IgG and Fc Receptor Genetic Variation Associates With Functional Antibody Responses in a DNA and Protein Candidate HIV Vaccine Trial.

BACKGROUND: The HVTN108 trial evaluated the safety and immunogenicity of a DNA prime, adjuvanted protein boost HIV vaccine in the United States and South Africa. The underlying factors influencing individual variation in vaccine responsiveness are unknown. In this study, we defined the IgG Fc and Fc receptor (FcR) genotypes in the HVTN108 cohort to test our hypothesis that IgG and FcR genetic variation can affect vaccine-elicited functional antibody responses. METHODS: IgG Fc and FcR alleles were determined by targeted PCR amplification and next-generation sequencing. Vaccine-elicited functional antibody responses, including binding antibody multiplex assay (BAMA), antibody-dependent cellular cytotoxicity (ADCC), and antibody-dependent cellular phagocytosis (ADCP) activity, were measured using standardized and qualified methods. Relationships between alleles and antibody responses were identified by linear regression controlling for treatment group and region. RESULTS: The distribution of many polymorphisms significantly differed between the United States and South Africa. Within the subset of the cohort tested for functional antibody responses (IgG, n = 41; FcR, n = 55), IgG genotypes such as IGHG1*12 ( P = 0.012), IGHG3*11 ( P = 0.033), IGHG2*02 ( P = 0.038), IGHG4*07 ( P = 0.076), and others were associated with ADCC antibody responses when corrected for vaccine group and regional effects. In the same way, we identified that the FCER1A rs2427827 mutation had a significant association with lower peak ADCC activity and the FCER2 rs2228137 mutation was associated with lower antibody binding to Con6 gp120 protein. CONCLUSIONS: Genetic variation in both antibodies and FcRs associated with levels of HIV-vaccine-elicited functional antibodies. Significant regional differences in distribution of this variation support the need for vaccine testing in diverse populations.

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