Humoral Immune Response Following SARS-CoV-2 mRNA Vaccination and Infection in Pediatric-Onset Multiple Sclerosis

Abstract

Objective

Currently, there are no data available on SARS-CoV-2 vaccine responses in pediatric-onset multiple sclerosis (POMS), and little is known about the course of SARS-CoV-2 infection in this age group. We therefore investigated humoral immune responses after COVID-19 vaccination and/or infection in POMS.

Methods

We retrospectively analyzed seroconversion rates and SARS-CoV-2–specific antibody levels in 30 POMS and one pediatric CIS patient treated with no disease-modifying therapy (no DMT), immunomodulatory DMT (IM-DMT), or immunosuppressive DMT (IS-DMT) from two Austrian MS centers.

Results

The median age at MS onset was 15.39 years (interquartile range [IQR]: 1.97). The median age at the first COVID-19 vaccination was 17.43 years (IQR: 2.76). After two vaccine doses, seroconversion (≥0.8 BAU/ml) was reached in 25 of 28 patients (89.3%). All patients with no DMT or IM-DMT generated robust immune responses to vaccination (seroconversion: no DMT: 6/6, IM-DMT: 7/7 [100%]; median titers: no DMT: 2075 BAU [IQR: 1268.50], IM-DMT: 2500 BAU [IQR: 0]). In the IS-DMT group, seroconversion was achieved in 12 of 14 patients (80%), and median titers were 50.8 BAU (IQR 254.63). Titers were significantly higher in no DMT versus IS-DMT (P = 0.012) and in IM-DMT versus IS-DMT (P = 0.001). Infection with SARS-CoV-2 occurred in 11 of 31 patients, and symptoms were mild in all cases. One relapse occurred after infection, but no relapses were documented after vaccination.

Conclusions

Generally, mRNA vaccinations were well tolerated in POMS patients with and without DMT. Immune response was significantly reduced in patients treated with IS-DMT. No unexpected adverse events or relapses related to vaccinations were observed.

Introduction

The SARS-CoV-2 pandemic has caused significant morbidity and mortality worldwide.¹ Compared to the general population, the risk of COVID-19 appears not to be increased in patients with multiple sclerosis (MS).² However, older age, disability, certain comorbidities, and the use of anti-CD20 B-cell depleting therapies have been associated with higher risks of hospitalizations, ICU admission, and possibly death.3, 4, 5, 6 Although the risk for severe disease courses is considered to be low in children and adolescents, COVID-19-associated hospitalization rates are 2-3 times higher than influenza-associated hospitalization rates in adolescents.⁷ Little is known about disease courses following SARS-CoV-2 infection in pediatric-onset MS (POMS) patients, particularly in those on immunosuppressive therapies.

Vaccination is the primary method for preventing and controlling the SARS-CoV-2 pandemic.⁸ On December 11, 2020, the US Food and Drug Administration approved the use of the Pfizer-BioNTech mRNA vaccine under emergency use authorization for the age group 16 years and older. On May 10, 2021, the authorization was expanded for individuals from 12 to 15 years of age. Similarly, the European Medicines Agency granted a conditional marketing authorization for the age group 16 years and older on December 21, 2020, and for 12- to 15-year-olds on May 25, 2021. On July 23, 2021, the European Medicines Agency approved the Spikevax (Moderna) vaccine for adolescents aged 12 to 17 years.

Although recommended by international MS societies and expert panels,^{9 , 10} vaccinating against SARS-CoV-2 is associated with significant patients’ concerns about the safety of vaccines.^{11 , 12} There is international consensus that mRNA vaccinations are safe in adult MS patients.^{9 , 13} While COVID-19 infections may be associated with increased relapse risk, this has not been observed for vaccinations.¹⁴

With respect to vaccine efficacy, the immune response to SARS-CoV-2 mRNA vaccination is decreased in adult-onset MS (AOMS) patients treated with sphingosine-1-phosphate receptor 1 (S1P1) modulators15, 16, 17 and might even be absent under treatment with anti-CD20 B-cell-depleting monoclonal antibodies.18, 19, 20

Published information on humoral immune response in POMS patients is lacking so far. Therefore, we retrospectively analyzed safety and immune response to SARS-CoV-2 mRNA vaccination in a cohort of POMS patients and evaluated the disease course in POMS patients infected with SARS-CoV-2.

Methods

Patients

For this retrospective study, we included patients with POMS who were followed up at the Medical University of Vienna (Department of Pediatrics and Adolescent Medicine and Department of Neurology) and the Medical University of Innsbruck (Department of Pediatrics I) between March 2020 and May 2022. Inclusion criteria were (1) diagnosis of POMS or pediatric clinically isolated syndrome (CIS) according to international diagnostic criteria²¹; (2) administration of at least one vaccination against SARS-CoV-2 before the age 21 years; (3) availability of SARS-CoV-2-spike antibody testing after vaccination; and (4) patients' or caregivers’ informed consent. Patients were included irrespective of SARS-CoV-2 infection occurring prior or after vaccination.

SARS-CoV-2 infection was determined by polymerase chain reaction (PCR) testing and/or the presence of SARS-CoV-2-spike-specific antibodies before the first vaccine dose, if available. A history of respiratory infection alone without laboratory evidence of SARS-CoV-2 infection was not sufficient to confirm COVID-19 disease. PCR tests were performed in patients with suspected SARS-CoV-2 infection and occasionally in asymptomatic people as routine testing according to national requirements.

Patients with MS onset below the age 18 years but older than 18 years at the time of vaccination (n = 11) were in part included as a substudy of the prospective cohort study “Characterization of the responsiveness after mRNA SARS-CoV-2 vaccination in patients with immunodeficiency or immunosuppressive therapy” (Eudra CT Nr. 2021-000291-11).²² In these patients, blood samples for SARS-CoV-2-spike antibody testing were taken prospectively according to the protocol as described in detail.²² In the other patients, blood samples were taken during routine visits as soon as the test was commercially available.

With respect to MS-specific treatments, we applied the following three categories²³: no-DMT, immunomodulatory DMT (IM-DMT: interferon-beta, glatiramer acetate, dimethyl fumarate, teriflunomide, natalizumab) and immunosuppressive DMT (IS-DMT: fingolimod [FGL] and rituximab [RTX]).

The study was performed with the understanding and written consent of each subject and conforms with the World Medical Association Declaration of Helsinki.²⁴

The study was approved by the ethics committees of the Medical University of Vienna (EK 1123/2015 and EK 1073/2021) and the Medical University of Innsbruck (AN4095).

Study variables

The following variables were assessed: (1) Patient characteristics (sex, age at MS diagnosis, MS treatment, Expanded Disability Status Scale [EDSS]); (2) data on SARS-CoV-2 vaccination (age at vaccination, type of vaccination, number of vaccinations received, adverse events to vaccination (obtained via patient interviews at standard visits or via telephone interviews within four weeks after the vaccination); (3) data on SARS-CoV-2 antibody testing (antibody titer [seroconversion rate, quantification], time from vaccination to antibody testing); and (4) clinical data on SARS-CoV-2 infection (proved by PCR testing and/or the presence of SARS-CoV-2-spike antibodies before the first vaccine dose).

Anti-SARS-CoV-2-antibody testing (Vienna)

For the quantitative determination of antibodies to the receptor-binding domain (RBD) of the viral spike (S) protein, the Elecsys Anti-SARS-CoV-2 S immunoassay was used.²⁵ In this test, quantitation ranges between 0.4 and 2500 binding antibody units per milliliter (BAU/ml), and values >0.8 BAU/ml were regarded as positive. Values below the limit of quantification were defined as 0.2 BAU/ml, and values above the limit of quantification were defined as 2500 BAU/ml to allow for calculations. A value of 264 BAU/ml or higher was considered protective, as defined by an 80% vaccine efficacy against symptomatic SARS-CoV-2 infection.²⁶ The tests were executed on a cobas e801 analyzer (Roche Diagnostics, Rotkreuz, Switzerland) at the Department of Laboratory Medicine, Medical University of Vienna (certified acc. to ISO 9001:2015 and accredited acc. to ISO 15189:2012).

Anti-SARS-CoV-2 antibody testing (Innsbruck)

For the quantitative determination of antibodies to the RBD of the viral spike (S) protein, the Abbott SARS-CoV-2 IgG assay immunoassay was used.²⁷ In this test, quantitation ranges between 2.98 and 5680 binding antibody units per milliliter (BAU/ml), and values >7 BAU/ml were regarded as positive. Values below the limit of quantification were defined as 0.2 BAU/ml, and values above the limit of quantification were defined as 2500 BAU/ml to allow for calculations. A value of 264 BAU/ml or higher was considered protective, as defined by an 80% vaccine efficacy against symptomatic SARS-CoV-2 infection.²⁶ The tests were executed on an Architect i2000SR analyzer (Abbott Laboratories Abbott Park, IL) at the Central Institute of Clinical and Chemical Laboratory Diagnostics, Medical University of Innsbruck (accredited acc. to ISO 15189:2012).

Statistical analysis

According to the distribution, continuous variables are represented as median with interquartile range (IQR). Differences in anti-SARS-CoV-2 IgG titers of unpaired groups were assessed using the Kruskal-Wallis test followed by a post hoc Wilcoxon rank-sum test. Bonferroni correction was used to adjust for multiple comparisons. Categorical variables are represented as the number and rate in percent. All titers are reported separated by vaccine dose and separated by the number of immunological events to account for the influence of immunization through COVID-19 infections. Missing values were omitted from analyses for each variable individually. Statistical analysis was performed using R 4.1.1 (R Core Team [2021], Vienna, Austria). The R packages “ggplot2,” “ggpubr,” and “viridis” were used for graphical representation of the data. The significance level was set at α = 0.05.

Results

Study population

Thirty-one patients (23 females, 74.2%) met the inclusion criteria of this study during the observation period. Of the respective 31 patients, 30 patients (96.8%) had a diagnosis of POMS and one patient (3.2%) was diagnosed with pediatric CIS. The median age at MS/CIS onset was 15.26 years (IQR: 2.17). Median EDSS at baseline (at the time of the first vaccination) was 0.0 (IQR: 0.0), and EDSS was 0.0 in 26 patients (86.7%) and 2.0 in 4 patients (13.3%). Seven patients (22.6%) had no DMT at baseline (1 patient received RTX after two vaccinations), seven patients (22.6%) were treated with IM-DMT (3 dimethyl fumarate, 2 glatiramer acetate, 1 interferon-beta, 1 natalizumab, 1 teriflunomide), and 16 patients (54.8%) with IS-DMT (5 FGL, 11 RTX).

SARS-CoV-2 infection in pediatric-onset multiple sclerosis

Out of 31 patients included in the study, 11 patients had laboratory-confirmed SARS-CoV-2 infection during the observation period. The median age at SARS-CoV-2 infection was 17.56 years (IQR: 1.6). One male patient was infected twice (December 2020 and January 2022). At the time of infection, one patient was not on DMT, four patients were on IM-DMT, and six patients were on IS-DMT (n = 5 RTX, n = 1 FGL). Infection occurred before vaccination in 5 individuals, in 3 after the second, in 2 after the third, and in 1 patient after the fourth vaccine dose. Prevaccination antibody values were available in three patients with a history of SARS-CoV-2 infection (n = 2 IM-DMT: 77.3 BAU/ml and 34 BAU/ml, respectively; n = 1; IS-DMT: 3.2 BAU/ml). All patients had mild COVID-19 disease courses. The most common symptoms were fever in seven patients (63.6%) and headache in six patients (54.5%). Detailed symptoms are depicted in Supplementary Table 3. One patient with IS-DMT (RTX) treatment presented with an MS relapse two weeks after the infection. SARS-CoV-2 infection occurred 5.5 months after the first dose of RTX, when B cells had already started repopulating. The patient recovered after treatment with intravenous methylprednisolone followed by RTX.

Humoral immune response to vaccination

The median age at the first SARS-CoV-2 vaccine doses was 17.43 years (IQR: 2.76). Thirty patients (96.8%) received at least two Pfizer-BioNtech vaccines, and one patient (3.2%) received the Moderna vaccine as the first and second dose. Twenty-nine out of 31 received their first SARS-CoV-2 vaccine dose between March and September 2021. Sixteen patients (51.6%) were vaccinated three times, and one patient was vaccinated four times (4^th dose Moderna). The median time from the 1^st to 2^nd dose was 27.0 days (8.0), and the median time from the 2^nd dose to first postvaccination titer determination was 53.0 days (68.0). Patient characteristics are shown in Table .

TABLE.

Demographic Data, Baseline Treatment, and Vaccination Information

	All (n = 31)
Sex (n, %)
Female	23 (74.2)
Male	8 (25.8)
Diagnosis (n, %)
CIS	1 (3.2)
POMS	30 (96.8)
Age at MS Onset (Median, IQR)	15.26 (2.17)
EDSS Score at Baseline (Median, IQR)	0.0 (0.0)
EDSS Score at Baseline (n, %)
0	26 (86.7)
1	0
2	4 (13.3)
Therapy at Baseline (n, %)
No DMT	7 (22.6)
Immunomodulatory DMT	8 (25.8)
DMF	3 (9.7)
GA	2 (6.5)
IFN	1 (3.2)
NTZ	1 (3.2)
TFL	1 (3.2)
Immunosuppressive DMT	16 (51.6)
FGL	5 (16.1)
RTX	11 (35.5)
Age at the Time of First Vaccine Dose (Median, IQR)	17.43 (2.76)
Vaccine Dose 1 and 2 (n, %)
Pfizer	30 (96.8)
Moderna	1 (3.2)
Vaccine Dose 3 (n, %)
Pfizer	16 (51.6)
Moderna	0
No 3rd dose	15 (48.3)
Vaccine Dose 4 (n, %)
Pfizer	0
Moderna	1 (6.3)
No 4th Dose	15 (93.8)
Vaccine Dose 1 – Dose 2, Days (Median, IQR)	27.0 (8.0)
Vaccine Dose 2 – Dose 3, Days (Median, IQR)	186.0 (48.5)
Vaccine Dose 2 – Titer, Days (Median, IQR)	53.0 (68.0)
Vaccine Dose 3 – Titer, Days (Median, IQR)	26.0 (14.0)
Time Last RTX to First Vaccine Dose, Days (Median, IQR)	127.00 (52.50)

Abbreviations:

CIS = Clinically isolated syndrome

DMF = Dimethyl fumarate

DMT = Disease-modifying therapy

EDSS = Expanded Disability Status Scale

FGL = Fingolimod

GA = Glatiramer acetate

IFN = Interferon-beta

IQR = Interquartile range

MS = Multiple sclerosis

No = Number

NTZ = Natalizumab

POMS = Pediatric-onset multiple sclerosis

RTX = Rituximab

TFL = Teriflunomid

After two vaccine doses, seroconversion of anti-SARS-CoV-2 IgG antibodies (≥0.8 BAU/ml) was observed in 25 of 28 patients (89.3%) and antibodies above the threshold considered protective (≥264 BAU/ml)²⁶ in 17 of 28 patients (60.7%) (Supplementary Table 1). The median anti-SARS-CoV-2 IgG antibody titer was 893.5 BAU/ml (IQR: 2459.33) after two vaccine doses. After three vaccine doses, seroconversion was seen in 11 of 12 patients (91.7%) and antibodies ≥264 BAU/ml in 8 of 12 patients (66.7%). The median titer was 774.5 BAU/ml (IQR: 2365.47).

After two vaccine doses (Fig 1 A, Supplementary Table 1), antibody titers were significantly higher in no DMT versus IS-DMT (P = 0.012; median 2075 BAU/ml [IQR: 1268.5] vs. 50.8 BAU/ml [IQR: 254.63]) and in IM-DMT versus IS-DMT (P = 0.001; median 2500 BAU/ml [IQR: 0] vs. 50.8 BAU/ml [IQR: 254.63]). In three patients, lack of seroconversion was observed after two vaccine doses (Refer to section “Nonresponders”). Similarly, after two immunological events (either infection or vaccination) (Fig 1B, Supplementary Table 2), antibody titers were significantly higher in no DMT versus IS-DMT (P = 0.009; median 2500 BAU/ml [IQR: 1129.0] vs. 10.3 [IQR: 220.1]). After three immunological events, antibody titers were significantly higher in IM-DMT versus IS-DMT (P = 0.005; median 2500 BAU/ml [IQR: 0] vs. 397 BAU/ml [IQR: 817.92]). Due to limited patient numbers in the treatment subgroups, we refrained from statistical analyses of individual treatments (Fig 1C and D). Trajectories of antibody titers after the two to four immunological events are depicted in Figs 2 and 3 .

FIGURE 1.

Anti-SARS-CoV-2 S IgG titers (BAU/ml) in POMS patients. (A) Titers by therapy group (no DMT, immunomodulatory DMT [IM-DMT], and immunosuppressive DMT [IS-DMT]) after two and three vaccine doses. (B) Titers by therapy group after two and three immunological events (vaccination and/or infection). (C) Titers by therapy after two and three vaccine doses. (D) Titers by therapy after two and three immunological events. The dashed horizontal lines indicate the cutoffs for seroconversion (0.8 BAU/ml) and protective antibodies (264 BAU/ml). Each point represents one participant. Similar to the error bars of a box-whisker plot, the error bars indicate the range of the data, excluding possible outliers. Outliers are defined as all values below 25% quantile − 1.5 ∗ IQR and above 75% quantile + 1.5 ∗ IQR. ∗P < 0.05; ∗∗P < 0.01. DMT, disease-modifying therapy; IQR, interquartile range. The color version of this figure is available in the online edition.

FIGURE 2.

Change in anti-SARS-CoV-2 S IgG titers (BAU/ml) after two and three immunological events (IE, vaccination and/or infection). The dashed horizontal lines indicate the cutoffs for seroconversion (0.8 BAU/ml) and protective antibodies (264 BAU/ml). Each point represents one participant. Dotted lines between points indicate the trajectories of the antibody titers. Triangles represent participants with a COVID-19 infection prior to titer measurement. Dark color (purple) indicates no disease-modifying therapy (no DMT). Medium color (blue) indicates immunomodulatory DMT (IM-DMT). Light color (green) indicates immunosuppressive DMT (IS-DMT). Similar to the error bars of a box-whisker plot, the error bars indicate the range of the data, excluding possible outliers. Outliers are defined as all values below 25% quantile − 1.5 ∗ IQR and above 75% quantile + 1.5 ∗ IQR. ∗∗P < 0.01. IQR, interquartile range. The color version of this figure is available in the online edition.

FIGURE 3.

Change in anti-SARS-CoV-2 S IgG titers (BAU/ml) and B-cell levels (cells/μl) over time in four individual POMS patients with no disease-modifying therapy (no DMT), immunomodulatory DMT (IM-DMT), and immunosuppressive DMT (IS-DMT). The day of the first vaccine dose was determined as the reference point (day 0). Dashed horizontal lines indicate the cutoffs for seroconversion (0.8 BAU/ml) and protective antibodies (264 BAU/ml). Vertical lines indicate vaccine doses (V), COVID-19 infections (C), or rituximab doses (RTX). Black points indicate anti-SARS-CoV-2 S IgG titers (BAU/ml) at a given time point. Gray points indicate B-cell levels (cells/μl) at a given time point. Lines connecting these points indicate the trajectories.

To confirm the results, sensitivity analysis excluding patients with SARS-CoV-2 infection prior to the respective blood draw was performed. Sensitivity analysis confirmed the results partially. After two vaccine doses, antibody levels were significantly higher in patients with no DMT than in those with IS-DMT (P = 0.006; median 2075 BAU/ml [IQR: 1268.5] vs. 10.3 BAU/ml [IQR: 220.1]). Due to the small sample sizes after excluding patients with SARS-CoV-2 infection, sensitivity analysis was not possible for IM-DMT after two vaccine doses. After three vaccine doses, only 11 patients did not have prior SARS-CoV-2 infection (1 no DMT, 2 IM-DMT, 8 IS-DMT); therefore, sensitivity analysis was not performed.

Nonresponders

In three female patients (all treated with RTX), lack of seroconversion was observed after two vaccine doses. All three had complete B-cell depletion at the time of the second vaccine dose.

Patient W2 received a third dose (Pfizer-BioNtech vaccine) after repopulation of B cells (14 cells/μl) 10 months after the last RTX administration. Five and eight weeks later, antibody titers remained undetectable. A fourth vaccine dose (Moderna) was administered 10 weeks after the third dose at a B-cell level of 49 cells/μl (3%). Three weeks later, the patient was infected with the SARS-CoV-2 delta variant but showed only a mild disease course. No antibody titers were available between the fourth vaccine dose and COVID infection. Antibody analysis two months later revealed an antibody tier of 1042 BAU/ml; at that time, B cells had increased to 117/μl (6%). The disease course of patient W2 is depicted in Fig 3 .

The other two patients were negative after two vaccine doses (Pfizer-BioNtech vaccine) and received a third dose (Pfizer-BioNtech vaccine) six months after the second vaccine dose. In both patients, seroconversion occurred after the third vaccine dose following the onset of B-cell repopulation (1.1 BAU/ml six weeks after vaccination and 149 BAU/ml six weeks after vaccination, respectively).

Adverse events to vaccination

Data on adverse events were available in 30 of 31 patients (Supplementary Figure 1, Supplementary Table 4). The most common side effects after the first vaccination were local reactions in 25 patients (83.3%), fatigue in 11 patients (36.6%), and headaches in 8 patients (26.7%). Adverse events were more frequent after the 2^nd administration, with local reactions in 24 patients (80.0%), headaches in 11 patients (36.7%), fatigue in 9 patients (30.0%), shivering in 7 patients (23.3%), fever in 7 patients (23.3%), and myalgia in 7 patients (23.3%). No severe adverse events were reported after the first or second vaccination.

Discussion

The rapid spread of SARS-CoV-2 throughout the world has stressed the importance of vaccinations to control the pandemic and to protect people at risk for severe disease courses. Recent data show excellent seroconversion rates in AOMS patients who are untreated or under IM-DMT that are comparable to healthy controls.²³ In contrast, IS-DMTs, such as anti-CD20 B-cell-depleting therapies and S1P1 receptor modulators, are associated with decreased seroconversion rates in AOMS.^{22 , 23} However, no data on immune responses to SARS-CoV-2 mRNA vaccinations in POMS patients are currently available.

In our cohort of patients with POMS, seroconversion rates and antibody titers were high in patients without treatment or under IM-DMT. Seroconversion rates and antibody titers were lower in patients treated with IS-DMT (FGL or RTX). Our findings correspond well to data from AOMS patients.²³ The administration of two vaccinations did not suffice to achieve detectable seroconversion in three patients, all of whom were under anti-CD20 B-cell-depleting therapy and showed complete B-cell depletion at the time of vaccination. After repopulation of B cells, patients seroconverted after an additional vaccine dose.

In this study, we performed anti-SARS-CoV-2 S immunoassays for quantitative determination of antibodies to the RBD of the viral spike (S) protein. We acknowledge that this method does not allow differentiation between natural infection and vaccine response. Since antibody values before the first vaccine dose were only available in 11 patients, we cannot rule out infection in the remaining 20 patients before vaccination. Asymptomatic infection may also have occurred during the observation periods in any of the patients. Sensitivity analysis excluding patients with SARS-CoV-2 infection prior to antibody testing confirmed significantly lower antibody titers in IS-DMT versus no DMT.

Recent data suggest that monitoring of B cells can help to increase the chances of favorable immune response to vaccination.^{22 , 28} However, it is currently not recommended to extend dosing intervals as this might cause reactivation of MS disease activity.²⁹ It has to be acknowledged that even patients with complete B-cell depletion can develop seroconversion and generally show robust T-cell responses.^{18 , 22} Specific T cells might provide some extent of protection against severe COVID-19 disease courses, even in patients who are not able to mount appropriate antibody titers.^{18 , 22} Insufficient humoral immune response in some patients under anti-CD20-B-cell-depleting therapies underlines the importance of fulfilling local vaccination schedules before such a therapy is started.

Apart from anti-CD20 B-cell-depleting therapies, patients on sphingosin-1 receptor modulators have shown poor vaccine responses, both on a humoral and on a cellular level.^{23 , 30 , 31} Our five patients on FGL produced antibody titers after two vaccinations; however, only three of them developed titers above the threshold considered to be protective (264 BAU/ml).²⁶

Generally, mRNA vaccinations were tolerated well in our cohort with only mild adverse effects comparable to healthy adolescents and young adults. In contrast to adult MS populations, none of the patients showed deterioration of pre-existing neurological symptoms after the vaccinations.²² However, it has to be acknowledged that most of our patients had none or only minor neurological sequelae at the time of vaccination.

All patients (n = 11) who were infected with SARS-CoV-2 during the observation period showed mild disease courses, including six with IS-DMT. Data on COVID-19 disease courses of patients with POMS are scarce. A recent publication by Oncel et al. including 13 patients with POMS reported no or only mild symptoms.³² In an earlier publication that included nine patients with POMS during the first SARS-CoV-2 wave in 2020, two were hospitalized and received supplemental oxygen.³³

Another matter of debate is whether an infection with SARS-CoV-2 can cause worsening of POMS disease. Deterioration of neurological symptoms and relapses have been reported in AOMS following SARS-CoV-2 infections^{14 , 34}; however, another publication reported no increased risk of relapses.³⁵ Overall, neurological complications were more common after infection than after vaccination.³⁶ One patient in our cohort presented with an MS relapse within two weeks after the infection. The patient was treated with RTX, and the relapse co-occurred with the repopulation of B cells. In contrast, Oncel et al. reported no relapses within three months after SARS-CoV-2 infection in POMS.³²

There are several limitations to be acknowledged. First, since the study was performed retrospectively, there was no standardized period between vaccinations and antibody testing in all patients. Although this reflects the real-world quality of our data, this might cause a bias. Second, the small number of patients does not allow direct comparison between treatment groups. Third, lack of a control group limits the interpretation of the data.

In summary, we report excellent immune responses and tolerability to SARS-CoV-2 vaccinations in a cohort of patients with POMS without treatment or IM-DMT. Immune responses were attenuated in patients treated with IS-DMT such as anti-CD20 B-cell-depleting therapies or FGL. Monitoring of B-cell repopulation can help to establish a favorable immune response to vaccination in these patients.

Supplementary data

Supplementary Figure 1.

Rate of adverse events (%) after 1^st, 2^nd, and 3^rd SARS-CoV-2 vaccine dose in 30 patients with pediatric-onset multiple sclerosis (POMS).