Fc Gamma Receptor Polymorphisms Modulated the Vaccine Effect on HIV-1 Risk in the HVTN 505 HIV Vaccine Trial

Area of Science:

• Immunology
• Genetics
• Vaccinology

Background:

• The HIV Vaccine Trials Network (HVTN) 505 trial evaluated a DNA/recombinant adenovirus 5 (rAd5) HIV vaccine regimen.
• The trial was halted early due to a lack of overall efficacy, but subsequent analyses suggested differential effects on HIV acquisition risk.

Purpose of the Study:

• To investigate the influence of host Fc gamma receptor (FcγR) genetic variations on the efficacy of the DNA/rAd5 HIV vaccine regimen.
• To determine if specific FcγR genetic profiles modulated HIV infection risk following vaccination.

Main Methods:

• Analysis of host Fc gamma receptor (FcγR) genetic variations, including specific haplotypes and single-nucleotide polymorphisms (SNPs).
• Correlative analyses of vaccine receipt, HIV acquisition risk, and immune responses (T-cell polyfunctionality, IgG, antibody-dependent cellular phagocytosis).
• Statistical evaluation of interactions between vaccine, placebo, and FcγR genetic variations on HIV risk.

Main Results:

• Participants with the FCGR2C-TATA haplotype showed a significantly increased risk of HIV acquisition after receiving the DNA/rAd5 vaccine compared to placebo (HR=9.79, P=0.035).
• Participants with the FCGR3B-AGA haplotype also exhibited an increased risk of HIV acquisition with the vaccine regimen (HR=2.78, P=0.058).
• FcγR genetic variations influenced the correlation between immune responses (Env-specific CD8+ T-cell polyfunctionality, IgG, FcγR-mediated phagocytosis) and HIV risk.

Conclusions:

• Host Fc gamma receptor (FcγR) genetic variations significantly modulate the effect of the DNA/rAd5 HIV vaccine regimen on HIV-1 acquisition risk.
• FcγR genetics also influenced immune responses generated by the vaccine.
• These findings underscore the importance of considering host FcγR genetics in the design and analysis of future HIV vaccine trials.