T cell responses to repeated SARS-CoV-2 vaccination and breakthrough infections in patients on TNF inhibitor treatment: a prospective cohort study

Abstract

Background: Understanding cellular responses to SARS-CoV-2 immunisations is important for informing vaccine recommendations in patients with inflammatory bowel disease (IBD) and other vulnerable patients on immunosuppressive therapies. This study investigated the magnitude and quality of T cell responses after multiple SARS-CoV-2 vaccine doses and COVID-19 breakthrough infection.

Methods: This prospective, observational study included patients with IBD and arthritis on tumour necrosis factor inhibitors (TNFi) receiving up to four SARS-CoV-2 vaccine doses. T cell responses to SARS-CoV-2 peptides were measured by flow cytometry before and 2-4 weeks after vaccinations and breakthrough infection to assess the frequency and polyfunctionality of responding cells, along with receptor-binding domain (anti-RBD) antibodies.

Findings: Between March 2, 2021, and December 20, 2022, 143 patients (118 IBD, 25 arthritis) and 73 healthy controls were included. In patients with either IBD or arthritis, humoral immunity was attenuated compared to healthy controls (median anti-RBD levels 3391 vs. 6280 BAU/ml, p = 0.008) after three SARS-CoV-2 vaccine doses. Patients with IBD had comparable quantities (median CD4 0.11% vs. 0.11%, p = 0.26, CD8 0.031% vs. 0.047%, p = 0.33) and quality (polyfunctionality score: 0.403 vs. 0.371, p = 0.39; 0.105 vs. 0.101, p = 0.87) of spike-specific T cells to healthy controls. Patients with arthritis had lower frequencies but comparable quality of responding T cells to controls. Breakthrough infection increased spike-specific CD8 T cell quality and T cell responses against non-spike peptides.

Interpretation: Patients with IBD on TNFi have T cell responses comparable to healthy controls despite attenuated humoral responses following three vaccine doses. Repeated vaccination and breakthrough infection increased the quality of T cell responses. Our study adds evidence that, in the absence of other risk factors, this group may in future be able to follow the general recommendations for COVID-19 vaccines.

Funding: South-Eastern Norway Regional Health Authority, Coalition for Epidemic Preparedness Innovations (CEPI), Norwegian Institute of Public Health, Akershus University Hospital, Diakonhjemmet Hospital.

Keywords: Arthritis; Inflammatory bowel disease; SARS-CoV-2; T cells; TNF inhibitors; Vaccination.

Fig. 1

Study design and patient recruitment. Longitudinal T cell sampling of patients after sequential SARS-CoV-2 vaccine doses. Throughout the study, additional recipients of third (V3) and fourth (V4) vaccine doses and patients infected with SARS-CoV-2 (breakthrough infections, BTI) were recruited.

Fig. 2

Humoral and cellular responses in patients on TNFi treatments after vaccination. (a) Anti-Wuhan-Hu-1 receptor-binding domain (RBDwt) IgG concentrations at baseline (V0) and after two (V2), three (V3), and four (V4) vaccine doses. Responses of under 5 binding antibody units (BAU)/ml were considered negative. (b and c) Frequency of spike-specific CD4 and CD8 T cell responses for all patients on TNFi treatments at baseline and after two, three, and four vaccine doses. (d and e) Polyfunctionality score for spike-specific CD4 and CD8 T cell responses. Box plots indicate median and interquartile range (IQR), whiskers indicate 1.5 × IQR extending from Q1 and Q3. Numbers per group are indicated on plots. Grey lines between points indicate paired samples. Points without lines indicate non-longitudinal samples which were not used for the statistics. Statistical analyses were calculated by dependent samples sign tests with false discovery rate (FDR) correction on the same individuals at different time points. All p-values are adjusted for multiple comparisons. PFS, polyfunctionality score.

Fig. 3

Immune responses after vaccination vary with diagnosis. (a) Anti-RBDwt IgG titres after two, three, and four vaccine doses in healthy controls (grey), patients with IBD (red), and patients with arthritis (blue). Lines indicate paired samples over time. (b and c) CD4 T cell spike-specific responses showing percentages of responding cells and polyfunctionality score at baseline and after two, three, and four vaccine doses in healthy controls, patients with IBD, and patients with arthritis. (d and e) CD8 T cell spike-specific responses showing percentages of responding cells and polyfunctionality score at the same four time points for the different diagnosis groups. Box-and-whisker plots indicate median, IQR and 1.5 × IQR from Q1 and Q3. Numbers per group are indicated on plots. V0, baseline; V2, vaccine dose two; V3, vaccine dose three; V4, vaccine dose four; HC, healthy controls; IBD, inflammatory bowel disease; PFS, polyfunctionality score. Statistical comparisons by multivariable linear regression analysis are described in the results.

Fig. 4

Immune responses following SARS-CoV-2 vaccination and breakthrough infection after vaccine doses three and four in patients on TNFi treatment. (a) IgG responses to RBD omicron before and after breakthrough infection for patients with three or four vaccine doses. (b) IgG responses to nucleocapsid after two, three, and four vaccine doses and after breakthrough infection. (c and d) CD4 T cell spike-specific responses showing percentages of responding cells and polyfunctionality score before and after SARS-CoV-2 infection after three or four vaccine doses. (e and f) CD8 T cell spike-specific responses showing percentages of responding cells and polyfunctionality score before and after SARS-CoV-2 infection after three or four vaccine doses. Box-and-whisker plots indicate median, IQR and 1.5 × IQR from Q1 and Q3. Numbers per group are indicated on plots. Blue and green shades indicate patients on TNFi, orange plots indicate healthy controls. Grey lines between points indicate paired samples. Points without lines indicate non-longitudinal samples. Polyfunctionality data for healthy controls after breakthrough infection are not available (d and f). HC, healthy control; V2, vaccine dose two; V3, vaccine dose three; V4, vaccine dose four; BTI, breakthrough infection; RBD, receptor-binding domain; PFS, polyfunctionality score. Statistical comparisons by multivariable linear regression analysis are described in the results.