BackgroundSARS-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.MethodsWe 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.FindingsOf 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]).InterpretationAncestral-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.FundingUS Centers for Diseases Control and Prevention.