Persistently reduced humoral and cellular immune response following third SARS-CoV-2 mRNA vaccination in anti-CD20-treated multiple sclerosis patients

Bajwa, Hamza Mahmood; Novak, Frederik; Nilsson, Anna Christine; Nielsen, Christian; Holm, Dorte Kinggaard; Østergaard, Kamilla; Witt, Agnes; Byg, Keld-Erik; Johansen, Işik Somuncu; Mittl, Kristen; Rowles, William; Zamvil, Scott S.; Bove, Riley; Sabatino, Joseph J.; Sejbæk, Tobias

doi:10.1101/2022.01.27.22269944

Cited by 3 publications

(4 citation statements)

References 28 publications

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“…Furthermore, the preliminary evidence indicates significant decline in seropositivity rates of pwMS on aCD20 six months after their second dose 50,51 . Homologous mRNA boosters in pwMS on aCD20 promoted T-cell responses 52 , while humoral responses were still heavily dependent on the serostatus following the priming regimen, and B-cell dynamics at the time of booster administration 33,51-53 ; In other words, the booster doses did not promote humoral immunization in pwMS on aCD20 who did not seroconvert following priming vaccination, unless their B-cells were reconstituted.…”

Section: Resultsmentioning

confidence: 95%

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Multiple sclerosis disease-modifying therapies and COVID-19 vaccines: A practical review and meta-analysis

Etemadifar

Nouri

Pitzalis

et al. 2022

Preprint

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Importance: An evidence-based appraisal of the COVID-19 vaccination policies among people with multiple sclerosis (pwMS) with respect to disease-modifying therapies (DMT) is important for our understandings and their further management. Objective: To synthesize the available evidence concerning the effect of DMTs on COVID-19 vaccination immunogenicity and effectiveness. Data Sources: We searched MEDLINE, Scopus, Web of Science, MedRxiv, and Google Scholar from January 2021 until January 2022. Study Selection: The exclusion criteria included: not a primary investigation; retracted/withdrawn; no eligible participants - people with no history/evidence of previous COVID-19 and corticosteroid administration within two months of vaccination; no eligible exposures - all nine DMT classes; and no eligible comparators - DMT-unexposed at the time of vaccination. Data Extraction and Synthesis: Entries were assessed independently by two reviewers for eligibility and quality. Dichotomized data was extracted by two reviewers in accordance with Cochrane guidelines, and were pooled using either Peto fixed-effects or Inverse-variance random-effects methods. Main Outcomes and Measures: Main outcomes were i) B-cell response, measured by seroconversion odds ratio (OR); ii) T-cell response, measured by interferon-gamma release response OR, and CD4+/CD8+ activation-induced marker+ OR. Further outcomes including immunity waning speed and breakthrough COVID-19 incidence/severity were synthesized narratively. Results: Data from 28 studies (5,025 pwMS and 1,635 healthy participants) after COVID-19 vaccination suggests mildly-lower B-cell responses in teriflunomide- and alemtuzumab-treated, extensively-lower B-cell responses in sphingosine-1-phosphate receptor modulator (S1PRM)- and anti-CD20 (aCD20)-treated, and lower T-cell responses in interferon-, S1PRM-, alemtuzumab- and cladribine-treated pwMS. Every ten-week increase in aCD20-to-vaccine period is associated with a 1.94-time (95%CI: 1.57, 2.41, P<0.00001) increase in odds of seroconversion. B-cell-depleting therapies seem to accelerate post-vaccination humoral waning, and booster immunogenicity is predictable with the same factors affecting the priming vaccination. Furthermore, comparatively-increased breakthrough COVID-19 incidence and severity is being observed only among S1PRM- and anti-CD20-treated pwMS - i.e., among the pwMS with extensively-blunted B-cell response, despite adequate T-cell responses in the aCD20-treated. To date, pwMS on only-T-cell-blunting DMTs have not shown increased susceptibility to breakthrough COVID-19. Conclusion and Relevance: The implemented vaccination strategy to date has been effective for pwMS on all DMTs other than S1PRM and aCD20. As B-cell immunity seems to be a more important predictor of vaccine effectiveness than T-cell immunity, optimization of humoral immunogenicity and ensuring its durability among pwMS on DMTs are the necessities of an effective COVID-19 vaccination policy.

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Section: Resultsmentioning

confidence: 95%

Section: Indicated Positive Adaptive T-cell Responses Among 100%mentioning

confidence: 93%

Multiple sclerosis disease-modifying therapies and COVID-19 vaccines: A practical review and meta-analysis

Etemadifar

Nouri

Pitzalis

et al. 2022

Preprint

View full text Add to dashboard Cite

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“…Furthermore, the preliminary evidence indicates significant decline in seropositivity rates of pwMS on aCD20 6 months after their second dose 44 45. Homologous mRNA boosters in pwMS on aCD20 promoted T-cell responses,46 while humoral responses were still heavily dependent on the serostatus following the first vaccination cycle, and the B-cell dynamics at the time of booster administration 27 45–47…”

Section: Resultsmentioning

confidence: 99%

Multiple sclerosis disease-modifying therapies and COVID-19 vaccines: a practical review and meta-analysis

Etemadifar

Nouri

Pitzalis

et al. 2022

J Neurol Neurosurg Psychiatry

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Studies among people with multiple sclerosis (pwMS) receiving disease-modifying therapies (DMTs) have provided adequate evidence for an appraisal of COVID-19 vaccination policies among them. To synthesise the available evidence addressing the effect of MS DMTs on COVID-19 vaccines’ immunogenicity and effectiveness, following the Cochrane guidelines, we systematically reviewed all observational studies available in MEDLINE, Scopus, Web of Science, MedRxiv and Google Scholar from January 2021 to January 2022 and extracted their relevant data. Immunogenicity data were then synthesised in a quantitative, and other data in a qualitative manner. Evidence from 28 studies suggests extensively lower B-cell responses in sphingosine-1-phosphate receptor modulator (S1PRM) treated and anti-CD20 (aCD20) treated, and lower T-cell responses in interferon-treated, S1PRM-treated and cladribine-treated pwMS—although most T cell evidence currently comprises of low or very low certainty. With every 10-week increase in aCD20-to-vaccine period, a 1.94-fold (95% CI 1.57 to 2.41, p<0.00001) increase in the odds of seroconversion was observed. Furthermore, the evidence points out that B-cell-depleting therapies may accelerate postvaccination humoral waning, and boosters’ immunogenicity is predictable with the same factors affecting the initial vaccination cycle. Four real-world studies further indicate that the comparative incidence/severity of breakthrough COVID-19 has been higher among the pwMS treated with S1PRM and aCD20—unlike the ones treated with other DMTs. S1PRM and aCD20 therapies were the only DMTs reducing the real-world effectiveness of COVID-19 vaccination among pwMS. Hence, it could be concluded that optimisation of humoral immunogenicity and ensuring its durability are the necessities of an effective COVID-19 vaccination policy among pwMS who receive DMTs.

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“…Although not all individuals on anti-CD20 therapies developed T cell responses, it further appears that T cell responses and antibody titres are not well correlated, and so a lack of antibody response is not in itself indicative of a failed response to vaccination (27). Additionally, data on the effect of a third vaccine dose on both antibody levels and T cell responses are mixed; some studies suggest no effect of additional vaccination on either humoral or cellular immune responses (28), whereas others find boosted responses (29,30).…”

Section: Introductionmentioning

confidence: 99%

T cell responses to SARS-CoV-2 vaccination in people with multiple sclerosis differ between disease-modifying therapies

Wolf

Ravussin

König

et al. 2022

Preprint

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Immune responses in people with multiple sclerosis (pwMS) on disease-modifying therapies (DMTs) have been of significant interest throughout the COVID-19 pandemic. Lymphocyte-targeting immunotherapies including anti-CD20 treatments and sphingosine-1-phosphate receptor (S1PR) modulators attenuate antibody responses after vaccination. Evaluation of cellular responses after vaccination is therefore of particular importance in these populations. In this study, we analysed CD4 and CD8 T cell functional responses to SARS-CoV-2 spike peptides in healthy controls and pwMS on five different DMTs by flow cytometry. Although pwMS on anti-CD20 and S1PR therapies had low antibody responses after both 2 and 3 vaccine doses, T cell responses in pwMS on anti-CD20 therapies were preserved after third vaccination, even when additional anti-CD20 treatment was administered between vaccine doses 2 and 3. PwMS taking S1PR modulators had low detectable T cell responses in peripheral blood. CD4 and CD8 T cell responses to SARS-CoV-2 variants of concern Delta and Omicron were lower than to the ancestral Wuhan-Hu-1 variant. Our results indicate the importance of assessing both cellular and humoral responses after vaccination and suggest that even in the absence of robust antibody responses vaccination can generate immune responses in pwMS.

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Persistently reduced humoral and cellular immune response following third SARS-CoV-2 mRNA vaccination in anti-CD20-treated multiple sclerosis patients

Cited by 3 publications

References 28 publications

Multiple sclerosis disease-modifying therapies and COVID-19 vaccines: A practical review and meta-analysis

Multiple sclerosis disease-modifying therapies and COVID-19 vaccines: A practical review and meta-analysis

Multiple sclerosis disease-modifying therapies and COVID-19 vaccines: a practical review and meta-analysis

T cell responses to SARS-CoV-2 vaccination in people with multiple sclerosis differ between disease-modifying therapies

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