Analysis of Neurological Adverse Events Reported in VigiBase From COVID-19 Vaccines

Background: Fifteen COVID-19 vaccines have been granted emergency approval before the completion of conventional phases of clinical trials. The present study aimed to analyze the neurological adverse events (AEs) post-COVID-19 vaccination and focuses on determining the association of AEs with the vaccine. Methodology: The neurological AEs reported for COVID-19 vaccines in the WHO pharmacovigilance database (VigiBase) were extracted from the System Organ Classes - neurological disorders and investigations. Descriptive statistics are reported as percentage and frequency and the disproportionality analysis was also conducted. Results: For the neurological system, 19,529 AEs were reported. Of these, 15,638 events were reported from BNT162b2 vaccine, 2,751 from AZD1222 vaccine, 1,075 from mRNA-1273 vaccine, eight from Vero vaccine, two from Covaxin, and for 55 AEs, vaccine name was not mentioned. The reason for more AEs reported with BNT162b2 can be maximum vaccination with BNT162b2 vaccine in the study period. According to the disproportionality analysis based on IC025 value, ageusia, anosmia, burning sensation, dizziness, facial paralysis, headache, hypoaesthesia, lethargy, migraine, neuralgia, paresis, parosmia, poor sleep quality, seizure, transient ischemic attack, and tremor are some of the AEs that can be associated with the administration of the vaccine. Conclusion: The vaccines should be monitored for these AEs till the causality of these AEs with COVID-19 vaccines is established through further long-term follow-up studies. These neurological AEs reported in VigiBase should not be taken as conclusive and mass vaccination should be carried out to control the pandemic until a definite link of these adverse effects is established.


Introduction
COVID-19 is an acute respiratory illness caused by the SARS-CoV-2 virus. Since its initial report in December 2019 in Wuhan, China, COVID-19 has rattled the global research to combat this deadly virus. As of now on April 7, 2021, it has infected 270,791,973 individuals including 5,318,216 deaths [1]. The sudden spike in the number of cases led to a shortage of various medicines and personal protective equipment in many countries and imposed a lockdown to stop the spread of the virus further worsening the daily life of people across the globe [2][3][4]. The research related to the COVID-19 virus is exploring mainly four arenasdissecting the virus itself, exploring the diagnostic tools, finding the prevention and the treatment modalities. Various modalities, repurposed drugs, complementary and alternative medicines, vitamins, nutraceuticals, and immune-boosters were being used to tackle the condition as there was no definitive treatment [5][6][7][8][9]. The drugs being explored for treatment include drugs like hydroxychloroquine, remdesivir, favipiravir, tocilizumab, ivermectin, baricitinib, etc. Numerous studies were conducted to observe the safety and efficacy of these drugs in COVID-19 [6,7,[10][11][12]. As of May 19, 2021, 15 vaccines were approved for COVID-19 namely Comirnaty (BNT162b2), Moderna COVID-19 vaccine (mRNA-1273), AstraZeneca COVID-19 vaccine (AZD1222); also known as Vaxzevria and Covishield, Sputnik V, Sputnik Light, COVID-19 vaccine Janssen (JNJ-78436735; Ad26.COV2.S), CoronaVac, BBIBP-CorV, EpiVacCorona, Convidicea (Ad5-nCoV), Covaxin, WIBP-CorV, CoviVac, ZF2001, and QazVac (QazCovid-in) [13]. In view of the initial pandemic scenario, all vaccines were granted emergency approval trials based on the data generated from the initial phases of clinical trials, before completion of all the phases of a clinical trial [14][15][16]. The remaining phases of clinical trials were continuing to confirm their safety and efficacy. Thus, it was imperative to monitor the adverse events reported post-COVID-19 vaccination. There were scattered reports of neurological adverse events following the COVID-19 vaccination [17][18][19]. Thus, the present study was planned by the authors in order to evaluate the neurological adverse events reported in the WHO pharmacovigilance database, VigiBase.
VigiBase is the global post-marketing pharmacovigilance database maintained by WHO, which contains the adverse events of approved drugs reported from all over the world [20]. VigiBase database had been used previously to analyze the safety profile of many drugs and vaccines including the therapies used for treatment and prevention of COVID-19 [6,7,10,11,21,22]. We evaluated all the neurological adverse events reported for COVID-19 vaccines in VigiBase. We also analyzed if there exists any relationship between the reported adverse events and the vaccines. This study was also planned to generate a safety signal for COVID-19 vaccines in the prime stage and provide a platform for other studies for generating or detecting the safety data of COVID-19 vaccines.

Materials And Methods
The authors used VigiBase for analysis of adverse events related to COVID-19 Vaccines reported between December 15, 2020, and January 24, 2021. VigiBase is a global pharmacovigilance database established in 1978 and consists of over 20 million reports of suspected adverse events reported since its origin by its 130 member countries which represent 90% of the world population [20,23,24].
VigiBase is linked with MedDRA, WHO-ART, WHO-ICD in order to facilitate uniform data entry, retrieval, and analysis. The adverse events are reported as Individual Case Safety Report (ICSR). ICSR is also termed as "spontaneous" or "voluntary" when the reports are generated in the post-marketing phase of the drug when it is available for general use [20,[23][24][25].
The adverse events reported in VigiBase are in a structured form that consists of information regarding three domains: patient (age, gender, country, and continent of residence), drug (name, start and end date, dose, route of administration, and the indication for use), and adverse event (type of event, onset date, seriousness, causality, and the outcome). The drugs are coded in VigiBase in alliance with the WHO Drug Dictionary enhanced including the Anatomical Therapeutic Classification. The adverse events are also reported and coded in accordance with the Medical Dictionary for Regulatory Authorities (MedDRA) and the WHO adverse reaction Terminology [25,26]. The information in the MedDRA is contained as highly standardized medical terminology to allow the global sharing of consistent regulatory information for drugs used by humans [27,28]. In the VigiBase, the information related to adverse events is recorded in accordance with MedDRA in a highly specific hierarchical order containing five levels: lowest level terms (LTTs), preferred terms (PTs), high-level terms (HLTs), high-level group terms (HLGTs), and system organ classes (SOCs) [28,29].
In the present study, the SOC and PT were used for analysis. The PT contains the specific disease, symptom, therapeutic indication, and surgical or medical procedures. The PT is arranged into SOC according to the etiology (infections and infestations), manifestation site (e.g., neurological disorder, musculoskeletal disorder), or purpose (medical or surgical procedure) [30].
The present study incorporated all suspected neurological adverse events reported in VigiBase after administration of COVID-19 vaccines -BNT162b2, AZD1222, mRNA-1273, Covaxin, and unknown vaccines (vaccine for which no name is mentioned in the ICSR form) between December 15, 2020, and January 24, 2021. The authors extracted SOC -neurological disorders and investigations from the database. The SOC investigation was cleaned further to remove all adverse events except for those related to the neurological system. The individual neurological adverse events are reported as frequency and percentage. The authors also used disproportionality analysis, the method of signal detection for the adverse events that are spontaneously reported in the database. In disproportionality analysis, the Frequentist and the Bayesian information component (IC) methods are applied to compare the drug adverse event pair with the other drug adverse events pairs of the database to evaluate if the observed frequency of the events for a drug is more than expected [31][32][33][34][35].
The IC was used by the authors to evaluate the relationship between the specific adverse events to COVID-19 vaccine administration. IC is a Bayesian method of signal generation, and it can avoid false-positive results when events are low [31,35]. In order to link a particular adverse event to a specific drug (COVID-19 vaccine in the current study), the lower limit of IC 025 should have a positive value. Since in the present study, the frequency of many adverse events was less than four, thus the authors used only IC 025 values and not the ROR or PRR values. Although, in this study, the reporting odds ratios (ROR) and proportional odds ratios (POR) were not used to link the events with the vaccines, but for the events with positive IC 025 , the ROR and POR with 95% credibility Interval were also mentioned. The event was not considered to be linked to the vaccine if its IC 025 value was negative and the ROR or PRR was more than 1. The IC 025 values were calculated separately for the different age groups and genders. Descriptive statistics were reported in the form of frequency and percentage. Statistical Package for Social Science version 17 (SPSS Inc., Chicago, IL, USA) was used for analysis. Institutional Ethics Committee exempted this project from the ethics review as this study is based on secondary data analysis which involves no direct contact with any human subject.

Results
This study is based on adverse events reported in the VigiBase database from December 15, 2020 to January 24,2021 . In this period, 103,954 adverse events were reported from 30,532 subjects who were administered  the COVID-19 vaccine. Out of 103,954, 19,529 AEs were related to clinical events and investigations related  to the neurological system. Total 15,638 events were reported from the BNT162b2 vaccine, 2,751 from  AZD1222 vaccine, 1,075 from mRNA-1273 vaccine, eight from Vero vaccine, two from Covaxin, and for 55  AEs vaccine name was not mentioned. Neurological AEs reported from the abovementioned vaccines are  summarized in Supplementary Tables 1-6.
As per the disproportionality analysis based on IC025 value, ageusia, allodynia, anesthesia, anosmia, aura, balance disorders, burning sensation, cervicobrachial syndrome, cluster headache, dizziness, postural dizziness, dysgeusia, exertional headache, facial paralysis, facial paresis, facial spasm, febrile convulsion, head discomfort, headache, hemiparaesthesia, hemiparesis, hyperaesthesis, hypersomnia, hypoaesthesia, hypogeusia, hyperresponsive to stimuli, hyposomnia, ischemic stroke, lethargy, loss of consciousness, migraine, migraine with aura, monoparesis, neuralgia, paraesthesia, paresis, parosmia, petit mal epilepsy, poor sleep quality, presyncope, seizure, sensory disturbance, sensory loss, sinus headache, syncope, taste disorder, tension headache, transient global amnesia, transient ischemic attack, tremor, tunnel vision, and unresponsive to stimuli are the AEs, which can be considered to be associated with the administration of the vaccine ( Table 1).  Frequently observed adverse events following vaccinations were headache, dizziness, paresthesia, hypoesthesia, lethargy, and migraine. Even though the total number of adverse events were high among individuals receiving BNT162b2 mRNA vaccine yet higher number of events in BNT162b2 mRNA vaccine can be explained as this is the first vaccine to receive emergency use authorization from USFDA, large number doses administration during the analysis period and a shorter interval between the two doses [36].
Polack et al. observed that frequently observed systemic adverse events following BNT162b2 mRNA vaccine second dose administration were fatigue (59%), headache (52%) in the younger population as compared to 51% and 39% among the older population, respectively [16]. In our analysis, headache accounted for 45.46% of the total adverse events with the BNT162b2 vaccine.
The fact sheet for healthcare providers administering BNT162b2 vaccine as published by FDA reported incidence of headache as 55.1% in participants of 16 years of age and older after the first dose and (75.5%) in adolescents of 12 through 15 years of age. In patients of age group 18-55 years reported that the prevalence of headache was 41.9% after dose 1 and 51.7% after dose 2 and 25.2% dose 1 and 39.0 % after dose 2 in 56 years of age and older vaccine recipients [37].
Similar adverse events were reported in the mRNA-1273 vaccine group. In clinical studies, adverse events were not presented as neurological per se, however, this analysis primarily focused on neurological manifestations. Headache was observed in 32.7 % of the total patients after the first vaccination and 58.6% after second vaccination and in both the instances the probability of headache was more in the ≥18 to <65 years group (first vaccination [ [41].
The disproportionality analysis of this study shows that the reactogenicity of the vaccine among individuals between 18 and 65 years was higher than the individuals above 65 years. This finding was supported by a few previously published clinical studies where a similar type of difference was observed with mRNA-1273, BNT162b2, and AZD1222 vaccines [16,38,42].
Early analysis of all adverse events following vaccination as reported in the COVID-19 vaccine safety update Advisory Committee on Immunization Practices (ACIP) by March 1, 2021, shows that more than 90% were non-serious in nature and headache was the commonest reported AE in both the mRNA vaccines with 20% with BNT162b2 and 23.4 % with the mRNA-1273 vaccine [43]. In a later report as of June 23, 2021, the ACIP in their early safety data of Pfizer-BioNTech vaccination in persons aged 12-15 years and 16-25 years old reported headache as one of the commonest reported adverse events [44]. Similar reports of headache (22.4%) were also reported by the Morbidity and Mortality Weekly Report by CDC, as per the data collected in VAERS in the early phase of vaccination [45]. This difference may be because of the inclusion of local and systemic adverse events, whereas in this study we have included only systemic neurological manifestations. The serious adverse events reported in the VigiBase need to be scrutinized for their association with vaccine administration. In the earlier clinical trials, the majority of serious adverse events were either unrelated to the vaccine or were coincidental due to age-related risk factors.
Immune reactogenicity to vaccines refers to a group of reactions that are observed immediately after vaccination and are a physical presentation of the inflammatory response to the vaccination. Reactogenicity is determined by either host factors such as age, gender, preexisting immunity or vaccine characteristics, or both [46]. Systemic manifestations of reactogenicity are either due to the vaccine or its adjuvants or both. Presentation of these manifestations varies from fever, headache, dizziness, to seizures and life-threatening anaphylaxis. The systemic pyrogens and other immune mediators cross-talk with the nervous system through the vagus nerve, at the blood-brain barrier, and circumventricular organs. All adjuvant systems induce transient systemic innate responses, which include an increase in the levels of IL-6 and C-reactive protein (CRP), usually peaking at 24 hours after vaccination and subsides to the baseline values within one to three days [47].
The vaccine adjunct can also have a role in reactogenicity. The mRNA vaccines enveloped with lipid nanoparticle (LNP) based delivery system mimics as virus and prevent them from enzymatic digestion along with enhancing immunogenicity without integrating with the genome. However, mRNA itself causes immunogenicity with activation of pro-inflammatory cytokines such as tumor necrosis factor-α (TNF-α), Interleukin (IL)-6 and IL-12 and other innate reactivity manifests as systemic reactions including neurological adverse events. LNP used as an adjuvant precipitates reactogenicity through B-cell amplification and antigen-specific CD4+ and CD8+ T cell responses [48].

Strength of study
This study is based on VigiBase, a large global database of spontaneous reports of AEs used by Uppsala Monitoring Centre, Sweden to generate AEs related signals and used in various published studies to link adverse events with drug use. To avoid any kind of false-positive association, the most conservative method of disproportionality analysis, i.e. IC 025 values, was used.

Limitations of the study
The data in this study were taken from VigiBase which includes information from varied sources. The probability that the suspected adverse effect is caused by the drug cannot be ascertained for all the cases. The information provided does not represent the opinion of the UMC or the WHO. The data in the study are from a limited duration and to draw conclusive evidence, larger studies with long-term data need to be analyzed.

Future prospects and conclusion
With numerous molecules being experimented with for the therapy of COVID-19, vaccines have given a ray of hope to curb this pandemic. Almost 15 approved vaccines around the world were being administered in different countries after receiving emergency approval from their respective licensing authorities. These vaccines, in view of an emergency need across the globe, were developed in a short period of time and tried in the clinical trials for a brief period as compared to usual vaccine development. The adverse events with these vaccines are known on the basis of the clinical trials done but long-term and rare adverse events were unclear and are now being revealed with the wide administration drives of vaccination across the globe. All the adverse events associated with any drug or therapy are ultimately reported to the international database called VigiBase hence it is better to analyze their data to find out the common adverse events associated with any therapy across the world. The neurological adverse events associated with these vaccines were not frequent and a headache was one of the common adverse events reported. There were some reported rare serious neurological adverse events but their causal association with the vaccines was to be established. As there can be many predisposing conditions in the patients and interaction with them could also lead to a particular adverse event, hence it was too early to associate a particular adverse event with the vaccines. These reported adverse events can serve as a preliminary signal for potential ADRs associated with these vaccines but based on these results one must not conclude the safety of the above-analyzed vaccines. Moreover, these reported events are adverse events and do not have adverse drug reactions hence definitive causality of the reported events could not be assessed. Therefore long-term robust follow-up studies or cohort studies must be conducted with close monitoring of the adverse events reported establishing the safety of these vaccines.
The current study tries to summarize various neurological manifestations reported in patients who received the vaccines by analyzing the VigiBase, which can help find the common neurological AEs, which can help the prescribers in better management of the public vaccination program and also help in building public awareness and alleviating existing public perceptions.        Additional Information

Conflicts of interest:
In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work.