Adjuvant-dependent innate and adaptive immune signatures of risk of SIVmac251 acquisition

Abstract

A recombinant vaccine containing Aventis Pasteur’s canarypox vector (ALVAC)–HIV and gp120 alum decreased the risk of HIV acquisition in the RV144 vaccine trial. The substitution of alum with the more immunogenic MF59 adjuvant is under consideration for the next efficacy human trial. We found here that an ALVAC–simian immunodeficiency virus (SIV) and gp120 alum (ALVAC–SIV + gp120) equivalent vaccine, but not an ALVAC–SIV + gp120 MF59 vaccine, was efficacious in delaying the onset of SIVmac251 in rhesus macaques, despite the higher immunogenicity of the latter adjuvant. Vaccine efficacy was associated with alum-induced, but not with MF59-induced, envelope (Env)-dependent mucosal innate lymphoid cells (ILCs) that produce interleukin (IL)-17, as well as with mucosal IgG to the gp120 variable region 2 (V2) and the expression of 12 genes, ten of which are part of the RAS pathway. The association between RAS activation and vaccine efficacy was also observed in an independent efficacious SIV-vaccine approach. Whether RAS activation, mucosal ILCs and antibodies to V2 are also important hallmarks of HIV-vaccine efficacy in humans will require further studies.

Relationship between Vaccine-Induced Antibody Capture of Infectious Virus and Infection Outcomes following Repeated Low-Dose Rectal Challenges with Simian Immunodeficiency Virus SIVmac251

“…1). This finding is consistent with data reported from the parent study indicating that MF59 results in higher antibody responses measured in a number of different assays (16). Although neutralizing activity against a neutralization-sensitive strain of SIV (SIVmac251.6) was higher in plasma of MF59-vaccinated animals, levels of antibody capable of neutralizing the challenge virus, SIVmac251, were very low in both groups (see below).…”

“…This implies that the vaccine-induced antibody response may have increased the likelihood of infection in some animals. Interestingly, in the parent study, we also found a direct correlation between the number of vaccine-induced CD4 ϩ KI67 ϩ cells that expressed either ␣4␤7 ϩ or CD38 ϩ and the number of T/F variants in the MF59 group, suggesting that not only the antibodies that capture well but neutralize poorly but also an increase in virus-susceptible target cells likely affect vaccine efficacy (16).…”

“…The protocol (AUP 491) was approved by Advanced BioScience Laboratories' Institutional Animal Care and Use Committee. The study design has been described previously (16). Briefly, 54 juvenile rhesus macaques were divided into two groups and immunized intramuscularly with ALVAC-SIV (which expressed SIV Gag, Pol, and Env from a mucosally transmitted/ founder [T/F] variant of SIVmac251) at weeks 0, 4, 12, and 24.…”

“…All sequences were obtained through singlegenome amplification (SGA) and directly sequenced as described previously (16). Individual sequence fragments were assembled and edited using Sequencher 5.0 (Gene Codes).…”

Adjuvanting a Simian Immunodeficiency Virus Vaccine with Toll-Like Receptor Ligands Encapsulated in Nanoparticles Induces Persistent Antibody Responses and Enhanced Protection in TRIM5α Restrictive Macaques

“…Vaccine approaches in many of these studies included priming with plasmid DNA encoding SIV/HIV immunogens followed by the administration of viral vectors (modified vaccinia virus Ankara, adenovirus type 5) (31,32,50) or priming with viral vectors followed by recombinant protein boosts (39,(51)(52)(53)(54)(55). Consistent with the findings of these studies, analysis of correlates of protection in our current study revealed that the magnitude of the Env-specific binding antibody titers at week 37 prechallenge correlated strongly with the protection induced by immunization with protein-NP (Fig.…”