Effects of MVA85A vaccine on tuberculosis challenge in animals: systematic review

Abstract

Background: The existing Bacillus Calmette–Guérin (BCG) vaccination provides partial protection against tuberculosis (TB). The modified vaccinia ankara virus-expressing antigen 85A (MVA85A) aims to boost BCG immunity. We evaluated the animal evidence supporting the testing of MVA85A in humans.Methods: Our protocol included in vivo preclinical studies of the MVA85A booster with BCG compared with BCG alone, followed by a TB challenge. We used standard methods for systematic review of animal studies, and summarized mortality, measures of pathology and lung bacterial load. The comprehensive literature search was to September 2014. Two independent investigators assessed eligibility and performed data extraction. We assessed study quality and pooled bacteria load using random effect meta-analysis.Findings: We included eight studies in 192 animals. Three experiments were in mice, two in guinea pigs, two in macaques and one in calves. Overall, study quality was low with no randomization, baseline comparability not described and blinding not reported. For animal death (including euthanasia due to severe morbidity), studies were underpowered, and overall no benefit demonstrated. No difference was shown for lung pathology measured on an ordinal scale or bacterial load. The largest mortality trial carried out in macaques had more deaths in the MVA85A vaccine group, and was published after a trial in South Africa had started recruiting children.Conclusions: This independent assessment of the animal data does not provide evidence to support efficacy of MVA85A as a BCG booster. More rigorous conduct and reporting of preclinical research are warranted, and we believe the results of studies should be publicly available before embarking on trials in humans, irrespective of the findings.

Can prospective systematic reviews of animal studies improve clinical translation?

“…This was also the case for low level laser therapy for wound healing; after a SR of human studies found that the treatment was ineffective in humans [22], the authors systematically reviewed the animal studies [23] and concluded that they had not provided unequivocal evidence to substantiate the decision to conduct clinical trials. Similar conclusions were drawn in the cases of fluid resuscitation for bleeding trauma patients [24][25][26], endothelin for chronic heart failure [27,28] and more recently, a booster vaccine (MVA85A) intended to confer extra protection against tuberculosis [29,30]. In all these cases, it would be reasonable to conclude that conducting prospective SRs of the animal studies might have prevented expensive and unnecessary or risky clinical trials from proceeding; indeed this is often called for following the failure of a clinical trial, or the halting of a clinical trial that turns out to be dangerous [31].…”

Evaluation of Immune Responses to a DNA Vaccine Encoding Ag85a-Cfp10 Antigen of Mycobacterium tuberculosis in an Animal Model

“…Despite potent immunogenicity of the Ag85a, a new vaccine based on this antigen was not promising. MVA85A, a modified vaccinia Ankara, expressing Ag85a, which initial research regarding this vaccine showed high levels of induction of longlasting cellular immunity in combination with the BCG vaccine, however, further results in clinical trials in 2015 were disappointing (14,(44)(45)(46).…”

Update on TB Vaccine Pipeline

“…Recent studies indicate that new TB vaccines that are compared to BCG should be interpreted cautiously with reference to a specific BCG formulation and not presumed to generalize to all BCGs [13]. In addition, testing the new concepts of vaccines in relevant animal models such as NHP, should be key before advancing into expensive clinical trials of efficacy [74,75]. Something that has been questioned in the MVA85A efficacy study [38] was that the efficacy experiments in NHP, which showed lack of efficacy by the tested clinical route and dose of administration [76,77].…”