The first case of SARS-CoV-2 was detected in the United States on January 20, 2020, and as of March 18, 2022, there have been more than 79 million cases and 967,769 deaths attributed to the virus in the United States (1). Inflammatory bowel disease (IBD), comprising ulcerative colitis (UC) and Crohn's disease, is a chronic inflammatory disorder of the gastrointestinal tract. The pathophysiology of IBD involves dysregulation of the mucosal immune system and is usually treated with immunomodulatory and/or immunosuppressive medications, which can lead to an increased risk of infection (2–4). Studies evaluating the interaction of SARS-CoV-2 and IBD have shown that vedolizumab (VDZ) and corticosteroids were associated with an increased risk of SARS-CoV-2 infection, and corticosteroids were linked with an increased risk of severe COVID-19 (5). However, further studies have shown that biologics have been associated with a decreased risk of adverse outcomes from SARS-CoV-2 (6). It was also found that vaccination had a greater than 80% effectiveness in preventing SARS-CoV-2 infection among patients with IBD exposed to a diverse group of medications (7).
Over the course of the pandemic, there have been different variants, with the most recent one being Omicron. By January 1, 2022, it accounted for 95% of new SARS-CoV-2 cases (8,9) and, to date, remains the predominant variant. It has been found to be more transmittable as compared to previous variants (1,10). Concurrently, the immunization strategy to protect against the virus has also evolved. The timing of the booster dose was revised, and currently, the Centers for Disease Control and Prevention (CDC) recommends that all adults should undergo a booster 5 months after the last vaccine, with the interval reduced to 3 months among those who are moderately or severely immunocompromised (11). For boosted patients, the CDC has updated the guidelines, and people older than 50 years are now eligible for an additional booster 4 months after their prior dose to further increase their protection.
Despite increased transmissibility of the Omicron variant and ample availability of the vaccine, a significant proportion of the population remains unvaccinated (12). As of March 18, 2022, only 44.5% of the fully vaccinated population has been boosted (12). There is a lack of data on the rate of uptake of the booster vaccine or its efficacy within the IBD population. Our aim was to evaluate the effectiveness of the booster dose in the IBD population and the potential impact of immunosuppressive medications. Our secondary aims were to evaluate the impact of booster vaccination on hospitalization related to COVID-19 infection and all-cause mortality. To achieve this aim, we studied a nationwide cohort of patients with IBD in the Veterans Health Administration (VHA). The VHA is the largest integrated health care system in the United States, serving more than 9 million veterans every year (13). The VHA has established a database of all patients who have tested positive for SARS-CoV-2 and has recorded associated hospitalizations, making it an ideal health care system in which to conduct such a study.
MATERIALS AND METHODS
Study design and cohort creation
This was a retrospective cohort study using data from a well-established cohort of patients with IBD in the VHA. Patients with IBD were identified using a validated algorithm and classified as Crohn's disease or UC, similar to previously published work in this cohort (5). In this study, we included adult patients with IBD who were diagnosed before the study index date, which was defined as January 2, 2022. Given that our goal was to evaluate the effectiveness of COVID-19 vaccination and boosting on patients with IBD with iatrogenic immunosuppression, we excluded patients who were not taking an IBD medication (defined below) at the time of the index date.
For each patient, the following granular data were obtained: demographics (age, sex, and race), body mass index (BMI), smoking status (never, past, or current), alcohol use, IBD type (Crohn's disease vs UC), US region (Continental, Midwest, North Atlantic, Pacific, or Southeast), and Charlson Comorbidity Index (CCI; 0–1, 2–3, or 4+). IBD medication exposure in the 6 months before the index date (January 2, 2022) was identified using the VHA pharmacy tables and was categorized as follows: 5-aminosalicylic acid, thiopurines (TPs), anti–tumor necrosis factor (anti-TNF) agents, anti-TNF + TPs, VDZ, ustekinumab, and tofacitinib. Corticosteroid use (prednisone, prednisolone, dexamethasone, budesonide, and methylprednisolone) was determined using data in the 3 months before the index date. Approaches to classify these exposure variables are detailed in prior studies from our group using this cohort (5,7,14). As the Omicron variant has mutations that can enable immune evasion and there are limited data regarding hybrid immunization with this variant, we chose to focus on the potential impact of booster vaccination alone. One study evaluating hybrid immunization against the Omicron variant found much lower effectiveness than other variants (15). Moreover, focus on booster vaccination is important given that this marks a modifiable risk factor relevant to clinical practice.
The key exposure was COVID-19 vaccination status, which was categorized as unvaccinated, second vaccine dose, and boosted. All COVID-19 vaccination data are catalogued in adjudicated tables in the VHA data set, which include capture of vaccination data from outside the VHA (16). We identified all first vaccine doses, second vaccine doses, and booster vaccine doses in the cohort. Patients were considered to be unvaccinated if they did not receive at least the second vaccine dose before the index date. Patients were considered to be boosted if they had received the booster dose before the index date. The remaining patients included those who received the second vaccine dose before the index date but who did not yet receive the booster dose. Vaccine type was classified as Moderna, Pfizer, Janssen, and AstraZeneca.
The primary outcome was SARS-CoV-2 infection, as determined through polymerase chain reaction results in the VHA and through a natural language processing–based algorithm that identifies SARS-CoV-2 infection diagnosed outside the VHA health system, a previously validated method that has been implemented nationally in the VHA system and used in numerous VHA studies related to COVID-19 (7,17–20). The timing of SARS-CoV-2 infection relative to the index date was also recorded through a maximum of 31 days of follow-up (i.e., the month of January 2022). This narrow window of observation was intentional, given the very high predominance of Omicron variant infections during this month (>95%) (21). Secondary outcomes included (i) hospitalization related to SARS-CoV-2 infection, defined as hospitalizations with a positive SARS-CoV-2 test in the 15 days before admission or during the hospitalization itself, and (ii) all-cause mortality.
Primary statistical analysis
Descriptive statistics for exposure variables were presented as medians and interquartile ranges for continuous data and as counts and percentages for categorical data. Data were stratified by vaccination status at the index date, and statistical comparisons were made using the Kruskal-Wallis test for continuous data and the χ2 or Fisher exact test for categorical data, as indicated. To evaluate the association between vaccination status and SARS-CoV-2 infection, we used a Cox regression analytic approach with time to SARS-CoV-2 infection as the outcome. Patients were right censored at maximum follow-up or death. First, we performed univariable analyses between continuous variables and the primary outcome to evaluate linearity using locally weighted scatterplot smoothing (LOWESS) curves. Given apparent nonlinearity between age and SARS-CoV-2 infection, age was categorized as <40 years, 40–60 years, 60–80 years, and >80 years. BMI was found to have a reasonably linear association with the outcome and was not transformed. An a priori, hypothesis-driven approach to multivariable analysis was used. Based on the prior literature, well-established risk factors for SARS-CoV-2 infection include age, BMI, and comorbidity burden (22). We therefore sequentially tested these variables as confounders. Given the aim of determining the impact of individual IBD medications on SARS-CoV-2 infection in this cohort, these were included in the final multivariable model. An a priori interaction was tested between vaccination status and anti-TNF vs no anti-TNF given the literature demonstrating potentially reduced immune response after COVID-19 vaccination in this population (23). Kaplan-Meier curves and Cox-adjusted survival curves were plotted to visualize the unadjusted and adjusted association between vaccination status and SARS-CoV-2 infection. The log-rank test was used to compare survival curves in Kaplan-Meier analysis. For all analyses, a 5% alpha threshold was used to determine statistical significance. Hazard ratios (HRs) and 95% confidence intervals (CIs) were reported for final Cox regression models. Vaccine effectiveness (relative to an unvaccinated state) was computed as . Finally, given that the significance of booster doses in initial Janssen and AstraZeneca recipients is less clear, a sensitivity analysis was performed excluding these patients.
To identify risk factors associated with reduced SARS-CoV-2 infection among patients who received booster vaccination, we constructed an additional multivariable Cox regression model in this subgroup. In particular, we explored the impact of time of booster receipt before the index date. We created kernel density plots to visualize the timing of booster (days before the index date) as stratified by IBD medication category. We then created LOWESS plots of this variable (timing of the booster dose) against the outcome of SARS-CoV-2 infection to identify nonlinearity. Based on these results, we transformed the variable using a restricted cubic spline, with knots placed at −130, −90, −45, and −20 days before the index date. In the final multivariable model, HRs and 95% CIs were reported, and adjusted vaccine effectiveness was plotted as a function of timing of the booster dose.
For secondary outcomes of SARS-CoV-2–related hospitalization and all-cause mortality, descriptive outcomes data were compared using the Fisher exact test. We then used multivariable logistic regression analysis to identify variables associated with each outcome. This method was chosen given the lack of censoring events and short follow-up timeframe. Because of relatively low event rates for all-cause mortality, we used logistic regression with Firth-type penalization (24,25). This method minimizes bias in effect sizes because of small sample sizes and/or rare events. Models for both outcomes were adjusted for the same covariates as in the primary Cox regression model above. Odds ratios and 95% CIs were presented to summarize effect size estimates, and vaccine effectiveness for reducing these outcomes was computed similar to methods detailed above.
This study was approved by the Institutional Review Board at the Michael J. Crescenz Philadelphia Veterans Affairs Medical Center. All data management and analyses were performed using STATA/BE 17.0 (College Station, TX).
A total of 22,756 patients with IBD were included in the analytic cohort, of whom 7,150 (31.5%) were unvaccinated, 7,632 (33.6%) received a second vaccine dose, and 7,919 (34.9%) were boosted (Table 1). Boosted patients were significantly older (median age 71 vs 56 years unvaccinated, P < 0.001), had a higher comorbidity burden (CCI 4+ 12.4% vs 4.5% unvaccinated, P < 0.001), and were more likely to be taking corticosteroids at baseline (6.6% vs 5.6% unvaccinated, P < 0.001). Of those who were vaccinated or boosted, most patients initially received Moderna (8,228, 52.7%), followed by Pfizer (7,132, 45.7%). A minority of patients received Janssen (242, 1.6%) or AstraZeneca (4, <0.1%). Timing of the first dose, second dose, and booster doses in the cohort relative to the index date is shown in Supplementary Digital Content (see Figure 1, https://links.lww.com/AJG/C750).
Association between vaccination status and SARS-CoV-2 infection
Over median follow-up of 31 days (interquartile range 31–31), a total of 622 patients (2.7%) were diagnosed with SARS-CoV-2 infection. In unadjusted analysis, the proportion of patients with SARS-CoV-2 infection was significantly lower in boosted vs unvaccinated patients (2.4% vs 3.1%, P = 0.02; Table 2), and in unadjusted Kaplan-Meier analysis (Figure 1a), unvaccinated patients had significantly poorer survival as compared to boosted patients (P = 0.01). In the final adjusted Cox regression model (Table 3, Figure 1b), boosted patients had a 30% reduced hazard of SARS-CoV-2 infection relative to unvaccinated patients (HR 0.70, 95% CI 0.56–0.88, P = 0.002). However, there was no significant difference between patients who had received 2 vaccination doses and those with an unvaccinated status (HR 0.87, 95% CI 0.70–1.08, P = 0.21). Increasing age, higher BMI, and high burden of comorbidities were each positively associated with SARS-CoV-2 infection (Table 3). IBD medications and corticosteroids were not significantly associated with infection. Adjusted estimates of vaccine effectiveness are shown in Table 4, with boosted status conferring a 25.05% effectiveness in reducing infection relative to an unvaccinated status. Finally, in a sensitivity analysis, excluding patients who received Janssen or AstraZeneca vaccines, Cox regression results were similar; the HRs for boosted vs unvaccinated and 2 vaccination doses vs unvaccinated were 0.70 (95% CI 0.55–0.88, P = 0.003) and 0.85 (95% CI 0.68–1.07, P = 0.16), respectively.
Boosted subgroup analysis
In a cohort restricted to patients who received a booster dose (n = 7,919), there was substantial variation in the timing of receiving the booster relative to the index date (Figure 2a). For example, patients on anti-TNF agents, ustekinumab, tofacitinib, or TPs tended to receive the booster dose early, whereas patients on 5-aminosalicylic acid or VDZ tended to receive the booster dose more proximal to the index date. In LOWESS curves, the probability of SARS-CoV-2 infection reduced with increasing time from the booster dose up until about 45 days, after which time the probability steadily rose until about 125 where the probability leveled off (Figure 2b). Similar patterns were noted for both Moderna and Pfizer vaccines. In the final adjusted regression model, increasing BMI and CCI were associated with infection; however, there was no significant association between age and any individual IBD medication groups (Table 3). Timing of the booster dose, however, was strongly associated with the probability of SARS-CoV-2 infection. This relationship is summarized in Figure 3, where vaccine effectiveness rose to over 35% (relative to no booster dose) between 6 and 7 weeks from the timing of the booster dose, followed by waning of effectiveness.
Secondary outcome analysis
During follow-up, a total of 63 (0.3%) patients were hospitalized related to COVID-19; these proportions did not differ across vaccination status in unadjusted analysis (P = 0.11, Table 2). However, in adjusted logistic regression models, boosted status was associated with a 65% reduced hazard of COVID-19 hospitalization (HR 0.35 vs unvaccinated status, 95% CI 0.16–0.74, P = 0.006; Table 5), translating to an adjusted effectiveness of 65.06% (Table 4). Regarding all-cause mortality, this occurred in 63 patients during follow-up, with significant unadjusted differences among vaccination status groups (P = 0.03, Table 2). In adjusted analysis, there was no significant association between vaccination status and all-cause mortality (each P > 0.05; Table 5). The point estimate for adjusted booster efficacy in reducing all-cause mortality was 51.14%; however, this was not statistically significant (Table 4).
In this nationwide cohort of patients with IBD followed in the VHA after Omicron became the dominant variant, we found that about a third of the patients had received a booster vaccine. Being boosted, but not receiving 2 vaccine doses, was associated with a reduced risk of contracting SARS-CoV-2 and COVID-19–related hospitalizations relative to patients who remained unvaccinated.
The SARS-CoV-2 pandemic has affected all aspects of health care including IBD since it was first discovered in Wuhan in December 2019 (26). However, the landscape was changed dramatically when in November 2021, a new variant called Omicron was discovered in South Africa (27). By January 1, 2022, Omicron accounted for 95% of new SARS-CoV-2 cases (8,9). It has continued to be the dominant variant, and as of March 12, 2022, different lineages of Omicron account for almost 100% of all new cases of SARS-CoV-2 (28). Omicron was found to have higher transmission rates as compared to previous variants (29). Studies have also shown a reduction in neutralizing activity by a factor of 20–40 in serum specimens obtained from recipients of 2 doses of BNT162b2 as compared to neutralization against early pandemic viruses and by a factor of at least 10 as compared to neutralization against the Delta variant (30–32).
In the general population, it has been shown that the receipt of 3 doses of mRNA vaccine, relative to being unvaccinated and to the receipt of 2 doses, was associated with protection against both the Omicron and Delta variants (29,33,34). However, there is a lack of data looking at the effectiveness of the booster dose in the IBD population specifically against the Omicron variant. Our study had several important findings. First, the high rate of SARS-CoV-2 infection among the population compared with previous timeframes (5,7) confirmed the higher transmissibility associated with Omicron. Second, it demonstrated that boosted status, but not second vaccination dose alone, was associated with a reduced risk of infection relative to an unvaccinated status. These findings are consistent with recent data from California, which showed that 2-dose vaccine effectiveness against Omicron infection was 23.5% at 91–180 days, 13.8% at 181–270 days, and 5.9% at >270 days. Similarly, a UK study showed that during the Omicron period, vaccine effectiveness against symptomatic disease after 2 BNT162b2 doses was 65.5% at 2–4 weeks, dropping to 8.8% at 25 or more weeks (33). The overall effectiveness of the booster in our IBD population was lower than what has been seen against previous variants. These findings are also in line with studies conducted in the general population (29,33,34) and among the immunocompromised population in which the 3-dose vaccine effectiveness against Omicron infection was 29.4% in the immunocompromised population compared with 70.5% in the immunocompetent population (29).
Among the factors associated with the effectiveness of vaccination in this study, time elapsed from the booster dose was the most strongly significant. In particular, we observed waning effectiveness beyond approximately 6 weeks from the time of the booster dose. It has been shown that antibody response to SARS-CoV-2 among patients with IBD diminishes over time with three-quarters of the patients being seropositive if tested within 2 months of diagnosis, whereas none remain seropositive after 4 months (35). In the general population, a 3-dose vaccine effectiveness against Omicron infection was 71.6% (69.7%–73.4%) at 14–60 days and 47.4% (40.5%–53.5%) at >60 days (29). Among BNT162b2 primary course recipients, vaccine effectiveness against symptomatic disease was 67.2% (95% CI 66.5–67.8) at 2–4 weeks after a BNT162b2 booster before declining to 45.7% (95% CI 44.7–46.7) at 10 or more weeks (33). During the same period, vaccine effectiveness in reducing COVID-19–associated emergency/urgent care encounters was 87% among those who received a booster within the past 2 months; however, effectiveness after 3 doses declined to 66% among those vaccinated 4–5 months prior (34). Ours is the first study in the IBD population to demonstrate similar findings. Patients with IBD, particularly those on immunosuppressive or immunomodulator therapy, were among the first patients to receive the booster dose. The waning of protection with time is clinically important and strengthens the justification for a second booster, especially in light of recent CDC guidance (34). Patients with IBD also have attenuated serological response to SARS-CoV-2 vaccination (36). With the lower effectiveness of the booster against Omicron and waning immunity, this group of patients is expected to benefit from a second booster.
Other factors associated with a higher risk of infection included advancing age and increased BMI. These findings are in line with serological studies among patients with IBD that have shown that advancing age is associated with decreased antibody response (35,37), although these were performed in the pre-Omicron period. In the general population, 3-dose vaccine effectiveness against Omicron infection was 70.9% (68.9%–72.9%) in those younger than 65 years and 64.3% (55.0%–71.7%) in those older than 65 years. With regard to BMI, vaccines against influenza (38), hepatitis B (39), rabies (40), and tetanus (41) have shown reduced responses in those who have obesity compared with those who are lean. We did not find that any specific IBD medication affected the effectiveness of the booster dose. The use of anti-TNF agents have been implicated in reduced serological response (22,42). However, these studies were performed before the onset of Omicron, and it has been shown that the neutralizing activity in response to vaccination against Omicron differs from prior variants (30,31).
In addition to the risk of acquiring SARS-CoV-2, we also evaluated the risk of COVID-19–related hospitalizations. We found that being boosted was associated with a 65% effectiveness in reducing hospitalization relative to an unvaccinated state. These findings are consistent with the general population, which also showed a high effectiveness with 3 vaccine doses against hospitalization with Omicron (29). Although the point estimate for adjusted booster effectiveness in reducing all-cause mortality was 51.14%, this was not statistically significant perhaps owing to a small event rate.
Major strengths of this study include the use of a national cohort of patients with IBD monitored in the VHA system, serving 9 million veterans every year (13). Every patient in the VHA has an SARS-CoV-2 status designation in the electronic health record (positive, negative, or not tested), even if diagnosed to be positive outside the VHA. The VHA has also developed a central database that updates all SARS-CoV-2 diagnoses and vaccination status. These features contribute to high confidence that vaccination events and SARS-CoV-2 diagnoses have been captured with minimal misclassification in this cohort. An additional strength of this study is the use of nationwide VHA pharmacy records for gathering IBD medication data. The VHA has a central pharmacy database, meaning that medications prescribed at different Veterans Affairs centers are linked for a given patient, thus decreasing the chance of missing or misclassified prescribed medications.
Notwithstanding, we acknowledge several important limitations in this study. First, there are inherent external validity limitations to the VHA cohort because it is largely composed of an older male population. Hence, there are also a higher proportion of patients with UC because older-onset UC is more common than Crohn's disease, with rates higher in elderly men than in women (43). However, because it has been shown that immunity wanes at a greater pace in the elderly, this is the group in which it is most important to evaluate the effectiveness of the booster dose. Second, patients are not proactively screened for SARS-CoV-2 in the VHA but rather are tested when symptomatic or for preventative measures such as before an elective procedure. Hence, our patient population could be biased toward detecting symptomatic patients with SARS-CoV-2 infection and could miss a substantial proportion of asymptomatic patients. However, outcomes misclassification to some extent should be mitigated by the robust VHA approach to capture both VHA and non-VHA diagnosed SARS-CoV-2 infections (through natural language processing), as demonstrated through prior validation efforts (16). Third, we were not able to determine to what extent a hospitalization resulted from complications related to SARS-CoV-2 infection. However, we applied a conservative standard to assume that hospitalizations accompanied by a positive test were in some way related to COVID-19. Fourth, unmeasured confounding could potentially affect model results, including that sicker patients requiring higher-intensity treatment of IBD might be more likely to mitigate infectious risk through lifestyle behaviors. Fifth, with the advent of home testing kits, many patients may test positive at home and, especially if asymptomatic, may not present to a health facility. Hence, their positive results would not be captured. Likewise, we were unable to compare the percentage of positive tests among those tested for different groups of patients. Finally, there is the possibility of misclassification of medication exposures, and records of medications prescribed outside the VHA may be incomplete. This issue may be most salient for corticosteroid use, which may be dynamic over even short periods of time. However, veterans have a strong adherence in using the VHA pharmacy, and depending on their benefit status, the medications are typically free or cheaper than non-VHA alternatives (44,45). Furthermore, we used a narrow ascertainment window for medications before the index date, and given the relatively short follow-up time, the impact of medication exposure misclassification in this study would be minimal.
In conclusion, we found that against the Omicron variant, being boosted but not receiving 2 vaccine doses alone was associated with a reduced hazard of infection relative to an unvaccinated status. Furthermore, boosted status was also associated with a significantly lower risk of COVID-19–associated hospitalization. The effectiveness of the booster vaccine waned significantly over time. Considering the lower effectiveness of the booster against Omicron and decline in effectiveness beyond approximately 6 weeks, patients with IBD, especially those who are immunosuppressed, should consider receiving a second booster as per CDC recommendations.
CONFLICTS OF INTEREST
Guarantor of the article: Nabeel Khan, MD.
Specific author contributions: N.K. has participated in study supervision, funding acquisition, study concept and design, acquisition of data, analysis and interpretation of data, drafting of the manuscript, and critical revision of the manuscript for important intellectual content. N.M. has participated in study concept and design, acquisition of data, formal statistical analysis, data visualization and presentation, analysis and interpretation of data, drafting of the manuscript, and critical review of the manuscript for important intellectual content.
Financial support: This study was supported by an unrestricted research grant from Pfizer Pharmaceuticals. Pfizer had no role in the study concept and design, acquisition or interpretation of data, statistical analysis, preparation of the manuscript, or critical review of the manuscript.
Potential competing interests: N.K. has received an unrestricted research grant from Pfizer, Luitpold, and Takeda Pharmaceuticals as well as Samsung BioEpis. N.M. is supported by an American College of Gastroenterology (ACG) Junior Faculty Development Award (ACG-JR-010-2020) and by the National Institutes of Health (K08-DK-124577-01A1).
Data availability statement: The identified data (data with patient identifiers) for this study, which was used to obtain data from patient charts, cannot be made available as per HIPAA guidelines. However, deidentified data can be made available on request.
WHAT IS KNOWN
- ✓ With the advent of the Omicron variant, there are concerns about the efficacy of current vaccinations, especially among immunocompromised/immunosuppressed patients.
WHAT IS NEW HERE
- ✓ Against the Omicron variant, being boosted but not receiving 2 vaccine doses alone was associated with a reduced hazard of infection relative to an unvaccinated status.
- ✓ The efficacy of the vaccine was lower than among previous variants and declined rapidly over time.
- ✓ Considering the lower effectiveness of the booster against Omicron and decline in effectiveness beyond approximately 6 weeks, patients with inflammatory bowel disease, especially those who are immunosuppressed, should receive a second booster as per CDC recommendations.
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