Severity of Self-Reported Systemic Reactions Following SARS-CoV-2 Vaccination and Immunological Response in the Danish National Cohort Study of Effectiveness and Safety of SARS-CoV-2/COVID-19 Vaccines (ENFORCE)

ABSTRACT

Background. Major side effects after vaccination can be caused by a reactive immune system. We investigate statistical association between severity of self-reported reactions to immunisation with SARS-CoV-2 vaccines and immunological response (SARS-CoV-2 spike immunoglobulin [IgG]) using data from ENFORCE, an openlabel, non-randomised, parallel group, phase IV study that enrolled over 6500 Danish adult citizens prior to their first SARS-CoV-2 vaccination. Methods. Participants were included with assessments of self-reported reactions 1-2 weeks after vaccination and subsequent assessment of total serum levels of SARS-CoV-2 spike IgG at the next visit, before next vaccine dose. A severity score was defined based on 7 systemic reactions (muscle pain, joint pain, fatigue, fever, headache, nausea, chills) scored as moderate (+1) or severe (+2) with a maximum score of 14. Linear regression was used to test association between severity score and log-transformed spike IgG after first and second vaccinations, adjusted for time from vaccination to spike IgG assessment, age, sex, Charlson Comorbidity Index, vaccine type, evidence of prior SARS-CoV-2 infection. We also looked at the effect of adjusting for spike IgG level measured prior to each dose. Results. Of 6918 eligible ENFORCE participants, 6192 and 5937 were included for first and second vaccinations, respectively, with characteristics displayed in Table 1. Adjusted geometric mean ratios are presented in Table 2. Following first vaccination, no significant association was found between severity score and spike IgG (p=0.537). Following second vaccination, the association was highly significant (p< 0.001) with scores of 2 or more having up to 25% higher spike IgG level than a score of 0. When pre-dose spike IgG was subsequently adjusted for (Table 3), the association was no longer significant (p=0.530). assessment, age, sex, Charlson Comorbidity Index (CCI), vaccine type, and evidence of prior SARS-CoV-2 infection. Means and differences were back-transformed to present geometric means, ratios, and 95% confidence intervals. Conclusion. An average of 4 weeks after first vaccination, the SARS-CoV-2 spike IgG level was similar regardless of severity of reactions experienced. Around 9 weeks after second vaccination, those who had at least 2 moderate or 1 severe reaction had a significantly higher spike IgG level than those with no moderate/severe reactions. However, adjustment for pre-existing immunity attenuated the association and warrants further investigation.