SARS-CoV-2 Omicron infection reveals imprinted antibody responses in the absence of vaccination

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.