The World Health Organization has endorsed single-dose human papillomavirus (HPV) vaccination, but data on the impact on HPV prevalence in high HIV burden settings are limited. A single-dose bivalent HPV vaccine was delivered to adolescent girls in grade 10 in a schools-based campaign in 1 district in South Africa. Impact on HPV 16 and 18 prevalence was evaluated using repeat cross-sectional surveys. A clinic-based survey in girls aged 17-18 years established HPV 16 and 18 prevalence in a prevaccine population (n = 506, including 157 living with HIV) in 2019 and was repeated in the same age group and sites in a single-dose eligible population in 2021 (n = 892, including 117 with HIV). HPV DNA was detected on self-collected vaginal swabs using the Seegene Anyplex II HPV 28. Population impact was estimated overall and by HIV status using prevalence ratios adjusted for differences in sexual behavior between surveys. Single-dose vaccination campaign coverage was 72% (4807 of 6673) of eligible girls attending high school (n = 66) in the district. HPV 16 and 18 prevalence was 35% lower in the postvaccine survey overall (adjusted prevalence ratio = 0.65, 95% confidence interval [CI] = 0.51 to 0.83; P < .001) and 37% lower in those living with HIV (adjusted prevalence ratio = 0.63, 95% CI = 0.41 to 0.95; P = .026). No protective effect was seen for nonvaccine oncogenic HPV types 33, 35, 39, 51, 52, 56, 58, 59, or 68 overall (adjusted prevalence ratio = 1.14, 95% CI = 1.03 to 1.26; P = .011) or in those living with HIV (adjusted prevalence ratio = 1.00, 95% CI = 0.83 to 1.21. P = 0.99). These data provide reassuring evidence of single-dose impact on population-level HPV 16 and 18 prevalence in a South African population, irrespective of HIV status.
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