Adverse Events and Serological Responses After SARS-CoV-2 Vaccination in Individuals With Inflammatory Bowel Disease

Abstract

INTRODUCTION:

We determined adverse events after 4 doses of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) vaccine in those with inflammatory bowel disease (IBD), associations between antibodies and injection site reactions (ISR), and risk of IBD flare.

METHODS:

Individuals with IBD were interviewed for adverse events to SARS-CoV-2 vaccine. Multivariable linear regression assessed the association between antibody titers and ISR.

RESULTS:

Severe adverse events occurred in 0.03%. ISR were significantly associated with antibody levels after the fourth dose (geometric mean ratio = 2.56; 95% confidence interval 1.18–5.57). No cases of IBD flare occurred.

DISCUSSION:

SARS-CoV-2 vaccines are safe for those with IBD. ISR after the fourth dose may indicate increased antibodies.

INTRODUCTION

The most common adverse event of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) vaccination in those with inflammatory bowel disease (IBD) is injection site reaction (ISR), with rare events such as idiopathic thrombocytopenic purpura (ITP) also reported (1–3). Gastrointestinal symptoms may follow SARS-CoV-2 vaccination, which could be confused for IBD disease activity (1,2). We assessed adverse events after up to 4 doses of SARS-CoV-2 vaccination, the relationship between serological responses and ISR, and the risk of disease flaring after vaccination in those with IBD.

METHODS

Participants with IBD were enrolled into a prospective cohort study of serological responses to SARS-CoV-2 vaccines in Calgary, Alberta (4–6). Participants were interviewed by trained research coordinators using the Adverse Events Following Immunization (AEFI) form, designed to capture any adverse events within 30 days of the first, second, third, and/or fourth dose of a monovalent mRNA SARS-CoV-2 vaccine (7). An adverse event was defined as those occurring within 30 days of vaccination and without an alternative cause. Severe adverse events were defined as those attributable to the vaccine and necessitating a visit to emergency department, admission to hospital, and/or did not fully recover by the time of interview (4). Participants who self-reported worsening gastrointestinal symptoms after vaccination were identified as having a potential IBD flare. Medical chart reviews objectively confirmed worsening disease activity within 30 days of vaccination, defined as either elevated fecal calprotectin, abnormal bowel imaging, and/or endoscopic disease activity leading to a change in medical management.

Serum samples were collected 1–12 weeks after each vaccine dose. The Abbott Architect assay series measured anti–SARS-CoV-2 nucleocapsid antibodies of SARS-CoV-2 (anti-N) to determine natural infection and anti–SARS-CoV-2 spike protein antibodies (anti-S) to quantify serological response to vaccination (5–7). Age, sex, IBD type, vaccine type and date, prior coronavirus disease 2019 diagnoses, and IBD medication status at each vaccine dose were chart reviewed. Prior SARS-CoV-2 infection was defined by PCR-confirmed diagnosis, positive rapid antigen test, and/or anti-N seroconversion.

Adverse events after each dose were reported as proportions, and McNemar tests compared between doses. ISR were selected a priori as the primary adverse event. χ² tests determined univariate associations between patient characteristics and ISR for each dose. Anti-S concentrations corresponding to each dose were reported as geometric mean titers (GMT) with 95% confidence intervals (CI), and GMT stratified by ISR status were compared using Mann-Whitney U tests. Multivariable linear regression models adjusted for age, sex, IBD type, IBD medications, vaccine type, and prior SARS-CoV-2 infection were used to assess the association between ISR and log₁₀-transformed anti-S concentration for each dose. Exponentiated coefficients represent the geometric mean ratio (GMR).

RESULTS

Adverse event rates after each dose are summarized in Table 1. Adverse event reporting was highest after the first (83.5%) and second doses (80.1%) compared with the third (77.0%) and fourth doses (67.7%) (Table 1). Severe adverse events occurred in 0.03%: 1 case of idiopathic thrombocytopenic purpura after a second dose of BNT162b2 vaccine. Table 2 describes ISR stratified by patient characteristics. ISR was the most common adverse event but occurred less frequently after the fourth dose vaccination (56.3%) compared with the other doses (70.9%–76.9%) (Table 2). Significantly increased ISR were observed for those younger than 65 years after the first, second, and third doses, female individuals after the first and second doses, and BNT162b2 vaccination after the second dose (Table 2).

Table 1.

Adverse events after first, second, third, and fourth doses of SARS-CoV-2 vaccination

Table 2.

Patient characteristics and proportions of patients stratified by ISR with associated univariate analyses

Anti-S concentration was highest after the fourth dose vaccination (GMT: 11,748 AU/mL; 95% CI 8,138–16,960 AU/mL), and significantly increased titers were observed for those with ISR than for those without ISR after the fourth dose (P = 0.041, Table 2, Figure 1). Multivariable linear regression determined significant associations between ISR and anti-S concentration after the fourth dose (GMR = 2.56; 95% CI 1.18–5.57) but no associations for the first (GMR = 0.98; 95% CI 0.59–1.63), second (GMR = 1.28; 95% CI 0.89–1.83), and third doses (GMR = 1.22; 95% CI 0.79–1.87). No IBD flares occurred within 30 days of vaccination.

Figure 1.

Log-transformed anti–SARS-CoV-2 spike antibody concentration across 4 doses of SARS-CoV-2 vaccine for participants who reported injection site reactions compared with participants who did not. IgG, immunoglobulin G; SARS-CoV-2, severe acute respiratory syndrome coronavirus-2.

DISCUSSION

Most of the participants experienced an adverse event after SARS-CoV-2 vaccination, with ISR being the most common and occurring at a rate consistent with prior studies in IBD and general populations (8–10). Severe adverse events were rare, and objective evidence of IBD flare within 30 days of a vaccine was not observed. Overall, those with IBD receiving up to 4 messenger RNA doses can be reassured of the safety of vaccination.

Our study presents novel data on associations between adverse events and serological response in the IBD population. Notably, we found that ISR was significantly associated with a subsequent 2.5-fold increased anti-S concentration 1–12 weeks after the fourth dose vaccination. This finding may assure individuals hesitant of subsequent doses because an ISR is implicative of improved vaccine immunogenicity. Contrary to Azzolini et al (11) who observed increased antibodies with adverse events after 2 doses, our study determined nonsignificant associations between anti-S concentration and ISR after the first, second, and third doses.

SARS-CoV-2 vaccination did not result in IBD flare within 30 days of vaccination across all 4 doses. These findings supports previous data indicating no association between SARS-CoV-2 vaccination and IBD flare (9,12,13).

There are several limitations to our study. Population-based sampling was not possible. Adverse event reporting after the first and second doses was subject to greater recall bias due to a longer duration between vaccination and interviews. Individuals with more pronounced adverse events after initial doses may have been reluctant to pursue subsequent doses, leading to potential self-selection bias. Our definition of severe adverse event was less encompassing than other studies and had less insight into the duration and intensity of adverse events. Finally, sample size decreased across doses, which reduced statistical power for additional subanalyses.

Our study substantiates the safety profile of 4 SARS-CoV-2 vaccine doses in those with IBD. While short-term adverse events are common, the frequency decreases across doses, and severe adverse events are rare. Individuals who experience an ISR after fourth dose vaccination have increased antibody levels (approximately 2.5-fold). Objective IBD flares were not observed across all doses. Future studies should explore predictive factors in other adverse event categories and continue to offer insight into safety profiles of novel SARS-CoV-2 vaccines.

CONFLICTS OF INTEREST

Guarantor of the article: Gilaad G. Kaplan, MD, MPH, FRCPC.

Specific author contributions: G.G.K. has full access to all data in the study and takes responsibility for the integrity of the data and accuracy of the data analysis. G.G.K., A.M., C.M., J.Q., J.K., G.T., and R.P. conceived and designed the study. G.G.K., C.M., R.P., N.S., M.H., R.J.I., and A.M. were responsible for clinical data. J.K. and G.T. were responsible for serological data. J.Q. and G.G.K. analyzed the data. A.M., J.Q., and G.K. drafted the manuscript. All authors interpreted the data and provided critical revisions of the manuscript for important intellectual content. All authors have approved the final draft of the manuscript.

Financial support: (i) Canadian Institutes of Health Research Operating Grant: COVID-19 Rapid Research Funding Opportunity funding reference number VR5-172684.·(ii) Crohn's and Colitis Canada COVID-19 and IBD Taskforce. (iii) Public Health Agency of Canada through the Vaccine Surveillance Reference Group (VSRG) and the COVID-19 Immunity Task Force (CITY). (iv) The Leona M. and Harry B. Helmsley Charitable Trust Grant #G-2209-05501.

Potential competing interests: C.G.K. has received honoraria for speaking or consultancy from AbbVie, Janssen, Pfizer, Amgen, and Takeda. He has received research support from Ferring, Janssen, AbbVie, GlaxoSmith Kline, Merck, and Shire. He has been a consultant for Gilead. He shares ownership of a patent: Treatment of Inflammatory Disorders, Autoimmune Disease, and PBC. UTI Limited Partnership, assignee. Patent WO2019046959A1·PCT/CA2018/051098 September 7, 2018.·C.N.B. is supported by the Bingham Chair in Gastroenterology. C.N.B. has served on advisory Boards for AbbVie Canada, Amgen Canada, Avir Pharmaceuticals, Bristol Myers Squibb Canada, Roche Canada, JAMP Pharmaceuticals Canada, Janssen Canada, Sandoz Canada, Takeda Canada, and Pfizer Canada; Consultant for Mylan Pharmaceuticals and Takeda; Educational grants from Abbvie Canada, Pfizer Canada, Takeda Canada, and Janssen Canada; speaker's panel for Abbvie Canada, Janssen Canada, and Takeda Canada. Received research funding from Abbvie Canada, Amgen Canada, Sandoz Canada, and Pfizer Canada. C.M. has received consulting fees from AbbVie, Alimentiv, Amgen, AVIR Pharma Inc., BioJAMP, Bristol Myers Squibb, Celltrion, Ferring, Fresenius Kabi, Janssen, McKesson, Mylan, Takeda, Pendopharm, Pfizer, and Roche; speaker's fees from AbbVie, Amgen, AVIR Pharma Inc., Alimentiv, Ferring, Janssen, Takeda, and Pfizer; research support from Ferring and Pfizer. R.P. has received consulting fees, speaker fees, and research support from AbbVie, Abbott, Alimentiv (formerly Robarts), Amgen, Arena Pharmaceuticals, AstraZeneca, Bristol Myers Squibb, Boehringer Ingelheim, Celgene, Celltrion, Cosmos Pharmaceuticals, Eisai, Elan, Eli Lilly, Ferring, Fresnius Kabi, Galapagos, Genentech, Gilead Sciences, Glaxo-Smith Kline, Janssen, Merck, Mylan, Oppilan Pharma, Pandion Pharma, Pfizer, Progenity, Protagonist Therapeutics, Roche, Satisfai Health, Sandoz, Schering-Plough, Shire, Sublimity Therapeutics, Theravance Biopharma, UCB, and Takeda Pharmaceuticals. E.I.B. has acted as a legal consultant for Hoffman La-Roche Limited and Peabody & Arnold LLP for matters unrelated to medications used to treat inflammatory bowel disease. He has also acted as a consultant for McKesson Canada and the Dairy Farmers of Ontario for matters unrelated to medications used to treat inflammatory bowel disease. K.E.-S. has received consulting fees and speaker fees from Janssen, Ferring, AstraZeneca, Sandoz, and Pfizer. The remaining authors report no conflict of interests.

Ethical considerations: All participants provided informed consent, and the study was approved by the University of Calgary's Conjoint Health Research Ethics Board (REB20-1082).

Data sharing: Data are available on an open-access online interactive dashboard found here: https://kaplan-gi.shinyapps.io/COVID_Serology/.