Results of TB vaccine trial give cause for optimism, say researchers

Results of a trial have been praised for “providing hard evidence about protection against tuberculosis in human beings”. The MVA85A vaccine did not confer any additional protection against tuberculosis (TB) or infection with Mycobacterium tuberculosis to infants who had already been immunised with the BCG vaccine (the standard vaccination against TB).

However, MVA85A was found to induce an anti-TB immune response and was safe. Investigators are hopeful that the study’s findings, which are published in The Lancet, will provide important insights in the quest for a new TB vaccine, and that the product may yet prove efficacious in adolescents and adults.

“MVA85A could potentially protect adolescents and adults against pulmonary tuberculosis, in view of the fact that immunologically immature infants do not respond as well to this vaccine as adults do,” write the authors.

TB is a global health problem. Key to the long-term control of the epidemic is the development of an effective vaccine. The existing BCG vaccine protects young children against disseminated TB, but its efficacy against pulmonary TB is highly variable. Moreover, its effectiveness against infection with Mycobacterium tuberculosis is questionable. There is therefore an urgent need for an improved infant TB vaccine regimen.

MVA85A has been developed as a booster for BCG. It has performed well in laboratory studies, and an early clinical trial in infants showed that it was well tolerated.

An international team of investigators wanted to find out more about the safety and efficacy of MVA85A.

They therefore designed a double-blind, placebo-controlled, phase 2b study involving 2797 South African infants. All were HIV negative and had received the BCG vaccine soon after birth. On a 1:1 basis, the infants were randomised to receive MVA85A or a placebo. They were monitored for localised and systemic adverse events and were followed every three months for evidence of TB disease or infection with Mycobacterium tuberculosis.

The median duration of follow-up was a little under 25 months. More infants in the MVA85A arm developed a localised adverse event than patients in the control group (89 vs 45%). “The high frequency of mild, self-limiting local reactions to MVA85A recipients is consistent with previous studies,” comment the investigations.

Systemic side-effects were common both study arms, occurring in 80% of MVA85A recipients and 76% of those in the placebo group.

A serious adverse event was observed in 18% of infants in each of the study arms. No serious adverse events was related to MVA85A.

MVA85A was found to induce a CD4 cell response. However, this did not appear to confer any additional protection against TB compared to that already provided by BCG vaccination.

A total of 32 (2%) of MVA85A recipients developed TB (incidence 1.15 per 100 person-years), as did 39 infants (3%) in the placebo arm (incidence 1.39 per 100 person-years). The 17% reduction in TB incidence associated with the investigational vaccine was not significant.

Infection with Mycobacterium tuberculosis occurred in 13% of infants in the MVA85A arm and 12% of patients in the control arm.

“MVA85A was well tolerated and immunogenic in healthy infants who had been previously vaccinated with BCG,” write the investigators. “We noted no significant efficacy tuberculosis or Mycobacterium tuberculosis infection.”

The study investigators and the authors of an accompanying editorial were positive about the findings of the research.

“Our study showed that a large efficacy trial of a new tuberculosis vaccine in a high-burden setting is feasible with a stringent and objective case definition,” comment the investigators.

The authors of the editorial believe that MVA85A may yet prove to be useful in the fight against TB. They note that the BCG vaccine already provides high levels of protection against TB disease to infants and additional efficacy may have been “asking too much of MVA85A”. The authors also suggest that further research should explore the use of the product as a BCG booster in adults, and they ask “Might this vaccine work if administered to people infected with HIV?” Trials are currently testing the vaccine in HIV-positive adults in South Africa and Senegal.

Two trials of TB vaccines of a similar type to MVA85A, sub-unit boosting vaccines, are currently underway, one in infants in South Africa  and an adult study of GSK M72, a vaccine being developed by Glaxo SmithKline.

Further research will also take place to identify immunological correlates of protection against TB infection in infants vaccinated in the MVA85A study; Christopher Dye of the World Health Organization and Paul Fine of the London School of Hygiene and Tropical Medicine comment: "The identification of of a valid measure of protective immunity against tuberculosis would be a discovery of overwhelming importance."