Patient-reported reactogenicity and safety of COVID-19 vaccinations vs. comparator vaccinations: a comparative observational cohort study

In December 2019, a novel viral infection associated with pneumonia as well as prominent general symptoms was reported for the first time in Wuhan, China [1]. Initially called the 2019 novel coronavirus (2019-nCoV), and later SARS-CoV-2, the infection spread rapidly across the globe. As a result of substantial efforts to expand research and development of vaccines against SARS-CoV-2, the first vaccine was already licensed in December 2020, followed by further vaccines on different pharmacological bases. Large randomised controlled trials have demonstrated the safety and efficacy of the vaccines BNT162b2 (Comirnaty®, INN Tozinameran from BioNTech and Pfizer), mRNA-1273 (Spikevax®, INN Elasomeran from Moderna), ChAdOx1 (Vaxzevria® from AstraZeneca and Oxford University) and Ad26.COV2.S (Jcovden® from Janssen-Cilag) [2‐5]. Starting with the administration of BNT162b2 in December 2020, the overall vaccination rate in countries of the European Economic Area has reached 72.8% as per August 2022 [6]. One reason for the insufficient vaccination rate against SARS-CoV-2 is a more fundamental vaccination scepticism for various reasons, e.g. the fear of vaccination consequences [7], fuelled by a general scepticism due to the fast development, the novel technology of mRNA vaccines, and media reports of very rare adverse events such as vaccine-induced immune thrombotic thrombocytopenia [8] or myocarditis [9, 10]. This scepticism fell on fertile ground: While established vaccinations are considered highly effective in preventing diseases and are one of the most significant public health achievements of the modern era [11], vaccination hesitancy has been identified by the WHO as a key threat of global health [12]. In 2016, citizens in Europe were more critical of the safety and benefits of vaccination than citizens in other regions of the world, and seven of the ten countries with the least confidence in vaccine safety were located in Europe [13]. In 2020, after the rise of SARS-CoV-2 and before the development of corresponding vaccines, only 68% of German citizens reported to be willing to take a vaccine against SARS-CoV-2 even if it was proven safe and effective [14].

Against this background, the Corona Vakzin Konsortium (CoVaKo) project tries to elucidate the efficacy and safety of the SARS-CoV-2 vaccines under real-world conditions. The CoVaKo safety study reported here aimed to assess reactogenicity and self-reported health problems compared with other common vaccinations such as those against influenza or pneumococcus [15, 16]. While the incidence of adverse events after administration of established vaccines varies widely and severe consequences are exceedingly rare [11], a comparison of the new SARS-CoV-2 vaccines with the established vaccines is still lacking. The work presented aims to contribute to bridging this research gap by comparing patient-reported outcomes after vaccination with SARS-CoV-2 vaccines or established vaccines.

We conducted a longitudinal online cohort observational study to assess health problems and healthcare utilisation after vaccination against SARS-CoV-2 and multiple other vaccinations. Reporting of the study is based on the STROBE (Strengthening the Reporting of Observational studies in Epidemiology) recommendations (see Additional file 1) [17].

A longitudinal observational study was conducted to contrast reactogenicity and medical consultations following SARS-CoV-2 and comparator vaccinations. In the comparator group, local and systemic reactions were less frequently reported. For both local and systemic reactions, those vaccinated with comparator vaccinations were more likely to report no consequences. If consequences were reported, medication intake and sick leave were most commonly reported in all groups. Multivariate regression analyses showed a strong influence of younger age, female gender, and more comorbidities on reporting local as well as systemic reactions. In the long-term survey and the follow-up survey, a comparable frequency of seeking medical consultation in all groups has been observed. Comparator-vaccinated patients were significantly less likely to suspect an association with the vaccination than patients who had received SARS-CoV-2 vaccination. In the follow-up survey, participants vaccinated with a regime including ChAdOx1 were less likely to report out- or inpatient medical consultations than participants in the comparator group.

Published data on side effects of the comparator vaccines differ strongly and are of limited comparability, e.g. due to the different approval status of sera in different countries, but also due to different survey designs, outcomes or study populations. Low incidences of local side effects in up to half of all patients have been reported after administration of different vaccines against influenza, FSME-Immun® (TBE), and Encepur® (TBE), with reports ranging between 6.7 and 44.7% of patients [25‐28]. In a second group of vaccinations — Shingrix® (herpes zoster), Pneumovax® 23 (pneumococcus), Boostrix® (Td), and Boostrix-Polio® (TdaP-IPV) — a higher incidence of local reactions has been found (75.9 to 88.0%) [29‐33]. Systemic adverse events show a similar distribution but on a lower level: Vaccinations against influenza and TBE remain a group with a low frequency of systemic side effects, ranging from 0.6 to 31.0% [25‐28]. This contrasts with vaccinations with Shingrix®, against pneumococcus, and against tetanus and diphtheria (with and without pertussis or poliomyelitis) as a group with a high frequency of systemic side effects, ranging from 64.8 to 82.1% [29‐33]. The reactogenicity reported in our study was roughly the same as observed in other studies. Similarly, the prevalence of systemic reactions was lower than the prevalence of local reactions. The SARS-CoV-2 vaccination group reported considerably higher prevalences of local as well as systemic reactions (SARS-CoV-2 vaccination group: 60.7 and 54.5%, respectively). However, higher reporting of adverse events after SARS-CoV-2 vaccination may partly also be attributed to a nocebo effect [34, 35]. This hypothesis is supported by corresponding results of recent research from New Zealand, in which media reports of vaccine-induced myocarditis led to increased reports of cardiac symptoms [36].

To our knowledge, consequences in the form of medication intake, sick leave, or medical consultations had rather been included as outcomes of the vaccination in vaccine studies before SARS-CoV-2 than as side effects of the vaccinations. Very few studies discussed these consequences as reactions to the vaccination itself, such as Nichol et al. who reported a work loss due to side effects of a influenza vaccination in healthy subjects of 2 days per 100 persons [37]. Seeking medical consultation due to vaccination side effects was a common consequence, with 4.7 to 7.6% of patients with vaccination against influenza, pneumococcus or tetanus and diphtheria reporting consultations [32, 38]. With the introduction of the SARS-CoV-2 vaccinations, the consequences of adverse events after vaccination were increasingly surveyed. In two German studies, 13.1 and 28.4% of participants reported taking at least 1 day of sick leave after the first and the second vaccination against SARS-CoV-2, respectively [39], and 8% of participants felt unable to work after the first vaccination with BNT162b2, increasing to 35% of participants after the second vaccination [40]. 5.6% of BNT162b2 vaccinees with at least one side effect reported a need for medical care [41]. We found considerably lower reports of consequences after SARS-CoV-2 vaccination, with consequences after comparator vaccinations even lower. In our study, no medical consultations due to local reactions were reported in the comparator group, and systemic reactions resulted in only 1.5% of that population reporting outpatient medical consultations. That proportion of outpatient consultations due to adverse events was slightly higher in participants with vaccination against SARS-CoV-2, with up to 2.0% for local reactions and up to 5.9% for systemic reactions. A similar pattern was also found for the medication intake and sick leave.

Female gender had a significant influence on reports of outpatient medical consultations, but not of inpatient medical consultations. Gender-related differences in consultation frequency have already been described and discussed several times and contrast different health behaviours in similar symptoms on one side with different symptom compositions on the other [42‐44]. One possible explanation for the pattern we observed may be a filtering function of primary care — while women presented more often as outpatients, they might have been referred to inpatient care just as often as men. This explanation assumes that women were more likely to present to outpatient care due to symptoms—which is supported by our short-term data—but were not more likely to have severe symptoms requiring inpatient care than men. A higher prevalence of adverse events in women has been reported before in vaccinations against SARS-CoV-2 [45, 46] as well as in the vaccines used as comparators [47‐50]. Despite the fact that antibody responses to specific vaccine doses often tend to be higher in females than in males, low dose vaccination of comparator vaccines for women to reduce the prevalence of side effects has not been systematically investigated or deliberated to our knowledge so far [51]. Yet, reduction of the vaccination dose against SARS-CoV-2 was discussed shortly after the start of the vaccination campaign and the observed increased side effect rate in women [52].

Due to the design as a prospective observational study, group sizes differed significantly. While 3063 participants responded to the first survey with SARS-CoV-2 vaccination, this number increased to a total of 9613 participants in the follow-up survey. For the comparator vaccinations, by contrast, responses were only by 203 (short-term survey), 337 (long-term survey) and 378 participants (follow-up survey), respectively. This pronounced difference makes comparisons of adverse events with a very low incidence particularly difficult, even more so because the survey was powered for an event rate of 0.1%. Therefore, we performed a multivariate logistic regression to consider the different vaccination recommendations with regard to gender and age, as descriptive results may not be transferable to the German population as a whole. Secondly, resulting from the limited number of participants who had received one of the comparator vaccinations, we opted to combine the corresponding group. Consequently, this group comprised above all, though not exclusively, adjuvanted inactivated vaccines for which greater reactogenicity has been reported [53]. Thus, we performed a subgroup analysis focusing on participants with influenza vaccination only. This analysis did not reveal significant changes in the odds ratios of reporting local or systemic reactions, as well as outpatient and inpatient consultations.

Participants in our survey tended to be younger than would be expected based on vaccination recommendations, presumably due to an age-related digital divide in the sense of a selection bias. As higher reactogenicity after vaccination against SARS-CoV-2 in younger patients has been reported before [54], we assume that we tend to overestimate the reactogenicity of some vaccinations. However, we could hardly find any data on age-related reactogenicity after other than SARS-CoV-2 vaccinations. We also consider the possibility of survivor bias, which means that very rare but fatal health problems may be underrepresented in our data.

One of the strengths of the survey is the reporting of adverse events by the participants themselves, i.e. patient-reported outcome measures. As the data basis does not consist of medical reports but of self-reports, this survey allows for a direct and unmediated comparison of the frequency of reactions and medical consultations. However, due to this direct reporting by patients, it must be considered that non-response bias might lead to a skewing of the results and are therefore subject to uncertainty.

Participants in the SARS-CoV-2 vaccination group were more likely to report local and systemic side effects 14 days after their vaccination than those in the comparator group. However, 16 weeks later, there was no higher reporting of seeking medical consultations in the SARS-CoV-2 vaccination group. Patients who had received ChAdOx1 at least once even reported significantly fewer outpatient and inpatient consultations than the comparator group. Adverse events and medical consultations were reported significantly more frequently by women, younger people and people with pre-existing medical conditions.