The influence of immunosuppressive therapy on the development of adaptive immunity after vaccination against SARS-CoV-2


In a recent study published on medRxiv* preprint server, researchers assessed the impact of immunosuppressive therapies on the induction of adaptive immunity following vaccination against coronavirus disease 2019 (COVID-19).

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


Certain immunosuppressive therapies, including tumor necrosis factor-alpha (TNF-γ) inhibitors, impair vaccine efficacy against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). There are no data on vaccine-induced serum immunoglobulin G (IgG) antibodies and their binding strength or avidity in patients with chronic inflammatory disease (DIC) on TNF-γ inhibitors. In addition, there are no data regarding the development of adaptive immunity in these patients.

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

About the study

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

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

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

Study results

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

On average, all patients taking anti-TNF-α therapy had 9153 peripheral blood IgA plasma cells/µL seven days after the second vaccination. However, at that time, the number of SARS-CoV-2-specific IgA plasma cells was lower in this group of patients. Fourteen days after the second vaccination, these patients also had a higher number of mature circulating differentiation clusters (DC)138+ plasma cells. Overall, these data indicated that patients taking TNF-α inhibitors had altered plasma cell populations compared to healthy controls and those on oDMARDs.

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


According to the authors, this is the first study to present a longitudinal evolution of adaptive immunity in CID patients vaccinated against COVID-19 and under treatment with TNF-α inhibitors. The study demonstrated an impaired immune response in these patients compared 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 after the second vaccination. Likewise, the neutralizing capacity of their vaccine-induced antibodies also decreased. Moreover, a booster injection did not help them acquire nAbs against Omicron’s BA.2 subvariant.

Accordingly, an early booster vaccination could benefit all CID patients on TNF-α inhibitor treatment without or with low levels of anti-SARS-CoV-2 nAb. Following a breakthrough SARS-CoV-2 infection, these patients may require close monitoring and early treatment with therapeutic monoclonal antibodies against the circulating variant of concern (VOC) or a vaccine suitable for the current VOC when it is available.

*Important Notice

medRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be considered conclusive, guide clinical practice/health-related behaviors, or treated as established information.


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