Vaccine protection against acquisition of neutralization-resistant SIV challenges in rhesus monkeys

Abstract

Summary Preclinical studies of HIV-1 vaccine candidates have typically shown post-infection virologic control, but protection against acquisition of infection has previously only been reported against neutralization-sensitive virus challenges1–3. Here we demonstrate vaccine protection against acquisition of fully heterologous, neutralization-resistant virus challenges in rhesus monkeys. Adenovirus/poxvirus and adenovirus/adenovirus vector-based vaccines expressing SIVsmE543 Gag, Pol, and Env antigens resulted in a ≥80% reduction in the per-exposure probability of infection4,5 against repetitive, intrarectal SIVmac251 challenges in rhesus monkeys. Protection against acquisition of infection exhibited distinct immunologic correlates as compared with post-infection virologic control and required the inclusion of Env in the vaccine regimen. These data demonstrate the first proof-of-concept that optimized HIV-1 vaccine candidates can block acquisition of stringent, heterologous, neutralization-resistant virus challenges in rhesus monkeys.

DNA and virus particle vaccination protects against acquisition and confers control of viremia upon heterologous simian immunodeficiency virus challenge

“…In agreement with those findings, we report that our SIVmac239-based vaccine elicited systemic and mucosal anti-Env humoral immune responses able to significantly delay acquisition of the heterologous SIVsmE660, and SIV-specific cellular responses that efficiently contribute to postacquisition control of viral replication. Cellular immune responses are important for limiting the levels of systemic viral replication early after infection, and this control of primary viremia can be very efficient, even when Env is not part of the vaccine (19,25,26). In addition, using CMV-based viral vectors as vaccine, it was shown that strong cellular immunity distributed in mucosal effector sites could efficiently control viral replication locally, preventing pathogenic viral dissemination and establishment of systemic infection (27).…”

“…The RV144 clinical trial showed modest protection against infection, and this protection apparently correlated with anti-Env bAb, especially IgG antibodies against the V1V2 region (22, 23), but no evidence of vaccine-induced virus control was found in the individuals who became infected. Clearly, a vaccine regimen able to prevent acquisition (11,19,20,24) and reduce viral replication after infection has become possible (11,19,24) using the macaque model. In agreement with those findings, we report that our SIVmac239-based vaccine elicited systemic and mucosal anti-Env humoral immune responses able to significantly delay acquisition of the heterologous SIVsmE660, and SIV-specific cellular responses that efficiently contribute to postacquisition control of viral replication.…”

Designing a Soluble Near Full-length HIV-1 gp41 Trimer

“…The soluble near fulllength gp41 might be an attractive candidate for detection of gp41 Abs in HIV infected individuals. The recent RV144 trial showed a correlation between protection against HIV-1 infection and generation of Abs to the gp120 variable loop V2 (6,69). The near full-length gp41 trimers can be used in conjunction with gp120 to further improve the immunogenicity of the vaccine to induce binding and neutralizing Abs as well as cellular responses.…”

Adenovirus-Based Vectors: Maximizing Opportunities and Optimizing a Rich Diversity of Vectors for Gene-Based Therapy

“…There has been substantial activity using HAdV-26 (Barouch et al, 2012) and chimpanzee adenovirus-based vectors (Ewer et al, 2013). Adenoviruses remain attractive for vaccine development since some of them prime innate and adaptive responses, and there have been clear advantages of maximizing and optimizing the breadth of properties within the Adenoviridae to define the most effective vectors in vaccine regimens.…”