Serological and cellular immune response to SARS-CoV-2 vaccination in pediatric multiple sclerosis on immunotherapy

PROJECT SUMMARY/ABSTRACT Mounting an effective antibody and cellular immune response to SARS-CoV-2 vaccination is critical for its efficacy to reduce the risk of severe complications and death in COVID-19. Patients with multiple sclerosis (pwMS) are at increased risk for severe COVID-19 and can have altered immune responses to SARS-CoV-2 vaccination. In addition, the type of disease-modifying therapy (DMT) further increases the risk for breakthrough COVID-19 infection and risk for severe COVID-19 and death in pwMS. For example, while anti- CD20 monoclonal antibodies (anti-CD20 mAbs) and sphingosine-1-phosphate receptor modulators (S1PMs) both decrease antibody response to SARS-CoV-2 in adult pwMS, the patient's SARS-CoV-2-specific T-cell responses are blunted in S1PMs but not anti-CD20 mAbs. Although much is known about adult pwMS, limited data is available on vaccine responses in pediatric-onset multiple sclerosis (POMS) on similar therapies. Vulnerable and understudied, children have different immune systems than adults and can mount different immune responses to SARS-CoV-2 immunization. Here, we propose investigating how different immunotherapies (anti-CD20 mAbs vs. S1PM) affect vaccine response in pwMS across age. We will use our new multiparameter technology, flowBEAT, to measure the type (IgM, IgG1, IgG2, IgG3, IgG4, IgA1, IgA2, IgE) and specificity (22 antigens, including structural and non-structural SARS-CoV-2 and HCoV proteins, and a panel to detect autoantibodies associated with COVID-19 severity) of antibody responses to SARS-CoV-2 vaccination and their ability to neutralize SARS-CoV-2 infection, along with pseudovirus neutralization assays (Aim 1). We will also characterize the phenotype and function of the patient's SARS-CoV-2-specific B-cell and T-cell subsets using Hi-D flow and mass cytometry (Aim 2). Characterizing the SARS-CoV-2-specific humoral (antibodies) and cellular (memory B and T cell) responses after vaccination will determine whether the different immunotherapy regimens, anti-CD20 mAbs vs. S1PMs, can affect the development of a protective vaccine response, including robust neutralizing antibodies in pwMS across age. Our preliminary data suggest deficient IgG1 responses in POMS on S1PM but not on anti-CD20 mAbs. Thus, we hypothesize that the immunotherapy type (anti-CD20 mAbs vs. S1PM) will predict the quality of the memory B- and T-cell responses, including alterations in neutralizing antibodies, and that this protective immune response will depend on age. We expect this work to inform therapeutic decisions prescribed to vulnerable MS patients and guide future vaccine strategies to maximize vaccine efficacy in other patients on similar immunotherapies.