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RESEARCH ARTICLE OPEN ACCESS
Effect of the Number of Vaccine Doses Before Starting
Anti-CD20 Therapy on Seroprotection Rates Against
Hepatitis B Virus in People With MS
Ren´
e Carvajal,
1,
* David Guananga-´
Alvarez,
2,
* Carmen Tur,
1
Juliana Esperalba,
3,4
Marta Rodr
´
ıguez-Barranco,
1
Ariadna Rando-Segura,
3,5
Blanca Borras-Bermejo,
2
Alvaro Cobo-Calvo,
1
Pere Carbonell-Mirabent,
1
Ricardo Zules-Oña,
2,6
Jose Angel Rodrigo-Pendas,
2
Xavier Mart
´
ınez-G´
omez,
2
Xavier Montalban,
1,7
Mar Tintore,
1,7,
†and Susana Otero-Romero
2,
†
Neurology®2025;104:e210281. doi:10.1212/WNL.0000000000210281
Correspondence
Dr. Carvajal
rcarvajal@cem-cat.org
Abstract
Background and Objectives
Hepatitis B vaccination (HBV) requires 6 months to complete and is recommended for
patients with multiple sclerosis (PWMS), particularly those who are candidates for anti-CD20
therapy. However, limited data exist on HBV immunogenicity in PWMS receiving disease-
modifying therapies (DMTs) and the impact of starting anti-CD20 therapy during immuni-
zation. We aimed to evaluate HBV immunogenicity in PWMS starting anti-CD20 therapy
during vaccination, focusing on the number of doses received before anti-CD20 initiation.
Methods
We conducted a retrospective analysis of a prospective cohort of adult PWMS at a single center
in Spain, from April 2015 to May 2023. Eligible participants completed a 4-dose HBV course
and underwent postvaccination serologic testing. We assess seroprotection rates (SRs), defined
as the percentage of patients achieving anti-hepatitis B surface antibody titers ≥10 IU/L,
focusing on those who switched to anti-CD20 therapy during vaccination, based on doses
received before starting anti-CD20 and type of DMT at vaccination start. A multivariate
generalized linear model (GLM) was used to identify factors associated with higher
seroconversion.
Results
A total of 289 PWMS (median [interquartile range (IQR)] age, 47.7 [42.8–54.4] years; 65.7%
female; median [IQR] disease duration, 14.8 [6.7–21.2] years) were included. SRs pro-
gressively declined with fewer doses before anti-CD20 initiation, from 92.8% (95% CI
87.1–96.5) for 4 doses to 24.0% (95% CI 9.4–45.1) for 1 dose. Patients transitioning from
sphingosine 1-phosphate (S1P) modulators showed the lowest SR at 25.0% (95% CI 7.3–52.4).
The multivariate GLM confirmed these findings, with 3 doses (SR ratio 3.23 [95% CI
1.68–6.23]; p= 0.0005) or 4 doses (SR ratio 3.76 [95% CI 1.96–7.24]; p< 0.0001) before anti-
CD20 therapy significantly associated with higher SRs, while starting S1P modulators at vac-
cination onset was significantly associated with lower SRs (SR ratio 0.42 [95% CI 0.23–0.78];
p= 0.0058). Female sex (SR ratio 1.15 [95% CI 1.01–1.32]; p= 0.0389) and younger age (SR
ratio 0.90 [95% CI 0.83–0.97]; p= 0.0036) were also significantly associated with higher SRs.
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Class of Evidence
Criteria for rating
therapeutic and diagnostic
studies
NPub.org/coe
*These authors contributed equally to this work as co-first authors.
†These authors contributed equally to this work as co-senior authors.
1
Department of Neurology-Neuroimmunol ogy and Multiple Sclerosis Centre of Catalo nia (Cemcat), Hospital Universitari Va ll d’Hebron, Universitat Aut`
onoma de Barcelona, Spain;
2
Department of Preventive Medicine an d Epidemiology, Hospital Universitar i Vall d’Hebron, Universitat Aut`
onoma de Barcelona, Spain;
3
Department of Microbiology, Hospital
Universitari Vall d’Hebron, Universitat Aut `
onoma de Barcelona, Spain;
4
CIBER de Enfermedades Infecciosas (CIBERI NFEC), Spain;
5
CIBER de Enfermedades Hep´
aticas y Digestivas
(CIBEREHD), Instituto de Salud Carlos III, Madrid, Spain;
6
Department of Preventiva Medicine, Hos pital Universitari de Girona Dr. Josep Tru eta, Spain; and
7
Faculty of Medicine,
University of Vic-Central University of Cata lonia (UVic-UCC), Vic/Manresa, Catalo nia, Spain.
The Article Processing Charge was funded by Instituto de Salud Carlos III (ISCIII) through the project PI19/01606 and co-funded by the European Union.
This is an open access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to
download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal.
Copyright © 2025 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.
e210281(1)
Discussion
Initiating anti-CD20 therapy during HBV negatively affects SRs, with a direct correlation with the number of doses received
before anti-CD20 initiation. Early planning and execution of required vaccinations are crucial in managing PWMS.
Classification of Evidence
This study provides Class III evidence that HBV during initiation of anti-CD20 therapy is less effective in establishing
seroprotection to hepatitis B than in patients in whom HBV is completed before initiation of anti-CD20 therapy.
Introduction
Immunization is a pivotal component of the risk management
strategies in patients with multiple sclerosis (PWMS).
1-3
Yet, its
effectiveness may be compromised because of exposure to
disease-modifying therapies (DMTs) that can potentially blunt
vaccine responses. Highly effective DMTs, notably sphingosine
1-phosphate (S1P) modulators and anti-CD20 therapies, have
demonstrated a reduction in immune responses to commonly
administered vaccines, including influenza,
4
pneumococcal,
5
and, more recently, coronavirus disease 2019 (COVID-19).
6
However, limited data are available for vaccines with longer
schedules, such as hepatitis B.
7
The hepatitis B vaccination (HBV) is a recombinant non-
infectious subunit viral vaccine recommended for PWMS who
do not have immunity against hepatitis B, especially those with
risk factors,
8
such as patients undergoing anti-CD20 therapy.
9-12
This is particularly important because there have been reports of
severe and fatal fulminant hepatitis in patients with de novo
hepatitis B infection while receiving anti-CD20 therapies.
13
Recommended HBV regimens involve 4 doses over an usual
6-month period (administered at 0, 1, 2, and 6–12 months).
14
HBV has an accepted protection correlate based on the level
of anti-hepatitis B surface antibodies (anti-HBs), and patients
are considered seroprotected if postvaccination titers are over
10 IU/L a threshold
15
because they strongly correlate with the
effective prevention of both acute hepatitis B infection and
chronic liver disease.
14,15
Current guidelines recommend completing vaccination with
inactivated vaccines at least 2 weeks before initiating treat-
ment to ensure a protective response.
9,10,16
However, this
recommendation poses challenges, particularly for highly ac-
tive patients, because it may entail a prolonged delay in
treatment onset in the case of vaccines with multiple-dose
schedules, such as HBV.
This study evaluated the effectiveness of HBV immunization
in PWMS who initiate anti-CD20 therapy during the vacci-
nation series, specifically assessing how the number of HBV
doses received before anti-CD20 initiation influences sero-
protection rates (SRs).
Methods
Design and Study Population
This study was conducted within the ongoing prospective co-
hort established in 1995 at the Multiple Sclerosis Centre of
Catalonia (Cemcat), as detailed in previous publications.
17-19
Starting in 2015, PWMS at Cemcat underwent routine referral
to the Preventive Medicine Department at Vall d’Hebron
University Hospital (HUVH) for baseline serostatus evaluation
and immunization in accordance with official guidelines.
For the purposes of this study, we included adult MS candi-
dates for HBV because of risk factors
8
and/or anticipated
initiation of anti-CD20 treatment who met the following
criteria: (1) completion of a 4-dose vaccination schedule for
HBV (administered at 0, 1, 2, and 6–12 months), within
a maximum span of 14 months between the first and last dose,
using either of the 2 recommended formulations (VHB 20 μg
adjuvanted or VHB 40 μg)
20
; (2) availability of a post-
vaccination serologic test measuring anti-HBs, performed
between 1 and 3 months after vaccination; and (3) not re-
ceiving anti-CD20 therapy before the beginning of the vac-
cination. The first vaccine dose was administered between
April 30, 2015, and April 30, 2022. Patients were followed up
until May 2023 to confirm the completion of the vaccination
course and postvaccination serology.
Standard Protocol Approvals, Registrations,
and Patient Consents
This study was approved by the clinical research ethics
committee at HUVH and followed the Strengthening the
Glossary
anti-HBs = anti-hepatitis B surface antibodies; COVID-19 = coronavirus disease 2019; DMT = disease-modifying therapy;
EDSS = Expanded Disability Status Scale; GLM = generalized linear regression model; IQR = interquartile range; OCR =
ocrelizumab; OMB = ofatumumab; PWMS = patients with multiple sclerosis; RTX = rituximab; S1P = sphingosine 1-
phosphate; HUVH = Vall d’Hebron University Hospital.
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Reporting of Observational Studies in Epidemiology report-
ing guideline. Databases have been developed according to
national and international standards on ethical aspects
(Declaration of Helsinki
21
and Declaration of Tokyo
22
). All
patients signed written informed consent according to the
Declaration of Helsinki.
21
Study Variables, Sources of Information,
and Outcomes
We collected data on demographics, clinical information,
vaccination history, and serologic test results. Demographic
data (such as sex and age) and clinical information had been
prospectively recorded in the Cemcat cohort database. We
extracted the date of the first clinical demyelinating episode,
disability status according to the Expanded Disability Status
Scale (EDSS) at the time of vaccination, and information
about the treatment received at the beginning and throughout
the vaccination course (including DMT start and stop dates)
from the Cemcat cohort database. Vaccination and serology
information was retrospectively collected from electronic
health records, including vaccine type, date, and dose, as well
as the date of serology and anti-HB titers. Serologic tests were
performed using the Atellica IM anti-hepatitis B surface
antigen 2.
23
Statistical Analysis
To assess the effect of DMTs on vaccine responses, we
established drug exposure for each DMT at the time of each
vaccination dose according to the drugs’mechanism of
actions.
10
Next, treatments were reclassified into 2 types
based on anticipated interference with vaccination responses,
according to current evidence: (1) high vaccine interference
(anti-CD20 monoclonal antibodies and S1P modulators) and
(2) low vaccine interference (first-line injectables [interferon-
βand glatiramer acetate], first-line orals [dimethyl fumarate
and teriflunomide], and natalizumab). In addition, we defined
2 groups of patients based on whether there was a change to
“anti-CD20”therapy during the course of vaccination.
A descriptive analysis was conducted, assessing absolute fre-
quencies and percentages for qualitative variables and
medians and interquartile ranges (IQRs) for quantitative
variables, because of the non-normal distribution of data. To
compare demographic and clinical characteristics at the time
of vaccination between groups, χ
2
tests were used for quali-
tative variables and Student tor Mann-Whitney Utests were
applied for quantitative variables, as appropriate.
We assessed the global SR, including 95% CIs calculated using
the exact Clopper-Pearson method. SR was defined as the
percentage of patients achieving an adequate humoral re-
sponse in the postvaccination serostatus evaluation, based on
the accepted cutofflevels for HBV (anti-HBs, 10 IU/L).
15
SRs
were calculated according to (1) type of DMT at the start
course of vaccination, (2) start of anti-CD20 therapy during
the course of vaccination, and (3) the number of vaccine
doses received before the start of anti-CD20. Furthermore,
postvaccination anti-HB median titers in seroprotected
patients were evaluated according to the number of vaccine
doses before anti-CD20 therapy.
A bivariate analysis was conducted to study the association
between anti-HB seropositivity and the rest of the de-
mographic, clinical, treatment, and vaccination variables. The
strength of association of the bivariate analysis was measured
through proportion ratios, whose 95% CIs were estimated
using Poisson regression models with robust variance and the
null hypothesis was tested bilaterally using the Wald test. A
multivariate generalized linear regression model (GLM) was
explored, using methodology analogous to that described
previously. For the inclusion of variables in the adjusted
model, those with marginal statistical significance in the bi-
variate analysis were considered (p< 0.10), as well as their
possible association with the outcome variable, according to
the literature. Nested models and interactions were evaluated
using the Wald test with sandwich covariance, applying a type
I error threshold of 5%. The statistical analysis was conducted
using version 4.3.2 of the R statistical software.
Data Availability
Anonymized patient data that support the findings of this
study are available on reasonable request from the corre-
sponding author. These data are not publicly available because
of privacy and ethical restrictions but can be shared with
qualified investigators for research purposes.
Results
A total of 977 PWMS were referred for vaccination evaluation
to the Preventive Medicine Department in the inclusion period.
Among them, 648 were identified as not having immunity
against hepatitis B and 348 completed a full immunization
schedule in our center using adjuvanted or high-load vaccines
during the study period. Of these, 59 were excluded because of
not fulfilling inclusion criteria (eFigure 1). A final cohort of 289
PWMS (median [IQR] age, 47.7 [42.8–54.4] years; 65.7%
female; median [IQR] disease duration; 14.8 [6.4–21.2] years;
median [IQR] EDSS score 3.5 [2.0–5.5]) met our inclusion
criteria and were included in the analysis. At the onset of vac-
cination, 140 (48.4%) were not receiving any DMT. The
remaining patients were on DMT, with most (19.4%) using
first-line injectables, followed by natalizumab (12.8%)
(Table 1). During the vaccination course, 151 PWMS (52.2%)
switched to anti-CD20 therapy while 138 (47.8%) did not.
Figure 1 illustrates the dynamic changes in DMT types
throughout the vaccination period. Of the 138 patients whodid
not switch to anti-CD20 during vaccination, 47 (34%) ulti-
mately changed after completing the full 4-dose vaccination
scheme, with a median (IQR) time of 321 (102.5–723.0) days.
Patients who started anti-CD20 therapy during the vaccina-
tion course, compared with those who did not, were older
(median [IQR] age, 49.0 [43.5–55.1] vs 46.5 [41.4–54.0]
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Table 1 Demographic and Clinical Characteristics at the Time of First Dose of the Hepatitis B Vaccine According to Change
to Anti-CD20 During the Vaccination
Characteristics Overall (N = 289) No change to anti-CD20 (N = 138) Change to anti-CD20 (N = 151) pValue
a
Sex, women, n (%) 190 (65.7) 95 (68.8) 95 (62.9) 0.3
Age, y, median (IQR) 47.7 (42.8–54.4) 46.5 (41.4–54.0) 49.0 (43.5–55.1) 0.032
Disease duration, y, median (IQR) 14.8 (6.4–21.2) 13.3 (4.6–20.7) 15.7 (8.1–22.1) 0.028
EDSS score, median (IQR) 3.5 (2.0–5.5) 2.5 (1.5–4.0) 4.0 (3.0–6.0) <0.001
DMT, n (%) 0.002
No treatment 140 (48.4) 69 (50.0) 71 (47.0)
First-line injectables 56 (19.4) 26 (18.8) 30 (19.9)
First-line orals 36 (12.5) 26 (18.8) 10 (6.6)
Natalizumab 37 (12.8) 13 (9.4) 24 (15.9)
S1P modulators 20 (6.9) 4 (2.9) 16 (10.6)
Vaccination formulation, n (%) <0.001
HBV 20 μg adjuvanted 108 (37.4) 66 (47.8) 42 (27.8)
HBV 40 μg128 (44.3) 55 (39.9) 73 (48.3)
Mixed 53 (18.3) 17 (12.3) 36 (23.8)
Abbreviations: DMT = disease modifying therapy; EDSS = Expanded Disability Status Scale; HBV = hepatitis B vaccine; IQR = interquartile range;
S1P = sphingosine-1-phosphate.
a
Pearson χ
2
test; Wilcoxon rank-sum test; Fisher exact test.
Figure 1 Dynamic Changes in Disease-Modifying Therapies Throughout the Vaccination Period According to Type of
Disease-Modifying Therapy and Their Impact in Vaccination
S1P = sphingosine-1-phosphate.
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years; p= 0.032); exhibited a longer disease duration (median
[IQR] 15.7 [8.1–22.1] vs 13.2 [4.6–20.7] years; p= 0.028);
had higher disability as measured using EDSS scores (median
[IQR] 4.0 [3.0–6.0] vs 2.5 [1.5–4.0]; p< 0.001); and were
more frequently treated with highly effective therapies before
switching to anti-CD20 (S1P modulators, 16 [10.6%] vs 4
[2.9%]; natalizumab, 24 [15.9%] vs 13 [9.4%]; p< 0.001)
(Table 1).
Seroprotection Rate
After a full 4-dose immunization course with the HBV, 206 of
289 patients developed a protective antibody response,
yielding an overall SR of 71.3% (95% CI 65.7–76.4).
Among the 138 PWMS who did not change to anti-CD20
therapy during the vaccination course, a SR of 92.8% (95% CI
87.1–96.5) was achieved, except for those vaccinated while on
S1P modulators, where the SR was 50.0% (95% CI 6.8–93.2)
(Table 2).
Conversely, among the 151 PWMS who transitioned to anti-
CD20 therapy (rituximab [RTX; n = 121], ocrelizumab
[OCR; n = 28], ofatumumab [OMB; n = 1], or ublituximab
[n = 1]) during the vaccination course, only 78 exhibited
successful antibody responses, resulting in a SR of 51.7%
(95% CI 43.4–59.9). A reduction in the postvaccination hu-
moral responses was observed for all patients, independent
of the therapy used before switching to anti-CD20 at the
beginning of vaccination. However, the most significant re-
duction in vaccine response was observed in patients pre-
viously treated with S1P modulators, with a final SR of 25.0%
(95% CI 7.3–52.4) (Table 2). These patients received a me-
dian (IQR) of 3 (2–3) doses of the HBV while on S1P before
the switch to anti-CD20.
We observed a progressive decrease in SR depending on the
number of vaccine doses received before the introduction of
anti-CD20 therapy. When the complete vaccination schedule
was administered before starting anti-CD20, the SR was
92.8% (95% CI 87.1–96.5). However, when only 1 dose was
given before initiating anti-CD20 therapy, the SR dropped to
24.0% (95% CI 9.4–45.1) (Figure 2, eTable 1).
Postvaccination Anti-HB Median Titers
In the group of 208 PWMS who achieved a protective anti-
body response (anti-HBs ≥10 IU/L) in their postvaccination
serology, median titers exceeded the cutofflevel by more than
4-fold (median [IQR] titers 617.81 [97.25–1,000.00]). How-
ever, there was a significant difference in median depending on
the number of HBV doses administered before the initiation
of anti-CD20 therapy. The median (IQR) titer for those who
received 4 doses before starting anti-CD20 therapy was
1,000.00 (386.72–1,000.00), compared with those who re-
ceived only 1 dose before anti-CD20, with a median (IQR) titer
of 14.88 (12.92–30.02). This difference was statistically sig-
nificant (p< 0.01) (Figure 3).
Multivariate GLM
After implementing a multivariate GLM, we found that with
each decade increase in age, the likelihood of achieving
seroprotection decreases by 10% (SR ratio of 0.90 [95% CI
0.83–0.97; p= 0.0036]). In addition, starting vaccination
while on S1P modulators was significantly associated with
lower SR (SR ratio of 0.42 [95% CI 0.23–0.78; p=
0.0058]). Conversely, female sex and higher number of
vaccine doses administered before starting anti-CD20
therapy were associated with a higher seroconversion
rate. Specifically, women were 15% more likely to achieve
seroprotection compared with men (SR ratio of 1.15 [95%
CI 1.01–1.32; p= 0.0389]). Receiving 3 doses of HBV
before anti-CD20 therapy resulted in a SR that was 3 times
higher (SR ratio of 3.23 [95% CI 1.68–6.23; p= 0.0005])
while4dosesofHBVledtoaSRthatwasalmost4times
higher (SR ratio of 3.76 [95% CI 1.96–7.24; p< 0.0001])
compared with those who received 1 dose before anti-
CD20 therapy (Figure 4).
Table 2 SRs According to Change to Anti-CD20 During the Course of Vaccination and Treatment at the Beginning of
Vaccination
Disease-modifying therapy
No change to anti-CD20 Change to anti-CD20
N1/N2 SR (95% CI) N1/N2 SR (95% CI)
No treatment 64/69 92.8 (83.9–97.6) 38/71 53.5 (41.3–65.5)
First-line injectables
a
26/26 100 (86.8–100) 17/30 56.7 (37.4–74.5)
First-line orals
b
23/26 88.5 (69.8–97.6) 5/10 50 (18.7–81.3)
Natalizumab 13/13 100 (75.3–100) 14/24 58.3 (36.6–77.9)
S1P modulators 2/4 50 (6.8–93.2) 4/16 25 (7.3–52.4)
Total 128/138 92.8 (87.1–96.5) 78/151 51.7 (43.4–59.9)
Abbreviations: anti-HBs = anti-hepatitis B surface antibodies; N1 = patients who achieved a protective antibody response (anti-HBs ≥10 IU/L); N2 = total
patients who receive vaccination; S1P = sphingosine-1-phosphate; SR = seroprotection rate.
a
Interferon βand glatiramer acetate.
b
Dimethyl fumarate and teriflunomide.
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This study provides Class III evidence that HBV during ini-
tiation of anti-CD20 therapy is less effective in establishing
seroprotection to hepatitis B than in patients in whom HBV is
completed before initiation of anti-CD20 therapy.
Discussion
In this cohort study examining the immunogenicity of the
HBV within a large group of MS candidates for anti-CD20
therapy, we observed that initiating anti-CD20 therapy during
the course of vaccination was associated with a reduction in
postvaccination humoral responses, regardless of the therapy
used at the start of vaccination. A critical finding is that the
number of HBV doses administered before anti-CD20 ex-
posure positively correlated with both the SR and the ach-
ieved anti-HB levels. Patients who completed the entire
vaccine schedule before starting anti-CD20 therapy achieved
a SR exceeding 90%, in contrast to those who received only 1
dose before anti-CD20 therapy initiation, of whom only 1 in 5
developed protective humoral responses. This observation
underscores the vital role of vaccine timing in relation to the
Figure 2 Seroprotection Rates According to the Number of Doses Before the Start of Anti-CD20 Therapy
Figure 3 Box Plot Showing IgG Titers in Seroprotected Patients According to the Number of Doses Before Anti-CD20
Therapy Initiation
AbHBs = total antibody to hepatitis B surface antigen; IgG = immunoglobulin G.
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introduction of anti-CD20 therapy for achieving optimal
immune responses, as advocated by existing guidelines,
9,10
especially in highly active patients where vaccination has
proven to be safe.
25
Our results align with previous studies
showing that patients on anti-CD20 therapies often experi-
ence significantly reduced postvaccination humoral responses
across various vaccines, including those for influenza, pneu-
mococcal, tetanus, and COVID-19.
5,26
This study contributes
valuable information regarding the HBV, an highly recom-
mended immunization for patients undergoing anti-CD20
therapy.
10,11,16,27
Despite low hepatitis B incidence in countries such as the
United States because of effective vaccination programs,
14
it
remains a significant global health threat, affecting 257 million
people and causing 820,000 deaths annually,
28
particularly in
regions such as South America, Asia, and Africa. Given these
disparities, it is essential to adopt a broader, more inclusive
vaccination approach, especially for vulnerable groups on
immunosuppressive therapies such as anti-CD20. Hepatitis B
is a major cause of liver disease, with B cells and humoral
immunity playing critical roles in its progression.
29
While it is
mandatory to screen for latent hepatitis B (total antibody to
hepatitis B core antigen positive) before starting anti-CD20
therapy,
30-33
the risk of exposure and primary infection in
PWMS receiving anti-CD20 treatment without immunity
against hepatitis B remains unclear. However, a study from
Taiwan
13
involving patients with B-cell lymphoma who re-
ceived rituximab indicated that 4 (4.2%) of 95 nonimmune
(hepatitis B surface antigen-negative) patients developed de
novo hepatitis B virus–related hepatitis during rituximab
therapy, with 2 cases resulting in fatal fulminant hepatitis.
Experts agree that anti-CD20 monoclonal antibodies pose
a uniquely high risk of hepatitis B virus–related hepatitis and
liver failure, sometimes leading to death, highlighting the need
for immunization against the hepatitis B virus in this pop-
ulation.
11
After vaccination, achieving anti-HB titers
of ≥10 IU/L is widely recognized as an effective threshold for
preventing both acute and chronic hepatitis B in both healthy
individuals and immunosuppressed populations.
34,35
Cellular
immune response monitoring is not typically recommended
for assessing protection against hepatitis B.
15
Other authors have explored alternative HBV schemes, such
as an accelerated schedule (0, 7, and 21 days and 12 months),
in PWMS before initiating anti-CD20 therapies, aiming to
achieve faster immune responses.
7
However, as observed in
a prospective single-center study conducted in France, this
accelerated schedule seems to be less immunogenic in this
population.
36
The authors found that in 17 patients vacci-
nated with the accelerated HBV schedule, the SR was 58.8%
after the first 3 doses (0, 7, 21 days) administered before the
initiation of anti-CD20 therapy.
36
Additionally the acceler-
ated vaccination schedule is only authorized for the regular
antigenic-load HBV (10 or 20 μg depending on the vaccine
brand), which is not recommended for immunosuppressed
populations.
37
Our study used the adjuvanted or high
antigenic-load vaccine in its standard scheme (0, 1, 2, 6–12
months), which is recommended for immunosuppressed
individuals or those at risk of future immunosuppression.
20,37
Figure 4 Forest Plot Illustrating the Multivariate Generalized Linear Regression Model to Identify Factors Associated With
an Increased Likelihood of Seroconversion
DMT = disease modifying therapy; HBV = hepatitis B vaccine; S1P = sphingosine-1-phosphate.
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The Centers for Disease Control and Prevention recommends
the accelerated schedule for specific situations, such as indi-
viduals traveling on short notice who might face imminent
hepatitis B virus exposure.
37
The main advantage of the stan-
dard HBV schedule is its established efficacy and long-term
immunity.
38
The gradual administration of doses over several
months allows for sustained stimulation of the immune system,
leading to a robust and durable immune response. This is
particularly crucial in the context of our study involving PWMS
who are considering anti-CD20 therapy, which is likely to lead
to long-term immunosuppression. Another important aspect is
that although our study did not find a statistically significant
difference, there seems to be a trend toward better SR with the
adjuvanted HBV over high-load HBV. Further studies are
needed to assess the effectiveness of adjuvanted vs high-load
HBV in PWMS.
It is important to highlight that about one-third of our vacci-
nated patients had not started anti-CD20 therapyby the study’s
conclusion. This may be due to some transitioning to anti-
CD20 therapy after the study ended in May 2023. It is im-
portant to note that our cohort follows an early immunization
approach to ensure protection before initiating immunosup-
pressive treatments such as S1P modulators or anti-CD20. This
strategy anticipates the potential reduction in vaccine response
in immunosuppressed patients. Regarding HBV, we advocate
for a broad vaccination strategy, supported by the 2022 Advi-
sory Committee on Immunization Practices guidelines rec-
ommending universal HBV for all adults aged 19–59 years,
which is particularly relevant for the population we studied.
14
However, we emphasize that these recommendations should
not replace individualized clinical decisions. Physicians should
carefully consider each patient’sspecific treatment context, risk
factors, and local disease prevalence when determining vacci-
nation needs.
Our study underscores several key aspects. First is the reduced
SR observed in older patients. It is well established that
immunosenescence—the gradual decline in immune function
with age—results in diminished vaccine responses.
39
More-
over, older age is a well-documented risk factor of increased
vulnerability to various types of infections.
40,41
Given this,
older PWMS who are treated with anti-CD20 require special
consideration. They face heightened risks of severe and op-
portunistic infections, malignancies, and reduced vaccine re-
sponse due to both age-related immunosenescence and the
immunosuppressive effects of anti-CD20 therapy.
42
We also
observed that female sex was associated with a higher
Figure 5 Proposed Algorithm for Immunizations Against Hepatitis B Virus in Patients With MS Who Are Potential Candi-
dates to Anti-CD20 Therapies
(A) The presence of total anti-HBc indicates previous or ongoing infection with HBV in an undefined time frame. People who have immunity to hepatitis B from
a vaccine do not develop anti-HBc.
50
(B) Consider vaccinating with adjuvanted or high-load HBV (0, 1, 2, and 6–12 months) if short-term immunosuppression is
anticipated. (C) Consider maintaining or switching depending on JC virus serology.
25
Anti-HBc = total antibody to hepatitis B core antigen; anti-HBs = total
antibody to hepatitis B surface antigen; DMT = disease-modifying therapy; HBsAG = hepatit is B surface antigen; HBV = hepatitis B vaccine; MAbs = monoclonal
antibodies; MS = multiple sclerosis; S1P = sphingosine-1-phosphate.
Neurology | Volume 104, Number 3 | February 11, 2025 Neurology.org/N
e210281(8)
likelihood of achieving protective seroconversion, which can
be explained by well-established biological differences in im-
mune responses between men and women.
43
Genetic and
hormonal influences contribute to greater immunoglobulin
production and stronger vaccine responses in women, as
demonstrated in numerous studies with different type of vac-
cines.
43
In addition, we observed a possible additive effect of
immunosuppression in PWMS. Patients who began vaccina-
tion under S1P modulator treatment and then transitioned to
anti-CD20 therapy showed the most impaired vaccination re-
sponse. It is well documented that S1P modulators, especially
the nonselective ones, affect postvaccination immune respon-
ses, both humoral and cellular.
4,24,44-46
These patients and
those on anti-CD20 therapy require a detailed and planned
strategy to minimize infection risks, such as optimizing vacci-
nation timing.
This study has multiple strengths. First, it is based on patients
belonging to a high-quality and deeply phenotyped pro-
spective ongoing cohort at Cemcat, which has provided nu-
merous outstanding publications.
18,19,25,47
In addition, the
close collaboration with the Department of Epidemiology and
Preventive Medicine at HUVH enabled to enroll a substantial
number of patients immunized with HBV, ensuring consistent
evaluations with a wealth of clinical, vaccine-related, and se-
rologic data. Second, although evidence has consistently
shown a significant impact on postvaccination humoral im-
mune responses with anti-CD20 therapies,
5,24
this study
attempts to demonstrate vaccine responses in relation to the
number of doses received. This information will enable us to
develop better strategies for those vaccines that require
multiple doses, not only for HBV but also for other important
vaccines such as the human papillomavirus vaccine or the
recombinant zoster vaccine, recommended for PWMS.
10,12
However, we also acknowledge some limitations. Although
we have a large number of patients who started vaccination
with another DMT and transitioned to anti-CD20 therapies
during the course of vaccination, none of them began with
immune reconstitution therapies such as alemtuzumab or
cladribine, limiting conclusions for this subset of patients. In
addition, although the number of patients who started vac-
cination while on S1P modulators was low, 80% of them
transitioned to anti-CD20 therapy during vaccination. This
group consistently showed the lowest SR, as confirmed by the
multivariate GLM, aligning with previous knowledge about
the impairment of vaccine responses during S1P therapy. The
potential additive immunosuppressive effects of these drugs in
PWMS require further study. Finally, most of our cohort re-
ceived RTX or OCR, limiting our conclusions regarding other
anti-CD20 therapies such as OMB, because of its more recent
approval. While available data suggest that OMB also impairs
humoral immune responses after severe acute respiratory
syndrome coronavirus 2 vaccination,
48
it seems to do so to
a lesser extent compared with RTX or OCR.
49
However, the
current evidence is limited, and larger studies are required to
better understand the potential differences in vaccine
responses among the various anti-CD20 therapies.
This study indicates that starting anti-CD20 therapy during
the HBV course impairs the development of a protective
humoral response. The likelihood of achieving seroconver-
sion is closely linked to the number of vaccine doses received
before initiating anti-CD20 therapy. Given the widespread use
of anti-CD20 treatments across the MS phenotypes, many
PWMS are likely to require these therapies at some point in
their disease. According to our results, it is crucial to advance
vaccination as much as possible, ideally administering at least
3 doses before starting anti-CD20 therapy, or to find alter-
native strategies to achieve adequate vaccine responses, such
as implementing bridging therapy approaches and/or using
enhance immunogenicity vaccines. Consequently, we pro-
pose an algorithm focused on hepatitis B risk prevention in
PWMS, emphasizing the importance of early planning and
completion of the HBV course (Figure 5). Our results could
have a broader impact because of the extensive use of anti-
CD20 therapies in various autoimmune conditions, beyond
inflammatory demyelinating diseases of the CNS.
Author Contributions
R. Carvajal: drafting/revision of the manuscript for content,
including medical writing for content; major role in the ac-
quisition of data; study concept or design; analysis or in-
terpretation of data. D. Guananga- ´
Alvarez: drafting/revision
of the manuscript for content, including medical writing for
content; major role in the acquisition of data; study concept
or design; analysis or interpretation of data. C. Tur: drafting/
revision of the manuscript for content, including medical
writing for content; major role in the acquisition of data;
study concept or design; analysis or interpretation of data.
J. Esperalba: drafting/revision of the manuscript for content,
including medical writing for content; major role in the ac-
quisition of data. M. Rodr´ıguez-Barranco: major role in the
acquisition of data. A. Rando-Segura: drafting/revision of the
manuscript for content, including medical writing for content;
major role in the acquisition of data. B. Borras-Bermejo:
drafting/revision of the manuscript for content, including
medical writing for content; major role in the acquisition of
data. A. Cobo-Calvo: drafting/revision of the manuscript for
content, including medical writing for content; major role in
the acquisition of data; study concept or design. P. Carbonell-
Mirabent: study concept or design. R. Zules-Oña: drafting/
revision of the manuscript for content, including medical
writing for content; major role in the acquisition of data. J.A.
Rodrigo-Pendas: drafting/revision of the manuscript for
content, including medical writing for content; major role in
the acquisition of data. X. Mart´ınez-G´omez: drafting/revision
of the manuscript for content, including medical writing for
content; major role in the acquisition of data. X. Montalban:
drafting/revision of the manuscript for content, including
medical writing for content; major role in the acquisition of
data; study concept or design. M. Tintore: drafting/revision
of the manuscript for content, including medical writing for
Neurology.org/N Neurology | Volume 104, Number 3 | February 11, 2025
e210281(9)
content; major role in the acquisition of data; study concept
or design; analysis or interpretation of data. S. Otero-Romero:
drafting/revision of the manuscript for content, including
medical writing for content; major role in the acquisition of
data; study concept or design; analysis or interpretation
of data.
Study Funding
This study has been funded by Instituto de Salud Carlos III
(ISCIII) through the project PI19/01606 and co-funded by
the European Union.
Disclosure
R. Carvajal is currently being funded by a research grant from
the European Charcot Foundation. In 2023, he received
a grant by “Vall d’Hebron Institut de Recerca.”In 2021, he
received an ECTRIMS Fellowship training performed during
2021–2022. He has also received speaking honoraria from
Roche, Novartis, Biogen, Merck and Sanofi. D. Guananga-
´
Alvarez reports no disclosures. C. Tur is currently being
funded by a Miguel Servet contract, awarded by the Instituto
de Salud Carlos III (ISCIII), Ministerio de Ciencia e
Innovaci´on de España (CP23/00117). She has also received
a 2020 Junior Leader La Caixa Fellowship (fellowship code:
LCF/BQ/PI20/11760008), awarded by “la Caixa”Founda-
tion (ID 100010434), a 2021 Merck’s Award for the In-
vestigation in MS, awarded by Fundaci´on Merck Salud
(Spain), a 2021 Research Grant (PI21/01860) awarded by
the ISCIII, Ministerio de Ciencia e Innovaci´on de España, and
a FORTALECE research grant (FORT23/00034) also by the
ISCIII, Ministerio de Ciencia e Innovaci´on de España. In
2015, she received an ECTRIMS Post-doctoral Research
Fellowship and has received funding from the UK MS Society.
She is a member of the Editorial Board of Neurology Journal
and Multiple Sclerosis Journal. She has also received honoraria
from Roche, Novartis, Merck, Immunic Therapeutics, and
Bristol Myers Squibb. She is a steering committee member of
the O’HAND trial and of the Consensus group on Follow-on
DMTs. J. Esperalba, M. Rodr´ıguez-Barranco, A. Rando-
Segura, and B. Borras-Bermejo report no disclosures. A.
Cobo-Calvo has received grant from Instituto de Salud Carlos
III, Spain (JR19/00007). P. Carbonell-Mirabent has received
support from traveling from Biogen, and his yearly salary is
supported by a grant from Biogen to Fundacio privada
Cemcat for statistical analysis. R. Zules-Oña and J.A. Rodrigo-
Pendas report no disclosures. X. Mart´ınez-G´omez reported
receiving personal fees from GlaxoSmithKline, SanofiPasteur
and Merck, Statens Serum Institut, and Janssen. X. Montalban
has received speaking honoraria and travel expenses for par-
ticipation in scientific meetings and has been a steering
committee member of clinical trials or participated in advisory
boards of clinical trials in the past years with Abbvie, Actelion,
Alexion, Biogen, Bristol Myers Squibb/Celgene, EMD
Serono, Genzyme, Hoffmann-La Roche, Immunic, Janssen
Pharmaceuticals, Medday, Merck, Mylan, Nervgen, Novartis,
Sandoz, Sanofi-Genzyme, Teva Pharmaceutical, TG Thera-
peutics, Excemed, MSIF and NMSS. M. Tintore has received
compensation for consulting services, speaking honoraria and
research support from Almirall, Bayer Schering Pharma,
Biogen-Idec, Genzyme, Immunic Therapeutics, Janssen,
Merck-Serono, Novartis, Roche, Sanofi-Aventis, Viela Bioand
Teva Pharmaceuticals. Data Safety Monitoring Board for
Parexel and UCB Biopharma, Relapse Adjudication Com-
mittee for IMCYSE SA. S. Otero-Romero has received
speaking and consulting honoraria from Genzyme, Biogen-
Idec, Novartis, Roche, Excemed and MSD, as well as research
support from Novartis. Go to Neurology.org/N for full
disclosures.
Publication History
Received by Neurology July 8, 2024. Accepted in final form
November 16, 2024. Submitted and externally peer reviewed. The
handling editor was Assistant Editor Marcello Moccia, MD, PhD.
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