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

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

Background

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

However, previous studies have shown that the CID patients treated with TNF-γ inhibitors showed a rapid decrease in the anti-SARS-CoV-2 peak (S). neutralizing antibodies (nAbs) six months after vaccination. Also, CID patients had decreased 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 established the quality of SARS-CoV-2-specific B and T cells, plasmablasts and nAbs at different times after the second COVID-19 vaccination dose. They also examined the development of Omicron-specific nAbs after a booster injection (or third vaccine dose) of the same vaccine.

The study cohorts consisted of 24 healthy subjects, 12 patients receiving anti-TNF-γ therapy, and 12 receiving other disease-modifying antirheumatic 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 matched their age and gender and had received either 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 study participants before and after the second and third vaccinations. The team used an enzyme-linked immunosorbent assay (ELISA), immunoblotting and live virus neutralization assay for the serum analyses. Furthermore, they used multicolor flow cytometry to analyze SARS-CoV-2 specific B and T cell subsets.

Study findings

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

On average, all patients receiving anti-TNF-α therapy had 9,153 peripheral blood plasma IgA cells/µL seven days after the second vaccination. However, at this 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 (CD)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 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 results of the fluorospot test indicated larger spot sizes in all patient groups, indicating 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 time point. Compared to other patient groups, patients receiving TNF-α therapy showed delayed activation of SARS-CoV-2 S-specific CD4^† T cells.

conclusions

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 treated with TNF-α inhibitors. The study demonstrated an altered 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 neutralization ability of their vaccine-induced antibodies also decreased. Moreover, a booster injection did not help them acquire nAbs against Omicron subvariant BA.2.

Accordingly, early booster vaccination could benefit all CID patients undergoing TNF-α inhibitor therapy with no or low anti-SARS-CoV-2 nAb levels. Following breakthrough SARS-CoV-2 infection, these patients may be closely monitored and treated early with therapeutic monoclonal antibodies against the circulating variant of care (VOC) or a vaccine adapted to the current VOC, if available.

*Important announcement

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