To Örebro University

Introduction: Some multiple sclerosis (MS) disease-modifying therapies (DMTs) are  associated with blunted humoral vaccination responses, but relevance for SARS-CoV-2 infection is unclear.

Objectives: To determine  SARS-CoV-2  exposure  rates  and  formation of antibody memory among participants of the COMparison Between   All   immunoTherapies   for   MS   (COMBAT-MS;   NCT03193866) and the Immunomodulation and MS Epidemiology (IMSE) studies.

Aim: To determine SARS-CoV2 serological response of people living with MS (pwMS).

Methods: Using  a  multiplex  bead-based  assay  we  determined  SARS-CoV-2  spike  and  nucleocapsid  antibody  levels  in  3,723  pwMS   in   paired   serum   samples   (n=7,157)   donated   prior   (<January  31st  2020)  and  during  the pandemic  (July-October  2020); 16.6% had natalizumab, 6.4% fingolimod, 9.7% dimethyl fumarate,  1.9%  interferon  beta,  50.4%  rituximab,  1.4%  cladribine, 7.6% other DMTs, and 6.1% were untreated. Median fluorescent  intensity  (MFI) and  bead-count  were  determined  for  spike  and nucleocapsid antibodies, and samples were regarded as positive only when reactive to both viral antigens. Hazard ratios, from multivariable Cox regression models, were derived to assess association  between  antibody  levels  above  cut-off  for  each  antigen, comparing  exposure  to  rituximab  or  fingolimod  at  time  of  sampling vs. other reference DMTs. All models were adjusted for age, sex, treatment center, time since reported infection, MS severity, disease duration, and number of previous DMTs.

Results: Specificity and sensitivity of the assay for SARS-CoV-2 was  100%  and  99.7%,  respectively.  The  proportion  of  positive  samples for SARS-CoV-2 differed moderately across DMTs with the highest values among cladribine-treated (7.4%) and the lowest number  among  rituximab-treated  pwMS  (3.9%). Similarly,  the  proportion of positive cases not reported in the Swedish MS registry varied from 100% for cladribine to 33.3% among untreated pwMS.  Comparing levels  of  antibodies  titers  showed  that  levels  were lower among those treated with rituximab or fingolimod vs interferon treated pwMS. Point estimates indicated a similar trend comparing rituximab or fingolimod vs untreated pwMS.

Conclusions: Overall  rates  of  SARS-CoV-2  antibody  positivity  after  the  first COVID-19  wave  differed  only  moderately  across  DMTs,  while  antibody  levels were  lower  with  rituximab  or  fingolimod  compared  to  interferon-treated pwMS.  This  indicates  quantitative  rather  than  qualitative  differences  in  the humoral  response to infection.