Abstract
BACKGROUND: DENV-infection and SARS-CoV-2 are now endemic in tropical regions; interactions may exist, given antigenic cross-reactivity and cross-protection. Risk of subsequent DENV-infection following prior COVID-19 was evaluated in a population-based adult cohort. METHODS: Retrospective cohort study including all Singaporeans ≥18 years. National registries were used to construct contemporaneous SARS-CoV-2-infected/test-negative cohorts from 1st Sept 2021-31st Dec 2022 during Delta/Omicron emergence. COVID-19 vaccination status was classified using the national-immunization-registry. Risk of DENV-infection recorded in the national registry 31-300 days post-COVID-19 was contrasted against test-negatives using overlap-weighted Cox regression. Risk of other infections (invasive-pneumococcal-disease/tuberculosis/melioidosis/leptospirosis) were assessed as negative-outcome controls, and risk of DENV-infection post-influenza vaccination was assessed as a negative-exposure control. FINDINGS: 1,324,250 COVID-19 cases (predominantly vaccine-breakthrough mild Omicron infections) and 1,434,851 test-negatives were included. Significantly increased risk of DENV-infection was observed 31-300 days post-COVID-19 (adjusted-hazards-ratio, aHR = 1.10[95%CI = 1.05-1.15]), during a DENV3 surge. Excess-burden of DENV-infection post-COVID-19 was 0.36 cases (95%CI = 0.11-0.61) per-1000-individuals. Risks of subsequent DENV-infection were numerically highest in unvaccinated COVID-19 cases but not elevated in doubly-boosted cases (≥4 vaccine-doses). Risk of negative-outcome controls (other-infections) was not significantly elevated 31-300 days post-COVID-19, and risk of DENV-infection was not significantly elevated post-influenza vaccination. INTERPRETATION: Increased risk of DENV-infection (primarily DENV3) was observed up to 300 days post-SARS-CoV-2 infection (predominantly Omicron). While not irrefutable proof for possible antibody-dependent enhancement of DENV3-infection post-Omicron COVID-19, given modest effect sizes, future studies can shed more light on potential interactions. Public health strategies (e.g., vaccination) remain important in tropical/subtropical regions where COVID-19/DENV are now endemic. FUNDING: National-Medical-Research-Council, Singapore.