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Review 1: "Multiple Effects of TNFα Inhibitors on the Development of the Adaptive Immune Response after SARS-CoV-2 Vaccination"

Published onOct 11, 2022
Review 1: "Multiple Effects of TNFα Inhibitors on the Development of the Adaptive Immune Response after SARS-CoV-2 Vaccination"
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key-enterThis Pub is a Review of
Multiple effects of TNFα inhibitors on the development of the adaptive immune response after SARS-CoV-2 vaccination

AbstractObjectivesThe humoral immune response to SARS-CoV-2 vaccination in patients with chronic inflammatory disease (CID) declines more rapidly with TNFα 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 neutralise a pre-VOC strain and the BA.2 virus were investigated in these at-risk patients.MethodsSerum levels of anti-SARS-CoV-2 IgG, IgG avidity and neutralising antibodies (NA) were determined in anti-TNFα patients (n=10) and controls (n=24 healthy individuals; n=12 patients under other disease-modifying anti-rheumatic drugs, oDMARD) before and after the second and third vaccination by ELISA, immunoblot and live virus neutralisation assay. SARS-CoV-2-specific B-and T cell subsets were analysed by multicolour flow cytometry.ResultsIgG avidity and anti-pre-VOC NA titres decreased faster in anti-TNFα recipients than in controls 6 months after the second vaccination (healthy individuals: avidity: p≤0.0001; NA: p=0.0347; oDMARDs: avidity: p=0.0012; NA: p=0.0293). Total plasma cell counts were increased in anti-TNFα patients (Healthy individuals: p=0.0344; oDMARDs: p=0.0254), whereas absolute numbers of SARS-CoV-2-specific cells were comparable 7 days after vaccination. These patients had lower BA.2 NA titres compared to both other groups, even after the third vaccination.ConclusionsWe show a reduced SARS-CoV-2 neutralising capacity in patients under TNFα blockade. In this cohort, the plasma cell response appears to be less specific and show 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 magnified.What is already known on this topicPatients with chronic inflammatory diseases treated with TNFα inhibitors show a greater decrease in SARS-CoV-2 IgG 6 months after the second vaccination than patients taking oDMARDs and healthy individuals.What this study addsAntibodies from patients taking TNFα blockers have a lower SARS-CoV-2 neutralising capacity and maturity. Plasma cells from these patients exhibit less specific immune reaction. SARS-CoV-2-specific T cells are less activated. Neutralisation against BA.2 is drastically reduced even after the third vaccination.How this study might affect research, practice or policyThis study emphasizes the need to protect vulnerable groups such as patients using TNF inhibitors. They could benefit from Omicron-adapted vaccination, but most likely they need to be protected by additional means other than vaccination.

RR:C19 Evidence Scale rating by reviewer:

  • Reliable. The main study claims are generally justified by its methods and data. The results and conclusions are likely to be similar to the hypothetical ideal study. There are some minor caveats or limitations, but they would/do not change the major claims of the study. The study provides sufficient strength of evidence on its own that its main claims should be considered actionable, with some room for future revision.



The preprint by Geisen et al addresses the potentially altered immune response to SARS-CoV2 vaccination in patients under TNF inhibitor (TNFi ) therapy. Overall, the manuscript is well-written and sound.

That patients under TNFi therapy exhibit lower anti-S IgG levels than healthy controls or patients with other DMARDs six months after vaccination (after initially mounting comparable responses) was shown before by the same group (Geisen et al, RMD Open 2021). They also already demonstrated the declining neutralizing capacity of TNFi user blood sera after six months. The current paper further investigates the influence of TNFi treatment on the adaptive immune response after proper vaccination against SARS-CoV-2.

As the main statement, the current paper claims a reduced SARS-CoV-2 neutralizing capacity in TNFi-treated patients. This conclusion is supported by quantitative (faster decreasing neutralizing antibody [NA] titres) and qualitative (faster decreasing antibody activity) changes six months after vaccination, each in comparison to healthy controls and patients with chronic inflammatory diseases with other therapies. Importantly, this differences seem to be pronounced regarding the variant of concern (VOC) BA.2, leading to significantly lower BA.2 NA titres in TNFi users 14 days after vaccination. After six months, NA titres were not detectable in any of the groups. Interestingly, after a third vaccination, BA.2 NA titres were found in all groups (heathy, other DMARD users) except the patients under TNFi therapy. Furthermore, the authors demonstrated less specific plasma cell reactions and a potentially delayed T cell activation in these patients.

The findings are very relevant and increase the understanding of SARS-CoV-2 immune response in the large group of people with inflammatory diseases receiving an anti-TNF therapy. Since these people are at an increased risk of severe COVID-19 disease, the proposed close monitoring of SARS-CoV-2 immunity is comprehensible and justified by the author’s findings. The main drawback of the study is the small sample size (n=10 patients with TNFi therapy) though. As the authors themselves already outlined in the RMD Open paper from 2021, the findings have to be validated in larger studies. Nevertheless, the discussed findings are of great interest and the claims are generally supported by the data and methods used.

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