BackgroundThe effectiveness of full Coronavirus Disease 2019 (COVID-19) vaccination against COVID-19 wanes over time. This study aimed to synthesize the clinical effectiveness of the first dose of COVID-19 booster by comparing it to the full vaccination.MethodsStudies in PubMed, Web of Science, Embase, and clinical trials databases were searched from 1 January 2021 to 10 September 2022. Studies were eligible if they comprised general adult participants who were not ever or currently infected with SARS-CoV-2, did not have impaired immunity or immunosuppression, and did not have severe diseases. The seroconversion rate of antibodies to S and S subunits and antibody titers of SARS-CoV-2, frequency, phenotype of specific T and B cells, and clinical events involving confirmed infection, admission to the intensive care unit (ICU), and death were compared between the first booster dose of COVID-19 vaccination group and full vaccination group. The DerSimonian and Laird random effects models were used to estimate the pooled risk ratios (RRs) and corresponding 95% confidence intervals (CIs) for the outcomes of clinical interest. While a qualitative description was mainly used to compare the immunogenicity between the first booster dose of COVID-19 vaccination group and full vaccination group. Sensitivity analysis was used to deal with heterogenicity.ResultsOf the 10,173 records identified, 10 studies were included for analysis. The first dose COVID-19 booster vaccine could induce higher seroconversion rates of antibodies against various SAS-CoV-2 fragments, higher neutralization antibody titers against various SARS-CoV-2 variants, and robust cellular immune response compared to the full vaccination. The risk of SARS-CoV-2 infection, the risk of admission to the ICU, and the risk of death were all higher in the non-booster group than those in the booster group, with RRs of 9.45 (95% CI 3.22–27.79; total evaluated population 12,422,454 vs. 8,441,368;I2= 100%), 14.75 (95% CI 4.07–53.46; total evaluated population 12,048,224 vs. 7,291,644;I2= 91%), and 13.63 (95% CI 4.72–39.36; total evaluated population 12,385,960 vs. 8,297,037;I2= 85%), respectively.ConclusionA homogenous or heterogeneous booster COVID-19 vaccination could elicit strong humoral and cellular immune responses to SARS-CoV-2. Furthermore, it could significantly reduce the risk of SARS-CoV-2 infection and severe COVID-19 clinical events on top of two doses. Future studies are needed to investigate the long-term clinical effectiveness of the first booster dose of the COVID-19 vaccine and compare the effectiveness between homogenous and heterogeneous booster COVID-19 vaccination.Systematic review registrationhttps://inplasy.com/inplasy-2022-11-0114/, identifier: INPLASY2022110114.