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Background With the emergence of SARS‐CoV‐2, influenza surveillance systems in Spain were transformed into a new syndromic sentinel surveillance system. The Acute Respiratory Infection Surveillance System (SiVIRA in Spanish) is based on a sentinel network for acute respiratory infection (ARI) surveillance in primary care and a network of sentinel hospitals for severe ARI (SARI) surveillance in hospitals. Methods Using a test‐negative design and data from SARI admissions notified to SiVIRA between January 1 and October 3, 2021, we estimated COVID‐19 vaccine effectiveness (VE) against hospitalization, by age group, vaccine type, time since vaccination, and SARS‐CoV‐2 variant. Results VE was 89% (95% CI: 83–93) against COVID‐19 hospitalization overall in persons aged 20 years and older. VE was higher for mRNA vaccines, and lower for those aged 80 years and older, with a decrease in protection beyond 3 months of completing vaccination, and a further decrease after 5 months. We found no differences between periods with circulation of Alpha or Delta SARS‐CoV‐2 variants, although variant‐specific VE was slightly higher against Alpha. Conclusions The SiVIRA sentinel hospital surveillance network in Spain was able to describe clinical and epidemiological characteristics of SARI hospitalizations and provide estimates of COVID‐19 VE in the population under surveillance. Our estimates add to evidence of high effectiveness of mRNA vaccines against severe COVID‐19 and waning of protection with time since vaccination in those aged 80 or older. No substantial differences were observed between SARS‐CoV‐2 variants (Alpha vs. Delta).

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