Impact of pre-Omicron COVID-19 vaccine boosters on the risk of Omicron variant infections: A systematic review and meta-regression

Background: An argument against COVID-19 vaccine boosters is that immune imprinting may impair immune responses to new SARS-CoV-2 variants, as some epidemiological studies found a paradoxical increase in Omicron variant infections correlated with the number of prior pre-Omicron vaccine doses. However, substantial variability between studies has left the true impact of boosters uncertain, warranting further investigation. Method(s): We systematically reviewed available data and applied meta-regression to identify sources of heterogeneity among studies that examined the impact of pre-Omicron COVID-19 vaccine boosters-compared with primary vaccination series without boosters-on the risk of Omicron variant infections and severe diseases. Result(s): We screened 1703 articles and included 35 eligible studies. Heterogeneities in the impact of pre-Omicron boosters on the risk of Omicron infections and severe diseases are attributable to differences in time after boosters, age, and vaccine products (meta-regression R2: 70.4 % and 67.7 %, respectively). During the first month post-vaccination, pre-Omicron mRNA boosters decrease-rather than increase-the risk of Omicron infections and severe diseases by 58 % (95 % CI: 54 %-62 %) and 80 % (95 % CI: 68 %-87 %). This effectiveness declines to 9 % (95 % CI: 7 %-23 %) and 55 % (95 % CI: 49 %-60 %) by the sixth and fifth month, respectively. The certainty for evidence is moderate for protection against infections and high for protection against severe diseases. Conclusion(s): Our findings refute the immune imprinting hypothesis that COVID-19 boosters impair immunity against new SARS-CoV-2 variants and support current recommendations to stay protected through updated booster vaccination once or twice a year. Copyright © 2025 Formosan Medical Association