Induction and stability of vaccine-specific antibodies in multiple sclerosis patients on different disease-modifying therapies

Most developed nations have created mass vaccination programs, aiming to protect the majority of their population from coronavirus disease 2019 (COVID-19), the disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and allow them to dismantle the costly and restrictive measures used to attempt to curb the transmission of the disease. Unfortunately, some individuals do not benefit from these vaccines to the same extent. In a study posted to the medRxiv* preprint server, researchers have investigated the lack of response to treatment in certain multiple sclerosis (MS) patients.

Study: SARS-CoV-2 mRNA vaccination fails to elicit humoral and cellular immune responses in multiple sclerosis patients receiving fingolimod. Image Credit: Miljan Zivkovic/ShutterstockStudy: SARS-CoV-2 mRNA vaccination fails to elicit humoral and cellular immune responses in multiple sclerosis patients receiving fingolimod. Image Credit: Miljan Zivkovic/Shutterstock

The study

The researchers analyzed 86 MS patients treated with DMT and compared them to 17 control patients - who had MS but were not treated with DMT. They collected clinical samples before vaccination and one, three, and six months post-vaccination.

They found that MS patients receiving fingolimod or aCD20-BCD therapies showed significantly lower anti-S1 IgG levels at both one and three months post-vaccination, to the extent that some patients showed no levels at all. Vaccination of untreated patients showed much higher success rates, with 91% of individuals showing seroconversion after the first dose of the vaccine. Only 8% of patients treated with aCD20-BCD seroconverted at one month, rising to 5% at three months. No patients treated with fingolimod seroconverted at one month, rising to 33% post-primary vaccination.

To further explore this, the researchers used SARS-CoV-2 whole spike peptide arrays to understand if the patients showed antibodies that would bind the spike protein at alternate sites. Unfortunately, both groups of treated patients showed far less diverse responses.

Following this, the scientists tested the serum of the MS patients using a pseudovirus neutralization assay, using the vaccine strain spike protein. Generally, the anti-S1 IgG levels correlated with the ability of the serum to neutralize the virus in controls, with the control patients again showing increased ability to combat the virus. None of the patients treated with aCD20-BCD or fingolimod showed the capacity to neutralize the virus after the first vaccination, with slightly better results after the second vaccination for fingolimod patients.

Direct staining of B cells with fluorescently labeled antigens followed by flow cytometry was used to define the magnitude of the response to the RBD and S2 regions of the spike (S) protein. Once again, both cohorts of patients showed worse results than the control groups, with 7% of aCD20-BCD patients showing responses to RBD, and 50% of fingolimod, with similar responses to the S2 subunit. Patients treated with other therapies showed similar responses to the control group. The researchers observed that very few of the RBD-specific B cells in aCD20-BCD patients were memory cells. In fingolimod patients, more of the cells that were reactive to the RBD and S2 subunits were of a naïve phenotype.

CD4+T cells responses to the S1 and S2 subunits following vaccination were examined next, with all untreated MS patients and MS patients treated with DMTs other than fingolimod showing a typically strong increase in reactive cells following both doses of the vaccine. Unfortunately, fingolimod-treated patients showed significantly reduced responses. Only one patient showed a reaction to the S1 peptide after the first dose of the vaccine, and three reacted to the S2 peptide. Fingolimod patients also showed significantly fewer circulating CD3+ cells, with the CD4/CD8 subset shifting more in favor of CD8+ cells.

Finally, the scientists performed correlation analyses to identify any other factors that could affect these patients' reduced response to the vaccines. They found negative correlation trends between antibody induction and disease duration and positive trends between B cell/T cell levels before vaccination and antibody induction. As expected, a strong negative correlation between treatment duration and neutralizing antibody induction was present in fingolimod-treated patients.

The conclusion

The authors highlight that they have confirmed that the antibody response in the treated patients was significantly lower than in the control groups, in some cases virtually absent, and that this is likely at least partially due to the impaired humoral responses seen in these groups. As well as this, the T cell response to the spike protein is significantly muted in fingolimod-treated patients. The correlation analyses helped show that the length of treatment and reduced capacity to respond to the antibody is likely linked. This research is likely to be of enormous import to healthcare workers and MS patients. Hopefully, it should warn of the lack of protection these individuals suffer, enabling them to take steps to protect themselves.

*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:
Sam Hancock

Written by

Sam Hancock

Sam completed his MSci in Genetics at the University of Nottingham in 2019, fuelled initially by an interest in genetic ageing. As part of his degree, he also investigated the role of rnh genes in originless replication in archaea.

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