Durability of protection of ancestral-strain COVID-19 third- and fourth-dose vaccine boosters against Omicron XBB/XBB.1 and JN.1 symptomatic infection, hospitalisation and mortality in Indonesian adults (2023-2024): a test-negative case control study

Background SARS-CoV-2 ancestral-strain vaccines have effectively reduced SARS-CoV-2-related severe illness and death worldwide. However, waning immunity over time has warranted revaccination to boost immunity. Indonesia, like most low- and middle-income countries, has not provided regular vaccine boosters post-pandemic. This study assessed the longer-term durability of protection from ancestral-strain third- and fourth-dose boosters. Methods We conducted a test-negative case control study among symptomatic adults seeking SARS-CoV-2 testing at 14 purposely selected test sites in the major cities of Yogyakarta and Jakarta (March 2023-May 2024). Test-positive individuals were cases and test-negative individuals were controls. SARS-CoV-2 variants were identified using whole genome sequencing. We used multivariable logistic regression to estimate absolute or incremental vaccine effectiveness (VE) against symptomatic infection and COVID-19-related hospitalisation or death, adjusted for main confounders. Findings Of 2439 participants (median age 35 years, 56.2 female), 388 were cases and 2051 controls. Vaccination with two primary doses, a third-dose or fourth-dose booster did not provide sustained protection against Omicron XBB/JN.1 symptomatic infection up to median 27, 20 or 13 months since administration, respectively. However, there was sustained incremental protection from the third-dose booster (administered median 20 month prior) against hospitalisation (VE 38.3 95% CI 3.9-60.3) and death (55.2% 17.7-75.6) for older individuals (aged >50 years), and against death (55.2% 12.8-76.9) for individuals with one or more comorbidities. There was also sustained incremental protection from the fourth-dose booster (administered median 13 months prior) against hospitalisation for older individuals (50.2% 10.3-72.3) and individuals with one or more comorbidities (74.4% 49.2-87.1). Interpretation Ancestral-strain vaccine boosters provided durable, moderate protection against severe or fatal outcomes from Omicron XBB/JN.1 infection for older and comorbid individuals. The findings highlight the benefits of improving access to revaccination for vulnerable groups in Indonesia. Funding US Centers for Diseases Control and Prevention. © 2025 The Author(s).