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MVA85A vaccine to enhance BCG for preventing tuberculosis

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References

Additional references

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Harris 2014a

Harris SA, Meyer J, Satti I, Marsay L, Poulton ID, Tanner R, et al. Evaluation of a human BCG challenge model to assess antimycobacterial immunity induced by BCG and a candidate tuberculosis vaccine, MVA85A, alone and in combination. Journal of Infectious Diseases 2014;209(8):1259‐68.

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Harris SA, Satti I, Matsumiya M, Stockdale L, Chomka A, Tanner R, et al. Process of assay selection and optimization for the study of case and control samples from a phase IIb efficacy trial of a candidate tuberculosis vaccine, MVA85A. Clinical and Vaccine Immunology 2014;21(7):1005‐11.

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Matsumiya M, Stylianou E, Griffiths K, Lang Z, Meyer J, Harris SA, et al. Roles for Treg expansion and HMGB1 signaling through the TLR1‐2‐6 axis in determining the magnitude of the antigen‐specific immune response to MVA85A. PLoS One 2013;8(7):e67922.

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Meyer J, Harris SA, Satti I, Poulton ID, Poyntz HC, Tanner R, et al. Comparing the safety and immunogenicity of a candidate TB vaccine MVA85A administered by intramuscular and intradermal delivery. Vaccine 2013;31(7):1026‐33.

Minassian 2011

Minassian AM, Rowland R, Beveridge NE, Poulton ID, Satti I, Harris S, et al. A Phase I study evaluating the safety and immunogenicity of MVA85A, a candidate TB vaccine, in HIV‐infected adults. BMJ Open 2011;1(2):e000223.

Minhinnick 2016

Minhinnick A, Satti I, Harris S, Wilkie M, Sheehan S, Stockdale L, et al. A first‐in‐human phase 1 trial to evaluate the safety and immunogenicity of the candidate tuberculosis vaccine MVA85A‐IMX313, administered to BCG‐vaccinated adults. Vaccine 2016;34(11):1412‐21.

NCT00395720

NCT00395720. The safety and immunogenicity of a TB vaccine; MVA85A, in healthy volunteers who are infected with HIV [A Phase I study evaluating the safety and immunogenicity of a new TB vaccine, MVA85A, in healthy volunteers who are infected with HIV]. clinicaltrials.gov/ct2/show/NCT00395720 (first received 25 August 2017).

NCT00423566

NCT00423566. A Phase I study of the safety and immunogenicity of a recombinant MVA vaccine encoding a secreted antigen from M. tuberculosis, antigen 85A, delivered intradermally by a needle injection in healthy volunteers. clinicaltrials.gov/ct2/show/NCT00423566 (first received 25 August 2017).

NCT00423839

NCT00423839. A Phase I study of the safety and immunogenicity of MVA85A in healthy Gambian volunteers. clinicaltrials.gov/ct2/show/NCT00423839 (first received 25 August 2017).

NCT00427453

NCT00427453. A Phase I study of the safety and immunogenicity of a recombinant MVA vaccine encoding a secreted antigen from M. tuberculosis, antigen 85A, delivered intradermally by a needle injection in healthy volunteers who have received BCG immunisation 1 month previously. clinicaltrials.gov/ct2/show/NCT00427453 (first received 25 August 2017).

NCT00427830

NCT00427830. A Phase I study of the safety and immunogenicity of a recombinant MVA vaccine encoding a secreted antigen from M. tuberculosis, antigen 85A, delivered intradermally by a needle injection in healthy volunteers who have previously received BCG. clinicaltrials.gov/ct2/show/NCT00427830 (first received 25 August 2017).

NCT00456183

NCT00456183. Safety and immunogenicity of MVA85A in volunteers latently infected with TB. clinicaltrials.gov/ct2/show/NCT00456183 (first received 25 August 2017).

NCT00460590

NCT00460590. Safety and immunogenicity of MVA85A, in healthy volunteers in Cape Town. clinicaltrials.gov/ct2/show/NCT00460590 (first received 25 August 2017).

NCT00465465

NCT00465465. A study of 2 doses of a new TB vaccine, MVA85A, in healthy volunteers previously vaccinated with BCG. clinicaltrials.gov/ct2/show/NCT00465465 (first received 25 August 2017).

NCT00480454

NCT00480454. Safety, immunogenicity, and impact of MVA85A, on the immunogenicity of the EPI vaccines. clinicaltrials.gov/ct2/show/NCT00480454 (first received 25 August 2017).

NCT00480558

NCT00480558. A study of MVA85A, in asymptomatic volunteers infected with TB, HIV or both. clinicaltrials.gov/ct2/show/NCT00480558 (first received 25 August 2017).

NCT00548444

NCT00548444. T−Cell turnover following vaccination with MVA85A. clinicaltrials.gov/ct2/show/NCT00548444 (first received 25 August 2017).

NCT00653770

NCT00653770. A Phase I study to assess the safety and immunogenicity of tuberculosis (TB) vaccine candidates FP85A and MVA85A. clinicaltrials.gov/ct2/show/NCT00653770 (first received 25 August 2017).

NCT00731471

NCT00731471. A Phase I study of a new tuberculosis (TB) vaccine, MVA85A, in healthy volunteers with HIV. clinicaltrials.gov/ct2/show/NCT00731471 (first received 25 August 2017).

NCT01181856

NCT01181856. Safety of tuberculosis vaccine, MVA85A, administered by the intramuscular route and the intradermal route. clinicaltrials.gov/ct2/show/NCT01181856 (first received 25 August 2017).

NCT01194180

NCT01194180. A BCG challenge model study to assess anti‐mycobacterial immunity induced by BCG and a candidate TB vaccine, MVA85A. clinicaltrials.gov/ct2/show/NCT01194180 (first received 25 August 2017).

NCT01497769

NCT01497769. Safety of tuberculosis vaccine, MVA85A, administered by the aerosol route and the intradermal route. clinicaltrials.gov/ct2/show/NCT01497769 (first received 25 August 2017).

NCT01683773

NCT01683773. Safety study of tuberculosis vaccines AERAS‐402 and MVA85A. clinicaltrials.gov/ct2/show/NCT01683773 (first received 25 August 2017).

NCT01829490

NCT01829490. Safety study of ChAdOx185A vaccination with and without MVA85A boost in healthy adults [Phase 1 trial to evaluate the safety and immunogenicity of a ChAdOx185A with or without MVA85A boost in healthy BCG vaccinated adults]. clinicaltrials.gov/show/NCT01829490 (first received 11 April 2013).

NCT01879163

NCT01879163. Phase I trial evaluating safety and immunogenicity of MVA85A‐IMX313 compared to MVA85A in BCG vaccinated adults. clinicaltrials.gov/ct2/show/NCT01879163 (first received 25 August 2017).

NCT01954563

NCT01954563. Study evaluating aerosol and intradermal administration of a candidate tuberculosis (TB) vaccine, MVA85A, as a way to increase immune response and avoid anti‐vector immunity. clinicaltrials.gov/ct2/show/NCT01954563 (first received 25 August 2017).

NCT02532036

NCT02532036. MVA85A aerosol versus intramuscular vaccination in adults with latent Mycobacterium tuberculosis (M. tb) Infection [A phase I trial to compare the safety and immunogenicity of candidate tuberculosis vaccine MVA85A administered by the aerosol inhaled route and the intramuscular route in healthy adult volunteers who are latently infected with Mycobacterium tuberculosis]. clinicaltrials.gov/show/NCT02532036 (first received 25 August 2015).

Nemes 2017

Nemes E, Hesseling A, Tameris M, Mauff K, Downing K, Mulenga H, et al. Safety and Immunogenicity of Newborn MVA85A Vaccination and Selective, Delayed Bacille Calmette‐Guerin (BCG) for Infants of HIV Infected Mothers: A Phase 2 Randomized Controlled Trial. Clinical Infectious Diseases 2017 Sept 26 [Epub ahead of print]. [DOI: 10.1093/cid/cix834]

Odutola 2012

Odutola AA, Owolabi OA, Owiafe PK, McShane H, Ota MOC. A new TB vaccine, MVA85A, induces durable antigen‐specific responses 14 months after vaccination in African infants. Vaccine 2012;30(38):5591‐4.

Ota 2011

Ota MO, Odutola AA, Owiafe PK, Donkor S, Owolabi OA, Brittain NJ, et al. Immunogenicity of the tuberculosis vaccine MVA85A is reduced by coadministration with EPIvaccines in a randomized controlled trial in Gambian infants. Science Translational Medicine 2011;3(88):88ra56.

Owiafe 2012

Owiafe P, Hill P, Ibanga HB, Brookes RH, McShane H, Sutherland JS, et al. Differential cytokine levels in adults induced by a novel candidate TB boost vaccine, MVA85A‐according to previous BCG vaccination status. Journal of Vaccines & Vaccination 2012;3(7):158.

Pathan 2007

Pathan AA, Sander CR, Fletcher HA, Poulton I, Alder NC, Beveridge NE, et al. Boosting BCG with recombinant modified vaccinia ankara expressing antigen 85A: different boosting intervals and implications for efficacy trials. PLoS One 2007;2(10):e1052.

Pathan 2012

Pathan AA, Minassian AM, Sander CR, Rowland R, Porter DW, Poulton ID, et al. Effect of vaccine dose on the safety and immunogenicity of a candidate TB vaccine, MVA85A, in BCG vaccinated UK adults. Vaccine 2012;30(38):5616‐24.

Perez‐Velez 2012

Perez‐Velez CM, Marais BJ. Tuberculosis in children. New England Journal of Medicine 2012;367(4):348‐61.

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Rowland 2012

Rowland R, Brittain N, Poulton ID, Minassian AM, Sander C, Porter DW, et al. A review of the tolerability of the candidate TB vaccine, MVA85A compared with BCG and Yellow Fever vaccines, and correlation between MVA85A vaccine reactogenicity and cellular immunogenicity. Trials in Vaccinology 2012;1:27‐35.

Rowland 2013

Rowland R, Pathan AA, Satti I, Poulton ID, Matsumiya MM, Whittaker M, et al. Safety and immunogenicity of an FP9‐vectored candidate tuberculosis vaccine (FP85A), alone and with candidate vaccine MVA85A in BCG‐vaccinated healthy adults: a phase I clinical trial. Human Vaccine Immunotherapy 2013;9(1):50–62.

Roy 2014

Roy A, Eisenhut M, Harris RJ, Rodrigues LC, Sridhar S, Habermann S, et al. Effect of BCG vaccination against Mycobacterium tuberculosis infection in children: systematic review and meta‐analysis. BMJ 2014;349:g4643. [DOI: 10.1136/bmj.g4643]

Sander 2009

Sander CR, Pathan AA, Beveridge NER, Poulton I, Minassian A, Alder N, et al. Safety and Immunogenicity of a New Tuberculosis Vaccine, MVA85A, in Mycobacterium tuberculosis‐infected Individuals. American Journal of Respiratory and Critical Care Medicine 2009;179(8):724‐33.

Satti 2014

Satti I, Meyer J, Harris SA, Manjaly Thomas ZR, Griffiths K, Antrobus RD, et al. Safety and immunogenicity of a candidate tuberculosis vaccine MVA85A delivered by aerosol in BCG‐vaccinated healthy adults: a phase 1, double‐blind, randomised controlled trial. Lancet. Infectious Diseases 2014;14(10):939‐46.

Scriba 2010

Scriba TJ, Tameris M, Mansoor N, Smit E, van der Merwe L, Isaacs F, et al. MVA85A, a novel TB vaccine, is safe in adolescents and children, and induces complex subsets of polyfunctional CD4+ T cells. European Journal of Immunology 2010;40(1):279–90.

Scriba 2012

Scriba TJ, Tameris M, Smit E, van der Merwe L, Hughes EJ, Kadira B, et al. A Phase IIa trial of the new tuberculosis vaccine, MVA85A, in HIV‐ and/or Mycobacterium tuberculosis–infected Adults. American Journal of Respiratory and Critical Care 2012;185(7):769–78.

Sharma 2012

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Sheehan 2015

Sheehan S, Harris SA, Satti I, Hokey DA, Dheenadhayalan V, Stockdale L, et al. A phase I, open‐label trial, evaluating the safety and immunogenicity of candidate tuberculosis vaccines AERAS‐402 and MVA85A, administered by prime‐boost regime in BCG‐vaccinated healthy adults. PLoS One 2015;10(11):e0141687.

Tameris 2013

Tameris MD, Hatherill M, Landry BS, Scriba TJ, Snowden MA, Lockhart S, et al. Safety and efficacy of MVA85A, a new tuberculosis vaccine, in infants previously vaccinated with BCG: a randomised, placebo‐controlled phase 2b trial. Lancet 2013;381(9871):1021‐8.

Tameris 2014

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Tanner 2014

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Wajja A, Kizito D, Nassanga B, Nalwoga A, Kabagenyi J, Kimuda S, et al. The effect of current Schistosoma mansoni infection on the immunogenicity of a candidate TB vaccine, MVA85A, in BCG‐vaccinated adolescents: An open‐label trial. PLoS Neglected Tropical Diseases 2017;11(5):e0005440.

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Table 1. Novel vaccines undergoing trials for tuberculosis prevention

Category

Vaccine

Clinical trial stage

Protein/adjuvant

M72/AS01

Phase IIb

H4/IC31

Phase IIa

H56/IC31

Phase IIa

ID93/GLA‐SE

Phase IIa

Viral vector

MVA85A (Aerosol)

Phase I

ChAdOx185A

Phase I

Ad5Ag85A

Phase I

TB FLu ‐04L

Phase II

Live Mycobacteria

MTBVAC

Phase I

VPM1002

Phase IIb

Mycobacteria whole cell/extract

Dar‐901 booster

Phase IIb

RUTI

Phase IIa

Vaccae

Phase III

Table adapted from WHO 2017.

Figures and Tables -
Table 1. Novel vaccines undergoing trials for tuberculosis prevention
Navigate to table in Protocol
Table 2. Summary of Phase 1 studies

NCT trial number

Route

Dates

Intervention and schedule details

Country

Participants (age)

HIV

Adverse events

Reference

NCT00423566

ID

2002‐3

MVA85A; 1 dose

UK

14 adults (18 to 45 years)

‐ve

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

McShane 2004, Rowland 2012

NCT00423839

ID

2003‐5

MVA85A; 1 dose, 2 doses

(5 x 107 PFU)

Gambia

21 adults

N/R

No serious AE attributable to the vaccine

Brookes 2008; Ibanga 2006; Owiafe 2012

NCT00427830

ID

2003‐5

MVA85A; 1 dose (5 x 107 PFU)

UK

21 adults

‐ve

No serious AE attributable to the vaccine

McShane 2004; Pathan 2007; Rowland 2012; Tanner 2014; Whelan 2009

NCT00427453

ID

2003‐5

MVA85A; 1 dose (5 x 107 PFU)

UK

10 adults

‐ve

No serious AE attributable to the vaccine

Pathan 2007;

Rowland 2012

NCT00456183

ID

2005‐7

MVA85A, (5 x 107 PFU)

UK

12 adults with latent tuberculosis

‐ve

No vaccine related serious adverse events

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

Rowland 2012; Sander 2009; Tanner 2014

NCT00465465

ID

2005‐7

MVA85A; 1 dose (1 x 108 PFU for 12 participants, and 1 x 107 PFU for 12 participants)

UK

24 adults

‐ve

No serious AE attributable to the vaccine

Griffiths 2011; Matsumiya 2013; Pathan 2012; Rowland 2012

NCT00460590

ID

2005‐8

MVA85A, (5 x 107 PFU)

South Africa

36 adults and adolescents

‐ve

No vaccine related serious adverse events

Hawkridge 2008; Scriba 2010; Tameris 2014; Tanner 2014

NCT00480454

ID

2006‐9

MVA85A;

1 dose MVA85A (2.5 x 107 PFU, 5 x 107 PFU)

Groups

  1. EPI vaccines:

  2. MVA85A + EPI:

  3. MVA85A + EPI 1 week later

The Gambia

214 infants (4 months)

N/R

No serious AE judged to be related to the vaccine

Odutola 2012; Ota 2011

NCT00395720

ID

2006‐10

MVA85A; 1 dose (5 x 107PFU for 10 participants, and 1 x 108 PFU for 10 participants)

UK

20 adults

+ve

No serious AE attributable to the vaccine

Minassian 2011

NCT00480558

ID

2007‐11

MVA85A; 1 dose (5 x 107 PFU)

4 groups with background of

  1. MTB

  2. HIV

  3. MTB + HIV

  4. HIV on ART

South Africa

48 adults (18 to 50 years)

+ve

No vaccine related serious adverse effects

Scriba 2012;

Tanner 2014;

Tameris 2014

NCT00653770

ID

2007‐10

FP85A, MVA85A (5 x 107PFU)

UK

31 adults

‐ve

No serious AE attributable to the vaccine

Rowland 2013

NCT00548444

ID

2007‐10

MVA85A; 1 dose

(1 x 108 PFU), administered as 2 injections (5 x 107 PFU each injection)

UK

12 adults

‐ve

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

Porter (unpublished data: source Rowland 2012)

NCT00731471

ID

2008‐11

MVA85A; 2 doses (spaced by 6 to 12 months) (1 x 108 PFU)

Senegal

24 adults

+ve

No serious AE attributable to the vaccine

Dieye 2013

NCT01181856

ID

IM

2010‐1

MVA85A; 1 dose (1 x 108 PFU)

UK

24 adults

‐ve

No serious AE attributable to the vaccine

Matsumiya 2013; Meyer 2013

NCT01194180

ID

2010‐2

MVA85A, BCG;

1 dose (1 x 108 PFU)

Group A: BCG naïve, no MVA85A
Group B: BCG naïve, 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 2014a; Harris 2014b;

Matsumiya 2013

NCT01497769

Aerosol

ID

2011‐3

MVA85A; 1 dose: 1 x 108, 1 x 107PFU

UK

24 adults

‐ve

No vaccine related serious adverse effects.

Satti 2014

NCT01683773

ID

2012‐4

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 adverse effects

Sheehan 2015

NCT01879163

ID

2013‐4

MVA85A IMX313;
Group A: low dose MVA85A‐IMX313 (1 x 107 PFU)

Group B: dose MVA85A‐IMX313 (5 x 107 PFU)

Group C: MVA85A (5 x 107 PFU)

UK

30 BCG vaccinated adults

‐ve

No vaccine related serious AE

Minhinnick 2016

NCT01829490

IM

2013‐6

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 x 108 PFU)

UK

42 adults

‐ve

No data reported yet

No publication

NCT01829490

NCT01954563

Aerosol

ID

2013‐6

MVA85A;
Group 1: aerosol then ID
Group 2: ID then aerosol
Group 3: ID then ID (5 x 107 PFU)

UK

37 adults

‐ve

No data reported yet

Manjaly Thomas 2016

(conference abstract)

NCT02532036

Aerosol

ID

2015‐8

MVA85A; 1 x 107 PFU aerosol inhaled,

5 x 107 aerosol and ID

UK

15 adults

‐ve

No data reported yet

NCT02532036

Abbreviations: ‐ve: negative; +ve: positive; intradermal: ID; intramuscular: IM; plaque‐forming unit: PFU; adverse event: AE; not reported: N/R.

Figures and Tables -
Table 2. Summary of Phase 1 studies
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Table 3. Adverse events risk of bias methods

Criterion

Assessment

Explanation

Patient‐reported symptoms

Was monitoring active or passive?

Active

Passive

Unclear

We will classify 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 will classify 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

Unclear

We will classify outcome data reporting as 'complete' when data was presented for all the time‐points where it was collected.

Were all participants included in reporting?

Yes

No

We will report the percentage of randomised participants included in adverse event reporting.

Was the analysis independent of study sponsor?

Yes

No

Unclear

We will classify 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 will extract the type and number of laboratory tests were taken.

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

Adequate

Inadequate

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

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

Complete

Incomplete

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

Independence of data analysis: was data analysis independent?

Yes

No

Unclear

We will classify 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.

Adapted from Bukirwa 2014.

Figures and Tables -
Table 3. Adverse events risk of bias methods
Navigate to table in Protocol