Interplay of Immunity, Climate, and Viral Evolution Explains Semiannual SARS-CoV-2 Dynamics with Implications for Control

In the three years since Omicron emergence, SARS-CoV-2 dynamics have exhibited persistent twice-yearly waves in the United States, peaking in late summer and winter, with heterogeneity in timing and intensity across states. This semiannual pattern sharply contrasts with typical annual respiratory pathogen dynamics in the US, yet their underlying mechanisms and whether this pattern will persist remain poorly understood. Here, we tested several hypothesized mechanisms and found that a combination of waning immunity, climatic factors of relative humidity and temperature, variant activity, and vaccination captured divergent patterns in COVID-19 hospitalization incidence across 10 US states, from January 2022-November 2024. Applying a compartmental disease model, we identified that waning infection-derived immunity was the dominant driver of semiannual SARS-CoV-2 dynamics, with climate factors shaping the timing and magnitude of seasonal waves across US states. Scenario analyses indicated that if infection-derived immunity remains short in duration, semiannual dynamics influenced by climate are likely to persist, with attenuation in severe disease over time. In contrast, more durable infection-derived immunity, or a slower rate of immune-evading viral evolution, could lead to an epidemiologic transition to annual dynamics. In some states, summer waves approached the magnitude of winter waves, likely reflecting local climatic influences on transmission, suggesting that optimal vaccination strategies may vary by state. These findings have broad implications for understanding epidemic dynamics and informing vaccine policy, including seasonal timing and two-dose vaccine schedules for high-risk persons.