MVA85A Tuberculosis Vaccine Prime and Selective Delayed BCG Boost in Infants of HIV Infected Mothers. (360G-Wellcome-096478_Z_11_Z)

Bacille Calmette Guerin (BCG) vaccine protects against childhood disseminated tuberculosis (TB) and meningitis, but efficacy against pulmonary TB is inconsistent. Administration of live attenuated BCG to known HIV infected infants is contraindicated by the World Health Organization (WHO), due to risk of disseminated BCG disease. BCG disease causes considerable morbidity, may be fatal, and may manifest as immune reconstitution inflammatory syndrome (IRIS) after starting antiretroviral treatment (ART). Developing countries, which lack capacity for integration of early HIV testing with infant vaccination schedules, have not implemented the WHO guidelines. Babies of HIV infected mothers, who constituted 29% of all babies born in South Africa in 2009, would benefit from a new TB vaccine regimen that delays BCG until after HIV infection has been excluded. We have shown in humans that delaying BCG vaccination until 10 weeks of age results in more optimal T cell immune responses. Animal studies suggest that the prime and boost sequence of BCG and new TB vaccines (heterologous prime and boost) is not critical for development of optimal immunity. One new vaccine, MVA85A, a non-replicating Vaccinia virus expressing M.tuberculosis antigen 85A, has been tested as a TB vaccine boost among infants, children and adults. We will build on a long-standing relationship with the vaccine developers, Oxford University and Emergent Biosolutions, to test whether MVA85A can be given as the priming TB vaccine at birth. Exceptional research capacity and immunology laboratory infrastructure has been established to conduct quality-assured TB vaccine trials at our trial sites near Cape Town, South Africa. This randomised controlled trial will test safety (local, regional, and systemic adverse events) and immunogenicity (serial measurements of CD4/CD8 T cell intracellular cytokine production, cytotoxic and proliferative potential) of MVA85A prime vaccination compared to placebo, in 340 newborns of HIV infected mothers, followed at 8 weeks by selective BCG boost, given only to infants confirmed HIV uninfected by PCR. The safety benefit gained by withholding BCG vaccination from HIV infected infants is the rationale for testing MVA85A prime among newborn infants of HIV infected mothers. The precedent safety and immunogenicity data from this strategically important trial will establish the equipoise to fast-track efficacy trials of this novel TB vaccine regimen among all infants, regardless of maternal HIV infection. The findings, which are of global health importance for vaccine safety, and TB control, among HIV exposed children, may lead to key improvements in the routine infant vaccination schedule.