The long term vaccine‐induced anti‐SARS‐CoV‐2 immune response is impaired in quantity and quality under TNFα blockade

Abstract

The humoral immune response to severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) vaccination in patients with chronic inflammatory disease (CID) declines more rapidly with tumor necrosis factor‐α (TNF‐α) inhibition. Furthermore, the efficacy of current vaccines against Omicron variants of concern (VOC) including BA.2 is limited. Alterations within immune cell populations, changes in IgG affinity, and the ability to neutralize a pre‐VOC strain and the BA.2 virus were investigated in these at‐risk patients. Serum levels of anti‐SARS‐CoV‐2 IgG, IgG avidity, and neutralizing antibodies (NA) were determined in anti‐TNF‐α patients ( n = 10) and controls ( n = 24 healthy individuals; n = 12 patients under other disease‐modifying antirheumatic drugs, oDMARD) before and after the second and third vaccination by ELISA, immunoblot and live virus neutralization assay. SARS‐CoV‐2‐specific B‐ and T cell subsets were analysed by multicolor flow cytometry. Six months after the second vaccination, anti‐SARS‐CoV‐2 IgG levels, IgG avidity and anti‐pre‐VOC NA titres were significantly reduced in anti‐TNF‐α recipients compared to controls (healthy individuals: avidity: p ≤ 0.0001; NA: p = 0.0347; oDMARDs: avidity: p = 0.0012; NA: p = 0.0293). The number of plasma cells was increased in anti‐TNF‐α patients (Healthy individuals: p = 0.0344; oDMARDs: p = 0.0254), while the absolute number of SARS‐CoV‐2‐specific plasma cells 7 days after 2nd vaccination were comparable. Even after a third vaccination, these patients had lower anti‐BA.2 NA titres compared to both other groups. We show a reduced SARS‐CoV‐2 neutralizing capacity in patients under TNF‐α blockade. In this cohort, the plasma cell response appears to be less specific and shows stronger bystander activation. While these effects were observable after the first two vaccinations and with older VOC, the differences in responses to BA.2 were enhanced.

Third and fourth vaccine doses broaden and prolong immunity to SARS-CoV-2 in immunocompromised adult patients

“…Irrespective of 1 to 4 doses of vaccine, anti-TNF treated patients consistently showed reduced Ab levels compared to healthy controls and non-TNF IMID patients, suggesting a long-term impact of anti-TNF treatment on the humoral response to vaccines. These results are consistent with another recent study (29). In contrast, T cell responses in anti-TNF and non-TNF IMID patients were similar.…”

“…While healthy controls had stable neutralization responses to WT and VOCs out to 3 months post vaccination after a third dose, IMID patients required a fourth dose to achieve this effect. Irrespective of the study group, neutralization activity against BA.1 and BA.5 VOCs was significantly weaker than neutralization of WT across 2 to 4 doses of vaccine, in line with studies demonstrating reduced geometric mean titers of neutralization against Omicron sub-lineages compared to the original Wildtype strain after 3 and 4 doses of vaccine (29, 35, 36). Regarding T cell responses to VOCs, we observed that IMID patients retain robust T-cell mediated immunity against Omicron variants, consistent with studies demonstrating T cells are largely unaffected by Omicron variants and important for providing potent protection against emerging variants capable of escaping neutralization responses (18, 37–39).…”

Primary SARS-CoV-2 infection in patients with immune-mediated inflammatory diseases: long-term humoral immune responses and effects on disease activity

“…In one study, it was hypothesized that anti-TNF leads to a reduced capacity to form de-novo long-lived SARS-CoV-2 speci c plasma cells, which could explain the more rapid decay of antibodies over time. 22 For patients who used one of the other common prescribed ISPs, the seropositivity rate after SARS-CoV-2 infection was comparable to the control group of patients not using ISPs and healthy controls.…”

“…3,21 Yet, multiple studies have shown a reduction in seropositivity rate, antibody titer and neutralizing capacity at six months after second vaccination in patients on anti-TNF. [22][23][24] Together, these results suggest that IMID patients on anti-TNF seem to be able to mount a relatively adequate humoral immune response, but also that this humoral response is less well maintained. In one study, it was hypothesized that anti-TNF leads to a reduced capacity to form de-novo long-lived SARS-CoV-2 speci c plasma cells, which could explain the more rapid decay of antibodies over time.…”

Working towards a comprehensive appraisal of vaccine-induced immunity against SARS-CoV-2 in IBD

“…Although this functional neutralising capacity reflects efficient protection against SARS-CoV-2 infection, it only partially informs on immunological protection. 4 , 5 T-cell-mediated immunity against SARS-CoV-2 is at least equally important in combating the infection when neutralising antibody concentrations decay. Further study of cellular immune responses could provide important additional insights.…”