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

Abstract

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 SIV Gag failed to reduce peak or setpoint viral loads following SIV challenge of rhesus monkeys that lacked the protective MHC class I allele Mamu-A*013. Here we show that an improved T cell-based vaccine regimen utilizing two serologically distinct adenovirus vectors afforded substantially improved protective efficacy in this stringent 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. Following SIVmac251 challenge, monkeys vaccinated with the heterologous rAd26/rAd5 regimen exhibited 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 over 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.

Partial protection against SIV challenge by vaccination of adenovirus and MVA vectors in rhesus monkeys

“…13,23,52 Numerous studies have verified the importance of CM CD4 T cells in suppressing viral replication and mortality after viral infections. 13,23,46 In the current study, memory CD4 T cells were present in the PBMC before and after SIV infection. After SIV infection, no significant difference was observed in the number of naive CD4 T cells and EM CD4 T cells between the vaccine and control groups ( Figure 5).…”

“…Unfortunately, the replication of the SIV challenge virus was not completely controlled, and further studies should be conducted to explore monkey mortality and to examine whether SIV replication can be controlled for a long period by antigen-specific immunity. Taking into consideration the recent failure of a large-scale clinical trial that involved the use of an Ad5 vector 14 and a recent study that compared the immunogenicity and protective immunity of a combination of the Ad26, Ad35 and Ad5 vectors, in which partial protection against SIV was observed, 46 we conclude that the …”

“…However, recent studies show that vaccination with viral vectors such as Ad vectors can elicit Ab-dependent cell-mediated virus inhibition by non-neutralizing antibodies. 46,53 Therefore, antibodies, including non-neutralizing antibodies, will be helpful for the control of HIV/SIV replication.…”

“…Naive CD4 T cells, EM CD4 T cells and CM CD4 T cells were identified as CD3 + CD4 + CD95 À CD28 + , CD3 + CD4 + CD95 + CD28 À and CD3 + CD4 + CD95 + CD28 + , respectively. 13,23,46 Tetramer assay…”

Polyvalent vaccine approaches to combat HIV‐1 diversity

“…While the level of vaccine responses to HIV‐1 proteins can be evaluated in NHPs, their protective capacity cannot be assessed, except for responses to the HIV‐1 Env glycoprotein, which can be tested using simian‐human immunodeficiency virus (SHIV) challenge models 40. Using SIVmac proteins instead, the number of vaccine‐elicited SIVmac Gag CTL responses has been correlated with improved viral control in NHPs of SHIVs and SIVmac 41, 42. These observations suggest that the improved T‐cell responses to HIV mosaics in NHPs may translate into better outcomes in human subjects.…”