tetano
Editor, Senior Moderator
Front Immunol
. 2025 Nov 19:16:1568157.
doi: 10.3389/fimmu.2025.1568157. eCollection 2025. Natalizumab and fumarate treatment differentially modulate CD4+ T cell and B cell subtypes in multiple sclerosis patients without impacting durable COVID-19 vaccine responses
Ryan Curtin[SUP] #[/SUP][SUP] 1 2 3 [/SUP], Yogambigai Velmurugu[SUP] #[/SUP][SUP] 1 2 3 [/SUP], Fatoumatta Dibba[SUP] 1 2 3 [/SUP], Yuan Hao[SUP] 4 [/SUP], Samantha Nyovanie[SUP] 1 2 3 [/SUP], Andrea Lopez[SUP] 1 2 [/SUP], David Mieles[SUP] 1 2 [/SUP], Courtney Ng[SUP] 1 2 3 [/SUP], Katherine Perdomo[SUP] 5 [/SUP], Nicole Scott[SUP] 6 [/SUP], James B Lewin[SUP] 6 [/SUP], Robin L Avila[SUP] 6 [/SUP], Jen Smrtka[SUP] 6 [/SUP], Yury Patskovsky[SUP] 1 2 3 [/SUP], Jonathan Howard[SUP] 3 5 [/SUP], Gregg J Silverman[SUP] 7 [/SUP], Michelle Krogsgaard[SUP] 1 2 3 [/SUP]
Affiliations
Background: There is a greater risk of complications from severe COVID-19 in immunocompromised patients with multiple sclerosis (pwMS) treated with certain disease-modifying therapies (DMTs), as well as a diminished vaccine response.
Methods: In this exploratory, observational study, we recruited 28 patients with Relapsing Remitting MS (RRMS, n=24) or Secondary Progressive MS (SPMS, n=4), that were receiving treatment with either natalizumab or fumarates (diroximel or dimethyl) prior to baseline sample collection. Blood samples were collected before vaccination (baseline), between 4 weeks and 6 months post vaccination, and post booster administration. A multiplex bead immunoassay (MBI) was used to measure anti-Spike IgG, while IFNγ and IL-2 ELISpot assays were used to determine T cell activation. A 35-color spectral flow cytometry panel was used to phenotype bulk B and T cells and SARS-CoV-2-specific T cells, while dimensionality reduction was performed for further phenotypic analysis.
Results: We observed a significantly increased absolute lymphocyte count (ALC) (p=0.0003) in natalizumab-treated pwMS when compared to fumarate-treated pwMS primarily due to increased circulating CD19+ B cells. Fumarate-treated pwMS exhibited a diminished Th1/Th2 ratio when compared to natalizumab-treated pwMS (p=0.0004) or healthy controls (p=0.0745), while natalizumab treatment marginally increased the Th1/Th2 ratio compared to healthy controls (p=0.1311). The observed increase in B cells in natalizumab-treated pwMS were predominantly memory B cells, and double negative (DN) B cells. However, no significant differences between the treatment groups were seen in terms of Spike IgG titers following the initial vaccination course or booster dose, nor in SARS-CoV-2-specific CD4+ responses, all of which remained robust for at least 6 months post-vaccination. The magnitude of humoral and cellular immune responses in both treatment groups were comparable to vaccinated healthy controls. Additionally, SARS-CoV-2 spike-specific CD4+ T cell phenotyping revealed a Th2 dominant response to booster dose in natalizumab-treated pwMS (p=0.0485) but not fumarate-treated pwMS.
Conclusion: pwMS treated with natalizumab or fumarates exhibit similarly robust and durable SARS-CoV-2 specific T cell and humoral responses following vaccination and booster dose. DMT-treated pwMS showing comparable responses to healthy individuals following initial vaccination supports the notion that treatment with these specific DMTs does not diminish strong, long-lasting immunity conferred by COVID-19 vaccination, despite the phenotypic differences modulated by each therapy.
Keywords: B cell; COVID-19; SARS-CoV-2; T cell; fumarate; multiple sclerosis (MS); natalizumab (Tysabri); vaccine.
. 2025 Nov 19:16:1568157.
doi: 10.3389/fimmu.2025.1568157. eCollection 2025. Natalizumab and fumarate treatment differentially modulate CD4+ T cell and B cell subtypes in multiple sclerosis patients without impacting durable COVID-19 vaccine responses
Ryan Curtin[SUP] #[/SUP][SUP] 1 2 3 [/SUP], Yogambigai Velmurugu[SUP] #[/SUP][SUP] 1 2 3 [/SUP], Fatoumatta Dibba[SUP] 1 2 3 [/SUP], Yuan Hao[SUP] 4 [/SUP], Samantha Nyovanie[SUP] 1 2 3 [/SUP], Andrea Lopez[SUP] 1 2 [/SUP], David Mieles[SUP] 1 2 [/SUP], Courtney Ng[SUP] 1 2 3 [/SUP], Katherine Perdomo[SUP] 5 [/SUP], Nicole Scott[SUP] 6 [/SUP], James B Lewin[SUP] 6 [/SUP], Robin L Avila[SUP] 6 [/SUP], Jen Smrtka[SUP] 6 [/SUP], Yury Patskovsky[SUP] 1 2 3 [/SUP], Jonathan Howard[SUP] 3 5 [/SUP], Gregg J Silverman[SUP] 7 [/SUP], Michelle Krogsgaard[SUP] 1 2 3 [/SUP]
Affiliations
- PMID: 41346586
- PMCID: PMC12672258
- DOI: 10.3389/fimmu.2025.1568157
Background: There is a greater risk of complications from severe COVID-19 in immunocompromised patients with multiple sclerosis (pwMS) treated with certain disease-modifying therapies (DMTs), as well as a diminished vaccine response.
Methods: In this exploratory, observational study, we recruited 28 patients with Relapsing Remitting MS (RRMS, n=24) or Secondary Progressive MS (SPMS, n=4), that were receiving treatment with either natalizumab or fumarates (diroximel or dimethyl) prior to baseline sample collection. Blood samples were collected before vaccination (baseline), between 4 weeks and 6 months post vaccination, and post booster administration. A multiplex bead immunoassay (MBI) was used to measure anti-Spike IgG, while IFNγ and IL-2 ELISpot assays were used to determine T cell activation. A 35-color spectral flow cytometry panel was used to phenotype bulk B and T cells and SARS-CoV-2-specific T cells, while dimensionality reduction was performed for further phenotypic analysis.
Results: We observed a significantly increased absolute lymphocyte count (ALC) (p=0.0003) in natalizumab-treated pwMS when compared to fumarate-treated pwMS primarily due to increased circulating CD19+ B cells. Fumarate-treated pwMS exhibited a diminished Th1/Th2 ratio when compared to natalizumab-treated pwMS (p=0.0004) or healthy controls (p=0.0745), while natalizumab treatment marginally increased the Th1/Th2 ratio compared to healthy controls (p=0.1311). The observed increase in B cells in natalizumab-treated pwMS were predominantly memory B cells, and double negative (DN) B cells. However, no significant differences between the treatment groups were seen in terms of Spike IgG titers following the initial vaccination course or booster dose, nor in SARS-CoV-2-specific CD4+ responses, all of which remained robust for at least 6 months post-vaccination. The magnitude of humoral and cellular immune responses in both treatment groups were comparable to vaccinated healthy controls. Additionally, SARS-CoV-2 spike-specific CD4+ T cell phenotyping revealed a Th2 dominant response to booster dose in natalizumab-treated pwMS (p=0.0485) but not fumarate-treated pwMS.
Conclusion: pwMS treated with natalizumab or fumarates exhibit similarly robust and durable SARS-CoV-2 specific T cell and humoral responses following vaccination and booster dose. DMT-treated pwMS showing comparable responses to healthy individuals following initial vaccination supports the notion that treatment with these specific DMTs does not diminish strong, long-lasting immunity conferred by COVID-19 vaccination, despite the phenotypic differences modulated by each therapy.
Keywords: B cell; COVID-19; SARS-CoV-2; T cell; fumarate; multiple sclerosis (MS); natalizumab (Tysabri); vaccine.