key: cord-0774275-j338bj9z
authors: Cerna, Karin; Duricova, Dana; Hindos, Miroslav; Hindos, Hrebackova Jana; Lukas, Martin; Machkova, Nadezda; Hruba, Veronika; Mitrova, Katarina; Kubickova, Kristyna; Kastylova, Kristyna; Teplan, Vladimir; Lukas, Milan
title: Cellular and humoral immune responses to SARS-CoV-2 vaccination in inflammatory bowel disease patients
date: 2022-03-31
journal: J Crohns Colitis
DOI: 10.1093/ecco-jcc/jjac048
sha: 8644ab0bb4165cd1f7abc354d3bcb9415f0e01d4
doc_id: 774275
cord_uid: j338bj9z

BACKGROUND AND AIMS: Knowledge on the immunogenicity of anti-SARS-CoV-2 vaccines in inflammatory bowel disease (IBD) patients is limited. Therefore, SARS-CoV-2-specific T-cell response and antibodies were analyzed in 60 IBD vaccine recipients and 30 controls. METHODS: SARS-CoV-2 IgG antibodies against the viral spike protein were measured at baseline and at 8 and 26 weeks after the second vaccine dose. SARS-CoV-2 IgG antibodies against the nucleocapsid antigens were measured at week 26. SARS-CoV-2 interferon-gamma released assay (IGRA) was performed in all vaccinees at week 26. RESULTS: At weeks 0 and 8, no differences were found in anti-spike antibodies between cohorts. At week 26, the decrease in antibody levels was more significant in the IBD cohort compared to the healthy cohort, and anti-nucleocapsid antibodies were not detected in either group. At week 26, 16 of 90 (18 %) vaccinated individuals had a negative IGRA test result, 7 of 90 (8 %) were borderline, and 67 (74 %) had a positive IGRA result; 22 of the 23 individuals with negative or borderline IGRA results belonged to the IBD cohort. However,the overall functional ability of T-lymphocytes to produce interferon-gamma after the unspecific mitogen stimulation was lower in IBD patients. In vaccinees with low or borderline IGRA, treatment with TNF-alpha inhibitors was the most frequent. In individuals with a significant drop in anti-spike antibody levels, plasmatic interferon-gamma concentrations after the specific SARS-CoV-2 stimulation were also insufficient. CONCLUSIONS: Simple humoral and cellular post-vaccination monitoring is advisable in IBD patients so that repeated vaccine doses may be scheduled.

Vaccine-established immunity to SARS-CoV-2 is acknowledged as the primary way to control the trajectory of the COVID-19 pandemic. As of the end of 2021, vaccination against SARS-CoV-2 has only been implemented for one year. The clear effectiveness of vaccination in different patient cohorts will therefore need to be proven with large and time-consuming efficacy trials. In the meantime, there is an urgent need for reliable immune correlates of anti-virus protection, as well as suitable laboratory tools to measure this protection in clinical practice.

Concerns have been raised about the susceptibility and increased risk of infection in inflammatory bowel disease (IBD) patients due to immune dysregulation, chronic inflammation, and immune-modifying treatment. Studies have shown that potential risk factors for SARS-CoV-2 infection in IBD patients include age, nutritional status, disease activity, numerous comorbidities, and high-dose systemic corticosteroid treatment. [1] Moreover, many studies have found post-vaccine seroconversion in IBD recipients of different anti-COVID-19 vaccines. [2] [3] [4] Our workgroup is one of several that has recently shown that positive levels of anti-SARS-CoV-2 IgG antibodies were achieved in all mRNA anti-SARS-CoV-2 vaccine IBD recipients and that a small percentage of vector-based vaccine recipients did not reach post-vaccination seroconversion, whereas vaccination with vectorbased vaccines was associated with lower quantitative IgG antibody levels compared to mRNA vaccine-induced protection in an IBD cohort. [5] However, there are legitimate concerns about the significance of anti-SARS-CoV-2 antibody levels since the cellular response from the T-and B-lymphocytes is more relevant.

[6] Particularly, it remains unclear whether lower antibody response in IBD patients under A c c e p t e d M a n u s c r i p t Manuscript Doi: 10.1093/ecco-jcc/jjac048 immunomodulatory regimens such as therapeutic monoclonal antibodies and their combination with thiopurines or methotrexate is also associated with an insufficient vaccine-induced SARS-CoV-2-specific T-cell response.

Recently, the diagnostic accuracy of interferon-gamma (IFN-γ) release assays (IGRA) to detect post-viral and post-vaccination T-cell antigen-specific response was proven. [7] IGRA assays, which perform a quantitative detection of plasmatic IFN-γ as a response to invitro stimulation by the S-protein of SARS-CoV-2 in human whole blood, are intended to be used as an aid in diagnosing specific T-cellular immune response of the SARS-CoV-2 spike protein after vaccination or infection. [8] In the current study, we aimed to measure the immunological cellular response to the SARS-CoV-2 vaccine (both mRNA and vector-based) by applying IGRA and correlating it to the IgG humoral response against spike (anti-S) and nucleocapsid (anti-N) antigens in IBD patients on biological treatment after the completion of a two-dose vaccination regimen, comparing an IBD cohort with healthy fully vaccinated individuals.

A non-interventional observational trial was conducted in a single tertiary IBD center during the year 2021.

For the study results reported here, two cohorts were created: an IBD patient cohort (IBD, n = 60) and a healthy healthcare professionals' cohort (CTRL, n = 30). As can be seen in the size of the cohorts, a 2:1 matched pair case-control strategy was applied. The CTRL AstraZeneca, UK). All vaccines were two-dosed. The study was conducted prior to the start of booster vaccine doses.

Study start (week 0, W0) was the day of the first vaccine dose. A c c e p t e d M a n u s c r i p t 

Baseline characteristics of both IBD and CTRL cohorts are shown in Table 1 . Table 1 A c c e p t e d M a n u s c r i p t 

At Table 2 . Table 2 In IBD patients with low or borderline IFN-γ plasmatic levels after the specific spike protein stimulation, treatment with the TNF-alpha inhibitors was the most frequent, as shown in Figure 1 . Except of treatment with the TNF-alpha inhibitors, no other differences such as IBD characteristics (disease activity, localization, or duration of the disease) were seen in IGRA-negative/borderline patients compared to individuals with sufficient cellular immune response. As can be seen in Table 3 , an agreement was found between the IFN-γ plasmatic levels and serum anti-S IgG concentrations: in individuals with a significant drop in anti-S IgG levels, plasmatic IFN-γ concentrations after the specific CoV-2 IGRA stimulation were insufficient. Table 3 3

At W0 and W8, no significant differences were found in IgG anti-S serum concentrations between the IBD and CTRL cohorts. At W26, the decrease in anti-S IgG serum levels was more significant in the IBD cohort. Moreover, IgG anti-N antibodies were not detected in the IBD or CTRL groups (median positivity indexes of 0.2 and 0.1, respectively) at W26. Therefore, it can be assumed that no contact with viral nucleocapsid antigen occurred in study subjects until W26, and that for the 8 PCR-positive individuals from 2020, antinucleocapsid humoral immunity had already evolved (see Table 4 ). Table 4 A c c e p t e d M a n u s c r i p t 

Vector Table 5 . Table 5 Discussion Vaccination against SARS-CoV-2 is the most important strategy to protect against infection. Currently we know that early post-vaccination antibody production is robust in most IBD patients, even those on immune-modifying therapies, but that antibody production is blunted right at the beginning by anti-TNF therapy and its combination with immunomodulators such as azathioprine. [11] However, there is still little information available on post-vaccination cellular immunity. Assessing cellular immunity for SARS-CoV-2 T-cell activation in CD patients after COVID-19 vaccination was recently reported in a single twin case. [17] In an Italian study on 35 rheumatoid arthritis (RA) patients, IFN-γ plasmatic levels after the specific stimulation by SARS-CoV-2 spike protein antigens were significantly lower in RA patients under TNF-α, IL-6, and CTLA-4 inhibitors. [18] When comparing spike protein T-cell response between IBD and CTRL individuals, a significant difference was found in cellular reactivity between the groups: IBD vaccinees produced less IFN-γ than healthy vaccinated persons, which may suggest some degree of cellular dysfunction or exhaustion. This premise is supported by another finding, namely the decreased T-cell response in the IBD cohort, even after the unspecific mitogen stimulation.

From a clinical perspective, it could be an important finding that there is a substantial A c c e p t e d M a n u s c r i p t correlation between serum anti-spike IgG antibody levels and the functional cellular test results. Since antibody tests are already widely available and affordable, they could serve to some extent as a sufficient indicator of both antibody and cellular immune response.

There are some limitations to our study. The first one is the sample size, which was mainly influenced by the limited availability and costliness of SARS-CoV-2 IGRA assays.

Deriving causal relationships in this setting is a challenge; the main concern is the effect of immune-modifying drugs. Cellular response primarily determines long-term postvaccination protection, but it is still less well understood. In anti-SARS-CoV-2 vaccinated IBD patients on immune-modifying therapy, the largest study with n = 303 patients is available as a preprint [19] . US workgroup has evaluated IBD patients who completed SARS-CoV-2 vaccination at four time points (1 st vaccine dose, 2 nd dose, 2 and 8 weeks after the 2 nd dose). Consistently with our observations, S-specific T cellular and anti-S antibody responses were significantly correlated (R = 0.19 to 0.21) in this work. Among IBD patients with low antibody response, T cell clonal breadth and depth were low, suggesting that those with impaired humoral vaccine response have similarly impaired cellular responses. Moreover, similar observations on immune-modifying treatment and vaccine type (reduced cellular and humoral response in vector vaccines) were found. Despite these suggestive signals, those differences should be interpreted with caution due to the already small number of examined vaccinees.

However, several notable strengths are to be highlighted, including the utilization of a standardized high throughput IGRA assay and validated serological platforms to accurately measure antibody response.

Our results need to be confirmed in a larger population adopting a similar therapeutic strategy to draw definite conclusions. Future studies are needed to further M a n u s c r i p t

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