Soluble HIV-1 Env trimers in adjuvant elicit potent and diverse functional B cell responses in primates

Abstract

Broadly neutralizing antibodies (bNAbs) against the HIV-1 envelope glycoproteins (Envs) have proven difficult to elicit by immunization. Therefore, to identify effective Env neutralization targets, efforts are underway to define the specificities of bNAbs in chronically infected individuals. For a prophylactic vaccine, it is equally important to define the immunogenic properties of the heavily glycosylated Env in healthy primates devoid of confounding HIV-induced pathogenic factors. We used rhesus macaques to investigate the magnitude and kinetics of B cell responses stimulated by Env trimers in adjuvant. Robust Env-specific memory B cell responses and high titers of circulating antibodies developed after trimer inoculation. Subsequent immunizations resulted in significant expansion of Env-specific IgG-producing plasma cell populations and circulating Abs that displayed increasing avidity and neutralization capacity. The neutralizing activity elicited with the regimen used was, in most aspects, superior to that elicited by a regimen based on monomeric Env immunization in humans. Despite the potency and breadth of the trimer-elicited response, protection against heterologous rectal simian-HIV (SHIV) challenge was modest, illustrating the challenge of eliciting sufficient titers of cross-reactive protective NAbs in mucosal sites. These data provide important information for the design and evaluation of vaccines aimed at stimulating protective HIV-1 immune responses in humans.

Achieving Potent Autologous Neutralizing Antibody Responses against Tier 2 HIV-1 Viruses by Strategic Selection of Envelope Immunogens

“…In our view, data from the A3R5 assay provide another comparative evaluation tool of the Ab responses elicited in vaccinated macaques. The neutralization breadth generated by these vaccines is as potent and comparable to that reported in a recent Env-based vaccine study using similar virus panels (13) and notably more potent than others (15,21,70), including the immunogenicity results of the studies using native-like trimers (58,71). Importantly, this study is unique because we show that the Env-specific vaccine-induced macaque polyclonal IgG was biased toward the same regions of Env mapped to NAb breadth in human subject plasma verified in our earlier studies.…”

“…Thus, efforts to design vaccines that rapidly elicit an effective and broadly cross-reactive neutralizing Ab (nAb) response seem rational based primarily on the observation that doses of bNmAbs are the only formula to date that has been shown to prevent infection and to provide sterilizing immunity in NHP. Despite multiple efforts to develop an immunogen or immunogens that can elicit bNAbs following vaccination, success has been limited (12)(13)(14)(15)(16)(17)(18)(19)(20)(21). Some incremental advances have been made, including our recent immunogenicity studies (22) and those of others (23)(24)(25) that have shown an advantage of coimmunization with DNA and protein immunogens, including the potential of contracting the vaccine regimen to a small number of immunizations to reach peak NAb responses.…”

Antibodies Elicited by Multiple Envelope Glycoprotein Immunogens in Primates Neutralize Primary Human Immunodeficiency Viruses (HIV-1) Sensitized by CD4-Mimetic Compounds

“…Six rhesus macaques were immunized with a soluble HIV-1 YU2 gp140-F trimer (with a fibritin foldon) administered in adjuvant (104). All six monkey plasma samples potently neutralized HIV-1 JR-FL that was sensitized by BNM-III-170 (Fig.…”

Envelope Variants Circulating as Initial Neutralization Breadth Developed in Two HIV-Infected Subjects Stimulate Multiclade Neutralizing Antibodies in Rabbits

“…Antibody affinity is a major characteristic of antibody-based vaccines (47,70,71), and due to the polyclonal nature of our samples, we assessed the apparent affinity of purified rabbit IgG samples to trimeric SF162 protein in the four highest responders of each vaccine group after the second, third, and fourth coimmunizations (weeks 6, 14, and 22, respectively) using biolayer interferometry. We measured each sample individually to determine overall kinetic binding characteristics, association constant (K on ), dissociation constant (K dis ), and K D (see Table S1 in the supplemental material).…”