This study presents the incidence of SARS-CoV-2 infection for the entire population of people with MS receiving a DMT in England and compares their risk of infection to the general population during two waves of the COVID-19 pandemic- before implementation of mass SARS-CoV-2 vaccination and when at least 74% and 56% of the adult population in England had received their first and second dose of vaccine, respectively (coronavirus.data.gov.uk/details/vaccinations?areaType=nation&areaName=England). To our knowledge, this is the first study to report changes in the incidence of SARS-CoV-2 infection in relation to mass vaccination in a population under immunomodulatory therapies. Although individual-level data on SARS-CoV-2 vaccination was not available at the time of the study, the MS population were expected to have a similar pattern of vaccination to the general population as they had a high willingness to receive the vaccine,6 or may have been vaccinated earlier (for example, people with severe neurological disabilities or those taking alemtuzumab or ocrelizumab) (www.gov.uk/government/publications/covid-19-the-green-book-chapter-14a). The study used SARS-CoV-2 test results to estimate the incidence rate of infection, which includes both symptomatic and asymptomatic infections.
Recognising these limitations, the findings of this study show a substantial increase in the risk of SARS-CoV-2 infection among people on ocrelizumab or fingolimod compared to the general population following liberalisation of COVID-19 restrictions and despite mass SARS-CoV-2 vaccination. There were no obvious changes in the risk of SARS-CoV-2 infection among people taking other MS DMTs.
Ocrelizumab is an anti-CD20 monoclonal antibody that causes B-cell depletion.7 People on ocrelizumab or rituximab, another anti-CD20 therapy used for treatment of MS in some countries,7 show reduced antibody and memory B-cell responses to SARS-CoV-2 vaccines.2,8−10 Nevertheless, a few studies reported that they can mount a T-cell response suggesting that vaccination may offer some protection against SARS-CoV-2 to people on B-cell depleting therapies.2,10 It was unknown, however, how this interplay between humoral and cellular immune responses translated into protecting people on anti-CD20 medications from infection. Fingolimod is a sphingosine-1-phosphate receptor modulator which inhibits lymphocyte egress from lymphoid tissues into the circulation.11 This MS DMT also seems to prevent the production of antibodies in response to SARS-CoV-2 vaccination.8,9
So far, assumptions about the impact of MS DMTs on the effectiveness of SARS-CoV-2 vaccines are mostly based on experiences with previous vaccinations and immunological studies rather than population-based studies.2, 8–10,12 Although a few studies have suggested that antibody levels serve as a correlate of protection from SARS-CoV-2 infection,13–15 it is undecided whether these antibodies are the main executors of this protection or they are simply biomarkers of the orchestrated function of the triggered immune system against the virus.16 Cohort studies of people taking immunomodulatory drugs are required to assess the effectiveness of SARS-CoV-2 vaccines in these populations. A few such studies have already been set up, but it will be a while before they are concluded.9,17 The findings of our study suggest that the humoral immune response to vaccines, which is suppressed by ocrelizumab and fingolimod and preserved by other MS DMTs,2,8−10 may be mainly responsible for the protection provided against SARS-CoV-2.
We noted also that the risk of SARS-CoV-2 infection associated with beta-interferons was lower than the general population, both pre- and post-vaccination, which is not unexpected given their antiviral effects.18
The effectiveness of SARS-CoV-2 vaccination in preventing symptomatic infections and severe disease among people taking MS DMT is yet to be determined. The timing of vaccination in relation to administration of some MS DMTs, such as alemtuzumab, cladribine, and ocrelizumab, can affect the development of an immune response to the vaccine depending on whether or not repopulation of the immune cells has occurred.12 This consideration was not applied in the present study because individual-level vaccination data were not available.
The findings of this study suggest that SARS-CoV-2 vaccines offer minimal, if any, protection against infection to people taking ocrelizumab or fingolimod. Large-scale population studies using individual-level data on SARS-CoV-2 vaccination status, antibody levels, incidence of infection along with severity of disease are required to establish the benefits of current vaccination programmes that are offering third dose vaccines to people with drug-induced immunosuppression.