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Taking RV144 beyond Thailand: The RV144 vaccine trial in Thailand is the only HIV vaccine to show efficacy against HIV infection to date. Gray et al. designed the HVTN 097 trial to test this regimen in South Africa, where clade C HIV circulates; this clade is heterologous to the vaccine antigens. They intently examined immune protective responses previously identified in the RV144 trial and found that the vaccine seemed to be even more immunogenic in South Africans. CD4+ T cell responses were stronger and more common in HVTN 097, and the magnitude of protective antibody responses was greater compared to RV144. Their results indicate that the RV144 regimen or others like it could be protective in areas where HIV is endemic. One of the most successful HIV vaccines to date, the RV144 vaccine tested in Thailand, demonstrated correlates of protection including cross-clade V1V2 immunoglobulin G (IgG) breadth, Env-specific CD4+ T cell polyfunctionality, and antibody-dependent cellular cytotoxicity (ADCC) in vaccinees with low IgA binding. The HIV Vaccine Trials Network (HVTN) 097 trial evaluated this vaccine regimen in South Africa, where clade C HIV-1 predominates. We compared cellular and humoral responses at peak and durability immunogenicity time points in HVTN 097 and RV144 vaccinee samples, and evaluated vaccine-matched and cross-clade immune responses. At peak immunogenicity, HVTN 097 vaccinees exhibited significantly higher cellular and humoral immune responses than RV144 vaccinees. CD4+ T cell responses were more frequent in HVTN 097 irrespective of age and sex, and CD4+ T cell Env-specific functionality scores were higher in HVTN 097. Env-specific CD40L+ CD4+ T cells were more common in HVTN 097, with individuals having this pattern of expression demonstrating higher median antibody responses to HIV-1 Env. IgG and IgG3 binding antibody rates and response magnitude to gp120 vaccine– and V1V2 vaccine–matched antigens were higher or comparable in HVTN 097 than in RV144 ADCC, and ADCP functional antibody responses were elicited in HVTN 097. Env-specific IgG and CD4+ Env responses declined significantly over time in both trials. Overall, cross-clade immune responses associated with protection were better than expected in South Africa, suggesting wider applicability of this regimen. [ABSTRACT FROM AUTHOR]