Guiding HIV-1 vaccine development with preclinical nonhuman primate research

Abstract

Purpose of the review: Nonhuman primates (NHPs) are seen as the closest animal model to humans in terms of anatomy and immune system makeup. Here, we review how preclinical studies in this model system are teaching the field of HIV vaccinology the basic immunology that is needed to induce broadly neutralizing antibodies (bnAbs) with vaccination and elicit protective T cell responses. These lessons are being translated into clinical trials to advance towards protective active vaccination against HIV-1 infection.

Recent findings: Preclinical vaccination studies in NHPs have shown that highly engineered HIV-1 immunogens can initiate bnAb precursors providing proof of concept for Phase I clinical trials. Additionally, NHP models of HIV-1 infection are elucidating the pathways for bnAb development while serving as systems to evaluate vaccine protection. Innovative immunization strategies have increased affinity maturation of HIV-1 antibodies in long-lived germinal centers. Preclinical studies in macaques have defined the protective level of neutralizing antibodies and have shown that T cell responses can synergize with antibody-mediated immunity to provide protection in the presence of lower neutralizing antibody titers.

Summary: The NHP model provides vaccine regimens and desired antibody and T cell responses that serve as benchmarks for clinical trials, accelerating HIV vaccine design.

Figure 1.. Recent Advancements And Achievements In Nonhuman Primate (NHP) Research And Preclinical Studies That Bolster HIV-1 Vaccine Design.

A. The NHP antibody repertoire has been sequenced for tens of macaques allowing a better understanding of the potential antibody responses that macaques can make in response to infection or vaccination. New programs such as IgDiscover have been generated to identify novel variable gene segment alleles. The improved understanding of NHP immunogenetics has facilitated comparisons with known human broadly neutralizing antibodies (bnAbs). B. Vaccination of NHPs has elicited fusion peptide bnAbs using engineered minimal immunogens. The broad neutralization by vaccine-elicited macaque fusion peptide antibody DFPH-a.01 is shown as a color-coded HIV phylogenetic tree. In other studies, the field has found structural evidence that vaccine-induced antibodies recapitulate the binding of human bnAbs. A negative stain electron microscopy 3D reconstruction of a macaque CD4bs antibody binding (pink) to Env (gray) is shown with the ribbon structure of a human CD4bs bnAb (blue) fit inside it. The perfect fit between the two structures shows accurate recapitulation of the human bnAb binding by the macaque antibody. C. Advances in the simian-human immunodeficiency virus (SHIV) infection model has led to multiple uses of this system. New SHIVs have been engineered recently to express relevant challenge viruses with transmitted/founder HIV-1 envelopes that mimic the hard-to-neutralize HIV-1 isolates that are currently circulating. Additionally, SHIVs are being designed to express bnAb precursor-targeting HIV-1 envelopes to elicit specific types of bnAbs in NHPs. The macaque bnAbs are assessed on large virus panels as shown here by the HIV-1 neutralization dendrogram. The induction of bnAbs in the SHIVs enables precise tracking of the bnAb lineage before and after infection, and the identification of virus sequence changes that select for specific bnAb lineage members.

Figure 2.. Vaccine and SHIV Induced Neutralizing Antibodies Target HIV-1 Env BnAb Epitopes Identified in Human Humoral Immune Responses.

A. Human bnAbs and their respective epitopes of vulnerability aligned using Pymol to a BG505:PGT145 model using gp120 or gp41 structure (PDB: 5V8L). Other bnAb models with Env masking: 10–1074 (8CZZ), VRC34.01 (5I8H), CH235.12 (5F96). B. SHIV and vaccine-induced nAbs from rhesus macaques aligned via gp120/gp41 to BG505 (5V8L): Ab874_NHP (6ORO), DFPH-a.15 (6N1W), RHA1.V2 (6XRT), DH1285 (EMD-27621 and EMD-27622). Induction of the rhesus nAbs validates the use of macaques as a model system for evaluating vaccine immunogens and studying antibody responses to virus infection.