An HIV Vaccine Targeting the V2 Region of the HIV Envelope Induces a Highly Durable Polyfunctional Fc-Mediated Antibody Response in Rhesus Macaques

• Published in: Journal of virology 2020-08, Vol.94 (17)
• Main Authors: Powell, Rebecca L, Weiss, Svenja, Fox, Alisa, Liu, Xiaomei, Itri, Vincenza, Jiang, Xunqing, Luo, Christina C, Spencer, David A, Pandey, Shilpi, Cheever, Tracy, Fuller, Deborah H, Totrov, Maxim, Hessell, Ann J, Haigwood, Nancy L, Kong, Xiang-Peng, Zolla-Pazner, Susan
• Format: Article
• Language: English
• Subjects: AIDS Vaccines - immunology; Animals; Antibody Formation; Disease Models, Animal; HIV Antibodies - immunology; HIV Antigens - genetics; HIV Antigens - immunology; HIV Envelope Protein gp120 - genetics; HIV Envelope Protein gp120 - immunology; HIV Infections - immunology; HIV Infections - prevention & control; HIV-1 - immunology; Immunization; Immunogenicity, Vaccine - immunology; Immunoglobulin Fc Fragments - immunology; Macaca mulatta - immunology; Viral Envelope Proteins - genetics; Viral Envelope Proteins - immunology
• ISSN: 0022-538X; 1098-5514
• DOI: 10.1128/JVI.01175-20

The HIV vaccine field now recognizes the potential importance of generating polyfunctional antibodies (Abs). The only clinical HIV vaccine trial to date to show significant efficacy (RV144) found that reduced infection rates correlated with the level of nonneutralizing Abs specific for the V2 region of the envelope glycoprotein. We have conducted a comprehensive preclinical reverse vaccinology-based vaccine program that has included the design and production and testing of numerous scaffolded V2 region immunogens. The most immunogenic vaccine regimen in nonhuman primates among those studied as part of this program consisted of a cocktail of three immunogens presenting V2 from different viruses and clades in the context of different scaffolds. Presently we demonstrate that the V2-specific Ab response from this regimen was highly durable and functionally diverse for the duration of the study (25 weeks after the final immunization). The total IgG binding response at this late time point exhibited only an ∼5× reduction in potency. Three immunizations appeared essential for the elicitation of a strong Ab-dependent cellular cytotoxicity (ADCC) response for all animals, as opposed to the Ab-dependent cellular phagocytosis (ADCP) and virus capture responses, which were comparably potent after only 2 immunizations. All functionalities measured were highly durable through the study period. Therefore, testing this vaccine candidate for its protective capacity is warranted. The only HIV vaccine trial for which protective efficacy was detected correlated this efficacy with V2-specific Abs that were effectively nonneutralizing. This result has fueled a decade of HIV vaccine research focused on designing an HIV vaccine capable of eliciting V2-focused, polyfunctional Abs that effectively bind HIV and trigger various leukocytes to kill the virus and restrict viral spread. From the numerous vaccine candidates designed and tested as part of our V2-focused preclinical vaccine program, we have identified immunogens and a vaccine regimen that induces a highly durable and polyfunctional V2-focused Ab response in rhesus macaques, described herein.