Strong T-cell activation in response to COVID-19 vaccination in multiple sclerosis patients receiving B-cell depleting therapies

Tisch Multiple Sclerosis Research Center of New York, New York, NY, United States

Immunocompromised individuals, including multiple sclerosis (MS) patients on certain immunotherapy treatments, are considered susceptible to complications from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and specific vaccination regimens have been recommended for suitable protection. MS patients receiving anti-CD20 therapy (aCD20-MS) are considered especially vulnerable due to acquired B-cell depletion and impaired antibody production in response to virus infection and COVID-19 vaccination. Here, the humoral and cellular responses are analyzed in a group of aCD20-MS patients (n=43) compared to a healthy control cohort (n=34) during the first 6 months after a 2-dose cycle mRNA-based COVID-19 vaccination. Both IgG antibodies recognizing receptor binding domain (RBD) from CoV-2 spike protein and their blocking activity against RBD-hACE2 binding were significantly reduced in aCD20-MS patients, with a seroconversion rate of only 23.8%. Interestingly, even under conditions of severe B-cell depletion and failed seroconversion, a significantly higher polyfunctional IFNγ+ and IL-2+ T-cell response and strong T-cell proliferation capacity were detected compared to controls. Moreover, no difference in T-cell response was observed between forms of disease (relapsing remitting- vs progressive-MS), anti-CD20 therapy (Rituximab vs Ocrelizumab) and type of mRNA-based vaccine received (mRNA-1273 vs BNT162b2). These results suggest the generation of a partial adaptive immune response to COVID-19 vaccination in B-cell depleted MS individuals driven by a functionally competent T-cell arm. Investigation into the role of the cellular immune response is important to identifying the level of protection against SARS-CoV-2 in aCD20-MS patients and could have potential implications for future vaccine design and application.

1 Introduction

Currently approved vaccines designed against the ancestral SARS-CoV-2 (CoV-2) spike protein are efficient in blocking infection, hospitalization and death in healthy individuals (1–3). Adaptive immune responses generated by mRNA-based COVID-19 vaccines (mRNA-1273, BNT162b2) induce the production of high levels of neutralizing antibodies and a strong and sustained T-cell response (4–6). Waning immunity and the rise of new CoV-2 variants of concern have created additional challenges and the need for boosters and potential new vaccine designs. Concern about the level of protection of naïve or vaccinated individuals with congenital or acquired immunosuppression has been raised during the pandemic. A recent CDC study has shown that immunocompromised populations receiving mRNA-based COVID-19 vaccines had lower protection against hospitalization than the general immunocompetent population (77% compared to 90%), although extensive differences were observed depending on type of disease and treatments (7). In addition to higher susceptibility to complications, protracted infections in immunodeficient individuals can potentially lead to the accumulation of CoV-2 mutations and the rise of new variants of concern (8–10). Overall, these and other factors highlight the need for a better understanding of the immune responses to CoV-2 in immunocompromised individuals.

Patients with multiple sclerosis under B-cell depleting anti-CD20 treatment (aCD20-MS) and other disease-modifying therapies (DMTs) are susceptible to severe acquired immunosuppression and prone to infections (11, 12). Moreover, infections might be responsible for disease exacerbation and only non-live vaccines are currently recommended for the application of immunizations (13). Under anti-CD20 treatment, the induced depletion of immature and mature/naïve B-cells can attenuate the production of antibodies needed for the neutralization of incoming pathogens and blocking of disease onset (14, 15). An important unknown is whether the remaining adaptive immune response, or other unaffected immune arms, can still provide protection against microbe infections. A better understanding of this limitation is essential for defining the level of protection of aCD20-MS patients in the context of the current COVID-19 pandemic, including immunological protection induced by CoV-2 infection or in response to the application of the various vaccines available.