MVA85A vaccine to enhance BCG for preventing tuberculosis

Abstract

BackgroundTuberculosis causes more deaths than any other infectious disease globally. Bacillus Calmette‐Guérin (BCG) is the only available vaccine, but protection is incomplete and variable. The modified Vaccinia Ankara virus expressing antigen 85A (MVA85A) is a viral vector vaccine produced to prevent tuberculosis.ObjectivesTo assess and summarize the effects of the MVA85A vaccine boosting BCG in humans.Search methodsWe searched the Cochrane Infectious Diseases Group Specialized Register; Central Register of Controlled Trials (CENTRAL); MEDLINE (PubMed); Embase (Ovid); and four other databases. We searched the WHO ICTRP and ClinicalTrials.gov. All searches were run up to 10 May 2018.Selection criteriaWe evaluated randomized controlled trials of MVA85A vaccine given with BCG in people regardless of age or HIV status.Data collection and analysisTwo review authors independently assessed the eligibility and risk of bias of trials, and extracted and analyzed data. The primary outcome was active tuberculosis disease. We summarized dichotomous outcomes using risk ratios (RR) and risk differences (RD), with 95% confidence intervals (CI). Where appropriate, we combined data in meta‐analyses. Where meta‐analysis was inappropriate, we summarized results narratively.Main resultsThe search identified six studies relating to four Phase 2 randomized controlled trials enrolling 3838 participants. Funding was by government bodies, charities, and philanthropic donors. Five studies included infants, one of them infants born to HIV‐positive mothers. One study included adults living with HIV. All trials included authors from Oxford University who led the laboratory development of the vaccine. Participants received intradermal MVA85A after BCG in some studies, and before selective deferred BCG in HIV‐exposed infants.The largest trial in 2797 African children was well conducted with low risk of bias for most parameters. Risk of bias was uncertain for selective reporting because there were no precise case definition endpoints for active tuberculosis published prior to the trial analysis.MVA85A added to BCG compared to BCG alone probably has no effect on the risk of developing microbiologically confirmed tuberculosis (RR 0.97, 95% CI 0.58 to 1.62; 3439 participants, 2 trials; moderate‐certainty evidence), or the risk of starting on tuberculosis treatment (RR 1.10, 95% CI 0.92 to 1.33; 3687 participants, 3 trials; moderate‐certainty evidence). MVA85A probably has no effect on the risk of developing latent tuberculosis (RR 1.01, 95% CI 0.85 to 1.21; 3831 participants, 4 trials; moderate‐certainty evidence). Vaccinating people with MVA85A in addition to BCG did not cause life‐threatening serious adverse effects (RD 0.00, 95% CI –0.00 to 0.00; 3692 participants, 3 trials; high‐certainty evidence). Vaccination with MVA85A is probably associated with an increased risk of local skin adverse effects (3187 participants, 3 trials; moderate‐certainty evidence), but not systemic adverse effect related to vaccination (144 participants, 1 trial; low‐c...

Development and Testing of a Spray-Dried Tuberculosis Vaccine Candidate in a Mouse Model

“…The gold-standard vaccine BCG protects against disseminated childhood TB, but protection against lung TB in adolescents and adults is variable and mostly poor. MVA85A administered as a booster to BCG was safe but not effective in reducing the risk of developing TB (Tameris et al, 2013;Kashangura et al, 2019). Interestingly, intranasal BCG vaccination has been reported to provide short-term enhancement of protection in the lung relative to subcutaneous immunization, with potent and extremely persistent splenic protective responses lasting for 10 months following respiratory immunization in mice (Derrick et al, 2014).…”

Enhancing TB Vaccine Efficacy: Current Progress on Vaccines, Adjuvants and Immunization Strategies

“…MVA85A, a live carrier vaccine combining MVA with Mtb major secreted protein antigen 85A, exhibits a favorable safety profile. Administering MVA85A after BCG vaccination proves more effective than MVA85A alone, thereby suggesting an enhanced immune response to pre-existing MTB antibodies [ 9 ]. This vaccine elicits and induces an immune response in antigen Ag85A T cells, resulting in robust and enduring CD4+ T cell proliferation and differentiation and increased IFN-γ, TNF-α, IL-2, IL-17 and GM-CSF secretions.…”

Bacille Calmette Guérin (BCG) and new TB vaccines: Specific, cross-mycobacterial and off-target effects

“…In the 2797 infants, followed for over 2 years, MVA85A did not show protection against TB infection (measured as IGRA conversion) or disease (based on the presence of clinical, radiological, and microbiological findings). The vaccine was used in further trials including in adults without success [87] , and only few viral vector base TB vaccines have been developed and tested in trials since. One interesting new approach using cytomegalovirus (CMV) as the viral vector is still in the preclinical phase and was tested in macaques [88] .…”