Binding and neutralizing antibody levels and vaccine efficacy/effectiveness compared between heterologous and homologous primary series COVID-19 vaccination: A systematic review and meta-analysis

Background: The data on the immunogenicity and efficacy of heterologous primary series COVID-19 vaccination are still limited. Objective: To investigate the immunogenicity and vaccine efficacy/effectiveness compared between heterologous and homologous primary series COVID-19 vaccination.Methods: We conducted a multi-source search for randomized controlled trials, prospective cohort, and case-control studies that investigated the immunogenicity or vaccine efficacy/effectiveness (VE) of heterologous primary series vaccination. Six online databases were searched from inception to June 2022. The primary outcome was the levels of binding antibodies and neutralizing antibodies (NAbs), and the secondary outcomes were VE against COVID-19 infection, hospitalization, and death.Results: Among the 28 included studies, 21 and 7 were included to investigate immunogenicity and VE outcome, respectively. Heterologous CoronaVac (CV)/ChAdOx1 (ChAd) induced higher anti-RBD IgG and NAbs against wild type and delta variants compared to homologous CV or ChAd. However, risk of documented infection of CV/ChAd was similar to homologous CV, but higher than homologous ChAd (odds ratio: 2.56, 95% CI: 1.02-6.37). Heterologous ChAd/BNT162b2 (BNT) elicited a higher anti-spike level than homologous ChAd or BNT, and induced a higher NAbs level against delta variants compared to homologous ChAd. The VE of ChAd/BNT and homologous ChAd or BNT against hospitalization were similar.Conclusions: Heterologous CV/ChAd induced higher binding and neutralizing antibody levels than homologous CV or ChAd; and, ChAd/BNT induced higher binding and neutralizing antibody levels than homologous ChAd. However, CV/ChAd demonstrated increased risk of infection compared to homologous ChAd. Therefore, immunogenicity findings and real-world vaccine efficacy/effectiveness should be integrated in clinical practice.