To investigate the rate of breakthrough SARS-CoV-2 infection and clinical outcomes in a cohort of MS patients who were treated with ocrelizumab before first, second, and third BNT162b2 mRNA vaccinations.

The study included participants from three MS clinics in Denmark and the University of California, San Francisco in the United States when omicron BA.1 and BA.2 were the dominating subtypes of SARS-CoV-2. Reduced humoral response is associated with ocrelizumab treatment of multiple sclerosis (MS).

The study was a prospective nonrandomized controlled observational multicenter trial. Participants were diagnosed with MS and received ocrelizumab treatment for >12 months prior to the three BNT162b2 mRNA vaccinations. The follow-up period was from January 2021 to May 2022. Clinical outcomes were evaluated using WHO progression scale. The humoral and cellular immunogenicity in participants were correlated with PCR confirmed breakthrough infection.

Out of 54 participants, 32 (59.3%) developed a positive SARS-CoV-2 PCR test in the study period. Mild infections were observed in all infected participants. After the third vaccination, the non-infected participants had higher mean antibody levels compared to the infected participants (54.3 vs. 26.5 BAU/mL, p=0.030). The difference in reactivity between spike-specific CD4⁺ and CD8⁺ T-lymphocytes in the two groups were non-significant. Additional results regarding levels of ocrelizumab, anti-ocrelizumab antibodies and SARS-CoV-2 nucleocapsid protein, together with the immunological effects of fourth vaccination will be presented at the conference.

Our results demonstrate high rates of breakthrough infections, along with mild disease courses after 3^rd SARS-CoV-2 mRNA vaccination in ocrelizumab treated MS participants. This suggests that vaccination of B-cell depleted patients provides low protection against breakthrough infection. The study findings point to the need for better prophylactic options or more specific vaccines to allow for better clinical protection.