Evaluation of immunological responses to third COVID-19 vaccine among people treated with sphingosine receptor-1 modulators and anti-CD20 therapy

Abstract

Importance: People living with multiple sclerosis (MS) and other disorders treated with immunomodulatory therapies remain concerned about suboptimal responses to coronavirus disease 2019 (COVID-19) vaccines. Important questions persist regarding immunological response to third vaccines, particularly with respect to newer virus variants. Objective: Evaluate humoral and cellular immune responses to third COVID-19 vaccine dose in people on anti-CD20 therapy and sphingosine 1-phosphate receptor (S1PR) modulators, including Omicron-specific assays. Design: Observational study evaluating immunological response to third COVID-19 vaccine dose in volunteers treated with anti-CD20 agents, S1PR modulators, and healthy controls. Neutralizing antibodies against USA-WA1/2020 (WA1) and B.1.1.529 (BA.1) severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) were measured before and after third vaccine. Cellular responses to spike peptide pools generated from WA1 and BA.1 were evaluated. Setting: Mount Sinai Hospital Participants: People treated with anti-CD20 therapy or S1PR modulators and healthy volunteers Exposure: Treatment with anti-CD20 therapy, S1PR modulator, or neither Main outcomes and measures: Serum neutralizing antibodies and ex vivo T cell responses against SARS-CoV-2 antigens. Results: This cohort includes 25 participants on anti-CD20 therapy, 12 on S1PR modulators, and 14 healthy controls. Among those on anti-CD20 therapy, neutralizing antibodies to WA1 were significantly reduced compared to healthy controls (ID50% GM post-vaccination of 8.1 ± 2.8 in anti-CD20 therapy group vs 452.6 ± 8.442 healthy controls, P<0.0001) and neutralizing antibodies to BA.1 were below the threshold of detection nearly universally. However, cellular responses, including to Omicron-specific peptides, were not significantly different from controls. Among those on S1PR modulators, neutralizing antibodies to WA1 were detected in a minority, and only 3/12 had neutralizing antibodies just at the limit of detection to BA.1. Cellular responses to Spike antigen in those on S1PR modulators were reduced by a factor of 100 compared to controls (median 0.0008% vs. 0.08%, p<0.001) and were not significantly ″boosted″ by a third injection. Conclusions and Relevance: Participants on immunomodulators had impaired antibody neutralization capacity, particularly to BA.1, even after a third vaccine. T cell responses were not affected by anti-CD20 therapies, but were nearly abrogated by S1PR modulators. These results have clinical implications warranting further study.

Vaccine-breakthrough SARS-CoV-2 infections in people with multiple sclerosis and related conditions: An observational study by the New York COVID-19 Neuro-Immunology Consortium (NYCNIC-2)

“…This attenuation in humoral responses to COVID-19 infection has been demonstrated in other cohorts. 6–9 A similarly poor antibody response has been found post-SARS-CoV-2-vaccination in patients treated with anti-CD20 therapies and sphingosine-1-phosphate (S1P) receptor modulators, 10–16 a trend seen previously with responses to other vaccines. 17–20 Postvaccination SARS-CoV-2 humoral responses are generally lower in magnitude and delayed in PwMS treated with these agents, and this attenuation persists after multiple vaccine doses.…”

“…It is possible that intact T-cell function in this population may offer some vaccine-related protection against severe infection. 11,12,14,21,22 While this study was designed to assess the severity, and not incidence, of infection, there was an overrepresentation of anti-CD20 therapy use by patients with infections in our cohort, nearly double the proportion found in our pre-vaccine NYCNIC1 cohort. 1 While we cannot rule out that this finding is related to changes in prescribing practices, patient habits, or reporting bias, these factors alone seem unlikely to account for the magnitude of overrepresentation.…”

“…To our knowledge, this is the first large multicenter study to examine COVID-19 clinical outcomes in PwMS and related conditions in the postvaccination era. While other studies have evaluated how DMTs may affect biomarkers of vaccine response (postvaccination antibody production and/or T-cell function), 2,[10][11][12][13][14][15][16]22,24,28,35 we assessed the real-world clinical impact of vaccination in a large cohort of PwMS and related conditions, before and during the first Omicron surge.…”

“…Reported SARS-CoV-2 spike-protein-specific seropositivity rates with anti-CD20 therapies following a primary course of two mRNA vaccine doses vary widely across studies, ranging from 13% to 89%, rising only slightly following a third vaccine dose. 11,14,15,[21][22][23][24][25][26][27] Similarly, reported seropositivity after vaccination in PwMS treated with S1P agents ranged widely from 3.8% to 85.7%, with only a small rise after a third dose. 10,14,15,[25][26][27] Variations in reported seropositivity rates may be due to differences in assays used, degree of cell depletion, and/or timing of infused medications and vaccination.…”

“…11,14,15,[21][22][23][24][25][26][27] Similarly, reported seropositivity after vaccination in PwMS treated with S1P agents ranged widely from 3.8% to 85.7%, with only a small rise after a third dose. 10,14,15,[25][26][27] Variations in reported seropositivity rates may be due to differences in assays used, degree of cell depletion, and/or timing of infused medications and vaccination. While SARS-CoV-2 spike protein-specific T-cell responses are preserved in PwMS treated with anti-CD20 therapies, 11,21,22,[25][26][27][28] raising the possibility of at least partially intact vaccine-mediated protection, the degree and spectrum of T-cell responses (CD4 and CD8) differed in patients with and without neutralizing antibodies.…”