Antibody decay, T cell immunity and breakthrough infections following two SARS-CoV-2 vaccine doses in infliximab- and vedolizumab-treated patients (preprint)

We report SARS-CoV-2 vaccine-induced immunity and risk of breakthrough infections in patients with inflammatory bowel disease treated with infliximab, a commonly used anti-TNF drug and those treated with vedolizumab, a gut-specific antibody targeting integrin a4b7 that does not impact systemic immunity. In infliximab-treated patients, the magnitude of anti-SARS-CoV2 antibodies was reduced 4-6-fold. One fifth of both infliximab- and vedolizumab-treated patients did not mount a T cell response. Antibody half-life was shorter in infliximab-treated patients. Breakthrough SARS-CoV-2 infections occurred more frequently in infliximab-treated patients and the risk was predicted by the level of antibody response after second vaccine dose. Overall, recipients of two doses of the BNT162b2 vaccine had higher anti-SARS-CoV-2 antibody concentrations, higher seroconversion rates, shorter antibody half-life and less breakthrough infections compared to ChAdOx1 nCoV-19 vaccine recipients. Irrespective of biologic treatment, higher, more sustained antibody levels were observed in patients with a history of SARS-CoV-2 infection prior to vaccination. Patients treated with anti-TNF therapy should be offered third vaccine doses.

Risk of severe COVID-19 outcomes associated with immune-mediated inflammatory diseases and immune modifying therapies: a nationwide cohort study in the OpenSAFELY platform (preprint)

BackgroundIt is unclear if people with immune-mediated inflammatory diseases (IMIDs) (joint, bowel and skin) and on immune modifying therapy have increased risk of serious COVID-19 outcomes. MethodsWith the approval of NHS England we conducted a cohort study, using OpenSAFELY, analysing routinely-collected primary care data linked to hospital admission, death and previously unavailable hospital prescription data. We used Cox regression (adjusting for confounders) to estimate hazard ratios (HR) comparing risk of COVID-19-death, death/critical care admission, and hospitalisation (March to September 2020) in: 1) people with IMIDs compared to the general population; and 2) people with IMIDs on targeted immune modifying drugs (e.g., biologics) compared to standard systemic treatment (e.g., methotrexate). FindingsWe identified 17,672,065 adults; of 1,163,438 (7%) with IMIDs, 19,119 people received targeted immune modifying drugs, and 200,813 received standard systemics. We saw evidence of increased COVID-19-death (HR 1.23, 95%CI 1.20, 1.27), and COVID-19 hospitalisation (HR 1.32, 95%CI 1.29, 1.35) in individuals with IMIDs overall compared to individuals without IMIDs of the same age, sex, deprivation and smoking status. We saw no evidence of increased COVID-19 deaths with targeted compared to standard systemic treatments (HR 1.03, 95%CI 0.80, 1.33). There was no evidence of increased COVID-19-related death in those prescribed TNF inhibitors, IL-12/23, IL7, IL-6 or JAK inhibitors compared to standard systemics. Rituximab was associated with increased COVID-19 death (HR 1.68, 95%CI 1.11, 2.56); however, this finding may relate to confounding. InterpretationCOVID-19 death and hospitalisation was higher in people with IMIDs. We saw no increased risk of adverse COVID-19 outcomes in those on most targeted immune modifying drugs for IMIDs compared to standard systemics. RESEARCH IN CONTEXTO_ST_ABSEvidence before this studyC_ST_ABSWe searched PubMed on May 19th, 2021, using the terms "COVID-19", "SARS-CoV-2" and "rheumatoid arthritis", "psoriatic arthritis" "ankylosing spondylitis", "Crohns disease" "ulcerative colitis" "hidradenitis suppurativa" and "psoriasis", to identify primary research articles examining severe COVID-19 outcome risk in individuals with immune-mediated inflammatory diseases (IMIDs) and those on immune modifying therapy. The studies identified (including matched cohort studies and studies in disease-specific registries) were limited by small sample sizes and number of outcomes. Most studies did not show a signal of increased adverse COVID-19 outcomes in those on targeted therapies, with the exception of rituximab. Additionally, disease- specific registries are subject to selection bias and lack denominator populations. Added value of the studyIn our large population-based study of 17 million individuals, including 1 million people with IMIDs and just under 200,000 receiving immune modifying medications, we saw evidence that people with IMIDs had an increased risk of COVID-19-related death compared to the general population after adjusting for potential confounders (age, sex, deprivation, smoking status) (HR 1.23, 95%CI 1.20, 1.27). We saw differences by IMID type, with COVID-19-related death being increased by the most in people with inflammatory joint disease (HR 1.47, 95%CI 1.40, 1.54). We also saw some evidence that those with IMIDs were more likely, compared to the general population, to have COVID-19-related critical care admission/death (HR 1.24, 95%CI 1.21, 1.28) and hospitalisation (HR 1.32, 95%CI 1.29, 1.35). Compared to people with IMIDs taking standard systemics, we saw no evidence of differences in severe COVID-19-related outcomes with TNF inhibitors, IL-17 inhibitors, IL-12/23 inhibitors, IL-6 inhibitors and JAK inhibitors. However, there was some evidence that rituximab was associated with an increased risk of COVID-19-related death (HR 1.68, 95%CI 1.11, 2.56) and death/critical care admission (HR 1.92, 95%CI 1.31, 2.81). We also saw evidence of an increase in COVID-19-related hospital admissions in people prescribed rituximab (HR 1.59, 95%CI 1.16, 2.18) or JAK inhibition (HR 1.81, 95%CI 1.09, 3.01) compared to those on standard systemics, although this could be related to worse underlying health rather than the drugs themselves, and numbers of events were small. This is the first study to our knowledge to use high-cost drug data on medicines supplied by hospitals at a national scale in England (to identify targeted therapies). The availability of these data fills an important gap in the medication record of those with more specialist conditions treated by hospitals creating an important opportunity to generate insights to these conditions and these medications Implications of all of the available evidenceOur study offers insights into future risk mitigation strategies and SARS-CoV-2 vaccination priorities for individuals with IMIDs, as it highlights that those with IMIDs and those taking rituximab may be at risk of severe COVID-19 outcomes. Critically, our study does not show a link between most targeted immune modifying medications compared to standard systemics and severe COVID-19 outcomes. However, the increased risk of adverse COVID-19 outcomes that we saw in people with IMIDs and those treated with rituximab merits further study.

Infliximab is associated with attenuated immunogenicity to BNT162b2 and ChAdOx1 nCoV-19 SARS-CoV-2 vaccines (preprint)

BackgroundDelayed second-dose SARS-CoV-2 vaccination trades maximal effectiveness for a lower level of immunity across more of the population. We investigated whether patients with inflammatory bowel disease treated with infliximab have attenuated serological responses to a single-dose of a SARS-CoV-2 vaccine. MethodsAntibody responses and seroconversion rates in infliximab-treated patients (n=865) were compared to a cohort treated with vedolizumab (n=428), a gut-selective anti-integrin 4{beta}7 monoclonal antibody. Our primary outcome was anti-SARS-CoV-2 spike (S) antibody concentrations 3-10 weeks after vaccination in patients without evidence of prior infection. Secondary outcomes were seroconversion rates, and antibody responses following past infection or a second dose of the BNT162b2 vaccine. FindingsGeometric mean [SD] anti-SARS-CoV-2 antibody concentrations were lower in patients treated with infliximab than vedolizumab, following BNT162b2 (6.0 U/mL [5.9] vs 28.8 U/mL [5.4] P<0.0001) and ChAdOx1 nCoV-19 (4.7 U/mL [4.9]) vs 13.8 U/mL [5.9] P<0.0001) vaccines. In our multivariable models, antibody concentrations were lower in infliximab-compared to vedolizumab-treated patients who received the BNT162b2 (fold change [FC] 0.29 [95% CI 0.21, 0.40], p<0.0001) and ChAdOx1 nCoV-19 (FC 0.39 [95% CI 0.30, 0.51], p<0.0001) vaccines. In both models, age [≥] 60 years, immunomodulator use, Crohns disease, and smoking were associated with lower, whilst non-white ethnicity was associated with higher, anti-SARS-CoV-2 antibody concentrations. Seroconversion rates after a single-dose of either vaccine were higher in patients with prior SARS-CoV-2 infection and after two doses of BNT162b2 vaccine. InterpretationInfliximab is associated with attenuated immunogenicity to a single-dose of the BNT162b2 and ChAdOx1 nCoV-19 SARS-CoV-2 vaccines. Vaccination after SARS-CoV-2 infection, or a second dose of vaccine, led to seroconversion in most patients. Delayed second dosing should be avoided in patients treated with infliximab. FundingRoyal Devon and Exeter and Hull University Hospital Foundation NHS Trusts. Unrestricted educational grants: F. Hoffmann-La Roche AG (Switzerland), Biogen GmbH (Switzerland), Celltrion Healthcare (South Korea) and Galapagos NV (Belgium). Research in contextO_ST_ABSEvidence before this studyC_ST_ABSFaced with further surges of SARS-CoV-2 infection, a growing number of countries, including the UK, have opted to delay second vaccine doses for all people. This strategy trades maximal effectiveness against a lower level of protective immunity across more of the at-risk population. We have previously shown that seroprevalence, seroconversion in PCR-confirmed cases, and the magnitude of anti-SARS-CoV-2 antibodies following SARS-CoV-2 infection are reduced in infliximab-compared with vedolizumab-treated patients. Whether single-doses of vaccines are effective in patients treated with anti-TNF therapies is unknown. We searched PubMed from 25 November 2019 to 23 March 2021 with the terms "anti-tumour necrosis factor" or "anti-integrin" or "infliximab" or "adalimumab" or "vedolizumab" or "biological therapy" or "biologic therapy" AND "SARS-CoV-2" or "coronavirus" or "COVID-19" or AND "seroprevalence" or "seroconversion" or "antibody" or "antibody response" or "magnitude" or "immunogenicity" AND "vaccine" or "vaccination" or "immunisation" or "immunization" or "ChAdOx1 nCoV-19" or "BNT162b2" or "mRNA-1273", without restriction on language. Serological responses to SARS-CoV-2 vaccines have been reported in registration trials and small observational cohorts of healthy volunteers. Two small studies, including one unpublished preprint, found that COVID-19 vaccine immunogenicity rates were lower in transplant recipients and patients with malignancy receiving immunosuppressive therapy, and fewer patients treated with potent immunosuppressants seroconverted than healthy controls. No studies have assessed the effect of anti-TNF therapy on immunogenicity following SARS-CoV-2 vaccination. Added value of this studyTo test if anti-TNF drugs attenuate serological responses to primary SARS-CoV-2 vaccines, we analysed anti-SARS-CoV-2 spike (S) antibody concentrations and seroconversion rates in 1293 patients with inflammatory bowel disease who received primary vaccinations with either the ChAdOx1 nCoV-19 or BNT162b2 vaccines. 865 were treated with the anti-TNF drug infliximab and outcomes were compared to a reference cohort of 428 patients treated with vedolizumab, a gut selective anti-integrin 4{beta}7 monoclonal antibody that is not associated with impaired systemic immune responses. Anti-SARS-CoV-2 antibody levels and rates of seroconversion were lower following primary vaccination with both the BNT162b2 and ChAdOx1 nCoV-19 vaccines in patients with IBD treated with infliximab compared to vedolizumab. Older age, immunomodulator use, Crohns disease (versus ulcerative colitis or inflammatory bowel disease unclassified), and current smoking were associated with lower anti-SARS-CoV-2 antibody concentrations, irrespective of vaccine type. Non-white ethnicity was associated with higher anti-SARS-CoV-2 (S) antibody concentrations following primary vaccination with both vaccines. Antibody concentrations and seroconversion rates were higher in patients with past SARS-CoV-2 infection prior to a single-dose of either vaccine, and after 2 doses of the BNT162b2 vaccine. Implications of the available evidenceOur findings have important implications for patients treated with anti-TNF therapy, particularly for those also treated with an immunomodulator. Poor antibody responses to a single-dose of vaccine exposes these patients to a potential increased risk of SARS-CoV-2 infection. However, higher rates of seroconversion in patients with two exposures to SARS-CoV-2 antigen, even in the presence of TNF blockade, suggest that all patients receiving these drugs should be prioritized for optimally timed second doses. Until patients receive a second vaccine dose, they should consider that they are not protected from SARS-CoV-2 infection and continue to practice enhanced physical distancing and shielding if appropriate. Even after two antigen exposures, a small subset of patients failed to mount an antibody response. Antibody testing and adapted vaccine schedules should be considered to protect these at-risk patients.