Response to COVID-19 boosters in seronegative multiple sclerosis patients

As of March 21, 2022, the coronavirus 2019 (COVID-19) has claimed the lives of almost 6.1 million globally. Vaccines have played a significant role in reducing overall COVID-19-related morbidity and mortality rates; however, their impact on patients with primary and secondary immunocompromising conditions is yet unknown. For example, many people with multiple sclerosis (MS) treated with anti-CD20 and Sphingosine-1-phosphate (S1P) modulators show a weakened immune response to the first two doses of COVID-19 immunization.

Study: Response to COVID-19 booster vaccinations in seronegative people with MS. Image Credit: Teeradej /

Study: Response to COVID-19 booster vaccinations in seronegative people with MS. Image Credit: Teeradej /

To date, a majority of COVID-19 research has concentrated on humoral immune responses. Nonetheless, the effect of booster vaccination in those with MS who do not respond well to the initial COVID-19 vaccine regimen is unknown.

In a recent study published on the preprint server medRxiv*, researchers report humoral T-cell responses in MS patients after receiving a third COVID-19 booster vaccine dose in those who were seronegative after their second vaccine.

Study methodology

A subset of people with MS who were actively participating in a seroprevalence study was selected to participate. The selection criteria for the current study included a negative immunoglobulin G (IgG) anti-spike SARS-CoV-2 antibody response between four and eight weeks after receiving the second vaccine dose, as well as a willingness to provide a second blood sample two to 12 weeks after the third COVID-19 vaccine.

Between November 2021 and January 2022, dried blood spot specimens were taken. Medical notes from January 2022 to February 2022 were used to extract information on demographics, MS type and treatment, and COVID-19 infection/vaccine dates.

Following a third COVID-19 immunization, humoral responses to the S1 subunit of the SARS-CoV-2 spike protein were assessed on dried blood spots using the United States Food and Drug Administration (FDA)-approved EuroImmun enzyme-linked immunosorbent assay (ELISA). The optical density (OD) of participants’ specimens was compared to the OD of the calibrator to calculate the results.

Study findings

A total of 79 individuals provided a dried blood spot sample, with 38 of them also giving a full blood sample; two people solely gave whole blood. Fifty-eight women, with an average age of 45.8 years, were prescribed ocrelizumab and 15 fingolimod, while nine others were given different immunosuppressants and two were not taking any disease-modifying therapies (DMTs). The average time between the third vaccine and blood draw was 5.9 weeks.

Anti-spike IgG results from dried blood spot samples revealed that 26 of the 79 individuals seroconverted after receiving the third COVID-19 vaccine. More specifically, eight of the 52 persons who received ocrelizumab and seven of the fifteen people who took fingolimod seroconverted.

Three individuals on ocrelizumab and three on fingolimod showed borderline results. Those who had received the CHAdOx1 nCoV-19 vaccine for their first and second immunization were more likely to seroconvert than those who received the BNT162b2 vaccine.

COVID-19 was reported in 14 of the 40 people tested, with two of them having previously tested positive for COVID-19. According to Fishers' exact test, no correlation between the presence or absence of laboratory evidence of prior COVID-19 infection and either T-cell response or anti-spike seroconversion after the third COVID-19 vaccine was reported. Comparatively, prior SARS-CoV-2 infection appeared to be linked to a stronger T-cell response.

There was no significant difference in quantitative IgG responses among individuals with and without evidence of past infection after excluding two outliers with very low IgG responses. Following the third vaccination and blood sampling, six of the 81 individuals had polymerase chain reaction (PCR)-confirmed COVID-19.

When evaluated prior to developing COVID-19, four of these six individuals exhibited either a T-cell or antibody response to the SARS-CoV-2 spike protein. However, all of these individuals recovered without requiring antivirals or hospitalization.


MS patients who have not responded to the first two COVID-19 vaccine doses appear to benefit from a third dose of the vaccine. Thus, all patients with MS should be urged to abide by vaccination regimens in order to get the most protection available.

T-cell and antibody testing of MS patients on specific DMTs may allow for more tailored infection-risk counseling. However, further longitudinal research is needed to determine the clinical correlations and longevity of these immunological responses.

*Important notice

medRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.

Journal reference:
Colin Lightfoot

Written by

Colin Lightfoot

Colin graduated from the University of Chester with a B.Sc. in Biomedical Science in 2020. Since completing his undergraduate degree, he worked for NHS England as an Associate Practitioner, responsible for testing inpatients for COVID-19 on admission.


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