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Antibody decay, T cell immunity and breakthrough infections following two SARS-CoV-2 vaccine dose

Updated: Oct 17, 2022

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

Simeng Lin, Nicholas A Kennedy, Aamir Saifuddin, Diana Muñoz Sandoval, Catherine J Reynolds, Rocio Castro Seoane, Sherine H Kottoor, Franziska P Pieper, Kai-Min Lin, David K Butler, Neil Chanchlani, Rachel Nice, Desmond Chee, Claire Bewshea, Malik Janjua, Timothy J McDonald, Shaji Sebastian, James L Alexander, Laura Constable, James C Lee, Charles D Murray, Ailsa L Hart, Peter M Irving, Gareth-Rhys Jones, Klaartje B Kok, Christopher A Lamb, Charlie W Lees, Daniel M Altmann, Rosemary J Boyton, James R Goodhand, Nick Powell, Tariq Ahmad, CLARITY IBD study

Published in: Nature Publications, March 2022.

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.

Introduction Vaccination programmes have reduced SARS-CoV-2 transmission, hospitalisation and deaths1. Patients treated with immunosuppressive drugs were excluded from the original trials for COVID-19 vaccines2,3. Consequently, data relating to the magnitude and durability of immune responses and subsequent vaccine effectiveness in this population are limited4. Drugs targeting tumour necrosis factor (TNF), such as infliximab, are the most frequently prescribed biologic therapies used in the treatment of immune-mediated inflammatory disorders (IMIDs). Observational studies indicate that most patients with inflammatory bowel disease (IBD), an archetypal IMID, mount serological responses following SARS-CoV-2 vaccines, although most were underpowered to discern the impact of specific drugs, including immunomodulators (azathioprine, mercaptopurine and methotrexate) and/or biologic therapies5,6,7,8. We reported that antibody responses following SARS-CoV-2 infection9,10 or a single dose of either the BNT162b2 or ChAdOx1 nCoV-19SARS-CoV-2 vaccines were impaired in anti-TNF treated patients when compared to vedolizumab-treated patients11. Vedolizumab, is a gut-selective anti-integrin α4β7 monoclonal antibody that, unlike anti-TNF drugs, is not associated with increased susceptibility to systemic infection or attenuated serological responses to vaccination12. In this work, we show that anti-SARS-CoV-2 spike antibody responses are attenuated and less durable following two doses of the BNT162b2 and ChAdOx1 nCoV-19 SARS-CoV-2 vaccines in infliximab-treated compared with vedolizumab-treated patients with IBD. Irrespective of biologic drug type, one-fifth of all patients do not mount a T cell response and a minority mount neither antibody nor T cell responses. Breakthrough SARS-CoV-2 infections, which are associated with lower antibody levels after the second dose of vaccine, are more common and occur earlier in infliximab-treated patients. Higher and more sustained antibody levels are observed in patients with a history of SARS-CoV-2 infection. Further work to define immunity after third primary and booster vaccine doses is needed to inform the need for adapted vaccination schedules in at-risk anti-TNF treated patients.

Results Patient characteristics Between September 22, 2020 and December 23, 2020, 7226 patients were recruited to the CLARITY study from 92 UK hospitals10. In this analysis we included 2279 infliximab-treated and 1031 vedolizumab-treated participants without a history of prior SARS-CoV-2 infection, who had received uninterrupted biologic therapy since recruitment and had an antibody test between 14 and 70 days after the second dose of either the BNT162b2 and ChAdOx1 nCoV-19 SARS-CoV-2 vaccines.


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