 5.75; RD 0.26, 95% CI 0.03 to 0.55; NNTH 3.8, 95% CI 1.8 to 33.3) (Analysis 1.2.7) (Hata 2016; NCT00886613; Vermeulen 2012); and vaccine‐related systemic adverse events (RR 1.30, 95% CI 1.07 to 1.58; RD 0.01, 95% CI 0.00 to 0.03; NNTH 100.0 95% CI 33.3 to 100.00) (Analysis 1.2.9) (Mills 2010; NCT00886613; Oxman 2005).

The vaccinated group had a higher incidence of adverse events at the injection site (RR 3.73, 95% CI 1.93 to 7.21; RD 0.28, 95% CI 0.15 to 0.41; NNTH 3.6, 95% CI 2.4 to 6.7) (Analysis 1.2.15) (Hata 2016; Mills 2010; Oxman 2005; Vermeulen 2012).

Specific injection site adverse events also occurred more frequently in the vaccinated group:

• participants with erythema: RR 4.30, 95% CI 2.66 to 6.94; RD 0.22, 95% CI 0.05 to 0.38; NNTH 4.5, 95% CI 2.6 to 20.0 (Analysis 1.2.16) (Hata 2016; NCT00886613; Oxman 2005; Vermeulen 2012);

• participants with pain: RR 6.47, 95% CI 2.67 to 15.68; RD 0.27, 95% CI 0.15 to 0.40; NNTH 3.7, 95% CI 2.5 to 6.7 (Analysis 1.2.17) (Hata 2016; NCT00886613; Oxman 2005; Vermeulen 2012);

• participants with pruritus: RR 4.32, 95% CI 1.49 to 12.48; RD 0.05, 95% CI 0.01 to 0.09; NNTH 20.0, 95% CI 11.1 to 100.0 (Analysis 1.2.18) (Hata 2016; NCT00886613; Oxman 2005; Vermeulen 2012);

• participants with swelling: RR 5.84, 95% CI 4.95 to 6.89; RD 0.18, 95% CI 0.07 to 0.29; NNTH 5.6, 95% CI 3.4 to 14.3 (Analysis 1.2.19) (Hata 2016; Oxman 2005; Vermeulen 2012);

• participants with warmth: RR 4.73, 95% CI 2.57 to 8.74; RD 0.01, 95% CI 0.01 to 0.02; NNTH 100.0, 95% CI 50.0 to 100.0 (Analysis 1.2.20) (Hata 2016; Oxman 2005; Vermeulen 2012);

• participants with rash: RR 3.26, 95% CI 1.31 to 8.11, but no significant RD (Analysis 1.2.21) (Oxman 2005);

• participants with mass: RR 7.05, 95% CI 1.91 to 26.05; RD 0.15, 95% CI −0.20 to 0.50; NNTH 6.7 (Analysis 1.2.23) (NCT00886613; Oxman 2005).

Varicella‐like rash at injection site (up to day 42) also occurred more frequently in the vaccinated group: RR 2.86, 95% CI 1.21 to 6.76, but without a significant RD due to the small number of events (Analysis 1.2.24) (Oxman 2005).

The risk of herpes zoster‐like rash up to 42 days postvaccination was lower in the vaccinated group (RR 0.47, 95% CI 0.27 to 0.84) than in the placebo group, but without a significant RD (Analysis 1.2.26) (Oxman 2005).

Duration of injection site adverse events

Injection site adverse events generally lasted longer in the zoster vaccine group. There were significant differences with respect to the duration of the following local adverse events: erythema MD 2.40 days (95% CI 1.56 to 3.24) (Analysis 1.3.1); pruritus MD 2.40 days (95% CI 1.32 to 3.48) (Analysis 1.3.3); and swelling MD 1.90 days (95% CI 1.35 to 2.45) (Analysis 1.3.4).

The duration of pain and haematoma did not differ significantly between the groups: MD 1.00 (95% CI −0.10 to 2.10) (Analysis 1.3.2) and MD −0.50 (95% CI −5.52 to 4.52) (Analysis 1.3.6), respectively.

The duration of rash was longer in the placebo group than in the vaccine group: RR −16.60 (95% CI −33.68 to 0.48) (Analysis 1.3.5).

High‐potency (∼207,000 pfu/0.65 mL) versus low‐potency (∼58,000 pfu/0.65 mL) zoster vaccine (Tyring 2007)

The comparison of high‐ versus low‐potency zoster vaccine yielded no significant differences between groups for the following adverse events: vaccine‐related adverse events, systemic vaccine‐related adverse events, and vaccine‐related serious adverse events (death).

NBP608 (minimum 27,400 pfu/0.5 ml) versus LZV (minimum 19,400 pfu/0.65 ml) (Choi 2019)

For the AEs evaluated, there were no statistical significances. The AEs were: solicited local AEs, pain, redness/erythema, induration/swelling, solicited systemic AEs, fever, fatigue/malaise, myalgia, headache, vomiting, diarrhoea, unsolicited AEs infections and infestations, musculoskeletal and connective tissue disorders, gastrointestinal disorders, skin and subcutaneous tissue disorders, nervous system disorders, immune system disorders, injury, poisoning, and procedural complications, other disorders, SAE within 6 weeks postvaccination, SAE within 26 weeks postvaccination.

Refrigerated versus frozen zoster vaccine

(Gilderman 2008)

There were no significant differences between the refrigerated versus the frozen zoster vaccine for the following adverse events: 1 or more adverse events, vaccine‐related adverse events, systemic adverse events, systemic vaccine‐related adverse events, serious adverse events, vaccine‐related serious adverse events or death. However, there were more injection site adverse events in the group receiving frozen vaccines (RR 0.77, 95% CI 0.60 to 0.98).

2 doses versus a single dose of LZV and 2 doses given at different intervals

(Vesikari 2013)

Zoster vaccine 1‐month schedule versus zoster vaccine 3‐month schedule

There was no statistical difference between participants who received the doses of zoster vaccine 2 months apart compared to those receiving them 3 months apart: SAE (RR 0.95, 0.14 to 6.70); withdrawal due to AE (RR 2.86, 95% CI 0.12 to 69.80); AE (RR 1.10, 95% CI 0.91 to 1.31); vaccine‐related AE (RR 1.00, 95% CI 0.81 to 1.24); systemic AE (RR 1.34, 95% CI 0.90 to 2.00); vaccine‐related systemic AE (RR 1.27, 95% CI 0.45 to 3.60); rash of interest non‐injection site rashes (RR 0.95, 95% CI 0.06 to 15.14); varicella/varicella‐like rash (RR 0.95, 95% CI 0.06 to 15.14); injection site reaction (RR 0.99, 95% CI 0.80 to 1.23); solicited injection site reaction (RR 1.00, 95% CI 0.81 to 1.25); unsolicited injection site reaction (RR 0.41, 95% CI 0.11 to 1.56); erythema injection site (RR 1.01, 95% CI 0.80 to 1.27); pain injection site (RR 0.84, 95% CI 0.57 to 1.25); swelling injection site (RR 1.05, 95% CI 0.75 to 1.47).

No participants from either group reported the following AEs: vaccine‐related SAE; vaccine‐related withdrawal due to AE; non‐serious vaccine‐related withdrawal due to AE; and herpes zoster/zoster‐like rash.

Zoster vaccine 1‐month schedule versus zoster vaccine single dose

Only participants with systemic AE: there were significant differences in favour of the 2 doses 1 month apart, with a higher incidence in the single‐dose group: RR 0.74, 95% CI 0.56 to 0.97; RD −0.07, 95% CI −0.13 to −0.01; NNTH 14.3, 95% CI 7.6 to 100.

There was no statistical difference for most adverse events: SAE (RR 0.72, 95% CI 0.16 to 3.30); withdrawal due to AE (RR 0.36, 95% CI 0.05 to 2.82); vaccine‐related withdrawal due to AE (RR 0.21, 95% CI 0.01 to 3.74); non‐serious vaccine‐related withdrawal due to AE (RR 0.21, 95% CI 0.01 to 3.74); AE (RR 0.92, 95% CI 0.80 to 1.05); vaccine‐related AE (RR 0.91, 95% CI 0.77 to 1.08); vaccine‐related systemic AE (RR 0.54, 95% CI 0.26 to 1.12); rash of interest non‐injection site rashes (RR 1.61, 95% CI 0.15 to 17.72); varicella/varicella‐like rash (RR 9.66, 95% CI 0.39 to 236.25); herpes zoster/zoster‐like rash (RR 0.64, 95% CI 0.03 to 13.36); injection site reaction (RR 0.93, 95% CI 0.78 to 1.10); solicited injection site reaction (RR 0.94, 95% CI 0.79 to 1.11); unsolicited injection site reaction (RR 0.35, 95% CI 0.11 to 1.13); injection site erythema (RR 0.98, 95% CI 0.81 to 1.17); injection site pain (RR 0.74, 95% CI 0.54 to 1.01); injection site swelling (RR 1.08, 95% CI 0.82 to 1.41).

There were no participants with vaccine‐related SAEs in either group.

Zoster vaccine 3‐month schedule versus zoster vaccine single dose

Participants in the single‐dose group had a higher incidence of the following AEs in comparison to the group that received 2 doses, 3 months apart: AE (RR 0.84, 95% CI 0.72 to 0.97; RD −0.09; 95% CI −0.17 to −0.02; NNTH 11.1, 95% CI 5.9 to 50); systemic AE (RR 0.55, 95% CI 0.39 to 0.76; RD −0.13, 95% CI −0.18 to −0.07; NNTH 7.6, 95% CI 5.6 to 14.3); vaccine‐related systemic AE (RR 0.42, 95% CI 0.18 to 0.98; RD −0.04, 95% CI −0.06 to −0.01; NNTH 25.0, 95% CI 16.6 to 100). There were no significant differences between groups for the following adverse events: SAE (RR 0.75, 95% CI 0.16 to 3.46); withdrawal due to AE (RR 0.18, 95% CI 0.01 to 3.04); vaccine‐related withdrawal due to AE (RR 0.23, 95% CI 0.01 to 3.93); non‐serious vaccine‐related withdrawal due to AE (RR 0.23, 95% CI 0.01 to 3.93); vaccine‐related AE (RR 0.91, 95% CI 0.77 to 1.08); rash of interest non‐injection site rashes (RR 1.69, 95% CI 0.15 to 18.60); varicella/varicella‐like rash (RR 10.14, 95% CI 0.41 to 247.92); herpes zoster/zoster‐like rash (RR 0.68, 95% CI 0.03 to 14.02); injection site reaction (RR 0.93, 95% CI 0.79 to 1.11); solicited injection site reaction (RR 0.93, 95% CI 0.78 to 1.11); unsolicited injection site reaction (RR 0.85, 95% CI 0.38 to 1.91); injection site erythema (RR 0.97, 95% CI 0.80 to 1.17); injection site pain (RR 0.87, 95% CI 0.65 to 1.17); injection site swelling (RR 1.03, 95% CI 0.77 to 1.36).

There were no participants with vaccine‐related SAE in either group.

LZV AMP versus LZV (NCT01505647)

There were no significant differences between LZV AMP versus LZV for the following adverse events: participants with 1 or more adverse events; injection site adverse events; injection site erythema; injection site pain; injection site pruritus; and injection site swelling. It is important to note that there was a significant difference for participants with 1 or more serious adverse events (RR 0.25, 95% CI 0.08 to 0.82; RD −0.04, 95% CI −0.07 to −0.00; NNTH 25.0, and no RD favourable to LZV). There were no deaths in this study.

Heat‐treated LZV versus LZV or placebo

(NCT00886613)

Heat LZV versus LZV

There was no SAE in this comparison. There were no significant differences between groups for the following adverse events: 1 or more AE, 1 or more vaccine‐related AE, 1 or more systemic AE, 1 or more vaccine‐related systemic AE, headache, injection site erythema, and injection site pruritus. On the other hand, for 1 or more injection site AE (RR 0.40, 95% CI 0.23 to 0.70; RD −0.40, 95% CI −0.60 to −0.20; NNTH 2.5, 95% CI 1.17 to 5.0); vaccine‐related 1 or more injection site AE (RR 0.48, 95% CI 0.27 to 0.85; RD −0.30, 95% CI −0.50 to −0.09; NNTH 3.3, 95% CI 2 to 11.1); injection site induration (RR 0.36, 95% CI 0.16 to 0.82; RD −0.26, 95% CI −0.45 to −0.08; NNTH 3.8, 95% CI 2.2 to 12.5); injection site pain (RR 0.18, 95% CI 0.07 to 0.48; RD −0.44, 95% CI −0.62 to −0.26; NNTH 2.3, 95% CI 1.6 to 3.8). All significant differences were favourable to heat LZV.

Heat LZV versus placebo

There was no SAE in this comparison. There was no significant difference between heat LZV and placebo for all adverse events reported.

LZV IM route versus LZV SC route

(Diez‐Domingo 2015)

The participants who received SC vaccines had a significantly higher incidence of the following adverse events:

• at least 1 AE: RR 0.68, 95% CI 0.56 to 0.82; RD −0.22, 95% CI −0.32 to −0.12; NNTH 4.5, 95% CI 3.1 to 8.33;

• vaccine‐related AE: RR 0.58, 95% CI 0.47 to 0.72; RD −0.28, 95% CI −0.38 to −0.18; NNTH 3.6, 95% CI 2.6 to 5.55;

• solicited injection site reaction: RR 0.53, 95% CI 0.42 to 0.67; RD −0.30, 95% CI −0.40 to −0.20; NNTH 1.8, 95% CI 2.5 to 5;

• injection site erythema: RR 0.30, 95% CI 0.21 to 0.44; RD −0.37, 95% CI −0.46 to −0.28; NNTH 2.7, 95% CI 2.1 to 3.5;

• injection site pain: RR 0.65, 95% CI 0.47 to 0.88; RD −0.14, 95% CI −0.24 to −0.04; NNTH 7.1, 95% CI 4.2 to 25;

• injection site swelling: RR 0.37, 95% CI 0.24 to 0.56; RD −0.24, 95% CI −0.32 to −0.15; NNTH 4.2, 95% CI 3.1 to 6.7;

• injection site pruritus: RR 0.27, 95% CI 0.08 to 0.97; RD −0.05, 95% CI −0.09 to −0.00; NNTH 20.0, 95% CI 0 to 11.0.

There were no significant differences between groups for the following adverse events: all systemic adverse events: RR 1.03, 95% CI 0.70 to 1.51; vaccine‐related systemic AE: RR 0.93, 95% CI 0.44 to 1.98; headache considered as vaccine‐related by the investigator: RR 0.75, 95% CI 0.17 to 3.32; unsolicited injection site reaction: RR 0.65, 95% CI 0.29 to 1.45; severe injection site erythema (> 10 cm): RR 0.67, 95% CI 0.11 to 3.96; severe injection site pain (inability to work or perform usual activity): RR 1.01, 95% CI 0.14 to 7.06; severe injection site swelling (> 10 cm): RR 0.25, 95% CI 0.03 to 2.23.

LZV intradermal route versus LZV SC route (Beals 2016)

Full‐dose intradermal versus full‐dose subcutaneous

There were significant differences in favour of LZV SC for 2 AEs: 1 or more injection site AEs (RR 1.53, 95% CI 1.12 to 2.09; RD 0.27, 95% CI 0.08 to 0.47; NNTH 3.7, 95% CI 2.1 to 12.5) and erythema (RR 2.49, 95% CI 1.59 to 3.89; RD 0.46, 95% CI 0.27 to 0.65; NNTH 2.2, 95% CI 1.5 to 3.7). There were no significant differences between groups for the following adverse events: pain, swelling, induration, pruritus, haematoma, anaesthesia, or rash.

1/3 dose intradermal versus full‐dose subcutaneous

There were significant differences in favour of full‐dose LZV SC for the following AEs: erythema (RR 1.95, 95% CI 1.20 to 3.18; RD 0.29, 95% CI 0.09 to 0.50; NNTH 3.4, 95% CI 2.0 to 11.1) and induration (RR 3.57, 95% CI 1.38 to 9.23; RD 0.25, 95% CI 0.07 to 0.42; NNTH 4.0, 95% CI 2.4 to 14.3). There was no significant difference between groups for the other adverse events.

1/10 dose intradermal versus full‐dose subcutaneous

There was no significant difference between groups for any adverse events.

1/27 dose intradermal versus full‐dose subcutaneous

Erythema (RR 1.72, 95% CI 1.03 to 2.88; RD 0.22, 95% CI 0.01 to 0.43; NNTH 4.5, 95% CI 2.30 to 100.0) and induration (RR 3.06, 95% CI 1.14 to 8.17; RD 0.20, 95% CI 0.03 to 0.37; NNTH 5.0, 95% CI 2.7.0 to 3.3). There was no significant difference between groups for the other adverse events.

Full‐dose intradermal versus 1/3 dose subcutaneous

There was a difference between the groups favourable to the subcutaneous 1/3 dose group, which had a significantly lower incidence of the following AEs: 1 or more injection site adverse events (RR 3.86, 95% CI 1.95 to 7.63; RD 0.59, 95% CI 0.40 to 0.77; NNTH 1.7, 95% CI 1.3 to 2.5); erythema (RR 5.20, 95% CI 2.27 to 11.93; RD 0.62, 95% CI 0.43 to 0.80; NNTH 1.6, 95% CI 1.2 to 2.3); and induration (RR 6.00, 95% CI 1.45 to 24.81; RD 0.29, 95% CI 0.12 to 0.47; NNTH 3.4, 95% CI 2.1 to 8.3). There was no significant difference between groups for the other adverse events.

1/3 dose intradermal versus 1/3 dose subcutaneous

There was no significant difference between groups for all adverse events reported.

1/10 dose intradermal versus 1/3 dose subcutaneous

There were significant differences in favour of 1/3 dose SC for the following AEs: 1 or more injection site adverse events (RR 2.71, 95% CI 1.32 to 5.60; RD 0.35, 95% CI 0.14 to 0.57; NNTH 2.9, 95% CI 1.8 to 7.1); erythema (RR 3.20, 95% CI 1.32 to 7.75; RD 0.32, 95% CI 0.12 to 0.53; NNTH 3.1, 95% CI 1.9 to 8.3); and induration (RR 5.50, 95% CI 1.32 to 22.98; RD 0.26, 95% CI 0.09 to 0.44; NNTH 3.8, 95% CI 2.3 to 11.1). There was no significant difference between groups for the other adverse events.

1/27 dose intradermal versus 1/3 dose subcutaneous

There were significant differences in favour of 1/3 dose SC for the following AEs: 1 or more injection site adverse events (RR 2.71, 95% CI 1.32 to 5.60; RD 0.35, 95% CI 0.14 to 0.57; NNTH 2.9, 95% CI 1.8 to 7.1); erythema (RR 3.60, 95% CI 1.51 to 8.59; RD 0.38, 95% CI 0.18 to 0.59; NNTH 2.6, 95% CI 1.7 to 5.6); and induration (RR 5.00, 95% CI 1.18 to 21.14; RD 0.24, 95% CI 0.06 to 0.41; NNTH 4.2, 95% CI 2.4 to 16.7). There was no significant difference between groups for the other adverse events.

LZV versus pneumo‐23 vaccine

(Berger 1998)

1 study compared 3 different concentrations of plaque‐forming units (pfu) of live attenuated VZV and reported the following adverse events:

3200 pfu VZV/dose versus pneumo‐23

There was a lower incidence of 1 or more injection site reactions in the group vaccinated with the 3200 pfu/dose zoster vaccine (RR 0.61, 95% CI 0.41 to 0.91) as well as pain at the injection site (RR 0.49, 95% CI 0.30 to 0.81).

There were no significant differences between the 3200 pfu/dose zoster vaccine and the pneumo‐23 vaccine for the following local adverse events: induration (≥ 2 cm diameter injection site), probably vaccine‐related injection site pain, redness (≥ 2 cm diameter injection site), pruritus or vesicles (no patients had vesicles in the 3200 pfu/dose zoster vaccine nor the pneumo‐23 groups).

8500 pfu VZV/dose versus pneumo‐23

There was a lower incidence of 1 or more injection site reaction in the group vaccinated with the 8500 pfu/dose zoster vaccine (RR 0.63, 95% CI 0.43 to 0.93).

There were no significant differences for the following injection site adverse events between participants who received the 8500 pfu/dose VZV vaccine and those who received the pneumo‐23 vaccine: induration (≥ 2 cm diameter injection site), pain (injection site), probably vaccine‐related injection site pain, redness, pruritus, and vesicles.

41,650 pfu VZV/dose VZV versus pneumo‐23

Participants receiving the 41,650 pfu/dose zoster vaccine had significantly lower rates of one or more injection site reaction (RR 0.41, 95% CI 0.24 to 0.68) and pain at injection site (RR 0.43, 95% CI 0.25 to 0.74) than those receiving the pneumo‐23 vaccine.

There were no significant differences between the groups for the following injection site adverse events: induration (≥ 2 cm diameter injection site), probably vaccine‐related injection site pain, redness (≥ 2 cm diameter injection site), pruritus, and vesicles (no patients had vesicles in the 41,650 pfu/dose zoster vaccine nor the pneumo‐23 vaccine groups).

LZV + IIV4 concomitant administration versus LZV + IIV4 sequential administration (Levin 2018)

There were no significant differences between groups for the following: death, serious adverse events, one or more adverse events, non injection‐site adverse events, non injection site vaccine‐related AE, injection‐site adverse events.

There were no vaccine‐related adverse events.

RZV versus placebo (Cunningham 2016; Lal 2015)

The adverse events related to RZV versus placebo were:

• deaths: RR 0.94, 95% CI 0.84 to 1.04 and no RD (Analysis 2.3.1);

• deaths within 30 days after vaccination: RR 1.15, 95% CI 0.42 to 3.16 and no RD (Analysis 2.3.2);

• serious adverse events: RR 0.97, 95% CI 0.91 to 1.03 and no RD (Analysis 2.3.3);

• with serious adverse events within 30 days after vaccination: RR 0.90, 95% CI 0.67 to 1.20 and no RD (Analysis 2.3.4);

• serious adverse events within 30 days after vaccination related to vaccination: RR 0.33, 95% CI 0.03 to 3.21 and no RD (Analysis 2.3.5);

• any symptom: RR 2.41, 95% CI 2.02 to 2.88; RD 0.47, 95% CI 0.45 to 0.49; NNTH 2.1, 95% CI 2.0 to 2.2 (Analysis 2.3.6);

• any symptom grade 3: RR 5.29, 95% CI 4.48 to 6.26; RD 0.12, 95% CI 0.08 to 0.16; NNTH 8.3, 95% CI 6.3 to 12.5 (Analysis 2.3.7);

• any symptom grade 3 related to vaccination: RR 8.37, 95% CI 6.69 to 10.47; RD 0.14, 95% CI 0.13 to 0.15; NNTH 7.1, 95% CI 6.7 to 7.7 (Analysis 2.3.8);

• any systemic symptom: RR 2.23, 95% CI 2.12 to 2.34; RD 0.33, 95% CI 0.24 to 0.41; NNTH 3.0, 95% CI 2.4 to 4.2 (Analysis 2.3.9);

• any systemic symptom grade 3: RR 4.29, 95% CI 3.01 to 6.11; RD 0.07, 95% CI 0.02 to 0.12; NNTH 14.3, 95% CI 8.3.0 to 50.0 (Analysis 2.3.10);

• potential immune‐mediated disease: RR 0.88, 95% CI 0.71 to 1.08 and no RD (Analysis 2.3.11);

• myalgia: RR 3.82, 95% CI 3.52 to 4.16; RD 0.33, 95% CI 0.31 to 0.35; NNTH 3.0, 95% CI 2.9 to 3.3 (Analysis 2.3.12);

• fatigue: RR 2.51, 95% CI 1.99 to 3.17; RD 0.24, 95% CI 0.12 to 0.35; NNTH 4.2, 95% CI 2.9 to 8.3 (Analysis 2.3.13);

• headache: RR 2.44, 95% CI 2.26 to 2.63; RD 0.22, 95% CI 0.21 to 0.24; NNTH 4.5, 95% CI 4.1 to 4.8 (Analysis 2.3.14);

• fever: RR 6.45, 95% CI 4.61 to 9.04; RD 0.14, 95% CI 0.06 to 0.23; NNTH 7.1, 95% CI 4.3 to 16.7 (Analysis 2.3.15);

• shivering: RR 4.35, 95% CI 3.26 to 5.81; RD 0.16, 95% CI 0.05 to 0.28; NNTH 6.3, 95% CI 3.6 to 20.0 (Analysis 2.3.16);

• gastrointestinal symptom: RR 1.75, 95% CI 1.21 to 2.55; RD 0.06, 95% CI 0.00 to 0.12 (Analysis 2.3.17);

• any local symptom: RR 6.89, 95% CI 6.37 to 7.45; RD 0.67, 95% CI 0.62 to 0.73; NNTH 1.5, 95% CI 1.4 to 1.6 (Analysis 2.3.18);

• any local symptom grade 3: RR 12.69, 95% CI 2.87 to 56.06; RD 0.09, 95% CI 0.08 to 0.10; NNTH 11.1, 95% CI 10 to 12.5 (Analysis 2.3.19);

• local redness: RR 28.93, 95% CI 22.62 to 37.00; RD 0.37, 95% CI 0.35 to 0.38; NNTH 2.7, 95% CI 2.6 to 2.9 (Analysis 2.3.20);

• local pain: RR 7.14, 95% CI 6.58 to 7.74; RD 0.64, 95% CI 0.57 to 0.72; NNTH 1.6, 95% CI 1.4 to 1.8 (Analysis 2.3.21);

• local swelling: RR 28.26, 95% CI 15.91 to 50.20; RD 0.24, 95% CI 0.21 to 0.27; NNTH 4.2, 95% CI 3.7 to 4.8 (Analysis 2.3.22);

• unsolicited report of adverse events: RR 1.07, 95% CI 1.00 to 1.14; RD 0.02, 95% CI 0.00 to 0.04 (Analysis 2.3.23);

• unsolicited report of adverse events grade 3: RR 1.38, 95% CI 1.12 to 1.69; RD 0.01, 95% CI 0.00 to 0.02 (Analysis 2.3.24).

RZV: lower or higher quantities of adjuvants plus gE subunit VZV versus unadjuvanted gE or saline

(Chlibek 2013)

The incidence of adverse events in participants randomised to 4 different groups was compared as follows:

1. Participants who received smaller amounts of adjuvant (AS01E) plus gE subunit VZV injection

2. Participants who received larger amounts of adjuvant (AS01B) plus gE subunit VZV injection

3. Participants who received unadjuvanted gE subunit VZV injection

4. Participants who received saline injections

We compared each of the groups with all of the other groups (total of 6 comparisons) as follows:

50 μg gE/AS01_E versus 50 μg gE/AS01_B

There was a significantly higher incidence of adverse events in participants who received a higher quantity of adjuvant (AS01_B):

• any symptom: RR 0.89, 95% CI 0.80 to 0.99; RD −0.09, 95% CI −0.18 to −0.01; NNTH 11.1, 95% CI 5.6 to 100.0;

• fatigue: RR 0.73, 95% CI 0.55 to 0.96; RD −0.13, 95% CI −0.24 to −0.02; NNTH 7.7, 95% CI 4.2 to 50.0;

• headache: RR 0.67, 95% CI 0.47 to 0.94; RD −0.13, 95% CI −0.23 to −0.02; NNTH 7.7, 95% CI 4.3 to 50.0;

• any local symptom: RR 0.85, 95% CI 0.75 to 0.96; RD −0.13, 95% CI −0.22 to −0.04; NNTH 7.7, 95% CI 4.5 to 25.0;

• local redness: RR 0.59, 95% CI 0.39 to 0.91; RD −0.12, 95% CI −0.21 to −0.02; NNTH 8.3, 95% CI 4.7 to 50.0;

• local pain: RR 0.84, 95% CI 0.74 to 0.95; RD −0.14, 95% CI −0.23 to −0.04; NNTH 7.1, 95% CI 4.3 to 25.0.

There were no significant differences between groups for all other adverse events: any grade 3 symptom, any general symptom, any general grade 3 symptom, grade 3 fatigue, fever, gastrointestinal symptoms, grade 3 gastrointestinal symptoms, grade 3 headache, myalgia, grade 3 myalgia, any grade 3 local symptom, local grade 3 pain, local grade 3 redness, local swelling and local grade 3 swelling, consent withdrawal, loss to follow‐up, and serious adverse events.

No participants had grade 3 fever in either group.

50 μg gE/AS01_E versus 50 μg gE/saline (unadjuvanted)

• any symptom: RR 1.76, 95% CI 1.34 to 2.32; RD 0.33, 95% CI 0.20 to 0.47; NNTH 3.0, 95% CI 2.1 to 5.0;

• any general symptom: RR 1.67, 95% CI 1.17 to 2.40; RD 0.22, 95% CI 0.09 to 0.36; NNTH 4.5, 95% CI 2.7 to 11.1;

• myalgia: RR 2.00, 95% CI 1.14 to 3.52; RD 0.16, 95% CI 0.05 to 0.28; NNTH 6.25, 95% CI 3.5 to 20.0;

• fever: RR 18.25, 95% CI 1.12 to 298.73; RD 0.12, 95% CI 0.06 to 0.18; NNTH 8.3, 95% CI 5.5 to 16.6;

• any local symptom: RR 3.05, 95% CI 1.99 to 4.69; RD 0.48, 95% CI 0.36 to 0.60; NNTH 2.0, 95% CI 1.6 to 2.7;

• local redness: RR 4.25, 95% CI 1.33 to 13.57; RD 0.13, 95% CI 0.06 to 0.21; NNTH 7.6, 95% CI 4.7 to 16.6;

• local pain: RR 3.64, 95% CI 2.25 to 5.90; RD 0.51, 95% CI 0.39 to 0.62; NNTH 1.9, 95% CI 1.6 to 2.5;

• local swelling: RR 4.08, 95% CI 1.27 to 13.08; RD 0.13, 95% CI 0.05 to 0.20; NNTH 7.6, 95% CI 5.0 to 20.

All these differences in incidence of adverse events favoured the unadjuvanted gE group.

There were no significant differences between groups for the following adverse events: any grade 3 symptom, any general grade 3 symptom, fatigue, grade 3 fatigue, gastrointestinal symptoms, grade 3 gastrointestinal symptoms, headache, grade 3 myalgia, any local grade 3 symptom, local grade 3 pain, local grade 3 redness and local grade 3 swelling, consent withdrawal, loss to follow‐up, and serious adverse events.

No participants had grade 3 fever or grade 3 headache in either group.

50 μg gE/AS01_B versus 50 μg gE/saline (unadjuvanted)

• any symptom: RR 1.98, 95% CI 1.51 to 2.58; RD 0.43, 95% CI 0.30 to 0.55; NNTH 2.3, 95% CI 1.8 to 3.3;

• any general symptom: RR 1.93, 95% CI 1.36 to 2.73; RD 0.30, 95% CI 0.17 to 0.44; NNTH 3.3, 95% CI 2.2 to 5.8;

• myalgia: RR 2.51, 95% CI 1.45 to 4.36; RD 0.25, 95% CI 0.13 to 0.36; NNTH 4.0, 95% CI 2.7 to 7.6;

• fatigue: RR 2.19, 95% CI 1.38 to 3.48; RD 0.26, 95% CI 0.14 to 0.38; NNTH 3.8, 95% CI 2.6 to 7.1;

• headache: RR 2.73, 95% CI 1.48 to 5.03; RD 0.24, 95% CI 0.13 to 0.35; NNTH 4.1, 95% CI 2.8 to 7.6;

• fever: RR 24.99, 95% CI 1.54 to 404.89; RD 0.17, 95% CI 0.10 to 0.23; NNTH 5.8, 95% CI 4.3 to 10.0;

• any local symptom: RR 3.61, 95% CI 2.36 to 5.50; RD 0.61, 95% CI 0.49 to 0.72; NNTH 1.6, 95% CI 1.3 to 2.0;

• local redness: RR 7.14, 95% CI 2.29 to 22.22; RD 0.25, 95% CI 0.17 to 0.34; NNTH 4.0, 95% CI 2.9 to 5.8;

• local pain: RR 4.35, 95% CI 2.70 to 7.00; RD 0.64, 95% CI 0.53 to 0.75; NNTH 1.5, 95% CI 1.3 to 1.8;

• local swelling: RR 3.73, 95% CI 1.16 to 12.02; RD 0.11, 95% CI 0.04 to 0.19; NNTH 9.0, 95% CI 5.2 to 25.

All these differences in incidence of adverse events favoured unadjuvanted gE.

There were no significant differences between groups for the following adverse events: any grade 3 symptom, any general grade 3 symptom, grade 3 fatigue, gastrointestinal symptoms, grade 3 headache, grade 3 myalgia, any local grade 3 symptom, local grade 3 pain, local grade 3 redness and local grade 3 swelling, consent withdrawal, loss to follow‐up, and serious adverse events.

No participants had grade 3 fever or grade 3 gastrointestinal symptoms in either group.

50 μg gE/AS01_E versus saline

• any symptom: RR 3.67, 95% CI 1.97 to 6.83; RD 0.56, 95% CI 0.42 to 0.71; NNTH 1.7, 95% CI 1.4 to 2.3;

• any general symptom: RR 2.99, 95% CI 1.51 to 5.92; RD 0.37, 95% CI 0.22 to 0.51; NNTH 9.1, 95% CI 1.9 to 4.5;

• myalgia: RR 6.25, 95% CI 1.59 to 24.55; RD 0.28, 95% CI 0.17 to 0.38; NNTH 3.5, 95% CI 2.6 to 5.8;

• any local symptom: RR 9.01, 95% CI 3.03 to 26.82; RD 0.63, 95% CI 0.52 to 0.74; NNTH 1.5, 95% CI 1.3 to 1.9;

• local pain: RR 8.84, 95% CI 2.97 to 26.33; RD 0.62, 95% CI 0.51 to 0.73; NNTH 1.6, 95% CI 1.3 to 1.9.

All these differences in incidence of adverse events favoured the saline group.

There were no significant differences between groups for the following adverse events: any grade 3 symptom, any general grade 3 symptom, fatigue, grade 3 fatigue, fever, gastrointestinal symptoms, grade 3 gastrointestinal symptoms, headache, grade 3 headache, grade 3 myalgia, any local grade 3 symptom, local grade 3 pain, local redness, local grade 3 redness, local swelling and local grade 3 swelling, consent withdrawal, loss to follow‐up, and serious adverse events.

No participants had grade 3 fever or grade 3 headache in either group.

50 μg gE/AS01_B versus saline

• any symptom: RR 4.12, 95% CI 2.22 to 7.64; RD 0.66, 95% CI 0.52 to 0.80; NNTH 1.5, 95% CI 1.2 to 1.9;

• any general symptom: RR 3.44, 95% CI 1.74 to 6.79; RD 0.45, 95% CI 0.30 to 0.59; NNTH 2.2, 95% CI 1.6 to 3.3;

• myalgia: RR 7.85, 95% CI 2.01 to 30.67; RD 0.36, 95% CI 0.25 to 0.47; NNTH 2.7, 95% CI 2.1 to 4.0;

• fatigue: RR 2.61, 95% CI 1.31 to 5.19; RD 0.30, 95% CI 0.15 to 0.44; NNTH 1.3, 95% CI 2.2 to 6.6;

• headache: RR 3.55, 95% CI 1.37 to 9.17; RD 0.27, 95% CI 0.14 to 0.39; NNTH 3.7, 95% CI 2.5 to 7.1;

• any local symptom: RR 10.64, 95% CI 3.58 to 31.59; RD 0.76, 95% CI 0.66 to 0.86; NNTH 1.3, 95% CI 1.1 to 1.5;

• local redness: RR 22.99, 95% CI 1.45 to 365.01; RD 0.29, 95% CI 0.21 to 0.37; NNTH 3.4, 95% CI 2.7 to 4.7;

• local pain: RR 10.56, 95% CI 3.55 to 31.34; RD 0.75, 95% CI 0.65 to 0.86; NNTH 1.3, 95% CI 1.1 to 1.5.

All these differences in incidence of adverse events favoured the saline group.

There were no significant differences between groups for the following adverse events: any grade 3 symptom, any general grade 3 symptom, grade 3 fatigue, fever, gastrointestinal symptoms, grade 3 gastrointestinal symptoms, grade 3 headache, grade 3 myalgia, any local grade 3 symptom, local grade 3 pain, local grade 3 redness, local swelling and local grade 3 swelling, consent withdrawal, loss to follow‐up, and serious adverse events.

No participants had grade 3 fever in either group.

50 μg gE/saline (unadjuvanted) versus saline

• any symptom: RR 2.08, 95% CI 1.07 to 4.06; RD 0.23, 95% CI 0.06 to 0.40; NNTH 4.3, 95% CI 2.5 to 16.6 (favouring saline).

There were no significant differences between groups for the following adverse events: any grade 3 symptom, any general symptom, any general grade 3 symptom, fatigue, grade 3 fatigue, fever, gastrointestinal symptoms, grade 3 gastrointestinal symptoms, headache, myalgia, grade 3 myalgia, any local symptom, local pain, local redness and local swelling, or consent withdrawal.

No participants in either group had grade 3 fever, grade 3 headache, any local grade 3 symptom, local grade 3 pain, local grade 3 redness, local grade 3 swelling, loss to follow‐up, and serious adverse events.

RZV: 3 groups of VZV subunit gE in 3 different quantities versus unadjuvanted gE or saline (Chlibek 2014)

The incidence of adverse events in participants randomised to 5 different groups was compared as follows:

1. Participants receiving 25 µg adjuvanted gE/AS01_B injection

2. Participants receiving 50 µg adjuvanted gE/AS01_B injection

3. Participants receiving 100 µg adjuvanted gE/AS01_B injection

4. Participants receiving 1 dose saline injection + 1 dose 100 µg gE 2 months later injection

5. Participants receiving 100 µg gE/saline

We compared each of the groups to all other groups (total of 10 comparisons) as follows:

25 µg gE/AS01_B versus 50 µg gE/AS01_B

There were no differences between groups in the incidence of the following adverse events: any fatigue, grade 3 fatigue, any fever, grade 3 fever, any headache, grade 3 headache, any myalgia, grade 3 myalgia, local pain, local grade 3 pain, local redness, local grade 3 redness, local swelling, local grade 3 swelling, consent withdrawal, loss to follow‐up, and serious adverse events.

25 µg gE/AS01_B versus 100 µg gE/AS01_B

There were no differences between groups in the incidence of the following adverse events: any fatigue, grade 3 fatigue, any fever, any headache, grade 3 headache, any myalgia, grade 3 myalgia, local pain, grade 3 local pain, local redness, local grade 3 redness, local swelling, local grade 3 swelling, consent withdrawal, loss to follow‐up, and serious adverse events.

50 µg gE/AS01_B versus 100 µg gE/AS01_B

• any myalgia: RR 1.26, 95% CI 1.01 to 1.59; RD 0.11, 95% CI 0.00 to 0.22; NNTH 9.0, 95% CI 0 to 4.5 (favouring 100 µg gE/AS01_B).

There were no differences between groups in the incidence of other adverse events: any fatigue, grade 3 fatigue, any fever, grade 3 fever, any headache, grade 3 headache, grade 3 myalgia, local pain, local grade 3 pain, local redness, local grade 3 redness, local swelling, local grade 3 swelling, consent withdrawal, and serious adverse events.

25 µg gE/AS01_B versus 100 µg gE/saline (unadjuvanted gE)

• any myalgia: RR 2.71, 95% CI 1.46 to 5.03; RD 0.28, 95% CI 0.16 to 0.41; NNTH 3.5, 95% CI 2.4 to 6.2;

• any fatigue: RR 1.89, 95% CI 1.11 to 3.22; RD 0.20, 95% CI 0.06 to 0.33; NNTH 5.0, 95% CI 3.0 to 16.6;

• local redness: RR 11.20, 95% CI 2.84 to 44.15; RD 0.38, 95% CI 0.29 to 0.47; NNTH 2.6, 95% CI 2.1 to 3.4;

• local pain: RR 4.21, 95% CI 2.30 to 7.70; RD 0.53, 95% CI 0.41 to 0.66; NNTH 1.8, 95% CI 1.5 to 2.4;

• local swelling: RR 14.49, 95% CI 2.04 to 102.66; RD 0.25, 95% CI 0.17 to 0.33; NNTH 4.0, 95% CI 3.0 to 5.8.

All these differences in incidence of adverse events favoured unadjuvanted gE.

There were no differences in the incidence of the following adverse events: grade 3 fatigue, any fever, any headache, grade 3 headache, grade 3 myalgia, local grade 3 pain, local grade 3 redness, local grade 3 swelling, consent withdrawal, loss to follow‐up, and serious adverse events.

No participants had grade 3 fever in either group.

50 µg gE/AS01_B versus 100 µg gE/saline (unadjuvanted gE)

• any myalgia: RR 3.22, 95% CI 1.74 to 5.94; RD 0.37, 95% CI 0.24 to 0.49; NNTH 2.7, 95% CI 2.0 to 4.1;

• any fatigue: RR 2.30, 95% CI 1.37 to 3.88; RD 0.29, 95% CI 0.16 to 0.42; NNTH 3.4, 95% CI 2.3 to 6.2;

• any headache: RR 2.13, 95% CI 1.14 to 4.01; RD 0.19, 95% CI 0.07 to 0.31; NNTH 5.2, 95% CI 3.2 to 14.2;

• local redness: RR 10.73, 95% CI 2.72 to 42.37; RD 0.36, 95% CI 0.27 to 0.45; NNTH 2.7, 95% CI 2.2 to 3.7;

• local pain: RR 4.37, 95% CI 2.39 to 8.00; RD 0.56, 95% CI 0.44 to 0.68; NNTH 1.7, 95% CI 1.4 to 2.2;

• local swelling: RR 10.73, 95% CI 1.50 to 76.64; RD 0.18, 95% CI 0.11 to 0.25; NNTH 5.5, 95% CI 4.0 to 9.0.

All these differences in incidence of adverse events favoured unadjuvanted gE.

There were no differences in the incidence of the following adverse events: grade 3 fatigue, any fever, grade 3 headache, grade 3 myalgia, local grade 3 pain, local grade 3 redness, local grade 3 swelling, consent withdrawal, loss to follow‐up, and serious adverse events.

No participants had grade 3 fever in either group.

100 µg gE/AS01_B versus 100 µg gE/saline (unadjuvanted gE)

• any myalgia: RR 2.55, 95% CI 1.37 to 4.74; RD 0.26, 95% CI 0.13 to 0.38; NNTH 3.8, 95% CI 2.6 to 7.6;

• any fatigue: RR 1.99, 95% CI 1.17 to 3.37; RD 0.22, 95% CI 0.09 to 0.35; NNTH 4.5, 95% CI 2.8 to 11.1;

• any headache: RR 1.85, 95% CI 0.98 to 3.51; RD 0.14, 95% CI 0.02 to 0.26; NNTH 7.1, 95% CI 3.8 to 50.0;

• local redness: RR 11.13, 95% CI 2.82 to 43.88; RD 0.38, 95% CI 0.28 to 0.47; NNTH 2.6, 95% CI 2.1 to 3.5;

• local pain: RR 4.44, 95% CI 2.43 to 8.11; RD 0.57, 95% CI 0.45 to 0.69; NNTH 1.7, 95% CI 1.4 to 2.2;

• local swelling: RR 14.73, 95% CI 2.08 to 104.31; RD 0.25, 95% CI 0.18 to 0.33; NNTH 4.0, 95% CI 3.0 to 5.5.

All these differences in incidence of adverse events favoured unadjuvanted gE.

There were no differences in the incidence of the following adverse events: grade 3 fatigue, any fever, grade 3 headache, grade 3 myalgia, local grade 3 pain, local grade 3 redness, local grade 3 swelling, consent withdrawal, loss to follow‐up, and serious adverse events.

No participants had grade 3 fever in either group.

25 µg gE/AS01_B versus saline + 100 µg gE/AS01_B

• any myalgia: RR 1.52, 95% CI 1.14 to 2.03; RD 0.15, 95% CI 0.05 to 0.26; NNTH 6.6, 95% CI 3.8 to 20;

• any fatigue: RR 1.48, 95% CI 1.09 to 2.00; RD 0.14, 95% CI 0.03 to 0.24; NNTH 7.1, 95% CI 4.1 to 33.3;

• local redness: RR 1.40, 95% CI 1.04 to 1.88; RD 0.12, 95% CI 0.01 to 0.22; NNTH 8.3, 95% CI 4.5 to 100.0;

• local pain: RR 1.24, 95% CI 1.05 to 1.47; RD 0.14, 95% CI 0.03 to 0.24; NNTH 7.1, 95% CI 4.1 to 33.3.

All differences in incidence of adverse events favoured saline + 100 µg gE/AS01_B.

There were no differences in the incidence of the following adverse events: any fatigue, grade 3 fever, any headache, grade 3 headache, grade 3 myalgia, local grade 3 pain, local grade 3 redness, local swelling, local grade 3 swelling, consent withdrawal, loss to follow‐up, and serious adverse events.

No participants had grade 3 fever in either group.

50 µg gE/AS01_B versus saline + 100 µg gE/AS01_B

• any myalgia: RR 1.81, 95% CI 1.37 to 2.37; RD 0.24, 95% CI 0.14 to 0.34; NNTH 4.1, 95% CI 2.9 to 7.1;

• any fatigue: RR 1.80, 95% CI 1.35 to 2.39; RD 0.23, 95% CI 0.12 to 0.33; NNTH 4.3, 95% CI 3.0 to 8.3;

• any headache: RR 1.63, 95% CI 1.14 to 2.32; RD 0.14, 95% CI 0.04 to 0.23; NNTH 7.1, 95% CI 4.3 to 25;

• local pain: RR 1.29, 95% CI 1.10 to 1.52; RD 0.17, 95% CI 0.06 to 0.27; NNTH 5.8, 95% CI 3.7 to 16.6.

All differences in incidence of adverse events favoured saline + 100 µg gE/AS01_B.

There were no differences in the incidence of the following adverse events: grade 3 fatigue, any fever, grade 3 fever, grade 3 headache, grade 3 myalgia, local grade 3 pain, local redness, local grade 3 redness, local swelling, local grade 3 swelling, consent withdrawal, loss to follow‐up, and serious adverse events.

100 µg gE/AS01_B versus saline + 100 µg gE/AS01_B

• any myalgia: RR 1.43, 95% CI 1.06 to 1.92; RD 0.13, 95% CI 0.02 to 0.23; NNTH 7.6, 95% CI 4.3 to 50.0;

• any fatigue: RR 1.55, 95% CI 1.15 to 2.09; RD 0.16, 95% CI 0.06 to 0.26; NNTH 6.2, 95% CI 3.8 to 16.6;

• any fever: RR 2.44, 95% CI 1.16 to 5.15; RD 0.08, 95% CI 0.02 to 0.14; NNTH 12.5, 95% CI 7.1 to 50;

• local redness: RR 1.39, 95% CI 1.03 to 1.87; RD 0.12, 95% CI 0.01 to 0.22; NNTH 8.3, 95% CI 4.5 to 100.0;

• local pain: RR 1.31, 95% CI 1.12 to 1.54; RD 0.18, 95% CI 0.07 to 0.28; NNTH 5.5, 95% CI 3.5 to 14.2.

All differences in incidence of adverse events favoured saline + 100 µg gE/AS01_B.

There were no differences in the incidence of the following adverse events: grade 3 fatigue, headache, grade 3 headache, grade 3 myalgia, local grade 3 pain, local grade 3 redness, local swelling, local grade 3 swelling, consent withdrawal, loss to follow‐up, and serious adverse events.

No participants had grade 3 fever in either group.

Saline + 100 µg gE/AS01_B versus 100 µg gE/saline (unadjuvanted gE)

• local redness: RR 8.02, 95% CI 2.02 to 31.88; RD 0.26, 95% CI 0.17 to 0.35; NNTH 3.8, 95% CI 2.8 to 5.8;

• local pain: RR 3.38, 95% CI 1.84 to 6.23; RD 0.40, 95% CI 0.27 to 0.52; NNTH 2.5, 95% CI 1.9 to 3.7;

• local swelling: RR 9.82, 95% CI 1.37 to 70.30; RD 0.16, 95% CI 0.09 to 0.23; NNTH 6.2, 95% CI 4.3 to 11.1.

All differences in incidence of adverse events favoured 100 µg gE/saline.

There were no differences in the incidence of the following adverse events: any fatigue, grade 3 fatigue, any fever, any headache, any myalgia, grade 3 myalgia, local grade 3 pain, local grade 3 redness, consent withdrawal, loss to follow‐up, and serious adverse events.

No participants had grade 3 fever, grade 3 headache, or local grade 3 swelling in either group.

RZV: 2 doses given at 3 different intervals (Lal 2018)

There were no statistically significant differences between groups for any of the 3 comparisons (RZV 2 doses 2 months apart versus RZV 2 doses 6 months apart; RZV 2 doses 2 months apart versus RZV 2 doses 12 months apart; and RZV 2 doses 6 months apart versus RZV 2 doses 12 months apart) in incidence of the following adverse events: at least 1 unsolicited AE symptom, at least 1 unsolicited AE symptom related to vaccination.

There were no significant differences between groups for the following general symptoms: fatigue, grade 3 fatigue, fever, grade 3 fever, headache, grade 3 headache, myalgia, grade 3 myalgia, gastrointestinal symptom, grade 3 gastrointestinal symptom. The average duration of solicited general symptoms was ≤ 2 days.

There were no significant differences between groups for the following local symptoms: local pain, grade 3 local pain, local redness, grade 3 redness, local swelling, grade 3 local swelling. The average duration of local symptoms was ≤ 3 days. There were no significant differences between groups for the following: SAE, withdrawn due to an SAE, consent withdrawal, lost to follow‐up. There were no cases of suspected zoster or autoimmune disease throughout the study in any of the groups.

RZV IM route versus RZV SC route (Vink 2017)

There was a significant difference between groups favouring the IM route for the following adverse events: injection site redness (RR 1.73, 95% CI 1.18 to 2.55; RD 0.37, 95% CI 0.15 to 0.58; NNTH 2.7, 95% CI 1.7 to 6.7); injection site swelling (RR 2.00, 95% CI 1.25 to 3.21; RD 0.40, 95% CI 0.17 to 0.63; NNTH 2.5, 95% CI 1.6 to 5.9); grade 3 injection site swelling (RR 5.00, 95% CI 1.19 to 20.92; RD 0.27, 95% CI 0.08 to 0.46; NNTH 3.7, 95% CI 2.2 to 12.5); injection site pruritus (RR 2.10, 95% CI 1.20 to 3.67; RD 0.37, 95% CI 0.13 to 0.60; NNTH 2.7, 95% CI 1.7 to 7.7). There were no differences between groups for all other adverse events.

There were no deaths or autoimmune diseases.

RZV versus pneumo‐23 (Maréchal 2018)

Serious adverse events within 30 days after vaccination

• any serious adverse event: RR 0.78, 95% CI 0.29 to 2.07 and no RD;

• potential immune‐mediated disease: RR 0.33, 95% CI 0.01 to 8.18 and no RD;

There were no serious adverse events or pIMDs that were considered vaccine‐related.

Serious adverse events from 30 days after last vaccination up to the end of study

• any serious adverse event: RR 1.00, 95% CI 0.32 to 2.38 and no RD;

• potential immune‐mediated disease: RR 3.01, 95% CI 0.12 to 73.71 and no RD;

There were no serious adverse events or pIMDs that were considered vaccine‐related.

When comparing the group that received RZV + pneumo‐23 versus the group that received only pneumo‐23, the following systemic adverse events occurred within 7 days after vaccination:

• any general symptom: RR 1.74, 95% CI 1.51 to 2.01; RD 0.27, 95% CI 0.21 to 0.34; NNTH 3.7, 95% CI 2.9 to 4.8;

• any general symptom grade 3: RR 5.90, 95% CI 2.95 to 11.81; RD 0.10, 95% CI 0.07 to 0.14; NNTH 10.0, 95% CI 7.1 to 14.3;

• myalgia: RR 2.18, 95% CI 1.75 to 2.70; RD 0.24, 95% CI 0.18 to 0.30; NNTH 4.2, 95% CI 3.3 to 5.6;

• myalgia grade 3: RR 2.78, 95% CI 1.31 to 5.90; RD 0.04, 95% CI 0.01 to 0.06; NNTH 25.0, 95% CI 16.7 to 100.0;

• pain local: RR 1.93, 95% CI 1.70 to 2.19; RD 0.37, 95% CI 0.31 to 0.43; NNTH 2.7, 95% CI 2.3 to 3.2;

• fatigue grade 3: RR 7.52, 95% CI 2.67 to 21.16; RD 0.06, 95% CI 0.03 to 0.09; NNTH 16.7, 95% CI 11.1 to 33.3;

• headache: RR 2.23, 95% CI 1.74 to 2.85; RD 0.20, 95% CI 0.14 to 0.26; NNTH 5.0, 95% CI 3.8 to 7.1;

• headache grade 3: RR 4.26, 95% CI 1.45 to 12.56; RD 0.03, 95% CI 0.01 to 0.05; NNTH 33.3, 95% CI 20.0 to 100.0;

• fever: RR 5.32, 95% CI 2.99 to 9.48; RD 0.13, 95% CI 0.09 to 0.17; NNTH 7.7, 95% CI 5.9 to 11.1;

• fever grade 3: RR 2.00, 95% CI 0.37 to 10.89; RD 0.00, 95% CI −0.01 to 0.02;

• shivering: RR 3.17, 95% CI 2.15 to 4.68; RD 0.02, 95% CI 0.00 to 0.04; NNTH 50.0; and no RD;

• shivering grade 3: RR 3.26, 95% CI 1.07 to 9.91; RD 0.32, 95% CI 0.30 to 0.34; NNTH 3.1, 95% CI 2.9 to 3.3;

• gastrointestinal symptom: RR 2.54, 95% CI 1.70 to 3.79; RD 0.11, 95% CI 0.06 to 0.15; NNTH 9.0, 95% CI 6.7 to 16.7;

• gastrointestinal symptom grade 3: RR 3.01, 95% CI 0.61 to 14.82; RD 0.01, 95% CI −0.00 to 0.02; and no RD.

Injection site AE

• any local symptom: RR 1.05, 95% CI 1.00 to 1.11; and no RD;

• any local symptom grade 3: RR 1.49, 95% CI 1.10 to 2.03; RD 0.07, 95% CI 0.02 to 0.11; NNTH 14.3, 95% CI 9.1 to 50.0;

• redness local: RR 5.61, 95% CI 3.90 to 8.08; RD 0.32, 95% CI 0.27 to 0.37; NNTH 3.1, 95% CI 2.7 to 3.7;

• redness local grade 3: RR 6.52, 95% CI 1.48 to 28.70; RD 0.03, 95% CI 0.01 to 0.04; NNTH 33.3, 95% CI 25.0 to 100.0;

• pain local: RR 1.93, 95% CI 1.70 to 2.19; RD 0.37, 95% CI 0.31 to 0.43; NNTH 2.7, 95% CI 2.3 to 3.2;

• pain local grade 3: RR 10.77, 95% CI 3.90 to 29.76; RD 0.09, 95% CI 0.06 to 0.12; NNTH 11.1, 95% CI 8.3 to 16.7;

• swelling local: RR 4.15, 95% CI 2.65 to 6.48; RD 0.16, 95% CI 0.12 to 0.20; NNTH 6.25, 95% CI 5.0 to 8.3;

• swelling local grade 3: RR 2.00, 95% CI 0.18 to 22.03; and no RD.

RZV + TDaPV co‐administration group versus RZV + TDaPV not co‐administration group (Strezova 2019)

There were no significant differences between groups for the following: death, serious adverse events, systemic adverse events, injection site adverse events, unsolicited vaccine‐related adverse events. There were no pIMDs.

RZV + IIV4 co‐administration group versus not co‐administration group (Schwarz 2017)

There were no deaths.

There were no significant differences between groups except for the following AEs:

• fatigue: RR 1.21, 95% CI 1.05 to 1.39; RD 0.09, 95% CI 0.03 to 0.16; NNTH 11.1, 95% CI 6.3 to 33.3;

• pain local: RR 1.09, 95% CI 1.02 to 1.16; RD 0.07, 95% CI 0.01 to 0.12; NNTH 14.3, 95% CI 8.3 to 100.0.

PCV13 vaccine + RZV concomitant administration (Co‐Ad) versus PCV13 vaccine + RZV sequential administration (Se‐Ad) (Min 2022)

There were no significant differences between groups for the following: death, serious adverse events, systemic adverse events, injection site adverse events, unsolicited vaccine‐related adverse events and pIMDs.

Dropouts (all included studies)

LZV versus placebo

The pooled data from the studies that compared zoster vaccine and placebo showed no differences in reasons for dropout (Analysis 1.4): for any reason (RR 0.99, 95% CI 0.91 to 1.08) (Analysis 1.4.1) (Mills 2010; Oxman 2005; Vermeulen 2012); discontinued due to vaccine‐related adverse events (RR 5.05, 95% CI 0.25 to 103.88) (Analysis 1.4.2) (Mills 2010; Vermeulen 2012); for clinical AE (RR 1.34, 95% CI 0.72 to 2.52) (Analysis 1.4.3) (Murray 2011; Vermeulen 2012); for physician decision (RR 0.20, 95% CI 0.01 to 4.17) (Analysis 1.4.4) (Murray 2011); for withdrawal of consent (RR 0.95, 95% CI 0.54 to 1.68) (Analysis 1.4.5) (Murray 2011; NCT00886613; Oxman 2005; Vermeulen 2012); for loss to follow‐up (RR 1.27, 95% CI 0.96 to 1.69) (Analysis 1.4.6) (Hata 2016; Murray 2011; NCT00886613; Oxman 2005; Vermeulen 2012); and for protocol deviation (RR 1.49, 95% CI 0.27 to 8.37) (Analysis 1.4.7) (Murray 2011; Vermeulen 2012). In Mills 2010, Oxman 2005, and Vermeulen 2012, consent was withdrawn after the intervention. In Murray 2011, some participants apparently withdrew consent after randomisation, but the exact number that withdrew consent after the intervention is not stated.

The pooled data from the studies that compared zoster vaccine versus placebo showed no differences in reasons for participants with no follow‐up (RR 1.05, 95% CI 0.74 to 1.48) (Analysis 1.5) (Mills 2010; Murray 2011; Oxman 2005).

High‐potency versus low‐potency zoster vaccine: there were no differences between groups (Tyring 2007).

NBP608 LZV versus LZV: there were no differences between groups (Choi 2019).

Refrigerated versus frozen zoster vaccine: there were no differences between groups (Gilderman 2008).

LZV IM route versus LZV SC route: there were no withdrawals due to adverse events in either group (Diez‐Domingo 2015).

LZV intradermal route versus LZV SC route: there were no significant differences between full‐dose intradermal versus full‐dose SC; 1/3 dose intradermal versus full‐dose SC; 1/10 dose intradermal versus full‐dose SC; 1/27 dose intradermal versus full‐dose SC; 1/3 dose intradermal versus 1/3 dose SC. There were no dropouts for full‐dose intradermal versus 1/3 dose SC; 1/10 dose intradermal versus 1/3 dose SC; and 1/27 dose intradermal versus 1/3 dose SC (Beals 2016).

2 doses of a zoster vaccine versus a single dose and 2 doses given at different intervals: there were no differences between groups for participant withdrawals due to adverse events (Vesikari 2013).

LZV AMP versus LZV: there were no differences between groups (NCT01505647).

LZV + IIV4 concomitant administration versus LZV + IIV4 sequential administration: for this comparison there were no significant differences for dropouts between groups (Levin 2018)

In all the comparisons of Chlibek 2013, there were no differences in dropouts between the groups. Similarly, in all the comparisons of Chlibek 2014, there were no differences in dropouts between the groups.

RZV versus placebo:Cunningham 2016 and Lal 2015 described 4 reasons for dropout: did not receive vaccine according to protocol (Analysis 2.4.1); received wrong vaccine (Analysis 2.4.2); had diagnosis of HZ less than 30 days after dose 2 (Analysis 2.4.3); and did not receive second dose (Analysis 2.4.4). There were no differences between groups for the first 2 outcomes. The third outcome had an RR of 0.32 (95% CI 0.14 to 0.71) but no RD. For the fourth outcome, the vaccine group had a higher dropout rate than the placebo group: RR 1.25, 95% CI 1.13 to 1.39; RD 0.01, 95% CI 0.01 to 0.01; NNTH 100, 95% 100.0 to 100.0.

RZV IM route versus RZV SC route: there was no difference in participant withdrawal between groups (Vink 2017).

RZV + TDaPV co‐administration group versus RZV + TDaPV not co‐administration group: there was no difference in dropouts between groups (Strezova 2019).

Co‐administration RZV + IIV4 versus not co‐administration group RZV + IIV4: there was no difference between groups for dropouts (Schwarz 2017).

PCV13 vaccine + RZV concomitant administration versus PCV 13 vaccine + RZV sequential administration: there was no difference between groups for dropouts (Min 2022).