Biology subjects

Bal, J.

Publications and source records attributed to Bal, J..

3 recordsLinked to original sources

bioRxiv2026

Rapid vaccine induction of macaque HIV-1 V2 Apex broadly neutralizing antibodies with immunogenetic signatures that are potentially translatable to humans

Due to the complex biology of HIV-1 broadly neutralizing antibodies (bnAbs), HIV-1 vaccines must target unmutated germline precursor antibodies with B cell receptors that have the appropriate specificity and genetic features to develop neutralization breadth. Previous work has shown that immunization or infection in macaques primes unmutated precursor antibodies that target the broadly neutralizing epitope composed of the second variable region and proximal glycans (termed V2-apex site) of HIV-1 envelope (Env). Macaque V2-apex bnAb precursors elicited thus far have homogeneous usage of the second reading frame of a diversity (D) gene found only in macaques, calling into question whether HIV-1 Env immunogens can elicit only this canonical, macaque-specific V2-apex antibody response, limiting human vaccination success. Here, we show that vaccination of rhesus macaques with Env conjugated to a ferritin nanoparticle (OPT4-scNP) rapidly elicited V2-apex bnAbs with distinct D gene segment usage and motifs that are not restricted only to macaques. After two priming immunizations, V2-apex antibodies with non-canonical HCDR3s exhibited greater neutralization potency and breadth than V2-apex antibodies with previously observed HCDR3 motifs. Following sequential boosting immunizations, a V2-apex bnAb lineage with a novel HCDR3-encoded EDGED motif increased its neutralization breadth, including neutralization of viral isolates bearing the N130 glycan, which shields the V2-apex from recognition. High-resolution structures of two members of this V2-apex bnAb lineage, called DH2050, defined a novel binding mode in which it used its EDGED motif to contact the C-strand peptide and the N160 glycan within the V2-apex site. Altogether, we define a novel bnAb binding mode to the V2 Apex and demonstrate that HIV-1 Env sequential vaccination elicits V2-apex bnAbs with immunogenetic signatures that are potentially translatable to the human immune system.

immunology↗

bioRxiv2023

Vaccine induction of CD4-mimicking broadly neutralizing antibody precursors in macaques

The CD4 binding site (CD4bs) is a conserved epitope on HIV-1 envelope (Env) that can be targeted by protective broadly neutralizing antibodies (bnAbs). HIV-1 vaccines have not elicited CD4bs bnAbs for many reasons, including the CD4bs is occluded by glycans, immunogen expansion of appropriate naive B cells, and selection of functional antibody mutations. Here, we demonstrate immunization of macaques with a CD4bs-targeting immunogen elicits neutralizing bnAb precursors with structural and genetic features of CD4-mimicking bnAbs. Structures of the CD4bs nAbs bound to HIV-1 Env demonstrated binding angles similar to human bnAbs and heavy chain second complementarity determining region-dependent binding characteristic of all known human CD4-mimicking bnAbs. Macaque nAbs were derived from variable and joining gene segments orthologous to the genes of human VH1-46-class bnAbs. This vaccine study initiated the B cells from which derive CD4bs bnAbs in primates, accomplishing the key first step in development of an effective HIV-1 vaccine.

immunology↗

bioRxiv2022

Mutation-Guided Vaccine Design: A Strategy for Developing Boosting Immunogens for HIV Broadly Neutralizing Antibody Induction

A major goal of HIV-1 vaccine development is induction of broadly neutralizing antibodies (bnAbs). While success has been achieved in initiating bnAb B cell lineages, design of boosting immunogens that select for bnAb B cell receptors with improbable mutations required for bnAb affinity maturation remains difficult. Here we demonstrate a process for designing boosting immunogens for a V3-glycan bnAb B cell lineage. The immunogens induced affinity-matured antibodies by selecting for functional improbable mutations in bnAb precursor knock-in mice. Moreover, we show similar success in prime and boosting with nucleoside-modified mRNA-encoded HIV-1 envelope trimer immunogens, with improved selection by mRNA immunogens of improbable mutations required for bnAb binding to key envelope glycans. These results demonstrate the ability of both protein and mRNA prime-boost immunogens for selection of rare B cell lineage intermediates with neutralizing breadth after bnAb precursor expansion, a key proof-of concept and milestone towards development of an HIV vaccine. One-Sentence SummaryA vaccine strategy for selecting key rare antibody mutations is shown to induce HIV broadly neutralizing antibodies in mice.

immunology↗