Adam Abdullahi, Rebecca Morse, Mark Tsz Kin Cheng, Fehintola Ige, James Onyemata, Martin Edun, Anežka Kramná, Benjamin Sievers, S. Richard Turner, Haruna Wisso, Emmanuel Jonathan, Olasinbo Balogun, Abideen Salako, Hafsat Abdulazeez-Oha, Ayorinde James, Adesola Musa, Onisile Oluwaseun, Bamidele Iwalokun, Oliver Ezechi, Abbas Anzaku, Evaezi Okpokoro, Sophia Osawe, Gospel Nwikue, Ibrahim M. Kida, Baba Maiyaki Musa, Hassan Adam Murtala, Bo Meng, Leah Rosenzweig, SH Aliyu, Derek Smith, Paul MacAry, Rainer Döffinger, Witold Więcek, Babatunde Salako, Chee Wah Tan, Alashʼle Abimiku, Ravindra Kumar Gupta
Distinct from vaccine-first models, infection-first exposures provide a critical context for understanding SARS-CoV-2 immune imprinting in unvaccinated populations. We analyzed neutralizing antibody responses in two independent unvaccinated Nigerian cohorts sampled in early 2023. Using a BA.1 receptor-binding domain (RBD)-based assay for Omicron exposure discrimination, we identified widespread pre-Omicron and partial Omicron exposure. Despite recent Omicron infection, plasma neutralization titers against Omicron lineages remained equal or lower compared to those against ancestral Wu-1, indicating infection-derived imprinting. Depletion of Wu-1 spike-binding antibodies abrogated neutralization of both Wu-1 and Omicron pseudoviruses, confirming dominance of ancestral cross-reactive antibodies. Following Wu-1-based vaccination, neutralizing responses increased across all variants, yet Omicron titers did not exceed Wu-1 titers even after breakthrough infection. These findings demonstrate durable infection-induced immune imprinting established before vaccination and only partially mitigated by repeated Omicron exposures, underscoring the influence of infection-first exposure sequence on antibody breadth and broader global relevance for vaccine design.