Pain adverse events, Bell’s palsy, and Guillain-Barré syndrome Following Vaccination

Objective Some individuals (vaccinees) experience pain related adverse events following vaccinations. The majority of these pain related vaccination reactogenicity adverse events resolve within days. Rare adverse events like Bell’s palsy and Guillain-Barré syndrome (GBS) have been associated with some vaccines. Herein, multiple working hypotheses are examined in the context of available characteristics of vaccinees and onset of these pain related adverse events post vaccination. The Vaccine Adverse Event Reporting System (VAERS) database was datamined for pain associated vaccine adverse events data by vaccine, age, gender, dose, and onset post vaccination. Results for vaccines with the highest number of pain related adverse events were compared.


Introduction
Vaccines are designed to protect vaccinees (vaccinated individuals) against viral and bacterial infectious disease. Some vaccinees experience one or more adverse events post vaccination. Vaccine reactogenicity refers to the subset of adverse events that occur soon after vaccination and are physical manifestations of the in ammatory response to vaccination [1]. Most reactogenicity adverse events resolve within days. Other adverse events have persistent symptoms that may last weeks, months, or longer. The etiology of these adverse events remains unknown.
The Vaccine Adverse Event System (VAERS) database tracks reported adverse events following vaccinations for the United States. Herein, VAERS is data mined for reports of pain associated adverse events. Multiple working hypotheses [69] are evaluated for pain related adverse events following vaccination leveraging these VAERS data mining results.

Methods
The Vaccine Adverse Event Reporting System (VAERS) database (https://vaers.hhs.gov) [70] was datamined for pain associated vaccine adverse events data by vaccine name or vaccine type, age, gender, dose, and onset post vaccination. The downloaded data includes all VAERS reports from 1990 until May 13, 2022. A Ruby program named vaers_slice.rb [71] was used to tally selected reported vaccine adverse events by vaccine. The vaers_slice.rb program takes as input a list of one or more symptoms and outputs a summary of to the yearly VAERS Symptoms, Vax, and Data les from 1990 to 2022. The output from vaers_slice.rb consists of ve reports: summaries by vaccine, summaries by age of onset of symptoms, summaries by day of onset of symptoms, and two summaries of additional symptoms reported (selected symptoms and all other symptoms). The VAERS adverse events by vaccine name were extracted for Abdominal pain, Abdominal pain lower, Abdominal pain upper, Arthralgia (pain in joint), Asthenia (abnormal physical weakness or lack of energy), Axillary pain, Back pain, Bell's palsy, Bone pain, Breast pain, Chest pain, Dysphagia (di culty or discomfort in swallowing), Ear pain, Eye pain, Facial pain, Facial paralysis, Facial paresis, Guillain-Barre syndrome, Hemiparesis, Hypoaesthesia (partial or total loss of sensation), Injection site pain, Lymph node pain,

Results
The results include all reports of selected adverse events from 1990 until May 13, 2022. These adverse events share a non-random pattern of onset; Figures 1 and 2 illustrate this onset pattern for 16 pain associated adverse events in VAERS. This onset pattern is also present for GBS and Bell's palsy (Figures 3 and 4). These adverse events also exhibit excess reports of pain associated adverse events post vaccination for females compared to males for twenty vaccines ( Figure 5). Summarized data, from vaers_slice.rb, for each VAERS pain associated adverse event are included in the supplemental data tables for days 0 to 120 for each vaccine with associated adverse event. Some vaccinees experience more than one adverse event; correlations of reports of multiple pain associated adverse events are summarized in Table 1 for the most frequently reported adverse events and Table   S1 for selected pain associated adverse events with all adverse events. Each vaers_slice.rb report in the Supplemental data includes correlations with all other reported adverse events; the top 35 for selected pain adverse events are illustrated in Supplemental Table S2.
Both GBS and Bell's palsy are rare adverse events reported post vaccination. The three most commonly reported adverse events for many vaccines are headache, fatigue, and pyrexia (fever). The proportion of GBS and Bell's palsy reports are compared to these commonly reported adverse events as a comparison metric for unrelated vaccines. Proportional enrichment by vaccine for GBS and Bell's palsy are calculated for three reactogenicity adverse events (headache, fatigue, and pyrexia/fever) in Tables 2 and 3.

Discussion
For all of the pain associated adverse events examined, the highest reports are within 24 hours of vaccination (day 0). For each pain associated adverse event, the number of reports for day 1 are roughly half that of day 0; likewise, the number of adverse events reported for day 2 are roughly half that of day 1 (Figures 1 and 2).
Females report pain associated adverse events between two and three fold more frequently than males ( Figure  5). Vaccinees sometimes report more than one pain associated adverse event (Table 1). For adverse events like injection site pain, this is consistent with expectations. Other adverse events reported by vaccinees are nausea, headache, pyrexia, fatigue, chills, and other. The consistency of the frequency patterns of these adverse events following vaccinations for multiple unrelated vaccines enables the exclusion of speci c vaccine components and excipients as speci cally causative entities; however, these components and excipients are likely the key determinants of the reactogenicity level associated with each vaccine. Possible working hypotheses of the causes of pain, paresis, or paralysis related adverse events following vaccination include innate immune responses, in ammation, latent virus reactivation, and autoimmune antibodies.
Vaccinations are designed to stimulate immune humoral (e.g., antibody) immune responses. Vaccines elicit immediate innate immune responses from vaccinees. These innate immune responses include the release of in ammatory molecules including chemokines, cytokines, interleukins, lymphokines, and monokines from immune cells [72][73][74][75]. The blood-nerve barrier is not as tight as the blood-brain barrier; it is possible for T cells and macrophages to leak in at in amed tissue [76]. Vaccination-induced autoimmune antibody responses would require either primary humoral immune response or memory humoral immune responses; these humoral immune responses would peak roughly 7 to 10 days post vaccination. Hence, autoimmune antibody responses are unlikely associated with the majority of observed immediate onset reactogenicity adverse responses observed ( Figures 1, 2, and supplemental data). Miller Fisher syndrome has some presentation overlaps with GBS [77]; like other examined adverse events, immediate onset signals also occur for Miller Fisher syndrome adverse events in VAERS associated with COVID-19 and in uenza vaccines (supplemental data table V_Miller_Fisher). Reactivation of latent viruses has been observed post SARS-CoV-2 vaccinations [78,79]; clinical and molecular evidence of reactivation of latent viruses associated with the majority of the reported pain associated adverse events is currently lacking. While reactivation of latent viruses has occurred post vaccinations, the onset timing of 7 to 21 days [78,79] is inconsistent with observed immediate onset of pain associated adverse events. Consistent with the observed immediate onset of reported pain associated adverse events, innate immune response molecules are known to be associated with pain. These innate immune responses include the release of in ammatory molecules, including histamine, interleukin 1β (IL-1β), interleukin 6 (IL-6), monocyte chemoattractant protein (MCP-1), prostaglandin E 2 (PGE 2 ), tumor necrosis factor (TNF; formerly TNFα), etc.; these innate immune cells include macrophages, granulocytes including mast cells, T helper cells, and other immune cells [72,73,80,81]. PGE 2 is a well-known lipid mediator that contributes to in ammatory, neuropathic, and visceral pain, see [81]. IL-1β, IL-6, and TNF are involved in the process of pathological pain [73]. Histamine is known to be algesic (cause pain) to peripheral nervous system [75]. Type I interferons have been proposed as a potential mechanism linking COVID-19 mRNA vaccines to Bell's palsy [82].

Guillain-Barré Syndrome (GBS)
VAERS reports for GBS illustrate a pattern of immediate onset timing associated with seven vaccines (Figure 3). The onset for the majority of the GBS reports are within 24 hours (day 0), roughly ½ this the next day (day 1), and roughly ¼ this the second day (Figure 3 and supplemental data table: V_Guillain_Barre). This onset pattern is too rapid for molecular mimicry, epitope sharing, and autoimmune antibodies to be causative prior to day 7. Similar patterns shared by COVID-19, In uenza, Shingles Zoster, human papillomavirus, and Pneumococcal vaccines support innate immune responses as a major component of disease early etiology. Three of the highest frequencies reactogenicity adverse events shared across the examined pain related adverse events are headache, fatigue, and pyrexia (fever). Examining the frequencies of GBS in proportion to these reactogenicity adverse events illustrates that the frequency of GBS is highest for In uenza vaccines with a lower frequency for COVID-19 vaccines ( Table 2). The general consistency of occurrence frequencies across all of the examined unrelated vaccines in Table 2 further supports the hypothesis that reactogenicity responses to vaccination in general are coupled to the frequency of GBS following vaccinations. Clinically, most GBS patients following COVID-19 vaccination showed typical demyelination neuropathy with albumin-cytological dissociation [83]; the timing suggests that demyelination neuropathy and albumin-cytological dissociation might be subsequent events in the disease etiology for patients with immediate onset adverse events. The immediate onset pattern of GBS following vaccination is different from the observed pattern for Zoster vaccines [84]; their reported Zoster vaccine onset pattern is consistent with the development of autoimmune antibodies in contrast to the immediate onset Zoster vaccine records in VAERS (Figure 3). Note that autoantibodies are detected for some GBS patients post COVID-19 vaccination [14,85]; onset of GBS for multiple patients is consistent with the development of autoantibodies [9,[13][14][15]19,[22][23][24][25][26][27][28][29][30][31].
In one report, nearly all GBS patients after COVID-19 vaccinations also had facial weakness or paralysis [86]. Another report included nine GBS patients with rare subtype known as Bilateral Facial Palsy with paresthesias (BFP) with ve vaccinated with Sputnick V and four with ChAdOx1. Of these nine patients, four tested positive with ganglioside antibody panel (2: anti-GM1, antig-GD1a, and anti-sulfatide) [40].

Bell's palsy
The frequency of Bell's palsy is highest for COVID-19 and lower for Zoster and In uenza vaccines (Table 3 and Figure 4). The frequencies for non-COVID-19 vaccines is low for vaccines but with enrichment for day 0 onsets for a few vaccines (supplemental data V_Bells_palsy). Onset of Bell's palsy within 5 hours of BNT162b2 vaccination [55] and 12 hours after mRNA-1273 vaccination [51] together with VAERS day 0 onset reports can be leveraged to limit candidate etiology possibilities. The association pattern for immediate onset is consistent with innate immune responses for very high reactogenicity vaccines (COVID-19 mRNA and adenovirus) or concomitant administration of vaccines. The working hypothesis for live Zoster vaccines reactivating latent Herpes family viruses is also consistent with current models for Bell's palsy [73].

Persistent pain models
Candidate models for persistent pain include autoimmune antibodies, nerve damage and/or demyelination, reactivated latent viruses, immune cells in ltration at blood-never barrier during in ammation (albumincytological dissociation seen in GBS), innate immune cells with feedback loops with nerve cells, mast cell and eosinophil paired couplets, and ongoing expression of vaccine protein [87] by innate immune cells. Immediate onset adverse event lymphadenopathy (Figure 2) is consistent with ongoing expression of vaccine protein by innate immune cells. Mast cells and eosinophils are known to form bidirectional interactions resulting in a hyperactivated state, reviewed [88]. Additional research is needed to resolve the pathogenesis model(s) of persistent pain adverse events following vaccinations. Immediate onset of pain related adverse events might suggest that early interventions might lessen the severity of symptoms and possibly even decrease the frequencies of occurrences. Cellular feedback loops are possible between nerve cells and mast cells driving neurogenic in ammation and nociceptive pain [89].

Histamine
Pain related in ammatory molecules released by innate immune responses include histamine. Histamine is known to be associated with peripheral nerve pain [75,90]. Elevated histamine levels are predicted as drivers of cardiac adverse events including myocarditis and pericarditis [71] and menstrual adverse events [91]. Ongoing vaccine expression in innate immune cells, lasting months [87], may drive localized release of in ammatory molecules including histamine.

Exploratory treatment candidates
Dampening histamine responses from innate immune mast cells may reduce the population frequency and severity of some pain adverse events following vaccinations. Antihistamine treatments exhibiting e cacy in treating COVID-19 patients may target possible granulocytes and mast cells associated with vaccine responses.

Supplementary Files
This is a list of supplementary les associated with this preprint. Click to download. Pain1.xlsx