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

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.Methods 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.Results For the pain related adverse events examined, the highest number of adverse events are reported within 1 day, roughly half this number the second day, and roughly a quarter this number by the third day. The day of onset for these pain related adverse events approximates a power of two decay pattern for the first three days. This same pattern is observed for all of the vaccines with the highest number of pain related adverse events. The consistency of these day of onset frequency patterns of examined adverse events following vaccinations for multiple unrelated vaccines enables the exclusion of specific vaccine components and excipients as specifically causative entities.Conclusion The 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.

Etiology Model for Clinical Studies’ Intramuscular Injection of Saline Solution Control Driving Innate Immune Response Associated Adverse Events in Volunteers (preprint)

Clinical studies include placebo controls to enable differentiation between treatment efficacy and adverse events from placebo effects. Intramuscular injection of saline solution was used in COVID-19 vaccine clinical trials as the placebo control. The underlying hypothesis is that intramuscular injection of saline solution does not cause adverse events. Herein, an alternative hypothesis is advanced that intramuscular injection of saline solution can stimulate innate immune responses in volunteers and that these adverse events are not placebo effects. This implies that clinical studies including intramuscular injection of saline solution controls are comparing vaccine associated adverse events with saline solution innate immune response adverse events. This article proposes that innate immune responses to intramuscular injection of saline solution triggers a temporary surge in histamine levels. Further, this temporary surge of histamine levels is causative for the local and systemic adverse events experienced by the control volunteers.

Etiology Model for Elevated Histamine Levels Driving High Reactogenicity Vaccines (including COVID-19) Associated Menstrual Adverse Events (preprint)

Introduction: Some women are experiencing menstrual changes, including altered menstrual duration, volume (heavier bleeding), increased dysmenorrhea, and worsened premenstrual syndrome (PMS) following Coronavirus disease 2019 (COVID-19) spike vaccinations. Appreciation of these as temporal adverse events associated with COVID-19 spike vaccinations was slow to develop. The etiology of these menstrual adverse events associated with COVID-19 spike vaccination remains unknown. Methods: The United States Department of Health and Human Services Vaccine Adverse Event Reporting System (VAERS) database was data mined for data reported adverse events affecting menstrual cycles by vaccine type.Hypothesis: This article proposes the hypothesis that vaccinations can induce a temporary surge in histamine levels immediately post vaccination as part of the innate immune response. Increasing histamine levels is known to increase estrogen levels. Further, it is proposed that this temporary surge in histamine levels causes temporary Histamine Intolerance in some women and causes the menstrual adverse events temporally associated with vaccinations.Conclusion: Prophylactic and therapeutic treatment of vaccinees with diamine oxidase and/or specific antihistamines may reduce the incidence rate and/or severity of menstrual adverse events associated with vaccines with high reactogenicity, including SARS-CoV-2 vaccines and boosters. This model predicts menstrual associated adverse events incidence levels correspond to vaccine reactogenicity.

Elevated Histamine Etiology Model for Most Major Vaccine Associated Adverse Events including SARS-CoV-2 Spike Vaccines (preprint)

Vaccinees experience no adverse events, mild adverse events, multiple adverse events, or serious adverse events post vaccination. Many of these vaccine adverse events occur with different vaccines with different occurrence frequencies. Many of these adverse events are generally considered as associated with immune responses to the active vaccine components (antigens) and/or to possibly one or more of the vaccine excipients. Most of these vaccine adverse events are self-limiting and resolve within days. Many of these adverse events symptoms overlap symptoms associated with elevated histamine levels. Based on these observations, the hypothesis that the majority of vaccine associated reactogenicity adverse events are caused by temporal histamine intolerance in vaccinees is proposed. This hypothesis is based on a model of innate immune responses releasing a surge of inflammatory molecules including histamine; this surge is hypothesized to exceed the normal histamine tolerance level for vaccinees with reactogenicity adverse events. Further, these symptoms resolve as histamine levels fall below the vaccinee’s tolerance threshold. This model can be evaluated by the detection of elevated histamine levels in vaccinees corresponding to timing of symptoms onset. If confirmed, a direct consequence of this model predicts that some antihistamine treatments, mast cell stabilizers, and possibly diamine oxidase enzyme may reduce the incidence or severity of adverse events experienced by vaccinees post vaccinations for most or all high reactogenicity vaccines including coronavirus disease 2019 (COVID-19) Spike vaccines.

COVID-19: Famotidine, Histamine, Mast Cells, and Mechanisms (preprint)

SARS-CoV-2 infection is required for COVID-19, but many signs and symptoms of COVID-19 differ from common acute viral diseases. Currently, there are no pre- or post-exposure prophylactic COVID-19 medical countermeasures. Clinical data suggest that famotidine may mitigate COVID-19 disease, but both mechanism of action and rationale for dose selection remain obscure. We explore several plausible avenues of activity including antiviral and host-mediated actions. We propose that the principal famotidine mechanism of action for COVID-19 involves on-target histamine receptor H2 activity, and that development of clinical COVID-19 involves dysfunctional mast cell activation and histamine release.

Medical Countermeasures Analysis of 2019-nCoV and Vaccine Risks for Antibody-Dependent Enhancement (ADE) (preprint)

Background: In 80% of patients, COVID-19 presents as mild disease1,2. 20% of cases develop severe (13%) or critical (6%) illness. More severe forms of COVID-19 present as clinical severe acute respiratory syndrome, but include a T-predominant lymphopenia3, high circulating levels of proinflammatory cytokines and chemokines, accumulation of neutrophils and macrophages in lungs, and immune dysregulation including immunosuppression4. Methods: All major SARS-CoV-2 proteins were characterized using an amino acid residue variation analysis method. Results predict that most SARS-CoV-2 proteins are evolutionary constrained, with the exception of the spike (S) protein extended outer surface. Results were interpreted based on known SARS-like coronavirus virology and pathophysiology, with a focus on medical countermeasure development implications. Findings: Non-neutralizing antibodies to variable S domains may enable an alternative infection pathway via Fc receptor-mediated uptake. This may be a gating event for the immune response dysregulation observed in more severe COVID-19 disease. Prior studies involving vaccine candidates for FCoV5,6 SARS-CoV-17-10 and Middle East Respiratory Syndrome coronavirus (MERS-CoV) 11 demonstrate vaccination-induced antibody-dependent enhancement of disease (ADE), including infection of phagocytic antigen presenting cells (APC). T effector cells are believed to play an important role in controlling coronavirus infection; pan-T depletion is present in severe COVID-19 disease3 and may be accelerated by APC infection. Sequence and structural conservation of S motifs suggests that SARS and MERS vaccine ADE risks may foreshadow SARS-CoV-2 S-based vaccine risks. Autophagy inhibitors may reduce APC infection and T-cell depletion12 13. Amino acid residue variation analysis identifies multiple constrained domains suitable as T cell vaccine targets. Evolutionary constraints on proven antiviral drug targets present in SARS-CoV-1 and SARS-CoV-2 may reduce risk of developing antiviral drug escape mutants. Interpretation: Safety testing of COVID-19 S protein-based B cell vaccines in animal models is strongly encouraged prior to clinical trials to reduce risk of ADE upon virus exposure.