COVID-19 mRNA Vaccine Short-Term Safety in Patients With Inflammatory Bowel Disease.

Botwin GJ, Li D, Figueiredo J, et al. Adverse events after SARS-CoV-2 mRNA vaccination among patients with inflammatory bowel disease. Am J Gastroenterol 2021;116:1746–1751.

The first coronavirus disease 2019 (COVID-19) messenger RNA (mRNA) vaccines were introduced to the market in December 2020. Understanding vaccine safety and effectiveness in specific patient populations is of the utmost importance to physicians and patients alike. Therefore, Botwin et al aimed to characterize adverse events after inoculation with COVID-19 mRNA vaccines in patients with inflammatory bowel disease (IBD).

The authors used a prospective study design in which patients with IBD intending to receive, or those who recently received, mRNA vaccines were enrolled. Patients were surveyed 8 days after vaccination or at time of enrollment if vaccination was >8 days prior. The survey inquired about symptoms and their severity, graded on a scale from mild to severe. For analysis, biologic medications and Janus kinase inhibitors were grouped as “advanced therapy.”

A total of 246 patients were enrolled. Of these, 67% had Crohn’s disease and 33% had indeterminate or ulcerative colitis. Patients had received either the Pfizer BNT162b2 (57%) or Moderna mRNA 1273 (43%) vaccine. The results were stratified into events after the first (D1) or second (D2) vaccine dose. Overall, 39% of participants had adverse events after D1 and 62% had events after D2. The most frequently reported adverse events were injection site reactions (38% and 56%), followed by fatigue/malaise (23% and 45%), headaches (14% and 34%), and fever/chills (5% and 29%), each after D1 and D2, respectively. For severe events, defined as affecting activities of daily living or requiring hospitalization, 16 participants reported 27 events after D1, the most common being malaise (3%). Three of these patients required hospitalization: 2 for fatigue/malaise and 1 for gastrointestinal symptoms. After D2, 24 participants reported 53 severe adverse events, including malaise (10%), fever/chills (8%), and headache (8%). Of these, 2 were hospitalized, 1 for fever and gastrointestinal symptoms and the other for fever, headache, and fatigue. In unadjusted analyses for each dose, adverse events were more commonly observed in those ≥50 years of age (D1 and D2), with history previous COVID-19 infection (D1), and with ulcerative colitis (D2). Fewer adverse events were observed in those on advanced therapy (D2). In analyses adjusted for age, IBD disease, and history of COVID-19, associations remained for age and advanced therapy. The authors concluded that these findings were similar to those found in the general population, with a lower risk of adverse events for those on advanced therapy.

Comment

In the general population, reports show that adverse events after mRNA COVID-19 vaccines are common; however, most are mild and are either local site reactions or milder systemic myalgias, fevers, or headaches that occur shortly after inoculation. There is generally increased frequency and severity after D2, and overall fewer events in the elderly (JAMA 2021;325:2201–2202; N Engl J Med 2021;384:403–416; N Engl J Med 2020;383:2603–2615). Compared with infection with COVID-19, the vaccine adverse event profile is favorable. Although vaccination may be associated with a mildly increased risk of myocarditis, lymphadenopathy, appendicitis, and herpes zoster infection, after COVID-19 infection the risk of myocarditis is higher and the risk of more severe events is much more marked, including acute kidney injury, pulmonary embolism, intracranial hemorrhage, and arrhythmias (N Engl J Med 2021;385:1078–1090). The present study by Botwin et al is reassuring to both physicians and patients because it demonstrates similar trends in adverse events between the general population and patients with IBD. Moreover, no differences were found between BNT162b2 or mRNA-1273, which may assuage concerns over which vaccine patients received.

The lesser risk of adverse events observed in patients on advanced therapies is particularly intriguing. This observation may be related to those of other studies whose findings suggest that immunosuppressant medications may attenuate vaccine humoral immune response. Kennedy et al found decreased antibody response to COVID-19 vaccines in patients with IBD taking anti-tumor necrosis factor (TNF) agents (Gut 2021;70:1884–1893). Wong et al additionally found decreased response in those on vedolizumab, although their sample size was limited (Gastroenterology 2021;161:715–718.e714). The decreased risk of adverse events seen in Botwin’s study may be due to a similar blunted immune response.

Another notable result was the change in frequency and severity of adverse events between doses. Although higher rates and severity of events after D2 compared with D1 may be anticipated from findings in the general population, in Botwin’s study patients with previous COVID-19 infection, and therefore prior spike protein exposure, had more events than COVID-naïve patients after D1 but not D2. This is in contrast with the Menni et al study in the general population in the UK, which reported more frequent reactions after both doses among those with previous COVID-19 infection (Lancet Infect Dis 2021;21:939–949). Because Botwin’s results were based on a small number of patients (9 of 246 had prior infection), additional larger studies are needed. Moreover, future studies can assess the impact of time interval between spike protein exposures on adverse events.

Botwin’s findings also demonstrate that severe adverse events tend to occur together in a limited number of patients. After D1, 27 severe events were reported in 16 patients. Similarly, there were 53 severe events after D2, which were experienced by only 24 participants. This finding may suggest an immune response threshold for severe adverse events, or perhaps a susceptibility among certain patients. The authors do not indicate if patients who had adverse events after D1 also had events after D2 or if the 2 patients hospitalized after D2 were from among the 3 patients hospitalized after D1. An area for future study is understanding the risk factors for severe adverse events after vaccination.

The choice to present adverse events after the first and second vaccine dose individually, rather than together as a complete series, has its benefits and limitations. Separating D1 and D2 is useful for considering dosage and effects by injection. Data indicate that there is dose-dependent vaccine benefit. This was demonstrated between first and second doses in the general population (N Engl J Med 2020;383:2603–2615; Lancet 2021;397:1819–1829; Ann Intern Med 2021;Epub ahead of print), as well as in small samples of patients with IBD (J Crohns Colitis 2021:Epub ahead of print). Counseling conversations about COVID-19 mRNA vaccines with patients with IBD can be further enriched when adding Botwin’s findings. This information is particularly valuable, because adverse events are a significant reason for COVID-19 vaccine hesitancy among patients with IBD. In a survey study, more than two-thirds of patients with IBD hesitant to receive COVID-19 vaccines said they would like providers to share information about vaccine safety and efficacy, and >80% of these patients indicated that their provider’s recommendations are important in their decisions (Clin Gastroenterol Hepatol 2021;19:1730–1732.e1732). With these data from Botwin’s study, physicians can manage patient expectations regarding outcomes after receiving each dose using more specific information. Although there are advantages to separating D1 and D2 adverse events, limited conclusions can be made about adverse event frequency over the course of the full completed vaccine series.

One limitation is the grouping of anti-TNF, anti-integrin, anti-interleukin, and Janus kinase inhibitors as advanced therapy. Other studies have demonstrated differences in vaccine immunogenicity between these medication classes, especially anti-TNF. Although small numbers may understandably preclude subgroup analyses, a study of outcomes by medication class will be informative. Furthermore, this study may be limited by recall bias and variation in timeframe of survey administration. Several unanswered questions remain to be explored, including the impact of IBD activity on adverse event outcomes, and, importantly, the long-term safety and durability of vaccines against COVID-19 in patients with IBD.

This study is one of the first to report on safety outcomes of COVID-19 mRNA vaccines in patients with IBD. Understanding the likelihood of adverse events will be important in decreasing vaccine hesitancy, especially when results suggest that most reactions are local or mild. The event profile demonstrated here may also be useful as booster doses are considered, though further research on events after additional doses is still needed. Overall, these data are reassuring and suggest that mRNA vaccines against COVID-19 are safe in the IBD patient population.