Safety of heterologous primary and booster schedules with ChAdOx1-S and BNT162b2 or mRNA-1273 vaccines: nationwide cohort study

Abstract

Objective To assess the risk of adverse events associated with heterologous primary (two dose) and booster (three dose) vaccine schedules for covid-19 with Oxford-AstraZeneca’s ChAdOx1-S priming followed by mRNA vaccines (Pfizer-BioNTech’s BNT162b2 or Moderna’s mRNA-1273) as compared with homologous mRNA vaccine schedules for covid-19. Design Nationwide cohort study. Setting Denmark, 1 January 2021 to 26 March 2022. Participants Adults aged 18-65 years who received a heterologous vaccine schedule of priming with ChAdOx1-S and one or two mRNA booster doses (with either the BNT162b2 or mRNA-1273 vaccine) were compared with adults who received a homologous BNT162b2 or mRNA-1273 vaccine schedule (ie, two dose v two dose, and three dose v three dose schedule). Main outcome measures The incidence of hospital contacts for a range of adverse cardiovascular and haemostatic events within 28 days after the second or third vaccine dose, comparing heterologous versus homologous vaccine schedules. Secondary outcomes included additional prioritised adverse events of special interest. Poisson regression was used to estimate incidence rate ratios with adjustment for selected covariates. Results Individuals who had had a heterologous primary vaccine (n=137 495) or a homologous vaccine (n=2 688 142) were identified, in addition to those who had had a heterologous booster (n=129 770) or a homologous booster (n=2 197 213). Adjusted incidence rate ratios of adverse cardiovascular and haemostatic events within 28 days for the heterologous primary and booster vaccine schedules in comparison with the homologous mRNA vaccine schedules were 1.22 (95% confidence interval 0.79 to 1.91) and 1.00 (0.58 to 1.72) for ischaemic cardiac events, 0.74 (0.40 to 1.34) and 0.72 (0.37 to 1.42) for cerebrovascular events, 1.12 (0.13 to 9.58) and 4.74 (0.94 to 24.01) for arterial thromboembolisms, 0.79 (0.45 to 1.38) and 1.09 (0.60 to 1.98) for venous thromboembolisms, 0.84 (0.18 to 3.96) and 1.04 (0.60 to 4.55) for myocarditis or pericarditis, 0.97 (0.45 to 2.10) and 0.89 (0.21 to 3.77) for thrombocytopenia and coagulative disorders, and 1.39 (1.01 to 1.91) and 1.02 (0.70 to 1.47) for other bleeding events, respectively. No associations with any of the outcomes were found when restricting to serious adverse events defined as stay in hospital for more than 24 h. Conclusion Heterologous primary and booster covid-19 vaccine schedules of ChAdOx1-S priming and mRNA booster doses as both second and third doses were not associated with increased risk of serious adverse events compared with homologous mRNA vaccine schedules. These results are reassuring but given the rarity of some of the adverse events, associations cannot be excluded.

A third vaccine dose equalizes the levels of effectiveness and immunogenicity of heterologous or homologous COVID-19 vaccine regimens

“…This booster dose was particularly important in immunosuppressed patients for whom vaccine efficacy was lower. Heterologous vaccine schedules of ChAdOx1-S priming and mRNA booster doses as both second and third doses were not associated with increased risk of serious adverse events compared with homologous mRNA vaccine schedules [8]. Recent reports demonstrated that most COVID-19 vaccines delivered as a third dose booster significantly enhanced both humoral and cellular anti-SARS-CoV-2 immunity [9].…”

Safety and immunogenicity of the protein-based PHH-1V compared to BNT162b2 as a heterologous SARS-CoV-2 booster vaccine in adults vaccinated against COVID-19: a multicentre, randomised, double-blind, non-inferiority phase IIb trial

“…Increasing evidence shows that heterologous vaccination is safe, with similar reactogenicity and adverse events compared to a homologous schedules. [14][15][16][17] Several recent clinical studies indicate that heterologous schedules may, in fact, elicit a more robust immune response and higher antibody titres, with consequent higher effectiveness, supporting a mix-and-match approach. [18][19][20] These data suggest that there is a strong case for more vaccine platforms to broaden vaccination options worldwide.…”

A third vaccine dose equalises the levels of effectiveness and immunogenicity of heterologous or homologous COVID-19 vaccine regimens, Lyon, France, December 2021 to March 2022

“…This booster dose was particularly important in immunocompromised patients for whom vaccine efficacy was lower. Heterologous vaccine schedules of Vaxzevria priming and mRNA booster doses as both second and third doses were not associated with increased risk of serious adverse events compared with homologous mRNA vaccine schedules [8].…”