1 ^st , 2 ^nd , and 3 ^rd + SARS-CoV-2 infections: associations of prior infections with protection and severity

Since the emergence of the antigenically distinct Omicron variant, SARS-CoV-2 reinfections have increased and are common. Yet, as we approach endemicity, the frequency, severity, and consequences of reinfections remain poorly understood. Using data from a household transmission study in Managua, Nicaragua (2020-2024), we evaluated protection conferred by one, two, and three+ prior infections and compared the severity of first, second, and third+ RT-PCR-confirmed SARS-CoV-2 infections. In adults, compared to those with no prior infections, after adjusting for vaccination, one, two, and three+ prior infections were associated with increasing protection from symptomatic infection: 46%, (95% Confidence Interval [CI]: 32-57%), 69% (95%CI: 56-78%), and 77% (95%CI: 58-88%), respectively. Compared to first infections, second and third+ infections were associated with decreasing severity in adults, adjusted for vaccination; 35% (95%CI: 11-52%) and 42% (95%CI: 6-65%) less moderate/severe disease, and 152% (95%CI: 46-336%) and 243% (95%CI: 82-545%) more subclinical disease, respectively.