Reproducing SIVΔnef vaccine correlates of protection

Abstract

Vaccination with SIVmac239Δnef provides robust protection against subsequent challenge with wild type SIV, but safety issues have precluded designing an HIV-1 vaccine based on a live attenuated virus concept. Safe immunogens and adjuvants that could reproduce identified immune correlates of SIVmac239Δnef protection therefore offer an alternative path for development of an HIV vaccine. Here we describe SIV envelope trimeric gp41 (gp41t) immunogens based on a protective correlate of antibodies to gp41t concentrated on the path of virus entry by the neonatal Fc receptor (FcRn) in cervical vaginal epithelium. We developed a gp41t immunogen-MPLA adjuvant liposomal nanoparticle for intra-muscular immunization and a gp41t-Fc immunogen for intranasal immunization for pilot studies in mice, rabbits, and rhesus macaques. Repeated immunizations to mimic persistent antigen exposure in infection elicited gp41t antibodies in rhesus macaques that were detectable in FcRn+ cervical vaginal epithelium, thus recapitulating one key feature of SIVmac239Δnef vaccinated and protected animals. While this strategy did not reproduce the system of local production of antibody in SIVmac239Δnef-vaccinated animals, passive immunization experiments supported the concept that sufficiently high levels of antibody can be concentrated by the FcRn at mucosal frontlines, thus setting the stage for assessing protection against vaginal challenge by gp41t immunization.

Immunogenicity of a novel Clade B HIV-1 vaccine combination: Results of phase 1 randomized placebo controlled trial of an HIV-1 GM-CSF-expressing DNA prime with a modified vaccinia Ankara vaccine boost in healthy HIV-1 uninfected adults

“…However, a gp41 subunit virosome vaccine regimen that elicited antiviral gp41 specific antibodies did protect nonhuman primates against vaginal SHIV challenges [ 48 ]. Additionally, in a nonhuman primate SIV immunization model, gp41 antibodies concentrated at the mucosa correlated with protection [ 49 , 50 ]. Thus, studies from multiple independent groups employing different strategies of passive infusion and vaccination studies in nonhuman primates have demonstrated the potential of gp41 antibodies to protect.…”

A recombinant multi-epitope protein MEP1 elicits efficient long-term immune responses against HIV-1 infection

“…Broadly neutralizing antibodies (BNAbs) against HIV-1 are of great interest and encouraging for researchers to prevent and treat AIDS, 1,8,15 however, how to elicit BNAbs by vaccination is still an unraveled question. 27,28 Besides BNAbs, potential correlates of protection also include ADCC antibodies 29 and effective T cell responses. 30,31 Efforts to elicit broadly-directed, codominant responses to conserved epitopes of protective CD4 and CD8 T cell responses have been sustained for many years 10,32,33 although such responses might lead to partial protection from HIV-1 infection, rather than sterile prevention or virus eradication.…”

Neutralizing monoclonal antibodies for COVID-19 treatment and prevention

“…The FcRn interacts with the Fc region of IgG and is involved in recycling of IgG within cells. This interaction is also involved in actively transporting IgGs to sites of pathogen encounter [ 96 ]. For example, the M428L and N434S (“LS”) mutations prolong antibody half-life without compromising antigen-binding or other Fc-mediated functions [ 97 ].…”

“…In the case of VRC01, the FcRn enhancing mutation VRC01-LS [ 95 ] lead to 2–3 fold higher in vivo half-life in macaques compared to VRC01. In addition, increased and prolonged levels of VRC01-LS were detected in vaginal and rectal mucosal tissue compared to the unmodified VRC01 [ 96 , 97 ]. Recently, Griffin and colleagues showed that a single intramuscular dose of Nirsevimab protected infants for an entire RSV season [ 98 ].…”