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Department of Neurology, West China Hospital, Sichuan University, No. 37 Guoxue Road, Chengdu, Sichuan 610041, ChinaDepartment of Neurology, Chengdu Shangjin Nanfu Hospital, Chengdu, Sichuan 611730, China
This is the first assessment of the safety of COVID-19 vaccines for people with autoimmune encephalitis.
•
A lower frequency of adverse events was found after either the first or second dose, and no serious adverse events were reported.
•
We found no evidence that vaccination with inactivated COVID-19 increases risk of relapse of autoimmune encephalitis.
•
This real-world survey indicates an overall favorable safety profile of the inactivated COVID-19 vaccine for people with autoimmune encephalitis.
Abstract
Objective
To assess safety data of the inactivated COVID-19 vaccines in a real-world sample of people with autoimmune encephalitis (pwAE).
Methods
A cross-sectional study was performed between 1 March and 30 April 2022. We invited pwAE from our previous ONE-WC (Outcome of Autoimmune Encephalitis Study in Western China) registration study database, to attend neurological clinics, at West China Hospital to participate in a face-to-face survey using a custom-designed questionnaire for this study. The ONE-WC study began in October 2011 and prospectively enrolled pwAE from four large comprehensive neurological centers in Sichuan province, China.
Results
Of the 387 pwAE, 240 (62.0%) completed the questionnaire. Half the 240 participants (121, 50.4%) reported receiving at least one dose of COVID-19 vaccine, which in all but two patients received inactivated COVID-19 vaccine. Among vaccinated pwAE, the median age was 35 years (range 15-69) and 57.8% of them were women. The most frequent reasons that unvaccinated individuals reported for not receiving the COVID-19 vaccine were concern about vaccine-induced relapse of AE (50.4%) and advice from a physician to delay vaccination (21.0%). Small proportions of vaccinated individuals reported adverse events after the first dose (11.5%) or the second dose (10.2%), and none of the adverse events was serious. Across the entire sample, one individual reported relapsing within 30 days after the first dose and three individuals reported relapsing more than 120 days after the first dose.
Conclusions
This real-world survey indicates an overall favorable safety profile of the inactivated COVID-19 vaccine for pwAE.
The on-going COVID-19 pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has led to high morbidity and mortality worldwide (
). A massive vaccination campaign to control the COVID-19 pandemic is being implemented in countries around the world. To date, the World Health Organization has evaluated the safety and efficacy of several COVID-19 vaccines including mRNA vaccines from Moderna and Pfizer/BioNTech, viral vector vaccines from Johnson & Johnson and Oxford/AstraZeneca, and inactivated vaccines from Sinopharm and Sinovac (
Safety, tolerability, and immunogenicity of an inactivated SARS-CoV-2 vaccine in healthy adults aged 18-59 years: a randomised, double-blind, placebo-controlled, phase 1/2 clinical trial.
Safety and efficacy of the ChAdOx1 nCoV-19 vaccine (AZD1222) against SARS-CoV-2: an interim analysis of four randomised controlled trials in Brazil, South Africa, and the UK.
), some expert committees recommend that COVID-19 vaccines may also apply to people with various autoimmune disorders, such as inflammatory rheumatic diseases (
Immunogenicity and safety of the BNT162b2 mRNA COVID-19 vaccine in adult patients with autoimmune inflammatory rheumatic diseases and in the general population: a multicentre study.
Controversial is whether COVID-19 vaccines should be administered to people with autoimmune encephalitis (pwAE), a recently discovered group of rare diseases due to immune responses induced by antibodies against self-antigens in the central nervous system (
). The disease appears to be initiated by antigens released by the viral destruction of neurons or tumors, which induced humoral immune responses involving memory B cells and antibody-producing plasma cells, as well as cytotoxic T-cell responses (
). Some evidence suggests that vaccines might inadvertently activate immune responses to auto-antigens in patients with autoimmune neurological disorders (
). The potential mechanisms for this process include molecular mimicry (shared epitopes between vaccine antigens and CNS proteins) and immune crossreaction (
). So, it is uncertain whether vaccination of COVID-19 can produce specific adverse effects in pwAE or whether immune mechanisms may be altered, leading to the activation of AE.
Currently, there are no available data on the safety of COVID-19 vaccines in AE. Here we explored the safety of COVID-19 vaccines and the occurrence of relapses of autoimmune encephalitis after vaccination in a large sample of pwAE.
2. Methods
2.1 Subjects
The study was conducted in West China Hospital from 1 March to 30 April 2022. All pwAE were from our previous ONE-WC (Outcome of Autoimmune Encephalitis Study in Western China) registration study database, which was registered with the World Health Organization international clinical trial registry platform (registration number: ChiCTR1800019762) and was described in more details in our previous publications (
). Briefly, the ONE-WC study consecutively and prospectively enrolled pwAE from the following four comprehensive neurological centers in Sichuan province, China, beginning in October 2011: West China Hospital, West China Second University Hospital, Sichuan Provincial People's Hospital and Chengdu Shangjin Nanfu Hospital. Data on clinicodemographics, treatments and long-term outcomes were recorded in the database.
We invited pwAE who had been registered in that database between October 2011 and April 2021 to participate in the present study. These pwAE met the following diagnostic criteria for AE (
): (a) rapid onset (<3 months) of 1 or more of the following symptoms-abnormal (psychiatric) behavior or cognitive dysfunction, speech dysfunction, seizures, movement disorder, decreased level of consciousness, and autonomic dysfunction or central hypoventilation and other encephalitis signs; (b) presence of antibodies associated with AE in the cerebrospinal fluid or serum based on a cell-based assay (Euroimmun, Lübeck, Germany); and (c) reasonable exclusion of alternative causes. We excluded pwAE who died before COVID-19 vaccination (n=53), those who were lost to follow-up (n=73), and those who were vaccinated against COVID-19 before being diagnosed with AE (n=3). Eligible individuals (n=387) were invited to come to neurological clinics, West China Hospital to participate in a face-to-face survey using a custom-designed questionnaire.
This study was approved by the Research Ethics Committee of West China Hospital, Sichuan University.Written informed consent was obtained from pwAE or their caregivers prior to enrollment in the study.
3. Questionnaire
The questionnaire included three parts. Part I requested general demographic and disease-related information, including age, sex, type of autoimmune encephalitis, current therapies and therapies at the time of vaccination, history of relapse and residual symptoms based on their/cargiver's answers and records from our previous database (
). Part II of the questionnaire collected data related to the safety profile of the COVID-19 vaccine. Subjects were asked whether they completed the full vaccination course, whether they had received a booster dose, date of vaccination, vaccine type and vaccination-related adverse effects, such as pain at the injection site, generalized muscle pain, headache, dizziness, fever, chills, fatigue and others. In case of new or worsening neuropsychiatric symptoms after the vaccination, additional information regarding timing of new or worsening neuropsychiatric symptoms, treatment and outcome was requested. Part III of the questionnaire was dedicated to the main self-reported reasons for vaccine hesitancy among unvaccinated pwAE.
3.1 Definitions
Vaccination against SARS-CoV-2 in China started at the end of 2020. According to national guidelines, complete vaccination was defined as having had full immunization according to the schedule required by the corresponding vaccine. The viral vector vaccine only requires one dose. The inactivated platforms require two doses, and the subunit vaccine requires three doses. Relapse of encephalitis was defined as new onset or worsening of existing neuropsychiatric symptoms after a period of at least two months when symptoms were improving or remained stable (
). The relapse event of autoimmune encephalitis was evaluated by two neurologists. Vaccine hesitancy is defined as the delay in acceptance or refusal of vaccination despite the availability of vaccination services (
Data were analyzed using SPSS 22.0 (IBM, Chicago, IL, USA). Descriptive statistics are presented as total counts and percentages, median and range. Fisher's exact test was used for comparison of nonparametric variables between groups. Multiple groups (age at onset, age at the time of vaccination and time from disease onset to first vaccine dose) were compared using the Kruskal–Wallis test. A two-sided P-value < 0.05 was considered statistically significant.
4. Results
4.1 Demographic and clinical features of pwAE with vaccination of COVID-19
Of 387 pwAE whom we invited to participate in the study, 240 (62.0%) completed the questionnaire, of whom 121 (50.4%) reported being vaccinated against COVID-19. Table 1 summarizes the demographic and clinical features of these pwAE with vaccination of COVID-19. Median age of vaccinated pwAE was 35 years (range, 15-69 years), and 70 (57.8%) were women. Sixteen vaccinated pwAE (13.2%) reported residual symptoms before vaccination and 10 (8.3%) experienced relapse prior to COVID-19 vaccination. The median interval from first dose until the face-to-face interview was 10 months (range, 4-16 months).
Table 1Clinicodemographic characteristics of 121 pwAE with vaccination of COVID-19, stratified by type of encephalitis.
4.2 The main self-reported reasons for COVID-19 vaccine hesitancy among unvaccinated pwAE
Fig. 1 summarizes the main self-reported reasons for vaccine hesitancy among unvaccinated pwAE. Among the 119 unvaccinated subjects, the most frequent reasons for vaccine hesitancy were concerns about potential vaccination-induced relapse of AE (50.4%) and advice from a physician to delay vaccination (21.0%).
Fig. 1The main self-reported reasons for COVID-19 vaccine hesitancy among 119 unvaccinated pwAE.
4.3 Comparison of clinicodemographic features between vaccinated and unvaccinated pwAE
Table 2 summarizes the clinical features of those vaccinated and those not vaccinated. Compared to vaccinated subjects in our sample, unvaccinated individuals showed significantly shorter median interval from disease onset until the study interview (28 vs 43 months, P < 0.001) and and higher prevalence of encephalitis relapse (23.5% vs 7.4%, P = 0.001). Unvaccinated individuals were also significantly more likely to be taking mycophenolate (P = 0.04) or anti-seizure medication (P = 0.05).
Table 2Comparison of clinicodemographic features between vaccinated and unvaccinated pwAE.
Characteristic
Vaccinated (n=121)
Unvaccinated (n = 119)
P-value
Age at study interview, yr
34 (15-69)
32 (15-81)
0.56
Age at encephalitis onset, yr
32 (14-69)
29 (14-80)
0.74
Female
70 (57.8)
65 (54.6)
0.61
Type of autoimmune encephalitis
Anti-NMDAR
86 (71.0)
76 (63.9)
0.23
Anti-GABABR
15 (12.4)
8 (6.7)
0.14
Anti-LGI1/Caspr2
15 (12.4)
31 (26.1)
0.007
Other
5 (4.1)
4 (3.4)
Interval from disease onset until study interview, mo
43 (12-93)
28 (12-99)
< 0.001
History of relapse
9 (7.4)
28 (23.5)
0.001
With residual symptoms
16 (13.2)
12 (10.1)
0.45
Ongoing treatment before vaccination
Mycophenolate
4 (3.3)
12 (10.1)
0.04
Prednisone
1 (0.8)
1 (0.8)
1.00
Anti-seizure medication
15 (12.4)
26 (21.8)
0.05
Data are n (%) or median (range), unless otherwise indicated.
121 vaccinated pwAE included partially and fully vaccinated individuals.
4.4 COVID-19 vaccine administration and adverse events
Of the 121 vaccinated subjects, 119 (98.3%) were received inactivated COVID-19 vaccine, 1 received a subunit vaccine (full schedule of three doses) and 1 received a viral-vector vaccine (full schedule of one dose). Of the 119 who received inactivated vaccines, 107 (89.9%) received the full schedule of two doses, and 12 (10.1%) received a third (booster) dose. The reason for receiving just one dose of the inactivated vaccine was personal or medical concern because of side effects after the first dose. None of vaccinated individuals had a COVID-19 infection after vaccination until the study interview.
The side effects of the COVID-19 vaccine are shown in Table 3. Among individuals receiving COVID-19 vaccine, adverse events occurred in 11.5% after the first dose and 10.2% after the second dose. All adverse events were transient and mild-to-moderate, and none required hospitalization. Adverse events included pain at the injection site, headache, fever, fatigue, drowsiness, muscle pain and vomiting. No serious adverse events were reported with the COVID-19 vaccine after either the first or second dose. None of the individuals who, at the time of vaccination, were receiving mycophenolate (n = 4) or anti-seizure medication (n = 15) reported serious adverse events after vaccination.
Table 3Adverse events reported by pwAE following COVID-19 vaccination.
Of the 121 individuals analyzed, 119 received inactivated vaccines, 1 received a subunit vaccine and 1 received a viral vector vaccine. Note: Adverse event rates were defined as the number of the events divided by the number of people who had the 1st/ 2nd dose of vaccine. pwAE: people with autoimmune encephalitis.
.
Value
Number of participants who had the 1st injection, n
121
Adverse event after 1st injection, n (%)
14 (11.5)
Pain at the injection site
6 (5.0)
Muscle pain
1 (0.8)
Fatigue
2 (1.7)
Headache
1 (0.8)
Drowsiness
2 (1.7)
Fever
2 (1.7)
Number of participants who had the 2nd injection, n
108
Adverse event after 2nd dose, n (%)
11 (10.2)
Pain at the injection site
4 (3.7)
muscle pain
1 (0.9)
Fatigue
1 (0.9)
Headache
1 (0.9
Drowsiness
2 (1.9)
Fever
1 (0.9)
Vomiting
1 (0.9)
Values are n or n (%).
Of the 121 individuals analyzed, 119 received inactivated vaccines, 1 received a subunit vaccine and 1 received a viral vector vaccine.Note: Adverse event rates were defined as the number of the events divided by the number of people who had the 1st/ 2nd dose of vaccine.pwAE: people with autoimmune encephalitis.
Of the 121 vaccinated subjects, 4 (3.3%) experienced relapse after vaccination of inactivated COVID-19, all of whom had anti-NMDAR encephalitis (Table 4). The median interval from disease onset until first vaccine dose was 21 months (range, 12-51 months). One (0.8%) individual reported relapse within 30 days after the first vaccine dose: the 38-year-old woman was taking mycophenolate and anti-seizure medication at the time of vaccination with inactivated COVID-19, and she suffered seizure relapse 27 days after the first dose. Adjusting her anti-seizure medication brought her seizures under control. The same women had experienced relapse within 6 months before her first vaccine dose, and her symptoms had resolved completely after intravenous rituximab, oral mycophenolate and anti-seizure medication.
Table 4Clinicodemographic characteristics of the four pwAE who experienced relapse after vaccination of inactivated COVID-19.
Sex, age at AE onset, type of AE
Interval from AE onset to vaccination, mo
Relapse before vaccination (Time from relapse to vaccination, mo)
Treatment at vaccination
Relapse after vaccination
Days from vaccination to relapse
Main Symptoms
Autoantibody titer in CSF
Treatment
Outcome (Months from relapse to study interview)
F, 38 yr, NMDAR
12
Yes (5)
Oral ASMs and mycophenolate
27
Seizures
unknown
Oral ASMs and mycophenolate
Seizure control (6)
F, 20 yr, NMDAR
15
No
Oral ASMs
181
Seizures; memory deficits
1:10
Oral ASMs and mycophenolate
Seizure control (4)
M, 32 yr, NMDAR
27
No
No
151
Seizures
unknown
Oral ASMs
Seizure control (5)
M, 45 yr, NMDAR
51
No
No
146
Psychiatric symptoms; sleep disorders
1:10
IVMP Oral prednisone, Mycophenolate and antipsychotics
Complete recovery (6)
pwAE, people with autoimmune encephalitis; ASM, anti-seizure medication; CSF, cerebrospinal fluid; IVMP, intravenous methylprednisolone.
Three (2.5%) individuals reported relapse more than 120 days after the first vaccine dose, none of whom had experienced relapses prior to vaccination. A 45-year-old man experienced relapse 146 days after the first dose of inactivated COVID-19 vaccine. During relapse, he experienced strong psychiatric symptoms and sleep disorder, all of which resolved within 6 months of taking intravenous steroids as well as oral prednisone, mycophenolate and anti-psychotics. Two individuals experienced seizure relapse more than 150 days after the first dose of inactivated vaccine, and their seizures were brought under control by initiating or adjusting anti-seizure medication. The detailed data of 4 pwAE with relapse after vaccination are shown in Table 4. Additionally, during the same observation period (from January 2021 to April 2022), 7 (7/76, 9.2 %) unvaccinated anti-NMDAR patients relapsed; 4 (4/86, 4.7%) vaccinated anti-NMDAR patients relapsed. There was no significant difference between the two groups (P = 0.25).
5. Discussion
To our knowledge, this is the first assessment of the safety of COVID-19 vaccines for pwAE. Only half the subjects in our study had received at least one dose of COVID-19 vaccine, much lower than the 89.7% in the general Chinese population (
). We found the rates of adverse events to be relatively low after the first dose (11.5%) and second dose (10.2%) of COVID-19 vaccine. These rates are lower than the corresponding rate of more than 18% reported for the general Chinese population after each of the two doses (
). None of the adverse events in our study was serious. Furthermore, we found no evidence that vaccination with inactivated COVID-19 increases risk of relapse of AE.
This study showed that vaccine hesitancy remains a widespread problem in our large cohort. The most common reasons for vaccine hesitancy in our study were individuals’ own concern about potential risk of relapse of autoimmune encephalitis, or advice from their physicians to delay vaccination, which likely reflected clinicians’ uncertainty about risk of relapse. Our study suggests that such concerns may be unfounded. Similar to our findings among individuals with autoimmune encephalitis, substantial vaccine hesitancy has been reported among individuals with multiple sclerosis or neuromyelitis optica spectrum disorder (
). Therefore, in order to resolve the patient's vaccine hesitancy, the necessary and timely educational support for both the patients and physicians about the value of vaccination was needed. The data reported here may be helpful in addressing their concerns related to the vaccine-induced relapse in both patients and physicians.
The spectrum of adverse events in our sample of individuals with autoimmune encephalitis is comparable to that in the general population in phase 1 or 2 clinical trials of inactivated COVID-19 vaccines in China (
Safety, tolerability, and immunogenicity of an inactivated SARS-CoV-2 vaccine in healthy adults aged 18-59 years: a randomised, double-blind, placebo-controlled, phase 1/2 clinical trial.
Safety, tolerability, and immunogenicity of an inactivated SARS-CoV-2 vaccine in healthy adults aged 18-59 years: a randomised, double-blind, placebo-controlled, phase 1/2 clinical trial.
). Also in line with what was reported in the general population, injection-site pain was still the most frequently reported adverse event in pwAE. However, the frequency of adverse events was lower in our sample of pwAE than in the general population (
). One possible explanation for this observation may be related to recall bias, since we asked subjects to recall their experiences from several months before. Another possible explanation for this observation may be related to the fact that individuals in our sample had previously been, or were currently, on immunosuppressive therapies, which may inhibit the activity of the immune system and reduce vaccination-induced adverse events. Since the occurrence of adverse events following vaccination is thought to be mediated by immunological responses (
Only four subjects in our study reported relapses, and only one case occurred within 30 days after the first vaccine dose, making a causal association challenging. The remaining three cases occurred more than 120 days after the first vaccine dose, which might have been coincidental or within the natural variation of relapse of AE. There was no evidence of an increased risk of relapse in this cohort, and it is impossible to interpret the causality given the absence of control data. Although we did not have a control group to assess whether the few relapses were caused by the vaccine, we made a comparison of relapses in the vaccinated group vs the unvaccinated group as a control group. In the same observation period, no significant difference was found in the number of anti-NMDAR patients with relapse between the two groups. In all four cases, the relapse symptoms were relatively mild and could be controlled. This relatively low rate of relapse following the COVID-19 vaccines is consistent with previous data that inactivated vaccines were not related to an increased risk of relapse of multiple sclerosis (
). Of note, the distinction between relapses and pseudorelapses is often challenging, since side effects of vaccination can cause new or worsening of neuropsychiatric symptoms. In this context, an antibody test should be performed to exclude the pseudorelapses.
Our study has several limitations. First, some data were collected through retrospective self-report, which increases risk of recall and reporting bias. Second, nearly all vaccinated individuals in our study received inactivated COVID-19 vaccines, so our conclusions may not be generalizable to other types of vaccines. Third, our analysis may underestimate the true rate of relapse after vaccination, given the relatively short interval from the first vaccine dose until the study interview.
Despite these limitations, our study provides the first safety assessment of COVID-19 vaccination in pwAE, and it has the advantage of drawing on a real-world sample. This survey indicates an overall favorable safety profile of the inactivated COVID-19 vaccine in pwAE.
Contributors
X. Liu drafted and revised the manuscript. K. Guo carried out the statistical analysis and interpreted the data. L. Lu, J. Liu and R. Luo collected the clinical data. D. Zhou conceptualized the manuscript. Z. Hong conceptualized and designed the study and revised the manuscript.
Declaration of Competing Interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Study funding
This work was supported by the National Natural Science Foundation of China (81971213).
Acknowledgments
The authors thank all participants for their participation.
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et al.
Effect of 2 inactivated SARS-CoV-2 vaccines on symptomatic COVID-19 infection in adults: a randomized clinical trial.
Immunogenicity and safety of the BNT162b2 mRNA COVID-19 vaccine in adult patients with autoimmune inflammatory rheumatic diseases and in the general population: a multicentre study.
Safety and efficacy of the ChAdOx1 nCoV-19 vaccine (AZD1222) against SARS-CoV-2: an interim analysis of four randomised controlled trials in Brazil, South Africa, and the UK.
Safety, tolerability, and immunogenicity of an inactivated SARS-CoV-2 vaccine in healthy adults aged 18-59 years: a randomised, double-blind, placebo-controlled, phase 1/2 clinical trial.
Of the 121 individuals analyzed, 119 received inactivated vaccines, 1 received a subunit vaccine and 1 received a viral vector vaccine.Note: Adverse event rates were defined as the number of the events divided by the number of people who had the 1st/ 2nd dose of vaccine.pwAE: people with autoimmune encephalitis.
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