Effectiveness of heterologous third and fourth dose COVID-19 vaccine schedules for SARS-CoV-2 infection during delta and omicron predominance in Thailand: a test-negative, case-control study

Background The Coronavirus disease 2019 (COVID-19) pandemic has evolved quickly, with numerous waves of different variants of concern resulting in the need for countries to offer continued protection through booster vaccination. To ensure adequate vaccination coverage, Thailand has proactively adopted heterologous vaccination schedules. While randomised controlled trials have assessed homologous schedules in detail, limited data has been reported for heterologous vaccine effectiveness (VE).Methods Utilising a unique active surveillance network established in Chiang Mai, Northern Thailand, we conducted a test-negative case control study to assess the VE of heterologous third and fourth dose schedules against SARS-CoV-2 infection among suspect-cases during Oct 1-Dec 31, 2021 (delta-predominant) and Feb 1-Apr 10, 2022 (omicron -predominant) periods.Findings After a third dose, effectiveness against delta infection was high (adjusted VE 97%, 95% CI 94-99%) in comparison to moderate protection against omicron (adjusted VE 31%, 95% CI 26-36%). Good protection was observed after a fourth dose (adjusted VE 75%, 95% CI 71-80%). VE was consistent across age groups for both delta and omicron infection. The VE of third or fourth doses against omicron infection were equivalent for the three main vaccines used for boosting in Thailand, suggesting coverage, rather than vaccine type is a much stronger predictor of protection. Interpretation Appropriately timed booster doses have a high probability of preventing COVID-19 infection with both delta and omicron variants. Our evidence supports the need for ongoing national efforts to increase population coverage of booster doses.