Reactogenicity after heterologous and homologous COVID-19 prime-boost vaccination regimens: descriptive interim results of a comparative observational cohort study

The efficacy and safety of the vaccines BNT162b2 (BioNTech/Pfizer), mRNA-1273 (Moderna), and ChAdOx1 (AstraZeneca) have been demonstrated in large randomized controlled trials [1‐3]. Administration of ChAdOx1 started in February 2021 in EU/EEA countries [4]. As of March 2021, an association between ChAdOx1 administration and the occurrence of thromboembolic events, later referred to as vaccine-induced immune thrombotic thrombocytopenia (VITT), has been detected [4‐6]. This safety signal led to different recommendations in EU/EEA countries: while some restricted the administration of ChAdOx1 to the elderly as done in Germany, others suspended its use completely [4]. As many people were already primed with ChAdOx1, some countries recommended a boost with BNT162b2 or mRNA-1273 [7‐10]. In Germany, this recommendation was first restricted to persons younger than 60 years. By July 2021 this heterologous regimen was extended to all individuals due to safety concerns and because initial data indicated an even better immunogenicity [8, 11]. Additionally, preclinical trials investigating the immune responses after different heterologous vaccination regimens show promising results [12‐15]. However, evidence on the safety and reactogenicity of the heterologous vaccination regimen was still scarce. Several studies have been published, though mostly with small sample sizes, a maximal follow-up time of two weeks, and, in some studies, a control group with a homologous regimen was missing [16‐22]. The reactogenicity of the heterologous vaccination regimen reported in these studies was comparable to or higher than that of the homologous vaccination regimens.

The safety study reported here is embedded in the CoVaKo project (Corona Vakzin Konsortium) that analyses the efficacy and safety of COVID-19 vaccines [23, 24]. In the CoVaKo safety study we aim to monitor reactogenicity and health problems after COVID-19 vaccination compared to other vaccinations like influenza or pneumococcal vaccination. A longitudinal online survey was used with the focus on health problems occurring within 18 weeks after vaccination and leading to medical consultation, medication intake, or sick-leave. Due to potential shortages of particular vaccines, practical considerations in the absence of single dose vaccine vials, and the potential need for a booster after initial immunization, in particular after vaccination with COVID-19 vector vaccines, evaluating the safety of heterologous vaccination regimens became very important as well. Therefore, this interim analysis of the safety study focusses on the comparison of reactogenicity and health problems after the second dose in a heterologous regimen with ChAdOx1 as prime and an mRNA-vaccine as boost in comparison to homologous regimens with ChAdOx1 or mRNA-vaccines, respectively.

A higher reactogenicity was reported with the heterologous vaccination regimen as compared to homologous regimens 14 to 19 days after the second COVID-19 vaccination. A medical consultation was reported by a comparable proportion with all three regimens 40 to 56 days after the second COVID-19 vaccination. Female gender was associated with a higher rate of reported reactions and medical consultations, respectively. In the short-term follow-up, younger age was associated with a higher rate of reported reactions, whereas in the long-term follow-up elderly people in ChAdOx1/ChAdOx1 and ChAdOx1/mRNA reported more medical consultations.

Previous studies showed that the heterologous regimen is tolerable and no serious adverse event occurred that were suspected to be due to the vaccination [21, 31]. However, the heterologous boost with mRNA leading to a higher reactogenicity is consistent with results of two studies from the UK [16, 18]. In these studies, the interval between prime and boost did not differ (widely) between the regimens. In contrast, two studies from Germany reported a largely comparable reactogenicity after boost with mRNA vaccine in heterologous and homologous regimens [19, 20]. Hillus et al. reported even a slight increase in systemic reactions after homologous mRNA (BNT162b2) boost compared to heterologous ChAdOx1/mRNA or homologous ChAdOx1/ChAdOx1 boost. In both studies, the mean interval between prime and boost vaccination differed largely with a longer interval in heterologous regimen [19]. The authors hypothesized that the extended interval in the heterologous cohort as compared to the homologous regimens with shorter intervals could have led to a decrease in reactogenicity in the heterologous group [19]. In our study, the difference between the intervals in the different cohorts was smaller, because since April 2021, a six-week interval was recommended in Germany for the homologous mRNA regimen instead of the initial three weeks interval. This was due to limited vaccine resources and a higher immunogenicity with a longer interval [8, 32]. It might be assumed, that the reactogenicity is higher with a heterologous mRNA boost but higher reactogenicity might also be associated with a smaller interval between the first and second dose of COVID-19 vaccination.

Female gender was associated with higher reactogenicity not only in our study but also in Powell et al. and Borobia et al. [16, 17]. This association was previously shown for a lot of virus vaccines other than COVID-19 along with a higher immunogenicity in female individuals [33]. Female participants also reported medical consultations in the long-term follow-up more frequently. This association as well does not seem to be specific for COVID-19 vaccinations. A scoping review revealed that female gender was frequently associated with an increased medical health care utilization in general [34]. Not only female gender but also younger age seems to be associated with a higher reactogenicity. Age as an influencing factor on the reporting of adverse events was also mentioned in other studies on COVID-19 vaccination. Similar to our results, studies showed that younger age was associated with the reporting of a higher reactogenicity [1, 2, 16, 17].

However, medical consultations in the long-term survey were reported more frequently in participants aged 55 years or older. As comorbidities were more common in this age group, the higher rate of medical consultations can possibly rather be attributed to participants’ comorbidities than to the vaccination. This hypothesis might be strengthened by the finding that the proportion of medical consultation reported in the long-term survey was comparable between the regimens. Additionally, participants assumed an association between the second vaccination and health problems in the long-term survey less frequently as compared to an association between the second vaccination and reactions in the short-term survey.

Participants were recruited on the day of vaccination to reduce selection bias. However, some participants registered with delay to their vaccination, possibly due to their reactions or health problems. As there was no higher rate of reported reactions in participants registered with delay, this potential bias is probably small. Since all information is given by the vaccinated persons themselves, certain groups of individuals (e.g. seriously ill, cognitively impaired) were not able to participate. This narrows generalizability of the results to some extent. Due to recommendations in vaccination strategy in Germany at the time of recruitment, characteristics of the groups differ in regard to age, gender, and vaccination interval, as well as in total size of study population. Therefore, subgroup analyses were performed separately for age and gender.

The reactogenicity of the heterologous regimen seems to be higher compared to homologous regimens. Until now, however, there is no signal that severe adverse events are more common with this regimen, although further research is necessary. Other factors like a higher efficacy and limited resources during the pandemic might overweight a tolerable higher reactogenicity in the recommendations of specific regimens.