DOI: https://doi.org/10.21203/rs.3.rs-1758910/v1
Some individuals (vaccinees) experience pain related adverse events following vaccinations. The majority of 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 datamining results of the Vaccine Adverse Event System (VAERS) database. Observed onset occurrences of examined pain associated adverse events are consistent with likely etiology relationship with innate immune responses to vaccinations for multiple vaccines including SARS-CoV-2 COVID-19, influenza, and additional vaccines. Innate immune responses may be contributing to the initial etiology of Bell’s palsy and GBS post SARS-CoV-2 mRNA and adenoviral vaccinations.
Vaccines are designed to protect vaccinees 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 inflammatory 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. Recently, it was proposed that the majority of the reactogenicity adverse events are caused by innate immune response to vaccination releasing inflammatory molecules including histamine [2].
Pain is a common element in a subset of the adverse events reported post vaccination. Some adverse events like “injection site pain” have obvious causal relationship with injection vaccinations. Other rare adverse events like Bell’s palsy and Guillain-Barré syndrome (GBS) can occur with causality difficult to assess with frequencies close to background occurrence frequencies [3, 4]. GBS has been associated with influenza [5] and COVID-19 vaccinations [6]. One etiology model for GBS following COVID-19 vaccination is autoimmune autoantibodies [6]; but, no serum anti-ganglioside antibodies were found in 15 of 17 patients tested [7]. Nearly all GBS patients after COVID-19 vaccinations also had facial weakness or paralysis [8].
Bell’s palsy is a disease characterized by a rapid and unilateral onset of peripheral paresis (paralysis) of the seventh cranial nerve. Bell’s palsy has been reported as an adverse event following immunization for influenza [9] and COVID-19 CoronaVac (Sinovac Biotech, Hong Kong) [10]. Burrows et al. [11] report a patient with sequential contralateral facial nerve palsies following the first and second doses of Pfizer-BioNTech BNT162b2 COVID-19 vaccine. Other studies do not detect an enrichment signal for Bell’s palsy or facial paralysis with COVID-19 vaccines [3, 12]. Some cases of facial paralysis may be caused by reactivation of latent herpes simplex virus (HSV) [13] or varicella zoster virus (VSV) in a mechanism similar to Ramsey Hunt syndrome. An increased risk for Bell’s palsy has been observed for concomitant administration of meningococcal conjugate vaccine with another vaccine [14].
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[15] are evaluated for pain related adverse events following vaccination leveraging these VAERS data mining results.
The Vaccine Adverse Event Reporting System (VAERS) database [16] 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 [17] 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 to summarize and the yearly VAERS Symptoms, Vax, and Data files from 1990 to 2022. The output from vaers_slice.rb consists of five 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 (difficulty 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, Lymphadenopathy (enlarged lymph nodes), Musculoskeletal chest pain, Musculoskeletal pain, Musculoskeletal stiffness, Myalgia (muscle pain), Neck pain, Neuralgia, Oropharyngeal pain (mouth and pharynx pain), Pain, Pain in extremity, Pain in jaw, Pain of skin, Paraesthesia (an abnormal sensation, typically tingling or pricking), Renal pain, Spinal pain, and Swelling face were extracted. The VAERS adverse events by vaccine type were extracted for Bell’s palsy, Fatigue, Guillain-Barre syndrome, Headache, Miller Fisher syndrome, and Pyrexia. Microsoft Excel was used create figures.
Figures 1 and 2 illustrate day of onset for 16 pain associated adverse events in VAERS. Figure 3 illustrates excess reports of pain associated adverse events post vaccination for females compared to males for twenty vaccines. Immediate onset of GBS and Bell’s palsy are illustrated in Figs. 4 and 5. Summarized data 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. Correlations 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 20 for selected pain adverse events are illustrated in Supplemental Table S2. 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.
| Adverse event | Arthralgia | Asthenia | Hypoaesthesia | Myalgia | Pain | Pain in extremity | Paraesthesia |
|---|---|---|---|---|---|---|---|
| Arthralgia | 8,315 | 4,195 | 26,645 | 19,818 | 18,744 | 4,982 | |
| Asthenia | 8,315 | 3,895 | 10,336 | 13,827 | 7,990 | 4,674 | |
| Hypoaesthesia | 4,195 | 3,895 | 2,731 | 6,556 | 8,138 | 16,237 | |
| Myalgia | 26,645 | 10,336 | 2,731 | 14,898 | 12,787 | 3,975 | |
| Pain | 19,818 | 13,827 | 6,556 | 14,898 | 28,608 | 7,683 | |
| Pain in extremity | 18,744 | 7,990 | 8,138 | 12,787 | 28,608 | 8,002 | |
| Paraesthesia | 4,982 | 4,674 | 16,237 | 3,975 | 7,683 | 8,002 |
| Vaccine | Headache | Guillain-Barré syndrome | Enrichment | Fatigue | Enrichment | Pyrexia | Enrichment |
|---|---|---|---|---|---|---|---|
| FLUX | 29,755 | 779 | 100.0% | 1,797 | 100.0% | 5,249 | 100.0% |
| FLUX(H1N1) | 2,681 | 65 | 92.6% | 228 | 65.8% | 581 | 75.4% |
| FLU3 | 97,513 | 1,386 | 54.3% | 3,576 | 89.4% | 12,757 | 73.2% |
| FLU(H1N1) | 9,179 | 139 | 57.8% | 458 | 70.0% | 1,065 | 87.9% |
| HEPAB | 5,707 | 84 | 56.2% | 424 | 45.7% | 636 | 89.0% |
| HPV2 | 4,798 | 61 | 48.6% | 394 | 35.7% | 513 | 80.1% |
| FLUN3 | 6,443 | 58 | 34.4% | 245 | 54.6% | 993 | 39.4% |
| YF | 4,239 | 50 | 45.1% | 284 | 40.6% | 871 | 38.7% |
| FLU4 | 37,252 | 297 | 30.5% | 1,794 | 38.2% | 3,956 | 50.6% |
| TYP | 9,923 | 77 | 29.6% | 551 | 32.2% | 1,592 | 32.6% |
| TDAP | 42,404 | 267 | 24.1% | 2,178 | 28.3% | 5,935 | 30.3% |
| MNQ | 26,174 | 132 | 19.3% | 1,007 | 30.2% | 2,957 | 30.1% |
| TD | 18,558 | 94 | 19.3% | 518 | 41.9% | 3,596 | 17.6% |
| HPV4 | 46,341 | 154 | 12.7% | 3,024 | 11.7% | 2,681 | 38.7% |
| HEPA | 41,067 | 131 | 12.2% | 1,092 | 27.7% | 5,691 | 15.5% |
| PNC13 | 38,876 | 137 | 13.5% | 1,079 | 29.3% | 7,916 | 11.7% |
| HEP | 71,720 | 219 | 11.7% | 1,805 | 28.0% | 11,117 | 13.3% |
| IPV | 43,249 | 81 | 7.2% | 474 | 39.4% | 8,900 | 6.1% |
| PPV | 68,903 | 199 | 11.0% | 2,215 | 20.7% | 14,372 | 9.3% |
| MMR | 86,556 | 133 | 5.9% | 1,185 | 25.9% | 21,749 | 4.1% |
| UNK | 23,789 | 78 | 12.5% | 2,356 | 7.6% | 3,450 | 15.2% |
| VARZOS | 105,019 | 270 | 9.8% | 9,752 | 6.4% | 14,461 | 12.6% |
| DTAP | 62,560 | 52 | 3.2% | 687 | 17.5% | 12,832 | 2.7% |
| VARCEL | 82,205 | 55 | 2.6% | 779 | 16.3% | 11,961 | 3.1% |
| COVID19 | 1,116,854 | 2,001 | 6.8% | 154,437 | 3.0% | 153,429 | 8.8% |
| Vaccine | Headache | Bell's palsy | Enrichment | Fatigue | Enrichment | Pyrexia | Enrichment |
|---|---|---|---|---|---|---|---|
| COVID19 | 1,116,854 | 5,711 | 100.0% | 154,437 | 100.0% | 153,429 | 100.0% |
| UNK | 23,789 | 49 | 40.3% | 2,356 | 56.2% | 3,450 | 38.2% |
| FLU4 | 37,252 | 40 | 21.0% | 1,794 | 60.3% | 3,956 | 27.2% |
| VARZOS | 105,019 | 94 | 17.5% | 9,752 | 26.1% | 14,461 | 17.5% |
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 [2]. 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 [22]. 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 [23]; 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 [27]. IL-1β, IL-6, and TNF are involved in the process of pathological pain [19]. Elevated histamine levels has been proposed to be causative for the majority of reactogenicity adverse events [2]. Histamine is known to be algesic (cause pain) to peripheral nervous system [21]. Type I interferons have been proposed as a potential mechanism linking COVID-19 mRNA vaccines to Bell’s palsy [28].
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 [29]; 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 [30]; 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).
Bell’s palsy
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 [19].
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[31] 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 [32]. 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 [33].
Histamine
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 [2], cardiac adverse events including myocarditis and pericarditis [17], and menstrual adverse events [2]. Ongoing vaccine expression in innate immune cells, lasting months, [31] 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 [39]. 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) [41] 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.
Data mining VAERS for pain associated adverse events illustrates likely etiology of innate immune responses driving pain related adverse events post vaccination including rare reports of Guillain-Barré syndrome and Bell’s palsy. Identification of likely role of innate immune responses in the etiology of pain related adverse events post vaccination suggest possible candidate treatments for evaluation in clinical studies.
COVID-19 Coronavirus Disease 2019
GBS Guillain-Barré syndrome
IL-1β Interleukin 1β
IL-6 Interleukin 6
MCP-1 Monocyte Chemoattractant Protein
PGE2 Prostaglandin E2
SARS-CoV-2 Severe Acute Respiratory Syndrome Coronavirus 2
TNF Tumor Necrosis Factor
VAERS Vaccine Adverse Event System
Acknowledgements
The authors thank Nora Smith for useful discussions.
Conflict of interest
The author declares that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Consent statement/ethical approval
Not required.
Funding
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