Multi-parameter exploration of HIV-1 virus-like particles as neutralizing antibody immunogens in guinea pigs, rabbits and macaques

Abstract

Virus-like particles (VLPs) offer a platform to test the hypothesis that, since antibody binding to native envelope glycoprotein (Env) trimers results in HIV-1 neutralization, that native Env trimers presented in membranes may be useful for inducing neutralizing antibodies (nAbs) in a vaccine setting. So far, VLPs have not fulfilled this potential. Here, using a “shotgun” approach, we evaluated a wide cross-section of variables in a series of VLP immunizations. We identified 3 tentative leads. First, that VLP doses may not have been sufficient for optimal nAb induction. Second, that dampening the antigenicity of non-functional Env (for example uncleaved gp160) using either protease digests or IgG masking may be useful. Third, that guinea pig sera preferentially target non-conserved epitopes and exhibit relatively high background activity, suggesting that rabbits may be preferable as small animal vaccine models. Recent immunogenicity studies in rabbits appear to bear out all 3 of these leads.

Effects of partially dismantling the CD4 binding site glycan fence of HIV-1 Envelope glycoprotein trimers on neutralizing antibody induction

“…Our previous immunogenicity studies suggested that VLP efficacy may be improved by i) eliminating antigenic interference by non-functional Env, ii) by using higher VLP doses and iii) by using rabbit models (Crooks et al, 2015; Tong et al, 2014). So far, at best, potent tier 2 nAbs developed in only 25% of rabbits, suggesting a need for further improvements (Crooks et al, 2015).…”

“…To this end, we have been developing virus-like particles (VLPs) (Crooks et al, 2007; Crooks et al, 2015; Tong et al, 2014). We previously suggested that non-functional Env present on VLP surfaces may interfere with their ability to induce nAbs (Tong et al, 2014).…”

“…To this end, we have been developing virus-like particles (VLPs) (Crooks et al, 2007; Crooks et al, 2015; Tong et al, 2014). We previously suggested that non-functional Env present on VLP surfaces may interfere with their ability to induce nAbs (Tong et al, 2014). To address this problem, we showed that a protease blast can selectively remove non-functional Env from VLP surfaces, leaving trimers intact (Crooks et al, 2011; Tong et al, 2012).…”

Antigenicity and Immunogenicity of a Trimeric Envelope Protein from an Indian Clade C HIV-1 Isolate

“…6A). Adjuplex has been shown to elicit high titer antibodies in rabbits and rhesus macaques (16,60). Significant antibody titers were seen in all the rabbits even after the second immunization and remained high during the course of the study (Fig.…”

Native‐like Env trimers as a platform for HIV‐1 vaccine design

“…Tested in animals, the protease-treated JR-FL SOS Env VLPs were able to induce sporadic autologous Tier-2 NAb responses that, for some sera, could be mapped to specific holes in the glycan shield (158,159). The poor immunogenicity of JR-FL-based soluble, native-like trimers alluded to earlier (131,155,156,157) may suggest that better results could be obtained in the VLP context if a different Env genotype were used instead.…”