ABSTRACT
Background: Prospective, deeply phenotyped research cohorts monitoring people with multiple sclerosis (MS) depend on careful participant engagement that was threatened by COVID19- related restrictions to in-clinic visits. Coincidentally, there was forced adoption of televideo-enabled care. Objective(s): To leverage a natural experiment of "going virtual" during the pandemic to evaluate two hypotheses pertaining to remote MS research: that (1) global costs of remote visits are lower, and (2) disability evaluations are non-inferior. Method(s): Between 3/2020 and 12/2021, 207 UCSF EPIC/ ORIGINS MS cohort participants underwent hybrid in-clinic and virtual research visits. Among these, 96 contributed 100 'matched visits', i.e. in-clinic (Neurostatus, NS-EDSS) and remote (televideo-, tele-EDSS;electronic patient-reported, ePR-EDSS) evaluations within 14 days. Clinical and socio/ demographic characteristics were collected. First, visit costs were compared. Then, the quality of data extracted was compared using non-inferiority design with NS-EDSS as primary outcome. Result(s): The 96 participants contributing 100 matched visits had mean age 41.4 years (SD 11.7) and MS duration 1.4 years (SD 3.4);69% were female and 72% White, 8% lived in lowincome zip codes;median driving distance was 70 miles (mean 545). The costs of remote visits to participants (travel, caregiver time), to research (facilities, personnel, parking, participant compensation), and carbon footprint were all lower than in-person visits (p<0.05 for each). Median cohort EDSS was similar, whether evaluated using NS-EDSS (2), tele-EDSS (1.5) or ePREDSS (2), with range 0-6.5. Utilizing a TOST for Non-inferiority, both remote evaluations were non-inferior to NS-EDSS within+/-0.5 EDSS point (p<0.01 for each). Year-to-year, the % of participants with worsening/stable/improved EDSS scores was similar, whether the annual evaluations both used NS-EDSS, or whether the annual evaluation switched from NS-EDSS to tele-EDSS. Discussion(s): "Going virtual" during the pandemic represented a natural experiment in which to test hypotheses about remote research visits. These visits lowered costs for investigators and participants. Further, remote assessments were non-inferior to NS-EDSS and for more precision, could be supplemented with biosensors. Together, these insights support the conduct of research that is more inclusive to participants regardless of geography, race, income, opportunity costs or ability level.
ABSTRACT
Introduction: MS disease-modifying therapies (DMTs) lead to distinct effects on humoral and cellular immunity. Effective vaccine- elicited immunity to severe acute respiratory syndrome coronavirus- 2 (SARS-CoV-2), the causative agent of the ongoing COVID-19 pandemic, requires robust antibody and CD4+ and CD8+ T cell responses against the SARS-CoV-2 spike protein. Understanding how different MS DMTs affect COVID-19 vaccine immunity is a vital clinical gap that needs to be urgently addressed. Objectives: The goal of this study is to assess COVID-19 vaccine- elicited antibody and T cell responses in MS patients on different of DMTs. Aims: To measure SARS-CoV-2 spike antigen-specific antibody and CD4+ and CD8+ T cell responses before and after COVID- 19 vaccination of MS patients on different DMTs. Methods: Enrolment included MS patients on no therapy, or treated with glatiramer acetate (GA), dimethyl fumarate (DMF), natalizumab (NAT), sphingosine-1-phosphate receptor (S1P) modulator, or anti-CD20 monoclonal antibody (mAb). Serum and peripheral blood mononuclear cells (PBMCs) were collected from all patients before and 2-4 weeks following final COVID-19 vaccination. Patient serum was tested on a Luminex bead-based assay to quantitatively measure IgG levels against the whole SARSCoV- 2 spike protein and the spike receptor binding domain (RBD). PBMCs were stimulated with pools of SARS-CoV-2 spike peptides to measure the frequencies of spike-specific CD4+ and CD8+ T cells by activation-induced marker expression. Results: Following COVID-19 vaccination, all untreated MS patients and patients on GA, DMF, and NAT were seropositive with similar high IgG titres to total spike and spike RBD. MS patients on S1P modulators and anti-CD20 mAb exhibited significantly reduced IgG titres to total spike and spike RBD antigens, with only a fraction of patients reaching seropositivity. Spike antigen-specific CD4+ and CD8+ T cell responses were present at similar levels across all DMT categories following COVID-19 vaccination. Conclusions: MS DMTs exhibited differential effects on COVID- 19 vaccine-elicited humoral, but not T cell immunity. Whereas IgG responses were unaffected in MS patients on GA, DMF, and NAT, IgG levels were reduced in MS patients on S1P modulators and anti-CD20 mAb. The findings of this study have important clinical implications for assessing potential risk of COVID-19 infection in vaccinated MS patients on specific DMTs.