Association of Self-reported Systemic Reactions Following SARS-CoV-2 Vaccination With Immunological Response in the Danish National Cohort Study of Effectiveness and Safety of SARS-CoV-2 Vaccines (ENFORCE)

Abstract

Background: Side effects to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines are a key concern contributing to vaccine hesitancy, but more individuals may be encouraged if SARS-CoV-2 vaccines were known to lead to a stronger immune response.

Methods: Included were adult participants from the Danish National Cohort Study of Effectiveness and Safety of SARS-CoV-2 Vaccines (ENFORCE) who completed a questionnaire to assess systemic reactions following SARS-CoV-2 vaccination (BTN162b2, mRNA-1273, ChAdOx1) and had SARS-CoV-2 spike immunoglobulin G (IgG) levels measured at baseline and post-vaccine. A symptom score was developed to measure severity of systemic adverse reactions (+1 for each moderate, +2 for each severe). Post-vaccination SARS-CoV-2 spike IgG levels were compared between participants with different scores using multivariable linear regression.

Results: A total of 6528 participants were included (56.3% females; median age [interquartile range], 64 [54-75] years). After the first vaccination, no association was found between symptom score and post-vaccine dose spike IgG level (P = .575). Following the second vaccination, significantly higher spike IgG levels were observed according to higher symptom scores (P < .001); adjusted geometric mean ratios were 1.16 (95% CI, 1.04-1.30), 1.24 (95% CI, 1.09-1.41), 1.25 (95% CI, 1.06-1.46), and 1.21 (95% CI, 1.08-1.35), for scores of 2, 3, 4, and ≥5, respectively, compared with a score of 0. After adjustment for pre-vaccine dose spike IgG, this association was attenuated.

Conclusions: An association was found between more severe adverse reactions and stronger antibody response after the second vaccination but not the first, likely attributed to higher levels of preexisting immunity gained from response to first vaccination. Regardless of side effects, most people experienced an effective immune response following vaccination.

Keywords: COVID-19 vaccines; SARS-CoV-2; adverse drug reactions; antibody response.

Figure 1.

Severity of self-reported systemic and local reactions following vaccination. Systemic reactions were chills, fatigue, fever, headache, joint pain, muscle pain, and nausea. Local reactions at the injection site were redness, swelling, and tenderness. Percentages are out of total participants who completed a questionnaire to assess adverse reactions within 1 week following each vaccination.

Figure 2.

Post–vaccine dose SARS-CoV-2 spike IgG levels according to symptom severity scores. Symptom severity scores are based on self-reported systemic reactions within 1 week after vaccination, counting +1 for each moderate and +2 for each severe reaction. Abbreviations: IgG, immunoglobulin G; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2.

Figure 3.

Comparison of post–vaccine dose SARS-CoV-2 spike IgG levels according to symptom severity score of self-reported systemic reactions following first vaccination (A) and second vaccination (B). [1] Primary: geometric mean ratios, 95% CIs, and P values are calculated from multivariable linear regression analysis adjusted for time from vaccination to spike IgG assessment, age, sex, CCI, vaccine type, and evidence of prior SARS-CoV-2 infection. [2] As per primary analysis but with additional adjustment for pre–vaccine dose SARS-CoV-2 spike IgG level. Abbreviations: CCI, Charlson Comorbidity Index; IgG, immunoglobulin G; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2.