A major event for new tuberculosis vaccines

972 www.thelancet.com Vol 381 March 23, 2013 One of the great quests of contemporary medical research is the search for an improved tuberculosis vaccine—one that provides greater and more consistent protection against tuberculosis than the BCG vaccine can achieve. The stakes are high. The venture is costly and risky, but has a huge potential payoff . A high-effi cacy vaccine could revolutionise control of tuberculosis, shifting the emphasis from treatment to prevention. As the case numbers slowly fall in high-burden countries, and as new strains of drug-resistant tuberculosis emerge, a novel and transformational technology for tuberculosis control would be cause for great celebration. US$70–100 million is spent on vaccine research for tuberculosis every year and the pipeline of candidate vaccines is now longer and wider than ever before. As each of the candidates moves from preclinical to clinical stages, passing tests for safety and immunogenicity, experi ments to assess effi cacy in human beings are major events. Against this background, Michele Tameris and colleagues report in The Lancet results of a phase 2b trial in infants in South Africa of the vaccine modifi ed Vaccinia virus Ankara expressing antigen 85A (MVA85A). Although the primary objective of the trial was to assess safety, it also made a preliminary assessment of effi cacy—and many readers will go, with halted breath, straight to the conclusions about effi cacy. They will be confronted with results that are, on the face of it, disappointing, show ing little evidence of effi cacy in terms of prevention of tuberculosis or infection with Mycobacterium tuberculosis. Although the trial raised no concerns about safety, the absence of any detectable effi cacy presents the tuberculosis vaccine community with a serious challenge. However, the fi ndings reported by Tameris and colleagues are not a terminal prognosis for MVA85A, or for any of the other tuberculosis vaccines in develop ment. To understand why, the results of this particular trial need to be put in a wider context. Two main strategies exist for development of tuberculosis vaccines. The fi rst is to replace the widely used BCG vaccine with an improved whole-organism vaccine, which is either a recombinant BCG or an attenuated strain of M tuberculosis. The second is to develop a subunit boosting vaccine, which is designed to enhance whatever protection is already provided by BCG. MVA85A is an example of the latter strategy. In their elegant randomised, placebo-controlled trial, Tameris and colleagues followed up 2794 BCGvaccinated infants for up to 37 months (median 24·6, IQR 19·2–28·1) in two nearly equal groups. 39 (2·8%) of 1395 infants in the placebo group (Candida skin test antigen) satisfi ed the primary defi nition of active tuberculosis, of whom 20 were microbiologically confi rmed. 32 (2·3%) of 1399 infants in the vaccine group (MVA85A) satisfi ed the primary defi nition of active tuberculosis, of whom 22 were microbiologically confi rmed. Thus, vaccine effi cacy was 17·3%, which was not distinguishable from zero (95% CI –31·9 to 48·2). Neither was there any evidence for protection against M tuberculosis infection, as determined by an in-vitro interferon γ release assay (QuantiFERON-TB Gold Intube; Cellestis, Australia). During the trial, 349 (13%) of 2792 participants became positive on this assay, 171 (12%) in the placebo group and 178 (13%) in the vaccine group. 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