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We performed a prospective, cross-sectional study of household contacts of symptomatic index case-patients with SARS-CoV-2 infection during the shift from Delta- to Omicron-dominant variants in Spain. We included 466 household contacts from 227 index cases. The secondary attack rate was 58.2% (95% CI 49.1%–62.6%) during the Delta-dominant period and 80.9% (95% CI 75.0%–86.9%) during the Omicron-dominant period. During the Delta-dominant period, unvaccinated contacts had higher probability of infection than vaccinated contacts (odds ratio 5.42, 95% CI 1.6–18.6), but this effect disappeared at ≈20 weeks after vaccination. Contacts showed a higher relative risk of infection (9.16, 95% CI 3.4–25.0) in the Omicron-dominant than Delta-dominant period when vaccinated within the previous 20 weeks. Our data suggest vaccine evasion might be a cause of rapid spread of the Omicron variant. We recommend a focus on developing vaccines with long-lasting protection against severe disease, rather than only against infectivity.