In a recent study posted to the medRxiv* preprint server, researchers characterized humoral and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike (S)-specific T cell responses in inflammatory bowel disease (IBD) patients who received two-dose messenger ribonucleic acid (mRNA)-based coronavirus disease 2019 (COVID-19) vaccination series. Notably, these IBD patients were on immune-modifying, antimetabolite (AM), or tumor necrosis factor inhibitors (TNFi) therapy.
Patients with chronic inflammatory diseases of autoimmune origin, such as Crohn’s disease, psoriasis, rheumatoid arthritis, etc., are prescribed immune-modifying agents, such as antimetabolites (AM), biologics, and anti-integrin antibodies for treatment.
Although AMs, TNFi, and anti-integrin antibodies help patients manage disease symptoms, reduce disease burden and improve quality of life, they are highly immunosuppressive. Therefore, it is necessary to protect this highly vulnerable population from the risk of SARS-CoV-2 infection, besides evaluating the impact of immune-modifying therapies on the immunogenicity of SARS-CoV-2 vaccination.
There is evidence that TNFi therapy reduces the ability of different COVID-19 vaccines, especially the mRNA-based vaccines, to produce S-specific neutralizing antibodies (NAbs) and recognize SARS-CoV-2 variants of concern (VoCs), including B.1.617.2 (Delta). Amid the rising global circulation of new SARS-CoV-2 Omicron (B.1.1.529) VoC, evaluating coordination of humoral and cellular immunity to combat current and future VoCs is also urgently needed. While it evades the majority of vaccine-induced NAbs due to its S mutations, S-specific T cell immunity remains mainly intact against Omicron.
However, NAbs are not the only determinant of vaccination-induced protective immunity. The other component of immunity that mRNA vaccines elicit is the S-specific T cell responses. T cells may not prevent infection but recognize and lyse virus-infected cells, activate macrophages, and support B cell maturation to prevent the unchecked spread of SARS-CoV-2 in the infected host.
S-specific type 1 T helper (Th1) cells secrete cytokines, such as interferon (IFN)-γ and interleukin (IL)-2, and anti-inflammatory IL-10. T cells endowed with anti-inflammatory potential might also be advantageous in the asymptomatic control of SARS-CoV-2 infection; additionally, there is evidence that TNFi therapy mediates induction of IL-10 that likely contributes to their ability to reduce inflammation. Although it has only started to be analyzed, in-depth insights into how different immune-modifying therapies impact vaccine-induced S-specific T cell immunity are urgently warranted.
About the study
In the present study, researchers studied cohorts of 83 IBD patients on AM, TNFi, or other biologic-based treatment and healthy controls (HCs) to characterize vaccine-induced cellular and humoral S-specific T cell immunity. These responses were analyzed from pre-vaccination time, up to three months following the second dose of the BNT162b2 or mRNA-1273 vaccine. The researchers also evaluated the impact of Omicron mutations on the S-specific T cells observed in IBD patients under different treatments ex vivo.
Of the 83 study participants, 57 and 26, i.e., 69% and 31% of patients had Crohn’s disease and ulcerative colitis, respectively. The median age in IBD and HC groups were similar, and 64% and 36% of males in IBD patients and HCs, respectively. Among all the IBD patients, 48% were on TNFi, and 52% were on an alternative non-TNFi immunotherapy.
Of all these, two and four patients in the TNFi and the non-TNFi group were on steroid treatment; likewise, eight from the TNFi group and six patients from the non-TNFi group received the mRNA-1273 vaccine. Among those undergoing TNFi therapy, 22 (55%) patients also had an additional antimetabolite.
One of the key study findings was that not only did IBD patients induce T cell response to levels similar to that in HC, but those responses also persisted longer and at higher levels in patients treated with TNFi.
Coordination between humoral and cellular arms of immunity is essential for rapid control and reduced SARS-CoV-2 pathogenicity. The authors could not ascertain whether increased T cell immunogenicity directly translated into better protection; nevertheless, the study patients, particularly those undergoing TNFi therapy, mounted a robust S-specific cellular immunity. They also noted that TNFi therapy did not completely abolish but only reduced the production of anti-SARS-CoV-2 NAbs after mRNA vaccination, thus indicating that cellular immunity compensated for the observed humoral defect.
Further, the TNFi therapy reduced B cell maturation. Still, it promoted a progressive expansion of T cells which is why Omicron, despite its remarkable immune-evading capabilities, could not impede recognition by vaccine-induced S-specific T cells in IBD patients.
The authors noted that of the six IBD patients who developed COVID-19 and had mild symptoms, four were on TNFi therapy. The vaccination of IBD patients undergoing TNFi therapy-induced T cell responses with an IFN-γ/IL-2/IL-10 secretion profile, similar to that induced by actual SARS-CoV-2 infection, thus showing why SARS-CoV-2 infection in different patients undergoing TNFi treatment was generally mild.
To summarize, the study findings demonstrated that S-specific T cell responses induced in IBD patients taking TNFi therapy were of higher magnitude and sustained for a longer duration. Furthermore, the observed T cell responses were mainly preserved against mutations present in Omicron and characterized by a Th1/IL-10 cytokine profile.
Despite the humoral response defects, IBD patients on immune-modifying therapies had a favorable profile of vaccine-induced T cell responses in them, hence they were protected against COVID-19. More importantly, the study data suggested ways to control SARS-CoV-2 infection with limited pathological sequelae.
medRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.