Author: Richard Lessells - 2013-02-21

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A phase IIb trial using the MVA85A vaccine as a boost to BCG vaccination demonstrates acceptable safety but fails to show any protective effect against TB infection or disease in HIV-uninfected children

There have been mixed responses to the results of a TB vaccine trial recently published in The Lancet. Understandably there was disappointment that the vaccine strategy explored in the trial failed to show any protective effect. However, there was also optimism not only about the lessons that could be learnt from the trial results but also around the fact that a large-scale vaccine trial had been conducted effectively in South Africa, at the epicentre of the global TB epidemic.

The need for a new TB vaccine in high-burden settings is obvious and has been re-emphasised by this trial, demonstrating a substantial force of infection where one in eight of the young children in the study was infected with TB over the two years of follow-up. The vaccine under investigation in this trial was the MVA85A vaccine, which incorporates a highly attenuated strain of Vaccinia virus expressing the M. tuberculosis antigen 85A. Phase I studies had demonstrated that the vaccine induced high levels of antigen-specific IFN-gamma-secreting T cells in adults and infants.

This phase IIb trial recruited healthy HIV-uninfected infants (4-6 months old) previously vaccinated with BCG and without evidence of TB infection (QuantiFERON-TB Gold In-Tube negative) from a rural community in the Western Cape. A total of 2797 infants were randomised to receive either the MVA85A vaccine or placebo and were then followed up for an average of two years. In terms of safety, there were no serious adverse events that were considered vaccine-related but local adverse events at the injection site were reported for almost all vaccine recipients (although there is quite limited information about these in the paper). It was demonstrated that vaccine induced an antigen-specific CD4+ T-lymphocyte response but this was less marked than that reported for adults.

Using TB disease as an endpoint in vaccine studies is complicated by the difficulties faced in accurately diagnosing active TB disease in young children (perhaps highlighted by the fact that 13% of the children across both arms were placed on treatment for active TB disease during the course of the study). The researchers here used carefully-constructed definitions for TB disease as the primary efficacy endpoint. During follow-up, 32/1399 (2.3%) in the vaccine group and 39/1395 (2.8%) in the placebo group developed TB disease, providing no evidence of a difference between vaccine and placebo. The secondary efficacy outcome of TB infection (based on QuantiFERON-TB Gold In-Tube conversion) was reached in 178/1399 (12.7%) of vaccine recipients and 171/1395 (12.3%) in the placebo group, providing no evidence of protection from TB infection.

There is discussion, both in the article itself and in the accompanying editorial, about why the vaccine may not have shown any protective efficacy. There is likely to be much additional work with the data and the samples collected for this study to give further insight into the lack of efficacy and to inform future studies. The vaccine has shown immunogenicity in HIV-infected adults and the efficacy for the prevention of TB disease is currently being investigated in another phase II trial with HIV-infected adults in South Africa and Senegal. Only time will tell whether or not these studies take us closer to the holy grail of a more effective TB vaccine.

Sources

Results of a TB vaccine trial - Tameris MD, Hatherill M, Landry BS, Scriba TJ, Snowden MA, Lockhart S, Shea JE, McClain JB, Hussey GD, Hanekom WA, Mahomed H, McShane H and the MVA85A 020 Trial Study Team. Safety and efficacy of MVA85A, a new tuberculosis vaccine, in infants previously vaccinated with BCG: a randomised, placebo-controlled phase 2b trial. Lancet 2013 Feb 4

Editorial - Dye C, Fine PEM. A major event for new tuberculosis vaccines. Lancet 2013 Feb 4

Immunogenicity paper - Scriba TJ, Tameris M, Smit E, van der Merwe L, Hughes EJ, Kadira B, et al. A phase IIa trial of the new TB Vaccine, MVA85A, in HIV and/or M. tuberculosis infected adults. Am J Respir Crit Care Med 2012; 185: 769-778

Phase II trial information - ClinicalTrials.gov. Protective efficacy against tuberculosis (TB) disease, safety, and immunogenicity of MVA85A/AERAS-485 in HIV-infected adults. NCT01151189

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