SummaryBackgroundNovel oral poliovirus vaccine type 2 (nOPV2) was administered in Liberia in response to an outbreak of circulating vaccine-derived poliovirus type 2 (cVDPV2) in 2021. We conducted a serological survey of polio antibodies after two national campaigns with nOPV2.MethodsThis clustered, cross-sectional, population-based seroprevalence survey was conducted in children aged 0–59 months, more than 4 weeks after the second nOPV2 vaccination round. We used a clustered sampling method in four geographical regions of Liberia, followed by a simple random sampling of households. One eligible child was randomly selected per household. Dried blood spot specimens were taken and vaccination history was recorded. The antibody titres against all three poliovirus serotypes were assessed using standard microneutralisation assays done at the US Centers for Disease Control and Prevention in Atlanta, GA, USA.FindingsAnalysable data were obtained from 436 (87%) of 500 enrolled participants. Of these, 371 (85%) children were reported via parental recall to have received two nOPV2 doses, 43 (10%) received one dose, and 22 (5%) received no doses. The seroprevalence against type 2 poliovirus was 38·3% (95% CI 33·7–43·0; 167 of 436 participants). No significant difference was observed between type 2 seroprevalence in children aged 6 months or older who were reported to have received two doses of nOPV2 (42·1%, 95% CI 36·8–47·5; 144 of 342), one dose (28·0%, 12·1–49·4; seven of 25), or no doses (37·5%, 8·5–75·5; three of eight; p=0·39). The seroprevalence against type 1 was 59·6% (54·9–64·3; 260 of 436), and the seroprevalence against type 3 was 53·0% (48·2–57·7; 231 of 436).InterpretationUnexpectedly, the data showed low type 2 seroprevalence after two reported doses of nOPV2. This finding is probably affected by the lower oral poliovirus vaccine immunogenicity previously demonstrated in resource-limited settings, with high prevalence of chronic intestinal infections in children and other factors discussed herein. Our results provide the first assessment of nOPV2 performance in outbreak response in the African region.FundingWHO and Rotary International.