Neutralising antibody potency against SARS-CoV-2 wild-type and omicron BA.1 and BA.4/5 variants in patients with inflammatory bowel disease treated with infliximab and vedolizumab after three doses of COVID-19 vaccine (CLARITY IBD): an analysis of a prospective multicentre cohort study.

BACKGROUND: Anti-TNF drugs, such as infliximab, are associated with attenuated antibody responses after SARS-CoV-2 vaccination. We aimed to determine how the anti-TNF drug infliximab and the anti-integrin drug vedolizumab affect vaccine-induced neutralising antibodies against highly transmissible omicron (B.1.1.529) BA.1, and BA.4 and BA.5 (hereafter BA.4/5) SARS-CoV-2 variants, which possess the ability to evade host immunity and, together with emerging sublineages, are now the dominating variants causing current waves of infection. METHODS: CLARITY IBD is a prospective, multicentre, observational cohort study investigating the effect of infliximab and vedolizumab on SARS-CoV-2 infection and vaccination in patients with inflammatory bowel disease (IBD). Patients aged 5 years and older with a diagnosis of IBD and being treated with infliximab or vedolizumab for 6 weeks or longer were recruited from infusion units at 92 hospitals in the UK. In this analysis, we included participants who had received uninterrupted biological therapy since recruitment and without a previous SARS-CoV-2 infection. The primary outcome was neutralising antibody responses against SARS-CoV-2 wild-type and omicron subvariants BA.1 and BA.4/5 after three doses of SARS-CoV-2 vaccine. We constructed Cox proportional hazards models to investigate the risk of breakthrough infection in relation to neutralising antibody titres. The study is registered with the ISRCTN registry, ISRCTN45176516, and is closed to accrual. FINDINGS: Between Sept 22 and Dec 23, 2020, 7224 patients with IBD were recruited to the CLARITY IBD study, of whom 1288 had no previous SARS-CoV-2 infection after three doses of SARS-CoV-2 vaccine and were established on either infliximab (n=871) or vedolizumab (n=417) and included in this study (median age was 46·1 years [IQR 33·6-58·2], 610 [47·4%] were female, 671 [52·1%] were male, 1209 [93·9%] were White, and 46 [3·6%] were Asian). After three doses of SARS-CoV-2 vaccine, 50% neutralising titres (NT50s) were significantly lower in patients treated with infliximab than in those treated with vedolizumab, against wild-type (geometric mean 2062 [95% CI 1720-2473] vs 3440 [2939-4026]; p<0·0001), BA.1 (107·3 [86·40-133·2] vs 648·9 [523·5-804·5]; p<0·0001), and BA.4/5 (40·63 [31·99-51·60] vs 223·0 [183·1-271·4]; p<0·0001) variants. Breakthrough infection was significantly more frequent in patients treated with infliximab (119 [13·7%; 95% CI 11·5-16·2] of 871) than in those treated with vedolizumab (29 [7·0% [4·8-10·0] of 417; p=0·00040). Cox proportional hazards models of time to breakthrough infection after the third dose of vaccine showed infliximab treatment to be associated with a higher hazard risk than treatment with vedolizumab (hazard ratio [HR] 1·71 [95% CI 1·08-2·71]; p=0·022). Among participants who had a breakthrough infection, we found that higher neutralising antibody titres against BA.4/5 were associated with a lower hazard risk and, hence, a longer time to breakthrough infection (HR 0·87 [0·79-0·95]; p=0·0028). INTERPRETATION: Our findings underline the importance of continued SARS-CoV-2 vaccination programmes, including second-generation bivalent vaccines, especially in patient subgroups where vaccine immunogenicity and efficacy might be reduced, such as those on anti-TNF therapies. FUNDING: Royal Devon University Healthcare NHS Foundation Trust; Hull University Teaching Hospital NHS Trust; NIHR Imperial Biomedical Research Centre; Crohn's and Colitis UK; Guts UK; National Core Studies Immunity Programme, UK Research and Innovation; and unrestricted educational grants from F Hoffmann-La Roche, Biogen, Celltrion Healthcare, Takeda, and Galapagos.

The gut microbiota and metabolome are associated with diminished COVID-19 vaccine-induced antibody responses in immunosuppressed inflammatory bowel disease patients.

BACKGROUND: Patients with inflammatory bowel disease (IBD) treated with anti-TNF therapy exhibit attenuated humoral immune responses to vaccination against SARS-CoV-2. The gut microbiota and its functional metabolic output, which are perturbed in IBD, play an important role in shaping host immune responses. We explored whether the gut microbiota and metabolome could explain variation in anti-SARS-CoV-2 vaccination responses in immunosuppressed IBD patients. METHODS: Faecal and serum samples were prospectively collected from infliximab-treated patients with IBD in the CLARITY-IBD study undergoing vaccination against SARS-CoV-2. Antibody responses were measured following two doses of either ChAdOx1 nCoV-19 or BNT162b2 vaccine. Patients were classified as having responses above or below the geometric mean of the wider CLARITY-IBD cohort. 16S rRNA gene amplicon sequencing, nuclear magnetic resonance (NMR) spectroscopy and bile acid profiling with ultra-high-performance liquid chromatography mass spectrometry (UHPLC-MS) were performed on faecal samples. Univariate, multivariable and correlation analyses were performed to determine gut microbial and metabolomic predictors of response to vaccination. FINDINGS: Forty-three infliximab-treated patients with IBD were recruited (30 Crohn's disease, 12 ulcerative colitis, 1 IBD-unclassified; 26 with concomitant thiopurine therapy). Eight patients had evidence of prior SARS-CoV-2 infection. Seventeen patients (39.5%) had a serological response below the geometric mean. Gut microbiota diversity was lower in below average responders (p = 0.037). Bilophila abundance was associated with better serological response, while Streptococcus was associated with poorer response. The faecal metabolome was distinct between above and below average responders (OPLS-DA R2X 0.25, R2Y 0.26, Q2 0.15; CV-ANOVA p = 0.038). Trimethylamine, isobutyrate and omega-muricholic acid were associated with better response, while succinate, phenylalanine, taurolithocholate and taurodeoxycholate were associated with poorer response. INTERPRETATION: Our data suggest that there is an association between the gut microbiota and variable serological response to vaccination against SARS-CoV-2 in immunocompromised patients. Microbial metabolites including trimethylamine may be important in mitigating anti-TNF-induced attenuation of the immune response. FUNDING: JLA is the recipient of an NIHR Academic Clinical Lectureship (CL-2019-21-502), funded by Imperial College London and The Joyce and Norman Freed Charitable Trust. BHM is the recipient of an NIHR Academic Clinical Lectureship (CL-2019-21-002). The Division of Digestive Diseases at Imperial College London receives financial and infrastructure support from the NIHR Imperial Biomedical Research Centre (BRC) based at Imperial College Healthcare NHS Trust and Imperial College London. Metabolomics studies were performed at the MRC-NIHR National Phenome Centre at Imperial College London; this work was supported by the Medical Research Council (MRC), the National Institute of Health Research (NIHR) (grant number MC_PC_12025) and infrastructure support was provided by the NIHR Imperial Biomedical Research Centre (BRC). The NIHR Exeter Clinical Research Facility is a partnership between the University of Exeter Medical School College of Medicine and Health, and Royal Devon and Exeter NHS Foundation Trust. This project is supported by the National Institute for Health Research (NIHR) Exeter Clinical Research Facility. The views expressed are those of the authors and not necessarily those of the NIHR or the UK Department of Health and Social Care.

COVID-19 vaccine-induced antibody and T-cell responses in immunosuppressed patients with inflammatory bowel disease after the third vaccine dose (VIP): a multicentre, prospective, case-control study.

BACKGROUND: COVID-19 vaccine-induced antibody responses are reduced in patients with inflammatory bowel disease (IBD) taking anti-TNF or tofacitinib after two vaccine doses. We sought to assess whether immunosuppressive treatments were associated with reduced antibody and T-cell responses in patients with IBD after a third vaccine dose. METHODS: VIP was a multicentre, prospective, case-control study done in nine centres in the UK. We recruited immunosuppressed patients with IBD and non-immunosuppressed healthy individuals. All participants were aged 18 years or older. The healthy control group had no diagnosis of IBD and no current treatment with systemic immunosuppressive therapy for any other indication. The immunosuppressed patients with IBD had an established diagnosis of Crohn's disease, ulcerative colitis, or unclassified IBD using standard definitions of IBD, and were receiving established treatment with one of six immunosuppressive regimens for at least 12 weeks at the time of first dose of SARS-CoV-2 vaccination. All participants had to have received three doses of an approved COVID-19 vaccine. SARS-CoV-2 spike antibody binding and T-cell responses were measured in all participant groups. The primary outcome was anti-SARS-CoV-2 spike (S1 receptor binding domain [RBD]) antibody concentration 28-49 days after the third vaccine dose, adjusted by age, homologous versus heterologous vaccine schedule, and previous SARS-CoV-2 infection. The primary outcome was assessed in all participants with available data. FINDINGS: Between Oct 18, 2021, and March 29, 2022, 352 participants were included in the study (thiopurine n=65, infliximab n=46, thiopurine plus infliximab combination therapy n=49, ustekinumab n=44, vedolizumab n=50, tofacitinib n=26, and healthy controls n=72). Geometric mean anti-SARS-CoV-2 S1 RBD antibody concentrations increased in all groups following a third vaccine dose, but were significantly lower in patients treated with infliximab (2736·8 U/mL [geometric SD 4·3]; p<0·0001), infliximab plus thiopurine (1818·3 U/mL [6·7]; p<0·0001), and tofacitinib (8071·5 U/mL [3·1]; p=0·0018) compared with the healthy control group (16 774·2 U/mL [2·6]). There were no significant differences in anti-SARS-CoV-2 S1 RBD antibody concentrations between the healthy control group and patients treated with thiopurine (12 019·7 U/mL [2·2]; p=0·099), ustekinumab (11 089·3 U/mL [2·8]; p=0·060), or vedolizumab (13 564·9 U/mL [2·4]; p=0·27). In multivariable modelling, lower anti-SARS-CoV-2 S1 RBD antibody concentrations were independently associated with infliximab (geometric mean ratio 0·15 [95% CI 0·11-0·21]; p<0·0001), tofacitinib (0·52 [CI 0·31-0·87]; p=0·012), and thiopurine (0·69 [0·51-0·95]; p=0·021), but not with ustekinumab (0·64 [0·39-1·06]; p=0·083), or vedolizumab (0·84 [0·54-1·30]; p=0·43). Previous SARS-CoV-2 infection (1·58 [1·22-2·05]; p=0·0006) was independently associated with higher anti-SARS-CoV-2 S1 RBD antibody concentrations and older age (0·88 [0·80-0·97]; p=0·0073) was independently associated with lower anti-SARS-CoV-2 S1 RBD antibody concentrations. Antigen-specific T-cell responses were similar in all groups, except for recipients of tofacitinib without evidence of previous infection, where T-cell responses were significantly reduced relative to healthy controls (p=0·021). INTERPRETATION: A third dose of COVID-19 vaccine induced a boost in antibody binding in immunosuppressed patients with IBD, but these responses were reduced in patients taking infliximab, infliximab plus thiopurine, and tofacitinib. Tofacitinib was also associated with reduced T-cell responses. These findings support continued prioritisation of immunosuppressed groups for further vaccine booster dosing, particularly patients on anti-TNF and JAK inhibitors. FUNDING: Pfizer.

Antibody decay, T cell immunity and breakthrough infections following two SARS-CoV-2 vaccine doses in inflammatory bowel disease patients treated with infliximab and vedolizumab.

Anti tumour necrosis factor (anti-TNF) drugs increase the risk of serious respiratory infection and impair protective immunity following pneumococcal and influenza vaccination. Here we report SARS-CoV-2 vaccine-induced immune responses and breakthrough infections in patients with inflammatory bowel disease, who are treated either with the anti-TNF antibody, infliximab, or with vedolizumab targeting a gut-specific anti-integrin that does not impair systemic immunity. Geometric mean [SD] anti-S RBD antibody concentrations are lower and half-lives shorter in patients treated with infliximab than vedolizumab, following two doses of BNT162b2 (566.7 U/mL [6.2] vs 4555.3 U/mL [5.4], p <0.0001; 26.8 days [95% CI 26.2 - 27.5] vs 47.6 days [45.5 - 49.8], p <0.0001); similar results are also observed with ChAdOx1 nCoV-19 vaccination (184.7 U/mL [5.0] vs 784.0 U/mL [3.5], p <0.0001; 35.9 days [34.9 - 36.8] vs 58.0 days [55.0 - 61.3], p value < 0.0001). One fifth of patients fail to mount a T cell response in both treatment groups. Breakthrough SARS-CoV-2 infections are more frequent (5.8% (201/3441) vs 3.9% (66/1682), p = 0.0039) in patients treated with infliximab than vedolizumab, and the risk of breakthrough SARS-CoV-2 infection is predicted by peak anti-S RBD antibody concentration after two vaccine doses. Irrespective of the treatments, higher, more sustained antibody levels are observed in patients with a history of SARS-CoV-2 infection prior to vaccination. Our results thus suggest that adapted vaccination schedules may be required to induce immunity in at-risk, anti-TNF-treated patients.

COVID-19 vaccine-induced antibody responses in immunosuppressed patients with inflammatory bowel disease (VIP): a multicentre, prospective, case-control study.

BACKGROUND: The effects that therapies for inflammatory bowel disease (IBD) have on immune responses to SARS-CoV-2 vaccination are not yet fully known. Therefore, we sought to determine whether COVID-19 vaccine-induced antibody responses were altered in patients with IBD on commonly used immunosuppressive drugs. METHODS: In this multicentre, prospective, case-control study (VIP), we recruited adults with IBD treated with one of six different immunosuppressive treatment regimens (thiopurines, infliximab, a thiopurine plus infliximab, ustekinumab, vedolizumab, or tofacitinib) and healthy control participants from nine centres in the UK. Eligible participants were aged 18 years or older and had received two doses of COVID-19 vaccines (either ChAdOx1 nCoV-19 [Oxford-AstraZeneca], BNT162b2 [Pfizer-BioNTech], or mRNA1273 [Moderna]) 6-12 weeks apart (according to scheduling adopted in the UK). We measured antibody responses 53-92 days after a second vaccine dose using the Roche Elecsys Anti-SARS-CoV-2 spike electrochemiluminescence immunoassay. The primary outcome was anti-SARS-CoV-2 spike protein antibody concentrations in participants without previous SARS-CoV-2 infection, adjusted by age and vaccine type, and was analysed by use of multivariable linear regression models. This study is registered in the ISRCTN Registry, ISRCTN13495664, and is ongoing. FINDINGS: Between May 31 and Nov 24, 2021, we recruited 483 participants, including patients with IBD being treated with thiopurines (n=78), infliximab (n=63), a thiopurine plus infliximab (n=72), ustekinumab (n=57), vedolizumab (n=62), or tofacitinib (n=30), and 121 healthy controls. We included 370 participants without evidence of previous infection in our primary analysis. Geometric mean anti-SARS-CoV-2 spike protein antibody concentrations were significantly lower in patients treated with infliximab (156·8 U/mL [geometric SD 5·7]; p<0·0001), infliximab plus thiopurine (111·1 U/mL [5·7]; p<0·0001), or tofacitinib (429·5 U/mL [3·1]; p=0·0012) compared with controls (1578·3 U/mL [3·7]). There were no significant differences in antibody concentrations between patients treated with thiopurine monotherapy (1019·8 U/mL [4·3]; p=0·74), ustekinumab (582·4 U/mL [4·6]; p=0·11), or vedolizumab (954·0 U/mL [4·1]; p=0·50) and healthy controls. In multivariable modelling, lower anti-SARS-CoV-2 spike protein antibody concentrations were independently associated with infliximab (geometric mean ratio 0·12, 95% CI 0·08-0·17; p<0·0001) and tofacitinib (0·43, 0·23-0·81; p=0·0095), but not with ustekinumab (0·69, 0·41-1·19; p=0·18), thiopurines (0·89, 0·64-1·24; p=0·50), or vedolizumab (1·16, 0·74-1·83; p=0·51). mRNA vaccines (3·68, 2·80-4·84; p<0·0001; vs adenovirus vector vaccines) were independently associated with higher antibody concentrations and older age per decade (0·79, 0·72-0·87; p<0·0001) with lower antibody concentrations. INTERPRETATION: For patients with IBD, the immunogenicity of COVID-19 vaccines varies according to immunosuppressive drug exposure, and is attenuated in recipients of infliximab, infliximab plus thiopurines, and tofacitinib. Scheduling of third primary, or booster, doses could be personalised on the basis of an individual's treatment, and patients taking anti-tumour necrosis factor and tofacitinib should be prioritised. FUNDING: Pfizer.

Health-Related Quality of Life in patients with Checkpoint Inhibitor Enterocolitis

IntroductionImmune checkpoint inhibitors (CPI) have transformed the treatment of many advanced cancers but cause immune related adverse events including enterocolitis (CPI-E). The conventional inflammatory bowel diseases ulcerative colitis (UC) and Crohn’s disease (CD) are associated with unfavourable health-related quality of life (HRQoL) outcomes, but there are currently no data on HRQoL in the setting of CPI-E. This study aimed to investigate HRQoL in CPI-E.MethodsA prospective study was conducted across two London hospital trusts between February-April 2021. UC, CD and CPI-E patient cohorts were recruited from outpatient clinics and the biologic infusion unit. Disease activity was assessed using non-invasive scoring systems: modified-Partial Mayo Score (m-PMS), modified-Harvey Bradshaw Index (m-HBI), Simple Crohn’s and Colitis Activity Index (SCCAI) and Common Terminology Criteria for Adverse Events (CTCAE). HRQoL outcomes were assessed using validated questionnaires: Patient Health Questionnaire-8 (PHQ-8), Generalised Anxiety Disorder-7 (GAD-7), IBD-Questionnaire (IBD-Q) and Multidimensional Assessment of Fatigue (MAF).ResultsSeventy-five patients (33 CD, 21 UC, 21 CPI-E) were recruited. 33 CD patients (100%) and 20 UC patients (95.2%) were receiving biologic therapy. Thirteen CPI-E patients (61.9%) received Anti-PD1/PDL1 monotherapy and (38.1%) received combination anti-PD1 and anti-CTLA-4 therapy. Twenty-four CD patients (72.7%), 11 UC patients (52.4%) and 16 CPI-E patients (76.2%) were shielding due to the COVID-19 pandemic. Using m-PMS, m-HBI, SCCAI and CTCAE, >80% in each of the three cohorts were either classed as being in remission or having mild disease activity. Three CPI-E patients (14.3%) had moderate depression (PHQ-8 ≥10) and a further 9 (42.9%) had mild depression (PHQ-8 score 5-9). Nine CPI-E patients (42.9%) had significant fatigue (MAF score ≥30) and 6 (28.6%) had mild or moderate anxiety (GAD-7 ≥5). There were no significant differences in PHQ-8, GAD-7, IBD-Q and MAF between CPI-E, CD and UC patients, suggesting comparable levels of psychological morbidity in the three groups. Significant correlations were found between CPI-E disease activity and IBD-Q and GAD-7 scores.ConclusionOur study suggests that psychological morbidity in CPI-E is common and comparable to rates in CD and UC, even in the setting of clinical remission. Clinicians should be aware of this complication and take a holistic approach to this patient group.

SARS-CoV-2 vaccination for patients with inflammatory bowel disease: a British Society of Gastroenterology Inflammatory Bowel Disease section and IBD Clinical Research Group position statement.

SARS-CoV-2 has caused a global health crisis and mass vaccination programmes provide the best opportunity for controlling transmission and protecting populations. Despite the impressive clinical trial results of the BNT162b2 (Pfizer/BioNTech), ChAdOx1 nCoV-19 (Oxford/AstraZeneca), and mRNA-1273 (Moderna) vaccines, important unanswered questions remain, especially in patients with pre-existing conditions. In this position statement endorsed by the British Society of Gastroenterology Inflammatory Bowel Disease (IBD) section and IBD Clinical Research Group, we consider SARS-CoV-2 vaccination strategy in patients with IBD. The risks of SARS-CoV-2 vaccination are anticipated to be very low, and we strongly support SARS-CoV-2 vaccination in patients with IBD. Based on data from previous studies with other vaccines, there are conceptual concerns that protective immune responses to SARS-CoV-2 vaccination may be diminished in some patients with IBD, such as those taking anti-TNF drugs. However, the benefits of vaccination, even in patients treated with anti-TNF drugs, are likely to outweigh these theoretical concerns. Key areas for further research are discussed, including vaccine hesitancy and its effect in the IBD community, the effect of immunosuppression on vaccine efficacy, and the search for predictive biomarkers of vaccine success.

The gut microbiome: an under-recognised contributor to the COVID-19 pandemic?

The novel coronavirus infection (COVID-19) caused by the SARS-CoV-2 virus has spread rapidly across the globe, culminating in major global morbidity and mortality. As such, there has been a rapid escalation in scientific and clinical activity aimed at increasing our comprehension of this virus. This volume of work has led to early insights into risk factors associated with severity of disease, and mechanisms that underpin the virulence and dynamics involved in viral transmission. These insights ultimately may help guide potential therapeutics to reduce the human, economic and social impact of this pandemic. Importantly, the gastrointestinal (GI) tract has emerged as an important organ influencing propensity to, and potentially severity of, COVID-19 infection. Furthermore, the gut microbiome has been linked to a variety of risk factors for COVID-19 infection, and manipulation of the gut microbiome is an attractive potential therapeutic target for a number of diseases. While data profiling the gut microbiome in COVID-19 infection to date are limited, they support the possibility of several routes of interaction between COVID-19, the gut microbiome, angiotensin converting enzyme 2 (ACE-2) expression in the small bowel and colon and gut inflammation. This article will explore the evidence that implicates the gut microbiome as a contributing factor to the pathogenesis, severity and disease course of COVID-19, and speculate about the gut microbiome's capability as a therapeutic avenue against COVID-19. LAY SUMMARY: It has been noted that certain baseline gut profiles of COVID-19 patients are associated with a more severe disease course, and the gut microbiome impacts the disease course of several contributory risk factors to the severity of COVID-19. A protein called ACE-2, which is found in the small intestine among other sites, is a key receptor for COVID-19 virus entry; there is evidence that the gut microbiome influences ACE-2 receptor expression, and hence may play a role in influencing COVID-19 infectivity and disease severity. Furthermore, the gut microbiome plays a significant role in immune regulation, and hence may be pivotal in influencing the immune response to COVID-19. In terms of understanding COVID-19 treatments, the gut microbiome is known to interact with several drug classes being used to target COVID-19 and should be factored into our understanding of how patients respond to treatment. Importantly, our understanding of the role of the gut microbiome in COVID-19 infection remains in its infancy, but future research may potentially aid our mechanistic understanding of viral infection, and new ways in which we might approach treating it.