Tuberculosis

Experimental MVA Tuberculosis Vaccine Fails to Protect Infants

An investigational tuberculosis (TB) vaccine did not provide significant additional protection for babies who were previously immunized with the partially effective standard BCG vaccine, though it did stimulate immune response, researchers reported in the February 4, 2013, advance online edition of The Lancet.

Worldwide, TB remains a leading cause of illness and death, and the primary killer of people with HIV. While TB vaccination is uncommon in the U.S., the Bacille Calmette-Guérin or BCG vaccine, made from a related cattle virus, is standard practice in many countries. BCG -- which was developed nearly a century ago -- does not provide complete protection, however, so a better alternative is a global public health priority.

Michele Tameris from the University of Cape Town and fellow investigators with the MVA85A 020 Trial Study Teamevaluated the safety and efficacy of an experimental vaccine made from modified vaccinia Ankara virus expressing the TB antigen 85A. MVA85A was not designed to work alone, but is intended to enhance the effectiveness of BCG.

This double-blind, placebo-controlled Phase 2b trial enrolled 2797 healthy infants (aged 4 to 6 months) in a rural region near Cape Town, South Africa, between July 2009 and May 2011. The infants were not infected with HIV and had previously received the BCG vaccine.

Participants were randomly assigned (1:1) to receive 1 intradermal dose of the MVA85A vaccine or an equal volume of Candida skin test antigen as a placebo. Infants were followed every 3 months for up to 37 months (median 25 months).

The primary outcome was safety (incidence of adverse events and serious adverse events) for all vaccinated participants. The primary efficacy endpoint was new cases of TB based on microbiological, radiological, and clinical criteria, with a secondary efficacy endpoint of a positive Mycobacterium tuberculosis test using the QuantiFERON TB Gold In-tube assay.

Results

• MVA85A was found to elicit immune responses.
• However, the MVA85A vaccine did not provide significantly more protection than the placebo injection.
• 2% of MVA85A recipients (32 of 1399) developed TB according to the primary efficacy criteria, compared with 3% of placebo recipients (39 of 1395).
• Incidence rates for the 2 groups were 1.15 and 1.39 cases per 100 person-years, respectively.
• 13% of MVA85A recipients became infected with M tuberculosisas indicated by positive TB test conversion, compared with 12% of placebo recipients.
• MVA85A efficacy against developing tuberculosis was 17.3%.
• Effectiveness against M tuberculosis infection was -3.8% -- that is, slightly worse than placebo.
• Infants who received the MVA85A vaccine were significantly more likely than placebo recipients to experience at least 1 local adverse event (89% vs 45%, respectively).
• However, the number of babies who had systemic adverse events (80% vs 76%) or serious adverse events (18% vs 18%) was similar in the MVA85A and placebo groups.
• 515 infants experienced a total of 648 serious adverse events, but these were not considered related to the MVA85A vaccine.

"MVA85A was well tolerated and induced modest cell-mediated immune responses," the study authors concluded. "Reasons for the absence of MVA85A efficacy against tuberculosis or M tuberculosis infection in infants need exploration."

"Our results suggest that the CD4-positive T cells induced by MVA85A -- at least at the modest frequencies noted in this trial -- do not correlate with protection against tuberculosis or M tuberculosis infection," they elaborated in their discussion.

"The vaccine induced modest immune responses against TB in the infants, but these were much lower than those previously seen in adults, and were insufficient to protect against the disease," senior author Helen McShane added in a media statement.

While the MVA85A candidate did not prevent M tuberculosis infection or TB disease, the researchers and some commentators nevertheless considered the outcome promising because it did show activity in evoking immune response.

In an accompanying editorial, Christopher Dye from the World Health Organization (WHO) and Paul Fine from the London School of Hygiene and Tropical Medicine called the study results disappointing, but said this was "not a terminal prognosis" for MVA85A or other TB vaccines currently in development.

While it does not add significantly to the efficacy of BCG for infants, MVA85A may provide some protection on its own. "It is...possible that BCG may have provided a plateau level of protection, with very little, if anything to be added on by MVA85A," according to a WHO Q&A document about the findings.

Investigators now plan to test MVA85A as a BCG booster for older individuals, as adolescents and adults typically are able to mount a stronger immune response than infants, and are also more likely to develop the contagious form of disease. And MVA85A may prove safer than BCG for people with HIV, a population especially in need of protection against TB; a trial of a 2-dose MVA85A regimen for HIV positive individuals is currently underway in Senegal.

2/12/13

References

MD Tameris, M Hatherill, BS Landry, H McShane et al (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. The Lancet. February 4, 2013 (Epub ahead of print).

C Dye and PEM Fine. A major event for new tuberculosis vaccines (commentary). The Lancet. February 4, 2013 (Epub ahead of print).

Other Source

World Health Organization. Questions and Answers on Tuberculosis. February 4, 2013.