Infection-acquired protection against SARS-CoV-2 infection and clinical severity by number of prior infections

SARS-CoV-2 reinfections have increased since Omicron 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. Compared to those with no prior infections, one, two, and three+ prior infections were associated with increasing protection from symptomatic infection, with incidence rate ratios of 0.39, (95% Confidence Interval [CI]: 0.26-0.61), 0.24 (95%CI: 0.13-0.42), and 0.20 (95%CI: 0.09-0.42), respectively. Among RT-PCR-confirmed infections, reinfections were associated with decreased severity; compared with first infections, second infections had 1.57 (95%CI: 1.15-2.16) times the proportion of subclinical disease and 0.65 (95%CI: 0.49-0.86) times the proportion of moderate/severe disease. Our findings suggest that protection generated from two prior infections may be stronger than one prior infection, although additional benefit beyond the second infection was not clearly observed. Together, our results suggest we are approaching an endemic phase of SARS-CoV-2 characterized by reduced severity relative to first infections, yet the burden remains high, underscoring the importance of maintaining immunity to manage ongoing disease.