Biology subjects

Nair, U.

Publications and source records attributed to Nair, U..

3 recordsLinked to original sources

bioRxiv2026

HIV broadly neutralizing antibody precursor maturation induced by mRNA vaccination in nonhuman primates

The induction of broadly neutralizing antibodies (bnAbs) is a principal goal of prophylactic HIV vaccines. For many bnAbs, priming ultrarare precursors from the naive B cell repertoire is the first major immunological hurdle. Previous studies have shown that the germline-targeting (GT) priming immunogen N332-GT5 delivered as adjuvanted protein to non-human primates (NHPs) activates bnAb precursor B cells for the human bnAb BG18 targeting the V3-glycan supersite on the HIV envelope (Env) glycoprotein. Here, we engineered N332-GT6 to improve binding affinity to diverse BG18-class precursor naive B cells by 9-fold. mRNA-LNP vaccines expressing N332-GT5 or N332-GT6 as membrane-bound (gp151) trimers were evaluated for their ability to prime BG18-class precursor B cells in NHPs across three related studies. Although N332-GT5 gp151 mRNA-LNP priming induced BG18-class precursor B cells in most animals after two vaccinations, the higher-affinity N332-GT6 gp151 induced responses more consistently after only one immunization. Sequential vaccination with two heterologous mRNA-LNP booster immunizations drove affinity maturation and induced BG18-class memory B cells capable of binding wildtype HIV Env. Together, these findings demonstrate that mRNA immunization can achieve GT priming, boosting, and early maturation of ultrarare bnAb-class B cells in NHPs.

immunology↗

bioRxiv2025

Antibody feedback establishes an affinity brake in the germinal center

Recent advances in mRNA vaccine technology have opened the door to novel types of antigen display, but little is yet known as to how B cells recognize and respond to these formats. By delivering an mRNA-LNP encoded membrane-bound immunogen displaying three conserved HIV-1 Envelope (Env) epitopes to knock-in mouse models with B cell receptors (BCRs) of defined affinities, we investigated how epitope-specific competition shapes germinal center (GC) responses. Co-activation of B cells targeting different epitopes did not alter GC kinetics observed in individual activations, but a striking inverse correlation was observed between BCR affinity and GC residence time in either scenario: high-affinity B cells exhibited shorter persistence in GCs, while those with lower affinity to the antigen were maintained. Furthermore, B cells were able to engage in GC reactions at equivalent rates in the presence or absence of clonal lineages binding the same epitope with similar affinities, while higher-affinity clones suppressed lower-affinity counterparts targeting the same epitope. Spatial transcriptomics revealed plasma-like cells within and adjacent to the GC which, together with the detection of early IgG in draining lymph nodes, suggests that local antibody production from these cells may contribute to feedback-driven kinetics. These findings indicate that a self-modulated local antibody feedback loop may act as a "brake" on epitope-specific recognition--dampening further affinity enhancement for high-affinity B cells and facilitating epitope spreading by redirecting the response toward alternative epitopes.

immunology↗

bioRxiv2025

Rapid acquisition of HIV-1 neutralization breadth in a rhesus V2 apex germline antibody mouse model after a single bolus immunization

Current vaccine strategies to elicit broadly neutralizing antibodies (bnAbs) against HIV-1 generally propose complex, multi-boost immunization regimens. In rhesus macaques, SHIV infection has been observed to rapidly drive the development of some classes of bnAbs that share structural similarities with those in humans. Here, we generated a knockin mouse model with B cells bearing the unmutated common ancestor (UCA) of the V2 apex-targeted bnAb lineage, V033-a. A single immunization of mice with a germline-targeting native-like trimer was sufficient to recapitulate the ontogeny of the mature rhesus bnAb in knockin mice--including rare, disfavored somatic mutations--leading to the induction of antibodies that exhibited potent neutralization against both autologous and heterologous tier 2 viruses. A boost with Env escape mutant trimers further improved breadth and potency, and cryo-EM structure revealed the structural basis for heterologous neutralization breadth. Non-human primate and mouse models can thus combine with structure to serve as a platform for identifying and confirming immunogens that streamline HIV-vaccination regimens.

immunology↗