Characterization and Implementation of a Diverse Simian Immunodeficiency Virus SIVsm Envelope Panel in the Assessment of Neutralizing Antibody Breadth Elicited in Rhesus Macaques by Multimodal Vaccines Expressing the SIVmac239 Envelope

Abstract

Antibodies that can neutralize diverse viral strains are likely to be an important component of a protective human immunodeficiency virus type 1 (HIV-1) vaccine. To this end, preclinical simian immunodeficiency virus (SIV)-based nonhuman primate immunization regimens have been designed to evaluate and enhance antibody-mediated protection. However, these trials often rely on a limited selection of SIV strains with extreme neutralization phenotypes to assess vaccine-elicited antibody activity. To mirror the viral panels used to assess HIV-1 antibody breadth, we created and characterized a novel panel of 14 genetically and phenotypically diverse SIVsm envelope (Env) glycoproteins. To assess the utility of this panel, we characterized the neutralizing activity elicited by four SIVmac239 envelope-expressing DNA/modified vaccinia virus Ankara vector-and protein-based vaccination regimens that included the immunomodulatory adjuvants granulocyte-macrophage colony-stimulating factor, Toll-like receptor (TLR) ligands, and CD40 ligand. The SIVsm Env panel exhibited a spectrum of neutralization sensitivity to SIV-infected plasma pools and monoclonal antibodies, allowing categorization into three tiers. Pooled sera from 91 rhesus macaques immunized in the four trials consistently neutralized only the highly sensitive tier 1a SIVsm Envs, regardless of the immunization regimen. The inability of vaccine-mediated antibodies to neutralize the moderately resistant tier 1b and tier 2 SIVsm Envs defined here suggests that those antibodies were directed toward epitopes that are not accessible on most SIVsm Envs. To achieve a broader and more effective neutralization profile in preclinical vaccine studies that is relevant to known features of HIV-1 neutralization, more emphasis should be placed on optimizing the Env immunogen, as the neutralization profile achieved by the addition of adjuvants does not appear to supersede the neutralizing antibody profile determined by the immunogen. IMPORTANCEMany in the HIV/AIDS vaccine field believe that the ability to elicit broadly neutralizing antibodies capable of blocking genetically diverse HIV-1 variants is a critical component of a protective vaccine. Various SIV-based nonhuman primate vaccine studies have investigated ways to improve antibody-mediated protection against a heterologous SIV challenge, including administering adjuvants that might stimulate a greater neutralization breadth. Using a novel SIV neutralization panel and samples from four rhesus macaque vaccine trials designed for cross comparison, we show that different regimens expressing the same SIV envelope immunogen consistently elicit antibodies that neutralize only the very sensitive tier 1a SIV variants. The results argue that the neutralizing antibody profile elicited by a vaccine is primarily determined by the envelope immunogen and is not substantially broadened by including adjuvants, resulting in the conclusion that the envelope immunogen itself should be the primary consideration in efforts to elicit antibodi...

Breakthrough of SIV strain smE660 challenge in SIV strain mac239-vaccinated rhesus macaques despite potent autologous neutralizing antibody responses

“…This result suggests that protected animals did not have substantially more potent neutralizing activity against the breakthrough T/F Env variants. This result is consistent with our previous finding that neutralizing activity against heterologous SIV Envs did not differ between infected and protected animals in the M11 and M12 trials (28). We also found no correlation between the nAb IC 50 titer of the vaccinated breakthrough animals and the peak viral load or the number of SIVsmE660 challenges required for infection (Fig.…”

“…3A demonstrates that the breakthrough T/F Env variants on the whole were highly susceptible to neutralization by antibodies in pooled serum. The majority of the T/F Envs from vaccinated animals were neutralized at an IC 50 titer of more than 1:1,000,000 by the serum antibody pool, typical of the extreme neutralization sensitivity of tier 1 SIVsmE660 variants such as E660.11 (27,28). In contrast, the T/F Envs from the control infections were less susceptible to neutralization (Fig.…”

Signatures in Simian Immunodeficiency Virus SIVsmE660 Envelope gp120 Are Associated with Mucosal Transmission but Not Vaccination Breakthrough in Rhesus Macaques

“…It is important to note that the trials analyzed here used entirely different vaccination strategies and challenge stocks from the Roederer et al study, which could explain the inconsistencies between our observations. Nevertheless, our findings do argue against positions 45 and 47 being a universal marker for neutralization resistance (14,36,37,39,40).…”

Diversification in the HIV-1 Envelope Hyper-variable Domains V2, V4, and V5 and Higher Probability of Transmitted/Founder Envelope Glycosylation Favor the Development of Heterologous Neutralization Breadth

“…On the other hand, Env diversity presented in the absence of the neutralizing antibody response that provided the selective pressure may be unable to fully recapitulate the evolution of bnAb in immunized animal models [134,135]. However, the strategic selection and presentation of the priming Env appears to be of vital importance, as we have shown for SIV vaccination in nonhuman primate studies [136]. …”