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HIV broadly neutralizing antibody precursors induced to the Apex epitope in non-human primates

ABSTRACT: HIV broadly neutralizing antibody precursors induced to the Apex epitope in non-human primates

PROVIDER: PRJNA1299323 | ENA |

REPOSITORIES: ENA

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HIV broadly neutralizing antibody precursors induced to the Apex epitope in non-human primates

Project description:An effective prophylactic HIV vaccine will likely need to induce broadly neutralizing antibodies (bnAbs). BnAbs to the Apex region of the HIV envelope glycoprotein (Env) are promising targets for vaccination due to their relatively low somatic hypermutation compared with other bnAbs. Most Apex bnAbs engage Env using an exceptionally long heavy chain complementarity determining region 3 (HCDR3) containing specific binding motifs, which reduces bnAb precursor frequency and makes priming of rare bnAb precursors a likely limiting step in the path to Apex bnAb induction. We found that adjuvanted protein or mRNA-LNP immunization of rhesus macaques with ApexGT6, an Env trimer engineered to bind Apex bnAb precursors, consistently induced Apex bnAb-related precursors with long HCDR3s bearing bnAb-like sequence motifs. Cryo-electron microscopy revealed that elicited Apex bnAb-related HCDR3s possessed structures combining elements of several prototype Apex bnAbs. These results achieve an important HIV vaccine development milestone in outbred primates.

2025-08-25 | GSE304129 | GEO

Human Immunoglobulin Repertoire-Guided Immunogen Design Targeting HIV V2-Apex Broadly Neutralizing Antibody Precursors

Project description:Broadly neutralizing antibodies (bnAbs) to the HIV envelope (Env) V2-apex region are important leads for HIV vaccine design. Most V2-apex bnAbs engage Env with an uncommonly long heavy chain complementarity-determining region 3 (HCDR3), suggesting that rarity of bnAb precursors poses a challenge for vaccine priming. We created precursor sequence definitions for V2-apex HCDR3-dependent bnAbs and searched for related precursors in human antibody heavy chain ultradeep sequencing data from 14 HIV-unexposed donors. We found potential precursors in a majority of donors for only two long-HCDR3 V2-apex bnAbs, PCT64 and PG9, identifying these bnAbs as priority vaccine targets. We then engineered ApexGT Env trimers that bind inferred germlines for PCT64 and PG9 and have higher affinities for bnAbs; determined cryo-EM structures of ApexGT trimers bound to inferred germline and bnAb forms of PCT64 and PG9; and developed an mRNA-encoded cell-surface trimer for our lead ApexGT candidate. The methods and immunogens developed here have promise to assist the development of an HIV vaccine.

2023-03-11 | PXD033766 | Pride

HIV Env apex broadly cross-reactive neutralizing antibodies by vaccination

Project description:HIV Env apex broadly cross-reactive neutralizing antibodies by vaccination

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HIV broadly neutralizing antibody precursors to the Apex epitope induced in nonhuman primates.

Project description: Not available

| S-EPMC12453070 | biostudies-literature

Vaccination elicits HIV broadly neutralizing antibodies in primates

Project description:Vaccination elicits HIV broadly neutralizing antibodies in primates

| PRJNA1446683 | ENA

Prediction of broadly neutralizing antibodies

Project description:Prediction of broadly neutralizing antibodies

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Simultaneous Induction of Multiple Classes of Broadly Neutralizing Antibody Precursors via Combination Germline-Targeting Immunization

Project description:Inducing broadly neutralizing antibodies (bnAbs) against HIV remains a key challenge in vaccine development. Germline targeting immunogens have successfully primed bnAb B cell lineages to individual HIV envelope epitopes in humans and non-human primates. However, eliciting consistent breadth will require the induction of multiple bnAb classes. We investigated whether immunization with a combination of germline-targeting immunogens could concurrently prime multiple bnAb lineages in non-human primates. Animals were immunized with three immunogens, targeting distinct epitopes: the V3-glycan/N332 supersite, the V2 Apex region and the membrane-proximal external region (MPER), either individually or in combinations of two or all three. Triple combination immunization transiently reduced V2 Apex and V3-glycan responses, but by 8 weeks post-boost bnAb-precursor lineages were observed to all three epitopes. Similar somatic hypermutation was observed across groups, indicative of permissive germinal center responses. These findings support combination germline-targeting immunization as a viable strategy to prime multiple bnAb lineages simultaneously.

2025-12-17 | GSE306570 | GEO

Vaccination elicits HIV broadly neutralizing antibodies in primates

Project description:The high antigenic diversity of HIV has been a major obstacle to development of a broadly protective vaccine. Nevertheless, protective HIV broadly neutralizing antibodies (bnAbs) exist and have been proposed as templates for vaccine development1-6. Germline-targeting is a conceptually radical vaccine design approach to elicit bnAbs, aiming to prime rare bnAb-precursor B cells possessing pre-determined human genetic and structural features shared with template bnAbs, and then guide B cell affinity maturation to potent bnAb evolution with heterologous boosters7-11. Although the approach has shown promise in clinical12-17 and pre-clinical18-34 studies, it faces many immunological challenges and, to date, has not succeeded in generating bnAbs in humans or nontransgenic animals. Here, we report an adjuvanted protein germline-targeting vaccine tested in outbred nonhuman primates that successfully generated bnAb-class memory B cells and sera capable of neutralizing diverse HIV clinical isolates. bnAb clonal lineages were generated in ≥50% of animals, achieving up to 46% neutralization breadth compared to the reference bnAb. Vaccine-induced bnAbs exhibited precise structural mimicry of human bnAb interactions with HIV envelope (Env), matching the germline-targeting predictions. Furthermore, serum bnAb activity developed in 44% of animals; in the most striking instance serum bnAb titers reached levels expected to confer protection against diverse HIV isolates. These results demonstrate proof of principle that germline-targeting vaccines can reproducibly elicit prespecified classes of bnAbs to prespecified epitopes under endogenous conditions, supporting further optimization of this approach for HIV vaccine development.

2026-06-24 | GSE326649 | GEO

Prediction of broadly neutralizing antibodies [Singleron]

Project description:Prediction of broadly neutralizing antibodies [Singleron]

| PRJNA952999 | ENA

Prediction of broadly neutralizing antibodies [10X]

Project description:Prediction of broadly neutralizing antibodies [10X]

| PRJNA952157 | ENA