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Polyclonal antibody responses to HIV Env immunogens resolved using cryoEM.

ABSTRACT: Engineered ectodomain trimer immunogens based on BG505 envelope glycoprotein are widely utilized as components of HIV vaccine development platforms. In this study, we used rhesus macaques to evaluate the immunogenicity of several stabilized BG505 SOSIP constructs both as free trimers and presented on a nanoparticle. We applied a cryoEM-based method for high-resolution mapping of polyclonal antibody responses elicited in immunized animals (cryoEMPEM). Mutational analysis coupled with neutralization assays were used to probe the neutralization potential at each epitope. We demonstrate that cryoEMPEM data can be used for rapid, high-resolution analysis of polyclonal antibody responses without the need for monoclonal antibody isolation. This approach allowed to resolve structurally distinct classes of antibodies that bind overlapping sites. In addition to comprehensive mapping of commonly targeted neutralizing and non-neutralizing epitopes in BG505 SOSIP immunogens, our analysis revealed that epitopes comprising engineered stabilizing mutations and of partially occupied glycosylation sites can be immunogenic.

SUBMITTER: Antanasijevic A

PROVIDER: S-EPMC8355326 | biostudies-literature | 2021 Aug

REPOSITORIES: biostudies-literature

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Polyclonal antibody responses to HIV Env immunogens resolved using cryoEM.

Antanasijevic Aleksandar A Sewall Leigh M LM Cottrell Christopher A CA Carnathan Diane G DG Jimenez Luis E LE Ngo Julia T JT Silverman Jennifer B JB Groschel Bettina B Georgeson Erik E Bhiman Jinal J Bastidas Raiza R LaBranche Celia C Allen Joel D JD Copps Jeffrey J Perrett Hailee R HR Rantalainen Kimmo K Cannac Fabien F Yang Yuhe R YR de la Peña Alba Torrents AT Rocha Rebeca Froes RF Berndsen Zachary T ZT Baker David D King Neil P NP Sanders Rogier W RW Moore John P JP Crotty Shane S Crispin Max M Montefiori David C DC Burton Dennis R DR Schief William R WR Silvestri Guido G Ward Andrew B AB

Nature communications 20210810 1

Engineered ectodomain trimer immunogens based on BG505 envelope glycoprotein are widely utilized as components of HIV vaccine development platforms. In this study, we used rhesus macaques to evaluate the immunogenicity of several stabilized BG505 SOSIP constructs both as free trimers and presented on a nanoparticle. We applied a cryoEM-based method for high-resolution mapping of polyclonal antibody responses elicited in immunized animals (cryoEMPEM). Mutational analysis coupled with neutralizati ...[more]

PMID: 34376662

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Project description:BackgroundWe report findings from an experimental medicine study of rationally designed prefusion stabilised native-like HIV envelope glycoprotein (Env) immunogens, representative of global circulating strains, delivered by sequential intramuscular injection.MethodsHealthy adult volunteers were enrolled into one of five groups (A to E) each receiving a different schedule of one of two consensus Env immunogens (ConM SOSIP, ConS UFO, either unmodified or stabilised by chemical cross-linking, followed by a boost with two mosaic Env immunogens (Mos3.1 and Mos3.2). All immunogens were co-formulated with liposomal Monophosphoryl-Lipid A (MPLA) adjuvant, and volunteers were followed up for 28 days post final Mosaic booster injection. Participants gave written informed consent to join the study. The study is registered on ClinicalTrials.gov ID NCT03816137.FindingsFifty-one participants (men n = 23 and women n = 28) aged 18-55 were enrolled. The seroconversion rate against Env was 100% with all participants having measurable anti-Env IgG antibodies after their second injection and throughout the study. Neutralisation was detected against the ConM pseudovirus in sera of those who had received both ConM and ConS immunogens. However, this activity was limited in breadth and was neither boosted nor broadened in those receiving the Mos3.1 and Mos3.2 immunogens. Neutralising antibody function correlated with binding to V1/V3 and V5 epitopes and peaked after the third injection.InterpretationRationally designed prefusion-stabilised native-like Env trimers are robustly immunogenic in a prime-boost schedule. When given alone they are insufficient to induce neutralising antibody titres of significant breadth, but they represent potentially valuable polishing immunogens after germline-targeting.FundingEuropean Aids Vaccine initiative (EAVI2020) received funding from EU Horizon 2020, grant number 681137. Structural studies were supported by the Bill and Melinda Gates Foundation (INV-002916).

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Polyclonal antibody responses to HIV Env immunogens resolved using cryoEM.

Publications

Polyclonal antibody responses to HIV Env immunogens resolved using cryoEM.

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