Immune dynamics in SARS-CoV-2 experienced immunosuppressed rheumatoid arthritis or multiple sclerosis patients vaccinated with mRNA-1273
- Sanquin, Netherlands
- University of Sydney, Australia
- Amsterdam University Medical Centers, Netherlands
- University of Melbourne, Australia
- Reade, Netherlands
Abstract
Background: Patients affected by different types of autoimmune diseases, including common conditions such as Multiple Sclerosis (MS) and Rheumatoid Arthritis (RA), are often treated with immunosuppressants to suppress disease activity. It is not fully understood how the SARS-CoV-2 specific humoral and cellular immunity induced by infection and/or upon vaccination is affected by immunosuppressants.
Methods: The dynamics of cellular immune reactivation upon vaccination of SARS-CoV-2 experienced MS patients treated with the humanized anti-CD20 monoclonal antibody ocrelizumab (OCR) and RA patients treated with methotrexate (MTX) monotherapy were analyzed at great depth via high-dimensional flow cytometry of whole blood samples upon vaccination with the SARS-CoV-2 mRNA-1273 (Moderna) vaccine. Longitudinal B and T cell immune responses were compared to SARS-CoV-2 experienced healthy controls (HC) before and 7-days after the first and second vaccination.
Results: OCR-treated MS patients exhibit a preserved recall response of CD8+ T central memory cells following first vaccination compared to healthy controls and a similar CD4+ circulating T follicular helper 1 and T helper 1 dynamics, whereas humoral and B cell responses were strongly impaired resulting in absence of SARS-CoV-2 specific humoral immunity. MTX treatment significantly delayed antibody levels and B reactivation following the first vaccination, including sustained inhibition of overall reactivation marker dynamics of the responding CD4+ and CD8+ T cells.
Conclusion: Together, these findings indicate that SARS-CoV-2 experienced MS-OCR patients still benefit from vaccination by inducing a broad CD8+ T cell response which can contribute to milder disease outcome. A delayed dynamics of vaccine-induced immunological recall in RA-MTX patients support repeated vaccine strategies to protect against future variants of concern, especially for these patients.
Funding: This research project was supported by ZonMw (The Netherlands Organization for Health Research and Development, #10430072010007), the European Union’s Horizon 2020 research and innovation program under the Marie Skłodowska-Curie grant agreement (#792532 and #860003), the European Commission (SUPPORT-E, #101015756) and by PPOC (#20_21 L2506), the NHMRC Leadership Investigator Grant (#1173871).
Data availability
All raw and processed data presented in this study are available at https://flowrepository.org/id/FR-FCM-Z52K
Article and author information
Author details
Niels JM Verstegen
Jet van den Dijssel
Katherine Kedzierska
Carolien E van de Sandt
Funding
ZonMw (#10430072010007)
- Taco W Kuijpers
- Filip Eftimov
- Theo Rispens
Horizon 2020 Framework Programme (#860003)
- Taco W Kuijpers
- Filip Eftimov
- Theo Rispens
- Carolien E van de Sandt
European Commission (#101015756)
- Niels JM Verstegen
Horizon 2020 Framework Programme (#792532)
- Carolien E van de Sandt
NHMRC (1173871)
- Joep Killestein
PPOC (#20_21 L2506)
- Taco W Kuijpers
- Filip Eftimov
- Theo Rispens
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Human subjects: This study was approved by the medical ethical committee (NL74974.018.20 and EudraCT 2021-001102-30, local METC nummer: 2020_194) and registered at Dutch Trial Register (Trial ID NL8900). Written informed consent was obtained from all study participants when enrolled. Participants were recruited between April 16th 2021 and May 20th 2021 at the MS Center Amsterdam, Amsterdam UMC and the Amsterdam READE Rheumatology and Immunology Center and vaccinated between April 19th 2021 and July 1st 2021 with the mRNA-1273 (Moderna) vaccine at an interval of six weeks, according to the Dutch national vaccination guidelines.
Copyright
© 2022, Verstegen et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
Metrics
-
- 1,300
- views
-
- 328
- downloads
-
- 16
- citations
Views, downloads and citations are aggregated across all versions of this paper published by eLife.
Download links
A two-part list of links to download the article, or parts of the article, in various formats.
Downloads (link to download the article as PDF)
Open citations (links to open the citations from this article in various online reference manager services)
Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)
Immune dynamics in SARS-CoV-2 experienced immunosuppressed rheumatoid arthritis or multiple sclerosis patients vaccinated with mRNA-1273
eLife 11:e77969.
https://doi.org/10.7554/eLife.77969
Further reading
-
- Immunology and Inflammation
- Microbiology and Infectious Disease
HIV and simian immunodeficiency virus (SIV) infections are known for impaired neutralizing antibody (NAb) responses. While sequential virus–host B cell interaction appears to be basally required for NAb induction, driver molecular signatures predisposing to NAb induction still remain largely unknown. Here we describe SIV-specific NAb induction following a virus–host interplay decreasing aberrant viral drive of phosphoinositide 3-kinase (PI3K). Screening of seventy difficult-to-neutralize SIVmac239-infected macaques found nine NAb-inducing animals, with seven selecting for a specific CD8+ T-cell escape mutation in viral nef before NAb induction. This Nef-G63E mutation reduced excess Nef interaction-mediated drive of B-cell maturation-limiting PI3K/mammalian target of rapamycin complex 2 (mTORC2). In vivo imaging cytometry depicted preferential Nef perturbation of cognate Envelope-specific B cells, suggestive of polarized contact-dependent Nef transfer and corroborating cognate B-cell maturation post-mutant selection up to NAb induction. Results collectively exemplify a NAb induction pattern extrinsically reciprocal to human PI3K gain-of-function antibody-dysregulating disease and indicate that harnessing the PI3K/mTORC2 axis may facilitate NAb induction against difficult-to-neutralize viruses including HIV/SIV.
-
- Immunology and Inflammation
The T6SS of Pseudomonas aeruginosa plays an essential role in the establishment of chronic infections. Inflammasome-mediated inflammatory cytokines are crucial for host defense against bacterial infections. We found that P. aeruginosa infection activates the non-canonical inflammasome in macrophages, yet it inhibits the downstream activation of the NLRP3 inflammasome. The VgrG2b of P. aeruginosa is recognized and cleaved by caspase-11, generating a free C-terminal fragment. The VgrG2b C-terminus can bind to NLRP3, inhibiting the activation of the NLRP3 inflammasome by rejecting NEK7 binding to NLRP3. Administration of a specific peptide that inhibits caspase-11 cleavage of VgrG2b significantly improves mouse survival during infection. Our discovery elucidates a mechanism by which P. aeruginosa inhibits host immune response, providing a new approach for the future clinical treatment of P. aeruginosa infections.
