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3.
EuropePMC; 2022.
Preprint in English | EuropePMC | ID: ppcovidwho-337281

ABSTRACT

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. 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. 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 = 0.021). 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 R 2 X 0.25, R 2 Y 0.26, Q 2 0.15;CV-ANOVA p = 0.038). Trimethylamine was associated with better response, while succinate, phenylalanine and the bile acids taurolithocholate and taurodeoxycholate were associated with poorer response. 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.

4.
Nat Commun ; 13(1): 1379, 2022 03 16.
Article in English | MEDLINE | ID: covidwho-1747222

ABSTRACT

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.


Subject(s)
COVID-19 , Inflammatory Bowel Diseases , Viral Vaccines , Antibodies, Monoclonal, Humanized/therapeutic use , COVID-19 Vaccines , Humans , Inflammatory Bowel Diseases/drug therapy , Infliximab/therapeutic use , SARS-CoV-2 , T-Lymphocytes , Tumor Necrosis Factor Inhibitors
5.
EuropePMC; 2021.
Preprint in English | EuropePMC | ID: ppcovidwho-315494

ABSTRACT

To inform healthcare policy for immunosuppressed patients there is a need to define SARS-CoV-2 vaccine responses. Here we report SARS-CoV-2 vaccine-induced antibody and T cell responses in patients treated with anti-tumour necrosis factor (anti-TNF), a commonly used biologic in inflammatory diseases, compared to patients treated with vedolizumab, a gut-specific antibody targeting integrin a4b7 that does not impair systemic immunity. In anti-TNF recipients, the magnitude of anti-SARS-CoV2 antibodies was reduced five-fold, and rapidly decayed towards the seroconversion threshold by 14 weeks after second dose of vaccine. In contrast, anti-SARS-CoV-2 antibodies were sustained up to 16 weeks in vedolizumab-treated patients. Anti-SARS-CoV2 antibody decay was not observed in vaccinated patients previously infected with SARS-CoV-2. T cell responses were absent in one-fifth of anti-TNF and vedolizumab-treated patients after a second dose of either vaccine. Our data have important implications for anti-TNF recipients, including the need for vaccine prioritization, booster doses, and social distancing strategies.

6.
Lancet Gastroenterol Hepatol ; 7(4): 342-352, 2022 04.
Article in English | MEDLINE | ID: covidwho-1665600

ABSTRACT

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.


Subject(s)
COVID-19 , Inflammatory Bowel Diseases , Adolescent , Adult , Antibody Formation , COVID-19/prevention & control , COVID-19 Vaccines , Case-Control Studies , Humans , Inflammatory Bowel Diseases/drug therapy , Prospective Studies , SARS-CoV-2
7.
BMJ Open Gastroenterol ; 9(1)2022 01.
Article in English | MEDLINE | ID: covidwho-1662311

ABSTRACT

INTRODUCTION: Acute severe ulcerative colitis (ASUC) traditionally requires inpatient hospital management for intravenous therapies and/or colectomy. Ambulatory ASUC care has not yet been evaluated in large cohorts. AIMS: We used data from PROTECT, a UK multicentre observational COVID-19 inflammatory bowel disease study, to report the extent, safety and effectiveness of ASUC ambulatory pathways. METHODS: Adults (≥18 years old) meeting Truelove and Witts criteria between 1 January 2019-1 June 2019 and 1 March 2020-30 June 2020 were recruited to PROTECT. We used demographic, disease phenotype, treatment outcomes and 3-month follow-up data. Primary outcome was rate of colectomy during the index ASUC episode. Secondary outcomes included corticosteroid response, time to and rate of rescue or primary induction therapy, response to rescue or primary induction therapy, time to colectomy, mortality, duration of inpatient treatment and hospital readmission and colectomy within 3 months of index flare. We compared outcomes in three cohorts: (1) patients treated entirely in inpatient setting; ambulatory patients subdivided into; (2) patients managed as ambulatory from diagnosis and (3) patients hospitalised and subsequently discharged to ambulatory care for continued intravenous steroids. RESULTS: 37% (22/60) participating hospitals used ambulatory pathways. Of 764 eligible patients, 695 (91%) patients received entirely inpatient care, 15 (2%) patients were managed as ambulatory from diagnosis and 54 (7%) patients were discharged to ambulatory pathways. Aside from younger age in patients treated as ambulatory from diagnosis, no significant differences in disease or patient phenotype were observed. The rate of colectomy (15.0% (104/695) vs 13.3% (2/15) vs 13.0% (7/54), respectively, p=0.96) and secondary outcomes were similar among all three cohorts. Stool culture and flexible sigmoidoscopy were less frequently performed in ambulatory cohorts. Forty per cent of patients treated as ambulatory from diagnosis required subsequent hospital admission. CONCLUSIONS: In a post hoc analysis of one of the largest ASUC cohorts collected to date, we report an emerging UK ambulatory practice which challenges treatment paradigms. However, our analysis remains underpowered to detect key outcome measures and further studies exploring clinical and cost-effectiveness as well as patient and physician acceptability are needed. TRIAL REGISTRATION NUMBER: NCT04411784.


Subject(s)
COVID-19 , Colitis, Ulcerative , Adolescent , Ambulatory Care , Cohort Studies , Colitis, Ulcerative/diagnosis , Colitis, Ulcerative/epidemiology , Colitis, Ulcerative/therapy , Humans , Inpatients , SARS-CoV-2 , United Kingdom/epidemiology
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