Comparative adverse effects, perceptions and attitudes related to BNT162b2, mRNA1273, or JNJ-78436735 SARS-CoV-2 vaccines: A population-based longitudinal cohort

SARS-CoV-2, vaccination, adverse effects, hesitancy, real-world data 25 26 Running title: SARS-CoV-2 vaccination adverse effects 27 28 Main Points: Our representative population -based cohort study demonstrated the safety of 29 three SARS -CoV-2 vaccines and provides real -world estimates on adverse effect incidence. 30 Transparent communication of expected adverse effects to vaccine-seeking individuals is pivotal 31 to build trust in current or future vaccination campaigns. 32 33 . CC-BY-NC-ND 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.(which was not certified by peer review)preprint The copyright holder for thisthis version posted September 27, 2022. ; https://doi.org/10.1101/2022.09.27.22280403doi: medRxiv preprint 3

34 Importance: Long-term control of SARS-CoV-2 requires effective vaccination strategies. This has 35 been challenged by public mistrust and spread of misinformation regarding vaccine safety. 36 Hence, better understanding and communication on the longer -term and comparative 37 experiences of general population individuals following SARS-CoV-2 vaccination are required. 38 39

To evaluate and compare self -reported adverse effects following SARS -CoV-2 40 vaccination, participants’ perceptions regarding vaccinations and their compliance with 41 recommended public health measures. 42 43 Design, Setting and Participants: Population-based longitudinal cohort of 575 adults, randomly 44 selected from all individuals presenting to the reference vaccination center of the Canton of 45 Zurich, Switzerland, for receipt of BNT162b2, mRNA1273, or JNJ-78436735. 46 47 Exposures: BNT162b2, mRNA1273, or JNJ-78436735 vaccines. 48 49 Main Outcomes and Measures: Primary outcomes included period prevalence, onset, duration, 50 and severity of self-reported adverse effects over 12 weeks following vaccination with a specific 51 focus on the proportion of participants reporting allergic reactions, menstrual irregularities, or 52 cardiac adverse effects, or requiring hospitalization. Secondary outcomes included risk factors 53 associated with reporting adverse effects, perception of vaccine importance, trust in public 54 . CC-BY-NC-ND 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.(which was not certified by peer review)preprint The copyright holder for thisthis version posted September 27, 2022. ; https://doi.org/10.1101/2022.09.27.22280403doi: medRxiv preprint 4 health authorities and pharmaceutical companies, and compliance with recommended public 55 health measures. 56 57

454 (79.0%) participants reported at least one adverse e ffect during 12 weeks after 58 vaccination. Prevalence was highest among mRNA-1273 recipients (88.7% vs. 77.3% after 59 BNT162b2, 69.1% after JNJ -78436735). Most adverse effects were systemic (72%), occurred 60 within 24 hours (67.9%), and resolved in less than thr ee days (76.3%). 85.2% were reported as 61 mild or moderate. Allergic reactions were reported by 0. 4% of participants , hospitalizations by 62 0.7%, cardiac adverse effects by 1.4%. Menstrual irregularities were reported by 9% of female 63 participants younger than 50 years. Female sex, younger age, higher education, and receipt of 64 mRNA-1273 were associated with reporting adverse effects. Compared to JNJ -78436735 65 recipients, a higher proportion of mRNA vaccine recipients agreed that vaccination is important 66 (87.5% vs. 28.5%), and trusted public health authorities (80.2% vs. 30.3%) and pharmaceutical 67 companies (71.7% vs. 23.6%). 68 69

and Relevance: Our population-based cohort provided real -world data on self -70 reported adverse effects following SARS -CoV-2 vaccin ation and highlights the importance of 71 transparent communication regarding adverse effects and building trust in public health 72 authorities to ensure successful future vaccination campaigns. 73 74 . CC-BY-NC-ND 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.(which was not certified by peer review)preprint The copyright holder for thisthis version posted September 27, 2022. ; https://doi.org/10.1101/2022.09.27.22280403doi: medRxiv preprint 5

75 Beginning with the first vaccinations against SARS -CoV-2 in December 2020, the largest global 76 vaccination campaign in recent history capture d the public and professional attention for 77 months. Apart from the obvious focus on efficacy, concerns about vaccine-related adverse 78 effects dominated the professional and public discourse during the campaign. The fast-track 79 authorization of the technologically new mRNA vaccines BNT162b2 (Pfizer -BioNTech) and 80 mRNA1273 (Moderna) in some countries and misinformation contributed to vaccine skepticism 81 and hesitancy.[1-5] This highligh ts the importance of understanding and accurately 82 communicating information regarding adverse effects , including vaccine safety profiles, to 83 improve vaccine confidence and uptake. 84 The current body of evidence on adverse effects following SARS-CoV-2 vaccination consists 85 mostly of data reported in randomized clinical trials (RCTs) and reports to government-based 86 surveillance systems, such as the European EudraVigilance, US VAERS (Vaccine Adverse Event 87 Reporting System), or Swiss ElViS (Electronic Vigilance System). Adverse effects reported in RCTs 88 have been primarily mild and self-limited,[6, 7] with systemic reactions (e.g. fatigue, headache, 89 pain) and local injection site reactions (e.g. pain, erythema, swelling) being the most frequent.[8-90 10] In contrast, severe adverse effects accounted for a significantly higher proportion of reports 91 in governmental surveillance systems.[11-13] This was to be expected as reporting to surveillance 92 systems is subject to several biases including underreporting of mild and common adverse effects 93 and increased reporting of those which are severe or widely reported in the media. [14, 15] 94 Although RCTs pr ovided important evidence on the safety of individual vaccines, they offered 95 little side-by-side comparisons. Furthermore, RCTs yield data collected on selected populations 96 . CC-BY-NC-ND 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.(which was not certified by peer review)preprint The copyright holder for thisthis version posted September 27, 2022. ; https://doi.org/10.1101/2022.09.27.22280403doi: medRxiv preprint 6 raising the issue of how well th is data correlates to “real -world” experiences. The few studies 97 eliciting patient-reported symptoms following different vaccines in real-world settings often had 98 cross-sectional designs and were conducted among very specific groups such as healthcare 99 workers or university students, which may not be representative of the general population.[6, 7] 100 In this population-based study, we aimed to deliver a comprehensive comparative analysis of 101 self-reported adverse effects up to 12 weeks after receipt of three SARS-CoV-2 vaccines approved 102 in Switzerland in 2021. Further objectives were to examine the general perception and attitudes 103 of individuals regarding SARS-CoV-2 vaccination and their compliance with recommended public 104 health measures. Thereby, we aim to improve our understanding of the adverse health e ffects 105 experienced following vaccination in the general population to provide an evidence base for 106 future vaccination campaigns in view of the likely implementation of additional booster 107 vaccinations and updated SARS-CoV-2 vaccines. 108 109

110 Study design, participants, and recruitment 111 This study is based on the Zurich SARS-CoV-2 Vaccine Cohort, an ongoing prospective population-112 based cohort study. We recruited participants between March 10, 2021, and January 27, 2022, 113 at the University of Zurich’s (UZH) vaccination center, the reference center for the Canton of 114 Zurich, Switzerland. All individuals scheduled to receive one of the SARS-CoV-2 vaccines approved 115 in Switzerland in 2021 , BNT162b2 (Pfizer -BioNTech), mRNA1273 (Moderna), or JNJ -78436735 116 (Johnson & Johnson), were screened for eligibility. Eligibility criteria were being 18 years or older, 117 . CC-BY-NC-ND 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.(which was not certified by peer review)preprint The copyright holder for thisthis version posted September 27, 2022. ; https://doi.org/10.1101/2022.09.27.22280403doi: medRxiv preprint 7 being able to follow study procedures, having sufficient knowledge of the German language and 118 residing in the Canton of Zurich . We excluded individuals who had already received a first dose 119 of a SARS -CoV-2 vaccine. A daily age -stratified (18-64 years, 65 years or older) random sample 120 was selected separately for each approved vaccine from all eligible individuals belonging to the 121 following vaccination groups as defined by the Canton of Zurich [16, 17]: “Over 75 years”, “over 122 65 years”, “ between 50 –64 years”, and “between 18 –49 years”. We excluded individuals 123 belonging to groups specific for “healthcare workers”, “caretakers of high -risk patients”, 124 “individuals living in communal facilities”, and “individuals with the highest risk diseases” to 125 ensure that that our sample was representative of the general population. [18, 19] Randomly 126 selected individuals were then invited to participate in our study. We obtained written informed 127 consent from all participants. We were unable to reach the desired sample size for JNJ-78436735 128 recipients 65 years or older, due to limited demand. 129 The study protocol was prospectively registered on the International Standard Randomized 130 Controlled Trial Number Registry (ISRCTN 15499304) and approve d by the ethics committee of 131 the Canton of Zurich (BASEC 2021-00273). 132 . CC-BY-NC-ND 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.(which was not certified by peer review)preprint The copyright holder for thisthis version posted September 27, 2022. ; https://doi.org/10.1101/2022.09.27.22280403doi: medRxiv preprint 8 133 Figure 1. Recruitment of study cohort 134 135 Data sources and measurements 136 Upon enrolment, all participants completed a baseline questionnaire including questions on their 137 sociodemographics, medical and smoking history, SARS-CoV-2 related information such as prior 138 infections, perceptions and attitudes regarding vaccination, trust in public health authorities and 139 pharmaceutical companies , and compliance wi th recommended public health measures 140 (including use of the SwissCovid digital proximity tracing app) . Perception, attitude, and 141 . CC-BY-NC-ND 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.(which was not certified by peer review)preprint The copyright holder for thisthis version posted September 27, 2022. ; https://doi.org/10.1101/2022.09.27.22280403doi: medRxiv preprint 9 compliance questions were collected using a numerical scale (0 “Very low opinion”, to 100 “Very 142 high opinion” for perception), or a 5-item Likert (ranging from “ Strongly disagree” to "Strongly 143 agree” for trust-related statements, and from “Never/Impossible” to “Always” for statements on 144 compliance with public health measures). We pooled BNT162b2 and mRNA-1273 recipients into 145 one “mRNA vaccine” group since they expressed similar perceptions towards vaccination and 146 compliance with recommended measures (Supplement 1). 147 We provided participants with a paper symptom diary and instructed them to record any adverse 148 effect they experienced during 12 weeks after vaccination, as free text , including start and end 149 dates, perceived severity (on a 5 -item Likert scale, ranging from "Very mild" to "Very severe"), 150 and consequences of the adverse effects (i.e., self-medication, need for healthcare services, or 151 hospitalizations). Symptom diaries were collected at the 12 -week follow -up visit. Participants 152 received additional electronic questionnaires at 4, 6, and 12 weeks, in which they were asked to 153 report any positive SARS -CoV-2 polymerase chain reaction (PCR) or rapid antigen test s. We 154 excluded all reported adverse effects starting within three days before and at any timepoint after 155 positive SARS-CoV-2 tests to ensure that reported symptoms were related to vaccination rather 156 than infection. To determine the proportion of participants with past SARS -CoV-2 infection, we 157 measured participants’ anti -SARS-CoV-2 Spike (S) -IgA and IgG antibodies at baseline using a 158 highly sensitive and specific Luminex technology-based assay.[20] 159 We collected and managed all study data using the Research Electronic Data Capture (REDCap) 160 system.[21, 22] 161 162 . CC-BY-NC-ND 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.(which was not certified by peer review)preprint The copyright holder for thisthis version posted September 27, 2022. ; https://doi.org/10.1101/2022.09.27.22280403doi: medRxiv preprint 10 Outcomes 163 Our primary outcomes included period prevalence, onset, duration, and severity of self-reported 164 adverse effects over 12 weeks following vaccinatio n, with a specific focus on the proportion of 165 participants reporting allergic reactions, menstrual irregularities, or cardiac adverse effects, or 166 requiring hospitalization. Secondary outcomes included risk factors associated with adverse 167 effect reports, general perceptions and attitudes regarding vaccination, trust in public health 168 authorities and pharmaceutical companies, and compliance with recommended public health 169 measures. 170 171 Statistical Analysis 172 We descriptively analyzed the characteristics and outcomes of interest for the overall cohort and 173 for each of the three vaccine groups . Continuous variables are reported as median with 174 interquartile range (IQR); categorical or ordinal variables as frequencies (N) and percentages 175 (%).We coded adverse effect data reported by participants in the symptom diary according to 176 the Medical Dictionary for Regulatory Activities (MedDRA) hierarchical terminology (Supplement 177 2).[23] The self-reported adverse effects were translated from German to the closest m atching 178 MedDRA “low level term”. All corresponding higher-level terms were included in the database, a 179 highest level of coding was added , labelling each adverse effect either as “local” or “systemic”. 180 We explored associations of several predictor variables on the outcome of reporting one or more 181 adverse e ffects using a multivariable logistic regression model . Age, sex, vaccine type and 182 education were included a priori variables in the model based on findings from other studies.[6] 183 . CC-BY-NC-ND 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.(which was not certified by peer review)preprint The copyright holder for thisthis version posted September 27, 2022. ; https://doi.org/10.1101/2022.09.27.22280403doi: medRxiv preprint 11

are presented as odds ratios (OR) with their 95% confidence intervals (CI) and two-sided 184 p-value. All analyses were performed using R (version 4.1.2). 185 186

187 Cohort characteristics 188 Of our 575 participants, 323 participants (56.2%) were female, and the median age was 59 years 189 (IQR 41 to 70) (Table 1). 411 (71.5%) participants received a mRNA-based vaccine (2 doses 3 to 4 190 weeks apart, 36.2% BNT162b2 and 35.3% mRNA-1273) and 164 (28.5%) received a vector-based 191 vaccine (1 dose, JNJ-78436735). The proportion of participants with a higher level of education 192 (39.8% vs 61.8%) was lower among JNJ -78436735 recipients compared to mRNA vaccine 193 recipients. 194 37 participants (6.4%) reported ever having a positive SARS-CoV-2 test prior to vaccination, with 195 a higher proportion among JNJ -78436735 recipients (9. 7% vs 6.4% of mRNA -1273 and 3. 7% of 196 BNT162b2 recipients). 19 (9.2%) BNT162b2 recipients, 24 (11.8%) mRNA-1273 recipients and 29 197 (17.6%) JNJ-78436735 recipients tested seropositive for a nti-SARS-CoV-2 S-IgA or -IgG before 198 receiving the first vaccination dose. 199 200 . CC-BY-NC-ND 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.(which was not certified by peer review)preprint The copyright holder for thisthis version posted September 27, 2022. ; https://doi.org/10.1101/2022.09.27.22280403doi: medRxiv preprint 12 Table 1. Demographic and clinical characteristics of study population 201 BNT162b2 (Pfizer/BioNTech) mRNA-1273 (Moderna) JNJ-78436735 (Johnson & Johnson) Overall (N=207) (N=203) (N=165) (N=575) Age, median (IQR) -in years 59 (36 to 75) 65 (42.5 to 69) 58 (45 to 70) 59 (41 to 70) Age distribution - no. of participants (%) <65 years 106 (51.2%) 99 (48.8%) 103 (62.4%) 308 (53.6%) ≥65 years 101 (48.8%) 104 (51.2%) 62 (37.6%) 267 (46.4%) Female sex - no. of participants (%) 115 (55.6%) 120 (59.1%) 88 (53.3%) 323 (56.2%) Presence of at least one preexisting medical condition (%) 80 (40.8%) 78 (42.2%) 64 (43.2%) 222 (42.0%) Highest educational level - no. of participants (%) None or mandatory school 9 (4.4%) 4 (2.0%) 7 (4.3%) 20 (3.5%) Vocational training or specialized baccalaureate 71 (34.5%) 72 (35.6%) 91 (55.8%) 234 (41.0%) Higher technical school or college 46 (22.3%) 44 (21.8%) 40 (24.5%) 130 (22.8%) University 80 (38.8%) 82 (40.6%) 25 (15.3%) 187 (32.7%) Missing 1 (0.5%) 1 (0.5%) 2 (1.2%) 4 (0.7%) Reported adverse effects - no. of participants (%) 160 (77.3%) 180 (88.7%) 114 (69.1%) 456 (79.3%) Tested seropositive for anti-SARS-CoV-2 S-IgA at baseline - no. of participants (%) 12 (5.8%) 14 (6.9%) 20 (12.1%) 46 (8.0%) Tested seropositive for anti-SARS-CoV-2 S-IgG at baseline - no. of participants (%) 15 (7.2%) 19 (9.4%) 24 (14.5%) 58 (10.1%) . CC-BY-NC-ND 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.(which was not certified by peer review)preprint The copyright holder for thisthis version posted September 27, 2022. ; https://doi.org/10.1101/2022.09.27.22280403doi: medRxiv preprint 13 Reported positive SARS-CoV-2 test prior to baseline - no. of participants (%) 8 (3.9%) 13 (6.4%) 16 (9.7%) 37 (6.4%) SARS-CoV-2 Infection prior to baseline (self-reported infection or tested seropositive)- no. of participants (%) 21 (10.1%) 28 (13.8%) 31 (18.8%) 80 (13.9%) Tested positive for anti-SARS-CoV-2 S- IgA or IgG at baseline with no report of prior SARS-CoV-2 Infection- no. of participants (%) 13 (6.3%) 15 (7.4%) 15 (9.1%) 43 (7.5%) 202 Frequency and characteristics of adverse effects 203 Overall, 79.0% (N= 454) of all participants reported at least one adverse effect up to three months 204 following vaccination, with a total of 2397 reported adverse effects. The highest proportion of 205 participants with adverse effects after vaccination was among mRNA-1273 recipients (88.7%, 206 N=180) compared to BNT162b2 (77.3%, N=160) and JNJ-78436735 ( 69.1%, N=114) recipients. 207 Based on a multivariable logistic regression model, we found strong to very strong evidence that 208 female sex (OR =4.05 (95% CI: 2.33 to 7.3), p<0.001), higher education levels (vs. none or 209 mandatory school, OR=6.26 (1.86 to 21.2), p=0.003) and receiving mRNA-1273 (vs. BNT162b2, 210 OR=2.38 (1.22 to 4.8), p=0.013) were associated wit h adverse effect reports. There was weak 211 evidence that younger age (<65 vs. ≥65 years, OR=1.65 (0.96 to 2.9 ), p=0.072) was associated 212 with adverse effect s. We found no evidence that JNJ-78436735 (vs. BNT162b2), preexisting 213 conditions, low opinion (opinion value <50) about vaccination and SARS-CoV-2 infections prior to 214 vaccination were associated with adverse effects (Supplement 3). 215 . CC-BY-NC-ND 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.(which was not certified by peer review)preprint The copyright holder for thisthis version posted September 27, 2022. ; https://doi.org/10.1101/2022.09.27.22280403doi: medRxiv preprint 14 More participants reported systemic (71.7%, N=412) than local adverse effects (54.8%, N=315). 216 Among mRNA vaccine recipients, the proportion of systemic among all adverse effects increased 217 after the 2 nd dose (63.9% to 77.2% in BNT162b2 and 59.1% to 78.0% in mRNA-1273 recipients, 218 Supplement 4). The most common adverse effect mentioned by mRNA vaccine recipients was 219 local pain ( 54.1% of BNT162b2 and 69.5% of mRNA-1273 recipients), followed by asthenia 220 (fatigue; 38.7% of BNT162b2 and 44.8% of mRNA-1273 recipients). JNJ-78436735 recipients most 221 frequently reported headache ( 36.4%), followed by local pain ( 30.9%) and asthenia ( 30.9%). 222 Other commonly reported adverse effects included nausea, vertigo, and sore throat (all >5%). Of 223 our participants, 0.4% ( n=2) (one BNT162b2 and one mRNA -1273 recipient) reported allergic 224 reactions. Adverse effects affecting menstruation were reported by 5 out of 47 (10.6%) female 225 participants younger than 50 among BNT162b2 recipients, 4 out of 42 (9.5%) among mRNA-1273 226 recipients and 2 out of 31 (6.5%) among JNJ-78436735 recipients (six participants reported cycle 227 irregularities, three heavy menstrual bleeding, three intermenstrual bleeding) . Tachycardia or 228 palpitations were reported by seven (1.2%) participants, four mRNA-1273, two JNJ-78436735 and 229 one BNT162b2 recipient. One BNT162b2 recipient reported pericardial effusion and atrial 230 fibrillation after the second dose. 231 Most adverse effects ( 83.9%) occurred in the first week following vaccination , 67.9% within 24 232 hours. Participants reported that adverse effects lasted for 3.9 days on average , and most 233 resolved within 3 ( 76.3%) days. Asthenia, extremity pain , and cough were most frequently 234 reported to last longer than a week. Adverse effect onset and duration were similar across the 235 three vaccines (Figure 2A, Supplement 5). 236 . CC-BY-NC-ND 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.(which was not certified by peer review)preprint The copyright holder for thisthis version posted September 27, 2022. ; https://doi.org/10.1101/2022.09.27.22280403doi: medRxiv preprint 15 The perceived severity of most adverse effects was mild ( 49.0%) or moderate ( 36.2%). 237 Meanwhile, 14.7% were described as severe (13.4%) or very severe (1.3%), with the highest 238 proportion of severe to very severe adverse effects reported after JNJ-78436735 (18.3% vs 16.1% 239 after mRNA-1273, 9.4% after BNT162b2). Asthenia (1 3.1%), headache (1 2.8%) and pain ( 9.4%) 240 were mostly reported as severe or very severe adverse effects. Hospitalization due to reported 241 adverse effects was reported by 0.7% (n=4) of participants (two BNT162b2 recipients with loss of 242 consciousness and bullous pemphigoid, one mRNA -1273 recipient with retinal detachment and 243 one JNJ-78436735 recipient with meningitis). 244 Most reported adverse effects resolved spontaneously ( Figure 2C). However, partici pants 245 reported using self -prescribed medications ( e.g., Paracetamol or Ibuprofen) or seeking 246 consultation with a healthcare provider for 448 (18.7%) and 84 (3.5%) of the adverse effects , 247 respectively. 248 . CC-BY-NC-ND 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.(which was not certified by peer review)preprint The copyright holder for thisthis version posted September 27, 2022. ; https://doi.org/10.1101/2022.09.27.22280403doi: medRxiv preprint 16 249 Figure 2. Frequency of any, local and systemic adverse effects. Panel A shows five most common systemic and local 250 adverse effects in overall sample (N=575). Panel B shows adverse effects by vaccine type (BNT162b2 N=208, mRNA-251 1273 N=203, JNJ-78436735 N=164). 252 78.96 71.65 54.78 52.87 38.61 35.3 19.83 18.96 15.3 5.39 4.7 2.96 1.91 0 20 40 60 80 Any Symptom Any Systemic Symptom Any Local Symptom Local Pain Asthenia (Fatigue) Headache Pyrexia Systemic Pain Chills Local Erythema Local Swelling Local Lymphnodes Local Pruritus Percentage of Participants [%] OverallA 77.29 65.7 55.56 54.11 38.65 28.02 11.599.66 5.8 2.9 1.930.97 0 88.67 82.27 72.41 69.46 44.83 41.87 26.11 25.62 18.23 13.79 9.85 4.433.94 69.09 66.06 36.36 32.12 30.91 30.91 24.85 23.64 20 3.03 1.210.61 0.61 JNJ−78436735 mRNA−1273 BNT162b2 Any Symptom Any Systemic Symptom Any Local Symptom Local Pain Asthenia (Fatigue) Headache Pyrexia Systemic Pain Chills Local Erythema Local Swelling Local Lymphnodes Local Pruritus 0 25 50 75 0 25 50 75 0 25 50 75 By VaccineB Any Adverse Effects Local Systemic Prevalence of Adverse Effects . CC-BY-NC-ND 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.(which was not certified by peer review)preprint The copyright holder for thisthis version posted September 27, 2022. ; https://doi.org/10.1101/2022.09.27.22280403doi: medRxiv preprint 17 253 Figure 3. Characteristics of self-reported adverse effects. Panel A shows the time of adverse effect onset by vaccine, 254 panel B perceived adverse effect severity by vaccine and panel C the consequences of adverse effects by vaccine. 255 (ER: Emergency Room) 256 257 Perceptions of vaccination and compliance with recommended public health measures 258 More mRNA vaccine recipients (87.5%) agreed completely or in part with the statement that it 259 was important to be vaccinated compared to 28.5% of JNJ-78436735 recipients. Similarly, more 260 mRNA vaccine recipients felt that vaccines were a part of a healthy lifestyle (63.6% vs. 28.9% of 261 JNJ-78436735 recipients). Trust in public health authorities (80.2% vs. 30.3%) and pharmaceutical 262 companies (71. 7% vs. 23. 6%) was higher among mRNA vaccine recipients compared to JNJ-263 . CC-BY-NC-ND 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.(which was not certified by peer review)preprint The copyright holder for thisthis version posted September 27, 2022. ; https://doi.org/10.1101/2022.09.27.22280403doi: medRxiv preprint 18 78436735 recipients. Both groups felt they had sufficient understanding of how the vaccine 264 helped the body fend off infectious diseases (89.3% mRNA vaccine recipients vs. 62.4% JNJ -265 78436735 recipients ) and reported similar compliance with recommended public health 266 measures (Figure 3B). Use of the SwissCovid digital proximity tracing app was higher among 267 mRNA vaccine recipients compared to JNJ-78436735 recipients (53.2% vs 27.4%). 268 269 Figure 4. Perception of vaccination and compliance with recommended public health measures. 270 271 mRNA−Vaccines JNJ−78436735 0% 25% 50% 75% 100% 0% 25% 50% 75% 100% I trust the Federal Office of Public Health (FOPH). I trust the vaccine producers and pharmaceutical companies in general. I understand how vaccines help my body to fend off infectious disease. Vaccines are part of a healthy lifestyle. I think it is important to be vaccinated. I disagree completely Rather disagree Neutral Rather agree I agree completely Trust in Vaccine and InstitutionsA 0% 25% 50% 75% 100% 0% 25% 50% 75% 100% I was able to work from home. I was able to adhere to recommended hygiene guidelines. I was able to practise social distancing. I wore a mask when away from home. I avoided larger crowds. Never/Impossible Rarely Sometimes Frequently Always Compliance with Recommended Public Health MeasuresB 0% 25% 50% 75% 100% 0% 25% 50% 75% 100% Do you currently use the Swiss Covid App? Yes, always Yes, sometimes No Swiss Covid App UseC . CC-BY-NC-ND 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.(which was not certified by peer review)preprint The copyright holder for thisthis version posted September 27, 2022. ; https://doi.org/10.1101/2022.09.27.22280403doi: medRxiv preprint 19

272 In this population-based cohort of 575 individuals who received a SARS-CoV-2 vaccine and were 273 followed-up over 12 weeks, participants commonly reported adverse effects, namely local pain, 274 fatigue, headache, and fever. Most adverse effects were mild to moderate and resolved with in 275 three days. Allergic reactions (0. 4%) and adverse effects requiring hospitalization (0. 7%) were 276 rare. Around 9% of female participants younger than 50 reported menstrual cycle changes, more 277 frequently among mRNA vaccine recipients. Female sex, receiving mRNA-1273, higher education 278 and younger age were associated with experiencing adverse effects. JNJ-78436735 recipients less 279 frequently perceived vaccination to be important and had lower trust in public health authorities 280 and pharmaceutical companies compared to mRNA vaccine recipients. There were no differences 281 between vaccine groups in compliance with preventive public health measures. 282 Our results on the prevalence and severity of adverse effects are in line with previously 283 reported data from RCTs and other observational studies.[6, 9, 10, 24-26] In an online survey 284 among individuals vaccinated with either BNT162b2, mRNA-1273, or JNJ-78436735, Beatty et 285 al. reported that 80.3% of participants experienced adverse effects, with comparable estimates 286 for each vaccine type.[6] Our data also matches the prevalence published in the RCTs for each 287 vaccine individually.[8-10]. The proportion of adverse effects that were self-assessed to be 288 severe or required hospitalization in our study (14.8%) was well below that of Swiss and 289 European governmental surveillance systems (37.9% in Swiss ElViS).[11, 12] US surveillance 290 reports also stated higher estimates of serious adverse events based on hospitalization rates, 291 serious illness and deaths (9.2% vs. our 0.7%).[13] These higher estimates from governmental 292 reporting systems are likely related to the underreporting of mild symptoms and underscore 293 . CC-BY-NC-ND 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.(which was not certified by peer review)preprint The copyright holder for thisthis version posted September 27, 2022. ; https://doi.org/10.1101/2022.09.27.22280403doi: medRxiv preprint 20 the importance of “real-world” data.[14, 15] There is wide variation in reports on prevalence of 294 anaphylaxis and severe allergic reactions ranging from 0.03% to 3%, due to differing 295 definitions.[6, 27, 28] In our study, two (0.4%) participants reported allergic reactions, without 296 requiring medical attention. 297 Our follow-up over 12 weeks allowed us to assess adverse effects that occur with some delay , 298 such as menstrual changes reported in 9% of female participants younger than 50 years. Few 299 studies have described menstrual irregularities following SARS -CoV-2 vaccination with 300 prevalence ranging between 0.3% and 46%.[29, 30] This large variability and the high prevalence 301 (37.8%) of menstrual irregularities in the general population regardless of vaccination underscore 302 the challenge of attributing changes in the menstrual cycle to vaccination. [31] Further research 303 is needed on the influence of SARS -CoV-2 vaccination on menstruation and the general impact 304 of vaccination on female recipients, as we and others observed that female recipients were 305 generally more likely to experience adverse effects.[32-35] 306 We also found that participants who were younger than 65 years and received mRNA-1273 were 307 more likely to report adverse effects possibly due to stronger immune responses among these 308 groups.[6, 13, 26] Similarly, other studies have found evidence that SARS-CoV-2 infections prior 309 to vaccination may be associated with adverse effects reports due to increased 310 immunogenicity.[6, 7] While we found that individuals with prior SARS-CoV-2 infections were 1.8 311 times more likely to report adverse effect s compared to those without, the findings were not 312 statistically significant, potentially due to insufficient power in our study. 313 mRNA vaccine recipients trusted vaccines in general and thus were mostly motivated to be 314 vaccinated as soon as SARS -CoV-2 vaccines became available. JNJ -78436735 recipients were 315 . CC-BY-NC-ND 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.(which was not certified by peer review)preprint The copyright holder for thisthis version posted September 27, 2022. ; https://doi.org/10.1101/2022.09.27.22280403doi: medRxiv preprint 21 more hesitant and waited for JNJ-78436735’s introduction to Switzerland, resulting in a higher 316 proportion of individuals with infections prior to vaccination compared to mRNA vaccine 317 recipients. Other studies describe these concerns about the rapid development and fears of 318 adverse effects to be among the main reasons to wait for non -mRNA-based vaccines or other 319 alternatives.[36-38] General skepticism and the presence of nocebo effects , as demonstrated by 320 a Amanzio et al, may have translated into a higher proportion of JNJ -78436735 recipients 321 perceiving adverse effects as sev ere. [38-40] Increasing awareness of these nocebo responses 322 and using positive framing around the low risk of severe adverse effects may contribute to 323 improving vaccine acceptance. 324 This study provided evidence from a representative cohort recruited from the general population 325 and followed-up over a 12 -week period. Data collected through symptom diaries and adverse 326 effect coding according to MedDRA terms generated a comprehensive dataset allowing a 327 comparative analysis of three common SARS-CoV-2 vaccines. 328 However, there are several limitations to our study. First, self-selection bias may have occurred 329 if individuals who are more health literate or less hesitant participate d in our study , leading to 330 overestimations of trust in public health authorities and more positive perceptions of vaccines. 331 However, we consider the data on the prevalence of adverse effects as broadly representative . 332 Second, our data is self -reported. While this allows for an accurate description of vaccine 333 recipients' experiences, it is subjective and no verification of the relation of adverse effects and 334 vaccination by a healthcare provider was possible . Third, the absolute numbers of reports for 335 some adverse effects when analyzed individually are relatively small (e.g., menstrual changes). 336 Finally, our analysis was restricted to basic immunization of the three SARS -CoV-2 vaccines 337 . CC-BY-NC-ND 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.(which was not certified by peer review)preprint The copyright holder for thisthis version posted September 27, 2022. ; https://doi.org/10.1101/2022.09.27.22280403doi: medRxiv preprint 22 approved in Switzerland at the time of study conduct . Further research on adverse effects 338 occurring after booster vaccinations , other types of vaccines and combinations of different 339 vaccines is needed. 340 341

342 This study demonstrates the safety of three SARS-CoV-2 vaccines in a representative population-343 based cohort and provides real-world estimates on adverse effect prevalence after vaccination. 344 Thereby, we importantly extend the evidence base for health-care providers to answer many of 345 the questions of individuals seeking vaccination. While further evidence on adverse effects after 346 booster vaccination and other vaccine types is required, our study suggests that transparent 347 communication regarding adverse effects and building trust in public health authorities are 348 pivotal future vaccination campaigns’ success. 349 350 . CC-BY-NC-ND 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.(which was not certified by peer review)preprint The copyright holder for thisthis version posted September 27, 2022. ; https://doi.org/10.1101/2022.09.27.22280403doi: medRxiv preprint 23 Funding 351 This work was supported by funds received within the Corona Immunitas research network, of 352 which this study is part of. The Corona Immunitas research network is coordinated by the Swiss 353 School of Public Health (SSPH+) and funded by fundraising of SSPH+ including funds of the Swiss 354 Federal Office of Public Health and private funders (ethical guidelines for funding stated by 355 SSPH+ were respected), by funds of the cantons of Switzerland (Vaud, Zurich, and Basel), and by 356 institutional funds of the Universities. Additional funding specific for this cohort was received 357 from the Uniscientia Foundation (Switzerland). TB received funding from the European Union’s 358 Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant 359 agreement No 801076, through the SSPH+ Global PhD Fellowship Programme in Public Health 360 Sciences (GlobalP3HS) of the SSPH+. DM received funding by the UZH Postdoc Grant, grant no. 361 FK-22-053. 362 363

364 The authors thank the study administration team and the team from the University of Zurich’s 365 (UZH) vaccination center, the reference center for the Canton of Zurich, Switzerland, for their 366 dedicated support of the study. They also thank the study participants for their valuable 367 contribution to this project. 368 369 Conflict of Interest 370 The authors of this manuscript state no conflict of interest. 371 . CC-BY-NC-ND 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.(which was not certified by peer review)preprint The copyright holder for thisthis version posted September 27, 2022. ; https://doi.org/10.1101/2022.09.27.22280403doi: medRxiv preprint 24

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