SARS-CoV-2 messenger RNA (mRNA) vaccines (BNT162b2 [Pfizer-BioNTech] and mRNA-1273 [Moderna]) are associated with local and systemic symptoms; however, whether postvaccination symptoms are associated with vaccine-induced antibody response is unknown. Previous studies1-3 of COVID-19 vaccine reactogenicity and immunogenicity were limited to convenience samples that may not be generalizable. We studied the association of self-reported postvaccination symptoms with anti–SARS-CoV-2 antibody response among Framingham Heart Study (FHS) participants contributing to the Collaborative Cohort of Cohorts for COVID-19 Research (C4R) study.4
The FHS is an ongoing, prospective cohort study evaluating cardiovascular disease risk factors. In February 2021, participants were invited to self-administer C4R questions on COVID-19 vaccination (and associated symptoms) and submit a dried blood spot to test for anti–SARS-CoV-2 antibodies (eFigure in the Supplement). This report includes participants who received 2 doses of mRNA vaccine at least 2 weeks before blood spot collection. Postvaccination symptoms were categorized as systemic symptoms (fever, chills, muscle pain, nausea, vomiting, headache, and/or moderate to severe fatigue) or local symptoms (injection site pain and/or rash). IgG antibodies to SARS-CoV-2 spike subunit were measured using microsphere immunoassay (Luminex), chosen for its successful use in population-based serosurveys. Results were reported as median fluorescence intensity (MFI), with batch-specific reactive antibody response MFI cutoffs.5 Associations between postvaccination symptoms and antibody response were assessed by χ2 test and multivariable linear regression, with complete case analyses adjusted for batch, time since vaccination, and sociodemographic and clinical characteristics. A 2-sided P < .05 was considered statistically significant. Protocols were approved by institutional review boards of participating institutions and the National Heart, Lung, and Blood Institute. Written informed consent was obtained from all participants. This study followed the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guideline.
Of 3200 FHS participants eligible to participate in C4R, 928 (29%) completed the C4R questionnaire and blood spot collection and reported 2 doses of BNT162b2 (414 [45%]) or mRNA-1273 (514 [55%]) vaccines (eFigure in the Supplement). Respondents’ mean (SD) age was 65 (12) years, 360 (39%) were men and 568 (61%) were women, 893 (96%) were non-Hispanic White, and 84 (9%) self-reported prior COVID-19 infection. After either vaccine dose, 446 participants (48%) reported systemic symptoms, 109 (12%) reported local symptoms only, and 373 (40%) reported no symptoms. In bivariate analysis, symptoms were associated with younger age, female sex, prior infection, and the mRNA-1273 vaccine (Table). Antibody reactivity was observed in 365 asymptomatic participants (98%), 108 participants (99%) with only local symptoms, and 444 participants (99%) with systemic symptoms (P = .08). In adjusted models, systemic symptoms were associated with greater antibody response, although associations were attenuated with sequential adjustment for potential confounders (Figure). Similar results were obtained with exclusion of participants with prior COVID-19 infection.
In a sample of twice-vaccinated, older, community-dwelling US adults, self-reported systemic symptoms after SARS-CoV-2 mRNA vaccination were associated with greater antibody response vs local-only or no symptoms, although associations were attenuated with sequential adjustment for potential confounders. These results agree with a previous report6 in US health care workers that showed higher postvaccination antibody measurements among those with significant symptoms after an mRNA vaccine. This report identifies age, sex, and Moderna vaccine as factors associated with both vaccine reactogenicity and immunogenicity, consistent with prior observations.3,6 No association was observed between symptoms after vaccination and race or ethnicity, body mass index, or comorbidities. In this generalizable cohort, nearly all participants exhibited a positive antibody response to complete mRNA vaccine series. Nonetheless, systemic symptoms remained associated with greater antibody response in multivariable-adjusted models, highlighting unexplained interpersonal variability. Further research on biological mechanisms underlying heterogeneity in vaccine response is needed. Limitations of this report include an older, predominantly non-Hispanic White, professional cohort; potential recall bias; and use of MFI, which is not standardized against neutralizing antibody titers. In conclusion, these findings support reframing postvaccination symptoms as signals of vaccine effectiveness and reinforce guidelines for vaccine boosters in older adults.
Accepted for Publication: September 7, 2022.
Published: October 21, 2022. doi:10.1001/jamanetworkopen.2022.37908
Correction: This article was corrected on November 28, 2022, to fix some incorrect row headers in the Figure and to add some missing information regarding attenuation of the reported associations in the first sentence of the Discussion.
Open Access: This is an open access article distributed under the terms of the CC-BY License. © 2022 Hermann EA et al. JAMA Network Open.
Corresponding Author: Emilia A. Hermann, MD, MPH, Division of General Medicine, Department of Medicine, Columbia University Medical Center, 630 W 168th St, PH 9 East, Room 105, New York, NY 10032 (eah2191@cumc.columbia.edu).
Author Contributions: Drs Hermann and Balte had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.
Concept and design: Hermann, Lee, Kirkpatrick, Oelsner.
Acquisition, analysis, or interpretation of data: Hermann, Balte, Xanthakis, Kirkpatrick, Cushman, Oelsner.
Drafting of the manuscript: Hermann, Lee, Kirkpatrick, Oelsner.
Critical revision of the manuscript for important intellectual content: All authors.
Statistical analysis: Hermann, Balte, Oelsner.
Obtained funding: Cushman, Oelsner.
Administrative, technical, or material support: Kirkpatrick, Cushman, Oelsner.
Supervision: Kirkpatrick, Oelsner.
Conflict of Interest Disclosures: Dr Balte reported receiving grants from the National Institutes of Health during the conduct of the study. Dr Oelsner reported receiving grants from the National Heart, Lung, and Blood Institute during the conduct of the study and outside the submitted work. No other disclosures were reported.
Funding/Support: This research was funded in part by agreement 1OT2HL156812 from the National Institutes of Health.
Role of the Funder/Sponsor: The funding source had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.
Disclaimer: The views and conclusions contained in this document are those of the authors and should not be interpreted as representing the official policies, either expressed or implied, of the National Institutes of Health.
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