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.

Fig 1

Cumulative incidence curves of the cardiovascular and haemostatic adverse events for the heterologous and homologous primary and booster vaccine schedules. Cumulative incidence curves of the main outcomes within the first 28 days after the last day of vaccination for the heterologous vaccine schedules of ChAdOx1-S priming and mRNA booster dose or doses (ie, two or three doses) and homologous primary and booster mRNA vaccine schedules (ie, two or three doses) with the corresponding 95% confidence intervals (shaded areas). The number of events of arterial thromboembolisms and myocarditis or pericarditis, as well as for thrombocytopenia and coagulative disorder for the three dose comparison, were low to none, which is why cumulative incidence curves for these outcomes were not estimated. Other bleeding events include a composite of bleeding-related diagnoses other than intracranial haemorrhages

Fig 2

Risk of adverse safety outcomes comparing heterologous primary vaccine schedules of ChAdOx1-S priming and an mRNA booster dose with homologous primary mRNA vaccine schedules. Incidence rate ratios (IRRs) for the outcomes within 28 days were adjusted for calendar period, sex, birth year (as a proxy for age), region of residency, birth country, vaccine priority group, hospital contact in the past six months, and comorbidities. Cerebrovascular infarction includes non-haemorrhagic strokes and transient ischaemic attacks. Other bleeding events include a composite of bleeding-related diagnoses other than intracranial haemorrhages. CI=confidence interval; NE=not estimated

Fig 3

Risk of adverse safety outcomes comparing heterologous booster vaccine schedules of ChAdOx1-S priming and two mRNA booster doses with homologous mRNA booster vaccine schedules. Incidence rate ratios (IRRs) for the outcomes within 28 days were adjusted for calendar period, sex, birth year (proxy for age), region of residency, birth country, vaccine priority group, hospital contact in the past six months, and comorbidities. Cerebrovascular infarction includes non-haemorrhagic strokes and transient ischaemic attacks. Other bleeding events includes a composite of bleeding-related diagnoses other than intracranial haemorrhages. CI=confidence interval; NE=not estimated

Fig 4

Sensitivity analysis of the associated risk of serious adverse events with heterologous primary and booster vaccine schedules. Shows the results of the sensitivity analysis where restricting the outcome definitions to serious adverse events, defined as excluding brief hospital contacts of less than 24 h. Top panel shows the results of the primary (two dose) vaccine schedules comparison while the booster (three dose) schedules comparison is presented in the bottom panel. Incidence rate ratios (IRRs) were adjusted for calendar period, sex, birth year (proxy for age), region of residency, birth country, vaccine priority group, hospital contact in the last six months, and comorbidities. Other bleeding events includes a composite of bleeding-related diagnoses other than intracranial haemorrhages. CI=confidence interval; NE=not estimated