Safety and immunogenicity of the Ad35/AERAS-402 tuberculosis vaccine in a phase 2 dose-finding clinical trial in BCG-vaccinated healthy infants (VAC5P.1119)

Despite widespread use of BCG, tuberculosis (TB) remains a global threat, with 9 million new cases and 1.5 million deaths reported in 2013. Current vaccine candidates in clinical trials are designed to replace BCG or boost the variable efficacy observed with BCG. One of these is AERAS-402, a replication-deficient Ad35 vaccine encoding a fusion protein of the M. tuberculosis antigens 85A, 85B, and TB10.4. This vaccine has been tested in adults, infants, HIV+ adults and patients on or following treatment for TB and shown to be safe and immunogenic. A phase 2 clinical trial of two doses of AERAS-402 was conducted in healthy infants in South Africa, Kenya, and Mozambique. The original study design consisted of a dose-finding phase followed by an efficacy phase at the selected dose. The trial design was modified to include a third dose of AERAS-402. AERAS-402 was well-tolerated at all dose levels and up to three doses. Despite the addition of a third dose, the predefined immunogenicity target was not met and the efficacy portion of the trial was removed. The third dose failed to increase immune responses, which consisted of a dominant polyfunctional (IFN-γ, IL-2, TNF) and bifunctional (IFN-γ, TNF) CD8 response and a lower magnitude polyfunctional and bifunctional (IL-2, TNF) CD4 responses. These responses were considerably lower than those observed in adults. Alternative methods to enhance responses to AERAS-402, such as heterologous prime-boost approaches, are warranted.