Homologous and heterologous booster of COVID-19 vaccines: A systematic review and meta-analysis

To address waves of SARS-CoV-2 infections caused by various variants of concern (VOC), experts have recommended heterologous booster vaccination as a strategy to enhance long-term immunity. Therefore, this study aimed to review available data from randomized controlled trials (RCTs) to compare the relative efficacy and safety of heterologous booster vaccines versus homologous booster vaccines. We conducted a comprehensive search of relevant studies up to July 10, 2024 using PubMed, Embase, Web of Science (core collection), Cochrane, and Scopus. From 13,476 potential articles screened at the title abstract level and 191 full-text articles, we included four RCTs that assessed the safety and efficacy of heterologous booster vaccines compared to homologous booster vaccines. The meta-analysis indicated that a heterologous booster vaccine likely results in little to no difference compared to a homologous booster vaccine in preventing confirmed COVID-19 infections. The relative efficacy of the heterologous booster compared to the homologous booster was estimated at 31 % (OR: 0.69, 95 % CI: 0.40 to 1.18), 4 trials, 3943 participants, moderate certainty of evidence). None of the Serious Adverse Events (SAEs) reported in the RCTs were assessed as related to vaccination. Although the relative efficacy evidence suggests little to no difference between heterologous and homologous boosters, a directional trend favoring heterologous booster regimens was observed. The variation in follow-up periods across included studies suggests the need for more in-depth and long-term studies to further investigate this issue. Such research will help policymakers develop informed vaccination strategies, particularly in situations of vaccine shortages and high demand during future outbreaks. Copyright © 2026 The Authors.