Professor Icahn School of Medicine, Mount Sinai New York, New York, United States
Introduction/Rationale: Antibodies against the V1V2 domain of the HIV envelope glycoprotein have been identified as a potential correlate of reduced infection risk in three large HIV vaccine efficacy trials. Although vaccine-elicited anti-V1V2 antibodies do not mediate potent virus-neutralizing activities, they mediate Fc-dependent effector functions. Strategies that enhance the magnitude and quality of these responses may improve HIV vaccine efficacy.
Methods: We examined a lipid nanoparticle-encapsulated mRNA (mRNA-LNP) vaccine encoding the V1V2 domain of CRF_01.AE244 on the 2J9C scaffold. Immunogenicity was assessed in three animal models: mice, rabbits, and rhesus macaques, following two or more immunizations. Antibody binding, cross-reactivity, and Fc-mediated functions were quantified using Luminex antigen-binding assays, virion- and cell-surface Env recognition assays, antibody-dependent cellular phagocytosis (ADCP), and Fc receptor binding.
Results: In mice two doses of the V1V2 mRNA-LNP vaccine elicited robust, cross-reactive serum IgG responses that recognized soluble Env and native Env on cells and virions. Importantly, murine IgG2a antibodies were generated that displayed Fc-mediated activities. However, in rabbits the elicited responses were directed mainly against the scaffold, with minimal V1V2-specific antibodies even after four vaccinations. In contrast, rhesus macaques developed high-level V1V2-specific antibodies responses after two vaccinations, comparable to those observed in mice.
Conclusion: The V1V2 mRNA-LNP vaccine is highly immunogenic in mice and rhesus macaques, eliciting cross-clade functional antibodies capable of recognizing native Env. The marked species-dependent differences, most notably the weak V1V2 targeting in rabbits, underscore the importance of selecting appropriate animal models for preclinical HIV vaccine evaluation and may provide insights relevant to vaccine testing against other pathogens.
