Reactogenicity and Immunogenicity of Heterologous ChAdOx1-nCoV19 and BNT162b2 Vaccination: A Systematic Review and Meta-Analysis of the Heterologous COVID-19 Vaccination Outcomes

Background: To date, the reactogenicity and immunogenicity of heterologous ChAdOx1-nCoV19/BNT162b2 (ChAd/BNT) vaccination remain unclear. Here, we systematically assessed the reactogenicity and immunogenicity of the heterologous ChAd/BNT vaccination regimens. Methods: The publicly available studies on heterologous COVID-19 vaccination were systematically searched on PubMed, Web of Science, Embase and MedRxiv for the available literature up to August 1, 2021. We evaluated the immunogenicity by the geometric mean titers (GMTs) of the neutralizing antibody and anti-spike IgG. The reactogenicity was evaluated using the pooled risk ratios (RRs) calculated by the random-effects model about the adverse events after vaccination. Subgroup analyses based on vaccination regimens and interval between the two doses of vaccines were conducted to evaluate the impact of the different regimens. Findings: Nine studies (n=4,286) were included in the analyses. Compared to the homologous ChAd/ChAd vaccination, the heterologous ChAd/BNT vaccination showed significantly higher immunogenicity (pooled GMTR [geometric mean titers ratio] in terms of the neutralizing antibody: 11·92 [95% CI 5·65-25·13, I2=49·1%, P<0·001]; and GMTR of anti-spike IgG: 8·18 [95%CI 5·57-12·03,I2=50·7%, P<0·001]), but at the same time displayed higher reactogenicity (RR: 1·47, 95%CI 1·02-2·11, P=0·04), especially for the local adverse reactions. Moreover, heterologous ChAd/BNT vaccination showed similar immunogenicity to the homologous BNT/BNT vaccination (GMTR of neutralizing antibody: 1·03 [95%CI 0·79-1·35, I2=36·9%, P=0·803]; and GMTR of anti-spike IgG: 1·02 [95%CI 0·86-1·21, I2=48·3%, P=0·826]) and similar reactogenicity (RR: 1·22, 95%CI 0·92-1·63, P=0·17). Additionally, there was no significant difference in immunogenicity among different ChAd/BNT vaccination intervals (4 weeks; 8-12 weeks). Interpretation: Heterologous ChAd/BNT vaccination showed robust immunogenicity and tolerable reactogenicity. Further studies are needed to determine the optimal vaccine combinations and vaccination intervals. Registration Details: Our study was registered with PROSPERO, CRD42021265165. Funding Information: This research work was supported by the SINO-GERMAN rapid response funding call for COVID-19 related research (C-0073). Declaration of Interests: All the authors declare no competing interest.