key: cord-0849689-sfww23x5
authors: Reuken, P A; Andreas, N; Grunert, P C; Glöckner, S; Kamradt, T; Stallmach, A
title: T cell response after SARS-CoV-2 vaccination in immunocompromised patients with inflammatory bowel disease
date: 2021-08-11
journal: J Crohns Colitis
DOI: 10.1093/ecco-jcc/jjab147
sha: f954208ecdee28f3b9b3630970e305126a5a0e4b
doc_id: 849689
cord_uid: sfww23x5

BACKGROUND: Vaccination is a promising strategy to protect vulnerable groups like immunocompromised inflammatory bowel disease (IBD) patients from an infection with SARS-CoV-2. These patients may have lower immune responses. Little is known about the cellular and humoral immune response after a SARS-CoV-2 vaccination in IBD. METHODS: 28 patients with IBD and 27 age- and sex-matched healthy controls were recruited at Jena University Hospital. Blood samples were taken before, after the first and in a subgroup of 11 patients after second dose of a SARS-CoV-2 vaccination. Cellular immune response including IFN-γ and TNF-α response and antibody titers were analyzed. RESULTS: Overall, 71.4% of the IBD-patients and 85.2% of the controls showed levels of anti-SARS-CoV-2 antibodies above the cutoff of 33.8 BAU/ml (p=0.329) after the first dose. Even in the absence of SARS-CoV-2 antibodies, IBD patients showed significant T cell responses after first SARS-CoV-2 vaccination compared to healthy controls, which was not influenced by different immunosuppressive regimens. Associated with the vaccination, we could also detect a slight increase of the TNF production among SARS-CoV-2-reactive T(H) cells in HD and IBD patients. After the second dose of vaccination, in IBD patients a further increase of humoral immune response in all but one patient was observed. CONCLUSIONS: Already after the first dose of a SARS-CoV-2 vaccination, cellular immune response in IBD patients is comparable to controls, indicating a similar efficacy. However, close monitoring of long-term immunity in these patients should be considered.

Since beginning of 2020, the severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) pandemic has led to significant challenges in the treatment of patients with IBD.

Although no increased susceptibility to SARS-CoV-2 infections or mortality is evident in patients with IBD, 17% of patients with IBD infected with SARS-CoV-2 had to be hospitalized worldwide 1 and patients with IBD express a great fear of getting infected 2 

Organization for the Study of Inflammatory Bowel Disease (IOIBD) and the COVID-19

European Crohn's and Colitis Organization (ECCO) taskforce recommended vaccinating all patients with IBD as soon as they are able to receive the vaccination, regardless of immunemodifying therapies 3, 4 . COVID-19 vaccines are safe in patients with IBD 5 but they were excluded from COVID-19 vaccine trials and therefore efficacy is largely unknowen. 6 A plethora of scientific reports describe impaired immunity after vaccination in IBD patients with immunosuppressive therapy. However, data regarding the effect of immunosuppressive therapies on the immune response is inconsistent. Upon vaccination against influenza 7-10 or pneumococci 11 , IBD patients treated with immunosuppressive agents such as TNF-αantibodies or receiving combination therapies developed lower humoral vaccine responses .

In line with this, the immunogenity of hepatitis B vaccination was reduced in patients with IBD under treatment with immunosuppressive drugs. 12 Recently, studies in patients after solid organ transplantation found reduced antibody levels after the first 13,14 and the second dose of the vaccine. 15 In contrast to this, comparable vaccination responses of immunosuppressed and non-immunosuppressed individuals have been detected after vaccination against Influenza. 16, 17 In patients with IBD and immunosuppressive therapy, the humoral immune response against SARS-CoV-2 was inadequate after first dose of vaccination 18 . Although in most of these studies the vaccination response was examined by detection of antibody titers, some concerns arose, whether it is adequate to only focus on humoral responses to estimate the potency and efficacy of different SARS-CoV-2 vaccines.

A c c e p t e d M a n u s c r i p t T-cell responses are as well crucial for immunity against SARS-CoV-2 19 and it is likely to develop after vaccination with SARS-CoV-2 vaccines. In the SARS-CoV T cells were associated with long-lasting immunity 20 while humoral response was only detectable for a short period. 21 The same kinetics of antibodies and T cells were described in SARS- However, in IBD patients with immunosuppression, a T cell-response towards a SARS-CoV-2 vaccine has not been described, yet. 18 Therefore, it is necessary to analyze T cells responses in parallel to humoral immunity to evaluate a vaccination response in immunocompromised patients.

The primary objective of this study was therefore, to analyze the T cell response in parallel to the humoral immune response after one dose of a SARS-CoV-2 vaccine in patients with IBD under immunosuppressive therapies in comparison to untreated controls.

Patients with IBD treated in our outpatient clinic at Jena University Hospital were included in the study, if they had an appointment to get a SARS-CoV-2 vaccination. Blood samples were taken before the first dose of the vaccination and three weeks after. Patients' charts were reviewed to extract data on age, sex, type, manifestation and current activity of IBD and the IBD-related medication. Patients with previous PCR-proven SARS-CoV-2 infection or positive anti-SARS-CoV-2 antibodies before the first dose of the vaccine were excluded from analysis.

Health care workers without immunosuppression receiving the vaccination were recruited as controls and were matched for age and sex. The study was approved by the local ethics committee (2020-2045-BO) and written informed consent was obtained from all patients and controls before inclusion in the study. According to the manufacturer, this assay has shown a positive agreement of 100% (Wilson 95% CI: 97.8-100%) when compared to a micro-neutralization assay, while the negative agreement is stated as 96.9% (Wilson 95% CI: 92.9-98.7%).

Statistical analysis was performed using SPSS v27 (IBM, Armonk, NY, USA) or Sigma Plot 13 (SYSTAT Software GmbH, Germany). Normal distribution was tested using the Shapiro Wilk test. If the test for normal distribution failed Mann-Whitney-U test was performed, otherwise significance was tested using a two-sided, non-paired Student's t-Test. Data are expressed as medians with interquartile range unless otherwise indicated. For categorial variables, the Fisher's exact test was used. P-values <0.05 were defined as significant. Despite we detected slightly increased S-Mix2-specific T H cells in naïve patients as described by Braun et al. 23 , this was not significant in both cohorts ( Figure 1C ). However, we observed the presence of S-Mix2-reactive T H cells prior vaccination at the level of IFNγproducing T H cells in HD and IBD patients ( Figure 1D ). Of note, the SARS-CoV-2 vaccination resulted in an increase in the frequencies of IFN-γ producers among SARS-CoV2-reactive T H cells in the HD as well as in the IBD cohort ( Figure 1D) . Associated with the vaccination, we could also detect a slight increase of the TNF production among SARS-CoV-2-reactive T H cells in HD and IBD patients (Figure 1 E) , but not of the IL-17A or IL-4 production (data not shown). Such vaccine-related immunogenic effects were similar between HD and IBD cohorts when separated by their deficiency of generating a sufficient A c c e p t e d M a n u s c r i p t SARS-CoV2-specific antibody response (Supplement- Figure 1A) . IBD patients, who received an organ transplant did as well generate detectable SARS-CoV-2-specific T H cell responses upon vaccination (Supplemental Figure 1B) .

A subcohort of the vaccinated subjects was reanalyzed after a second round of vaccination, in this group, the observed vaccine-related induction of SARS-CoV2-reactive T H cells did remain in IBD patients (Figure 1 F) We have included 3 patients with additional solid organ transplantation (2 LTX and 1 HTX).

As these patients have a more complex immunosuppressive therapy, we performed a separate analysis comparing the transplant and non-transplant IBD-patients. The antibody response in these patients showed a huge variety between the lower limit of detection in the patients after HTX and one of the LTX patients, up to 1550 BAU/ml in the other LTX patient.

The IBD patients without concomitant solid organ transplantation had a median level of 57.5 BAU/ml. (Figure 3 Recent studies raised concerns about the efficacy of the SARS-CoV-2 vaccination in immunosuppressed patients. Antibody levels after vaccination were found to be up to 20% lower compared to healthy controls after a single dose of a vaccine in transplant patients 14 .

In line with this, kidney transplant recipients showed positive SARS-CoV-2 antibodies after vaccination in only 5-10% 13,15 and presented a weak T-cell response measured by ELISPOT assay as well 15 . A recent study in patients vaccinated with the BioNTech/Pfizer vaccine after liver transplantation (LTX) found antibodies in 47.5% of the patients and 100% of the controls. 25 The authors identified co-medication with mycophenolate or steroids as a risk factor for vaccination failure, both were used only in the transplant patients in our cohort.

Additionally, higher age was associated with an increased risk of vaccination failure 25 .

Another recent study found adequate antibody response in 86% of rheumatologic patients following a SARS-CoV-2 vaccination, which is in line with our findings. 26 . The authors could identify treatment with rituximab as a risk factor for non-response to the vaccine, which was not used in our cohort. We did include two patients with IBD and LTX due to PSC and one patient with HTX. Of these three patients, one patient developed antibodies. However, our patients with IBD were younger than the patients in the transplant cohorts. A recent study on transplant patients found positive antibodies in 40% of patients after the second dose and the authors were able to increase these proportion to 68% using a third dose of an mRNA SARS-CoV-2 vaccine. 27 Data on the immune response in patients with IBD after vaccination are sparse. A recent study reported adequate humoral immune responses after the second dose or after one dose and prior infection, which is in line with our findings, but antibody M a n u s c r i p t titers in this study were lower in patients treated with Infliximab compared to vedolizumab. 18 Additionally, the same group reported the same differences in antibody titers in patients with IBD after confirmed SARS-CoV-2 infection 28 29 Interestingly and in accordance with our data, they found no differences in humoral or cellular immune response between the transplant patients and controls.

In patients with negative antibody titers after the first vaccination, 3 out of 4 patients had detectable levels after the second dose, which were on the same level als titers after first vaccination in controls and IBD patients, who had yet positive titers after the first dose. It is tempting to speculate, that these patients might have a benefit of another booster vaccination dose as recently shown in transplant patients 27 previous infections with common coronaviruses. 23 Collectively, we could show that IBD M a n u s c r i p t patients independent from their medical history do partially possess cross-reactive SARS-CoV-2-specific T H cells comparable to healthy donors, and that vaccination of IBD patients did induce a robust T H cell-mediated immune response against the viral spike protein.

Two of the IBD patients showed low levels of TNF-and IFN-producing CD137 + /CD154 + CD4 + T cells following the vaccination, indicating a potential weaker response. However, low frequency of positive cells has to be taken in to account in interpreting these results. Nevertheless, both of these patients had positive anti-SARS-CoV-2 antibodies following vaccination.

Our study has some limitations. First, we mainly examined the response following the vaccination after the first dose, and only in a smaller subcohort after the second dose.

However, for all vaccines used in the participants, a second dose is strongly recommended.

In line with other studies, who detected a sufficient T-cell response after one dose of a SARS-CoV-2 vaccine 33,34 , we observed a robust increase of SARS-CoV-2-specific T H cells in immunosuppressed IBD patients, which was preserved throughout a second vaccination.

Second, we included both, AstraZeneca and BioNTech/Pfizer vaccines. In the current discussion about SARS-CoV-2 vaccinations, the recommendations regarding the AstraZeneca vaccine, which was used in the majority of the patients as the first dose, changed several times. As our patients were younger than 60 years, they will get another type of vaccine as the second dose, following current German recommendations, which is the BioNTech/Pfizer vaccine in most cases. We therefore decided to include both types of vaccine in the current study. Third, data on the duration of the immune response is lacking and we cannot exclude a shorter duration of immunity following vaccination in immunosuppressed IBD patients. While we still detected SARS-CoV-2-specific Th cells with an increased tendency of IFNγ production upon the second vaccination, a monitoring of a robust long term immune response is lacking. Forth, the sample size is still small and larger cohort studies are needed to validate the observed vaccination-induced immune protection of immunosuppressed IBD patients from SARS-CoV-2.

A c c e p t e d M a n u s c r i p t Nevertheless, our data indicates an adequate humoral and cellular immune response in immunosuppressed patients with IBD, indicating a comparable efficacy to healthy controls. Therefore, monitoring of the vaccination effect and long-term immunity should be considered.

PAR, and NA performed statistical analyses and wrote the manuscript. NA and SG performed experiments. PAR and AS conceived the study. PAR, PG and AS provided patient samples. AS and TK gave important intellectual input and interpreted the data. All authors critically revised the manuscript for important intellectual content. The authors thank Prof. A. Scherag for help with statistical analyses.

The data underlying this article is available on reasonable request from the corresponding author M a n u s c r i p t A c c e p t e d M a n u s c r i p t 

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A c c e p t e d M a n u s c r i p t A c c e p t e d M a n u s c r i p t A c c e p t e d M a n u s c r i p t