Immune control of an SIV challenge by a T-cell-based vaccine in rhesus monkeys

Abstract

Recent setbacks have prompted a major re-evaluation of the AIDS vaccine field. One question that has been asked is whether to continue development of T-cell-based HIV-1 vaccines. Now a study of a new vaccine in monkeys challenged with simian immunodeficiency virus (SIV) suggests that the T-cell-based strategy remains potentially viable. The vaccine was prepared using two adenovirus vectors (rAd26 prime/rAd5 boost) expressing SIV Gag protein. It induced potent T-cell immune responses and some protection from infection. These findings provide pointers to the design of a new generation of T-cell-based vaccine candidates for HIV-1. Vaccine elicted Gag specific cellular immune responses are shown to provide a measure of protection from disease in Mamu-A*01-negative rhesus monkeys challenged with SIVMAC251. A recombinant adenovirus serotype 5 (rAd5) vector-based vaccine for HIV-1 has recently failed in a phase 2b efficacy study in humans1,2. Consistent with these results, preclinical studies have demonstrated that rAd5 vectors expressing simian immunodeficiency virus (SIV) Gag failed to reduce peak or setpoint viral loads after SIV challenge of rhesus monkeys (Macaca mulatta) that lacked the protective MHC class I allele Mamu-A*01 (ref. 3). Here we show that an improved T-cell-based vaccine regimen using two serologically distinct adenovirus vectors afforded substantially improved protective efficacy in this challenge model. In particular, a heterologous rAd26 prime/rAd5 boost vaccine regimen expressing SIV Gag elicited cellular immune responses with augmented magnitude, breadth and polyfunctionality as compared with the homologous rAd5 regimen. After SIVMAC251 challenge, monkeys vaccinated with the rAd26/rAd5 regimen showed a 1.4 log reduction of peak and a 2.4 log reduction of setpoint viral loads as well as decreased AIDS-related mortality as compared with control animals. These data demonstrate that durable partial immune control of a pathogenic SIV challenge for more than 500 days can be achieved by a T-cell-based vaccine in Mamu-A*01-negative rhesus monkeys in the absence of a homologous Env antigen. These findings have important implications for the development of next-generation T-cell-based vaccine candidates for HIV-1.