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)

Wendy P Bannister; Dorthe Raben; Palle Valentiner-Branth; Martin Tolstrup; Lykke Larsen; Britta Tarp; Mette Brouw Iversen; Ole Schmeltz Søgaard; Sisse Rye Ostrowski; Nina Breinholt Stærke; Marie Louise Jakobsen; Susan Olaf Lindvig; Maria Ruwald Juhl; Isik Somuncu Johansen; Ahmed B Mustafa; Lars Østergaard; Fredrikke Dam Larsen; Lene Surland Knudsen; Vibeke Klastrup; Lothar Wiese; Thomas Benfield; Kristine Toft Petersen; Kasper K Iversen; Henrik Nielsen; Joanne Reekie; Jens Lundgren; ENFORCE Study Group

doi:10.1093/ofid/ofad248

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)

Open Forum Infect Dis. 2023 May 8;10(6):ofad248. doi: 10.1093/ofid/ofad248. eCollection 2023 Jun.

Authors

Wendy P Bannister¹, Dorthe Raben¹, Palle Valentiner-Branth², Martin Tolstrup^{3

4}, Lykke Larsen⁵, Britta Tarp⁶, Mette Brouw Iversen⁷, Ole Schmeltz Søgaard^{3

4}, Sisse Rye Ostrowski^{8

9}, Nina Breinholt Stærke³, Marie Louise Jakobsen¹, Susan Olaf Lindvig⁵, Maria Ruwald Juhl¹⁰, Isik Somuncu Johansen^{5

11}, Ahmed B Mustafa^{8

12}, Lars Østergaard^{3

4}, Fredrikke Dam Larsen^{3

4}, Lene Surland Knudsen⁷, Vibeke Klastrup³, Lothar Wiese⁷, Thomas Benfield^{8

12}, Kristine Toft Petersen¹⁰, Kasper K Iversen¹³, Henrik Nielsen^{10

14}, Joanne Reekie¹, Jens Lundgren^{1

8}; ENFORCE Study Group

Collaborators

ENFORCE Study Group:
L J Østergaard, L Krohn-Dehli, D K Petersen, Hvidovre K Fogh, E H Mikkelsen, P Bek, V Klastrup, F Larsen, S H Rasmussen, M H Schleimann, S Schieber, A Søndergaard, B Tarp, M Tousgaard, Y Yehdego, J Bodilsen, K T Petersen, M Ruwald, R K Thisted, S F Caspersen, M Iversen, L S Knudsen, J L Meyerhoff, L G Sander, C Abildgaard, I K Holden, N E Johansen, L Larsen, S O Lindvig, L W Madsen, A Øvrehus, N A Kruse, H Lomholdt, T G Krause, P Valentiner-Branth, Statens Seruminstitut, B Søborg, T K Fischer, C Erikstrup, S R Ostrowski, H Nielsen, I S Johansen, L J Østergaard, M Tolstrup, N B Stærke, O S Søgaard, T Benfield, J Lundgren, D Raben, H Nielsen, L J Østergaard, M Tolstrup, N B Stærke, O S Søgaard, L Wiese, T Benfield, J Lundgren, D Raben, E Jylling, D Hougaard, S D Andersen, K Lykkegaard, N B Stærke, O S Søgaard, M Tolstrup, L J Østergaard, S R Andreasen, E Baerends, L L Dietz, A K Hvidt, A K Juhl, R Olesen, M Tolstrup, K K Andersen, W Bannister, C Bjernved, T W Elsing, F V Esmann, M A Ghafari, E Gravholdt, S F Jakobsen, M L Jakobsen, C M Jensen, T Ø Jensen, D Kristensen, L R Kumar, J Lundgren, C Matthews, N Normand, C Olsson, D Raben, J Reekie, A Traytel, T Weide, A M Hvas, H Støvring

Affiliations

¹ Centre of Excellence for Health, Immunity and Infections (CHIP), Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.
² Department of Infectious Disease Epidemiology and Prevention, Statens Serum Institut, Copenhagen, Denmark.
³ Department of Infectious Diseases, Aarhus University Hospital, Aarhus, Denmark.
⁴ Department of Clinical Medicine, Aarhus University, Aarhus, Denmark.
⁵ Department of Infectious Diseases, Odense University Hospital, Odense, Denmark.
⁶ Diagnostic Centre, University Research Clinic for Innovative Patient Pathways, Silkeborg Regional Hospital, Silkeborg, Denmark.
⁷ Department of Medicine, Zealand University Hospital, Roskilde, Denmark.
⁸ Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark.
⁹ Department of Clinical Immunology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.
¹⁰ Department of Infectious Diseases, Aalborg University Hospital, Aalborg, Denmark.
¹¹ Department of Clinical Research, University of Southern Denmark, Odense, Denmark.
¹² Department of Infectious Diseases, Copenhagen University Hospital-Amager and Hvidovre, Hvidovre, Denmark.
¹³ Department of Cardiology and Department of Emergency Medicine, Herlev-Gentofte Hospital, Herlev, Denmark.
¹⁴ Department of Clinical Medicine, Aalborg University, Aalborg, Denmark.

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.