We monitored SARS-CoV-2 antibody changes following implementation of a national COVID-19 vaccination campaign and assessed implications for immunological protection against variants of concern. Between March 2021 and August 2022, we prospectively enrolled 2,300 patients seeking care for undifferentiated febrile illnesses across two study sites in the Dominican Republic. Sera was tested for total anti-spike antibodies (anti-S) and simultaneously collected nasopharyngeal samples by RT-PCR for acute SARS-CoV-2 infection. Geometric mean anti-S titers increased from 6.6 BAU/ml (95% CI 5.1-8.7) to 1,332 BAU/ml (CI 1055-1,682) during the study period. Multivariable binomial odds ratios for acute SARS-CoV-2 infection were 0.55 (0.40-0.74), 0.38 (0.27-0.55), and 0.27 (0.18-0.40) for the second, third, and fourth versus the first anti-S quartile, with similar findings by viral strain. Integrated serological and virological screening present an opportunity to rethink existing surveillance platforms by simultaneously monitoring population-level immunological markers and implications for emerging variant transmission.