Безопасность персонала COVID-19 Вакцины у пациентов с множественным склерозом: перекрестное исследование из центра третьей реабилитации в Саудовской Аравии.

Introduction

Multiple sclerosis (MS) is a demyelinating neurodegenerative disorder of unknown origin, presenting a variety of physical, cognitive, and sometimes psychiatric symptoms [ 1 ]. In 2020, the estimated prevalence of MS in Saudi Arabia was approximately 40.40 per 100,000 individuals [ 2 ]. The World Health Organization (WHO) Strategic Advisory Group of Experts on Immunization (SAGE) has reaffirmed its prior recommendations regarding COVID-19 vaccination and the necessity of revaccination for high-risk groups [ 3 ]. Although many COVID-19 vaccines are deemed safe, some have been associated with significant adverse effects (AEs), particularly thrombotic events and anaphylaxis [ 4 ].

The National Multiple Sclerosis Society and other organizations advocate for COVID-19 vaccination in all MS patients, despite prevalent concerns and misconceptions contributing to vaccine hesitancy in this population [ 5 ]. Previous research highlighted the potential for increased reactogenicity in MS patients post-vaccination, particularly among younger individuals and those on disease-modifying therapies (DMTs) [ 6 ]. While several studies indicate that vaccine responses in MS patients are comparable to those in healthy individuals, the variability in immune response and a lack of extensive clinical trials necessitate a deeper understanding of the safety and efficacy of COVID-19 vaccines in this patient population [ 2 , 4 , 6 - 9 ].

Sultan Bin Abdulaziz Humanitarian City (SBAHC) in Riyadh serves as a major rehabilitation facility for patients with various disabilities and neurological disorders [ 10 ]. Limited data exists regarding the safety profile of COVID-19 vaccines for MS patients in Saudi Arabia [ 2 , 4 ], prompting the present study to investigate AEs reported by MS patients admitted to this tertiary rehabilitation center.

Materials and methods

Study design and setting

SBAHC is a prominent rehabilitation hospital that treats patients with various disabilities and neurological disorders, including adults and children. This cross-sectional analysis was conducted at SBAHC between January 2023 and January 2024.

Study population

All MS patients admitted for rehabilitation or receiving outpatient follow-up registered in the facility's electronic medical records were eligible for enrollment (n=124). Participants were approached for face-to-face or phone interviews to complete a questionnaire concerning their COVID-19 vaccination status, demographic details, clinical history, and any AEs experienced post-vaccination. AEs included both local and systemic reactions following each vaccine dose. The AEs were graded according to the FDA’s Toxicity Grading scale as follows: grade 1 (mild), grade 2 (moderate), grade 3 (severe), and grade 4 (serious or life-threatening). Patients with cognitive disabilities (n=6) or those unwilling to participate (n=10) were excluded.

Ethical considerations

All patients gave their informed consent, and the study was approved by the SBAHC Institutional Review Board (Number 65-2022-IRB).

Statistical analysis

Data analysis was performed using SPSS Statistics Software version 27.0 (IBM Corp., Armonk, NY, USA). Chi-square tests were used to compare characteristics of study subjects and the incidence of reactions or side effects following COVID-19 vaccination. Binary logistic regression analysis assessed the correlation between sociodemographic and clinical variables with vaccine side effects. A p-value of <0.05 was considered statistically significant.

Results

Demographic and clinical data

The study included 108 participants, comprising 58 males (53.7%) and 50 females (46.3%), with a mean age of 38.8 ± 9.7 years (range 17-66 years). The relapsing-remitting subtype was most common (n=53, 49%), followed by primary progressive (n=27, 25%) and secondary progressive (n=22, 20.4%). Fourteen (13%) participants had comorbid medical conditions, while 60 (55.6%) out of 108 were undergoing treatment. Comorbid medical conditions were hypertension, diabetes mellitus, and coronary heart disease in six (5.5%), four (3.7%), and three (2.7%) patients, respectively (Table 1 shows these demographics).

Table 1 Demographic and clinical characteristics of the enrolled subjects (n=108) MS, multiple sclerosis
Item

No (%)

Age (years)

Median, range

37.5, 17-66

Mean ± SD

38.8 ± 9.7

Gender

Male

58 (53.7)

Female

50 (46.3)

Marital status

Single

28 (26)

Married

68 (63)

Divorced

12 (11)

Type of MS

Primary progressive

27 (25.0)

Relapsing-remitting

53 (49.0)

Secondary progressive

22 (20.4)

Clinically isolated syndrome

3 (2.8)

Radiologically isolated syndrome

1 (0.9)

Unknown

2 (1.9)

Duration of MS (years)

Mean ± SD

13.7 ± 6.7

Range

2-29

Past history of MS relapse

No

73 (67.5)

Yes

15 (14.0)

Unknown

20 (18.5)

Medical comorbidities

No

94 (87.0)

Yes

14 (13.0)

COVID-19 vaccination

No

8 (7.4)

Yes

100 (92.6)

Current MS treatment

Yes

60 (55.6)

No/unknown

48 (44.4)

Previous adverse effects of injections other than COVID-19 vaccine

Yes

12 (11.0)

No

73 (67.5)

Unknown

23 (21.5)

Demographic and clinical characteristics of the enrolled subjects (n=108)

MS, multiple sclerosis

Motor symptoms, such as difficulties with walking, spasticity, and hand function, were reported by 79 (73%) of 108 patients, with sensory symptoms (n=68, 63%) and fatigue (n=66, 61.1%) also prevalent. Many patients reported multiple symptoms.

Safety profile and adverse events of the given COVID-19 vaccines

A total of 100 (92.6%) patients received one or more COVID-19 vaccine doses. The BNT162b2 mRNA vaccine from Pfizer-BioNTech was the most frequently administered (n=58, 53.7%), followed by the ChAdOx1 nCoV-19 vaccine from Oxford-AstraZeneca (n=41, 38.0%) and Moderna (n=1, 0.9%) (Figure 1 ).

Types of COVID-19 vaccines given

Five (4.6%) patients received a single vaccine dose, while 27 (25.0%) and 56 (52.0%) received two and three doses, respectively. Adverse events were reported by 56 (52%) participants within two days (n=88, 81%) and up to one week (n= 8, 7%), with common reactions including headache (n=41, 38%), pain or tenderness (n=82, 76%), fatigue (n=72, 66.7%), fever (n=63, 58%), and muscle aches (n=68, 63%). Most reported AEs were mild (n=79, 73.3%), while moderate and severe AEs were noted in 27 (24.7%) and 3 (2.0%) subjects, respectively. Two (1.8%) patients experienced MS relapses within two days post-vaccination. They was one 58-year-old female who had MS relapse after receiving the second dose of Oxford-AstraZeneca vaccine. She was on teriflunomide. She had MS for 18 years and experienced MS one time before. The second patient was a 32-year-old male who had MS relapse after receiving the third dose of the Pfizer-BioNTech vaccine. He was on rituximab. He had MS for eight years and had no history of relapse before. Both patients needed to visit their neurologist for this relapse. Six (5.0%) patients reported worsening of pre-existing MS symptoms, which were transient and related to mild fever (Table 2 ).

Table 2 Adverse effects or reactions of COVID-19 vaccines (n=302)* *This represents the total number of reactions or adverse effects, not the patients  MS, multiple sclerosis
Variable

No (%)

Immediate allergic reaction

2 (0.6)

Pain, soreness, or tenderness at the injection site

82 (27.0)

Fever

63 (20.8)

Dizziness

33 (11.0)

Chills

10 (3.0)

Fatigue

72 (23.8)

Headache

41 (13.5)

Muscle aches

68 (22.5)

Malaise

75 (24.8)

Joint pain

22 (7.0)

Shortness of breath

9 (3.0)

Redness (injection site)

33 (11.0)

Swelling (injection site)

16 (5.0)

Itching (injection site)

12 (4.0)

Menstrual cycle changes

2 (0.6)

Nausea

4 (1.0)

MS relapse

2 (0.0)

Worsening of pre-existing MS symptoms

16 (5.0)

None

46 (15.0)

Adverse effects or reactions of COVID-19 vaccines (n=302)*

*This represents the total number of reactions or adverse effects, not the patients

MS, multiple sclerosis

Association between the vaccines’ adverse events and the clinical/demographic characteristics

The study evaluated the correlation between patient characteristics (age, gender, MS type and duration, comorbidities, and previous relapses), vaccine-related factors (vaccine type and doses), and AEs. The Oxford-AstraZeneca vaccine showed a significant association with a higher incidence of AEs (39/56, 70.0%) compared to other vaccines (p < 0.001). Other factors such as age, gender, MS type, number of doses, and treatment for MS did not display significant associations with vaccine AEs (Table 3 ).

Table 3 Association between the COVID-19 vaccine adverse events and clinical/demographic variables *A p-value of <0.05 is considered statistically significant MS, multiple sclerosis
Variable

Adverse effects of COVID-19 vaccines

p-Value*

 

Yes (no %)

No (no %)

 

 

56 (52%)

52 (48%)

 

Age groups

<30 years

10 (18)

7 (13)

0.603

≥30 years

46 (82)

45 (87)

Gender

Males

29 (52)

29 (56)

0.703

Females

27 (48)

23 (44)

Type of MS

Primary progressive

15 (27)

12 (23)

0.494

Relapsing-remitting

27 (48)

26 (50)

Secondary progressive

10 (18)

12 (23)

Clinically isolated syndrome

3 (5)

0 (0)

Radiologically isolated syndrome

0 (0)

1 (2.0)

Unknown

1 (2)

1 (2.0)

MS duration

<15 years

30 (53.5)

29 (56)

0.849

≥15 years

26 (46.5)

23 (44)

Doses of COVID-19 vaccines

One

4 (7)

1 (2)

0.595

Two

13 (23)

14 (27)

Three

28 (50)

28 (54)

No/unknown

11 (20)

9 (17)

Type of the vaccine

Pfizer-BioNTech

17 (30)

41 (79)

 0.001

Oxford-AstraZeneca

39 (70)

2 (4)

Moderna

0 (0)

1 (2)

No/unknown

0 (0)

8 (15)

Comorbidities

Yes

10 (18)

4 (8)

0.155

No

46 (82)

48 (92)

Previous MS relapse

Yes

10 (18)

5 (10)

0.264

No

34 (61)

39 (75)

Unknown

12 (21)

8 (15)

MS treatment

Ocrelizumab

9 (16)

15 (29)

0.165

Dimethyl fumarate

5 (9)

0 (0)

Terifluonomide

3 (5)

1 (2)

Rituximab

3 (5)

3 (6)

Beta-interferons

4 (7)

7 (13)

Fingolimod

3 (5)

1 (2)

Almetuzumab

0 (0)

1 (2)

Glatiramer acetate

1 (2.5)

0 (0)

Natalizumab

1 (2.5)

3 (6)

No/unknown

27 (48)

21 (40)

Association between the COVID-19 vaccine adverse events and clinical/demographic variables

*A p-value of <0.05 is considered statistically significant

MS, multiple sclerosis

Binary logistic regression analysis identified the Oxford-AstraZeneca vaccine as the sole significant factor linked to COVID-19 vaccination AEs (odds risk 5.337, p< 0.001) (Table 4 ).

Table 4 Association between the COVID-19 vaccine adverse events and clinico-demographic variables (binary logistic regression analysis) *A p-value of <0.05 is considered statistically significant OR, odds ratio; MS, multiple sclerosis Variable OR (95% confidence interval) p-Value* Age group (≥30 years) 0.236 (0.030–1.862) 0.171 Gender (female) 0.764 (0.330–1.761) 0.562 Type of the vaccine (AstraZeneca) 5.337 (0.022–18.980) <0.001 Number of doses of the vaccine  1.272 (0.534–3.029) 0.587 Comorbidities (yes) 0.864 (0.046–1.687) 0.164 Type of MS 0.779 (0.435–1.395) 0.400 Duration of MS 0.867 (0.647–1.161) 0.337 Previous MS relapse (yes) 0.554 (0.282–1.092) 0.088

Association between the COVID-19 vaccine adverse events and clinico-demographic variables (binary logistic regression analysis)

*A p-value of <0.05 is considered statistically significant

OR, odds ratio; MS, multiple sclerosis

Discussion

This study aimed to evaluate the safety profile and AEs of COVID-19 vaccines in MS patients admitted or treated at a large rehabilitation center in Saudi Arabia. The clinical and demographic characteristics of the participants were consistent with typical profiles of MS patients globally, with the relapsing-remitting subtype being the most common. The mean age of participants was 38.8 ± 9.7 years, and the mean disease duration was 13.7 ± 6.7 years. More than half of the patients (55.6%) were actively receiving immunomodulatory therapy with various DMTs.

Only 14 (13.0%) of patients had medical comorbidities, which could be explained by the relatively young age of enrolled subjects. Moreover, the symptoms of enrolled subjects align with the previously reported and known figures for autonomic, visual, motor, and sensory problems [ 1 ]. Also, 66 (61.0%) of our cohorts reported that fatigue was a predominant symptom at presentation, which agrees with previous studies [ 11 ].

Of our enrolled cohorts, 52% experienced one or more adverse events after the administration of the COVID-19 vaccines. This is typically similar to those figures reported previously [ 12 , 13 ]. In a recently published meta-analysis of 19 observational studies comprising 14,755 MS patients who received 23,088 COVID-19 vaccines, Stefanou et al. [ 13 ] observed that adverse events were reported in 52.8% of MS patients. However, our reported COVID-19 vaccine-related AEs are less than those reported by studies from Saudi Arabia [ 2 ] and Kuwait [ 9 ]. This might be attributable to the differences in enrolled subjects' number, clinical and demographic characteristics, and the effects of the currently used DMTs.

Importantly, our reported rates of vaccine-related AEs are similar to those rates reported from the normal population [ 14 , 15 ], real-life studies on MS patients [ 16 ], and MS patients who used other vaccinations [ 17 ]. Therefore, these findings suggest that patients with MS did not have a higher risk for vaccine-induced adverse events. Local reactions such as redness, pain, and swelling at the injection site were the most common encountered local adverse events [ 14 , 15 ].

In our MS cohort, fatigue was reported in 72 (76.0%), headache in 41 (38.0%), and pain, soreness, or tenderness in 82 (76.0%). Our results agree with those of Achiron et al. [ 18 ], who reported fatigue in 20% of patients and headache in 9% of patients with MS. Notably, most reported adverse events in our cohorts were mild.

Six (5%) of our participants reported worsening of pre-existing MS symptoms following the vaccination. This concurred with the results by Alroughani et al. [ 9 ]. However, our results are lower than those of Lotan et al. [ 16 ], who reported a 15% worsening of MS symptoms. The low rate of worsening pre-existing MS symptoms, in addition to its overall mild severity, supports previous studies on other non-live-attenuated vaccines that were not related to an increased risk of worsening MS symptoms [ 19 ].

We reported MS relapse in two (1.8%) cases after receiving the second dose of Oxford-AstraZeneca and the third dose of Pfizer-BioNTech. Alroughani et al. [ 9 ] reported MS relapse in five (1.3%) cases shortly after the first dose of the vaccine, three cases after Pfizer-BioNTech, and two cases after Oxford-AstraZeneca vaccines. Similarly, Maniscalco et al. [ 20 ] reported a female patient presented with weakness in her left side of the body and paresthesia two days after receiving the mRNA COVID-19 vaccine.

The association between the patient's clinical characteristics, vaccine-related factors, and the AEs of COVID-19 vaccination revealed interesting results.

The Oxford-AstraZeneca vaccine was significantly associated with a higher incidence of adverse events (70%) than the other vaccines. Other factors, such as age, gender, type of MS, number of COVID-19 vaccine doses, and treatment for MS, were not significantly associated with AEs of COVID-19 vaccines. The type of vaccine (manufactured by Oxford-AstraZeneca) was the only significant factor associated with AEs of COVID-19 vaccination (odds risk 5.337, p< 0.001).

This was consistent with the findings of the recent Saudi study by Aladdin et al. [ 2 ]. Similarly, Briggs et al. [ 6 ], in a large study involving 718 patients, found a higher prevalence in patients receiving the Oxford-AstraZeneca vaccine compared to those who received Pfizer-BioNTech and mRNA-1273 SARS-CoV-2 vaccines.

Notably, our results were similar to those of Aladdin et al. [ 2 ] and Alroughani et al. [ 9 ], denoting no significant association between the adverse events of the COVID-19 vaccines and the use of DMT. Previous studies observed that COVID-19-vaccinated MS patients can develop protective humoral responses [ 21 ].

The current study's results showed that COVID-19 vaccines were tolerated in our cohorts with MS, and the side effects were comparable to those reported in other countries [ 9 , 12 , 13 , 16 , 18 , 22 ]. The results of the current study could have important clinical implications.

Given the tolerability and acceptable side effects of COVID-19 vaccines, together with the negative impacts of COVID-19 and its long-term sequelae on patients with MS, patients with MS are highly encouraged to receive COVID-19 vaccines. Weighted against the risks of SARS-CoV-2-related complications and MS exacerbations, these safety data provide compelling pro-vaccination arguments for MS patients.

Our findings provide a piece of additional safety information related to COVID-19 vaccination in patients with this neurological disorder and support the given recommendations to encourage and not delay vaccination for the COVID-19 pandemic. Moreover, our study highlights the supportive analysis of the benefits/risk assessment against possible minor risks of COVID-19 vaccines in those patients actively using DMTs. More prospective multicenter studies should validate these findings to assess the longstanding sequelae of COVID-19 vaccines in MS patients.

Limitations

The study's limitations include its single-center design, which may restrict the generalizability of the results. Additionally, the analysis focused solely on short-term adverse events, with plans for future evaluations to assess long-term effects.

Conclusions

The findings indicate that the safety profile of COVID-19 vaccines in MS patients is comparable to the general population, with similar rates of minor, self-limiting AEs. The Oxford-AstraZeneca vaccine was significantly associated with a higher incidence of adverse events compared to other vaccines and was the primary independent factor linked to these effects. The results support the safety of COVID-19 immunization in MS patients and advocate for timely vaccination against COVID-19. Further multicenter prospective studies are warranted to explore these findings comprehensively.

Acknowledgments

The authors thank the Sultan Bin Abdelaziz Humanitarian City Research Center team for their valuable contribution to data collection.

Disclosures

Human subjects: Consent for treatment and open access publication was obtained or waived by all participants in this study. Sultan Bin Abdelaziz Humantarian City Institutional Review Board issued approval 65-2022-IRB.

Animal subjects: All authors have confirmed that this study did not involve animal subjects or tissue.

Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following:

Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work.

Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work.

Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work.

Author Contributions

Concept and design:   Sherif Mohamed, Maaz A. Elkarim, Shuja'a A. Al-Jaberi

Drafting of the manuscript:   Sherif Mohamed, Maaz A. Elkarim, Shuja'a A. Al-Jaberi

Critical review of the manuscript for important intellectual content:   Sherif Mohamed, Maaz A. Elkarim

Supervision:   Sherif Mohamed

Acquisition, analysis, or interpretation of data:   Maaz A. Elkarim, Shuja'a A. Al-Jaberi

References