Neutralising Antibody Potency Against SARS-CoV-2 Ancestral and Omicron BA.1 and BA.4/5 Variants in Patients with Inflammatory Bowel Disease after Three Doses of COVID-19 Vaccine: A Prospective Multicentre Cohort Study (CLARITY)

Background: Anti-tumour necrosis factor (TNF) drugs such as infliximab are associated with attenuated antibody responses after COVID-19 vaccination. It is unknown how infliximab impacts vaccine-induced serological responses against highly transmissible Omicron variants, which possess the ability to evade host immunity and are now the dominating variants causing current waves of infection.Methods: CLARITY IBD is a prospective, multicentre, observational cohort study investigating the impact of infliximab and vedolizumab, a gut-specific anti-integrin monoclonal antibody, on SARS-CoV-2 infection and vaccination in patients with inflammatory bowel disease (IBD). The primary outcome was neutralising antibody responses against SARS-CoV-2 ancestral and Omicron BA.1 and BA.4/5 variants after three doses of COVID-19 vaccination in 1288 patients with IBD without prior COVID-19 infection, who were established on either infliximab (n=871) or vedolizumab (417). Cox proportional hazards models were constructed to investigate the risk of breakthrough infection in relation to neutralising antibody titres.Findings: Following three doses of COVID-19 vaccine, neutralising antibody NT50 (half-inhibitory neutralising titre) was significantly diminished in patients treated with infliximab as compared to patients treated with vedolizumab, against ancestral (geometric mean [95% CI], 1990 [1781 to 2223] vs 3212 [2780 to 3712], p<0·0001), BA.1 (95·46 [82·80 to 110·0] vs 599·1 [492·6 to 728·6], p<0·0001) and BA.4/5 (30·73 [26·26 to 35·96] vs 212·2 [177·0 to 254·4], p<0·0001) variants. Breakthrough infection was significantly more frequent in patients treated with infliximab (13·66%, [11·49% to 16·16%], 119/871) compared to patients treated with vedolizumab (6·95%, [4·79% to 9·95%], 29/417, p=0·0004). Cox proportional hazards models of time to breakthrough infection after the third dose showed infliximab treatment to be associated with a higher hazard risk of 1·71 [1·08 to 2·71] p=0·022) compared to vedolizumab. Higher neutralising antibody titres against BA.4/5 were associated with a lower hazard risk and a longer time to breakthrough infection (HR 0·91 [0·84 to 0·99] p=0·030).Interpretation: Following a third COVID-19 vaccine dose, patients established on infliximab treatment have significantly lower neutralising titres against SARS-CoV-2, which were especially low against Omicron variants. Increased breakthrough infection in infliximab recipients was associated with lower neutralising antibody levels against BA.4/5. These data underline the importance of continued COVID-19 vaccination programs, including second-generation bivalent vaccines, especially in patient subgroups where vaccine immunogenicity and efficacy may be reduced.Trial Registration Details: The study was registered with the ISRCTN registry ISRCTN45176516 and the protocol is available online at https://www.clarityibd.org.Funding Information: Royal Devon and Exeter NHS Foundation Trust, Hull University Teaching Hospital NHS Trust, NIHR Imperial Biomedical Research Centre, Crohn’s and Colitis UK (M2021/1), Guts UK, NCSi programme UKRI (award to RB, DA, NP and TA, MR/W020610/1) and unrestricted educational grants from F. Hoffmann-La Roche (Switzerland), Biogen (USA), Celltrion Healthcare (South Korea), Takeda (UK) and Galapagos (Belgium).Declaration of Interests: Authors declare that there is no conflict of interests. Ethics Approval Statement: The Surrey Borders Research Ethics committee approved the study (REC reference: 20/HRA/3114) in September 2020. Patients were included after providing informed, written consent.