Darrell O. Ricke

In recent studies, novel candidate safety signals were detected for infants younger than 1 year of age for specific vaccines. Herein, the Vaccine Adverse Events Reporting System (VAERS) database was retrospectively examined for possible novel candidate safety signals for children one year of age. Novel candidate safety signals were detected for multiple vaccines. Two candidate manufacturing irregularities or possible unknown contaminants were identified associated with adverse event (AE) autism for VAERS nondomestic Measles, Mumps, and Rubella (MMR II) vaccine lots from 1993 to 1995 and AE hyperpyrexia for nondomestic MMRV lots from 2019 to 2024. The candidate manufacturing irregularities were named alpha for MMR II and beta for Measles, Mumps, Rubella, and Varicella (MMRV) ProQuad vaccines. The hypothesized higher levels of alpha in the nondomestic data, MMR II appear to have been reduced or eliminated sometime soon after 1995; identification of alpha would contribute to future avoidance of possible associated AEs. Reduction of beta in the nondomestic MMRV vaccine is hypothesized to reduce hyperpyrexia and also higher pyrexia AEs not observed associated with domestic MMRV vaccine.

Some vaccine recipients can develop serious adverse events (SAEs) following coronavirus disease 2019 (COVID-19) immunization. In a retrospective study of the Vaccine Adverse Event Reporting System (VAERS) menstrual AEs following immunization, statistically significant differences were observed for multiple manufacturing lots of the COVID-19 Pfizer–BioNTech and the COVID-19 Moderna vaccines. Other candidate manufacturing contaminants associated with AEs may be detectable by comparing normalized frequency rates between predicted higher-contamination lots or vaccines and lower-contamination lots or vaccines. This retrospective study identified candidate pattern signatures for the most frequently reported AEs in VAERS for identified COVID-19 vaccine lots associated with these menstrual AEs, as well as differences in AE frequencies between three human papillomavirus (HPV) vaccines. Six candidate AE patterns (AEPs) were identified: hemorrhage (female), gynecologic including hemorrhage pattern, myopericarditis (male-biased), HPV vaccine-associated, neuropathy, and fetus patterns. The hemorrhage pattern was identified in six vaccines, including four influenza vaccines. The gynecologic pattern was identified in seven vaccines, including three COVID-19 and three HPV vaccines. The myopericarditis pattern was identified in 14 vaccines, including five COVID-19 vaccines, with two bivalent COVID-19 vaccines and three smallpox vaccines. The myopericarditis pattern appears to be associated with possible contaminant microbial protein activation of immune responses and live attenuated virus vaccines. The four AEPHPV AEs were elevated primarily among HPV vaccines. One or more of the five AEPneuropathy AEs were elevated in 11 vaccines, while one or more of the AEPfetus AEs were elevated in 11 vaccines.

Background/Objectives: Kawasaki’s disease (KD) is a leading cause of heart disease in children. The multisystem inflammatory syndrome (MIS) associated with the SARS-CoV-2 virus is similar to KD. The etiologies of KD and MIS are unknown. Both diseases are associated with pathogens and immunizations. Methods: The Vaccine Adverse Event Reporting System (VAERS) was retrospectively examined for etiology insights into both KD and MIS. Results: Statistically significant, elevated AE MIS safety signals were observed for several COVID-19 Pfizer-BioNTech manufacturing lots. Elevated AE MIS normalized frequencies were observed in children of all ages. Immediate-onset AE KD safety signals were detected for specific vaccines and coadministered combinations of these vaccines (including specific live, attenuated virus vaccines and other specific vaccines) for young infants; a subset of these safety signals has a male sex bias, whereas others appear to be unbiased. Conclusions: Both KD and MIS are hypothesized to involve two activation pathways. The first pathway is hypothesized to involve high titers of immune complexes that activate Fc receptors on mast cells, platelets, and other immune cells. Immune complex titers higher than primary immune response levels are hypothesized to be required to activate low-affinity IgGFcγR2α receptors on immune cells and platelets. IVIG treatment is hypothesized to directly compete with immune complex binding to FcγR2α receptors. The second hypothesized pathway is proposed to directly activate mast cells and other immune cells without involving immune complexes and Fc receptors; lack of Fc receptor competition by immune complexes is hypothesized as a possible explanation for IVIG nonresponders for KD and MIS, worthy of future studies. The proposed etiology models for both KD and MIS may be consistent with being novel mast cell activation syndromes (MCAS). MIS is hypothesized to be KD-associated with the SARS-CoV-2 virus or the COVID-19 spike protein (MIS-V).

Background/Objectives: Kawasaki’s disease (KD) is a leading cause of heart disease in children. The multisystem inflammatory syndrome (MIS) associated with the SARS-CoV-2 virus is similar to KD. The etiologies of KD and MIS are unknown. Both diseases are associated with pathogens and immunizations. Methods: The Vaccine Adverse Event Reporting System (VAERS) was retrospectively examined for etiology insights into both KD and MIS. Results: Immediate-onset KD-associated safety signals were detected for specific vaccines and coadministered combinations of these vaccines for young infants; a subset of these associations have a male sex bias, whereas others appear to be sex neutral. These specific vaccines may contain manufacturing contaminants (e.g., endotoxins) that are activating mast cells via Toll-like receptors. MIS-V cases were enriched in children of all ages. Conclusions: Both KD and MIS appear to involve two activation pathways. The first pathway involves high titers of immune complexes that activate Fc receptors on mast cells, platelets, and other immune cells. Immune complex titers higher than primary immune response levels are predicted to be required to activate low-affinity IgG FcgR2α receptors on immune cells and platelets. IVIG treatment is predicted to directly compete with immune complex binding to FcgR2α receptors. The second pathway appears to directly activate mast cells and other immune cells without involving immune complexes or Fc receptors. Cardiac adverse events, coronary artery aneurysms (CAAs), myocarditis, transient left ventricular dysfunction, and acquired heart disease are predicted to result from pressure induced lesions indirectly caused by cardiac capillary vasoconstrictions. Second, mast cell activation (e.g., endotoxin contaminants) or persistent infections are likely causes of IVIG nonresponders for KD and MIS. MIS appears to be KD associated with the SARS-CoV-2 virus or the COVID-19 spike protein (MIS-V).

Immune responses naturally decline with age in the elderly; this process is named immunosenescence. The risks for adverse events (AEs) can increase, decrease, or be uncorrelated with increasing age. Safety signals associated with vaccines can be detected within the Vaccine Adverse Event Reporting System (VAERS). Herein, VAERS was retrospectively examined for safety signals associated with the elderly. In general, common AEs include normal immune responses and also injection site-related AEs. For multiple COVID-19 vaccines, breakthrough infections and COVID-19-related AEs had unexpectedly high normalized frequencies. The normalized frequency for AE death was elevated for multiple vaccines, including COVID-19 vaccines; the associated risk appears to be additive for coadministered combinations of the COVID-19 Janssen vaccine with either the COVID-19 Pfizer-BioNTech BNT162b2 or the COVID-19 Moderna mRNA-1273 vaccine. Multiple manufacturing lots for the COVID-19 Janssen, COVID-19 Pfizer-BioNTech BNT162b2, and Moderna mRNA-1273 vaccines have high AE death normalized frequencies. These observations, combined with rapid AE death onset following vaccination, likely point to possible manufacturing contamination of specific manufacturing lots; endotoxins are a possible causative constituent. The sensitivity to these causative constituent(s) increases with age in the elderly.

Introduction: Safety signals were detected for infants aged 0 for epilepsy, bradycardia, cardiac arrest, and gastrointestinal adverse events (AEs) for specific vaccines and coadministered vaccine combinations. From these observations, additional elevated infant age 0 AEs safety signals are suspected. This study examines additional AEs, examining elevated infant age 0 AEs safety signals to provide etiology insights. Methods: Herein, the Vaccine Adverse Events Reporting System (VAERS) was retrospectively examined for candidate AE safety signals for infants aged 0. Results: Additional safety signals were identified for multiple AEs affecting infants. Safety signals were detected for specific vaccines, specific concomitantly administered vaccines, and live attenuated vaccines. Conclusions: Specific vaccines (including live, attenuated viral vaccines) and specific concomitant vaccine combinations are resulting in elevated frequencies of multiple infant AEs. Elevated normalized frequencies of AEs for multiple concomitant vaccine combinations have additive normalized frequencies. Elevated normalized frequencies for multiple manufacturing lots are consistent with possible manufacturing contaminants (e.g., endotoxins) as causative components for multiple elevated AE frequencies.

Serious adverse events (SAEs) develop following coronavirus disease 2019 (COVID-19) immunization in some vaccine recipients. Adverse events (AEs) after immunization are represented by a combination of background AEs and possibly vaccine-associated AEs. When vaccine-associated events occur, they are related to one or more vaccine components, adjuvants, excipients, potentially manufacturing contaminants, or a combination of these constituents. In a retrospective study of Vaccine Adverse Event Reporting System (VAERS) menstrual AEs following immunization, statistically significant differences were observed for multiple manufacturing lots of the COVID-19 Pfizer-BioNTech and the COVID-19 Moderna vaccines. Manufacturing contaminants are likely causative candidates consistent with the observed data for menstrual AEs. Other manufacturing contaminants associated AEs may be detectable by contrasting the normalized frequency rates between predicted higher contamination lots or vaccines compared to lower contamination lots or vaccines. This retrospective study identified candidate pattern signatures for the most frequently reported AEs to VAERS for identified COVID-19 vaccine lots associated with these menstrual AEs and differences in AE frequencies between three human papillomavirus (HPV) vaccines. Six candidate pattern signatures were identified: hemorrhage (female), gynecologic including hemorrhage pattern, myopericarditis (male-biased), HPV vaccine-associated, neuropathy, and fetus patterns. The hemorrhage pattern was identified in six vaccines, including four influenza vaccines. The gynecologic pattern was identified in seven vaccines, including three COVID-19 and three HPV vaccines. And the myopericarditis pattern was identified in 14 vaccines, including five COVID-19 vaccines with two bivalent COVID-19 vaccines, and three smallpox vaccines. The four MCHPV AEs are elevated primarily in HPV vaccines. One or more of the five MCneuropathy AEs were elevated in 11 vaccines. One or more of the MCfetus AEs were elevated in 11 vaccines. For the identified safety signals for vaccines with more SAE and AE reports in VAERS, the observed differences in normalized frequencies of SAEs and AEs between lots for the same vaccine and comparisons between related vaccines are consistent with predicted differences in manufacturing contamination levels.

Some women are experiencing menstrual adverse events (AEs), including heavier bleeding, following the coronavirus disease 2019 (COVID-19) spike immunization. The etiology of these menstrual AEs associated with the COVID-19 spike immunization remains unknown. The United States Department of Health and Human Services Vaccine Adverse Event Reporting System (VAERS) database was retrospectively analyzed for data-reported AEs affecting menstrual cycles by vaccine. Elevated normalized frequencies for menstrual AEs were detected for multiple vaccines, including COVID-19 vaccines (Pfizer BioNTech: 4,442, Pfizer BioNTech bivalent: 686, Moderna: 2,038, and Moderna bivalent: 463, all/100,000 VAERS reports) and human papillomavirus (HPV) vaccines (HPV Cervarix: 6,090, HPV Gardasil: 2,959, and HPV Gardasil 9: 1,556 all/100,000 VAERS reports). Lower normalized frequencies were detected for both COVID-19 bivalent vaccines and the HPV Gardasil 9 vaccine, compared to higher normalized frequencies for COVID-19 Pfizer-BioNTech, COVID-19 Moderna, HPV Cervarix, and HPV Gardasil vaccines. χ2 (2 × 2) statistically significant differences in normalized frequencies were observed between different COVID-19 Pfizer-BioNTech lots (p<0.00001) and also COVID-19 Moderna lots (p<0.00001). Manufacturing contaminants (e.g., endotoxins) are likely candidates, consistent with the observed data, for the reported menstrual AEs that vary by vaccine version and batch lot.

Vagus nerve-related adverse events (AEs) can be triggered by gastrointestinal infections. This raises the question of whether AE data from live-attenuated virus vaccination can be leveraged to investigate potential vagus nerve involvement. In this study, data from the Vaccine AEs Reporting System were retrospectively analyzed for candidate vagus nerve-related AEs in infants aged 0 and 1. Live-attenuated rotavirus vaccinations were associated with elevated normalized frequencies across all 16 selected vagus nerve-related AEs in both age groups, with the majority showing higher normalized frequencies in infants aged 0 than in those aged 1. These findings suggest that oral, live-attenuated virus vaccination may provide valuable insights into vagus nerve-related AEs. Furthermore, the higher normalized frequencies of AEs observed in infants aged 0 could indicate that the administered dose or minimum infectious units may be excessive for a subset of younger infants.

Some women are experiencing menstrual adverse events including heavier bleeding following Coronavirus disease 2019 (COVID-19) spike immunization. The etiology of these menstrual adverse events associated with COVID-19 spike immunization remains unknown. The United States Department of Health and Human Services Vaccine Adverse Event Reporting System (VAERS) database was retrospectively analyzed for data reported adverse events affecting menstrual cycles by vaccine. Elevated normalized frequencies for menstrual adverse events were detected for multiple vaccines, including COVID-19 vaccines and human papillomavirus (HPV) vaccines. Lower normalized frequencies were detected for both COVID-19 bivariant vaccines and the HPV Gardasil 9 vaccines compared to higher normalized frequencies for COVID-19 Pfizer-BioNTech, COVID-19 Moderna, HPV Cervarix, and HPV Gardasil vaccines. Chi-squared 2x2 statistically significant differences in normalized frequencies were observed between different COVID-19 Pfizer-BioNTech lots (p < 0.00001) and also COVID-19 Moderna lots (p < 0.00001). Manufacturing contaminants (e.g., endotoxins) are likely candidates consistent with the observed data for reported menstrual adverse events.