Article
Reference
Rabies vaccination and multiple sclerosis relapse: A retrospective cohort study
CSAKI HUTTNER, Angela, et al.
Abstract
No studies assessing rabies vaccine (RV) tolerability in persons with multiple sclerosis (MS) have been conducted. Given the lack of safety data, RV is recommended essentially only for post-exposure prophylaxis, which is difficult to administer effectively in many rabies-endemic countries. We sought to determine whether RV administration as pre-exposure prophylaxis was associated with MS relapse.
CSAKI HUTTNER, Angela, et al . Rabies vaccination and multiple sclerosis relapse: A retrospective cohort study. Multiple Sclerosis and Related Disorders , 2021, vol. 51, p.
102906
DOI : 10.1016/j.msard.2021.102906 PMID : 33827005
Available at:
http://archive-ouverte.unige.ch/unige:153686
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Multiple Sclerosis and Related Disorders 51 (2021) 102906
Available online 18 March 2021
2211-0348/© 2021 The Author(s). Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license
(http://creativecommons.org/licenses/by-nc-nd/4.0/).
Original article
Rabies vaccination and multiple sclerosis relapse: A retrospective cohort study
Angela Huttner
a,b,1, Agustina M. Lascano
c,1, Serge Roth
c, Jean-Marc Schwob
d, Gilles Eperon
d, Claire-Anne Siegrist
a,e, Patrice H. Lalive
c,e,f,*aCenter for Vaccinology, University of Geneva, Geneva, Switzerland
bDivision of Infectious Diseases, Geneva University Hospitals, Geneva, Switzerland
cDepartment of Neurosciences, Division of Neurology, Unit of Neuroimmunology and Neuromuscular Diseases, Geneva University Hospitals, Geneva, Switzerland
dDivision of Tropical and Humanitarian Medicine, Geneva University Hospitals, Geneva, Switzerland
eDepartment of Pathology and Immunology, Faculty of Medicine, University of Geneva, Geneva, Switzerland
fDivision of Laboratory Medicine, Department of Diagnostic, Geneva University Hospitals, Geneva, Switzerland
A R T I C L E I N F O Keywords:
Multiple sclerosis Immunization Exacerbation
Disease-modifying therapy Toxicity
A B S T R A C T
Background: No studies assessing rabies vaccine (RV) tolerability in persons with multiple sclerosis (MS) have been conducted. Given the lack of safety data, RV is recommended essentially only for post-exposure prophylaxis, which is difficult to administer effectively in many rabies-endemic countries. We sought to determine whether RV administration as pre-exposure prophylaxis was associated with MS relapse.
Methods: This retrospective cohort study compared the clinical courses of MS patients in the year before and after rabies vaccination. The year before vaccination was defined as the pre-exposure risk period, the three months thereafter as the exposure-risk period, and the following nine months as the post-risk period. All adult MS pa- tients immunized with RV between 2014 and 2018 and with available medical records in the two-year window were included. The primary outcome was the incidence of symptomatic MS relapse in the exposure-risk period versus the pre-exposure period.
Results: Fifty-five patients received at least one dose of RV. Most (38/55, 69%) were female; mean age was 38.5 years (SD ±9.2). While 21 (38%) patients experienced 24 relapses in the year before vaccination, only three (5%) experienced one relapse each in the post-vaccination exposure-risk period; three others (5%) experienced a total of four relapses in the subsequent post-risk period. The annualized relapse rates in the pre-exposure, exposure- risk, and post-risk periods were 0.44, 0.22, and 0.10, respectively (rate ratio for exposure-risk to pre-exposure periods, 0.509 [95% CI 0.098–1.677]).
Conclusions: In this cohort, rabies vaccination was not associated with clinical MS relapse. Larger, prospective studies are needed to confirm these results.
1. Introduction
Rabies is a rapidly progressive neurodegenerative infection caused by rabies lyssavirus, which infects animals worldwide. The incubation period varies from weeks to months, but once clinical symptoms appear, rabies is almost always fatal, as no effective antiviral therapy has been developed (Hemachudha et al., 2013). Pre-exposure prophylaxis with vaccination is thus an important strategy, particularly given that access to post-exposure prophylaxis in many rabies-endemic countries is limited or non-existent.
The first rabies vaccines (RV) were made from the spinal cords or brains of rabies-infected animals (Fuenzalida et al., 1964). Their high concentrations of myelin caused various neurological adverse events including acute disseminated encephalomyelitis (ADEM). The incidence of ADEM following brain-based RV administration was as high as 1/300 to 1/7000 (Scott, 1967), with more frequent reactions following more numerous injections (Appelbaum and Nelson, 1953), strongly support- ing causality. Current RVs, grown on human diploid cells or chicken fibroblasts, are deemed considerably more tolerable (Plotkin and Wik- tor, 1978) and highly effective (Wilde, 2007). Yet similarities between
* Corresponding author at: Division of Neurology, Geneva University Hospitals, Rue Gabrielle-Perret-Gentil 4, 1205 Geneva, Switzerland.
E-mail addresses: [email protected] (A. Huttner), [email protected] (P.H. Lalive).
1 Equal contribution
Contents lists available at ScienceDirect
Multiple Sclerosis and Related Disorders
journal homepage: www.elsevier.com/locate/msard
https://doi.org/10.1016/j.msard.2021.102906
Received 21 January 2021; Received in revised form 2 March 2021; Accepted 14 March 2021
Multiple Sclerosis and Related Disorders 51 (2021) 102906
2 post-RV encephalomyelitis and the progressive form of MS have been described (Kulkarni et al., 2004), and demyelination following RV continues to be reported occasionally (Britton et al., 1978). To date, no studies have described RV tolerability in MS patients. In an effort to begin filling this knowledge gap, we report the outcomes of 55 MS pa- tients who underwent pre-exposure rabies vaccination at our center in recent years.
2. Methods
2.1. Study design, population and entry criteria
In this single-center retrospective cohort study, the clinical courses of MS patients in the year before and the year after rabies vaccination were compared; this self-controlled design was chosen for consistency with that used by Farez et al. in a previous study examining MS relapse after yellow-fever vaccination (Farez and Correale, 2011). The 12 months preceding vaccination were defined as the pre-exposure risk period, the three months thereafter as the exposure-risk period, and the following nine months as the post-risk period (Figure S1). The exposure-risk time period of three months was chosen because most vaccine-related events occur soon after vaccination; causality becomes increasingly difficult to confirm thereafter (Ramsay, 2017). The primary outcome was the relative incidence of MS relapse in the exposure-risk period versus that of the pre-exposure risk period. Other outcomes included the presence of new T2-weighted (T2) or T1-weighted gadolinium-positive (T1Gd+) magnetic resonance imaging (MRI) lesions.
All adult patients diagnosed with MS according to the 2010 and 2015 McDonald criteria (Thompson et al., 2018), (Polman et al., 2011) and vaccinated with at least one dose of either Rabipur® (GSK Vaccines) or M´erieux inactivated RV (MIRV, Sanofi Aventis) from January 2014 through June 2018 were eligible for inclusion. The start date was chosen in line with the availability of medical records: the recording of struc- tured MS clinical data into the hospital’s electronic health record began in early 2013. During this period, our center used the Rabipur® vaccine, replaced by MIRV only when there were shortages in the supply chain (during the month of January 2015 and between July and September of 2018).
As described elsewhere (Huttner et al., 2020), persons with MS receive vaccines in our center at the clinician’s discretion after joint neurology and travel-medicine consultation, which includes a careful risk-benefit analysis tailored to the patient’s potential exposures; pa- tients who expect to travel to rabies-endemic countries may be offered pre-exposure vaccination if the benefit-risk ratio allows it. Of note, the city of Geneva is home to 38 international institutions and roughly 750 non-governmental organizations (NGOs), with a high proportion of their employees actively involved in humanitarian projects in the field. Spe- cific recommendations for vaccination against rare and tropical diseases are in place in many of these organizations, with pre-travel vaccination mandatory for many of our patients. In our institution, however, MS relapse in the preceding 4–6 weeks is an absolute contraindication to rabies and other vaccinations.
Routine clinical follow-up with MRI is performed annually, and additionally in the event of suspected relapse; relapses were either patient-reported or data were collected from pre-scheduled visits. These procedures were identical in the pre- and post-exposure periods. Study exclusion criteria were age <18 years, pregnancy with delivery in the six months after vaccination (given studies reporting fewer relapses during pregnancy (Harbo et al., 2013)) and/or unavailable medical records.
The study was approved by the Geneva Cantonal Ethics Commission (2018–01663). Informed consent was waived given the study’s obser- vational and retrospective nature.
2.2. Definitions
An MS relapse was defined as a monophasic clinical episode with
patient-reported symptoms and objective findings typical of MS, reflecting a focal or multifocal inflammatory demyelinating event in the central nervous system (CNS), developing acutely or subacutely, with a duration of at least 24 h, with or without recovery, in the absence of fever or infection (Thompson et al., 2018).
2.3. Statistical analysis
There was no sample size calculation: all patients meeting entry criteria were included. Relapse rates were calculated by dividing the total number of relapses by the time contributed by each individual during the three different observation periods. Univariate logistic models were constructed to evaluate associations between relapse and demographic and clinical characteristics. Descriptive analyses were performed to summarize data (Stata 16, College St., Texas).
3. Results
Fifty-five MS patients receiving at least one dose of RV were included (Fig. 1). Mean age was 38.5 years (SD ±9.2) and most (38/55, 69%) were female (Table 1). Disease courses were identified as follows: 47 relapsing-remitting MS (RRMS), one secondary progressive MS (SPMS) and six primary progressive MS (PPMS). The mean baseline (pre-inclu- sion) expanded disability status scale (EDSS) score was 1.82 (SD ±1.16).
Thirty-one patients (56%) were receiving disease-modifying therapy (DMT) at the time of vaccination, and an additional eight patients (15%) would begin DMT within the following three months. The median number of rabies shots received was 3 (IQR 3–4, range 1–7). Fourteen patients (25%) received at least one other vaccine within seven days before or after the first rabies immunization, and 50 (91%) received at least one other vaccine in the study period (Table 1).
In the year before immunization (pre-exposure period), 21 patients (38%) experienced 24 relapses (annualized relapse rate [ARR] 0.44, 95% CI 0.30–0.58). The median time from the most recent relapse to RV administration was 161 days (IQR 71–208). In the three-month expo- sure-risk period, only three patients experienced one relapse each (ARR 0.22, 95% CI 0.05–0.51); one occurred four days and two occurred 38 days after vaccination, respectively (Table 2). Only one of these three patients (33%) was receiving DMT at the time of vaccination, while 30/
52 (58%) of those who did not relapse in the exposure-risk period were receiving DMT at the time of vaccination (p =0.575). The rate ratio of relapse incidence in the exposure-risk period over that of the pre- exposure period was 0.50 (95% CI 0.10–1.65). In the nine-month post- risk period, three other patients experienced a total of four relapses (ARR 0.10, 95% CI 0.03–0.23). These began 96, 160, 186 and 283 days
Fig. 1.Study flow diagram. (RV: rabies vaccination; MS: multiple sclerosis).
A. Huttner et al.
after vaccination, respectively. Of these six patients experiencing a relapse in the year after rabies immunization, four (67%) had also experienced a relapse in the pre-exposure period.
Patients who experienced relapse required high-dose methylpred- nisolone for 15/27 (56%) of relapses overall, with 11/21 (52%), 2/3 (67%) and 2/3 (67%) patients requiring steroid therapy in the pre- exposure, exposure-risk, and post-risk periods, respectively. Mean EDSS scores for patients with relapses during the pre-exposure, expo- sure-risk, and post-risk periods were 2.15 (SD ±0.96), 2.00 (SD 0), and 3.16 (SD ±1.44), respectively.
In the pre-exposure, exposure-risk and post-risk periods, 34/51 (71%), 8/22 (36%), and 9/46 (20%) patients had new brain and/or spinal lesions on T2-weighted or gadolinium-positive MRI imaging, respectively. The lesions were not associated with an MS relapse in 13/
38 (38%), 5/8 (63%), and 6/9 (67%) patients, respectively (Table S1).
In univariate analyses, neither baseline demographic (sex, age) nor other clinical factors (DMT at the time of vaccination, MS subtype, number of rabies shots) were associated with relapse in the exposure- risk period (Table S2).
4. Discussion
In this cohort of 55 MS patients undergoing rabies vaccination, we could not identify any risk for relapse in the year following vaccination, even among those who received up to seven repeated doses of RV.
Indeed, we found a sharp decrease in the annualized relapse rate, from 0.44 in the year preceding immunization to 0.22 and then 0.10 in the three-month exposure-risk period and the nine-month post-exposure period, respectively. This may be partially due to our center’s routine practice of, whenever possible, vaccinating persons with MS at least four weeks before disease-modifying therapy (DMT) is anticipated: relapses are less likely given the efficacy of current MS therapy. Vaccination before DMT initiation is not always feasible: several patients were already receiving DMT at the time of the first rabies shot. Nonetheless, in this cohort at least, immunosuppression at the time of vaccination was also not a risk factor for vaccine-related complications. Only one of three patients (33%) with MS relapse in the exposure-risk period was receiving DMT at the time of vaccination, while 30/52 (58%) of those who did not relapse were receiving DMT at the time of vaccination.
Most original safety data on rabies vaccines derive from an earlier era, when brain- and spinal-cord-based formulations with high myelin content were being administered. Given that currently used rabies vaccines do not contain myelin and induce little reactogenicity (Ertl, 2019), there is arguably less biologic plausibility to the notion that these vaccines could trigger MS exacerbations. Nonetheless, the frequent neurological complications following the use of brain-derived RVs and the dearth of clinical-outcomes information among rabies-vaccinated persons with MS have allowed a certain level of vaccine hesitancy to persist among physicians. This hesitancy is fueled by reports of adverse events following immunization (AEFI). Remarkably, the analysis of all AEFI spontaneously reported by physicians following the administration of Sanofi Pasteur MSD vaccines between January 2000 to June 2010 in France ranged from 0.7 (flu vaccine) to 20.9 (RVs) (Okais et al., 2011).
Among 288 AEFI, nervous system disorders were the most frequently reported. It is unlikely, however, that the injection of a few micrograms of protein extracted from a pathogen would directly result in very organ-specific AEFI. Instead, a nocebo phenomenon may be at play, subordinated to preconceptions held by patients and/or physicians that a particular intervention may preferentially adversely affect a given Table 1
Baseline demographic and clinical characteristics of study patients.
Characteristic All
patients n =55
Patients with relapse after rabies vaccination§ n =6
Patients without relapses after rabies vaccination n =49
Female sex (%) 38 (69) 4 (67) 34 (69)
Mean age, years (SD) 38.5
(±9.2) 34.8 (±11.0) 39.0 (±9.0) Median time since MS
diagnosis, years (IQR) 4.1
(0.9–11.3) 4.0 (2.0–8.0) 3.0 (0.9–7.0) Type of MS
- Relapsing-remitting
(%) 48 (87) 6 (100) 42 (86)
- Secondary progressive
(%) 1 (2) 0 (0) 1 (2)
- Primary progressive
(%) 6 (11) 0 (0) 6 (13)
Mean EDSS (SD) at time of
vaccination 1.82
(±1.16) 2.17 (±0.93) 1.79 (±1.19) DMT at time of first rabies
vaccination (%) 31 (56) 3 (50) 28 (57)
- Fingolimod (%) 12 (39) 2 (66) 10 (36)
- Natalizumab (%) 11 (35) 0 (0) 11 (39)
- Dimethyl fumarate
(%) 7 (23) 1 (33) 6 (21)
- Interferon-beta-1 (%) 1 (3) 0 (0) 1 (4)
DMT at time of or within the three months after first rabies vaccination (%)*
35 (64)* 3 (50) 32 (65)*
- Fingolimod (%) 14 (40) 2 (33) 12 (38)
- Natalizumab (%) 12 (34) 0 (0) 12 (38)
- Dimethyl fumarate
(%) 8 (23) 1 (17) 7 (22)
- Rituximab (%) 3 (9) 0 (0) 3 (9)
- Ocrelizumab (%) 1 (3) 0 (0) 1 (3)
- Interferon-beta-1 (%) 1 (3) 0 (0) 1 (3)
Other vaccinations received within seven days of the first rabies vaccination** (%)
14 (25) 2 (33) 12 (25)
Receipt of other vaccinations in the study period** (%)
50 (91) 6 (100) 44 (90)
Experienced a relapse in the pre-exposure risk period (%)
21 (38) 4 (67) 17 (35)
DMT: disease-modifying therapy; EDSS: expanded disability status scale; MS:
multiple sclerosis; RV: rabies vaccination.
§These patients had a relapse in either the exposure-risk period (n =3) or the post-risk period (n =3).
*Some patients received more than one type of DMT in the three months after vaccination.
**Other vaccines received: Boostrix-Polio® (combined diphtheria, tetanus, acellular pertussis and inactivated poliomyelitis vaccine), Encepur® (tick-borne encephalitis vaccine), Engerix B® (hepatitis B vaccine), Fluarix-Tetra® (influ- enza A and B vaccine), Havrix® (hepatitis A vaccine), Ixiaro® (Japanese en- cephalitis vaccine), Menveo® (Neisseria meningitidis vaccine), Prevnar® (pneumococcal vaccine), Revaxis® (combined diphtheria, tetanus and inacti- vated poliomyelitis vaccine), Stamaril® (yellow-fever vaccine), Twinrix® (combined hepatitis A and B vaccine), Typhim Vi® (typhoid vaccine).
Table 2
Multiple sclerosis relapses in the pre-exposure risk period, the exposure-risk period, and the post-risk period (the 12 months before, the three months after, and the four to 12 months after the first rabies vaccination, respectively).
Pre-exposure
period Exposure risk
period Post-risk
period
Number of relapses 24 3* 4
Number of patients with
relapses (%) 21 (38) 3 (5) 3 (5)
Incidence rate (95%
CI)**,§ 0.44
(0.30–0.58) 0.22
(0.05–0.51) 0.10 (0.03–0.23)
* One ERP relapse occurred four days and two occurred 38 days after rabies vaccination, respectively.
** Incidence rate is the number of relapses per patient-years.
§Rate ratio is 0.50 (95% CI 0.10–1.65) for the exposure risk period versus the pre-exposure period.
Multiple Sclerosis and Related Disorders 51 (2021) 102906
4 organ (Okais et al., 2011).
The findings reported here require confirmation in prospective trials.
This study is limited by its retrospective nature and its relatively small sample size and low event rate, which do not allow for adjusted analyses that might take confounders such as DMT into account or that might provide more information on risk in relation to the number of vaccine doses received. Nonetheless, it provides the first structured safety data on rabies vaccination in persons with MS, as well as a ‘real-world’ description of the incidence of MS relapse after repeated vaccination with contemporary rabies vaccines.
To date, the National Multiple Sclerosis Society deems rabies vac- cines only “probably safe”; their use is essentially recommended for post-exposure prophylaxis (Loebermann et al., 2012), which is difficult to administer effectively in many rabies-endemic countries. While this study’s observations need confirmation in prospective studies, they add significantly to a disproportionately meager evidence base. They may help to open a discussion among physicians who hesitate to recommend cell-based RVs, which do not currently appear to be biologically or epidemiologically associated with relapse or with signs of disease ac- tivity on imaging, as pre-exposure prophylaxis against a disease with high mortality and no proven therapy.
Funding
This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
Availability of data
The data that support the findings of this study are available from the corresponding author upon reasonable request.
CRediT authorship contribution statement
Angela Huttner: Data curation, Formal analysis, Methodology, Writing - original draft. Agustina M. Lascano: Data curation, Formal analysis. Serge Roth: Data curation. Jean-Marc Schwob: Data cura- tion. Gilles Eperon: Data curation. Claire-Anne Siegrist: Conceptual- ization, Methodology, Supervision, Writing - review & editing. Patrice H. Lalive: Conceptualization, Methodology, Project administration, Supervision, Validation, Writing - review & editing.
Declaration of Competing Interest
Dr P. H. Lalive received honoraria for speaking from Biogen-Idec, CSL Bering, Merck Serono, Novartis, Sanofi-Aventis, Teva, Roche;
consulting fees from Biogen-Idec, Geneuro, Genzyme, Merck Serono,
Novartis, Sanofi-Aventis, Teva; and research grants from Biogen-Idec, Merck Serono, and Novartis.
All other authors declare no conflict of interest.
Acknowledgments
We thank Fabienne Marechal-Rouiller and Nathalie Soumet Trin- quart for preparation of the case-report form.
Supplementary materials
Supplementary material associated with this article can be found, in the online version, at doi:10.1016/j.msard.2021.102906.
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