Exploring Novel B-cell Specific Immunomodulatory Adjuvants and Future Implications for HIV Vaccines
Year: 2026
Type: dissertation
Abstract: Eliciting broadly neutralizing antibodies (bNAbs) against human immunodeficiency virus-1 (HIV-1). HIV-1 infects CD4 T cells through its envelope glycoprotein trimer (Env), which is the only virally encoded protein on the viral surface and thus serves as a key target for vaccine development. By binding to conserved epitopes of HIV-1 Env, bNAbs confer protection against multiple clades of HIV-1. To elicit bNAbs, engineered Env proteins that are stable and mimic native Env are required. BG505 SOSIP.664 (BG505) are recombinant Env trimers locked in the pre-fusion conformation and mimic native Env. Despite displaying many epitopes for bNAbs, BG505 failed to activate B cells expressing the germline precursor of bNAbs, or elicit bNAbs in mouse models. In this study we tested protein nanoparticles as a vaccine platform for BG505 to activate B cells expressing a potent bNAb, VRC01 and its germline precursor (gVRC01). We hypothesized that presentation of BG505, together with a CD19 targeting antibody, a key B cell coreceptor which enhances BCR signaling, on protein nanoparticles would enhance activation of gVRC01-BCR. We found that nanoparticle-mediated co-engagement of VRC01-BCR and CD19 synergistically enhanced B cell signaling in vitro, including elevated calcium flux, CD19 and total tyrosine phosphorylation, and downstream signaling. Notably, such enhanced activation did not translate into increased Env-specific IgG in a wild type mouse model. However, we found that incorporating germline-targeting (GT) Env variants on anti-CD19-Fab-incorporated nanoparticles enhanced gVRC01-BCR signaling. Heterologous immunizations using nanoparticles displaying anti-CD19 and GT-Env variants with increasing resemblance to native Env resulted in increased Env-specific IgM but not IgG. In contrast, engaging CD19 only during prime polarized the immune response towards IgG and increased T follicular helper cells. Although these antibodies were non-neutralizing to BG505 pseudoviruses (PsV), elicited antibodies were neutralizing to the near-native N276D BG505 PsV. Our study was the first to demonstrate that antibody responses during a multi-dosage immunization regimen with low affinity antigen such as HIV-1 is highly dependent on the timing of CD19 co-engagement. The findings of our current study could be instructive in guiding future immunogen designs and immunization strategies for HIV-1 and other infectious agents.
Source: TSpace (University of Toronto)
Author: Zhao, Tiantian
Language: English
Topic: HIV Research and Treatment
Subfield: Virology
Field: Immunology and Microbiology
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W7203962041