key: cord-0792846-hzly29sz authors: Lu, Lu; Xiong, Weixi; Mu, Jie; Zhang, Qi; Zhang, Hesheng; Zou, Ling; Li, Weimin; He, Li; Sander, Josemir W.; Zhou, Dong title: The potential neurological effect of the COVID‐19 vaccines: A review date: 2021-03-29 journal: Acta Neurol Scand DOI: 10.1111/ane.13417 sha: 48ae41ac0b229d1887d4f8175ca770ed9680e0c5 doc_id: 792846 cord_uid: hzly29sz The coronavirus disease 2019 caused by the severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) has become a pandemic with people infected in almost all countries. The most efficient solution to end this pandemic is a safe and efficient vaccine. Classic platforms are used to develop vaccines including live‐attenuated vaccine, inactivated vaccine, protein subunit vaccine, and viral vector. Nucleic acid vaccine uses next‐generation platforms for their development. Vaccines are now rushing to the market. Eleven candidates are in advance development. These comprise inactivated vaccines, viral vector vaccine, nucleic acid vaccine, and the protein subunit vaccine platform, which are now quite advanced in trials in various geographic and ethnic populations. The reported severe adverse effects raised the worries about their safety. It becomes critical to know whether these vaccines will cause neurologic disorders like previously recognized vaccine‐related demyelinating diseases, fever‐induced seizure, and other possible deficits. We reviewed the most promising COVID‐2 vaccines with a particular interest in mechanism(s) and adverse effect(s). We exemplify potential neurological problems these vaccines could cause by looking at previous studies. The current evidence indicated a minor risk of the acute neurological disorders after the application. The observation of the long‐time effect is still needed. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged in December 2019 and caused the coronavirus disease 2019 (COVID- 19) , which is now pandemic. To date, the COVID-19 has infected over one million people worldwide, and more than two million deaths were reported. The secondary wave of the pandemic was just about to left. The most promising solution remains to be an efficient vaccine. The development of the vaccines starts as soon as the virus genome was published in early January. 1 The most significant difference in developing a COVID-19 vaccine is the wide range of technology platforms used. 2 Some of these platforms, however, have not been widely used previously. 3 The Pfizer-BioNTech vaccine has become the first licensed product. Vaccines against coronaviruses have not been previously licensed in humans. 4 A frequently asked question is whether the speed of development may compromise the vaccine's safety and efficiency. Research suggests that the willingness of people getting immunization for COVID varies from 55% to 90%. 5-7 Over the past decades, vaccine hesitancy has steadily grown, partly due to fear of side effects arising from vaccination. Some reports have shown the neurologic side effects after immunization, mainly demyelinating diseases (Table 1) . Some studies also suggest that post-vaccination demyelination is most likely acting as triggers of clinical disease expression in individuals who already have an underlying disease process. 8 Another frequently reported adverse effect is acute systematic seizures. Some previously reported vaccine-induced seizures were reported in Dravet syndrome, in which it seems that vaccinationinduced fever acts as a seizures trigger. 9 Currently, a number of COVID-19 vaccines have been launching to the market, and the others are still in phase 3 clinical trials. Different techniques and mechanism are in use to develop them. Given the speed of this development and issuing, concerns exist. It becomes increasingly vital to emphasize the safety of the coming vaccination options in neurological disorders. We systematically reviewed the released information of the 11 vaccine candidates entered phase 3 trials announced by the world health organization by November 2011. 10 None of them had finished all the phase 3 endpoints per protocol by February 2021. 11 We also discussed the mechanism and neurological adverse effects reported in the four vaccine platforms in which they are developed. We aim to clarify the potential neurological effects these vaccines may have based on previous experience. The review was designed based on the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) protocol. 12 We searched systematically in PubMed and medRxiv using the keywords "COVID-19" or "SARS-CoV-2" and "vaccination" or "vaccine," to identify all studies from 1 January 2020, up to 28 February 2021. We also searched systematically in Google using the keywords "COVID-19" or "SARS-CoV-2," "vaccination" or "vaccine" and "adverse effect," to identify the official statement from the manufactures of the vaccine candidates and the drug authorities. We excluded reviews, editorials, letters, and animal studies. Those in-human phase 3 trial cited in the draft landscape of WHO were included. The inclusion criteria were as follows: (1) Participants were healthy adults older than 18 years without previous history of COVID-19 infection or previous underlying medical history; (2) randomized, placebo-controlled design, and (3) safety and efficiency were evaluated. The selected studies were then independently reviewed by three co-authors (LL, WX, and JM) for adverse effect with a particular interest in neurological issues. The frequency of neurological adverse events and the differences in efficiency parameters between vaccine candidates and their control were pooled and stratified. We initially identified 505,214 articles in PubMed and 11693 in me-dRxiv. Forty-eight was selected for detailed reviewing. No major or significant neurological adverse effect was reported. Data on neurological adverse effects reported in COVID-19 vaccine candidates are shown in Table 2 . Due to the limitation of reliable forthcoming evidence, we transformed this into a narrative review. Previous reports 28 The vaccine's goal is to produce antibodies that can neutralize pathogens or flag them for destruction by the immune system. Despite different platforms used, modern vaccines share components with risk of neurological adverse effects (shown in Table 3 ). Different technological platforms have been used to introduce the selected antigen to the immune system. Eleven candidate vaccines are undergoing large-scale development programs worldwide using four different platforms. The varied components in those candidates and their mode of action raised a range of potential adverse effects. The inactivated vaccine is one of the most traditional platforms. Chemicals or heat renders the virus uninfectious. This platform's safety and efficiency have been previously proved in vaccines against the influenza virus. The non-infective nature of the attenuated virus requires enhancing immunogenicity and stimulation of cellular immunity using adjuvants. 30 The degree to which inactivated vaccines are tolerated depends on the purification techniques used to remove other proteins associated with the infectious agent and the nature of the adjuvants. 31 A febrile reaction after inactivated vaccines is a common adverse reaction. The mechanisms responsible for the febrile response remain unclear. One hypothesis is that high inflammatory cytokines are associated with more robust immune responses and a febrile reaction. 32 But no febrile seizure was reported so far in the COVID-19 trials. Another concern is about the associations between vaccines and autoimmune disorders, including Guillain-Barré syndrome (GBS), multiple sclerosis (MS), and other demyelinating disorders. A recent systematic review about the association between different inactivated vaccines (HPV, influenza, tetanus, Bacillus Calmette-Guérin (BCG), polio, or diphtheria) and central demyelinating disorders, however, found no relationship between these vaccines and MS. 33 Similarly, another review of e vaccine-associated neurological adverse events found no direct evidence of increased risk of GBS and anti-NMDA receptor encephalitis after vaccination. 34 Adjuvants are used in such vaccines. They raise concerns about the potential adverse effect they could have, particularly at the injection site and the mediators' responses and inflammatory influx. Most candidates in this platform use alum adjuvant. To date, no related severe adverse effect (SAE) has been reported. Immunization stress-related response (ISRR) was also reported in this platform. 35 The primary concern in this platform is raised from the vaccine These two trials shared a same phase 3 protocol; b Posted in the pre-print site MedRxiv A subunit vaccine is based on the synthetic peptides or recombinant antigenic proteins. It is composed of at least one type of viral antigen produced in heterologous expression systems. 43 The subunit vaccine was considered to be safer because its components only contain recombinant proteins or synthetic peptides, without the involvement of infectious viruses. The S Protein and its antigenic fragments are the prime targets for the institution of the subunit vaccine. 44 Since the subunit vaccine exhibits low immunogenicity, they require additional support of an adjuvant to potentiate the immune responses. The only candidate from this section in phase 3 was NVX- Nucleic acid-based vaccines consist of DNA or mRNA and can be adapted quickly when new viruses emerge. The mRNA works by introducing an mRNA sequence that is coded for the S protein or RBD. Once interacting with the host's cells, it produces the specific antigen outside the cell surface to activate the immune system. Only one among the 11 candidates in phase 3 stage has released the data in large-scale population. Preliminary results suggest that neurologic adverse effect is rare. Cases of demyelinating disease were reported in the viral vector vaccine. Fever was one of the most frequent effects on all platforms, particularly in the mRNA platform. It could lower the seizure threshold, as the international league against epilepsy warns. 49 Whether the vaccine could cause or trigger neurological disorders or incidentally lead to them need long-time monitoring-a cautious optimism toward the vaccine's safety in terms of neurological effect is appropriate. 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