Selective presentation of MVA85A tuberculosis booster vaccine preclinical animal data

The recent paper by Kashangura et al. reviewed the preclinical animal data on the Mycobacterium tuberculosis booster vaccine MVA85A and concluded that ‘this independent assessment of the animal data does not provide evidence to support efficacy of MVA85A as a BCG booster’; furthermore, ‘the largest mortality trial in macaques had more deaths in the experimental group’. In fact 5/6 BCG-immunized, MVA85A-boosted animals reached their humane endpoint before the termination of the study, compared with 2/6 BCG-only controls. Kashangura et al. further noted that this study was difficult to find because MVA85A was not among the keywords or mentioned in the abstract, and that several studies did not report a conflict of interest, although in two studies some authors were ‘co-inventors of MVA85A and shareholders in the joint venture developing the vaccine’. The authors who declared a conflict of interest were among the authors of several of the other studies. Additionally, the researchers leading the development of MVA85A have been highly selective in presenting the animal study results in many of their publications. Stating, for example, that ‘In preclinical studies, MVA85A can improve BCG-induced protection in mice, guinea pigs, nonhuman primates and cattle’ or ‘...MVA85A, which has been shown to improve efficacy over BCG alone when given as a boost in preclinical animal models’. The references are almost invariably to only four earlier papers. The first is a mouse study in which improved protection over intranasal BCG was seen when MVA85A was given by the intranasal route, and the second is a guinea pig experiment in which parenteral BCG was followed by both MVA85A and fowlpox-85A boosts. Since mucosal immunization clearly has very different effects from parenteral immunization, these mouse data have little relevance to clinical studies carried out with MVA85A, which use a parenteral route of immunization. In the guinea pig experiment it is not possible to determine whether the improved protection was due to the MVA85A or the fowlpox-85A boost, but in another guinea pig experiment an MVA85A boost alone had no effect. Neither this second guinea pig experiment nor mouse experiments in which parenteral BCG was followed by parenteral MVA85A, with no improvement in protection in the MVA85Aboosted group, are referenced. Thus irrelevant mouse and guinea pig experiments are repeatedly referenced and relevant experiments are not. The remaining studies referenced are macaque and bovine experiments. Although in both these studies there may be a trend toward improved protection in the BCG/MVA85A groups, in neither case is there a statistically significant difference between BCG only and BCG/ MVA85A. It is surely misleading therefore, to refer to these studies as showing ‘improved protection’ without further qualification. In a recent review of preclinical animal models for TB vaccine evaluation, McShane and Williams discuss the same mouse, guinea pig, bovine and macaque papers but again fail to refer to the mouse paper showing no effect of a parenteral boost with MVA85A. The review also mentions the macaque study that is difficult to find, the only reference to this paper by the developers of MVA85A since its publication. The authors of the review state, ‘The only read-out which demonstrated a protective effect of vaccination in this study was a significant reduction in overall pulmonary disease burden, and an equivalent effect was seen in both BCG and BCGMVA85A vaccinated animals’, a clear statement that the MVA85A boost had no beneficial effect. Nevertheless, the authors of the review once more conclude that, ‘This preclinical work demonstrated that MVA85A can improve BCG induced protection in these animal models’. These highly selective and misleading references to the preclinical data and the repeated unqualified statements that parenteral MVA85A improves protection over BCG alone, have led to a belief in the TB vaccine community that MVA85A does indeed boost protection in multiple animal models. In the same review, McShane and Williams go on to say that MVA85A had ‘a variable and modest level of efficacy in animals that failed to predict efficacy in BCG-vaccinated infants to a level required for progression of the vaccine International Journal of Epidemiology, 2016, Vol. 45, No. 2 581