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 (Figs. 1 and 2). Females report pain associated adverse events between two and three fold more frequently than males (Fig. 3). 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 onset of pain associated adverse events coincides with the same onset as these reactogenicity adverse events . The consistency of the frequency patterns of these adverse events following vaccinations for multiple unrelated vaccines enables the exclusion of specific vaccine components and excipients as specifically causative entities; however, these components and excipients are likely the key determinates 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, inflammation, 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 inflammatory molecules including chemokines, cytokines, interleukins, lymphokines, and monokines from immune cells [18–21]. 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 inflamed tissues . 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 (Figs. 1, 2, and supplemental data). Miller Fisher syndrome has some presentation overlaps with GBS ; like other examined adverse events, immediate onset signals also occur for Miller Fisher syndrome adverse events in VAERS associated with COVID-19 and influenza vaccines (supplemental data table V_Miller_Fisher). Reactivation of latent viruses has been observed post SARS-CoV-2 vaccinations [24, 25]; clinical and molecular evidence of reactivation of latent viruses associated with the majority of the reported pain associated adverse events is current lacking. While reactivation of latent viruses has occurred post vaccinations, the onset timing of 7 to 21 days [24, 25] 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 inflammatory molecules, including histamine, interleukin 1β (IL-1β), interleukin 6 (IL-6), monocyte chemoattractant protein (MCP-1), prostaglandin E2 (PGE2), tumor necrosis factor (TNF; formerly TNFα), etc. from macrophages, granulocytes including mast cells, T helper cells, and other immune cells [18, 19, 26, 27]. PGE2 is a well-known lipid mediator that contributes to inflammatory, neuropathic, and visceral pain, see . IL-1β, IL-6, and TNF are involved in the process of pathological pain . Elevated histamine levels has been proposed to be causative for the majority of reactogenicity adverse events . Histamine is known to be algesic (cause pain) to peripheral nervous system . Type I interferons have been proposed as a potential mechanism linking COVID-19 mRNA vaccines to Bell’s palsy .
Guillain-Barré Syndrome (GBS)
VAERS reports for GBS illustrate a pattern of immediate onset timing associated with seven vaccines (Figure 4). 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 4 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, Influenza, 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 Influenza 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 ; 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 ; 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 4).
The frequency of Bell’s palsy is highest for COVID-19 and lower for Zoster and Influenza vaccines (Table 3 and Figure 5). 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). 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 .
Persistent pain models
Candidate models for persistent pain include autoimmune antibodies, nerve damage and/or demyelination, reactivated latent viruses, immune cells infiltration at blood-never barrier during inflammation (albumin-cytological 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 by innate immune cells. Immediate onset adverse event lymphadenopathy (Figure 3) 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 . 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 lesson 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 inflammation and nociceptive pain .
Pain related inflammatory molecules released by innate immune responses include histamine. Histamine is known to be associated with peripheral nerve pain [21,34]. Elevated histamine levels are predicted as drivers of most post vaccination adverse events including reactogenicity adverse events , cardiac adverse events including myocarditis and pericarditis , and menstrual adverse events . Ongoing vaccine expression in innate immune cells, lasting months,  may drive localized releases of inflammatory 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 efficacy in treating COVID-19 patients are may target possible granulocytes and mast cells associated with vaccine responses. Candidate treatments for evaluation include high dose famotidine [35–38], cetirizine [39,40], and dexchlorpheniramine . Oral treatment with diamine oxidase may also be beneficial. Alternatively, if mast cell and eosinophil couplets are involved, targeting them with anti-IL-5 (mepolizumab)  may be beneficial. Evaluation of these treatments and treatment combinations on vaccinees in case reports, case series, etc. can inform subsequent randomized controlled clinical trials for reducing vaccine pain adverse events.