Enhancing Functional Antibody Responses against HIV Envelope V1V2 through Vaccine Formulations

Clauvis Kungkeng Yengo^1,2Xiaomei Liu^1,2Gabriel Laghalli²Seokchan Park²Jéromine Klingler^1,2Christina C Luo³Xunqing Jiang³Xiang-Peng Kong³Priyanka G. Rao²Chitra Upadhyay²Matthew J. Wiest⁴Hiromi Muramatsu⁵Bruno G De Geest⁶Pamela T Wong⁴Ying Tam⁷Norbert Pardi⁵Michael Schotsaert²Catarina E. Hioe^1,2*

• ¹James J Peters VA Medical Center, New York, United States
• ²Icahn School of Medicine at Mount Sinai, New York, United States
• ³New York University Grossman School of Medicine, New York, United States
• ⁴University of Michigan, Ann Arbor, United States
• ⁵University of Pennsylvania, Philadelphia, United States
• ⁶Universiteit Gent, Ghent, Belgium
• ⁷Acuitas Therapeutics Inc, Vancouver, Canada

Background: Despite decades of research, the development of an effective HIV vaccine remains a significant challenge. Recent findings from three large vaccine efficacy trials have identified antibodies against the V1V2 domain of the HIV envelope glycoprotein as a potential correlate of reduced infection risk, offering a promising avenue for improving vaccine efficacy. Vaccine-elicited anti-V1V2 antibodies do not mediate potent virus-neutralizing activities, but they mediate Fc-dependent effector functions. Methods: This study evaluated the capacity of V1V2-scaffold vaccines in different formulations to generate antibody responses with Fc-mediated functions. BALB/c mice were immunized with V1V2-scaffold proteins formulated with one of the following adjuvants: MF59-like squalene-based oil-in-water emulsion (Addavax), a combination of TLR7/8 and RIG-I agonists (IMDQ-PC/IVT), nanoemulsion and RIG-I agonist (NE/IVT), or empty lipid nanoparticles (eLNP). All formulations were administered intramuscularly except NE/IVT, which was given intranasally. For comparison, we also tested a V1V2-scaffold-expressing mRNA-LNP vaccine delivered intramuscularly and an Env gp140 protein with liposomal MPLA/DDA adjuvant administered subcutaneously. Results: Among the six vaccine formulations tested, V1V2-scaffold immunogens adjuvanted with LNP (eLNP and mRNA-LNP) elicited the most robust and cross-reactive serum IgG responses that recognized native Env on cell surfaces or virions. The eLNP and mRNA-LNP groups, along with IMDQ-PC/IVT, also elicited functional IgG2a, and correspondingly displayed Fc-mediated activities, as measured by antibody-dependent cellular phagocytosis and FcγRIV binding. Notably, IMDQ-PC/IVT elicited predominantly IgG2a with minimal IgG1, eLNP stimulated IgG1 and IgG2a with IgG1 dominance, whereas mRNA-LNP yielded more balanced IgG2a/IgG1 responses. Conclusions: Data from this study provide new insights into the utility of novel formulations for V1V2-scaffold immunogens as a strategy for optimizing the induction of functional V1V2-specific antibodies to improve HIV vaccine efficacy.