In a recent study posted to the medRxiv* preprint server, researchers evaluated the impact of immunosuppressive therapies on the induction of adaptive immunity after coronavirus disease 2019 (COVID-19) vaccination.

Study: Multiple effects of TNFα inhibitors on the development of the adaptive immune response after SARS-CoV-2 vaccination. Image Credit: Andreas Prott/Shutterstock
Study: Multiple effects of TNFα inhibitors on the development of the adaptive immune response after SARS-CoV-2 vaccination. Image Credit: Andreas Prott/Shutterstock


Some immunosuppressive therapies, including tumor necrosis factor-alpha (TNF-γ) inhibitors, hampers the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine efficacy. There is no data on the vaccine-induced serum immunoglobulin G (IgG) antibodies and their binding strength or avidity in patients with chronic inflammatory disease (CID) on TNF-γ inhibitors. Additionally, there is no data regarding the development of adaptive immunity in such patients.

However, previous studies have demonstrated that the CID patients treated with TNF-γ inhibitors showed a rapid decline of the anti-SARS-CoV-2 spike (S) neutralizing antibodies (nAbs) six months after vaccination. Also, CID patients had reduced anti-S IgA serum levels at all time points tested after COVID-19 vaccination, indicating a compromised mucosal immunity.

About the study

In the present study, researchers quantified and ascertained the quality of SARS-CoV-2-specific B and T cells, plasmablasts, and nAbs at different time points after the second COVID-19 vaccination dose. They also investigated the development of Omicron-specific nAbs after a booster shot (or third-vaccine dose) of the same vaccine.

The study cohorts comprised 24 healthy individuals, 12 patients on anti-TNF-γ therapy and 12 on other disease-modifying anti-rheumatic drugs (oDMARDs), who received their first COVID-19 vaccination dose in January 2021. These patients received a second vaccination dose five or three weeks later. The team also analyzed samples from 12 patients taken seven days after the booster dose. All three patient groups were age and gender-matched and had either received the BNT1262b or messenger ribonucleic acid (mRNA)-1273 COVID-19 vaccines.

The researchers measured serum levels of anti-SARS-CoV-2 IgG, IgG avidity, and nAbs for all the study participants before and after the second and third vaccination. The team used an enzyme-linked immunosorbent assay (ELISA), immunoblotting, and live virus neutralization assay for the serum analyses. Further, they used multicolor flow cytometry to analyze SARS-CoV-2-specific B- and T cell subsets.

Study findings

The authors observed that anti-S IgG-antibodies were much reduced in patients on TNF-α inhibitor therapy after the second vaccine dose compared to healthy controls and those on oDMARDs. At this time, the IgG avidity and neutralization capacity also remained high across all the study groups. However, IgG avidity and nAb titers significantly decreased only in TNF-α inhibitor-treated vaccinees within 14 days of the second vaccination. At six months post-primary vaccination, anti-Omicron nAb titers became undetectable. The booster shot again increased anti-Omicron nAbs in all subjects except patients taking TNF-α inhibitor therapy.

On average, all the patients taking anti-TNF-α therapy had 9.153 peripheral blood IgA plasma cells/µL seven days after the second vaccination. However, at this time, SARS-CoV-2-specific IgA-plasma cell counts were lower in this group of patients. Fourteen days after the second vaccination, these patients also had a higher number of mature circulating clusters of differentiation (CD)138+ plasma cells. Overall, this data indicated that patients taking TNF-α inhibitors had altered plasma cell populations compared to healthy controls and those on oDMARDs.

Further, the authors observed an increase in the number of SARS-CoV-2 specific antibody-secreting cells (ASCs) of the IgM isotype in anti-TNF-α patients on day seven after the second vaccination. The fluorospot assay results indicated larger spot sizes across all patient groups suggesting increased antibody secretion by all ASCs. They also found a correlation between the number of ASCs, SARS-CoV-2 serum IgG levels, and the number of SARS-CoV-2 positive plasmablasts at the same timepoint. Compared to other patient groups, patients on TNF-α therapy showed a delayed activation of SARS-CoV-2 S-specific CD4+ T cells.


According to the authors, this is the first study to present a longitudinal course of adaptive immunity in CID patients vaccinated against COVID-19 and under treatment with TNF-α inhibitors. The study demonstrated an altered immune response in these patients relative to healthy controls and oDMARD patients, albeit in the absence of breakthrough SARS-CoV-2 infection. These patients showed a strong decrease in IgG avidity six months following the second vaccination. Likewise, the neutralization capacity of their vaccine-induced antibodies also declined. Moreover, a booster shot did not help them acquire nAbs against Omicron sub-variant BA.2.

Accordingly, an early booster vaccination could benefit all the CID patients on TNF-α inhibitor therapy with no or low anti-SARS-CoV-2 nAb levels. Following a breakthrough SARS-CoV-2 infection, these patients might require close monitoring and early treatment with therapeutic monoclonal antibodies against circulating variant of concern (VOC) or a vaccine adapted to the current VOC when available.

*Important notice

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.


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