National Academies Press: OpenBook
« Previous: 2 Immunologic Response to COVID-19 Vaccines
Suggested Citation:"3 Neurologic Conditions and COVID-19 Vaccines." National Academies of Sciences, Engineering, and Medicine. 2024. Evidence Review of the Adverse Effects of COVID-19 Vaccination and Intramuscular Vaccine Administration. Washington, DC: The National Academies Press. doi: 10.17226/27746.
×
Page 53
Suggested Citation:"3 Neurologic Conditions and COVID-19 Vaccines." National Academies of Sciences, Engineering, and Medicine. 2024. Evidence Review of the Adverse Effects of COVID-19 Vaccination and Intramuscular Vaccine Administration. Washington, DC: The National Academies Press. doi: 10.17226/27746.
×
Page 54
Suggested Citation:"3 Neurologic Conditions and COVID-19 Vaccines." National Academies of Sciences, Engineering, and Medicine. 2024. Evidence Review of the Adverse Effects of COVID-19 Vaccination and Intramuscular Vaccine Administration. Washington, DC: The National Academies Press. doi: 10.17226/27746.
×
Page 55
Suggested Citation:"3 Neurologic Conditions and COVID-19 Vaccines." National Academies of Sciences, Engineering, and Medicine. 2024. Evidence Review of the Adverse Effects of COVID-19 Vaccination and Intramuscular Vaccine Administration. Washington, DC: The National Academies Press. doi: 10.17226/27746.
×
Page 56
Suggested Citation:"3 Neurologic Conditions and COVID-19 Vaccines." National Academies of Sciences, Engineering, and Medicine. 2024. Evidence Review of the Adverse Effects of COVID-19 Vaccination and Intramuscular Vaccine Administration. Washington, DC: The National Academies Press. doi: 10.17226/27746.
×
Page 57
Suggested Citation:"3 Neurologic Conditions and COVID-19 Vaccines." National Academies of Sciences, Engineering, and Medicine. 2024. Evidence Review of the Adverse Effects of COVID-19 Vaccination and Intramuscular Vaccine Administration. Washington, DC: The National Academies Press. doi: 10.17226/27746.
×
Page 58
Suggested Citation:"3 Neurologic Conditions and COVID-19 Vaccines." National Academies of Sciences, Engineering, and Medicine. 2024. Evidence Review of the Adverse Effects of COVID-19 Vaccination and Intramuscular Vaccine Administration. Washington, DC: The National Academies Press. doi: 10.17226/27746.
×
Page 59
Suggested Citation:"3 Neurologic Conditions and COVID-19 Vaccines." National Academies of Sciences, Engineering, and Medicine. 2024. Evidence Review of the Adverse Effects of COVID-19 Vaccination and Intramuscular Vaccine Administration. Washington, DC: The National Academies Press. doi: 10.17226/27746.
×
Page 60
Suggested Citation:"3 Neurologic Conditions and COVID-19 Vaccines." National Academies of Sciences, Engineering, and Medicine. 2024. Evidence Review of the Adverse Effects of COVID-19 Vaccination and Intramuscular Vaccine Administration. Washington, DC: The National Academies Press. doi: 10.17226/27746.
×
Page 61
Suggested Citation:"3 Neurologic Conditions and COVID-19 Vaccines." National Academies of Sciences, Engineering, and Medicine. 2024. Evidence Review of the Adverse Effects of COVID-19 Vaccination and Intramuscular Vaccine Administration. Washington, DC: The National Academies Press. doi: 10.17226/27746.
×
Page 62
Suggested Citation:"3 Neurologic Conditions and COVID-19 Vaccines." National Academies of Sciences, Engineering, and Medicine. 2024. Evidence Review of the Adverse Effects of COVID-19 Vaccination and Intramuscular Vaccine Administration. Washington, DC: The National Academies Press. doi: 10.17226/27746.
×
Page 63
Suggested Citation:"3 Neurologic Conditions and COVID-19 Vaccines." National Academies of Sciences, Engineering, and Medicine. 2024. Evidence Review of the Adverse Effects of COVID-19 Vaccination and Intramuscular Vaccine Administration. Washington, DC: The National Academies Press. doi: 10.17226/27746.
×
Page 64
Suggested Citation:"3 Neurologic Conditions and COVID-19 Vaccines." National Academies of Sciences, Engineering, and Medicine. 2024. Evidence Review of the Adverse Effects of COVID-19 Vaccination and Intramuscular Vaccine Administration. Washington, DC: The National Academies Press. doi: 10.17226/27746.
×
Page 65
Suggested Citation:"3 Neurologic Conditions and COVID-19 Vaccines." National Academies of Sciences, Engineering, and Medicine. 2024. Evidence Review of the Adverse Effects of COVID-19 Vaccination and Intramuscular Vaccine Administration. Washington, DC: The National Academies Press. doi: 10.17226/27746.
×
Page 66
Suggested Citation:"3 Neurologic Conditions and COVID-19 Vaccines." National Academies of Sciences, Engineering, and Medicine. 2024. Evidence Review of the Adverse Effects of COVID-19 Vaccination and Intramuscular Vaccine Administration. Washington, DC: The National Academies Press. doi: 10.17226/27746.
×
Page 67
Suggested Citation:"3 Neurologic Conditions and COVID-19 Vaccines." National Academies of Sciences, Engineering, and Medicine. 2024. Evidence Review of the Adverse Effects of COVID-19 Vaccination and Intramuscular Vaccine Administration. Washington, DC: The National Academies Press. doi: 10.17226/27746.
×
Page 68
Suggested Citation:"3 Neurologic Conditions and COVID-19 Vaccines." National Academies of Sciences, Engineering, and Medicine. 2024. Evidence Review of the Adverse Effects of COVID-19 Vaccination and Intramuscular Vaccine Administration. Washington, DC: The National Academies Press. doi: 10.17226/27746.
×
Page 69
Suggested Citation:"3 Neurologic Conditions and COVID-19 Vaccines." National Academies of Sciences, Engineering, and Medicine. 2024. Evidence Review of the Adverse Effects of COVID-19 Vaccination and Intramuscular Vaccine Administration. Washington, DC: The National Academies Press. doi: 10.17226/27746.
×
Page 70
Suggested Citation:"3 Neurologic Conditions and COVID-19 Vaccines." National Academies of Sciences, Engineering, and Medicine. 2024. Evidence Review of the Adverse Effects of COVID-19 Vaccination and Intramuscular Vaccine Administration. Washington, DC: The National Academies Press. doi: 10.17226/27746.
×
Page 71
Suggested Citation:"3 Neurologic Conditions and COVID-19 Vaccines." National Academies of Sciences, Engineering, and Medicine. 2024. Evidence Review of the Adverse Effects of COVID-19 Vaccination and Intramuscular Vaccine Administration. Washington, DC: The National Academies Press. doi: 10.17226/27746.
×
Page 72
Suggested Citation:"3 Neurologic Conditions and COVID-19 Vaccines." National Academies of Sciences, Engineering, and Medicine. 2024. Evidence Review of the Adverse Effects of COVID-19 Vaccination and Intramuscular Vaccine Administration. Washington, DC: The National Academies Press. doi: 10.17226/27746.
×
Page 73
Suggested Citation:"3 Neurologic Conditions and COVID-19 Vaccines." National Academies of Sciences, Engineering, and Medicine. 2024. Evidence Review of the Adverse Effects of COVID-19 Vaccination and Intramuscular Vaccine Administration. Washington, DC: The National Academies Press. doi: 10.17226/27746.
×
Page 74
Suggested Citation:"3 Neurologic Conditions and COVID-19 Vaccines." National Academies of Sciences, Engineering, and Medicine. 2024. Evidence Review of the Adverse Effects of COVID-19 Vaccination and Intramuscular Vaccine Administration. Washington, DC: The National Academies Press. doi: 10.17226/27746.
×
Page 75
Suggested Citation:"3 Neurologic Conditions and COVID-19 Vaccines." National Academies of Sciences, Engineering, and Medicine. 2024. Evidence Review of the Adverse Effects of COVID-19 Vaccination and Intramuscular Vaccine Administration. Washington, DC: The National Academies Press. doi: 10.17226/27746.
×
Page 76
Suggested Citation:"3 Neurologic Conditions and COVID-19 Vaccines." National Academies of Sciences, Engineering, and Medicine. 2024. Evidence Review of the Adverse Effects of COVID-19 Vaccination and Intramuscular Vaccine Administration. Washington, DC: The National Academies Press. doi: 10.17226/27746.
×
Page 77
Suggested Citation:"3 Neurologic Conditions and COVID-19 Vaccines." National Academies of Sciences, Engineering, and Medicine. 2024. Evidence Review of the Adverse Effects of COVID-19 Vaccination and Intramuscular Vaccine Administration. Washington, DC: The National Academies Press. doi: 10.17226/27746.
×
Page 78
Suggested Citation:"3 Neurologic Conditions and COVID-19 Vaccines." National Academies of Sciences, Engineering, and Medicine. 2024. Evidence Review of the Adverse Effects of COVID-19 Vaccination and Intramuscular Vaccine Administration. Washington, DC: The National Academies Press. doi: 10.17226/27746.
×
Page 79
Suggested Citation:"3 Neurologic Conditions and COVID-19 Vaccines." National Academies of Sciences, Engineering, and Medicine. 2024. Evidence Review of the Adverse Effects of COVID-19 Vaccination and Intramuscular Vaccine Administration. Washington, DC: The National Academies Press. doi: 10.17226/27746.
×
Page 80
Suggested Citation:"3 Neurologic Conditions and COVID-19 Vaccines." National Academies of Sciences, Engineering, and Medicine. 2024. Evidence Review of the Adverse Effects of COVID-19 Vaccination and Intramuscular Vaccine Administration. Washington, DC: The National Academies Press. doi: 10.17226/27746.
×
Page 81
Suggested Citation:"3 Neurologic Conditions and COVID-19 Vaccines." National Academies of Sciences, Engineering, and Medicine. 2024. Evidence Review of the Adverse Effects of COVID-19 Vaccination and Intramuscular Vaccine Administration. Washington, DC: The National Academies Press. doi: 10.17226/27746.
×
Page 82
Suggested Citation:"3 Neurologic Conditions and COVID-19 Vaccines." National Academies of Sciences, Engineering, and Medicine. 2024. Evidence Review of the Adverse Effects of COVID-19 Vaccination and Intramuscular Vaccine Administration. Washington, DC: The National Academies Press. doi: 10.17226/27746.
×
Page 83
Suggested Citation:"3 Neurologic Conditions and COVID-19 Vaccines." National Academies of Sciences, Engineering, and Medicine. 2024. Evidence Review of the Adverse Effects of COVID-19 Vaccination and Intramuscular Vaccine Administration. Washington, DC: The National Academies Press. doi: 10.17226/27746.
×
Page 84
Suggested Citation:"3 Neurologic Conditions and COVID-19 Vaccines." National Academies of Sciences, Engineering, and Medicine. 2024. Evidence Review of the Adverse Effects of COVID-19 Vaccination and Intramuscular Vaccine Administration. Washington, DC: The National Academies Press. doi: 10.17226/27746.
×
Page 85
Suggested Citation:"3 Neurologic Conditions and COVID-19 Vaccines." National Academies of Sciences, Engineering, and Medicine. 2024. Evidence Review of the Adverse Effects of COVID-19 Vaccination and Intramuscular Vaccine Administration. Washington, DC: The National Academies Press. doi: 10.17226/27746.
×
Page 86
Suggested Citation:"3 Neurologic Conditions and COVID-19 Vaccines." National Academies of Sciences, Engineering, and Medicine. 2024. Evidence Review of the Adverse Effects of COVID-19 Vaccination and Intramuscular Vaccine Administration. Washington, DC: The National Academies Press. doi: 10.17226/27746.
×
Page 87
Suggested Citation:"3 Neurologic Conditions and COVID-19 Vaccines." National Academies of Sciences, Engineering, and Medicine. 2024. Evidence Review of the Adverse Effects of COVID-19 Vaccination and Intramuscular Vaccine Administration. Washington, DC: The National Academies Press. doi: 10.17226/27746.
×
Page 88
Suggested Citation:"3 Neurologic Conditions and COVID-19 Vaccines." National Academies of Sciences, Engineering, and Medicine. 2024. Evidence Review of the Adverse Effects of COVID-19 Vaccination and Intramuscular Vaccine Administration. Washington, DC: The National Academies Press. doi: 10.17226/27746.
×
Page 89
Suggested Citation:"3 Neurologic Conditions and COVID-19 Vaccines." National Academies of Sciences, Engineering, and Medicine. 2024. Evidence Review of the Adverse Effects of COVID-19 Vaccination and Intramuscular Vaccine Administration. Washington, DC: The National Academies Press. doi: 10.17226/27746.
×
Page 90
Suggested Citation:"3 Neurologic Conditions and COVID-19 Vaccines." National Academies of Sciences, Engineering, and Medicine. 2024. Evidence Review of the Adverse Effects of COVID-19 Vaccination and Intramuscular Vaccine Administration. Washington, DC: The National Academies Press. doi: 10.17226/27746.
×
Page 91
Suggested Citation:"3 Neurologic Conditions and COVID-19 Vaccines." National Academies of Sciences, Engineering, and Medicine. 2024. Evidence Review of the Adverse Effects of COVID-19 Vaccination and Intramuscular Vaccine Administration. Washington, DC: The National Academies Press. doi: 10.17226/27746.
×
Page 92
Suggested Citation:"3 Neurologic Conditions and COVID-19 Vaccines." National Academies of Sciences, Engineering, and Medicine. 2024. Evidence Review of the Adverse Effects of COVID-19 Vaccination and Intramuscular Vaccine Administration. Washington, DC: The National Academies Press. doi: 10.17226/27746.
×
Page 93
Suggested Citation:"3 Neurologic Conditions and COVID-19 Vaccines." National Academies of Sciences, Engineering, and Medicine. 2024. Evidence Review of the Adverse Effects of COVID-19 Vaccination and Intramuscular Vaccine Administration. Washington, DC: The National Academies Press. doi: 10.17226/27746.
×
Page 94
Suggested Citation:"3 Neurologic Conditions and COVID-19 Vaccines." National Academies of Sciences, Engineering, and Medicine. 2024. Evidence Review of the Adverse Effects of COVID-19 Vaccination and Intramuscular Vaccine Administration. Washington, DC: The National Academies Press. doi: 10.17226/27746.
×
Page 95
Suggested Citation:"3 Neurologic Conditions and COVID-19 Vaccines." National Academies of Sciences, Engineering, and Medicine. 2024. Evidence Review of the Adverse Effects of COVID-19 Vaccination and Intramuscular Vaccine Administration. Washington, DC: The National Academies Press. doi: 10.17226/27746.
×
Page 96
Suggested Citation:"3 Neurologic Conditions and COVID-19 Vaccines." National Academies of Sciences, Engineering, and Medicine. 2024. Evidence Review of the Adverse Effects of COVID-19 Vaccination and Intramuscular Vaccine Administration. Washington, DC: The National Academies Press. doi: 10.17226/27746.
×
Page 97
Suggested Citation:"3 Neurologic Conditions and COVID-19 Vaccines." National Academies of Sciences, Engineering, and Medicine. 2024. Evidence Review of the Adverse Effects of COVID-19 Vaccination and Intramuscular Vaccine Administration. Washington, DC: The National Academies Press. doi: 10.17226/27746.
×
Page 98
Suggested Citation:"3 Neurologic Conditions and COVID-19 Vaccines." National Academies of Sciences, Engineering, and Medicine. 2024. Evidence Review of the Adverse Effects of COVID-19 Vaccination and Intramuscular Vaccine Administration. Washington, DC: The National Academies Press. doi: 10.17226/27746.
×
Page 99
Suggested Citation:"3 Neurologic Conditions and COVID-19 Vaccines." National Academies of Sciences, Engineering, and Medicine. 2024. Evidence Review of the Adverse Effects of COVID-19 Vaccination and Intramuscular Vaccine Administration. Washington, DC: The National Academies Press. doi: 10.17226/27746.
×
Page 100
Suggested Citation:"3 Neurologic Conditions and COVID-19 Vaccines." National Academies of Sciences, Engineering, and Medicine. 2024. Evidence Review of the Adverse Effects of COVID-19 Vaccination and Intramuscular Vaccine Administration. Washington, DC: The National Academies Press. doi: 10.17226/27746.
×
Page 101
Suggested Citation:"3 Neurologic Conditions and COVID-19 Vaccines." National Academies of Sciences, Engineering, and Medicine. 2024. Evidence Review of the Adverse Effects of COVID-19 Vaccination and Intramuscular Vaccine Administration. Washington, DC: The National Academies Press. doi: 10.17226/27746.
×
Page 102
Suggested Citation:"3 Neurologic Conditions and COVID-19 Vaccines." National Academies of Sciences, Engineering, and Medicine. 2024. Evidence Review of the Adverse Effects of COVID-19 Vaccination and Intramuscular Vaccine Administration. Washington, DC: The National Academies Press. doi: 10.17226/27746.
×
Page 103
Suggested Citation:"3 Neurologic Conditions and COVID-19 Vaccines." National Academies of Sciences, Engineering, and Medicine. 2024. Evidence Review of the Adverse Effects of COVID-19 Vaccination and Intramuscular Vaccine Administration. Washington, DC: The National Academies Press. doi: 10.17226/27746.
×
Page 104
Suggested Citation:"3 Neurologic Conditions and COVID-19 Vaccines." National Academies of Sciences, Engineering, and Medicine. 2024. Evidence Review of the Adverse Effects of COVID-19 Vaccination and Intramuscular Vaccine Administration. Washington, DC: The National Academies Press. doi: 10.17226/27746.
×
Page 105
Suggested Citation:"3 Neurologic Conditions and COVID-19 Vaccines." National Academies of Sciences, Engineering, and Medicine. 2024. Evidence Review of the Adverse Effects of COVID-19 Vaccination and Intramuscular Vaccine Administration. Washington, DC: The National Academies Press. doi: 10.17226/27746.
×
Page 106
Suggested Citation:"3 Neurologic Conditions and COVID-19 Vaccines." National Academies of Sciences, Engineering, and Medicine. 2024. Evidence Review of the Adverse Effects of COVID-19 Vaccination and Intramuscular Vaccine Administration. Washington, DC: The National Academies Press. doi: 10.17226/27746.
×
Page 107
Suggested Citation:"3 Neurologic Conditions and COVID-19 Vaccines." National Academies of Sciences, Engineering, and Medicine. 2024. Evidence Review of the Adverse Effects of COVID-19 Vaccination and Intramuscular Vaccine Administration. Washington, DC: The National Academies Press. doi: 10.17226/27746.
×
Page 108
Suggested Citation:"3 Neurologic Conditions and COVID-19 Vaccines." National Academies of Sciences, Engineering, and Medicine. 2024. Evidence Review of the Adverse Effects of COVID-19 Vaccination and Intramuscular Vaccine Administration. Washington, DC: The National Academies Press. doi: 10.17226/27746.
×
Page 109
Suggested Citation:"3 Neurologic Conditions and COVID-19 Vaccines." National Academies of Sciences, Engineering, and Medicine. 2024. Evidence Review of the Adverse Effects of COVID-19 Vaccination and Intramuscular Vaccine Administration. Washington, DC: The National Academies Press. doi: 10.17226/27746.
×
Page 110
Suggested Citation:"3 Neurologic Conditions and COVID-19 Vaccines." National Academies of Sciences, Engineering, and Medicine. 2024. Evidence Review of the Adverse Effects of COVID-19 Vaccination and Intramuscular Vaccine Administration. Washington, DC: The National Academies Press. doi: 10.17226/27746.
×
Page 111
Suggested Citation:"3 Neurologic Conditions and COVID-19 Vaccines." National Academies of Sciences, Engineering, and Medicine. 2024. Evidence Review of the Adverse Effects of COVID-19 Vaccination and Intramuscular Vaccine Administration. Washington, DC: The National Academies Press. doi: 10.17226/27746.
×
Page 112

Below is the uncorrected machine-read text of this chapter, intended to provide our own search engines and external engines with highly rich, chapter-representative searchable text of each book. Because it is UNCORRECTED material, please consider the following text as a useful but insufficient proxy for the authoritative book pages.

3 Neurologic Conditions and COVID-19 Vaccines This chapter describes the potential relationship between COVID-19 vaccines and potential neurological harms Guillain-Barré syndrome (GBS), chronic inflammatory demyelinating polyneuropathy, Bell’s palsy (BP), transverse myelitis (TM), chronic headache, and postural orthostatic tachycardia syndrome (POTS) (see Boxes 3-1 through 3-6 for all conclusions in this chapter). GUILLAIN-BARRÉ SYNDROME BOX 3-1 Conclusions for Guillain-Barré syndrome Conclusion 3-1: The evidence favors rejection of a causal relationship between the BNT162b2 vaccine and Guillain-Barré syndrome. Conclusion 3-2: The evidence favors rejection of a causal relationship between the mRNA- 1273 vaccine and Guillain-Barré syndrome. Conclusion 3-3: The evidence favors acceptance of a causal relationship between the Ad26.COV2.S vaccine and Guillain-Barré syndrome. Conclusion 3-4: The evidence is inadequate to accept or reject a causal relationship between the NVX-CoV2373 vaccine and Guillain-Barré syndrome. Background GBS is an acute, monophasic, immune-mediated disorder, or group of disorders, that primarily affects the peripheral nerves and roots. The typical clinical features include progressive symmetric muscle weakness and absent or depressed deep tendon reflexes. Patients may also experience tingling or prickling sensations (paresthesia) along with autonomic dysfunction, including fluctuations in blood pressure, heart rate, and respiratory distress. Cranial nerve involvement can result in facial weakness, difficulty swallowing, and speech problems, and some individuals experience significant pain, particularly in the back or legs. Symptoms usually progress over 1–2 weeks and generally plateau before 4 weeks (Fokke et al., 2014). Diagnosing GBS is a multifaceted process that involves a comprehensive clinical evaluation, cerebrospinal fluid (CSF) analysis, and electrodiagnostic studies. A thorough clinical history and neurological examination are critical to assess the pattern of weakness and reflex PREPUBLICATION COPY—Uncorrected Proofs

54 VACCINE EVIDENCE REVIEW abnormalities. Analysis of CSF often reveals elevated protein levels without a significant increase in white blood cells. Electrophysiological tests can confirm the diagnosis by revealing evidence of nerve demyelination in demyelinating variants of GBS and identifying pathological changes affecting both the roots and nerves. GBS is a relatively rare disease, with a global incidence of 0.81–1.91 cases per 100,000 person-years (Shahrizaila et al., 2021). The U.S. incidence of GBS is generally in line with the global average, with an estimated 1–2 cases per 100,000 individuals each year (Bragazzi et al., 2021). Although all age groups are affected, the incidence increases by approximately 20 percent with every 10-year increase beyond the first decade of life, with a peak incidence reported between 50–69 years and a slight male predominance (Leonhard et al., 2022). The pathophysiology of GBS remains incompletely understood and is likely heterogeneous, reflecting phenotypic variability among what is likely a group of related disorders rather than a single nosological entity. Despite this heterogeneity, more than two-thirds of patients report a history of upper respiratory tract or gastrointestinal infection weeks before the onset of neurologic symptoms, suggesting infection plays an important pathogenic role in all GBS variants (Leonhard et al., 2022). Although GBS is a global disease, regional differences occur in the distribution of variants. Demyelinating forms dominate in Europe and North America, but acute inflammatory demyelinating polyradiculoneuropathy (AIDP) accounts for 80–90 percent of cases and is characterized by ascending limb weakness. Other demyelinating variants with prominent and early cranial nerve involvement affecting eye movements and facial muscles, including the Miller-Fisher and facial diplegia with limb paresthesia variant, are rare. Axonal subtypes, such as acute motor axonal neuropathy (AMAN), dominate in Asia, particularly Bangladesh and north China (Leonhard et al., 2022). Seasonal variation of incidence track with infections. The risk is higher during the winter, particularly in Europe and North America, where it is associated primarily with upper respiratory infections. A summer peak occurs in Northern China, India, Bangladesh, and Latin America, where diarrheal illnesses can be more common. Incidence can also rise during outbreaks of infection, such as with Zika virus in South America or other arthropod infections, such as dengue and chikungunya (Shahrizaila et al., 2021). Globally, commonly implicated pathogens include Campylobacter jejuni, cytomegalovirus, Epstein-Barr virus, Mycoplasma pneumoniae, Haemophilus influenzae, influenza A virus, and Zika virus (Shahrizaila et al., 2021). C. Jejuni is the most commonly and extensively reported, and robust evidence suggests that molecular mimicry between microbial antigens and nerves is implicated in developing GBS. In addition to infection, GBS cases after vaccination have also been reported, especially with the 1976 swine-influenza and seasonal 2009 H1N1 monovalent influenza vaccines. However, the overall risk of influenza vaccines if present at all appears to be small, approximately 1–2 excess cases of GBS per million people vaccinated (Vellozzi et al., 2014). While some have reported an increased risk of GBS after SARS-CoV-2 infection, the actual incidence of GBS decreased during the pandemic, possibly due to an overall reduction in other communicable diseases (Keddie et al., 2021). The latency period between exposure to a triggering event (infection or vaccination) and GBS can vary, but it typically occurs within a few days to a few weeks. It is crucial to understand that not everyone exposed to these risk factors will develop GBS, and the exact mechanisms continue to be the subject of ongoing research. The epidemiology of GBS can be influenced by various factors, including changes in diagnostic techniques, vaccination practices, and evolving patterns of infectious diseases, so ongoing surveillance and research are crucial to continually monitor and understand it. PREPUBLICATION COPY—Uncorrected Proofs

NEUROLOGIC CONDITIONS 55 Mechanisms GBS is heterogeneous because it is likely a group of related disorders. Demyelinating variants, such AIDP, differ from axonal variants, such as AMAN, in both the range and extent of pathological changes. Nevertheless, nerve injury appears to be immune mediated, with antecedent infection being a common potential trigger. Autopsy studies demonstrate infiltrates of lymphocytes and macrophages involved in macrophage-mediated demyelination (Asbury et al., 1969; Wanschitz et al., 2003). Complement deposition can be demonstrated within the endoneurium, on the surface of myelinated fibers, and on mononuclear cells at sites of myelin breakdown, particularly in acute cases of less than 4 weeks duration, suggesting a role for antibody-mediated injury, whereas granzyme-expressing CD8+ T cells (i.e., cytotoxic T cells) are described in cases of longer duration (Wanschitz et al., 2003). By contrast, patients with AMAN demonstrate primary axonal injury with a paucity of inflammatory infiltrates or demyelination. IgG and complement-mediated humoral immune response are directed against epitopes in the axonal membrane. Animal models of GBS have been generated by immunizing rats with myelin proteins, galactocerebroside, adoptive transfer of myelin-specific T cells (AIDP), or immunization with GM1 ganglioside, resulting in circulating anti-GM1 antibodies (AMAM) (Figure 3-1) (Shahrizaila et al., 2021). These animal models implicate T cells and macrophages in AIDP but suggest that autoantibodies may play a greater role in AMAM (Shahrizaila et al., 2021). The mechanism of antibody-mediated damage may include interference with ion channel function, complement-dependent cytotoxicity, and/or interference with nerve regeneration; different clinical subtypes of GBS are associated with different anti-ganglioside antibodies (Shahrizaila et al., 2021). FIGURE 3-1 Overview of the pathogenesis and therapeutic targets of the two major Guillain-Barré syndrome subtypes. SOURCE: Shahrizaila et al., 2021. Evidence for molecular mimicry is best supported for C. jejuni-associated AMAN, where the reasoning is as follows (Yuki et al., 2004): PREPUBLICATION COPY—Uncorrected Proofs

56 VACCINE EVIDENCE REVIEW ● Patients with GBS after C. jejuni, but not patients with C. jejuni enteritis, have antibodies to GM1 ganglioside in their serum (Sheikh et al., 1998). ● The specific serotype of C. jejuni most commonly isolated from patients with GBS (PEN19) is rare in patients with C. jejuni enteritis. ● The GM1 ganglioside has an antigenic similarity with the lipopolysaccharide of C. jejuni serotype PEN19 (Yuki et al., 1993). ● Rabbits sensitized to C. jejuni LPS develop AMAM and flaccid limb weakness with pathological findings similar to GBS. ● Anti-GM1 IgG from patients with GBS can block muscle action potentials in muscle- spinal cord coculture, although they do not induce weakness when injected into mice (Yuki et al., 2004). C. jejuni infection can also generate antibodies against GQ1b gangliosides, which are associated with the Miller-Fisher GBS variant (Jacobs et al., 1997). Anti-ganglioside antibodies, however, are not found in association with all GBS variants. In addition, as mentioned in the background section, GBS is associated with a variety of pathogens, including potentially SARS- CoV-2, arguing against molecular mimicry as the single unifying mechanism in all forms of it. A few in silico studies have sought peptide antigens in SARS-CoV-2 with the potential to induce antibodies that cross-react with proteins in the peripheral or central nervous system, thereby activating complement and mediating neuronal damage (Chen et al., 2022b; Kadkhoda, 2022). One such study demonstrated similarity between a peptide in SARS-CoV2 and the NCAM L1–like protein in the myelin sheath and argued that cross-reactive antibodies might explain GBS after infection (Kadkhoda, 2022; Morsy, 2020). However, the shared peptide was in the SARS-CoV-2 envelope protein, not the spike protein, and would not provide mechanistic evidence for GBS occurring after COVID-19 vaccination. Epidemiological evidence suggests a possible association between adenoviral vector (AV) COVID-19 vaccines and GBS but not for the messenger ribonucleic acid (mRNA) vaccines (Hanson et al., 2022; Keh et al., 2023). This suggests the possibility of a platform-specific mechanism or immune response as opposed to one related to immune responses to the spike protein itself (such as molecular mimicry) (Rzymski, 2023). One study found high levels of complement-fixing antibodies to cytomegalovirus in a cohort of patients with GBS but no comparable antibodies to adenovirus in the same patients (Dowling et al., 1977), and adenovirus has not been historically linked with GBS in epidemiological studies. This suggests that natural adenoviral infection may not be associated with GBS. ChAdOx1-S 1 has high affinity for the coxsackie and adenoviral receptor (CAR), whereas HAdV26 has much lower CAR affinity (Baker et al., 2021; Hemsath et al., 2022; Rzymski, 2023). CAR is widely expressed in the body, including the central nervous system (Zussy et al., 2016); however, whether it is expressed in the peripheral nervous system has not been established. Therefore, it is unknown whether ChAdOx1-S could target peripheral nerves directly. Epidemiological Evidence Clinical trial results submitted to FDA for Emergency Use Authorization and full approval do not indicate a signal regarding GBS and any of the vaccines under study (FDA, 2021, 2023a, 2023b, 2023c). Table 3-1 presents eight studies that contributed to the causality assessment. 1 Refers to the COVID-19 vaccine manufactured by Oxford-AstraZeneca. PREPUBLICATION COPY—Uncorrected Proofs

NEUROLOGIC CONDITIONS 57 TABLE 3-1 Epidemiological Studies in the Guillain-Barré Syndrome Evidence Review Study Design and Control Age Number of Results Author Group Location Data Source Vaccine(s) Range N Events (95% CI) 9 cases 8.8 meeting BNT162b2 million Brighton doses criteria 1–3 during 1–21- day risk period RR 20.56 (6.94–64.66) Cohort/ 9 cases vaccinated 15.5 excess VSD/ meeting concurrent 5.8 cases in risk Hanson et al. EMR mRNA-1273 ≥12 Brighton comparators US million interval per (2022) (physician years criteria 1–3 and doses million doses of adjudicated) during 1–21- historical Ad26.COV2.S day risk period controls compared to mRNA 8 cases vaccines meeting Ad26.COV2 483,053 Brighton .S doses criteria 1–3 during 1–21- day risk period PREPUBLICATION COPY—Uncorrected Proofs

58 VACCINE EVIDENCE REVIEW TABLE 3-1 Continued Study Design and Control Age Number of Results (95% Author Group Location Data Source Vaccine(s) Range N Events CI) 11.5 No excess BNT162b2 21 cases million risk of GBS National in 0–42 days doses observed 0–42 immunization days following Cohort/ database/ Keh et al. ≥18 BNT162b2 vaccinated UK National 300,000 (2023) mRNA-1273 years 1 vaccine GBS cases immune- doses compared globulin to vaccinated database 20.3 cases in ChAdOx1-S million 176 control period doses 6.8 BNT12b2 and Cohort/ BNT162b2 million BNT12b2 and mRNA-1273 Klein et al. vaccinated VSD/ ≥16 doses mRNA-1273 combined US (2021) concurrent EMR years 5.1 combined: comparators mRNA-1273 million 10 RR 0.70 doses (0.22–2.31) PREPUBLICATION COPY—Uncorrected Proofs

NEUROLOGIC CONDITIONS 59 Study Design and Control Age Number of Results Author Group Location Data Source Vaccine(s) Range N Events (95% CI) UK Dose 1: UK 1.7 million UK N/A vaccinees Dose 1: <5 Dose 2: Dose 2: <5 1.2 million BNT162b2 vaccinees (UK and Spain) Spain Dose 1: Spain 1.9 million Spain Dose 1: vaccinees Dose 1: 5 Primary care SIR 0.79 Dose 2: Dose 2: <5 Cohort/ databases (0.33–1.91) Li et al. UK and ≥18 1.3 million historical linked to vaccinees (2022) Spain years background hospital data/ EMR Dose 1: 244,913 Dose 1: 0 mRNA-1273 vaccinees Dose 2: <5 N/A (Spain only) Dose 2: cases 160,213 vaccinees Ad26.COV2 Dose 1: .S (Spain 120,731 Dose 1: 0 N/A only) vaccinees PREPUBLICATION COPY—Uncorrected Proofs

60 VACCINE EVIDENCE REVIEW UK Dose 1: 3.8 million UK UK vaccinees Dose 1: 11 SIR 0.74 Dose 2: Dose 2: <5 (0.41–1.33) 1.1 million ChAdOx1-S vaccinees (UK and Spain) Spain Dose 1: 592,860 Spain Spain vaccinees Dose 1: <5 N/A Dose 2: Dose 2: 0 1.3 million vaccinees BNT162b2 1 mRNA- 1 1273 2.6-fold 24 patients (1.98–3.51) admitted increase in EMR with acute Case-control admissions (physician onset Loo et al. study/ ≥16 compared UK adjudicated) polyradicul (2021) historical years with the oneuropath background average for y between ChAdOx1- the same period January– 14 S in the previous June 2021 3 years PREPUBLICATION COPY—Uncorrected Proofs

NEUROLOGIC CONDITIONS 61 TABLE 3-1 Continued Study Design and Control Age Number of Results Author Group Location Data Source Vaccine(s) Range N Events (95% CI) Dose 1: RI 0.85 10.8 (0.49–1.48) BNT162b2 million Dose 1: 19 vaccinees Dose 2: 30 Dose 2: RI 1.30 (0.80–2.10) Dose 1: RI 6.83 1.7 (2.14–21.85) mRNA- Dose 1: 7 million 1273 Dose 2: 5 Morciano et Cohort/self- Multi-regional ≥12 vaccinees Dose 2: Italy al. (2022) controlled databases/EMR years RI 7.41 (2.35–23.38) Dose 1: Ad26.COV 581,796 Dose 1: 7 RI 1.94 2.S vaccinees (0.32–11.69) Dose 1: RI 6.52 2.9 (2.88–14.77) ChAdOx1- Dose 1: 34 million S Dose 2: 6 vaccinees Dose 2: RI 3.56 (0.31–40.29) 34 cases IRR 0.86 12.1 BNT162b2 during 1–28 (0.54–1.36) English million days risk Patone et al. Cohort/self- immunization ≥16 vaccinees England interval (2021) controlled records years 20.4 /EMR ChAdOx1- 153 IRR 2.04 million S 1–28 days (1.60–2.60) vaccinees PREPUBLICATION COPY—Uncorrected Proofs

62 VACCINE EVIDENCE REVIEW TABLE 3-1 Continued Study Design and Control Age Number of Results Author Group Location Data Source Vaccine(s) Range N Events (95% CI) 6.5 IRR 1.10 BNT162b2 million 16 (0.56–2.15) doses mRNA- 727,047 No cases N/A Primary and 1273 doses Sturkenboom Cohort/back European secondary care Varied et al. (2022) ground rate countries databases/EMR Ad26.COV 242,349 IRR 5.65 2 2.S doses (1.4–22.83) 4.6 ChAdOx1- IRR 1.43 million 15 S (0.85–2.40) doses 5.7 BNT162b2 IRR 1.00 million 283 (0.61–1.64) vaccinees Self- Walker et al. mRNA- ≥18 255,446 controlled UK EMR No cases N/A (2022) 1273 years vaccinees cohort 7.8 ChAdOx1- IRR 2.85 million 517 S (2.33–3.47) vaccinees NOTES: BNT162b2 refers to the COVID-19 vaccine manufactured by Pfizer-BioNTech under the name Comirnaty®. mRNA-1273 refers to the COVID-19 vaccine manufactured by Moderna under the name Spikevax®. Ad26.COV2.S refers to the COVID-19 vaccine manufactured by Janssen. The primary series for Ad26.COV2.S is one dose. ChAdOx1-S refers to the COVID-19 vaccine manufactured by Oxford-AstraZeneca. ChAdOx1-S appears in this table because it provides for support for Conclusion 3-3. The primary series for Ad26.COV2.S is one dose. Keh et al. (2023) refers to BNT162b2 as Tozinameran (Pfizer). Number of events refers to events in vaccinees only. EMR: electronic medical record; IRR: incidence rate ratio; N/A: not applicable; RI: relative incidence; RR: rate ratio; SIR: standardized incidence ratio; VSD: Vaccine Safety Datalink. SOURCES: Hanson et al., 2022; Keh et al., 2023; Klein et al., 2021; Li et al., 2022; Morciano et al., 2023; Patone et al., 2021; Sturkenboom et al., 2022; Walker et al., 2022. PREPUBLICATION COPY—Uncorrected Proofs

NEUROLOGIC CONDITIONS 63 Keh et al. (2023) retrospectively analyzed data from the National Immunoglobulin Database linked to the National Immunisation Management System, which records all intravenous immunoglobulin (IVIg) prescriptions for GBS patients in England (IVIg is given to an estimated 86 percent of UK patients with GBS). IVIg approval requires adjudication by an independent physician panel (Keh et al., 2023). The study included 11.5 million doses of BNT162b2 2 and 300,000 doses of mRNA-1273. 3 Of 196 postvaccinal cases, 21 occurred with BNT162b2 and one with mRNA-1273. Using case numbers from days 43–84 after first-dose vaccination as a comparison group, the first 42 days postvaccination with BNT162b2 had no excess risk of GBS (Keh et al., 2023). Patone et al. (2021) investigated the association between BNT162b2 and GBS among 32.6 million vaccinees, 12.1 million of whom received BNT162b2. This retrospective self-controlled cohort study compared the incidence rate of GBS in England at several intervals (1–7, 8–14, 15– 21, 22–28, and 1–28 days after vaccination) with the rate of GBS during periods outside of this interval. GBS was defined using International Classification of Diseases 10 (ICD-10) codes and identified as the first hospital admission or as a cause of death recorded on the death certificate. Vaccination status was identified in the English National Immunisation Database of COVID-19 vaccination. Only 34 cases of GBS were observed for BNT162b2 during the risk interval. The study found no association between BNT162b2 and GBS at any interval, including the 1–28-day period; incidence rate ratio (IRR) 0.86 (95% confidence interval [CI]: 0.54–1.36) (Patone et al., 2021). The results do not suggest increased incidence, but the estimate is imprecise; the results are consistent with no association but could also be consistent with a small increased risk (Patone et al., 2021). Klein et al. (2021) conducted a surveillance study within the Vaccine Safety Datalink (VSD), which includes data from eight U.S. integrated health care organizations with electronic health records. They compared incidence of GBS among vaccine recipients 1–21 days after either dose 1 or 2 of a messenger ribonucleic acid (mRNA) vaccine with that of concurrent comparators who, on the same calendar day, had received their most recent dose 22–42 days earlier. After 11.8 million doses (57 percent BNT162b2), 10 GBS cases were identified in the risk interval compared with six in the controlled interval, RR 0.70 (95% CI: 0.22–2.31) (Klein et al., 2021). Few events were observed, so the authors were unable to precisely estimate the measure of association. The results would be consistent with no association but could also be consistent with a small increase in risk. Hanson et al. (2022) also analyzed data from VSD. In their primary analysis, they compared the incidence of GBS cases among vaccine recipients at two time intervals, 1–21 and 1– 42 days with that of vaccinated concurrent comparators, who, on the same calendar day, had received their most recent dose 22–42 and 43–84 days earlier, respectively. In addition, incidence of GBS for individual vaccines was compared to prepandemic historical background rate (Hanson et al., 2022). GBS cases were physician adjudicated according to Brighton Collaboration criteria (Sejvar et al., 2011), and the analysis included Brighton Criteria 1–4. Level 1 has the highest level of diagnostic certainty; Level 4 includes suspected cases. The study included 14.6 million doses of mRNA vaccines (BNT162b2 or mRNA-1273) and 483,053 doses of Ad26.COV2.S. 4 During the 1–84 days following mRNA vaccines, 36 cases of GBS were confirmed, with nine cases meeting Brighton criteria 1–3 in the 1–21 days risk period. Eleven cases of GBS were confirmed 1–84 days 2 Refers to the COVID-19 vaccine manufactured by Pfizer-BioNTech under the name Comirnaty®. 3 Refers to the COVID-19 vaccine manufactured by Moderna under the name Spikevax®. 4 Refers to the COVID-19 vaccine manufactured by Janssen. PREPUBLICATION COPY—Uncorrected Proofs

64 VACCINE EVIDENCE REVIEW after Ad.26.COV2.S, with eight cases meeting Brighton criteria 1–3 in the 1–21 days period. Scan statistics identified days 1–14 after vaccination as a statistically significant cluster (p = .003). In a comparison of Ad26.COV2.S and mRNA vaccines, the adjusted rate ratio in the 1–21 days risk period was 20.56 (95% CI: 6.94–64.66) (Hanson et al., 2022). No association appeared between GBS and any of the vaccines based on the comparison with unvaccinated comparators (Hanson et al., 2022). However, the unadjusted incidence rate at 1–21 and 1–42 days after Ad26.COV2.S was higher than the historical background rate (p < .001). Excluding Brighton Level 4 cases did not significantly alter results. Sturkenboom et al. (2022) conducted a cross-national multi-database retrospective dynamic cohort study using primary and/or secondary health care data from four European countries: Italy, the Netherlands, the United Kingdom, and Spain. They compared the incidence of GBS in vaccine recipients with nonvaccinated persons in 2020 within 28 days after each dose. Of 25.7 million people, 16 GBS cases were identified after BNT162b2, two after Ad26.COV2.S, and none after mRNA-1273. They found an increased risk of GBS 28 days after Ad26.COV2.S (IRR 5.65, 95% CI: 1.40–22.83), but no increased risk after BNT162b2 (IRR 1.10, 95% CI: 0.56–2.15). Results for BNT162b2 suggest no association, but the authors were unable to precisely estimate risk, and results could also be consistent with a small increase in risk (Sturkenboom et al., 2022). Walker et al. (2022) analyzed primary care data from over 17 million patients in England linked to emergency care, hospital admission, and mortality records in OpenSAFELY, which is a secure analytics platform for the National Health Service electronic health records. They used a self-controlled case-series analytical approach where the risk interval was 4–28 days after vaccination. Among 5.7 million recipients of BNT162b2, 283 GBS cases were identified during the risk and controlled intervals; none were identified among 255,446 recipients of mRNA-1273. The results from the study suggested no association between the first dose of BNT162b2 and GBS, although the measure was imprecise and could suggest a small increase in risk (IRR 1.09, 95% CI: 0.75–1.57). Adjusting for calendar time and history of COVID-19 infection did not significantly change the measure of association (IRR 1.00, 95% CI: 0.61–1.64). Li et al. (2022) compared rates of GBS identified through medical records among vaccinees with historical background rates. They used the Clinical Practice Research Datalink (CPRD) AURUM, which contains routinely collected data from UK primary care practices and Spain’s Information System for Research in Primary Care (SIDIAP), a primary care database that covers 80 percent of the population in Catalonia. The study included 3.6 million people who received BNT162b2, 244,913 who received mRNA-1273, 120,731 who received Ad26.CoV.2.S, and 14.3 million people from the general population (Li et al., 2022). Of the BNT162b2 vaccinees, <5 cases occurred within 1–21 days after a first and second dose in CPRD AURUM, compared with 10.4 and 9 expected. SIDIAP showed five cases after the first dose of BNT162b2 and <5 cases after the second dose, compared with 6.3 and 5.3 expected, respectively. For mRNA-1273, <5 cases were diagnosed after the second dose compared with 0.7 expected. No cases were observed with the first dose of mRNA-1273 or after Ad26.COV2.S (Li et al., 2022). Morciano et al. (2023) investigated the association between COVID-19 vaccines and GBS in the population older than 12 years using a self-controlled case-series design with data from several regional health care databases in Italy. They evaluated relative incidence (RI) of GBS during a risk interval of 0–42 days after vaccination and an unexposed interval defined as any time of observation before, between, or after the risk intervals. Of 1.7 million individuals who received mRNA-1273, 25 developed GBS during the study period, with seven and five cases observed with the first and second doses, respectively, during the risk interval (RI 6.83, 95% CI: 2.14–21.85 for PREPUBLICATION COPY—Uncorrected Proofs

NEUROLOGIC CONDITIONS 65 dose 1 and RI 7.41, 95% CI: 2.35–23.38 for dose 2) (Morciano et al., 2023). This corresponded with an estimated 0.4 and 0.3 excess number of cases per 100,000 vaccinated for doses 1 and 2, respectively. The RI of GBS was not significantly increased in the 10.8 million and 581,796 individuals who received BNT162b and Ad26.COV2.S (Morciano et al., 2023). Loo et al. (2022) conducted a retrospective case-control study of all patients admitted for acute polyradiculoneuropathy to two UK neuroscience centers between January 1 and June 30, 2021. They compared vaccinees from the preceding 4 weeks to all GBS patients admitted to their centers between 2005 and 2019. A 2.6-fold (95% CI: 1.98–3.51) increase in admissions for GBS was noted during the time frame, compared to the same period in the preceding 3 years. Of 24 GBS patients, 16 were postvaccine, and all but two (one BNT162b, one mRNA-1273) occurred after ChAdOx1-S (Loo et al., 2022). Although some studies relied on physician adjudication for case ascertainment (Hanson et al., 2022; Keh et al., 2023; Loo et al., 2022), others relied on ICD codes from electronic data without chart confirmation. Some GBS cases identified by the ICD codes might not be true cases, which could have biased the measure of association. In addition, some studies used historical cohorts as a comparator group. Several studies have shown that annual GBS incidence decreased during the pandemic, which could have biased the measure of association. Pharmacovigilance and Surveillance Table 3-2 presents five pharmacovigilance studies that contributed to the committee’s assessment based on their size, design, analytic approach, and region surveilled. PREPUBLICATION COPY—Uncorrected Proofs

66 VACCINE EVIDENCE REVIEW TABLE 3-2 Pharmacovigilance Studies in the Guillain-Barré Syndrome Evidence Review Study Design and Control Age Number of Results Author Group Location Data Source Vaccine(s) Range N Events (95% CI) 266.9 BNT162b2 million O:E <1 doses 202.8 Cohort/ VAERS mRNA-1273 million 21 days: 209 O:E < 1 Abara et al. ≥18 doses historical US (physician 42 days: 253 (2023) years background adjudicated) 1–21 days 17.9 O:E 3.79 (2.88–4.88) Ad26.COV2.S million doses 1–42 days O:E 2.34 (1.83–2.94) 16.6 Unadjusted Incidence BNT162b2 million 32 1.92 (1.36– 2.71) doses 2.3 Unadjusted Incidence mRNA- 1273 million 3 Mexican 1.29 (0.44–3.81) doses Epidemiolog ical 1.0 Garcia- Cohort/ Surveillance ≥18 million 4 Unadjusted Incidence Grimshaw et historical Mexico Ad26.COV2.S System/ years doses 3.86 (1.50–9.93) al. (2022) background EMR (physician adjudicated) 38.5 Unadjusted incidence ChAdOx1-S million 37 0.96 (0.70–1.32) doses PREPUBLICATION COPY—Uncorrected Proofs

NEUROLOGIC CONDITIONS 67 TABLE 3-2 Continued Study Design and Control Age Number of Results Author Group Location Data Source Vaccine(s) range N Events (95% CI) Gyeonggi mRNA mRNA Infectious vaccines: 26 vaccines IR Disease cases BNT162b, 38.8 0.80 per million doses Ha et al. South Control ≥12 Cohort mRNA-1273, million (0.49–1.11) (2023) Korea Center/ years Adenovirus- Ad26.COV2.S doses Adenovirus-vectored IR EMR vectored 4.49 per million doses (physician vaccines: 29 (2.85–6.12) adjudicated) cases 488 mRNA 142/1,256 vaccines of GBS cases Cohort/mR vaccinees with facial NA BNT162b, Facial paresis more frequent VigiBase paresis (26 Pegat et al. vaccines to US, UK, mRNA-1273, Not with adenovirus vectored (physician 788 mRNA (2021) Adenovirus Europe Ad26.COV2.S, stated vaccines adjudicated) Adenovirus vaccines, - vectored ChAdOx1 -vectored 28 vaccines vaccines adenovirus- vaccinees vectored) National Open-label Electronic phase 3b Vaccination Takuva et implementa South ≥18 477,234 Data Ad26.COV2.S 4 cases O:E 5.09 (1.39–13.02) al. (2021) tion study/ Africa years vaccinees System/EM historical R (physician background adjudicated) PREPUBLICATION COPY—Uncorrected Proofs

68 VACCINE EVIDENCE REVIEW TABLE 3-2 Continued NOTES: BNT162b2 refers to the COVID-19 vaccine manufactured by Pfizer-BioNTech under the name Comirnaty®. mRNA-1273 refers to the COVID-19 vaccine manufactured by Moderna under the name Spikevax®. Ad26.COV2.S refers to the COVID-19 vaccine manufactured by Janssen. ChAdOx1-S refers to the COVID-19 vaccine manufactured by Oxford-AstraZeneca. ChAdOx1-S appears in this table because it provides for support for Conclusion 3-3. Ha et al. (2023) combined the number of events from adenoviral vector vaccines (Ad26.COV2.S and ChAdOx1-S). CI: confidence interval; EMR: electronic medical record; IR: incidence rate; O:E: observed to expected ratio; VAERS: Vaccine Adverse Events Reporting System. SOURCES: Abara et al., 2023; García-Grimshaw et al., 2022; Ha et al., 2023; Pegat et al., 2022; Takuva et al., 2022. PREPUBLICATION COPY—Uncorrected Proofs

NEUROLOGIC CONDITIONS 69 Abara et al. (2023) analyzed data from the Vaccine Adverse Event Reporting System, which is comanaged by the Centers for Disease Control and Prevention and Food and Drug Administration. Of 487.7 million COVID-19 vaccine doses, 209 and 253 reports of GBS occurred within 21 and 42 days, respectively. Observed-to-expected ratios (O:E) were 3.79 (95% CI: 2.88–4.88) for days 1–21 and 2.34 (95% CI: 1.83–2.94) for days 1–42 after Ad26.COV2.S and less than 1 (not significantly increased) after BNT162b2 and mRNA-1273 for both postvaccination periods (Abara et al., 2023). Pegat et al. (2022) analyzed data from VigiBase, the World Health Organization pharmacovigilance database, and the French pharmacovigilance database to compare the frequency of facial paralysis in GBS cases after adenovirus-vector (AV) vaccines to that after mRNA vaccines and found that 142 of 1,256 GBS patients in VigiBase had associated facial paralysis (11.3 percent). This included 26 of 488 who received mRNA vaccines (12/328 BNT162b2, 14/160 mRNA-1273), 114 of 744 who received AV vaccines (28/114 Ad26.COV2.S, 86/630 ChAdOx1-S), and 2 of 24 who received other vaccines. Facial paralysis was significantly more frequent after AV vaccines (χ2: p = 6.44 × 10−8) (Pegat et al., 2022). García-Grimshaw et al. (2022) conducted a retrospective analysis of a nationwide passive registry of GBS among recipients of 81.8 million doses of seven COVID-19 vaccines in Mexico. The overall observed incidence was 1.19 per 1 million doses (95% CI: 0.97–1.45), which was higher for Ad26.COV2.S (3.86 per 1 million doses, 95% CI: 1.50–9.93) and BNT162b2 (1.92 per 1 million doses, 95% CI: 1.36–2.71) (García-Grimshaw et al., 2022). Ha et al. (2023) conducted a prospective regional surveillance study for GBS in the Gyeonggi Province, South Korea. Out of 38.8 million vaccine doses, 55 cases of physician adjudicated GBS were identified. The incidence rate of GBS after AV vaccines (Ad26.COV2.S, ChAdOx1-S) was 4.49 per million doses (95% CI: 2.85–6.12), compared to 0.80 per million doses after mRNA vaccines (BNT162b2, mRNA-1273) (95% CI: 0.49–1.11) (Ha et al., 2023). Takuva et al. (2022) evaluated the incidence rate of GBS in all health care workers in South Africa registered in the national Electronic Vaccination Data System after receiving Ad26.COV2.S. Four cases of GBS were recorded, with an observed-to-expected ratio of 5.09 (95% CI: 1.39–13.02) (Takuva et al., 2022). From Evidence to Conclusions The totality of the evidence included several large studies that minimized confounding bias by using self-controlled or concurrent cohort design or by relying on chart review for case ascertainment; none of the epidemiological studies reported a significant risk of GBS after BNT162b2. This is reinforced by the pharmacovigilance data; although they were more prone to confounding bias, multiple large studies surveilling different population cohorts worldwide consistently identified an increased risk with AV but not mRNA vaccines despite potential differing coding trends, seasonality, co-infections, and co-administration of other vaccines. Conclusion 3-1: The evidence favors rejection of a causal relationship between the BNT162b2 vaccine and Guillain-Barré syndrome. In general, relatively few mRNA-1273 doses were included in the studies. Only one study reported an increased risk of GBS after the first and second dose, although the CIs for the measure of association were very wide (Morciano et al., 2023). The study also reported that the PREPUBLICATION COPY—Uncorrected Proofs

70 VACCINE EVIDENCE REVIEW excess number of cases was very small (<1 case per 100,000 doses). Morciano et al. (2023) was the only study to utilize the relatively longer risk period of 0–42 days without relying on chart review for case ascertainment. Although the study used a self-controlled strategy to minimize bias, its reliance on ICD codes combined with the prolonged risk interval may have led to inclusion of some historical cases rather than true incident cases. Two other studies included a larger number of vaccines and used a vaccinated concurrent cohort design (Hanson et al., 2022; Klein et al., 2021). As noted, the pharmacovigilance data also favored lack of an association between GBS and the mRNA vaccines, and the platforms used in mRNA-1273 and BNT162b2 are similar. Additionally, strong mechanistic evidence linking mRNA vaccines to GBS is lacking. Conclusion 3-2: The evidence favors rejection of a causal relationship between the mRNA-1273 vaccine and Guillain-Barré syndrome. Four epidemiology studies included patients who received Ad26.COV2.S. One study found an increased risk of GBS compared to a historical cohort, even though it did not find an association in its primary analysis, which used a vaccinated concurrent cohort design (Hanson et al., 2022). Unlike other studies reviewed, cases were physician adjudicated according to Brighton Criteria, and the increased risk was still observed when Level 4 cases (suspected GBS) were excluded. Although the analysis included two risk periods, 1–21 and 1–42 days, the vast majority of cases occurred in the first period, which is in keeping with expected latency based on historical precedent and presumed mechanism. Sturkenboom et al. (2022) also found an increased risk when comparing Ad26.COV2.S recipients with a 2020 cohort of unvaccinated individuals, although the total number of events was small and the CI wide. No association was observed in the other two studies (Li et al., 2022; Morciano et al., 2023). Li et al. had a comparatively low number of vaccinees. Although ChAdOx1-S was not formally within the purview of the committee, five of the studies observed an increased risk of GBS (Keh et al., 2023; Loo et al., 2022; Morciano et al., 2023; Patone et al., 2021; Walker et al., 2022). These included studies with a large number of participants and designs that minimize confounding bias. Additionally, two studies reported a higher rate of the facial paresis variant in patients who received either AV vaccine compared to historical cohorts (Hanson et al., 2022; Loo et al., 2022). This trend was not observed in Keh et al. (2023) despite reporting an increased risk of GBS after ChAdOx1-S. Evidence from pharmacovigilance databases spanning different regions worldwide also documented an increased risk with the AV vaccines, and one study (Pegat et al., 2022) observed an increased rate of facial paresis associated with AV but not mRNA vaccines. The epidemiological association between GBS and ChAdOx1-S but not mRNA vaccines suggests that the mechanism is unlikely to relate to immune responses to the spike protein itself. In addition, the reported increased rates of a rare variant (facial paresis) after vaccination with both related, albeit not identical, AV vaccines suggest a potential shared mechanism, although no definitive one was identified by the committee in the mechanistic literature, and this pattern was not observed in all studies. Differences in the AV platforms and their respective receptor, however, should give pause when extrapolating from one such vaccine to another. The totality of evidence for Ad26.COV2.S includes two well-designed, positive epidemiological studies and pharmacovigilance data, strong supporting epidemiological evidence PREPUBLICATION COPY—Uncorrected Proofs

NEUROLOGIC CONDITIONS 71 from ChAdOx1-S, and the potential for a platform-specific mechanism in both AV vaccines. No epidemiological literature evaluated the relationship between NVX-CoV2373 5 and GBS. Conclusion 3-3: The evidence favors acceptance of a causal relationship between the Ad26.COV2.S vaccine and Guillain-Barré syndrome. Conclusion 3-4: The evidence is inadequate to accept or reject a causal relationship between the NVX-CoV2373 vaccine and Guillain-Barré syndrome. 5 Refers to the COVID-19 vaccine manufactured by Novavax. PREPUBLICATION COPY—Uncorrected Proofs

72 VACCINE EVIDENCE REVIEW CHRONIC INFLAMMATORY DEMYELINATING POLYNEUROPATHY BOX 3-2 Conclusions for Chronic Inflammatory Demyelinating Polyneuropathy Conclusion 3-5: The evidence is inadequate to accept or reject a causal relationship between the BNT162b2 vaccine and chronic inflammatory demyelinating polyneuropathy. Conclusion 3-6: The evidence is inadequate to accept or reject a causal relationship between the mRNA-1273 vaccine and chronic inflammatory demyelinating polyneuropathy. Conclusion 3-7: The evidence is inadequate to accept or reject a causal relationship between the Ad26.COV2.S vaccine and chronic inflammatory demyelinating polyneuropathy. Conclusion 3-8: The evidence is inadequate to accept or reject a causal relationship between the NVX-CoV2373 vaccine and chronic inflammatory demyelinating polyneuropathy. Background Chronic inflammatory demyelinating polyneuropathy (CIDP), also known as “chronic inflammatory demyelinating polyradiculoneuropathy,” is an acquired, immune-mediated disorder affecting the peripheral nerve and roots. As with GBS, CIDP is now considered a group of disorders all sharing clinical and electrodiagnostic features but with probable heterogenous underlying mechanisms. Typical CIDP, the most prevalent CIDP variant, accounts for 50–60 percent of cases, presents as relapsing-remitting or gradually progressive symmetric limb weakness over a period of months. Sensory loss is common, and deep tendon reflexes are absent or reduced. Cranial nerve involvement occurs in 10–20 percent of cases. Acute onset resembling GBS can occur in 5–16 percent of cases but, unlike GBS, where symptom progression ends within 4 weeks, symptoms continue to progress beyond 8 weeks (McCombe et al., 1987; Thomas et al., 1987) (a minimum of 2 months of symptoms is required to make the diagnosis per CIDP diagnostic criteria; Van den Bergh et al., 2010). The reported incidence of CIDP is 0.3–1.6 cases per 100,000 person-years (Laughlin et al., 2009), with a male predominance and incidence rising with advancing age and some studies reporting a mean age at presentation of 60 years (Hafsteinsdottir and Olafsson, 2016). Electrodiagnostic evidence of nerve demyelination and elevated CSF protein with a normal leukocyte count supports the diagnosis. A nerve biopsy demonstrating segmental demyelination with or without inflammation can be diagnostic but is rarely needed. CIDP variants are recognized, and their distinctive clinical characteristics are included in European Academy of Neurology/Peripheral Nerve Society diagnostic criteria (Van den Bergh et al., 2021). These include typical, distal (or distal acquired demyelinating distal neuropathy), multifocal (or multifocal acquired demyelinating sensory and motor neuropathy), focal, motor, and sensory CIDP (Van den Bergh et al., 2021). Definitions of what constitute CIDP continue to evolve, and certain conditions classed as CIDP variants in the past, including chronic immune sensory PREPUBLICATION COPY—Uncorrected Proofs

NEUROLOGIC CONDITIONS 73 polyradiculopathy and the autoimmune paranodopathies, were excluded from the most recent criteria because the underlying nerve injury is not definitively demyelinating. Mechanisms Although the pathophysiology of CIDP and its variants is not known, evidence supports an immune-mediated mechanism as the main cause. Characteristic features include segmental demyelination and remyelination and varying degrees of endoneurial macrophage infiltration (Dalakas, 2011). Levels of T helper 17 cells are increased in the peripheral blood and CSF, as are levels of soluble adhesion molecules, chemokines, and metalloproteinases (Dalakas, 2011). The apparent effectiveness of plasmapheresis, which purportedly removes pathogenic antibodies along with other inflammatory mediators, suggests that circulating humoral factors and autoantibodies may be involved. Complement fixation on the myelin sheath of nerves of some with CIDP also suggests a potential antibody-mediated mechanism (Dalakas and Engel, 1980). Antibodies directed against nodal and paranodal proteins, such as contactin-1, and neurofascin isoforms, are found in a subset of patients with clinical features suggestive of CIDP. However, nerve biopsies in these patients do not show the distinctive features of CIDP, and this is now considered a separate entity (autoimmune paranodopathies) (Van den Bergh et al., 2021). One study identified potentially cross-reactive epitopes shared between the SARS-CoV-2 spike protein and neuronal structures using a bioinformatics approach (Felipe Cuspoca et al., 2022), suggesting that molecular mimicry as a cause of potential neurological harms of COVID- 19 vaccines is plausible, but evidence supporting this hypothesis is lacking. Epidemiological Evidence Clinical trial results submitted to FDA for Emergency Use Authorization and/or full approval do not indicate a signal regarding CIDP and any of the vaccines under study (FDA, 2021, 2023a, 2023b, 2023c). Table 3-3 summarizes one study that contributed to the causality assessment. PREPUBLICATION COPY—Uncorrected Proofs

74 VACCINE EVIDENCE REVIEW TABLE 3-3 Epidemiological Study in the Chronic Inflammatory Demyelinating Polyradiculoneuropathy Evidence Review Study Design and Control Data Age Number Author Group Location Source Vaccine(s) Range N of Events Results 24 patients 4 cases admitted reclassified BNT162b2 1 with acute onset as acute Case-control EMR Loo et al. ≥16 polyradiculo- onset CIDP; study/historical UK (physician (2021) years neuropathy No cases background adjudicated) between followed mRNA-1273 1 January–June mRNA 2021 vaccines NOTES: BNT162b2 refers to the COVID-19 vaccine manufactured by Pfizer-BioNTech under the name Comirnaty®. mRNA-1273 refers to the COVID-19 vaccine manufactured by Moderna under the name Spikevax®. Number of events refers to events in vaccinees only. EMR: electronic medical record. SOURCE: Loo et al., 2022. PREPUBLICATION COPY—Uncorrected Proofs

NEUROLOGIC CONDITIONS 75 Loo et al. (2021) conducted a retrospective case-control study of all patients admitted with acute-onset polyradiculoneuropathy to two UK neuroscience centers, January 1–June 30, 2021. Of 24 GBS patients, 16 were postvaccination and all but two (1 BNT162b, 1 mRNA-1273) were after ChAdOx1-S. Four cases initially classified as GBS were eventually reclassified as acute-onset CIDP due to progression or relapse past 8 weeks from onset; all four had received ChAdOx1-S. 6 From Evidence to Conclusions Epidemiological and mechanistic evidence are absent. Only one small case-control study evaluated the association between COVID-19 vaccines and CIDP; four cases initially classified as GBS were later reclassified as acute-onset CIDP, and no historical background rate was offered for comparison. Conclusion 3-5: The evidence is inadequate to accept or reject a causal relationship between the BNT162b2 vaccine and chronic inflammatory demyelinating polyneuropathy. Conclusion 3-6: The evidence is inadequate to accept or reject a causal relationship between the mRNA-1723 vaccine and chronic inflammatory demyelinating polyneuropathy. Conclusion 3-7: The evidence is inadequate to accept or reject a causal relationship between the Ad26.COV2.S vaccine and chronic inflammatory demyelinating polyneuropathy. Conclusion 3-8: The evidence is inadequate to accept or reject a causal relationship between the NVX-CoV2373 vaccine and chronic inflammatory demyelinating polyneuropathy. 6 ChAdOx1-S refers to the COVID-19 vaccine manufactured by Oxford-AstraZeneca. PREPUBLICATION COPY—Uncorrected Proofs

76 VACCINE EVIDENCE REVIEW BELL’S PALSY BOX 3-3 Conclusions for Bell’s Palsy Conclusion 3-9: The evidence favors rejection of a causal relationship between the BNT162b2 vaccine and Bell’s Palsy. Conclusion 3-10: The evidence favors rejection of a causal relationship between the mRNA-1273 vaccine and Bell’s Palsy. Conclusion 3-11: The evidence is inadequate to accept or reject a causal relationship between the Ad26.COV2.S vaccine and Bell’s Palsy. Conclusion 3-12: The evidence is inadequate to accept or reject a causal relationship between the NVX-CoV2373 vaccine and Bell’s Palsy. Background BP is an idiopathic, unilateral, self-limited, acute facial nerve paresis or paralysis. It occurs with equal frequency on either side of the face and usually resolves within weeks or months. It can lead to severe temporary oral insufficiency and an incapability to close the eyelids, resulting in potentially permanent eye injury. In approximately 25 percent of patients, moderate-to-severe facial asymmetry may persist and affect quality of life (Zhang et al., 2020b). BP is the most common acute mononeuropathy (Zhang et al., 2020b), with an incidence of 11.5–53.3 per 100,000 person-years (Baugh et al., 2013). It is estimated that every year, about 40,000 U.S. people are affected (NORD, 2022). The risk factors are poorly understood. Risk may increase with age, but no indication exists that one sex or geographical area is more at risk (Kim and Park, 2021). BP symptoms typically develop quickly, with maximum symptoms occurring within 72 hours (W. Zhang et al., 2020). Mechanisms The etiology of BP is unknown, but theories fall into five categories: anatomical, viral, ischemic, inflammatory, and due to cold exposure (based on season or local climate) (W. Zhang et al., 2020). When considering the possibility of a vaccine trigger of BP, it is unlikely that anatomy, ischemia, or cold stimulation would play a role. Evidence supporting inflammation includes demonstrated gadolinium enhancement of the facial nerve on MRI of the brain and CSF pleocytosis in many patients with BP (Steiner and Mattan, 1999). Histopathology from one autopsy study demonstrated a lymphohistiocytic infiltrate within all layers of the nerve and inflammation that extended to the geniculate ganglion but spared most ganglion cells (Liston and Kleid, 1989). Infection may be a cause of BP. Infectious facial palsy has been most clearly linked to Borrelia burgdorferi (the bacteria that causes Lyme disease), and varicella zoster virus reactivation (Ramsay Hunt syndrome). Many have argued for a link between herpes simplex virus type 1 (HSV-1) reactivation and BP (W. Zhang et al., 2020), and acyclovir is routinely PREPUBLICATION COPY—Uncorrected Proofs

NEUROLOGIC CONDITIONS 77 prescribed to patients with BP. Arguments against a pathophysiological role for HSV-1 include that it resides in the peripheral sensory ganglia and reactivation is not associated with motor weakness, that it tends to recur, whereas BP tends to be monophasic, and that HSV-1 outbreaks are common, whereas BP is rare (Steiner and Mattan, 1999). Finally, in a randomized controlled trial with a factorial design in which patients received 10 days of prednisolone, acyclovir, both, and placebo, prednisolone significantly improved outcomes, whereas acyclovir did not (Sullivan et al., 2007). Infection may also cause BP via a post-infectious immune-mediated mechanism rather than by direct invasion of the nerve. Such mechanisms could include bystander activation, epitope spreading or polyclonal activation of previously dormant self-reactive lymphocytes (Chapter 2). Arguments favoring an infectious trigger of BP include that it can occur in epidemic clusters (Leibowitz, 1969) and displays seasonal variation (Kim and Park, 2021). Potential triggers include cytomegalovirus, Epstein-Barr virus, mumps, rubella, and HIV (Steiner and Mattan, 1999). An intranasal influenza vaccine which has since been removed from the market was associated with BP (Wratten et al., 1977). In this case-control study, BP most often occurred within 31-60 days following vaccination arguing against a direct toxic effect and in favor of an immune-mediated mechanism. Recent evidence has suggested a possible association between COVID-19 infection and BP (Rafati et al., 2023). The fact that there are multiple putative viral triggers argues against molecular mimicry as a mechanism. Patients with BP have been shown to have elevated levels of the cytokines IL-6, IL-8, and TNF-alpha compared to controls (Yılmaz et al., 2002). Some have argued that cytokine- mediated neuronal damage, in particular by type 1 interferon (type 1 IFN), might mediate neurological adverse events after COVID-19 vaccination (Chen et al., 2022a; Shemer et al., 2021). Because BP has been seen as a complication of type 1 IFN treatment for hepatitis C (Hwang et al., 2004), some have postulated that an elevation of type 1 IFN after COVID-19 vaccination could be associated with it (Shemer et al., 2021). Single-cell transcriptomics demonstrate a strong interferon signature after booster mRNA vaccination (Arunachalam et al., 2021), but this has not been correlated with neurological harms. Adenoviral vaccines have also been shown to induce an interferon signature, at least in mice (Sheerin et al., 2021). However, no studies link cytokine responses after vaccination to neurological events. Epidemiological Evidence Clinical trial results submitted to FDA for Emergency Use Authorization and/or full approval do not indicate a signal regarding Bell’s Palsy and any of the vaccines under study (FDA, 2021, 2023a, 2023b, 2023c). Table 3-4 presents 11 studies that contributed to the causality assessment. PREPUBLICATION COPY—Uncorrected Proofs

78 VACCINE EVIDENCE REVIEW TABLE 3-4 Epidemiological Studies in the Bell’s Palsy Evidence Review Study Design and Control Data Age Number Results Author Group Location Source Vaccine(s) Range N of Events (95% CI) Dose 1: 8.7 Dose 1: Dose 1: 17 Ab million IRR 1.32 (0.77– 2.24) Self- Rahman vaccinees controlled Malaysia EMR BNT162b2 ≥12 years et al. Dose 2: case series (2022) 6.7 Dose 2: 10 Dose 2: million IRR 0.88 (0.45– 1.73) vaccinees BNT162b2 6.8 million doses BNT12b2 Cohort with and BNT12b2 and Klein vaccinated mRNA- mRNA-1273 et al. US EMR ≥16 years concurrent 5.1 1273 combined: (2021) mRNA- comparators million combined: RR 1.00 (0.86–1.17) 1273 535 doses PREPUBLICATION COPY—Uncorrected Proofs

NEUROLOGIC CONDITIONS 79 UK Dose 1: UK UK 1.7 Dose 1: 46 Dose 1: million SIR 0.40 (0.30–0.53) vaccinees Dose 2: Dose 2: 24 SIR 0.24 (0.16–0.36) Dose 2: 1.2 SCCS million IRR 0.83 (0.66–1.02) BNT162b2 EMR vaccinees (UK and Clinical Spain) Practice Spain Spain Research Dose 1: 1.9 Dose 1: Datalink million SIR 0.86 (0.70 – 1.04) Spain AURUM vaccinees Dose 2: Cohort and Dose 1:100 database Dose 2: SIR 0.88 (0.71–1.08) self- Dose 2: 85 (UK) 1.3 controlled/Ba million SCCS: Li et al. UK and Informatio ckground >18 years vaccinees IRR 0.83 (0.66–1.02) (2022) Spain n System rates and for self- Dose 1: Dose 1: Research in controlled 244,913 SIR 0.92 (0.54–1.55) Primary mRNA- Care vaccinees Dose 1: 14 Dose 2: 1273 (SIDIAP) Dose 2: 5 SIR 0.44 (0.18–1.06) (Spain database Dose 2: only) (Spain) 160,228 SCCS: vaccinees IRR 0.99 (0.54–1.64) Ad26.COV Dose 1: 2.S Dose 1: 6 120,731 SIR 1.15 (0.52–2.56) (Spain vaccinees only) PREPUBLICATION COPY—Uncorrected Proofs

80 VACCINE EVIDENCE REVIEW TABLE 3-4 Continued Study Design and Control Data Age Number Results Author Group Location Source Vaccine(s) Range N of Events (95% CI) Self- Dose 1: Patone et controlled 12.1 247 UK EMR BNT162b2 ≥ 16 years IRR 1.06 (0.90–1.26) al. (2021) case series million vaccinees Matched Dose 1: Shasha et cohort 233,159 RR 0.96 (0.54–1.70) al. (2021) vaccinated Israel EMR BNT162b2 ≥16 years 23 vaccinees vs. unvaccinated Shemer et Hospitaliza 50.9 + al. (2021) Case control Israel BNT162b2 37 cases 21 OR 0.84 (0.37–1.90) -tion data 20.2 years Dose 1: 2.6 132 million SIR 1.36 (1.14–1.61) Shibli et Cohort using vaccinees al. (2021) background Israel EMR BNT162b2 ≥16 years Dose 2: 2.4 rate million 152 SIR 1.16 (0.99–1.36) vaccinees BNT162b2 (booster 1,674 IRR 1.13 (0.77–1.65) Claims- dose) based Self- Shoaibi et data with 6.2 million controlled US mRNA- ≥65 years al. (2023) medical vaccinees case series 1273 record 1,594 IRR 1.02 (0.70–1.50) (booster review dose) PREPUBLICATION COPY—Uncorrected Proofs

NEUROLOGIC CONDITIONS 81 TABLE 3-4 Continued Study Design and Control Data Age Number of Results Author Group Location Source Vaccine(s) Range N Events (95% CI) 54% of 12.1 IRR 0.87 (0.69–1.10) Sturken- BNT162b2 million 149 Italy, vaccinees boom Cohort using Netherlan total et al. background EMR Varied ds UK and mRNA- (2022) rate 6% 27 IRR 0.99 (0.68–1.45) Spain 1273 Ad26.COV 2% 6 IRR 1.08 (0.45–2.60) 2.S Dose 1: Dose 1: Cohort: IRR 1.14 (0.27– 4.89) Cohort and 136,667 Dose 1: 1 Takeuchi mRNA Dose 2: self- vaccinees Dose 2: 1 et al. (BNT162b IRR 0.60 (0.08–4.49) controlled Japan EMR ≥ 18 years (2022) 2, mRNA- Dose 1: case series Dose 2: SCCS: 1273) IRR 1.03 (0.20–5.31) (SCCS) 127,322 Dose 1: 15 vaccinees Dose 2: Dose 2: 15 IRR 0.47 (0.05–4.18) BNT162b2 Dose 1: IRR 0.88 (0.76–1.02) Self- 5,729,152 3,609 Walker et 18–105 Dose 2: controlled England EMR IRR 0.92 (0.78–1.10) al. (2022) years case series mRNA- Dose 1: 255,446 78 1273 IRR 0.80 (0.24–2.62) PREPUBLICATION COPY—Uncorrected Proofs

82 VACCINE EVIDENCE REVIEW TABLE 3-4 Continued NOTES: BNT162b2 refers to the COVID-19 vaccine manufactured by Pfizer-BioNTech under the name Comirnaty®. mRNA-1273 refers to the COVID-19 vaccine manufactured by Moderna under the name Spikevax®. Ad26.COV2.S refers to the COVID-19 vaccine manufactured by Janssen. The primary series for Ad26.COV2.S is one dose. Number of events refers to events in vaccinees only. CI: confidence interval; EMR: electronic medical record; IRR: incidence rate ratio; OR: odds ratio; RR: relative risk; SCCS: self-controlled case series; SIR: standardized incidence ratio. SOURCES: Ab Rahman et al., 2022; Klein et al., 2021; Li et al., 2022a; Patone et al., 2021; Shasha et al., 2022; Shemer et al., 2021; Shibli et al., 2021; Shoaibi et al., 2023; Sturkenboom et al., 2022; Takeuchi et al., 2022; Walker et al., 2022. PREPUBLICATION COPY—Uncorrected Proofs

NEUROLOGIC CONDITIONS 83 Patone et al. (2021) investigated the association between BNT162b2 and BP among 12.1 million vaccinees in England using a self-controlled case series (SCCS) study. They compared the incidence rate of BP in the interval of 1–28 days after vaccination with that during periods outside of this interval. BP was defined using ICD-10 codes and identified as the first hospital admission or as a cause of death recorded on the death certificate (Patone et al., 2021). Vaccination status was identified in the English National Immunization Database of COVID-19 vaccination; they identified 250 BP cases and found no association with BNT162b2 (incidence rate ratio (IRR) 1.06 (95 percent confidence interval (CI): 0.80–1.25) (Patone et al., 2021). Walker et al. (2022) analyzed primary care data from more than 17 million patients in England linked to emergency care, hospital admission, and mortality records in the OpenSAFELY platform (Walker et al., 2022). They excluded BP cases that occurred before the study start date. Cases were determined from any primary care, emergency department, hospital admission, or mortality records. They used an SCCS analytical approach where the risk interval was 4–28 days after vaccination. Among 5.7 million recipients of BNT162b2, 3,609 BP cases were identified, and among 255,446 recipients of mRNA-1273, 78 BP cases were identified. They found no association between the first dose of BNT162b2 and BP (IRR 0.89, 95% CI: 0.76–1.03) or the second dose (IRR 0.92, 95% CI: 0.78–1.10). Similarly, no association appeared with mRNA-1273 after the first or second dose (IRR 0.59, 95% CI: 0.13–2.62 and IRR 0.80, 95% CI: 0.24–2.62, respectively) (Walker et al., 2022). Ab Rahman et al. (2022) conducted a self-controlled case-series study among hospitalized BP cases in Malaysia. Vaccination status was determined from the national COVID- 19 register data. The incidence of BP was assessed during a 21-day risk interval after vaccination relative to a control period using conditional Poisson regression with adjustment for calendar time. After more than 15 million doses of BNT162b2, 27 cases of BP were identified in the risk interval. Compared with the control interval, no significant increased risk of BP occurred after the first (IRR 1.32, 95% CI: 0.77–2.24) or second (IRR 0.88, 95% CI: 0.45–1.73) dose. The IRR after any dose was 1.11 (95% CI: 0.77–1.75) (Ab Rahman et al., 2022). Li et al. (2022b) evaluated the association between vaccination and BP using two study designs: a population-based cohort design where they compared rates of BP identified through medical records among vaccinees with historical background rates and an SCCS analysis. They used CPRD AURUM and SIDIAP. The study included 3.6 million people who received BNT162b2, 244,913 who received mRNA-1273, 120,731 who received Ad26.CoV.2, and 14.3 million people from the general population. Of the BNT162b2 vaccinees, 46 and 24 BP cases occurred after a first and second dose in CPRD AURUM, compared with 116.4 and 99.5 expected. The standardized incidence ratio (SIR) was 0.40 (95 percent CI: 0.30–0.53) for the first and 0.24 (95 percent CI: 0.16–0.36) for the second dose. SIDIAP had 100 and 85 BP cases after the first and second dose of BNT162b2, compared with 116.7 and 97.1 expected. SIR was 0.86 (95% CI: 0.70–1.04) for the first and 0.88 (95% CI: 0.71–1.08) for the second dose. For mRNA- 1273, 14 and 5 cases occurred after the first and second dose compared with 15.2 and 11.3 expected. The corresponding SIRs are 0.92 (95% CI: 0.54–1.55) and 0.4 (95% CI: 0.18–1.06). For Ad26.COV2.S, six BP cases were identified compared with 5.2 expected, corresponding to an SIR of 1.15 (95% CI: 0.52–2.56) (Li et al., 2022). The SCCS analysis was only sufficiently powered to study those with a first dose of BNT162b2 and mRNA-1273. In CPRD AURUM, the adjusted IRR of BP 1–21 days after vaccination was 0.83 (95% CI: 0.61–1.10) for BNT162b2. In SIDIAP, the adjusted IRR was 0.83 (95% CI: 0.66–1.02) for BNT162b2 and 0.99 (95% CI: 0.54–1.64) for mRNA-1273 (Li et al., 2022). PREPUBLICATION COPY—Uncorrected Proofs

84 VACCINE EVIDENCE REVIEW Shibli et al. (2021) used data from the computerized database of Clalit Health Services, which provides inclusive health care for more than half of the Israeli population, to assess whether BNT162b2 was associated with increased risk by comparing BP rates in vaccinees with historical rates in the general population. They assessed rates 21 days after the first dose and 30 days after the second dose. Overall, 132 cases of BP were reported in 2.6 million vaccinees with the first dose compared with 97.1 expected, and 152 cases in 2.4 million vaccinees were reported compared with 130.49 expected after the second dose. The age- and sex-weighted SIRs were 1.36 (95% CI: 1.14–1.61) and 1.16 (95% CI: 0.99–1.36) after the first and second doses, respectively. Although more cases were observed than expected, the attributable risk fraction was 0.26 for the first and 0.14 for the second dose. The attributable risk per 100,000 vaccinees was 1.35 for the first and 0.86 for the second dose (Shibli et al., 2021). Shasha et al. (2021) conducted a matched cohort study in which they compared risk of BP in 233,159 BNT162b2 vaccinees with that in 233,159 age- and sex-matched unvaccinated individuals. BP cases were identified by ICD-10 code and confirmed by chart review. Of the 123 cases identified by ICD-10 codes, 76 were excluded because they were not incident cases or not consistent with BP. Vaccinated and unvaccinated individuals had 23 versus 24 cases of BP (RR 0.96, 95% CI: 0.54–1.70). Sturkenboom et al. (2022) conducted a cross-national multi-database retrospective dynamic cohort study using primary and/or secondary health care data from four European countries: Italy, the Netherlands, the United Kingdom, and Spain. Individuals were required to have at least 365 days of data availability before cohort entry. The end of follow-up was the earliest dates of BP occurrence, last data collection, or death. Person-time after the start of the study was divided in two main periods, nonvaccinated and vaccinated; the latter started at the first of any of the COVID-19 vaccine and lasted for a maximum of 28 days after dose 1 and 28 days after dose 2 or until the date of last data available. Of the 25.7 million people included, 149 BP cases were identified after BNT162b2, 27 after mRNA-1273, and 6 after Ad26.COV2.S. They found no increased risk of BP 28 days after BNT162b2 (IRR 0.87, 95% CI: 0.69–1.10), mRNA-1273 (IRR 0.99, 95% CI: 0.68–1.45), or Ad26.COV2.S (IRR 1.08, 95% CI: 0.45–2.60) (Sturkenboom et al., 2022). Shemer et al. (2021) conducted a case-control study using data from the emergency department of a tertiary referral center in central Israel. Patients admitted for facial nerve palsy (37 BP confirmed cases) were matched by age, sex, and date of admission with 72 controls admitted for other reasons and assessed against the odds of BNT162b2 vaccination. The odds of vaccination were not different between cases and controls. The odds ratio for vaccination was 0.84 (95% CI: 0.37–1.90) (Shemer et al., 2021). Shoaibi et al. (2023) conducted an SCCS study of BNT162b2 and mRNA-1273 among U.S. Medicare beneficiaries aged 65+ to evaluate association with BP after only a booster dose (Shoaibi et al., 2023). The study included 6.2 million individuals. Of 79 cases identified through electronic health records, chart reviews determined that 10 were confirmed or probable, for a positive predictive value of 12.66 percent. After adjusting for outcome misclassification, they found no significant association between BNT162b2 and BP (IRR 1.13, 95% CI: 0.77–1.65) or mRNA-1273 and BP (IRR 1.02, 95% CI: 0.70–1.50) (Shoaibi et al., 2023). In addition to these studies that evaluated individual vaccines, two studies evaluated the association of mRNA vaccines with risk of BP. Takeuchi et al. (2022) evaluated BP risk after any BNT162b2 and mRNA-1273 in administrative claims data using a cohort study design and an SCCS design. BP was defined by ICD codes from hospitalized claims data. The study PREPUBLICATION COPY—Uncorrected Proofs

NEUROLOGIC CONDITIONS 85 included 136,644 people who received one dose, 127,268 who received two doses, and 183,990 unvaccinated. The vaccinees had two BP cases 21 days after dose 1 and one BP case after dose 2 compared with 18 cases among the unvaccinated. The adjusted IRR of BP was 1.14 (95% CI: 0.27–4.89) and 0.60 (95% CI 0.08–4.49) after dose 1 and dose 2, respectively, compared with unvaccinated. The results of the SCCS analysis indicated no increased risk of BP after dose 1 (IRR 1.03, 95% CI: 0.20–5.31) or dose 2 (IRR 0.47, 95% CI: 0.05–4.18) (Takeuchi et al., 2022). Klein et al. (2021) conducted a surveillance study within VSD. They compared incidence of BP 1–21 days after either dose 1 or 2 of an mRNA vaccine with that of concurrent comparators who, on the same calendar day, had received their most recent dose 22–42 days earlier. After 11.8 million doses, 535 BP cases were identified in the risk interval compared with 301 in the controlled interval. The adjusted IRR was 1.00 (95% CI: 0.86–1.17). In a supplemental analysis comparing vaccinated with unvaccinated people, they found no risk association with an mRNA vaccine (RR 1.06, 95% CI: 0.95–1.17) (Klein et al., 2021). From Evidence to Conclusions Among the 11 epidemiology studies reviewed, only one reported a significantly increased risk of BP after the first dose of BNT162b2 (Shibli et al., 2021). Its results are prone to confounding because it used historical BP rate as the comparator. Factors associated with that rate may be very different from those during the pandemic. Furthermore, comparing vaccinated with unvaccinated is problematic because, without randomization, it is practically impossible to balance their confounding factors. Although informative, this study weakly contributed to the final conclusion because of its limitations including using historical background rates as comparators; studies using concurrent comparators did not find an association between BP and mRNA vaccines. The main limitation is that most of the studies relied on ICD codes from electronic data without chart confirmation. Some cases of BP identified by the ICD codes might not be true or incident cases, which could have biased the measure of association. Studies may have missed cases because they were not based on active surveillance, and the majority of the cases included are likely more severe, as those with mild symptoms may not have sought medical attention during the pandemic. Furthermore, some studies may have incompletely measured or adjusted for some confounding. Conclusion 3-9: The evidence favors rejection of a causal relationship between the BNT162b2 vaccine and Bell’s Palsy. Conclusion 3-10: The evidence favors rejection of a causal relationship between the mRNA-1273 vaccine and Bell’s Palsy. Only two of the 11 studies evaluated the relationship between Ad26.COV2.S and BP; neither showed an increased risk. No studies evaluated the relationship between BP and NVX- CoV2373. Conclusion 3-11: The evidence is inadequate to accept or reject a causal relationship between the Ad26.COV2.S vaccine and Bell’s Palsy. Conclusion 3-12: The evidence is inadequate to accept or reject a causal relationship between the NVX-CoV2373 vaccine and Bell’s Palsy. PREPUBLICATION COPY—Uncorrected Proofs

86 VACCINE EVIDENCE REVIEW TRANSVERSE MYELITIS BOX 3-4 Conclusions for Transverse Myelitis Conclusion 3-13: The evidence is inadequate to accept or reject a causal relationship between the BNT162b2 vaccine and transverse myelitis. Conclusion 3-14: The evidence is inadequate to accept or reject a causal relationship between the mRNA-1273 vaccine and transverse myelitis. Conclusion 3-15: The evidence is inadequate to accept or reject a causal relationship between the Ad26.COV2.S vaccine and transverse myelitis. Conclusion 3-16: The evidence is inadequate to accept or reject a causal relationship between the NVX-CoV2373 vaccine and transverse myelitis. Background Spinal cord dysfunction of any cause is referred to as “myelopathy”; “myelitis” designates inflammation of the spinal cord. Acute TM refers to a group of acquired, acute-onset, focal inflammatory myelopathies. Consensus diagnostic criteria that rely on clinical and radiographic features have been published, and the diagnosis requires bilateral (although not necessarily symmetric) weakness and sensory deficits, with a clearly defined sensory level, evidence of inflammation by CSF or MRI gadolinium enhancement, and clinical progression to nadir between 4 hours and 21 days (Transverse Myelitis Consortium Working Group, 2002). This clinicoradiologic syndrome can be a manifestation of other inflammatory central nervous system disorders (disease-associated TM), including demyelinating disorders, such as neuromyelitis optica spectrum disorder, acute disseminated encephalomyelitis (ADEM), where up to 50 percent of patients have antibodies to myelin oligodendrocyte glycoprotein, and multiple sclerosis (MS) (Lopez Chiriboga, 2021). Spinal cord infections, paraneoplastic autoimmune syndromes, and systemic inflammatory disorders can also present as disease- associated TM (Flanagan et al., 2016; Jain et al., 2023). When the etiology is unknown, it is called “idiopathic TM.” Confusingly, noninflammatory causes of myelopathy, such as ischemic or hemorrhagic stroke, nutritional deficiencies, and neoplasms, can mimic this clinical and radiographic picture. In one study, 70 percent of patients referred to a tertiary care center with a diagnosis of idiopathic TM had a more specific disease-associated TM, such as myelin oligodendrocyte glycoprotein antibody–associated disease or MS, but a quarter of them did not have an inflammatory myelopathy at all (Zalewski et al., 2019). Idiopathic TM is therefore a diagnosis of exclusion (of known causes of disease-associated TM and noninflammatory myelopathies that can mimic TM). Another study, based on retrospective review of Veterans Health Administration electronic medical records, found that 57.6 percent of patients assigned an ICD code of TM lacked CSF testing, which is a core feature of current diagnostic criteria (Abbatemarco et al., 2021). As the aforementioned studies suggest, existing criteria lack specificity, which can affect the accuracy of epidemiological studies, especially those relying on ICD codes. PREPUBLICATION COPY—Uncorrected Proofs

NEUROLOGIC CONDITIONS 87 Idiopathic TM is rare, with a reported incidence of 1.34–4.6 per million per year, with bimodal peaks between ages 10–19 and 30–39 years and no sex predisposition (Bhat et al., 2010). It has been reported a few weeks after vaccination, although a large retrospective cohort study from VSD, a collaboration between the Centers for Disease Control and Prevention’s Immunization Safety Office and several integrated health care systems across the United States, did not find an increased risk in association with routine vaccines (Baxter et al., 2016). Mechanisms The pathophysiology of idiopathic TM is unknown, but postinfectious immune-mediated injury is the most widely accepted mechanism. This could be due to bystander activation, epitope spreading or polyclonal activation of previously dormant self-reactive lymphocytes (Chapter 2). Up to 40 percent of TM cases follow an infection, most commonly Coxsackie viruses and mycoplasma pneumoniae, and infectious agents have sometimes been isolated from the spinal fluid (Bhat et al., 2010; Krishnan et al., 2004). TM has also been reported after a variety of vaccines, including hepatitis B, rabies, and rubella (Agmon-Levin et al., 2009). The fact that TM has been associated with many different viruses and vaccines argues against molecular mimicry as a mechanism. In England in 1922–1923, over 200 cases of encephalomyelitis were reported after smallpox and rabies vaccination, and autopsy studies revealed inflammatory cells and demyelination in the spinal cord (Krishnan et al., 2004; Rivers, 1932). More recent pathological studies demonstrate focal infiltrates of monocytes and lymphocytes in the spinal cord and perivascular space, astroglial and microglial activation, and involvement of both white and gray matter (Krishnan et al., 2004). In the acute phase, heavy infiltration by CD4+ and CD8+ T cells and monocytes is found, whereas the subacute phase is characterized by macrophage infiltration and demyelination (Krishnan et al., 2004). Most patients with TM have CSF pleocytosis suggesting breakdown of the blood–brain barrier (Bhat et al., 2010; Krishnan et al., 2004). Patients with TM have been shown to have elevated levels of interleukin-6 (IL-6) in their CSF and, in acute TM, CSF IL-6 levels correlate with the ultimate level of clinical disability (Kaplin et al., 2005). In an animal model, IL-6 can be shown to mediate cord injury by inducing nitric oxide production, which is associated with oligodendrocyte injury, demyelination, and axonal injury (Kaplin et al., 2005). Epidemiological Evidence Clinical trial results submitted to FDA for Emergency Use Authorization and/or full approval do not indicate a signal regarding TM and any of the vaccines under study (FDA, 2021, 2023a, 2023b, 2023c). Table 3-5 presents five studies that contributed to the causality assessment. PREPUBLICATION COPY—Uncorrected Proofs

88 VACCINE EVIDENCE REVIEW TABLE 3-5 Epidemiological Studies in the Transverse Myelitis Evidence Review Study Design and Control Age Number of Results Author Group Location Data Source Vaccine(s) Range N Events (95% CI) 6.8 BNT162b2 BNT162b2 million BNT162b2 Cohort/ doses and and Klein et al. vaccinated ≥16 mRNA-1273 US VSD/EMR mRNA-1273 (2021) concurrent years combined: 5.1 combined: comparators RR 1.45 mRNA-1273 million 2 (0.10–47.73) doses UK: Dose 1: <5 3.6 Dose 2: No BNT162b2 million cases vaccinees (UK and Spain) Spain: Cohort/ Primary care Dose 1: <5 self- databases Dose 2: No UK and ≥18 SIR not Li et al. (2022) controlled linked to cases Spain years calculated and historical hospital Dose 1: background data/EMR mRNA-1273 244,913 No cases (Spain only) vaccinees Dose 2: <5 Ad26.COV2.S 120,731 Dose 1: No (Spain only) vaccinees cases English 12.1 BNT162b2 Patone et al. Cohort/self- ≥16 UK immunization BNT162b2 million 68 IRR 1.02 (2021) controlled years records/EMR vaccinees (0.75–1.40) PREPUBLICATION COPY—Uncorrected Proofs

NEUROLOGIC CONDITIONS 89 TABLE 3-5 Continued Study Design and Control Age Number of Results Author Group Location Data Source Vaccine(s) Range N Events (95% CI) BNT162b2 6.5 9 BNT162b2 million IRR 1.88 doses (0.37–9.60) Cohort/ Primary and Sturkenboom et European background secondary care Varied al. (2022) countries 727,047 rate databases/EMR mRNA-1273 No cases N/A doses 242,349 Ad26.COV2.S No cases N/A doses 5.7 BNT162b2 million IRR 1.49 109 Walker et al. Cohort/Self- doses (0.71–3.10) UK EMR ≥18 (2022) controlled 255,446 mRNA-1273 No cases N/A doses NOTES: BNT162b2 refers to the COVID-19 vaccine manufactured by Pfizer-BioNTech under the name Comirnaty®. mRNA-1273 refers to the COVID-19 vaccine manufactured by Moderna under the name Spikevax®. Ad26.COV2.S refers to the COVID-19 vaccine manufactured by Janssen. The primary series for Ad26.COV2.S is one dose. Number of events refers to events in vaccinees only. CI: confidence interval; EMR: electronic medical record; IRR: incidence rate ratio; N/A: not applicable; RR: rate ratio. SOURCES: Klein et al., 2021; Li et al., 2022b; Patone et al., 2021; Sturkenboom et al., 2022; Walker et al., 2022. PREPUBLICATION COPY—Uncorrected Proofs

90 VACCINE EVIDENCE REVIEW Klein et al. (2021) conducted a surveillance study within VSD comparing TM incidence 1–21 days after either dose 1 or 2 of a mRNA vaccine with that of vaccinated concurrent comparators who, on the same calendar day, had received their most recent dose 22–42 days earlier. After 11.8 million doses (57 percent BNT162b2), two cases were identified in the risk interval compared with one in the controlled interval, with an adjusted rate ratio of 1.45 (95% CI: 0.10–47.73) and excess cases of 0.1 (95% CI: -1.6–0.2) risk interval per million doses (Klein et al., 2021). Li et al. (2022b) compared TM rates identified through medical records among vaccinees with historical background rates and conducted an SCCS analysis. They used data from CPRD AURUM and SIDIAP. The study included 3.6 million people who received BNT162b2, 244,913 who received mRNA-1273, 120,731 who received Ad26.CoV.2, and 14.3 million people from the general population. Of the BNT162b2 vaccinees, fewer than five cases occurred within 1–21 days after a first dose in CPRD AURUM, compared with 4.7 expected. SIDIAP had <5 cases after the first dose of BNT162b2, compared with 0.9 expected. For mRNA-1273, <5 cases were diagnosed after the second dose compared with 0.1 expected. No cases were observed with the second dose of BNT162b2, first dose of mRNA-1273, or Ad26.COV2.S. Walker et al. (2022) analyzed primary care data from more than 17 million patients in England linked to emergency care, hospital admission, and mortality records in OpenSAFELY. They used an SCCS analytical approach where the risk interval was 4–28 days after vaccination. Among 5.7 million recipients of BNT162b2, 109 TM cases were identified during the risk and controlled periods, and none were identified among 255,446 recipients of mRNA-1273. They found no significant association between the first dose of BNT162b2 and TM (IRR 1.62, 95% CI: 0.86–3.03). Few events were observed, so they were unable to precisely estimate the risk association. Adjusting for calendar time or history of COVID-19 infection did not significantly change the measure of association (IRR 1.49, 95% CI: 0.71–3.10) (Walker et al., 2022). Sturkenboom et al. (2022) conducted a cross-national multi-database retrospective dynamic cohort study using primary and/or secondary health care data from four European countries: Italy, the Netherlands, the United Kingdom, and Spain. They compared TM incidence in vaccine recipients with nonvaccinated persons in 2020 within 28 days after each dose. Of 25.7 million people, nine cases were identified after BNT162b2 (IRR 1.88, 95% CI: 0.37–9.6) and none after mRNA-1273 and Ad26.COV2.S (Sturkenboom et al., 2022). The results are consistent with an increased risk, but few events were observed, and the authors were unable to precisely estimate risk and results; this could also be consistent with no or decreased risk. Patone et al. (2021) investigated the association between BNT162b2 with potential neurological harms among 32.6 million vaccinees, 12.1 million of whom received BNT162b2 (Patone et al., 2021). An ICD-10 code for TM was included in the category “acute demyelinating events” (ADE), which contained ICD-10 codes for other demyelinating syndromes, such as ADEM. This retrospective self-controlled cohort study compared the incidence rate at several intervals (1–7, 8–14, 15–21, 22–28, and 1–28 days) after vaccination with that during periods outside of this interval. Sixty-eight events were observed after BNT162b2 during the risk period. They found no association for BNT162b2 at any interval, including in the 1–28 days period (IRR 1.02, 95% CI: 0.75–1.40). Few events were observed, so the authors were unable to precisely estimate the risk; the results would be consistent with no increased risk but also with slightly increased risk. PREPUBLICATION COPY—Uncorrected Proofs

NEUROLOGIC CONDITIONS 91 From Evidence to Conclusions The main limitation of the reviewed studies is their reliance on ICD codes from electronic data without chart confirmation. In addition, the studies used varying nomenclature when designating cases of vaccine-associated myelitis. Most had TM as a stand-alone adverse event, but one (Patone et al., 2021) included ICD codes for TM within the larger category “acute demyelinating events,” which also included ICD codes for other central nervous system inflammatory disorders. Three studies (Klein et al., 2021; Li et al., 2022; Patone et al., 2021) included a separate category “encephalitis/myelitis/encephalomyelitis,” and cases clinically and radiographically consistent with TM may have been classed within this category based on their ICD code, resulting in a lower number of total reported events. None of the five epidemiology studies suggested a causal association between TM and BNT162b2, and no evidence suggests a large association. However, the limited number of studies, along with the overall low number of events reported, raises the concern that a small association may have been missed, given that TM is a very rare disorder. Four studies included a few mRNA-1273 recipients, with no TM cases reported in two of the studies. Only one study included patients who received Ad26.COV2.S, with a comparatively low number of vaccinees and no cases reported (Li et al., 2022). Conclusion 3-13: The evidence is inadequate to accept or reject a causal relationship between the BNT162b2 vaccine and transverse myelitis. Conclusion 3-14: The evidence is inadequate to accept or reject a causal relationship between the mRNA-1273 vaccine and transverse myelitis. Conclusion 3-15: The evidence is inadequate to accept or reject a causal relationship between the Ad26.COV2.S vaccine and transverse myelitis. Conclusion 3-16: The evidence is inadequate to accept or reject a causal relationship between the NVX-CoV2373 vaccine and transverse myelitis. PREPUBLICATION COPY—Uncorrected Proofs

92 VACCINE EVIDENCE REVIEW CHRONIC HEADACHE BOX 3-5 Conclusions for Chronic Headache Conclusion 3-17: The evidence is inadequate to accept or reject a causal relationship between the BNT162b2 vaccine and chronic headache. Conclusion 3-18: The evidence is inadequate to accept or reject a causal relationship between the mRNA-1273 vaccine and chronic headache. Conclusion 3-19: The evidence is inadequate to accept or reject a causal relationship between the Ad26.COV2.S vaccine and chronic headache. Conclusion 3-20: The evidence is inadequate to accept or reject a causal relationship between the NVX-CoV2373 vaccine and chronic headache. Background Headache is a frequently reported symptom of systemic illness, cerebrovascular disorders, intracranial disease, or craniocervical trauma. It is also reported commonly and can be a symptom of substance withdrawal. When a headache results from a separate medical condition, it is called a “secondary headache.” Most headaches, however, occur as the principal manifestation of a primary headache disorder; these are characterized by recurrent headaches of varying characteristics, frequency, and accompanying symptoms and signs. Although the frequency and severity of individual headache episodes vary over the lifetime, primary headache disorders are usually considered lifelong conditions. They have no biological markers, and their diagnosis is made with reasonable precision based on consensus diagnostic criteria set forth in the International Classification of Headache Disorders (ICHD-3), which was last revised in 2018 (International Headache Society, 2018). Ancillary studies, mostly brain and vascular imaging and occasionally lumbar puncture, are used to rule out various forms of secondary headaches. Tension-type headache (TTH) and migraine are by far the more common primary headache disorders, with an estimated lifetime prevalence in the general population of 46 and 14 percent, respectively (Stovner et al., 2007). Geographic variations exist, but it is unclear whether these are driven by genetic differences or methodological differences between studies. Other primary headache disorders, such as cluster headache, are much rarer, with a lifetime prevalence of 0.06–0.3 percent (Jensen and Stovner, 2008). The frequency, duration, and severity of headache varies significantly even within the same primary headache disorder: from infrequent, short, and mild to continuous and/or disabling. Migraine is more common in women compared to men, with a ratio of 2:1 to 3:1 (Jensen and Stovner, 2008). The female:male ratio for TTH is 5:4 (Jensen and Stovner, 2008). The prevalence of migraine peaks between the second and third decades of life but can affect people of all ages, including children. Data regarding age dependence in TTH are more limited, but prevalence peaks around the fourth decade of life. Cluster headache has a male:female ratio of 4.3:1 (Fischera et al., 2008), with prevalence peaking between the second and fourth decades of life. PREPUBLICATION COPY—Uncorrected Proofs

NEUROLOGIC CONDITIONS 93 No single consensus diagnostic criteria exist for chronic headache. Rather, ICHD-3 provides diagnostic criteria for chronic forms of individual headache subtypes based on frequency and duration. These include chronic migraine headache, chronic TTH, chronic cluster headache, hemicrania continua, new daily persistent headache, and medication overuse headache, which is a form of secondary headache (International Headache Society, 2018). In most, but not all, chronicity is based on a frequency of more than 15 headache days per month for longer than 3 months. Although ICHD-3 criteria for secondary headache does not specify measures of chronicity, they do specify that when a pre-existing primary headache becomes chronic shortly after a known causative disorder, both chronic primary headache and secondary headache diagnoses should be given (International Headache Society, 2018). Data on chronic headaches is relatively scarce, but prevalence as a group is estimated as 3–4 percent in the general population (Jensen and Stovner, 2008). Systemic infection, including with COVID-19, can be associated with headache (Togha et al., 2022), and “headache attributed to systemic infection” is included as a subtype of secondary headache in ICHD-3. Headache was also a frequently reported symptom in the clinical trials for the various COVID-19 vaccines (Baden et al., 2021; Heath et al., 2021; Polack et al., 2020; Sadoff et al., 2021). Most of these headaches occurred within 24 hours of vaccination and were frequently accompanied by systemic symptoms, such as fatigue, fever, chills, and myalgia (Göbel et al., 2021a, 2021b). In most, headaches lasted less than 72 hours, with only a small minority reporting more than 3 days. Pre-existing migraine was associated with more severe and long-lasting headaches in some but not all studies (Silvestro et al., 2021) and may predispose someone to postvaccine headache (Sekiguchi et al., 2022). Although ICHD-3 does include “headache attributed to use or exposure to a substance” as a subtype of secondary headache, vaccines are not listed within the known causes (International Headache Society, 2018). Evidence suggests that headache may be common with other vaccines as well, and some have proposed that postvaccination headache should be included in the next iteration of the ICHD (Garces et al., 2022). Headache is also one of the main symptoms of cerebral venous sinus thrombosis (CVST), a manifestation of vaccine-induced immune thrombotic thrombocytopenia (VITT). VITT has been reported in association with the AV COVID-19 vaccines and is discussed elsewhere in this report (See et al., 2021). Unlike the more common postvaccination headache, which occurs shortly after vaccination, the headache secondary to VITT-associated CVST is approximately a week after vaccination (García-Azorín et al., 2021). Mechanism The pathophysiology of primary headache disorders remains ill-defined and is different for individual disorders. Postvaccination headache is not included as a type of secondary headache in ICHD-3; however, it may bear some resemblance to “headache attributed to systemic infection,” which is included. The more widely accepted hypothesis is that postvaccination headache is secondary to downstream effects stemming from the immune response to the vaccine (Garces et al., 2022). Vaccines, including COVID-19 vaccines, are associated with the release of inflammatory mediators, such as prostaglandin E, and proinflammatory cytokines. It is conjectured that these are responsible for the headache and frequently associated systemic symptoms. Some have proposed that inflammatory mediators may modulate the release of calcitonin gene–related peptide (CGRP), which plays an important role in migraine via activation of the trigeminovascular system. Similarly, substance P, a PREPUBLICATION COPY—Uncorrected Proofs

94 VACCINE EVIDENCE REVIEW nociceptive neuropeptide released by trigeminal sensory fibers and implicated in migraine, is also produced by mast cells, suggesting a link between immune activation and migraines (Suvas, 2017). Data supporting this hypothesis are limited. One study found increased levels of inflammatory and nociceptive molecules in COVID-19 hospitalized patients with headache compared to those without; CGRP levels, however, did not differ significantly between the two groups (Bolay et al., 2021). Finally, some have hypothesized direct modulation of the trigeminal nerve when the spike protein, which is either synthetized intracellularly or introduced directly after vaccination, binds the ACE2 receptor. However, it remains unclear whether ACE2 is expressed in the relevant neural structures (Caronna et al., 2023), and some studies suggest that headache is more common after the second dose (Ceccardi et al., 2022), which appears counterintuitive given the probable presence of neutralizing antibodies against the spike protein Epidemiological Evidence Chronic headache is not a single diagnostic entity with widely accepted diagnostic criteria. The committee relied on ICHD-3, which provides diagnostic criteria for the subtypes. Although a self-limited headache was a commonly reported symptom after BNT162b2, mRNA- 1273, Ad26.COV2.S, and NVX-CoV2373, none of the studies reviewed included a stand-alone category for chronic headache, nor did they include chronic headache subtypes as defined in ICHD-3. Clinical trial results submitted to FDA for Emergency Use Authorization and/or full approval do not indicate a signal regarding chronic headache and any of the vaccines under study (FDA, 2021, 2023a, 2023b, 2023c). None were included in the final report for analysis. From Evidence to Conclusions The epidemiological and mechanistic literature are absent regarding the relationship between COVID-19 vaccines and chronic headache. Conclusion 3-17: The evidence is inadequate to accept or reject a causal relationship between the BNT162b2 vaccine and chronic headache. Conclusion 3-18: The evidence is inadequate to accept or reject a causal relationship between the mRNA-1273 vaccine and chronic headache. Conclusion 3-19: The evidence is inadequate to accept or reject a causal relationship between the Ad26.COV2.S vaccine and chronic headache. Conclusion 3-20: The evidence is inadequate to accept or reject a causal relationship between the NVX-CoV2373 vaccine and chronic headache. PREPUBLICATION COPY—Uncorrected Proofs

NEUROLOGIC CONDITIONS 95 POSTURAL ORTHOSTATIC TACHYCARDIA SYNDROME BOX 3-6 Conclusions for Postural Orthostatic Tachycardia Syndrome Conclusion 3-21: The evidence is inadequate to accept or reject a causal relationship between the BNT162b2 vaccine and postural orthostatic tachycardia syndrome. Conclusion 3-22: The evidence is inadequate to accept or reject a causal relationship between the mRNA-1273 vaccine and postural orthostatic tachycardia syndrome. Conclusion 3-23: The evidence is inadequate to accept or reject a causal relationship between the Ad26.COV2.S vaccine and postural orthostatic tachycardia syndrome. Conclusion 3-24: The evidence is inadequate to accept or reject a causal relationship between the NVX-CoV2373 vaccine and postural orthostatic tachycardia syndrome. Background POTS is marked by symptoms of orthostatic intolerance despite relative preservation of autonomic reflexes. The hallmark is an exaggerated increase in heart rate in response to standing or tilt without a drop in blood pressure as seen in classic autonomic failure (Cutsforth-Gregory, 2020). POTS is defined as a sustained heart rate increase of 30 beats per minute (bpm) or increase to 120 bpm within the first 10 minutes of orthostasis, along with symptoms of orthostatic intolerance, including dizziness, palpitations, weakness, and tremulousness. For children and adolescents (12–19 years), the required increment is 40 bpm (Vernino et al., 2021). POTS predominantly affects a younger and primarily female (at a ratio of 4:1) demographic, with the typical age range of onset being 12–50 (Vernino et al., 2021). Epidemiologically, it is a relatively common condition in developed countries, with prevalence estimates of 0.2–1.0 percent of the U.S. population, which represents 1–3 million people (Cutsforth-Gregory, 2020; Vernino et al., 2021). Orthostatic symptoms are probably driven by both cerebral hypoperfusion (dizziness, lightheadedness, vision, and hearing changes) and sympathoexcitation (palpitations, chest pain, difficulty breathing, tremulousness, sweating, and coldness of the extremities) (Cutsforth- Gregory, 2020). Particularly tachycardia, can be triggered either directly by influencing the sinus rate control system via adrenergic and muscarinic receptors or indirectly as a compensatory response to peripheral vasodilation. This indirect response may involve adrenergic, angiotensin, and other potential vasoactive receptors (Figure 3-2). POTS patients, however, frequently experience other symptoms as well, including sleep disturbances, headache, fatigue, cognitive impairment, gastrointestinal complaints, urinary frequency, and exercise intolerance (Vernino et al., 2021). The sheer variety and nonspecificity of these symptoms make it difficult to attribute all of them to a single clinical entity sharing the same underlying mechanism. A variety of comorbid conditions are associated with POTS, including migraine, somatic hypervigilance, irritable bowel syndrome, hypermobile Ehlers-Danlos syndrome (EDS), mast cell activation syndrome, systemic autoimmune disease, small-fiber neuropathy, and fibromyalgia and chronic fatigue syndrome (Gradin et al., 1987; Low et al., 2009; Shibao et al., 2005). It is unclear PREPUBLICATION COPY—Uncorrected Proofs

96 VACCINE EVIDENCE REVIEW whether the presence of these diagnoses defines unique pathophysiological subsets (Vernino et al., 2021). In either case, the diagnostic criteria emphasize symptoms and heart rate increment in response to an orthostatic challenge as the core feature, which is appropriate, as an excessive heart rate is the most consistent and reproducible of various indexes of orthostatic intolerance (Vernino et al., 2021). Symptoms alone in the absence of orthostatic tachycardia cannot be used to make the diagnosis and the syndrome must be present for at least 3 months (Vernino et al., 2021). The diagnostic approach begins with a comprehensive clinical assessment focused on orthostatic intolerance symptoms. Excessive increase in heart rate without orthostatic hypotension within 3–10 minutes from standing should be confirmed at bedside or with a tilt- table test (Freeman et al., 2011; Vernino et al., 2021). Laboratory tests play an important role in excluding other conditions that might mimic POTS symptoms. Further autonomic testing and/or skin biopsy may be warranted to explore the full spectrum of autonomic dysfunction and assess for underlying small-fiber neuropathy (Vernino et al., 2021). A 12-lead electrocardiography should be performed in all patients, but expanded cardiac evaluation, may be indicated in some (Cutsforth-Gregory, 2020). Between 20 and 50 percent of patients report a viral illness before the onset of symptoms. In these cases, POTS symptoms appear to arise abruptly weeks after the acute illness, but in others, the symptoms appear slowly (Thieben et al., 2007). Other triggers include surgery, and head trauma, although these are less well established (Olshansky et al., 2020). Patients have developed POTS symptoms at the time of or within 6 weeks of acute SARS-CoV-2 infection (Goodman et al., 2021), but latency can be longer, and POTS is considered a phenotype of postacute or “long” COVID-19 (Fedorowski and Sutton, 2023). POTS has also been reported in association with the COVID-19 vaccine (Kwan et al., 2022). Mechanisms The pathophysiology of POTS remains ill defined, and it is unlikely that it is a single disorder. Rather, it is probably a heterogeneous syndrome that can arise in various clinical scenarios resulting from distinct but overlapping pathophysiologic mechanisms (Benarroch, 2012). Several mechanisms have been proposed and account for some of its phenotypic variability. These include catecholamine excess (hyperadrenergic POTS), sympathetic denervation leading to impaired vasoconstriction of the lower limbs (neuropathic POTS), volume dysregulation, and deconditioning (Vernino et al., 2021). The clinical picture with hyperadrenergic POTS is dominated by palpitations, sweating, tremulousness, and orthostatic hypertension. Some of these patients have high plasma norepinephrine concentrations during orthostasis (Fedorowski and Sutton, 2023), although in others, the hyperadrenergic state may be secondary to medications, such a tricyclic antidepressants or methylphenidate (Cheshire, 2016). Neuropathic POTS may be secondary to a length-dependent autonomic neuropathy leading to impaired vasomotor tone in the lower limbs. Autonomic testing in some patients demonstrates loss of sweating in the feet and reduced increment of norepinephrine in the lower limbs when standing, which is consistent with a length- dependent autonomic neuropathy. The etiology of this autonomic neuropathy is not usually evident, although several lines of evidence suggest a potential immune-mediated mechanism in some cases. Reports of an earlier viral illness in up to one-half of patients suggests a postinfectious autoimmune process (Sandroni et al., 1999; Vernino et al., 2021). In addition, several small studies have demonstrated higher levels of functionally active antibodies to G- PREPUBLICATION COPY—Uncorrected Proofs

NEUROLOGIC CONDITIONS 97 protein-coupled adrenergic receptors α1 and α2 in individuals with POTS than in healthy controls (Fedorowski and Sutton, 2023; Kharraziha et al., 2020; Li et al., 2014; Vernino et al., 2021). These findings, plus reports of the successful treatment of POTS with intravenous immunoglobulin (Rodriguez et al., 2021; Weinstock et al., 2018), suggest an autoimmune etiology, at least in a subset of patients. However, a recent randomized control trial of IVIg in POTS found no difference in symptom response compared to albumin infusion (Vernino, 2023). Most patients have some degree of hypovolemia. Studies have demonstrated that many of them have low levels of plasma-renin activity and aldosterone compared with controls (Raj et al., 2005), and some have reduced ACE2 activity (Stewart et al., 2009). The excessive venous pooling that occurs with vasomotor impairment in neurogenic POTS can lead to reduced cardiac preload and capillary leakage upon standing with associated net loss of plasma volume (Cutsforth-Gregory, 2020). In those with poor oral intake or excess fluid loss, such as in irritable bowel syndrome, managing the primary disorder will improve orthostatic intolerance. Finally, physical deconditioning can lead to orthostatic intolerance. Many patients show evidence of deconditioning: reduced stroke volume and left ventricular mass and persistent tachycardia and reduced peak oxygen when standing or exercising (Fu et al., 2010; Masuki et al., 2007). POTS has been reported in association with SARS-CoV-2 infection (Kwan et al., 2022; Miglis et al., 2020), including in patients with post-acute COVID-19 (Fedorowski and Sutton, 2023). However, caution is needed when assessing the literature because, although orthostatic intolerance is commonly reported in patients with post-acute COVID-19, many may not meet diagnostic criteria for POTS. In one study of patients with de novo orthostatic intolerance after COVID-19, only 22 percent fulfilled criteria for POTS (Shouman et al., 2021); the symptoms may be driven by deconditioning in some of these patients. In addition to POTS, small-fiber neuropathy, which can cause autonomic dysfunction and a POTS phenotype, has been described after COVID-19, including in post-acute COVID-19 (Abrams et al., 2022; Oaklander et al., 2022). POTS has also been reported after COVID-19 vaccination (Kwan et al., 2022). Many of these reports postulate an immune-mediated mechanism, but definitive evidence is lacking. One study demonstrated elevated inflammatory cytokines and markers of autoimmunity in patients presenting with POTS after COVID-19, although this study did not include relevant controls. One in silico study identified a variety of SARS-CoV-2 amino acid sequences, including in the spike protein, that are also present in vagal nuclei and ganglia (Marino Gammazza et al., 2020). This raises the theoretical possibility that molecular mimicry could induce cross-reactive immune responses resulting in low vagal tone after infection or vaccination. PREPUBLICATION COPY—Uncorrected Proofs

98 VACCINE EVIDENCE REVIEW FIGURE 3-2 Postulated mechanisms of orthostatic intolerance and tachycardia in POTS. SOURCE: Fedorowski et al., 2017. Epidemiological Evidence Clinical trial results submitted to FDA for Emergency Use Authorization and/or full approval do not indicate a signal regarding POTS and any of the vaccines under study (FDA, 2021, 2023a, 2023b, 2023c). Table 3-6 summarizes one study that contributed to the causality assessment. TABLE 3-6 Epidemiological Study in the Postural Orthostatic Tachycardia Syndrome Evidence Review Study Design and Results Control Data Age Sample Number of (95% Author Group Location Source Vaccine(s) Range Size Events CI) 284,592 763 events BNT162b2 patients per OR Kwan (62.2%) Cohort/self- ≥12 100,000 1.52 et al. US EMR controlled years POTS (1.36– (2022) mRNA- 31% cases 1.71) 1273 during PREPUBLICATION COPY—Uncorrected Proofs

NEUROLOGIC CONDITIONS 99 exposure Ad26.COV period 6.9% 2.S compared to 501 per 100,000 NVX- <1% pre- CoV2373 other* exposure NOTES: BNT162b2 refers to the COVID-19 vaccine manufactured by Pfizer-BioNTech under the name Comirnaty®. mRNA-1273 refers to the COVID-19 vaccine manufactured by Moderna under the name Spikevax®. Ad26.COV2.S refers to the COVID-19 vaccine manufactured by Janssen. NVX-CoV2373 refers to the COVID-19 vaccine manufactured by Novavax. *<0.1% of other vaccines includes ChAdOx1-S, NVX-CoV2373, and CoronaVac. Number of events refers to events in vaccinees only. CI: confidence interval; EMR: electronic medical record; OR: odds ratio. SOURCE: Kwan et al., 2022. Kwan et al. (2022) derived cohorts from the diverse patient population of the Cedars- Sinai Health System in Los Angeles County, California. The authors identified patients who had at least one COVID-19 vaccination between 2020 and 2022 and excluded those with a documented COVID-19 infection 90 days before or after vaccination (n = 5,070). The final sample was 284,592 patients (age 52 ± 20 years; 57 percent female; 63 percent White, 10 percent Asian, 8.9 percent African American, and 12 percent Hispanic). Among the sample, 62 percent received BNT162b2, 31 percent mRNA-1273, 6.9 percent Ad26.COV2.S, and less than 0.1 percent other vaccines. POTS was identified using diagnosis codes (ICD-9 I49.8; ICD-10 G90.9) and modeled as both a single diagnosis and a combination of POTS-associated diagnoses (POTS diagnosis codes, Fatigue, Dysautonomia, EDS, and mast cell disorders). Only outpatient encounters were used. From the 90-day prevaccination to 90-day postvaccination periods, the incidence of new diagnoses of POTS increased from 176 per 100,000 to 268 per 100,000 vaccinees (the authors did not report incidence per 100,000 for the combined diagnoses). Relative to the prevaccination period, the odds of a new diagnosis of POTS and POTS-associated diagnoses increased 52 percent, OR 1.52 (95% CI: 1.36–1.71) and 33 percent, OR 1.33 (95% CI: 1.25–1.41) in the postvaccination period, respectively. Limitations exist from unmeasured confounding, lack of inclusion of COVID-19 infection, and open nature of the dataset, as patients could have had encounters in other health systems as well. In addition, the measure of effect was calculated for all vaccines combined, and conclusions cannot be drawn regarding a potential association between POTS and individual vaccines or platforms. The committee also reviewed a case series (Eldokla and Numan, 2022) of five patients who developed de novo POTS within 21 days of an mRNA vaccine (four BNT162b, one mRNA- 1273). All five underwent detailed autonomic testing and met diagnostic criteria for POTS. Two had elevated proinflammatory cytokines, and two had mildly elevated autoantibodies (thyroid peroxidase antibodies and antinuclear antibodies), without other signs or symptoms of systemic autoimmune disease. One had a low titer of acetylcholine receptor ganglionic antibodies; at higher titers, this has been associated with autoimmune autonomic failure. PREPUBLICATION COPY—Uncorrected Proofs

100 VACCINE EVIDENCE REVIEW From Evidence to Conclusions The totality of the evidence included one epidemiological study with methodological limitations and one case series with adequate case identification but no comparator group. No definitive mechanism was identified in the literature. Conclusion 3-21: The evidence is inadequate to accept or reject a causal relationship between the BNT162b2 vaccine and postural orthostatic tachycardia syndrome. Conclusion 3-22: The evidence is inadequate to accept or reject a causal relationship between the mRNA-1273 vaccine and postural orthostatic tachycardia syndrome. Conclusion 3-23: The evidence is inadequate to accept or reject a causal relationship between the Ad26.COV2.S vaccine and postural orthostatic tachycardia syndrome. Conclusion 3-24: The evidence is inadequate to accept or reject a causal relationship between the NVX-CoV2373 vaccine and postural orthostatic tachycardia syndrome. PREPUBLICATION COPY—Uncorrected Proofs

NEUROLOGIC CONDITIONS 101 REFERENCES Ab Rahman, N., M. T. Lim, F. Y. Lee, S. C. Lee, A. Ramli, S. N. Saharudin, T. L. King, E. B. Anak Jam, N. A. Ayub, R. K. Sevalingam, R. Bahari, N. N. Ibrahim, F. Mahmud, S. Sivasampu, and K. M. Peariasamy. 2022. Risk of serious adverse events after the BNT162b2, CoronaVac, and ChAdOx1 vaccines in Malaysia: A self-controlled case series study. Vaccine 40(32):4394–4402. https://doi.org/10.1016/j.vaccine.2022.05.075. Abara, W. E., J. Gee, P. Marquez, J. Woo, T. R. Myers, A. DeSantis, J. A. G. Baumblatt, E. J. Woo, D. Thompson, N. Nair, J. R. Su, T. T. Shimabukuro, and D. K. Shay. 2023. Reports of Guillain- Barré syndrome after COVID-19 vaccination in the United States. JAMA Network Open 6(2):e2253845. https://doi.org/10.1001/jamanetworkopen.2022.53845. Abbatemarco, J. R., J. R. Galli, M. L. Sweeney, N. G. Carlson, V. C. Samara, H. Davis, S. Rodenbeck, K. H. Wong, M. M. Paz Soldan, J. E. Greenlee, J. W. Rose, A. Delic, and S. L. Clardy. 2021. Modern look at transverse myelitis and inflammatory myelopathy: Epidemiology of the National Veterans Health Administration population. Neurology Neuroimmunology & Neuroinflammation 8(6). https://doi.org/10.1212/nxi.0000000000001071. Abrams, R. M. C., D. M. Simpson, A. Navis, N. Jette, L. Zhou, and S. C. Shin. 2022. Small fiber neuropathy associated with SARS-CoV-2 infection. Muscle and Nerve 65(4):440–443. https://doi.org/10.1002/mus.27458. Agmon-Levin, N., S. Kivity, M. Szyper-Kravitz, and Y. Shoenfeld. 2009. Transverse myelitis and vaccines: A multi-analysis. Lupus 18(13):1198–1204. https://doi.org/10.1177/0961203309345730. Arunachalam, P. S., M. K. D. Scott, T. Hagan, C. Li, Y. Feng, F. Wimmers, L. Grigoryan, M. Trisal, V. V. Edara, L. Lai, S. E. Chang, A. Feng, S. Dhingra, M. Shah, A. S. Lee, S. Chinthrajah, S. B. Sindher, V. Mallajosyula, F. Gao, N. Sigal, S. Kowli, S. Gupta, K. Pellegrini, G. Tharp, S. Maysel-Auslender, S. Hamilton, H. Aoued, K. Hrusovsky, M. Roskey, S. E. Bosinger, H. T. Maecker, S. D. Boyd, M. M. Davis, P. J. Utz, M. S. Suthar, P. Khatri, K. C. Nadeau, and B. Pulendran. 2021. Systems vaccinology of the BNT162b2 mRNA vaccine in humans. Nature 596(7872):410–416. https://doi.org/10.1038/s41586-021-03791-x. Asbury, A. K., B. G. Arnason, and R. D. Adams. 1969. The inflammatory lesion in idiopathic polyneuritis. Its role in pathogenesis. Medicine 48(3):173–215. https://doi.org/10.1097/00005792- 196905000-00001. Baden, L. R., H. M. El Sahly, B. Essink, K. Kotloff, S. Frey, R. Novak, D. Diemert, S. A. Spector, N. Rouphael, C. B. Creech, J. McGettigan, S. Khetan, N. Segall, J. Solis, A. Brosz, C. Fierro, H. Schwartz, K. Neuzil, L. Corey, P. Gilbert, H. Janes, D. Follmann, M. Marovich, J. Mascola, L. Polakowski, J. Ledgerwood, B. S. Graham, H. Bennett, R. Pajon, C. Knightly, B. Leav, W. Deng, H. Zhou, S. Han, M. Ivarsson, J. Miller, and T. Zaks. 2021. Efficacy and safety of the mRNA- 1273 SARS-CoV-2 vaccine. New England Journal of Medicine 384(5):403–416. https://doi.org/10.1056/NEJMoa2035389. Baker, A. T., R. J. Boyd, D. Sarkar, A. Teijeira-Crespo, C. K. Chan, E. Bates, K. Waraich, J. Vant, E. Wilson, C. D. Truong, M. Lipka-Lloyd, P. Fromme, J. Vermaas, D. Williams, L. Machiesky, M. Heurich, B. M. Nagalo, L. Coughlan, S. Umlauf, P. L. Chiu, P. J. Rizkallah, T. S. Cohen, A. L. Parker, A. Singharoy, and M. J. Borad. 2021. ChAdOx1 interacts with CAR and PF4 with implications for thrombosis with thrombocytopenia syndrome. Science Advances 7(49):eabl8213. https://doi.org/10.1126/sciadv.abl8213. Baugh, R. F., G. J. Basura, L. E. Ishii, S. R. Schwartz, C. M. Drumheller, R. Burkholder, N. A. Deckard, C. Dawson, C. Driscoll, M. B. Gillespie, R. K. Gurgel, J. Halperin, A. N. Khalid, K. A. Kumar, A. Micco, D. Munsell, S. Rosenbaum, and W. Vaughan. 2013. Clinical practice guideline: Bell’s palsy executive summary. Otolaryngology—Head and Neck Surgery 149(5):656–663. https://doi.org/10.1177/0194599813506835. PREPUBLICATION COPY—Uncorrected Proofs

102 VACCINE EVIDENCE REVIEW Baxter, R., E. Lewis, K. Goddard, B. Fireman, N. Bakshi, F. DeStefano, J. Gee, H. F. Tseng, A. L. Naleway, and N. P. Klein. 2016. Acute demyelinating events following vaccines: A case-centered analysis. Clinical Infectious Diseases 63(11):1456–1462. https://doi.org/10.1093/cid/ciw607. Benarroch, E. E. 2012. Postural tachycardia syndrome: A heterogeneous and multifactorial disorder. Mayo Clinic Proceedings 87(12):1214–1225. https://doi.org/10.1016/j.mayocp.2012.08.013. Bhat, A., S. Naguwa, G. Cheema, and M. E. Gershwin. 2010. The epidemiology of transverse myelitis. Autoimmunity Reviews 9(5):A395–A399. https://doi.org/10.1016/j.autrev.2009.12.007. Bolay, H., Ö. Karadas, B. Oztürk, R. Sonkaya, B. Tasdelen, T. D. S. Bulut, Ö. Gülbahar, A. Özge, and B. Baykan. 2021. HMGB1, NLRP3, IL-6 and ACE2 levels are elevated in COVID-19 with headache: A window to the infection-related headache mechanism. Journal of Headache and Pain 22(1):94. https://doi.org/10.1186/s10194-021-01306-7. Bragazzi, N. L., A. A. Kolahi, S. A. Nejadghaderi, P. Lochner, F. Brigo, A. Naldi, P. Lanteri, S. Garbarino, M. J. M. Sullman, H. Dai, J. Wu, J. D. Kong, H. Jahrami, M. R. Sohrabi, and S. Safiri. 2021. Global, regional, and national burden of Guillain-Barré syndrome and its underlying causes from 1990 to 2019. Journal of Neuroinflammation 18(1):264. https://doi.org/10.1186/s12974- 021-02319-4. Caronna, E., T. C. van den Hoek, H. Bolay, D. Garcia-Azorin, A. B. Gago-Veiga, M. Valeriani, T. Takizawa, K. Messlinger, R. E. Shapiro, P. J. Goadsby, M. Ashina, C. Tassorelli, H. C. Diener, G. M. Terwindt, and P. Pozo-Rosich. 2023. Headache attributed to SARS-CoV-2 infection, vaccination and the impact on primary headache disorders of the COVID-19 pandemic: A comprehensive review. Cephalalgia 43(1). https://doi.org/10.1177/03331024221131337. Ceccardi, G., F. Schiano di Cola, M. Di Cesare, P. Liberini, M. Magoni, C. Perani, R. Gasparotti, R. Rao, and A. Padovani. 2022. Post COVID-19 vaccination headache: A clinical and epidemiological evaluation. Frontiers in Pain Research 3:994140. https://doi.org/10.3389/fpain.2022.994140. Chen, Y., Z. Xu, P. Wang, X. M. Li, Z. W. Shuai, D. Q. Ye, and H. F. Pan. 2022a. New-onset autoimmune phenomena post-COVID-19 vaccination. Immunology 165(4):386–401. https://doi.org/10.1111/imm.13443. Chen, Y. J., P. L. Cheng, W. N. Huang, H. H. Chen, H. W. Chen, J. P. Chen, C. T. Lin, K. T. Tang, W. T. Hung, T. Y. Hsieh, Y. H. Chen, Y. M. Chen, and T. H. Hsiao. 2022b. Single-cell RNA sequencing to decipher the immunogenicity of ChAdOx1 NCOV-19/AZD1222 and mRNA-1273 vaccines in patients with autoimmune rheumatic diseases. Frontiers in Immunology 13:920865. https://doi.org/10.3389/fimmu.2022.920865. Cheshire, W. P. 2016. Stimulant medication and postural orthostatic tachycardia syndrome: A tale of two cases. Clinical Autonomic Research 26(3):229–233. https://doi.org/10.1007/s10286-016-0347-9. Cutsforth-Gregory, J. K. 2020. Postural tachycardia syndrome and neurally mediated syncope. Continuum 26(1):93–115. https://doi.org/10.1212/con.0000000000000818. Dalakas, M. C. 2011. Advances in the diagnosis, pathogenesis and treatment of CIDP. Nature Reviews: Neurology 7(9):507–517. https://doi.org/10.1038/nrneurol.2011.121. Dalakas, M. C., and W. K. Engel. 1980. Immunoglobulin and complement deposits in nerves of patients with chronic relapsing polyneuropathy. Archives of Neurology 37(10):637–640. https://doi.org/10.1001/archneur.1980.00500590061010. Dowling, P., J. Menonna, and S. Cook. 1977. Cytomegalovirus complement fixation antibody in Guillain- Barré syndrome. Neurology 27(12):1153–1156. https://doi.org/10.1212/wnl.27.12.1153. Eldokla, A. M., and M. T. Numan. 2022. Postural orthostatic tachycardia syndrome after mRNA COVID- 19 vaccine. Clinical Autonomic Research 32(4):307–311. https://doi.org/10.1007/s10286-022- 00880-3. FDA (Food and Drug Administration). 2021. Emergency use authorization (EUA) amendment for an unapproved product review memorandum. Food and Drug Administration. https://www.fda.gov/media/153439/download (accessed May 3, 2023). PREPUBLICATION COPY—Uncorrected Proofs

NEUROLOGIC CONDITIONS 103 FDA. 2023a. BLA clinical review memorandum - COMIRNATY. Food and Drug Administration. https://www.fda.gov/media/172333/download?attachment (accessed December 5, 2023). FDA. 2023b. BLA clinical review memorandum - SPIKEVAX. Food and Drug Administration. https://www.fda.gov/media/172357/download?attachment (accessed December 5, 2023). FDA. 2023c. Emergency use authorization (EUA) for an unapproved product review memorandum. Food and Drug Administration. https://www.fda.gov/media/168233/download?attachment (accessed December 5, 2023). Fedorowski, A. 2019. Postural orthostatic tachycardia syndrome: Clinical presentation, aetiology and management. Journal of Internal Medicine 285(4):352–366. https://doi.org/10.1111/joim.12852. Fedorowski, A., H. Li, X. Yu, K. A. Koelsch, V. M. Harris, C. Liles, T. A. Murphy, S. M. S. Quadri, R. H. Scofield, R. Sutton, O. Melander, and D. C. Kem. 2017. Antiadrenergic autoimmunity in postural tachycardia syndrome. Europace: European Pacing, Arrhythmias, and Cardiac Electrophysiology 19(7):1211–1219. https://doi.org/10.1093/europace/euw154. Fedorowski, A., and R. Sutton. 2023. Autonomic dysfunction and postural orthostatic tachycardia syndrome in post-acute COVID-19 syndrome. Nature Reviews: Cardiology 20(5):281–282. https://doi.org/10.1038/s41569-023-00842-w. Felipe Cuspoca, A., P. Isaac Estrada, and A. Velez-van-Meerbeke. 2022. Molecular mimicry of SARS- CoV-2 spike protein in the nervous system: A bioinformatics approach. Computational and Structural Biotechnology Journal 20:6041–6054. https://doi.org/10.1016/j.csbj.2022.10.022. Fischera, M., M. Marziniak, I. Gralow, and S. Evers. 2008. The incidence and prevalence of cluster headache: A meta-analysis of population-based studies. Cephalalgia 28(6):614–618. https://doi.org/10.1111/j.1468-2982.2008.01592.x. Flanagan, E. P., T. J. Kaufmann, K. N. Krecke, A. J. Aksamit, S. J. Pittock, B. M. Keegan, C. Giannini, and B. G. Weinshenker. 2016. Discriminating long myelitis of neuromyelitis optica from sarcoidosis. Annals of Neurology 79(3):437–447. https://doi.org/10.1002/ana.24582. Fokke, C., B. van den Berg, J. Drenthen, C. Walgaard, P. A. van Doorn, and B. C. Jacobs. 2014. Diagnosis of Guillain-Barré syndrome and validation of Brighton criteria. Brain 137(Pt 1):33–43. https://doi.org/10.1093/brain/awt285. Freeman, R., W. Wieling, F. B. Axelrod, D. G. Benditt, E. Benarroch, I. Biaggioni, W. P. Cheshire, T. Chelimsky, P. Cortelli, C. H. Gibbons, D. S. Goldstein, R. Hainsworth, M. J. Hilz, G. Jacob, H. Kaufmann, J. Jordan, L. A. Lipsitz, B. D. Levine, P. A. Low, C. Mathias, S. R. Raj, D. Robertson, P. Sandroni, I. Schatz, R. Schondorff, J. M. Stewart, and J. G. van Dijk. 2011. Consensus statement on the definition of orthostatic hypotension, neurally mediated syncope and the postural tachycardia syndrome. Clinical Autonomic Research 21(2):69–72. https://doi.org/10.1007/s10286-011-0119-5. Fu, Q., T. B. Vangundy, M. M. Galbreath, S. Shibata, M. Jain, J. L. Hastings, P. S. Bhella, and B. D. Levine. 2010. Cardiac origins of the postural orthostatic tachycardia syndrome. Journal of the American College of Cardiology 55(25):2858–2868. https://doi.org/10.1016/j.jacc.2010.02.043. Garces, K. N., A. N. Cocores, P. J. Goadsby, and T. S. Monteith. 2022. Headache after vaccination: An update on recent clinical trials and real-world reporting. Current Pain and Headache Reports 26(12):895–918. https://doi.org/10.1007/s11916-022-01094-y. García-Azorín, D., T. P. Do, A. R. Gantenbein, J. M. Hansen, M. N. P. Souza, M. Obermann, H. Pohl, C. J. Schankin, H. W. Schytz, A. Sinclair, G. G. Schoonman, and E. S. Kristoffersen. 2021. Delayed headache after COVID-19 vaccination: A red flag for vaccine induced cerebral venous thrombosis. Journal of Headache and Pain 22(1):108. https://doi.org/10.1186/s10194-021- 01324-5. García-Grimshaw, M., J. A. Galnares-Olalde, O. Y. Bello-Chavolla, A. Michel-Chávez, A. Cadena- Fernández, M. E. Briseño-Godínez, N. E. Antonio-Villa, I. Núñez, A. Gutiérrez-Romero, L. Hernández-Vanegas, M. Del Mar Saniger-Alba, R. Carrillo-Mezo, S. E. Ceballos-Liceaga, G. Carbajal-Sandoval, F. D. Flores-Silva, J. L. Díaz-Ortega, R. Cortes-Alcalá, J. R. Pérez-Padilla, H. PREPUBLICATION COPY—Uncorrected Proofs

104 VACCINE EVIDENCE REVIEW López-Gatell, E. Chiquete, G. Reyes-Terán, A. Arauz, and S. I. Valdés-Ferrer. 2022. Incidence of Guillain-Barré syndrome following SARS-CoV-2 immunization: Analysis of a nationwide registry of recipients of 81 million doses of seven vaccines. European Journal of Neurology 29(11):3368-3379. https://doi.org/10.1111/ene.15504. Göbel, C. H., A. Heinze, S. Karstedt, M. Morscheck, L. Tashiro, A. Cirkel, Q. Hamid, R. Halwani, M. H. Temsah, M. Ziemann, S. Görg, T. Münte, and H. Göbel. 2021a. Clinical characteristics of headache after vaccination against COVID-19 (coronavirus SARS-CoV-2) with the BNT162b2 mRNA vaccine: A multicentre observational cohort study. Brain Communications 3(3):fcab169. https://doi.org/10.1093/braincomms/fcab169. Göbel, C. H., A. Heinze, S. Karstedt, M. Morscheck, L. Tashiro, A. Cirkel, Q. Hamid, R. Halwani, M. H. Temsah, M. Ziemann, S. Görg, T. Münte, and H. Göbel. 2021b. Headache attributed to vaccination against COVID-19 (coronavirus SARS-CoV-2) with the ChAdOx1 NCOV-19 (AZD1222) vaccine: A multicenter observational cohort study. Pain Therapy 10(2):1309–1330. https://doi.org/10.1007/s40122-021-00296-3. Goodman, B. P., J. A. Khoury, J. E. Blair, and M. F. Grill. 2021. COVID-19 dysautonomia. Frontiers in Neurology 12:624968. https://doi.org/10.3389/fneur.2021.624968. Gradin, K., J. Hedner, T. Hedner, A. C. Towle, A. Pettersson, and B. Persson. 1987. Effects of chronic salt loading on plasma atrial natriuretic peptide (ANP) in the spontaneously hypertensive rat. Acta Physiologica Scandinavica 129(1):67–72. https://doi.org/10.1111/j.1748-1716.1987.tb08041.x. Ha, J., S. Park, H. Kang, T. Kyung, N. Kim, D. K. Kim, H. Kim, K. Bae, M. C. Song, K. J. Lee, E. Lee, B. S. Hwang, J. Youn, J. M. Seok, and K. Park. 2023. Real-world data on the incidence and risk of Guillain-Barré syndrome following SARS-CoV-2 vaccination: A prospective surveillance study. Scientific Reports 13(1):3773. https://doi.org/10.1038/s41598-023-30940-1. Hafsteinsdottir, B., and E. Olafsson. 2016. Incidence and natural history of idiopathic chronic inflammatory demyelinating polyneuropathy: A population-based study in Iceland. European Neurology 75(5–6):263–268. https://doi.org/10.1159/000445884. Hanson, K. E., K. Goddard, N. Lewis, B. Fireman, T. R. Myers, N. Bakshi, E. Weintraub, J. G. Donahue, J. C. Nelson, S. Xu, J. M. Glanz, J. T. B. Williams, J. D. Alpern, and N. P. Klein. 2022. Incidence of Guillain-Barré syndrome after COVID-19 vaccination in the Vaccine Safety Datalink. JAMA Network Open 5(4):e228879. https://doi.org/10.1001/jamanetworkopen.2022.8879. Heath, P. T., E. P. Galiza, D. N. Baxter, M. Boffito, D. Browne, F. Burns, D. R. Chadwick, R. Clark, C. Cosgrove, J. Galloway, A. L. Goodman, A. Heer, A. Higham, S. Iyengar, A. Jamal, C. Jeanes, P. A. Kalra, C. Kyriakidou, D. F. McAuley, A. Meyrick, A. M. Minassian, J. Minton, P. Moore, I. Munsoor, H. Nicholls, O. Osanlou, J. Packham, C. H. Pretswell, A. San Francisco Ramos, D. Saralaya, R. P. Sheridan, R. Smith, R. L. Soiza, P. A. Swift, E. C. Thomson, J. Turner, M. E. Viljoen, G. Albert, I. Cho, F. Dubovsky, G. Glenn, J. Rivers, A. Robertson, K. Smith, and S. Toback. 2021. Safety and efficacy of NVX-CoV2373 COVID-19 vaccine. New England Journal of Medicine 385(13):1172–1183. https://doi.org/10.1056/NEJMoa2107659. Hemsath, J. R., A. M. Liaci, J. D. Rubin, B. J. Parrett, S. C. Lu, T. V. Nguyen, M. A. Turner, C. Y. Chen, K. Cupelli, V. S. Reddy, T. Stehle, M. K. Liszewski, J. P. Atkinson, and M. A. Barry. 2022. Ex vivo and in vivo CD46 receptor utilization by Species D human adenovirus serotype 26 (HADV26). Journal of Virology 96(3):e0082621. https://doi.org/10.1128/JVI.00826-21. Hwang, I., T. B. Calvit, B. D. Cash, and K. C. Holtzmuller. 2004. Bell’s palsy: A rare complication of interferon therapy for hepatitis C. Digestive Diseases and Sciences 49(4):619–620. https://doi.org/10.1023/b:ddas.0000026389.56819.0c. International Headache Society. 2018. Headache classification committee of the international headache society (IHS) the international classification of headache disorders, 3rd edition. Cephalalgia 38(1):1–211. https://doi.org/10.1177/0333102417738202. Jacobs, B. C., M. P. Hazenberg, P. A. van Doorn, H. P. Endtz, and F. G. van der Meché. 1997. Cross- reactive antibodies against gangliosides and campylobacter jejuni lipopolysaccharides in patients PREPUBLICATION COPY—Uncorrected Proofs

NEUROLOGIC CONDITIONS 105 with Guillain-Barré or Miller Fisher Syndrome. Journal of Infectious Diseases 175(3):729–733. https://doi.org/10.1093/infdis/175.3.729. Jain, S., A. Khormi, S. R. Sangle, and D. P. D’Cruz. 2023. Transverse myelitis associated with systemic lupus erythematosus (SLE-TM): A review article. Lupus 32(9):1033–1042. https://doi.org/10.1177/09612033231185612. Jensen, R., and L. J. Stovner. 2008. Epidemiology and comorbidity of headache. Lancet Neurology 7(4):354–361. https://doi.org/10.1016/s1474-4422(08)70062-0. Kadkhoda, K. 2022. Post-adenoviral-based vaccines Guillain-Barré syndrome: A proposed mechanism. Medical Hypotheses 160:110792. https://doi.org/10.1016/j.mehy.2022.110792. Kaplin, A. I., D. M. Deshpande, E. Scott, C. Krishnan, J. S. Carmen, I. Shats, T. Martinez, J. Drummond, S. Dike, M. Pletnikov, S. C. Keswani, T. H. Moran, C. A. Pardo, P. A. Calabresi, and D. A. Kerr. 2005. IL-6 induces regionally selective spinal cord injury in patients with the neuroinflammatory disorder transverse myelitis. Journal of Clinical Investigation 115(10):2731–2741. https://doi.org/10.1172/JCI25141. Keddie, S., J. Pakpoor, C. Mousele, M. Pipis, P. M. Machado, M. Foster, C. J. Record, R. Y. S. Keh, J. Fehmi, R. W. Paterson, V. Bharambe, L. M. Clayton, C. Allen, O. Price, J. Wall, A. Kiss-Csenki, D. P. Rathnasabapathi, R. Geraldes, T. Yermakova, J. King-Robson, M. Zosmer, S. Rajakulendran, S. Sumaria, S. F. Farmer, R. Nortley, C. R. Marshall, E. J. Newman, N. Nirmalananthan, G. Kumar, A. A. Pinto, J. Holt, T. M. Lavin, K. M. Brennan, M. S. Zandi, D. L. Jayaseelan, J. Pritchard, R. D. M. Hadden, H. Manji, H. J. Willison, S. Rinaldi, A. S. Carr, and M. P. Lunn. 2021. Epidemiological and cohort study finds no association between COVID-19 and Guillain-Barré syndrome. Brain 144(2):682–693. https://doi.org/10.1093/brain/awaa433. Keh, R. Y. S., S. Scanlon, P. Datta-Nemdharry, K. Donegan, S. Cavanagh, M. Foster, D. Skelland, J. Palmer, P. M. Machado, S. Keddie, A. S. Carr, M. P. Lunn, and BPNS/ABN COVID-19 Study Group. 2023. COVID-19 vaccination and guillain-barre syndrome: Analyses using the national immunoglobulin database. Brain 146(2):739–748. https://doi.org/10.1093/brain/awac067. Kharraziha, I., J. Axelsson, F. Ricci, G. Di Martino, M. Persson, R. Sutton, A. Fedorowski, and V. Hamrefors. 2020. Serum activity against G protein–coupled receptors and severity of orthostatic symptoms in postural orthostatic tachycardia syndrome. Journal of the American Heart Association 9(15):e015989. https://doi.org/10.1161/jaha.120.015989. Kim, M. H., and S. Y. Park. 2021. Population-based study and a scoping review for the epidemiology and seasonality in and effect of weather on Bell’s palsy. Scientific Reports 11(1):16941. https://doi.org/10.1038/s41598-021-96422-4. Klein, N. P., N. Lewis, K. Goddard, B. Fireman, O. Zerbo, K. E. Hanson, J. G. Donahue, E. O. Kharbanda, A. Naleway, J. C. Nelson, S. Xu, W. K. Yih, J. M. Glanz, J. T. B. Williams, S. J. Hambidge, B. J. Lewin, T. T. Shimabukuro, F. DeStefano, and E. S. Weintraub. 2021. Surveillance for adverse events after COVID-19 mRNA vaccination. JAMA 326(14):1390–1399. https://doi.org/10.1001/jama.2021.15072. Krishnan, C., A. I. Kaplin, D. M. Deshpande, C. A. Pardo, and D. A. Kerr. 2004. Transverse myelitis: Pathogenesis, diagnosis and treatment. Frontiers in Bioscience 9:1483–1499. https://doi.org/10.2741/1351. Kwan, A. C., J. E. Ebinger, J. Wei, C. N. Le, J. R. Oft, R. Zabner, D. Teodorescu, P. G. Botting, J. Navarrette, D. Ouyang, M. Driver, B. Claggett, B. N. Weber, P. S. Chen, and S. Cheng. 2022. Apparent risks of postural orthostatic tachycardia syndrome diagnoses after COVID-19 vaccination and SARS-COV-2 infection. Nature Cardiovascular Research 1(12):1187–1194. https://doi.org/10.1038/s44161-022-00177-8. Laughlin, R., P. Dyck, L. R. Melton, C. Leibson, J. Ransom, and P. Dyck. 2009. Incidence and prevalence of CIDP and the association of diabetes mellitus. Neurology 73(1):39–45. Leibowitz, U. 1969. Epidemic incidence of Bell’s palsy. Brain 92(1):109–114. https://doi.org/10.1093/brain/92.1.109. PREPUBLICATION COPY—Uncorrected Proofs

106 VACCINE EVIDENCE REVIEW Leonhard, S. E., A. A. van der Eijk, H. Andersen, G. Antonini, S. Arends, S. Attarian, F. A. Barroso, K. J. Bateman, M. R. Batstra, L. Benedetti, B. van den Berg, P. Van den Bergh, J. Bürmann, M. Busby, C. Casasnovas, D. R. Cornblath, A. Davidson, A. Y. Doets, P. A. van Doorn, C. Dornonville de la Cour, T. E. Feasby, J. Fehmi, T. Garcia-Sobrino, J. M. Goldstein, K. C. Gorson, V. Granit, R. D. M. Hadden, T. Harbo, H. P. Hartung, I. Hasan, J. V. Holbech, J. K. L. Holt, I. Jahan, Z. Islam, S. Karafiath, H. D. Katzberg, R. P. Kleyweg, N. Kolb, K. Kuitwaard, M. Kuwahara, S. Kusunoki, L. W. G. Luijten, S. Kuwabara, E. Lee Pan, H. C. Lehmann, M. Maas, L. Martín-Aguilar, J. A. L. Miller, Q. D. Mohammad, S. Monges, V. Nedkova-Hristova, E. Nobile-Orazio, J. Pardo, Y. Pereon, L. Querol, R. Reisin, W. Van Rijs, S. Rinaldi, R. C. Roberts, J. Roodbol, N. Shahrizaila, S. H. Sindrup, B. Stein, T. Cheng-Yin, H. Tankisi, A. P. Tio-Gillen, M. J. Sedano Tous, C. Verboon, F. H. Vermeij, L. H. Visser, R. Huizinga, H. J. Willison, and B. C. Jacobs. 2022. An international perspective on preceding infections in Guillain-Barré syndrome: The IGOS-1000 cohort. Neurology 99(12):e1299–e1313. https://doi.org/10.1212/wnl.0000000000200885. Li, H., X. Yu, C. Liles, M. Khan, M. Vanderlinde-Wood, A. Galloway, C. Zillner, A. Benbrook, S. Reim, D. Collier, M. A. Hill, S. R. Raj, L. E. Okamoto, M. W. Cunningham, C. E. Aston, and D. C. Kem. 2014. Autoimmune basis for postural tachycardia syndrome. Journal of the American Heart Association 3(1):e000755. https://doi.org/10.1161/jaha.113.000755. Li, X., B. Raventos, E. Roel, A. Pistillo, E. Martinez-Hernandez, A. Delmestri, C. Reyes, V. Strauss, D. Prieto-Alhambra, E. Burn, and T. Duarte-Salles. 2022. Association between COVID-19 vaccination, SARS-CoV-2 infection, and risk of immune mediated neurological events: Population-based cohort and self-controlled case series analysis. British Medical Journal 376:e068373. https://doi.org/10.1136/bmj-2021-068373. Liston, S. L., and M. S. Kleid. 1989. Histopathology of Bell’s palsy. Laryngoscope 99(1):23–26. https://doi.org/10.1288/00005537-198901000-00006. Loo, L. K., O. Salim, D. Liang, A. Goel, S. Sumangala, A. S. Gowda, B. Davies, and Y. A. Rajabally. 2022. Acute-onset polyradiculoneuropathy after SARS-COV2 vaccine in the west and north Midlands, United Kingdom. Muscle and Nerve 65(2):233–237. https://doi.org/10.1002/mus.27461. Lopez Chiriboga, S., and E. P. Flanagan. 2021. Myelitis and other autoimmune myelopathies. Continuum (Minneap Minn) 27(1):62–92. https://doi.org/10.1212/CON.0000000000000900. Low, P. A., P. Sandroni, M. Joyner, and W. K. Shen. 2009. Postural tachycardia syndrome (POTS). Journal of Cardiovascular Electrophysiology 20(3):352–358. https://doi.org/10.1111/j.1540- 8167.2008.01407.x. Marino Gammazza, A., S. Légaré, G. Lo Bosco, A. Fucarino, F. Angileri, E. Conway de Macario, A. J. Macario, and F. Cappello. 2020. Human molecular chaperones share with SARS-CoV-2 antigenic epitopes potentially capable of eliciting autoimmunity against endothelial cells: Possible role of molecular mimicry in COVID-19. Cell Stress and Chaperones 25(5):737–741. https://doi.org/10.1007/s12192-020-01148-3. Masuki, S., J. H. Eisenach, W. G. Schrage, C. P. Johnson, N. M. Dietz, B. W. Wilkins, P. Sandroni, P. A. Low, and M. J. Joyner. 2007. Reduced stroke volume during exercise in postural tachycardia syndrome. Journal of Applied Physiology 103(4):1128–1135. https://doi.org/10.1152/japplphysiol.00175.2007. McCombe, P. A., J. G. McLeod, J. D. Pollard, Y. P. Guo, and T. J. Ingall. 1987. Peripheral sensorimotor and autonomic neuropathy associated with systemic lupus erythematosus. Clinical, pathological and immunological features. Brain 110 (Pt 2):533–549. https://doi.org/10.1093/brain/110.2.533. Miglis, M. G., T. Prieto, R. Shaik, S. Muppidi, D. I. Sinn, and S. Jaradeh. 2020. A case report of postural tachycardia syndrome after COVID-19. Clinical Autonomic Research 30(5):449–451. https://doi.org/10.1007/s10286-020-00727-9. PREPUBLICATION COPY—Uncorrected Proofs

NEUROLOGIC CONDITIONS 107 Morciano, C., S. Spila Alegiani, F. Menniti Ippoliti, V. Belleudi, G. Trifirò, G. Zanoni, A. Puccini, E. Sapigni, N. Mores, O. Leoni, G. Monaco, E. Clagnan, C. Zappetti, E. Bovo, R. Da Cas, and M. Massari. 2023. Post-marketing active surveillance of Guillan Barré syndrome following vaccination with anti-COVID-19 vaccines in persons aged ≥12 years in Italy: A multi-database self-controlled case series study. medRxiv:2023.2001.2017.23284585. https://doi.org/10.1101/2023.01.17.23284585. Morsy, S. 2020. NCAM protein and SARS-CoV-2 surface proteins: In-silico hypothetical evidence for the immunopathogenesis of Guillain-Barre syndrome. Medical Hypotheses 145:110342. https://doi.org/10.1016/j.mehy.2020.110342. NORD (National Organization for Rare Disorders). 2022. Bell's palsy. https://rarediseases.org/rare- diseases/bells-palsy (accessed February 20, 2024). Oaklander, A. L., A. J. Mills, M. Kelley, L. S. Toran, B. Smith, M. C. Dalakas, and A. Nath. 2022. Peripheral neuropathy evaluations of patients with prolonged long COVID. Neuroimmunology & Neuroinflammation 9(3). https://doi.org/10.1212/nxi.0000000000001146. Olshansky, B., D. Cannom, A. Fedorowski, J. Stewart, C. Gibbons, R. Sutton, W. K. Shen, J. Muldowney, T. H. Chung, S. Feigofsky, H. Nayak, H. Calkins, and D. G. Benditt. 2020. Postural orthostatic tachycardia syndrome (POTS): A critical assessment. Progress in Cardiovascular Diseases 63(3):263–270. https://doi.org/10.1016/j.pcad.2020.03.010. Patone, M., L. Handunnetthi, D. Saatci, J. Pan, S. V. Katikireddi, S. Razvi, D. Hunt, X. W. Mei, S. Dixon, F. Zaccardi, K. Khunti, P. Watkinson, C. A. C. Coupland, J. Doidge, D. A. Harrison, R. Ravanan, A. Sheikh, C. Robertson, and J. Hippisley-Cox. 2021. Neurological complications after first dose of COVID-19 vaccines and SARS-CoV-2 infection. Nature Medicine 27(12):2144–2153. https://doi.org/10.1038/s41591-021-01556-7. Pegat, A., A. Vogrig, C. Khouri, K. Masmoudi, T. Vial, and E. Bernard. 2022. Adenovirus COVID-19 vaccines and Guillain-Barré syndrome with facial paralysis. Annals of Neurology 91(1):162–163. https://doi.org/10.1002/ana.26258. Polack, F. P., S. J. Thomas, N. Kitchin, J. Absalon, A. Gurtman, S. Lockhart, J. L. Perez, G. Pérez Marc, E. D. Moreira, C. Zerbini, R. Bailey, K. A. Swanson, S. Roychoudhury, K. Koury, P. Li, W. V. Kalina, D. Cooper, R. W. Frenck, Jr., L. L. Hammitt, Ö. Türeci, H. Nell, A. Schaefer, S. Ünal, D. B. Tresnan, S. Mather, P. R. Dormitzer, U. Şahin, K. U. Jansen, and W. C. Gruber. 2020. Safety and efficacy of the BNT162b2 mRNA COVID-19 vaccine. New England Journal of Medicine 383(27):2603–2615. https://doi.org/10.1056/NEJMoa2034577. Rafati, A., Y. Pasebani, M. Jameie, Y. Yang, M. Jameie, S. Ilkhani, M. Amanollahi, D. Sakhaei, M. Rahimlou, and A. Kheradmand. 2023. Association of SARS-CoV-2 vaccination or infection with Bell palsy: A systematic review and meta-analysis. JAMA Otolaryngology—Head & Neck Surgery 149(6):493–504. https://doi.org/10.1001/jamaoto.2023.0160. Raj, S. R., I. Biaggioni, P. C. Yamhure, B. K. Black, S. Y. Paranjape, D. W. Byrne, and D. Robertson. 2005. Renin-aldosterone paradox and perturbed blood volume regulation underlying postural tachycardia syndrome. Circulation 111(13):1574–1582. https://doi.org/10.1161/01.Cir.0000160356.97313.5d. Rivers, T. M. 1932. Viruses. Science 75(1956):654–656. https://doi.org/10.1126/science.75.1956.654. Rodriguez, B., R. Hoepner, A. Salmen, N. Kamber, and W. J. Z’Graggen. 2021. Immunomodulatory treatment in postural tachycardia syndrome: A case series. European Journal of Neurology 28(5):1692–1697. https://doi.org/10.1111/ene.14711. Rzymski, P. 2023. Guillain-Barré syndrome and COVID-19 vaccines: Focus on adenoviral vectors. Frontiers in Immunology 14:1183258. https://doi.org/10.3389/fimmu.2023.1183258. Sadoff, J., G. Gray, A. Vandebosch, V. Cárdenas, G. Shukarev, B. Grinsztejn, P. A. Goepfert, C. Truyers, H. Fennema, B. Spiessens, K. Offergeld, G. Scheper, K. L. Taylor, M. L. Robb, J. Treanor, D. H. Barouch, J. Stoddard, M. F. Ryser, M. A. Marovich, K. M. Neuzil, L. Corey, N. Cauwenberghs, T. Tanner, K. Hardt, J. Ruiz-Guiñazú, M. Le Gars, H. Schuitemaker, J. Van Hoof, F. Struyf, and PREPUBLICATION COPY—Uncorrected Proofs

108 VACCINE EVIDENCE REVIEW M. Douoguih. 2021. Safety and efficacy of single-dose Ad26.COV2.S vaccine against COVID- 19. New England Journal of Medicine 384(23):2187–2201. https://doi.org/10.1056/NEJMoa2101544. Sandroni, P., T. L. Opfer-Gehrking, B. R. McPhee, and P. A. Low. 1999. Postural tachycardia syndrome: Clinical features and follow-up study. Mayo Clinic Proceedings 74(11):1106–1110. https://doi.org/10.4065/74.11.1106. See, I., J. R. Su, A. Lale, E. J. Woo, A. Y. Guh, T. T. Shimabukuro, M. B. Streiff, A. K. Rao, A. P. Wheeler, S. F. Beavers, A. P. Durbin, K. Edwards, E. Miller, T. A. Harrington, A. Mba-Jonas, N. Nair, D. T. Nguyen, K. R. Talaat, V. C. Urrutia, S. C. Walker, C. B. Creech, T. A. Clark, F. DeStefano, and K. R. Broder. 2021. U.S. case reports of cerebral venous sinus thrombosis with thrombocytopenia after Ad26.COV2.S vaccination, March 2 to April 21, 2021. JAMA 325(24):2448–2456. https://doi.org/10.1001/jama.2021.7517. Sejvar, J. J., K. S. Kohl, J. Gidudu, A. Amato, N. Bakshi, R. Baxter, D. R. Burwen, D. R. Cornblath, J. Cleerbout, K. M. Edwards, U. Heininger, R. Hughes, N. Khuri-Bulos, R. Korinthenberg, B. J. Law, U. Munro, H. C. Maltezou, P. Nell, J. Oleske, R. Sparks, P. Velentgas, P. Vermeer, and M. Wiznitzer. 2011. Guillain-Barré Syndrome and Fisher Syndrome: Case definitions and guidelines for collection, analysis, and presentation of immunization safety data. Vaccine 29(3):599–612. https://doi.org/10.1016/j.vaccine.2010.06.003. Sekiguchi, K., N. Watanabe, N. Miyazaki, K. Ishizuchi, C. Iba, Y. Tagashira, S. Uno, M. Shibata, N. Hasegawa, R. Takemura, J. Nakahara, and T. Takizawa. 2022. Incidence of headache after COVID-19 vaccination in patients with history of headache: A cross-sectional study. Cephalalgia 42(3):266–272. https://doi.org/10.1177/03331024211038654. Shahrizaila, N., H. C. Lehmann, and S. Kuwabara. 2021. Guillain-Barré Syndrome. Lancet 397(10280):1214–1228. https://doi.org/10.1016/S0140-6736(21)00517-1. Shasha, D., R. Bareket, F. H. Sikron, O. Gertel, J. Tsamir, D. Dvir, D. Mossinson, A. D. Heymann, and G. Zacay. 2022. Real-world safety data for the Pfizer BNT162b2 SARS-CoV-2 vaccine: Historical cohort study. Clinical Microbiology and Infection 28(1):130–134. https://doi.org/10.1016/j.cmi.2021.09.018. Sheerin, D., C. Dold, D. O’Connor, A. J. Pollard, and C. S. Rollier. 2021. Distinct patterns of whole blood transcriptional responses are induced in mice following immunisation with adenoviral and poxviral vector vaccines encoding the same antigen. BMC Genomics 22(1):777. https://doi.org/10.1186/s12864-021-08061-8. Sheikh, K. A., I. Nachamkin, T. W. Ho, H. J. Willison, J. Veitch, H. Ung, M. Nicholson, C. Y. Li, H. S. Wu, B. Q. Shen, D. R. Cornblath, A. K. Asbury, G. M. McKhann, and J. W. Griffin. 1998. Campylobacter jejuni lipopolysaccharides in Guillain-Barré syndrome: Molecular mimicry and host susceptibility. Neurology 51(2):371–378. https://doi.org/10.1212/wnl.51.2.371. Shemer, A., E. Pras, A. Einan-Lifshitz, B. Dubinsky-Pertzov, and I. Hecht. 2021. Association of COVID- 19 vaccination and facial nerve palsy: A case-control study. JAMA Otolaryngology—Head & Neck Surgery 147(8):739–743. https://doi.org/10.1001/jamaoto.2021.1259. Shibao, C., C. Arzubiaga, L. J. Roberts, II, S. Raj, B. Black, P. Harris, and I. Biaggioni. 2005. Hyperadrenergic postural tachycardia syndrome in mast cell activation disorders. Hypertension 45(3):385–390. https://doi.org/10.1161/01.Hyp.0000158259.68614.40. Shibli, R., O. Barnett, Z. Abu-Full, N. Gronich, R. Najjar-Debbiny, I. Doweck, G. Rennert, and W. Saliba. 2021. Association between vaccination with the BNT162b2 mRNA COVID-19 vaccine and Bell’s palsy: A population-based study. Lancet Regional Health—Europe 11:100236. https://doi.org/10.1016/j.lanepe.2021.100236. Shoaibi, A., P. C. Lloyd, H. L. Wong, T. C. Clarke, Y. Chillarige, R. Do, M. Hu, Y. Jiao, A. Kwist, A. Lindaas, K. Matuska, R. McEvoy, M. Ondari, S. Parulekar, X. Shi, J. Wang, Y. Lu, J. Obidi, C. K. Zhou, J. A. Kelman, R. A. Forshee, and S. A. Anderson. 2023. Evaluation of potential adverse events following COVID-19 mRNA vaccination among adults aged 65 years and older: Two self- PREPUBLICATION COPY—Uncorrected Proofs

NEUROLOGIC CONDITIONS 109 controlled studies in the U.S. Vaccine 41(32):4666–4678. https://doi.org/10.1016/j.vaccine.2023.06.014. Shouman, K., G. Vanichkachorn, W. P. Cheshire, M. D. Suarez, S. Shelly, G. J. Lamotte, P. Sandroni, E. E. Benarroch, S. E. Berini, J. K. Cutsforth-Gregory, E. A. Coon, M. L. Mauermann, P. A. Low, and W. Singer. 2021. Autonomic dysfunction following COVID-19 infection: An early experience. Clinical Autonomic Research 31(3):385–394. https://doi.org/10.1007/s10286-021- 00803-8. Silvestro, M., A. Tessitore, I. Orologio, P. Sozio, G. Napolitano, M. Siciliano, G. Tedeschi, and A. Russo. 2021. Headache worsening after COVID-19 vaccination: An online questionnaire-based study on 841 patients with migraine. Journal of Clinical Medicine 10(24). https://doi.org/10.3390/jcm10245914. Soeiro, A. M., and P. M. Pego-Fernandes. 2021. Post-COVID-19 cardiological alterations. Sao Paulo Medical Journal 139(6):543–544. https://doi.org/10.1590/1516-3180.2021.139628062021. Steiner, I., and Y. Mattan. 1999. Bell’s palsy and herpes viruses: To (acyclo)vir or not to (acyclo)vir? Journal of the Neurological Sciences 170(1):19–23. https://doi.org/10.1016/s0022- 510x(99)00187-2. Stewart, J. M., A. J. Ocon, D. Clarke, I. Taneja, and M. S. Medow. 2009. Defects in cutaneous angiotensin-converting enzyme 2 and angiotensin-(1-7) production in postural tachycardia syndrome. Hypertension 53(5):767–774. https://doi.org/10.1161/hypertensionaha.108.127357. Stovner, L., K. Hagen, R. Jensen, Z. Katsarava, R. Lipton, A. Scher, T. Steiner, and J. A. Zwart. 2007. The global burden of headache: A documentation of headache prevalence and disability worldwide. Cephalalgia 27(3):193–210. https://doi.org/10.1111/j.1468-2982.2007.01288.x. Sturkenboom, M., D. Messina, O. Paoletti, A. de Burgos-Gonzalez, R. Zabner, P. García-Poza, C. Huerta, A. Llorente García, M. Martin-Perez, M. Martinez, I. Martin, J. Overbeek, M. Padros-Goossens, P. Souverein, K. Swart, O. Klungel, and R. Gini. 2022. Cohort monitoring of 29 adverse events of special interest prior to and after COVID-19 vaccination in four large European electronic health care data sources. medRxiv:2022.2008.2017.22278894. https://doi.org/10.1101/2022.08.17.22278894. Sullivan, F. M., I. R. Swan, P. T. Donnan, J. M. Morrison, B. H. Smith, B. McKinstry, R. J. Davenport, L. D. Vale, J. E. Clarkson, V. Hammersley, S. Hayavi, A. McAteer, K. Stewart, and F. Daly. 2007. Early treatment with prednisolone or acyclovir in Bell’s palsy. New England Journal of Medicine 357(16):1598–1607. https://doi.org/10.1056/NEJMoa072006. Suvas, S. 2017. Role of substance P neuropeptide in inflammation, wound healing, and tissue homeostasis. Journal of Immunology 199(5):1543–1552. https://doi.org/10.4049/jimmunol.1601751. Takeuchi, Y., M. Iwagami, S. Ono, N. Michihata, K. Uemura, and H. Yasunaga. 2022. A post-marketing safety assessment of COVID-19 mRNA vaccination for serious adverse outcomes using administrative claims data linked with vaccination registry in a city of Japan. Vaccine 40(52):7622–7630. https://doi.org/10.1016/j.vaccine.2022.10.088. Takuva, S., A. Takalani, I. Seocharan, N. Yende-Zuma, T. Reddy, I. Engelbrecht, M. Faesen, K. Khuto, C. Whyte, V. Bailey, V. Trivella, J. Peter, J. Opie, V. Louw, P. Rowji, B. Jacobson, P. Groenewald, R. E. Dorrington, R. Laubscher, D. Bradshaw, H. Moultrie, L. Fairall, I. Sanne, L. Gail-Bekker, G. Gray, A. Goga, and N. Garrett. 2022. Safety evaluation of the single-dose Ad26.COV2.S vaccine among healthcare workers in the Sisonke study in South Africa: A phase 3b implementation trial. PLoS Medicine 19(6):e1004024. https://doi.org/10.1371/journal.pmed.1004024. Thieben, M. J., P. Sandroni, D. M. Sletten, L. M. Benrud-Larson, R. D. Fealey, S. Vernino, V. A. Lennon, W. K. Shen, and P. A. Low. 2007. Postural orthostatic tachycardia syndrome: The Mayo Clinic experience. Mayo Clinic Proceedings 82(3):308–313. https://doi.org/10.4065/82.3.308. PREPUBLICATION COPY—Uncorrected Proofs

110 VACCINE EVIDENCE REVIEW Thomas, P. K., R. W. Walker, P. Rudge, J. A. Morgan-Hughes, R. H. King, J. M. Jacobs, K. R. Mills, I. E. Ormerod, N. M. Murray, and W. I. McDonald. 1987. Chronic demyelinating peripheral neuropathy associated with multifocal central nervous system demyelination. Brain 110 (Pt 1):53–76. https://doi.org/10.1093/brain/110.1.53. Togha, M., S. M. Hashemi, N. Yamani, F. Martami, and Z. Salami. 2022. A review on headaches due to COVID-19 infection. Frontiers in Neurology 13:942956. https://doi.org/10.3389/fneur.2022.942956. Transverse Myelitis Consortium Working Group. 2002. Proposed diagnostic criteria and nosology of acute transverse myelitis. Neurology 59(4):499–505. https://doi.org/10.1212/wnl.59.4.499. Van den Bergh, P. Y., R. D. Hadden, P. Bouche, D. R. Cornblath, A. Hahn, I. Illa, C. L. Koski, J. M. Léger, E. Nobile‐Orazio, and J. Pollard. 2010. European Federation of Neurological Societies/Peripheral Nerve Society guideline on management of chronic inflammatory demyelinating polyradiculoneuropathy: Report of a joint task force of the European Federation of Neurological Societies and the Peripheral Nerve Society—first revision. European Journal of Neurology 17(3):356–363. Van den Bergh, P. Y. K., P. A. van Doorn, R. D. M. Hadden, B. Avau, P. Vankrunkelsven, J. A. Allen, S. Attarian, P. H. Blomkwist-Markens, D. R. Cornblath, F. Eftimov, H. S. Goedee, T. Harbo, S. Kuwabara, R. A. Lewis, M. P. Lunn, E. Nobile-Orazio, L. Querol, Y. A. Rajabally, C. Sommer, and H. A. Topaloglu. 2021. European Academy of Neurology/Peripheral Nerve Society guideline on diagnosis and treatment of chronic inflammatory demyelinating polyradiculoneuropathy: Report of a joint task force—second revision. Journal of the Peripheral Nervous System 26(3):242–268. https://doi.org/10.1111/jns.12455. Vellozzi, C., S. Iqbal, and K. Broder. 2014. Guillain-Barré syndrome, influenza, and influenza vaccination: The epidemiologic evidence. Clinical Infectious Diseases 58(8):1149–1155. https://doi.org/10.1093/cid/ciu005. Vernino, S., K. M. Bourne, L. E. Stiles, B. P. Grubb, A. Fedorowski, J. M. Stewart, A. C. Arnold, L. A. Pace, J. Axelsson, J. R. Boris, J. P. Moak, B. P. Goodman, K. R. Chémali, T. H. Chung, D. S. Goldstein, A. Diedrich, M. G. Miglis, M. M. Cortez, A. J. Miller, R. Freeman, I. Biaggioni, P. C. Rowe, R. S. Sheldon, C. A. Shibao, D. M. Systrom, G. A. Cook, T. A. Doherty, H. I. Abdallah, A. Darbari, and S. R. Raj. 2021. Postural orthostatic tachycardia syndrome (POTS): State of the science and clinical care from a 2019 national institutes of health expert consensus meeting—part 1. Autonomic Neuroscience 235:102828. https://doi.org/10.1016/j.autneu.2021.102828. Vernino, S., Hopkins, S., Bryarly, M., Hernandez, R., Salter, A. 2023. Randomized controlled trial of intravenous immunoglobulin for autoimmune postural tachycardia syndrome (ISTAND). Clinical Autonomic Research. Walker, J. L., A. Schultze, J. Tazare, A. Tamborska, B. Singh, K. Donegan, J. Stowe, C. E. Morton, W. J. Hulme, H. J. Curtis, E. J. Williamson, A. Mehrkar, R. M. Eggo, C. T. Rentsch, R. Mathur, S. Bacon, A. J. Walker, S. Davy, D. Evans, P. Inglesby, G. Hickman, B. MacKenna, L. Tomlinson, A. Ca Green, L. Fisher, J. Cockburn, J. Parry, F. Hester, S. Harper, C. Bates, S. J. Evans, T. Solomon, N. J. Andrews, I. J. Douglas, B. Goldacre, L. Smeeth, and H. I. McDonald. 2022. Safety of COVID-19 vaccination and acute neurological events: A self-controlled case series in England using the OpenSafely platform. Vaccine 40(32):4479–4487. https://doi.org/10.1016/j.vaccine.2022.06.010. Wanschitz, J., H. Maier, H. Lassmann, H. Budka, and T. Berger. 2003. Distinct time pattern of complement activation and cytotoxic T cell response in Guillain-Barré syndrome. Brain 126(Pt 9):2034–2042. https://doi.org/10.1093/brain/awg207. Weinstock, L. B., J. B. Brook, T. L. Myers, and B. Goodman. 2018. Successful treatment of postural orthostatic tachycardia and mast cell activation syndromes using naltrexone, immunoglobulin and antibiotic treatment. BMJ Case Reports. https://doi.org/10.1136/bcr-2017-221405. PREPUBLICATION COPY—Uncorrected Proofs

NEUROLOGIC CONDITIONS 111 Wratten, S. J., D. J. Faulkner, K. Hirotsu, and J. Clardy. 1977. Trimethylenemethane. A reversible, temperature dependent transformation from higher to lower symmetry as observed by electron spin resonance spectroscopy. Journal of the American Chemical Society 99(8):2824-2825. https://doi.org/10.1021/ja00450a083. Yılmaz, M., M. Tarakcioglu, N. Bayazit, Y. A. Bayazit, M. Namiduru, and M. Kanlikama. 2002. Serum cytokine levels in Bell’s palsy. Journal of the Neurological Sciences 197(1–2):69–72. https://doi.org/10.1016/s0022-510x(02)00049-7. Yuki, N., T. Taki, F. Inagaki, T. Kasama, M. Takahashi, K. Saito, S. Handa, and T. Miyatake. 1993. A bacterium lipopolysaccharide that elicits Guillain-Barré syndrome has a GM1 ganglioside-like structure. Journal of Experimental Medicine 178(5):1771–1775. https://doi.org/10.1084/jem.178.5.1771. Yuki, N., K. Susuki, M. Koga, Y. Nishimoto, M. Odaka, K. Hirata, K. Taguchi, T. Miyatake, K. Furukawa, T. Kobata, and M. Yamada. 2004. Carbohydrate mimicry between human ganglioside GM1 and campylobacter jejuni lipooligosaccharide causes Guillain-Barré syndrome. Proceedings of the National Academy of Sciences of the United States of America 101(31):11404–11409. https://doi.org/10.1073/pnas.0402391101. Zalewski, N. L., A. A. Rabinstein, K. N. Krecke, R. D. Brown, Jr., E. F. M. Wijdicks, B. G. Weinshenker, T. J. Kaufmann, J. M. Morris, A. J. Aksamit, J. D. Bartleson, G. Lanzino, M. M. Blessing, and E. P. Flanagan. 2019. Characteristics of spontaneous spinal cord infarction and proposed diagnostic criteria. JAMA Neurology 76(1):56–63. https://doi.org/10.1001/jamaneurol.2018.2734. Zhang, W., L. Xu, T. Luo, F. Wu, B. Zhao, and X. Li. 2020. The etiology of Bell’s palsy: A review. Journal of Neurology 267(7):1896–1905. https://doi.org/10.1007/s00415-019-09282-4. Zussy, C., F. Loustalot, F. Junyent, F. Gardoni, C. Bories, J. Valero, M. G. Desarmenien, F. Bernex, D. Henaff, N. Bayo-Puxan, J. W. Chen, N. Lonjon, Y. de Koninck, J. O. Malva, J. M. Bergelson, M. di Luca, G. Schiavo, S. Salinas, and E. J. Kremer. 2016. Coxsackievirus adenovirus receptor loss impairs adult neurogenesis, synapse content, and hippocampus plasticity. Journal of Neuroscience 36(37):9558–9571. https://doi.org/10.1523/JNEUROSCI.0132-16.2016. PREPUBLICATION COPY—Uncorrected Proofs

112 VACCINE EVIDENCE REVIEW PREPUBLICATION COPY—Uncorrected Proofs

Next: 4 Sensorineural Hearing Loss, Tinnitus, and COVID-19 Vaccines »
Evidence Review of the Adverse Effects of COVID-19 Vaccination and Intramuscular Vaccine Administration Get This Book
×
 Evidence Review of the Adverse Effects of COVID-19 Vaccination and Intramuscular Vaccine Administration
Buy Prepub | $37.00 Buy Paperback | $28.00
MyNAP members save 10% online.
Login or Register to save!
Download Free PDF

Vaccines are a public health success story, as they have prevented or lessened the effects of many infectious diseases. To address concerns around potential vaccine injuries, the Health Resources and Services Administration (HRSA) administers the Vaccine Injury Compensation Program (VICP) and the Countermeasures Injury Compensation Program (CICP), which provide compensation to those who assert that they were injured by routine vaccines or medical countermeasures, respectively. The National Academies of Sciences, Engineering, and Medicine have contributed to the scientific basis for VICP compensation decisions for decades.

HRSA asked the National Academies to convene an expert committee to review the epidemiological, clinical, and biological evidence about the relationship between COVID-19 vaccines and specific adverse events, as well as intramuscular administration of vaccines and shoulder injuries. This report outlines the committee findings and conclusions.

READ FREE ONLINE

  1. ×

    Welcome to OpenBook!

    You're looking at OpenBook, NAP.edu's online reading room since 1999. Based on feedback from you, our users, we've made some improvements that make it easier than ever to read thousands of publications on our website.

    Do you want to take a quick tour of the OpenBook's features?

    No Thanks Take a Tour »
  2. ×

    Show this book's table of contents, where you can jump to any chapter by name.

    « Back Next »
  3. ×

    ...or use these buttons to go back to the previous chapter or skip to the next one.

    « Back Next »
  4. ×

    Jump up to the previous page or down to the next one. Also, you can type in a page number and press Enter to go directly to that page in the book.

    « Back Next »
  5. ×

    To search the entire text of this book, type in your search term here and press Enter.

    « Back Next »
  6. ×

    Share a link to this book page on your preferred social network or via email.

    « Back Next »
  7. ×

    View our suggested citation for this chapter.

    « Back Next »
  8. ×

    Ready to take your reading offline? Click here to buy this book in print or download it as a free PDF, if available.

    « Back Next »
Stay Connected!