NCT trial number

Route

Dates

Intervention and schedule details

Country

Participants (age)

HIV

Adverse events

Reference

NCT00423566

ID

2002–2003

MVA85A; 1 dose

UK

14 adults (18–45 years)

–ve

7 trials (112 participants); combined in 1 report: no serious AE attributable to the vaccine

McShane 2004; Rowland 2012

NCT00423839

ID

2003–2005

MVA85A; 1 dose, 2 doses

(5 × 10⁷ pfu)

Gambia

21 adults

NR

No serious AE attributable to the vaccine

Brookes 2008; Ibanga 2006; Owiafe 2012

NCT00427830

ID

2003–2005

MVA85A; 1 dose (5 × 10⁷ pfu)

UK

21 adults

–ve

No serious AE attributable to the vaccine

McShane 2004; Pathan 2012; Rowland 2012; Tanner 2014; Whelan 2009

NCT00427453

ID

2003–2005

MVA85A; 1 dose (5 × 10⁷ pfu)

UK

10 adults

–ve

No serious AE attributable to the vaccine

Pathan 2012; Rowland 2012

NCT00456183

ID

2005–2007

MVA85A, (5 × 10⁷ pfu)

UK

12 adults with latent tuberculosis

–ve

No vaccine‐related serious AEs

7 trials (112 participants; data combined in 1 report)

Rowland 2012; Sander 2009; Tanner 2014

NCT00465465

ID

2005–2007

MVA85A; 1 dose (1 × 10⁸ pfu for 12 participants, and 1 × 10⁷ pfu for 12 participants)

UK

24 adults

–ve

No serious AE attributable to the vaccine

Griffiths 2011; Matsumiya 2013; Pathan 2007; Rowland 2012

NCT00460590

ID

2005–2008

MVA85A (5 × 10⁷ pfu)

South Africa

36 adults and adolescents

–ve

No vaccine‐related serious AEs

Hawkridge 2008; Scriba 2010; Tameris 2014; Tanner 2014

NCT00480454

ID

2006–2009

MVA85A;

1 dose MVA85A (2.5 × 10⁷ pfu, 5 × 10⁷ pfu)

Groups

• EPI vaccines:

• MVA85A + EPI:

• MVA85A + EPI 1 week later

The Gambia

214 infants (4 months)

NR

No serious AE judged to be related to the vaccine

Odutola 2012; Ota 2011

NCT00395720

ID

2006–2010

MVA85A; 1 dose (5 × 10⁷pfu for 10 participants, and 1 × 10⁸ pfu for 10 participants)

UK

20 adults

+ve

No serious AE attributable to the vaccine

Minassian 2011

NCT00480558

ID

2007–2011

MVA85A; 1 dose (5 × 10⁷ pfu)

4 groups with background of

• MTB

• HIV

• MTB + HIV

• HIV on ART

South Africa

48 adults (18–50 years)

+ve

No vaccine‐related serious AEs

Scriba 2012; Tanner 2014; Tameris 2014

NCT00653770

ID

2007–2010

FP85A, MVA85A (5 × 10⁷ pfu)

UK

31 adults

–ve

No serious AE attributable to the vaccine

Rowland 2013

NCT00548444

ID

2007–2010

MVA85A; 1 dose

(1 × 10⁸ pfu), administered as 2 injections (5 × 10⁷ pfu each injection)

UK

12 adults

–ve

7 trials (112 participants); data combined in 1 report: no serious AE attributable to the vaccine

Porter (unpublished data: source Rowland 2012)

NCT00731471

ID

2008–2011

MVA85A; 2 doses (spaced by 6–12 months) (1 × 10⁸ pfu)

Senegal

24 adults

+ve

No serious AE attributable to the vaccine

Dieye 2013

NCT01181856

ID

IM

2010–2011

MVA85A; 1 dose (1 × 10⁸ pfu)

UK

24 adults

–ve

No serious AE attributable to the vaccine

Matsumiya 2013; Meyer 2013

NCT01194180

ID

2010–2012

MVA85A, BCG;

1 dose (1 × 10⁸ pfu)

Group A: BCG naive, no MVA85A
Group B: BCG naive, MVA85A

Group C: BCG vaccinated, no MVA85A

Group D: BCG vaccinated, MVA85A.

UK

49 adults recruited; 48 completed study

–ve

No serious AE attributable to the vaccine

; Harris 2014b;

Matsumiya 2013

NCT01497769

Aerosol

ID

2011–2013

MVA85A; 1 dose: 1 × 10⁸, 1 × 10⁷ pfu

UK

24 adults

–ve

No vaccine related serious adverse effects.

Satti 2014

NCT01683773

ID

2012–2014

AERAS‐402 MVA85A;

Group A: 2 doses AERAS‐402 then MVA85A

Group B: 1 dose AERAS‐402 then MVA85A

UK

40 adults

–ve

No vaccine related serious AEs

Sheehan 2015

NCT01879163

ID

2013–2014

MVA85A IMX313;

Group A: low‐dose MVA85A‐IMX313 (1 × 10⁷ pfu)

Group B: dose MVA85A‐IMX313 (5 × 10⁷ pfu)

Group C: MVA85A (5 × 10⁷ pfu)

UK

30 BCG vaccinated adults

–ve

No vaccine‐related serious AE

Minhinnick 2016

NCT01829490

IM

2013–2016

MVA85A, ChAdOx1 85A;

Group A: 1 dose ChAdOx1 85A

Group B: 1 dose ChAdOx1 85A then MVA85A

Group C: 2 doses ChAdOx1 85A then MVA85A (1 × 10⁸ pfu)

UK

42 adults

–ve

No data reported yet

No publication

NCT01829490

NCT01954563

Aerosol

ID

2013–2016

MVA85A;

Group 1: aerosol then ID

Group 2: ID then aerosol

Group 3: ID then ID (5 × 10⁷ pfu)

UK

37 adults

–ve

No data reported yet

Manjaly 2016

(conference abstract)

NCT02532036

Aerosol

ID

2015–2018

MVA85A; 1 × 10⁷ pfu aerosol inhaled,

5 × 10⁷ aerosol and ID

UK

15 adults

–ve

No data reported yet

NCT02532036

Criterion

Assessment

Explanation

Participant‐reported symptoms

Was monitoring active or passive?

Active

Passive

Unclear

We classified monitoring as 'active' when authors reviewed participants at set time points and enquired about symptoms.

Was blinding for participants and outcome assessors adequate?

Adequate

Inadequate

Unclear

We classified blinding as 'adequate' when both participants and outcome assessors were blinded to the intervention group, and the methods of blinding (including use of a placebo) were described.

Was outcome data reporting complete or incomplete?

Complete

Incomplete

We classified outcome data reporting as 'complete' when data were presented for all the time points where it was collected.

Were all participants included in reporting?

Yes

No

We reported the percentage of randomized participants included in adverse event reporting.

Was the analysis independent of study sponsor?

Yes

No

Unclear

We classified the analysis of trials sponsored by pharmaceutical companies as independent of the sponsor when it was clearly stated that the sponsor had no input to the trial analysis

Laboratory tests

Number of tests undertaken

—

We extracted the type and number of laboratory tests were taken.

Timing of tests: was number and timing of tests adequate?

Adequate

Inadequate

We classified the number and timing of tests as 'adequate,' when tests were taken at baseline, plus 2 other time points within the first week after treatment, plus the last day of the study. We classified the number of test taken as 'inadequate,' if either the laboratory controls in the first week or controls at 4 weeks were not performed.

Reporting of test results: was reporting of test results complete?

Complete

Incomplete

We classified reporting as 'complete' when test results of all time points were reported. For the trials with inadequate number of tests taken, we considered completeness of reporting as inconsequential, and therefore did not record a judgement.

Independence of data analysis: was data analysis independent?

Yes

No

Unclear

We classified the analysis of trials sponsored by pharmaceutical companies as independent of the sponsor when it is clearly stated that the sponsor had no input to the trial analysis.

Study

Endpoint 1

Endpoint 2

Endpoint 3

Tameris 2013

Any of the following criteria.

• Isolation of M tuberculosis from any site.

• Identification of M tuberculosis by an approved molecular diagnostic technique from any site.

• Histopathology diagnostic for TB disease (e.g. caseating granulomas).

• Choroidal tubercle diagnosed by an ophthalmologist.

• Miliary pattern on chest x‐ray in an HIV‐negative infant.

• Clinical diagnosis of TB meningitis (CSF protein concentrations > 0.6 g/L and pleocytosis of > 50 cells/μL with > 50% mononuclear cells) with features of basal meningeal enhancement and hydrocephalus on head CT.

• Vertebral spondylosis.

• 1 smear or histology specimen positive for auramine‐positive bacilli from a normally sterile body site.

• 1 of each of the following:

  • evidence of mycobacterial infection defined as 2 acid‐fast positive smears (each from a separate collection) that were morphologically consistent with mycobacteria from either sputum or gastric aspirate that were not found to be non‐tuberculous mycobacteria bacteria on culture; QuantiFERON‐TB Gold In‐tube test conversion from negative to positive; or tuberculin skin test ≥15 mm and

  • radiographic findings compatible with TB defined as ≥ 1 of the following factors identified independently by ≥ 2 of 3 paediatric radiologists serving on a masked review panel: calcified Ghon focus, pulmonary cavity, hilar or mediastinal adenopathy, pleural effusion, or airspace opacification and

  • clinical manifestations compatible with TB defined as cough without improvement for > 2 weeks; weight loss > 10% of bodyweight for > 2 months; or failure to thrive, defined as crossing > 1 complete major centile band (< 97th–90th, < 90th–75th, < 75th–50th, < 50th–25th, < 25th–10th, and < 10th–3rd weight‐for‐age centiles) downward for > 2 months.

"Included all infants who met endpoint 1 criteria; had marginally less stringent criteria to define TB infection and household exposure."

Any of the following numerical categories.

• Isolation of M tuberculosis from any site.

• Identification of M tuberculosis by an approved molecular diagnostic technique from any site.

• Histopathology diagnostic for TB disease (such as caseating granulomas).

• Choroidal tubercle diagnosed by an ophthalmologist.

• Miliary pattern on chest x‐ray in a HIV‐negative infant.

• Clinical diagnosis of TB meningitis (CSF protein > 0.6 g/L and pleocytosis > 50/mm³ with mononuclear cell > 50%) or^a features of basal meningeal enhancement and hydrocephalus on head CT.

• Vertebral spondylosis

• A single smear/histology specimen positive for auramine‐positive bacilli from a normally sterile body site.

• 1 of each of the following:

  • evidence of mycobacterial infection defined as:

    • 2 acid fast‐positive smears each from a separate collection morphologically consistent with mycobacteria from either sputum or gastric aspirate that are not found to be non‐tuberculous mycobacteria bacteria on culture, or

    • QFT conversion from negative to positive, or

    • Tuberculin skin test ≥ 10 mm,^a or

    • household contact with AFB smear positive person^a and

  • radiographic findings compatible with TB defined as ≥ 1 of the following identified independently by at least 2 out of 3 paediatric radiologists serving on a blinded review panel: calcified Ghon focus, pulmonary cavity, hilar/mediastinal adenopathy, pleural effusion, or airspace opacification and

  • clinical manifestations compatible with TB defined as either

    • cough without improvement for > 2 weeks, or

    • weight loss ≥ 10% of bodyweight for ≥ 2 months, or

    • failure to thrive (crossing ≥ 1 entire major centile band downward) for ≥ 2 months, where the major centile bands are defined as < 97th–90th, < 90th–75th, < 75th–50th, < 50th–25th, < 25th–10th, and < 10th–3rd weight‐for‐age centiles.

All participants placed on treatment for TB by a health professional with the intent of treating TB regardless of whether they have met the other efficacy endpoints.

Andrews 2017

Revised endpoint 1 from Tameris 2013 that removed QFT conversion from the diagnostic criteria to avoid bias towards association with QFT status.

Not used

Not used

Bunyasi 2017

Not used

Not used

Same definition as for Tameris 2013.

Ndiaye 2015

Any of the following numerical categories.

• Isolation of M tuberculosis from any site.

• Identification of M tuberculosis by an approved molecular diagnostic technique from any site.

• Histopathology diagnostic for TB disease (such as caseating granulomas).

• Choroidal tubercle diagnosed by ophthalmologist.

Any of the following numerical categories:

• Isolation of M tuberculosis from any site.

• Identification of M tuberculosis by an approved molecular diagnostic technique from any site.

• Histopathology diagnostic for TB disease (such as caseating granulomas).

• Choroidal tubercle diagnosed by ophthalmologist.

• A single smear/histology specimen positive for AFB from a normally sterile body site.

• 2 acid‐fast smears positive each from a separate collection morphologically consistent with mycobacteria from either pulmonary or gastric sampling that are not found to be non‐tuberculous mycobacteria bacteria on culture, and ≥ 1 of the following:

  • a compatible radiographic feature: airspace opacification, cavity, hilar or mediastinal adenopathy, or pleural effusion;

  • a compatible clinical feature, i.e. > 2 weeks of fever, night sweats, anorexia, cough, or weight loss (≥ 5 kg by history or noticeable change in clothing fit); or ≥ 1 episodes of haemoptysis.

Same definition as for Tameris 2013.

Scriba 2011

Not applicable

Not applicable

Not applicable

Nemes 2018

Outcomes not specified in the methods section.

In results, authors specified that 8 participants were diagnosed as TB:

"of whom one was M.tb [Mycobacterium tuberculosis] culture positive and 7 were diagnosed on clinical/ radiographic grounds and TB contact history. Two of the TB cases were QFT positive."

Not used

Not used

Study

Protocol

Published findings

Differences between protocol and published findings

Stated outcomes published prior to commencement of trial that differ to published outcomes

Measurement of outcome as stated a priori

Measurement of outcome as stated in published findings

Reported findings

Andrews 2017

No protocol published.

Bunyasi 2017

No protocol published (extended post‐trial follow‐up of Tameris 2013).

Ndiaye 2015

Adverse events: blood tests ^a

"Percentage of participants with adverse events" AEs measured up to day 28

SAEs measured up to 6 months.

"Phlebotomy for routine haematological and biochemical analysis was done at screening, before booster vaccination, and on days 7 and 28 after each vaccination."

"Routine haematological and biochemical test results did not differ between study groups (data not shown)."

Haematological and biochemical blood tests not outlined as a measure of safety in the study protocol. Blood test findings reported unclearly.

Nemes 2018

Safety

Clinicaltrials.gov – local, regional, and systemic AEs and SAEs which would be reported as cumulative 12‐month incidences.

"Infants followed for safety end points at weeks 1, 4, 6, and 8 after MVA85A/control vaccination and thereafter, at weeks 9, 12, and 16 (corresponding to weeks 1, 4, and 8 following delayed BCG vaccination at 8 weeks of age), and at week 52."

Reported total events for AEs per group after MVA85A and before BCG and for whole follow‐up period. Data including for laboratory AEs were not disaggregated as prespecified.

Data including for laboratory AEs were not disaggregated as prespecified.

Scriba 2011

Safety^a

Local and systemic AEs for the first week.

Diary cards

Local and systemic AEs reported on ≥ 1 day of the first 7 days after MVA85A vaccination.

None

Blood tests (days 7, 28)

Biochemical and haematological tests (days 7, 28)

Reported number and percentages of participants with abnormal results and reported that, "all except one patient that had elevated liver enzymes remained unresolved by day 28."

Immunology

ESAT‐6/CFP‐10

Infants converted – suggestive of TB infection but seemed to be reported as safety data not efficacy.

Tameris 2013

Safety profile – AEs^a

AEs measured up to day 28

SAEs measured throughout follow‐up.

Collected data on solicited and unsolicited local and systemic AEs.

Active surveillance for SAEs.

AEs broken down by type of event and reported in supplementary material. Only local events at the injection site were considered to be related to the vaccine.

Causal relationship with AEs other than local injection site reactions was not reported.

Safety profile – blood tests^a

Testing up to 28 days postvaccination.

"Peripheral blood for routine haematological and biochemical tests was taken at screening and on day 7 and day 28 after vaccination in an initial safety cohort of at least 330 infants."

Not reported

Primary outcome not reported

Efficacy of MVA85A^b

Using an endpoint derived from epidemiological cohort surveys in BCG vaccinated infants.

Not reported – simply stated clinical endpoints 'developed.'

Composite clinical endpoints 1, 2, 3 (see Table 3)

Microbiologically confirmed cases reported in appendix.

The "primary efficacy endpoint" was measured using an endpoint not derived from cohort studies.

The endpoint definition differed from all other implied or reported ways of measuring efficacy in the other studies. The point estimate showed clinically significant benefit for endpoint 1 (no benefit seen at the 95% confidence level). This endpoint was reported as the main efficacy finding. All other point estimates show no clinically significant benefit or harm.

Study

Participant reported adverse events

Outcome data reporting

Laboratory tests

Monitoring active or passive

Blinding of participants or outcome assessors

Times data collected

Times data reported

Complete/not complete

Percentage of participants reported on

Analysis independent of study sponsor

Number of tests taken

Timing of tests and adequacy

Complete reporting of test results

Independence of data analysis

Scriba 2011

Active

Inadequate

60 min, D 2, 7, 28, 84, and 168

D 7, 28

Incomplete

100%

Unclear

Biochemistry and haematology

Inadequate

Inconsequential

Unclear

Ndiaye 2015

Active

Inadequate

D 7, 28, and 84 after boost 3 monthly until end of study

NR

Incomplete

99.8%

No

Haematology, chemistry, virological markers

Adequate

Incomplete

No

Tameris 2013

Active

Adequate

Baseline, D 7 and 28, throughout up to D 84

NR

Incomplete

99.9%

No

Biochemistry and haematology

Inadequate

Incomplete

No

Nemes 2018

Active

Adequate

Week 1, 4, 6, 8, 16, and 52

NR

Incomplete

85.9%

Unclear

Not specified

Adequate

Incomplete

Unclear

Active TB

Tameris 2013

Andrews 2017

Bunyasi 2017

Ndiaye 2015

Scriba 2011

Nemes 2018

MVA85A

Placebo

MVA85A

Placebo

MVA85A

Placebo

MVA85A

Placebo

MVA85A

Placebo

MVA85A

Placebo

Endpoint 1^a

32/1399 (2.3%)

39/1395 (2.8%)

58/2797 (2.1%) with NDD

N/A

N/A

6/320 (1.9%)

9/325 (2.8%)

N/A

N/A

5/123 (4.1%)

3/125 (2.4%)

Endpoint 2^a

55/1399 (3.9%)

52/1395 (3.7%)

N/A

N/A

N/A

N/A

6/320 (1.9%)

9/325 (2.8%)

N/A

N/A

N/A

N/A

Endpoint 3^a

196/1399 (14.0%)

177/1395

(12.6%)

N/A

N/A

3.3/100 pyo

(95% CI 2.9 to 3.9)

3.0/100 pyo (95% CI 2.6 to 3.5)

8/320 (2.5%)

9/325 (2.8%)

N/A

N/A

N/A

N/A

Study

MVA85A

Placebo

Breakdown

Author conclusions

Number of participants with ≥ 1 event caused by the intervention

Total participants

Number of participants with ≥ 1 event caused by the control

Total participants

Detailed AEs

MVA85A

Placebo

Ndiaye 2015

318

324

307

325

Solicited AEs^a

288

235

"Solicited adverse events were more common in MVA85A group and most were local injection site reactions."

Nemes 2018

105^b

123

30^b

125

Not detailed

N/A

N/A

"Infants in MVA85A arm were more likely to experience an AE than in control arm. Injection site reactions were more frequent in MVA85A recipients and mild."

Scriba 2011

106^c

108^c

6

36

Injection site^d

106

6

"Desquamation significantly increased with greater vaccine dose."

Malaise

6

1

Lethargy

6

2

Tactile fever

18

0

Documented fever

13

2

Vomiting

6

2

Elevated liver enzyme levels

13

4

Increased white cell count

0

1

Tameris 2013

Local 1251^e

1399

Local 628^e

1396

Not detailed

1251

628

None

Study

Adverse events of any severity

MVA85A

Placebo

Tameris 2013

1120/1399 (80.1%)

1059/1396 (75.9%)

Andrews 2017

NR

NR

Bunyasi 2017

NR

NR

Ndiaye 2015

321/324

(99.1%)

312/325

(96%)

Scriba 2011

2.5 × 10⁷

pfu = 35 μL

5 × 10⁷

pfu = 70 μL

1 × 10⁸

pfu = 135 μL

1/36

1/36

3/36

6/36

Nemes 2018

Mild 122/123

(99.2%)

121/125

(96.8)

Moderate 62/123

(50.4%)

54/125

(3.6%)

Severe 11/123

(8.9%)

14/125

(11.2%)

Study

Haematological blood tests

Biochemical blood tests

MVA85A

Placebo

MVA85A

Placebo

Tameris 2013

NR

NR

NR

NR

Andrews 2017

NR

NR

NR

NR

Bunyasi 2017

NR

NR

NR

NR

Ndiaye 2015

NR^a

NR^a

NR^a

NR^a

Scriba 2011

0/108^b

1/36^b

2.5 × 10⁷

pfu = 35 μL

5 × 10⁷

pfu = 70 μL

1 × 10⁸

pfu = 135 μL

4/36

(11%)

1/36

(2.8%)

3/36

(8.3%)

9/36

(25%)

Nemes 2018

NR

NR

14/123 (11.4%)

13/125

(10.4%)