Is the attenuated humoral response to COVID-19 vaccination in anti-TNF users relevant?

The COVID-19 pandemic has led to considerable morbidity, mortality, and strain on health-care services across the world, causing more than 5 million deaths since it began. Systemic immunosuppression might increase the risk of COVID-19-associated complications, and, as a result, individuals with inherent or acquired immunosuppression have been prioritised for vaccination and for receiving booster doses. Approximately a third of individuals living with inflammatory bowel disease (IBD) use immunosuppressive biologic medications chronically, and 5–10% of people with IBD in any given year are exposed to corticosteroids. The CLARITY-IBD study was the first to show that the immune response to a single dose of COVID-19 vaccine was attenuated in patients treated with anti-tumour necrosis factor (TNF) medications. However, whether this reduced immune response among people on anti-TNF therapies persists in those who receive subsequent doses of COVID-19 vaccines is not well described, and the efficacy of COVID-19 vaccination in people on immunosuppressive therapies commonly used in IBD has not yet been assessed.

In The Lancet Gastroenterology & Hepatology, James L Alexander and colleagues have addressed this important knowledge gap, showing a persistent reduction in anti-SARS-CoV-2 spike protein antibody titres among individuals with IBD being treated 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) in the 53–92 days following the second dose of a COVID-19 vaccine. Importantly, ustekinumab, vedolizumab, and thiopurine monotherapy did not affect the immunogenicity of vaccination.

Antibody titres are recognised as an important indicator of vaccine effectiveness in the general population, with lower antibody titres after COVID-19 vaccination being associated with a higher risk of breakthrough infections.3, 4 Globally, the reduction of antibody titres with time has led to the widespread adoption of booster doses to maintain immunity and protection from COVID-19-related hospitalisation and death. Alexander and colleagues' findings suggest that a considerable proportion of patients with IBD could be functionally unvaccinated, despite being adherent to the recommended vaccination regimen at the time, and indicate that individuals with IBD on anti-TNF agents might require early booster vaccinations or serological confirmation of an antibody response to vaccination. In some countries, fourth doses are being offered to individuals being treated with immunosuppressive medications on the basis of concerns regarding suboptimal serological responses to COVID-19 vaccination.

Despite concerns surrounding the robustness of the immune response to vaccination among people being treated with anti-TNF therapies, these same patients do not seem to be at an increased risk of contracting COVID-19 compared with people with IBD not on biological therapy and the age-matched general population.5, 6, 7 In fact, anti-TNF use might be a protective factor against severe COVID-19-related outcomes among individuals with autoimmune diseases, which could be due to these therapies inhibiting the maladaptive systemic inflammatory response that often characterises severe COVID-19. This reduction in the risk of severe outcomes might also be related to the association between anti-TNF therapy and reduced IBD-related disease activity; higher levels of disease activity in IBD have been shown to increase the risk of adverse COVID-19-related outcomes. Furthermore, individuals with IBD have been shown to have high levels of adherence to physical distancing and isolation recommendations, which might decrease their likelihood of being exposed to infection.

Given the paucity of data showing the relationship between humoral antibody titres and SARS-CoV-2 infection risk in people on anti-TNF therapies, and the lack of evidence that anti-TNF increases the risk of severe COVID-19, it remains unclear as to whether people being treated with anti-TNF truly require accelerated booster dosing or monitoring for antibody responses. Recommending additional or earlier booster doses is not without a downside; because patients with IBD often have high baseline levels of health anxiety, the messaging that users of anti-TNF might be insufficiently protected by COVID-19 vaccination could have negative mental health consequences or result in increased social isolation. There is also a concern that this heightened concern about the attenuated immunological response to vaccination might lead to hesitancy in initiating biologic therapy that is otherwise indicated among individuals with moderate-to-severe IBD.

Most frustratingly, even with the rapidity of the generation and publication of new findings, the contours of the pandemic change faster still. With the emergence of the omicron variant (B.1.1.529) and the transition towards endemicity, the relevance of this study's findings has waned. Clinicians are currently concerned with the timing of a fourth dose of COVID-19 vaccine in the immunosuppressed, and thus a study assessing antibody titres after two doses might have more reduced clinical applicability than it did when this project was conceived and conducted.

As the COVID-19 pandemic evolves, clinicians will need to continue to adjust their practice on the basis of emerging evidence regarding the effectiveness and impact of COVID-19 vaccines among patients with IBD and the risk of severe COVID-19-related outcomes among people being treated with immunomodulating medications. At this time, encouraging booster doses among individuals on anti-TNF medications 3–4 months after the most recent vaccine dose is reasonable, especially for those with additional risk factors for serious COVID-19, such as advanced age and other markers of frailty. Patient education will be of utmost importance; first and subsequent vaccine doses need to be reinforced as the most crucial measure to prevent COVID-19 in patients with IBD as we enter the next stages of the pandemic.

TC declares no competing interests. LET has received grants and consulting fees from AbbVie Canada, Pfizer Canada, Takeda Canada, Janssen Canada, Roche Canada, Merck Canada, Sandoz Canada, and Janssen Canada; consulting fees from Celltron Canada; and payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or education events from Takeda Canada, Janssen Canada, and AbbVie Canada.