COVID-19 vaccination uptake in people with multiple sclerosis compared to the general population

Abstract

Objective

To determine the COVID-19 vaccine uptake among people with multiple sclerosis (pwMS) compared to the general population in Croatia.

Methods

Data from all pwMS entered in the MS Base register until March 24th, 2022 were extracted including age, sex, MS phenotype, disease-modifying therapy (DMT), and date of COVID-19 vaccination. Data on the general population of Croatia were obtained from the vaccination register of the Croatian Institute of Public Health.

Results

64.4% pwMS were fully COVID-19 vaccinated which was comparable to 66.3% of the general population. More pwMS were fully vaccinated in the age group 20–24 (74.1% vs 51.7%), and fewer pwMS were fully vaccinated in the age group 65–69 (33.3% vs 80.4%) compared to the general population of the same age group, respectively. PwMS who received at least one dose of any COVID-19 vaccine were older (40.5 vs 37.6 years, p = 0.01), had higher EDSS (2.0 vs 1.0, p = 0.025), and had longer disease duration (6.39 vs 5.35 years, p = 0.02), were more likely to have progressive disease course (p = 0.049) and were on high efficacy DMTs (p = 0.045) compared to unvaccinated pwMS. Longer disease duration positively predicted vaccine uptake.

Conclusion

Croatia has suboptimal COVID-19 vaccination uptake without a significant difference between the general population and pwMS.

Introduction

Although the rate of COVID-19 infection among people with multiple sclerosis (pwMS) seems to be similar to the general population, it has been suggested that pwMS are at higher risk for hospitalization due to COVID-19 infection [1]. Furthermore, certain risk factors such as progressive disease course, comorbidities, male sex, and anti-CD20 antibodies have been associated with the unfavorable outcome of COVID-19 infection in pwMS [2]. Despite the favorable data considering the efficacy and safety of COVID-19 vaccines [3–5], global willingness for vaccine uptake varied depending on the region of the world, age group, level of education, or income [6]. A recent systematic review and meta-analysis on willingness, unwillingness, and hesitancy to get COVID-19 vaccine in pwMS, which included 10 studies, found that pooled prevalence of willingness, unwillingness, and hesitancy to get COVID-19 vaccine was 76%, 2%, and 0%, respectively [7]. However the data on the actual frequency of COVID-19 vaccination in pwMS in comparison with the general population are missing. This study might help define specific factors influencing COVID-19 vaccine uptake among pwMS in certain regions such as Croatia which might improve future public health campaigns aiming at this population. We hypothesized that the rate of vaccination in pwMS is similar to the general population. Therefore, the present study aimed to assess the rate of COVID-19 vaccine uptake among pwMS in comparison to the general population of Croatia. Furthermore, we investigated differences between vaccinated and unvaccinated pwMS and explored factors associated with the vaccination status in pwMS.

Methods

The Population-Exposure-Comparator-Outcome (PECO) statement and data collection

This was a case–control study. The population included the cohort of consecutive Croatian pwMS entered in the MSBase registry database [8], site HR-001, from Sep 16, 2021, until the database lock on March 24th, 2022. Site HR-001 is the largest MS center in Croatia taking care of more than half of all pwMS in the country, therefore the included population is representative of the whole Croatian pwMS population. Inclusion criteria were diagnosis of MS, enrollment in the MS base register, and available vaccination status. Patient-level demographic and clinical data were extracted from MSBase registry including age, sex, MS phenotype, disease duration, EDSS at the last visit, currently used type of the disease-modifying therapy (DMT), COVID-19 infection. DMTs were categorized in the following way: injectable DMTs (interferon beta and glatiramer acetate), 1st line oral DMT (teriflunomide and dimethyl-fumarate), and high efficacy treatment (HET) (natalizumab, alemtuzumab, fingolimod, ocrelizumab, cladribine tablets, and siponimod). Diagnosis of MS and other demographic or clinical data was determined and entered into the MSBase registry by the treating neurologist.

The exposure was COVID-19 vaccination, including type of vaccine and date of vaccination (1st, 2nd and/or 3rd dose). The vaccination status of each pwMS in the MSBase register was entered by the treating neurologist. In order to approve data quality, and reduce missing data and bias, vaccination status (unvaccinated pwMS, pwMS with 1, 2, or 3 doses of the COVID-19 vaccine) was once again crossed checked against the national vaccination registry which is linked to the hospital electronic system by one of the co-authors (MKS). For all pwMS. All study participants were considered fully vaccinated if they received either two doses in any combination of BNT162b2 (Pfizer-BioNTech), mRNA-1273 (Moderna), and ChAdOx1 (Astra-Zeneca) or a single dose of Ad26.CoV2.S (Janssen).

Ethical approval was obtained from the Ethics committee of the University Hospital Center Zagreb. All patients gave written informed consent to be included in the registry for research and clinical purposes.

The comparator was vaccine uptake in the general population of Croatia. Data on the general population vaccination status were obtained on March 24th, 2022 from the publicly available vaccination register [9] conducted by Croatian Institute of Public Health. The estimated number of inhabitants in Croatia on March 24th, 2022 was based on preliminary data of the 2021 population census that are also publicly available [10]. Study participants were divided into different age groups: 15–19 years, 20–24 years, 25–29 years, 30–34 years, 35–39 years, 40–44 years, 45–49 years, 50–54 years, 55–59 years, 60–64 years, 65–66 years and > 70 years.

The primary objective of the study was to compare the rate of COVID-19 vaccine uptake between pwMS and the general population of Croatia. The secondary objectives were to investigate differences between vaccinated and unvaccinated pwMS and to explore factors associated with the vaccination status in pwMS.

Statistical analysis

Statistical analysis was performed using the IBM SPSS software, version 25, and the online tool for the Chi-square test [11]. The Kolmogorov–Smirnov test was used for the normality of the distribution. Differences in the distribution of qualitative variables were determined with the Chi-square test, while the differences in quantitative variables were determined with the use of an independent sample t-test or a non-parametric Mann–Whitney test. Univariable binary logistic regression model analysis was performed to see which variables are possible predictors for the likelihood that pwMS will be vaccinated (age, disease duration, EDSS at the last visit, DMTs). DMTs were divided into groups according to the type of the medications (treatment naïve, no DMT at the moment of analysis, injectable therapies, 1st line oral therapies, and high efficacy therapies (HET)). Medications from the HET group with a frequency higher than 10 were included as independent variables. Statistically significant variables were included in the multiple regression logistic model, to see which variables are statistically significant predictors for vaccination status. P values less than 0.05 were considered significant.

Results

Demographics

We identified 464 consecutive pwMS who fulfilled the inclusion criteria. 317 (68.3%) were females, with a median age of 38.1 (15.2–73.9) years, disease duration of 6.1 (0.03–48.4) years, and median EDSS 1.5 (0–7.5). The relapsing–remitting disease course was identified in 386 (83.2%) pwMS, 26 had (5.6%) primary progressive and 19 (4.1%) secondary progressive phenotypes, while 16 (3.4%) had a clinically isolated syndrome. Fifty-six (12.1%) pwMS were treatment naïve, 21 (4.5%) were not on DMT at the moment of the last visit, 134 (28.9%) were on injectable DMTs (interferon beta n = 89, glatiramer-acetate n = 45), 84 (18.1%) on 1st line oral DMTs (teriflunomide n = 44, dimethyl-fumarate 40), and 169 (36.4%) were on high efficacy DMTs (fingolimod n = 7, alemtuzumab n = 12, rituximab n = 1, cladribine n = 30, siponimod n = 13, ocrelizumab n = 91, natalizumab n = 15). COVID-19 infection was observed in 118 (25.4%) pwMS.

According to the data from the 2021 population census [10], on March 24th, 2022 there were 2,973,709 inhabitants in Croatia in the age range from 15 to 74 years.

The proportion of participants within each age range group of the Croatian pwMS cohort and the Croatian population is shown in Fig. 1.

Fig. 1.

Age ranges and proportion of all participants within each age range group

COVID-19 vaccine uptake between pwMS and the general population

The frequency of vaccination uptake between pwMS and the general population was similar: 64.4% pwMS (N = 299) were fully COVID-19 vaccinated compared to 66.2% (N = 1,970,060) of the general population (Fig. 2). Similarly, 67.5% (N = 313) pwMS received at least one dose of the COVID-19 vaccine compared to 68.5% (N = 2,035,939) of the general population. The third booster dose was received by 22.4% pwMS (N = 104) which was comparable to 23.7% (N = 703,854) of the general population. Only 5.4% (N = 25) of pwMS were vaccinated with a combination of different vaccines (the most frequent combination was Vaxzevria^® and Comirnaty^®), while all others were vaccinated with the same vaccine type. Furthermore, one dose of COVID-19 vaccine that is given in two doses was received by 3.0% of pwMS (1 Vaxzevria^®, 2 Spikevax^® and 11 Comirnaty^®).

Fig. 2.

The proportion of fully vaccinated participants within each age range group

More pwMS were fully vaccinated in the age group 20–24 (74.1% vs 51.7%), and fewer pwMS were fully vaccinated in the age group 65–69 (33.3% vs 80.4%) compared to the general population of the same age group, respectively. A comparison of the proportion of participants in each age group for the Croatian MSBase cohort and the Croatian population is shown in Fig. 2.

Differences between vaccinated and unvaccinated pwMS and factors associated with the vaccination status in pwMS

Differences between pwMS who received at least one dose of any COVID-19 vaccine and unvaccinated pwMS are presented in Table 1. pwMS who received at least one dose of any COVID-19 vaccine were older, had higher EDSS, had longer disease duration, were more likely to have progressive disease course and were more frequently on high efficacy DMTs compared to unvaccinated pwMS.

Table 1.

Differences between pwMS who received at least one dose of any COVID-19 vaccine and unvaccinated pwMS

	Vaccinated MS population, N = 313	Unvaccinated MS population, N = 151	P value
Sex (female, N (%))	212 (67.7%)	105 (69.5%)	0.750
Age (years)	40.5 ± 11.1	37.6 ± 11.2	0.010
Disease duration (years)	6.38 (0.12–48.35)	5.35 (0.03–24.22)	0.020
EDSS at last MSBase entry	2 (0–7.5)	1 (0–6.5)	0.025
MS phenotype (N (%))			0.049
CIS	13 (4.2%)	3 (2%)
RRMS	252 (80.5%)	134 (88.7%)
SPMS	14 (4.5%)	5 (3.3%)
PPMS	23 (7.3%)	3 (2%)
DMTs (N (%)) at last MSBase entry			0.045
Treatment naïve	32 (10.2)	24 (15.9)
No DMT	12 (3.8)	9 (6)
INJ	87 (16.9)	47 (31.1)
1st line oral DMT	53 (41.2)	31 (20.5)
HET	129 (89.8)	40 (26.5)

EDSS Expanded Disability Status Scale, CIS clinically isolated syndrome, RRMS relapsing–remitting multiple sclerosis, PPMS primary progressive multiple sclerosis, SPMS secondary progressive multiple sclerosis, NO DMT not on disease-modifying treatment at the moment of the last visit, INJ injectable DMTs; interferon beta and glatiramer acetate, 1st line oral DMT-teriflunomide, dimethyl-fumarate, HET high efficacy treatment

Results of the univariable and multivariable regression analysis investigating possible predictors of COVID-19 vaccine uptake in pwMS are presented in Table 2. In the univariable model older age, longer disease duration, higher EDSS, primary progressive disease phenotype, being on HET in general, and being on ocrelizumab increased the likelihood of vaccine uptake. In a multivariable logistic regression model only longer disease duration positively predicted vaccine uptake (Exponent B = 1.041, 95% C.I. for Exp (B) = 1.000–1.082, p = 0.048).

Table 2.

Results of the univariable and multivariable regression model for predicting vaccination status

	Univariable logistic regression			Multivariable logistic regression
	OR	95% C.I. for OR	p value	OR	95% C.I. for OR	p value
Vaccination status
Age (years)	1.024	1.006–1.043	0.011	1.009	0.987–1.032	0.438
Sexa	0.920	0.604–1.399	0.695
Disease duration (years)	1.048	1.014–1.082	0.005	1.041	1.000–1.082	0.048
EDSS	1.161	1.034–1.303	0.012	1.050	0.903–1.220	0.527
Disease courseb
PPMS	4.077	1.202–13.826	0.024	2.550	0.635–10.234	0.187
SPMS	1.489	0.525–4.223	0.454	0.722	0.207–2.522	0.610
RIS or CIS	2.304	0.645–8.228	0.199	3.008	0.830–10.900	0.094
Treatment naïve	0.603	0.342–1.065	0.081
No DMT	0.629	0.259–1.527	0.306
INJ	0.852	0.557–1.302	0.459
ORAL 1st line	0.789	0.482–1.292	0.346
HET	1.946	1.271–2.978	0.002
Natalizumab	1.339	0.419–4.275	0.623
Ocrelizumab	1.783	1.047–3.036	0.033	1.365	0.744–2.505	0.315
Cladribine	2.535	0.951–6.758	0.063
Siponimod	1.088	0.330–3.591	0.890
Alemtuzumab	0.668	0.208–2.140	0.497

Bold indicates statistically significant results

OR odds ratio, C.I. confidence interval, EDSS Expanded Disability Status Scale, RIS radiologically isolated syndrome, CIS clinically isolated syndrome, RRMS relapsing–remitting multiple sclerosis, PPMS primary progressive multiple sclerosis, SPMS secondary progressive multiple sclerosis, NO DMT not on disease modifying treatment at the moment of the last visit, INJ injectable therapies; interferon beta and glatiramer acetate, oral 1st line-teriflunomide, dimethyl-fumarate, HET high efficacy treatment

^aMale sex is reference category

^bRRMS is reference category

Discussion

The Croatian population is suboptimally vaccinated against COVID-19. As of July 21st, 2022, only 57% of the Croatian population regardless of age has received at least one dose of a COVID-19 vaccine compared to 66.8% of the world population [12]. Identified factors that might influence the suboptimal vaccination rate in Croatia is a limited level of pre-vaccination COVID-19 vaccine literacy in the Croatian adult population [13]. A study that included 1227 participants, lower education level, lower age, employment status (participants who were employed), presence of chronic diseases, medication use, or daily alcohol consumption were associated with a lower level of vaccine literacy.

In the present study, we did not find any differences between COVID-19 vaccine uptake among people with a chronic disorder, namely MS, and the general population. Although we did not investigate education, employment, and socioeconomic status, one can extrapolate these data on the pwMS population, as chronic diseases were associated with a lower level of pre-vaccination COVID-19 literacy in adult Croatian population [13].

Several studies on other chronic immune-mediated inflammatory diseases showed similar results [14, 15]. Similar to our study, individuals with chronic immune-mediated inflammatory diseases in the youngest age group initially had earlier uptake than the corresponding age grouop of the general population. Age-related associations with potential vaccine acceptance have been detected in a global survey of vaccine willingness in the general population. In that study people aged 18–24 were less likely to accept the vaccine than those who were aged 25–54, 55–64, and 65+ [6]. This data is in discordance with our findings and might imply that having a chronic disorder like MS might influence younger people’s decision on vaccine uptake.

Three survey-based studies assessed actual COVID-19 vaccine uptake in pwMS, and the vaccine uptake ranged from 84.6 to 87.8% [16–18]. These are significantly larger percentages compared to our study. Global variations in vaccine uptake are country-dependent and factors that influence vaccine decisions include also socioeconomic characteristics and individual perceptions of vaccine efficacy and safety, all of which may explain the lower vaccination rate in Croatia [19].

In our pwMS cohort vaccinated individuals were older, had higher EDSS, had longer disease duration, were more likely to have progressive disease phenotype, and were more frequently on high efficacy DMTs compared to unvaccinated pwMS. The only independent predictor of COVID-19 vaccine uptake was a longer disease duration. Similar findings were observed in the other two studies investigating differences between vaccinated and unvaccinated pwMS [16, 17]. Older age, being on DMTs and progressive disease course were associated with increased odds, while younger age and having untreated MS with decreased odds of vaccine uptake. Furthermore, pwMS who were not planning to receive the vaccine were more worried about MS worsening than COVID-19 and warier of vaccine safety/side effects [17].

The limitations of our study are that socioeconomic, educational, and psychological factors influencing vaccine decisions were not assessed. Furthermore, we haven’t explored the reasons why participants did not choose to receive the COVID-19 vaccine. The reason for this lies in the methodology, where demographic and disease-specific determinants of vaccine uptake of our MS cohort were obtained from the MSBase registry with a well-defined minimum dataset [20]. The strength of the study is the comparison with the general population, which gives us insight into similarities and differences in the COVID-19 vaccination uptake in people with chronic diseases like MS.

In conclusion, there is suboptimal COVID-19 vaccination uptake in Croatia without a significant difference between the general population and pwMS, although Croatian national policy regarding COVID-19 vaccination uptake emphasized that vaccination is especially recommended to people with chronic disorders and elderly individuals [21]. Bearing in mind that COVID-19 vaccination uptake changes with COVID-19 risk [22] and that attitudes among pwMS might have changed within the last 12 months we recommend that special emphasis should be put on younger patients with shorter disease duration and relapsing disease phenotype as well as on those who are not receiving HET, since they might be more COVID-19 vaccine-hesitant.

Author contributions

Study concept and design: MH. Acquisition of data: DM, BB, KL, SL, TG, MKS, MH. Analysis and interpretation of data: DM, BB, KL, SL, TG, MKS, MH. Drafting of the manuscript: BB. Critical revision of the manuscript for important intellectual content: DM, BB, KL, SL, TG, MKS, MH. Administrative, technical, and material support: DM, BB, KL, SL, TG, MKS, MH.

Funding

No funding was received for this study.

Data availability statement

The data that support the findings of this study are available from the corresponding author upon reasonable request.

Declarations

Conflict of interest

DM: Nothing to disclose. BB: Participated as a clinical investigator and/or received consultation and/or speaker fees from: Biogen, Sanofi Genzyme, Merck, Bayer, Novartis, Pliva/Teva, Roche, Alvogen, Actelion, Alexion Pharmaceuticals. KL: Nothing to disclose. SL: Nothing to disclose. IA: Participated as a clinical investigator and/or received consultation and/or speaker fees from: Biogen, Sanofi Genzyme, Merck, Bayer, Novartis, Pliva/Teva, Roche, Alvogen, Actelion, Alexion Pharmaceuticals, TG Pharmaceuticals. TG: Participated as a clinical investigator and/or received consultation and/or speaker fees from: Biogen, Sanofi Genzyme, Merck, Bayer, Novartis, Pliva/Teva, Roche, Alvogen, Actelion, Alexion Pharmaceuticals. MKS: received consultation and/or speaker fees from: Sanofi Genzyme, Roche. MH: Participated as a clinical investigator and/or received consultation and/or speaker fees from: Biogen, Sanofi Genzyme, Merck, Bayer, Novartis, Pliva/Teva, Roche, Alvogen, Actelion, Alexion Pharmaceuticals, TG Pharmaceuticals.