OBJECTIVE: One recurrent question is whether an HIV-1 preventive vaccine requires adaptation to geographic and/or ethnicity background. A recent attempt to improve the Thai RV144 vaccine efficacy in South Africa resulted in non-efficacy. The potential reasons for this disappointing outcome are probably multifactorial; the role of ethnicity could not be investigated given the trials' demographics. DESIGN: To assess the role of ethnicity in the immune responses induced in HIV vaccine trials, we considered the HVTN 204 vaccine trial, which was conducted in the USA and South Africa. METHODS: Univariate and multivariate analysis of antibody responses were conducted to assess ethnicity, geographic location, Fc-receptor polymorphism, sex at birth, age and geographic location. RESULTS: We found that Black South Africans displayed higher total Immunoglobulins compared to White Americans. Noteworthy, Black South Africans showed lower HIV-specific binding IgG following vaccination. As they also showed lower background at baseline, differences between ethnic groups were narrowed after baseline background subtraction, referred to as delta values for the vaccine response outcome. CONCLUSIONS: The observed modifications of HIV-specific Ab immune responses to the HVTN 204 vaccine according to genetic, geographic location and ethnic background warrants further investigation. Additional studies of immunological differences, especially with vaccine platforms inducing high HIV-specific antibodies that correlate with vaccine efficacy may help decipher the impact of ethnicity on HIV-vaccine efficacy.Read less <