{'fraction_non_alphanumeric': 0.02799907631913174, 'fraction_numerical': 0.032906130931763075, 'mean_word_length': 4.884171195652174, 'pattern_counts': {'":': 0, '<': 1, '<?xml version=': 0, '>': 1, 'https://': 0, 'lorem ipsum': 0, 'www.': 0, 'xml': 0}, 'pii_count': 0, 'substrings_counts': 0, 'word_list_counts': {'cursed_substrings.json': 7, 'profanity_word_list.json': 0, 'sexual_word_list.json': 0, 'zh_pornsignals.json': 0}}
Adverse Events Following Immunization with mRNA and Viral Vector Vaccines in Individuals with Previous SARS-CoV-2 Infection from the Canadian National Vaccine Safety Network

Abstract Background Adults previously infected with SARS-CoV-2 develop short-term immunity and may have increased reactogenicity to COVID-19 vaccines. This prospective, multi-center active surveillance cohort study examined the short-term safety of COVID-19 vaccines in adults with a prior history of SARS-CoV-2. Methods Canadian adults vaccinated between December 22, 2020 and November 27, 2021 were sent an electronic questionnaire 7 days post dose 1, dose 2 and dose 3 vaccination. The main outcome was health events occurring in the first 7 days after each vaccination that prevented daily activities, resulted in work absenteeism or required a medical consultation, including hospitalization. Results Among 684,998 vaccinated individuals, 2.6% (18,127/684,998) reported a prior history of SARS-CoV-2 infection a median of 4 months (interquartile range 2-6 months) previously. After dose 1, individuals with moderate (bedridden) to severe (hospitalized) COVID-19 who received BNT162b2, mRNA1273 or ChAdox1-S vaccines had higher odds of a health event preventing daily activities, resulting in work absenteeism or requiring medical consultation; adjusted odds ratio (AOR) 3.96 (95% CI 3.67–4.28) for BNT162b2, 5.01 (4.57–5.50) for mRNA1273 and 1.84 (1.54–2.20) for ChAdox1-S compared to no infection. Following dose 2 and 3, the greater risk associated with previous infection was also present but attenuated compared to dose 1. For all doses, the association was lower or absent after mild or asymptomatic infection. Conclusion Adults with moderate or severe previous SARS-CoV-2 infection were more likely to have a health event sufficient to impact routine activities or require medical assessment in the week following each vaccine doses.

Frequencies and proportions were calculated for primary and secondary outcomes in participants with 10 and without previous SARS-CoV-2 infection after each dose of vaccine for each of the three vaccine 11 products. Participants whose dose 2 was a different vaccine product than their dose one were classified 12 as mixed schedule recipients at dose 2. Multivariable logistic regression was used to determine whether 13 previous SARS-CoV-2 infection increased the risk for AEFI for each vaccine product after each dose 14 after controlling for age, sex, health status and (for Dose 2 estimate only) experience of health event in 15 Dose 1. Previous infection was dichotomized as yes or no at each dose, but once an individual had an 16 infection they were not included in the uninfected group for any subsequent analyses. For example, 17 individuals who were infected between dose 1 and 2 were included in the uninfected group for the dose 18 1 analysis and then in the infected group for the dose 2 analyses. Those who were infected prior to dose 19 1 were in the infected group for all analyses. Estimates with 95% Wald confidence intervals were 20 calculated. Estimates were considered significant when the 95% confidence interval did not cross one.   Table 1. An overall median of 2 months, elapsed between the first 11 and second vaccine dose ( Table 2). The interval between dose 2 and 3 was not captured, but the national 12 recommendation was for at least a 6-month interval between the primary series and first booster dose 13 [25].
14 15 Health Events following Vaccination 16 In the week following dose 1 vaccination, a higher percentage of previously SARS-CoV-2 infected 17 participants had events of sufficient severity to prevent daily activities, result in work or school 18 absenteeism or require a medical consultation (main outcome) for all three vaccine types (12% to 16% 19 for previously infected vs. 3% to 12% for non-infected) (Table 1). Additionally, a higher percentage of 20 previously infected participants reported serious AEFI (emergency room or hospitalization) (0.6% to 21 0.7% previously infected vs. 0.2% to 0.5% non-infected) ( Table 1).

23
In the week following dose 2 vaccination, results were similar with a higher percentage of previously 24 SARS-CoV-2 infected participants reporting events of sufficient severity to prevent daily activities, result in work or school absenteeism or require a medical consultation (main outcome) for all three 1 vaccine types and for the mixed schedules (Table 2).

3
In the week following dose 3 vaccination with either BNT162b2 or mRNA1273, a higher proportion of 4 previously-infected participants reported events of sufficient severity to prevent daily activities, result in 5 work or school absenteeism or require a medical consultation than those not infected (Table 3). After adjusting for age, sex and health status, individuals with previous SARS-CoV-2 infection of any 8 severity who were vaccinated with either of the mRNA vaccines had a higher odds of reporting events 9 of sufficient severity to prevent daily activities or result in work absenteeism or require a medical 10 consultation after their first dose, while only individuals with a moderate/severe SARS-CoV-2 infection 11 had higher odds of a health event after their first dose of ChAdox1-S vaccine (Figures 2-4). For mRNA 12 vaccine recipients, moderate/severe infection was also associated with an increased odds of emergency 13 department visits or hospitalizations (serious AEFI) in the week following dose 1 vaccination while 14 asymptomatic/mild infections were not (Figures 2-4). For ChAdox1-S vaccine recipients at dose 1, 15 previous infection was not associated with an increased probability of emergency department visits or 16 hospitalizations (serious AEFI).

18
Following dose 2 the relationship between previous infection and AEFI was attenuated compared to 19 dose 1 after adjusting for age, sex and health status. Individuals with asymptomatic or mild infections 20 did not have an increased risk for health events following their second dose, for either mRNA vaccine 21 product and for a heterologous vaccine schedule (e.g. ChAdox1-S followed by either mRNA vaccine or 22 one mRNA vaccine followed by a different mRNA vaccine product). The risk for health events was still 23 slightly elevated for those with moderate to severe previous infections (Figures 2-4). The risk could not 24 be calculated for recipients of the ChAdox1-S vaccine as too few people who were previously infected received a homologous vaccine schedule with this product. For serious events following mRNA 1 vaccines, although the number of serious events in previously infected 2-dose vaccine recipients was 2 small, the risk was still increased for BNT162b2 vaccine recipients with a moderate or severe previous 3 infection compared to those without an infection. However, the effect is also attenuated compared to the 4 first dose (Figures 2-4).

6
Following dose 3 vaccination, the relationship between previous infection and AEFI was similar to dose 7 1 after adjusting for age, sex and health status, but with smaller effect sizes compared to the first dose

11
Injection site reactions were solicited for all participants and occurred significantly more frequently 12 among previously SARS-CoV-2 infected participants for all vaccine products after dose 1 (Table 4), 13 while it only occurred significantly more frequently in previously infected participants who received 14 BNT162b2 and ChAdox1-S after dose 2 (Table 5). A significantly higher proportion of previously 15 infected participants who received mRNA-1273 for their third dose reported injection site reactions, 16 while rates were similar for BNT162b2 recipients (Table 6).

18
The remaining specific health events were only solicited for those who reported a health event. Among 19 this group, most types of events were reported more frequently by individuals with prior SARS-CoV-2 20 infection after dose 1, with the greatest differences being in general systemic symptoms (e.g. 21 malaise/myalgia, fever and joint pain, headache) and nausea/vomiting/diarrhea. By dose 2, these 22 differences were still present for BNT162b2, but had decreased with mRNA-1273 and ChAdox1-S for 23 many symptoms (Table 5). Although a greater proportion of previously infected individuals reported 24 some neurologic symptoms such as vertigo, paresthesia, loss of taste or smell after the first dose of mRNA vaccines these differences were no longer apparent after the second dose. Following dose 3 the 1 proportions reporting systemic symptoms in the previously infected group further decreased for both 2 mRNA vaccines (Table 6). For all doses the frequency of reported symptoms was higher with mRNA-3 1273 compared to BNT162b2. Health events started within the first 24 hours of dose 1 vaccination for the majority of participants, 7 regardless of infection status or vaccine product. However, a larger proportion of mRNA vaccine 8 recipients who were previously infected (75% to 80%) had onset within the first 24 hours following 9 vaccination compared with just over 50% for non-infected individuals (Supplemental Figure 1).

10
Duration of symptoms was similar regardless of infection status with most symptoms lasting 1-3 days 11 (Supplemental Figure 1).

13
Following dose 2 vaccination, onset was generally similar among infected and non-infected participants 14 with a slightly higher proportion of BNT162b2 dose 2 previously infected recipients experiencing onset 15 of symptoms within the first 24 hours of vaccination compared to non-infected participants, while the 16 reverse was true for ChAdox1-S vaccine recipients (i.e., more non-infected experienced onset within the 17 first 24 hours). Duration of symptoms was similar for infected and non-infected participants for the 18 three vaccine products and the mixed schedule (Supplemental Figure 2). For all three doses, health events that prevent work, daily activities or require medical care were more 3 likely to occur in the first week following initiation of vaccination with a COVID-19 vaccine in 4 individuals with a prior moderate to severe SARS-CoV-2 infection and occurred more frequently after 5 mRNA-1273 than BNT162b2, regardless of dose. The association was smaller or absent after 6 asymptomatic or mild infections, compatible with the greater immune response that has been identified 7 in persons with more circulating antibody [7,8,15]. Compared to the first dose, the association was 8 decreased after the second and third doses for mRNA vaccines. Reassuringly, most frequently reported 9 AEFI symptoms were fever, myalgia and headache, and were self-limited in nature and resolved within 10 24 to 72 hours after vaccination. Less than 1% required emergency care or hospitalization. marketing pharmacovigilance study including more than 1.1 million vaccinees from Hong Kong 16 revealed no association between previous SARS-CoV-2 infection and AEFI or emergency room visit or 17 hospitalization after 1 dose of vaccine [29]. Although this study compared infected individuals with non-18 infected individuals who had received 2-doses which may account for the lack of association, given the 19 attenuation of effect we found in our data following the second dose. Additionally, the duration between 20 doses in Canada (median 2 months for primary series and at least 6 months for booster dose) was greater 21 than that used in other countries. This longer duration may also have reduced reactogenicity.
These data have strengths and limitations. CANVAS is a multi-center, prospective study with sites 1 across Canada and captures data from the start of the COVID-19 vaccination program. It is based on 2 self-report, thus we are unable to verify reported events through review of medical charts. Therefore, 3 with the exception of injection site reactions, the specific symptoms reported by our participants may be 4 unrelated to the vaccine except via a temporal association. Self-reporting of health events is subjective 5 and may be subject to recall bias and people with prior SARS-CoV-2 infection (especially if they have 6 had a more severe infection) may be more sensitized to their own health. However, self-report data has 7 been shown to be a reliable proxy for health care utilization and absenteeism for recall periods of up to 8 one month [30] and self-report of AEFI has been shown to describe more serious events than those 9 reported by health care providers [31]. Our study is limited in the information captured beyond 7 days.

10
Differential misclassification of asymptomatic infection may have occurred in our non-exposed group, 11 which could potentially bias the result toward the null. We expect this to be minimal as testing was 12 widely available at no charge even for mild symptoms or close contacts without symptoms through the 13 enrollment period of the study. Ethnicity was not captured until the dose 2 survey and the majority of 14 our participants who reported ethnicity were White, thus our results may not be fully generalizable to 15 other groups. Participation in CANVAS required individuals to actively enroll and complete an 16 electronic survey and such individuals may differ from the general population.

18
In this large, prospective observational study, health events were increased in the week following 19 vaccination with BNT162b2, mRNA1273 and ChAdox1-S vaccines in individuals with a prior SARS-20 CoV-2 infection and this association increased according to the severity of infection, which is suggestive 21 of a dose response. The association is stronger after the first dose than after the second and third doses.

22
The potential signal identified by our study requires further investigation via data linkage or other 23 observational methods that do not rely on self-report. Providers should consider additional vaccine counseling on expected adverse effects for SARS-CoV-2 previously infected individuals prior to We gratefully acknowledge the expert assistance provided by our public health colleagues. We would 13 like to thank the CANVAS coordinators and research staff for their continued contribution to the project. 14 We would like to thank the CANVAS-COVID participants. Foundation for Health Research. for National Advisory Committee on Immunization as a member (volunteer, unpaid participation). All 24 funds have been paid to their institute, and they have not received any personal payments. CoV-2 naïve and recovered individuals following mRNA vaccination. Sci Immunol 2021; 6(58). NACI. An Advisory Committee Statement National Advisory Committee on Immunization: Guidance on 9 booster COVID-19 vaccine doses in Canada -update December 3, 2021. Accessed August 5, 2022.

SARS-CoV-2 infection and vaccination (months, IQR)
2 (1 -9) 2 (1 -8)  Note: event categories are not mutually exclusive 1 a All participants were asked about injection site reactions; only those who indicated a severe health event were provided the list of symptoms to select. 2 Participants could select more than one symptom. 3 b Other neurologic was defined as:weakness or paralysis of the arms or legs/confusion/change in personality/behavior or difficulty with urination or 4 defecation. 5 c Coagulation symptoms was defined as: symptoms of blood clot or bleeding: swelling/pain in legs/blood clot/ bruising or pinpoint dark rash. 6 A C C E P T E D M A N U S C R I P T   Note: event categories are not mutually exclusive 1 a All participants were asked about injection site reactions; only those who indicated a severe health event were provided the list of symptoms to select. 2 Participants could select more than one symptom.. 3 b Other neurologic was defined as:weakness or paralysis of the arms or legs/confusion/change in personality/behavior or difficulty with urination or 4 defecation. 5 c Coagulation symptoms was defined as: symptoms of blood clot or bleeding: swelling/pain in legs/blood clot/ bruising or pinpoint dark rash.  Note: event categories are not mutually exclusive 1 a All participants were asked about injection site reactions; only those who indicated a severe health event were provided the list of symptoms to select. 2 Participants could select more than one symptom.. 3 b Other neurologic was defined as:weakness or paralysis of the arms or legs/confusion/change in personality/behavior or difficulty with urination or 4 defecation. 5 c Symptoms of blood clot or bleeding: swelling/pain in legs/blood clot/ bruising or pinpoint dark rash.   Figure 3 Note: 95% confidence intervals > 1 means health events more likely to occur in 5 individuals with a previous SARS-CoV-2 infection; 95% confidence intervals < 1 means events 6 less likely to occur in individuals with a previous SARS-CoV-2 infection; 95% CI crosses 1 7 means no association between health event incidence and previous SARS-CoV-2 infection. The 8 reference group is participants with no previous SARS-COV-2 infection. Odds ratios are 9 adjusted for age group, sex, health status, province and experience of health event in Dose 1. infection; 95% CI crosses 1 means no association between health event incidence and previous 20 SARS-CoV-2 infection. The reference group is participants with no previous SARS-COV-2 21 infection. Odds ratios are adjusted for age group, sex and health status.