Abstract

• There have been reports associated with the development of neurological adverse events (AEs) post-vaccination. Here, we retrospectively examine the Vaccine Adverse Events Reporting System (VAERS) database for neurological AEs reported following vaccination. Since VAERS is a passive reporting system, to minimize reporting bias and to reduce background events, this retrospective study examines both age-stratified AE reports made with onset within 24 h of immunization, and age-stratified AE reports regardless of timeframe from immunization. Immediate temporal onset data patterns for febrile convulsion, seizure, and syncope AEs were observed for multiple vaccines. For age-stratified AEs in infants up to 3 years of age, the following patterns of high association were observed: (i) Aphasia, autism spectrum disorder, and speech disorder were found to be highly associated with the measles, mumps, and rubella and hepatitis B (HepB) vaccines; (ii) febrile convulsion and syncope were found to be highly associated with the meningococcal group B vaccine; and (iii) seizures were found to be highly associated with diphtheria and tetanus toxoids and whole-cell pertussis (DTP) vaccines.

...

4. Discussion 

4.1. Neurological AEs post-vaccination 

• Multiple vaccines exhibited different patterns of neurological AEs post-immunization (Figure 1). Syncope and autoimmune diseases (complex regional pain syndrome [CRPS], postural orthostatic tachycardia syndrome [POTS], and chronic fatigue syndrome [CFS]) post-HPV vaccination have been previously noted in a cluster analysis of reports in VigiBase.52 Post-marketing surveillance of AEs following meningococcal B vaccination reported low frequencies of AEs following immunization with the majority of serious AEs reported in 2- to 11-month-old children.53 As demonstrated for Dravet syndrome,4,36 immunization may trigger AEs in children with genetic risk factors like those reported by Charzewska et al.38 

4.2. COVID-19 and influenza vaccines 

• In the case of the COVID-19 vaccine, these retrospective results (Figure 3 and Table S3) support a causal relationship between COVID-19 vaccines and adverse neurologica 
• AEs—contrary to the conclusion of a recently published systematic review.54 The authors found significantly more neurological AEs reported following Janssen (AD26. CoV2.S) vaccination when compared to either Pfizer– BioNTech (BNT162b2) or Moderna (mRNA-1273) vaccination;55 however, their calculations do not include the reporting bias ( riX ) term. Influenza vaccinees have higher normalized frequencies for ages of 0 – 9 years compared to older ages for abnormal behavior, aphasia, coordination abnormal, seizure, and speech disorder (Tables S2 and S3); therefore, the risk of neurological AEs may decrease with increasing child age. In the case of the COVID-19 products, the normalized frequencies for mental status changes were found to increase when compared to influenza for adults older than 60 (Tables S2 and S3), with upward trends for older adults with multiple AEs reported for both vaccines. The etiology for these observations remains unknown and there could be other contributing factors, including lower resiliency associated with aging and unknown effects of repeat “boosting” with COVID-19-modified mRNA and adenoviral platforms. A retrospective cohort study of older adults in the United States found a low risk for AEs in the context of the modified mRNA products while noting that the risk of all AEs increased with greater frailty.56 In the case of tinnitus, COVID-19 vaccines have the highest normalized frequency (Table S1). COVID-19 vaccine-associated tinnitus has been documented57 and the observed immediate onset of tinnitus (within 24 h of vaccination) may not be consistent with the proposed possible mechanisms of molecular mimicry and autoimmune reactions or antibody-antigen complexes leading to type III hypersensitivity reaction. COVID-19 vaccines have been suggested to act as a trigger event for serious neurological AEs following immunization.58 

4.3. Comparing normalized frequencies 

• Examining AEs by age across all vaccines enables the identification of safety signals (Table 1). Comparing and contrasting normalized frequencies between equivalent vaccines can better inform consent and future dosing recommendations. Examining yearly normalized frequencies can illuminate impacts of changes to excipient compositions and manufacturing quality improvements. 

4.4. Study limitations 

• This study is based on AEs reported to the VAERS database. Only a small subset of AEs experienced by vaccines was reported to VAERS due to under-reporting. This study infers that AEs within VAERS proportionally reflect those experienced by vaccinees. Exclusion of reported AEs or reporting biases would potentially prevent VAERS from representing the immunized populations accurately. Relative proportions could be compared with detailed AE tracking in large clinical trials to detect possible perturbations in the VAERS database such that as the timeframe widens post-immunization, the fraction of AEs reported decreases. For example, a clinical study to reveal differences in reporting bias could be conducted by comparing two matched populations by tracking VAERS reports: Group A based on the current VAERS reporting while group B based on the reporting of all AEs. Adverse events for group A would be tracked (as done currently) and all AEs are collected for group B. These results could then be compared to larger clinical studies using adjustments for asymptomatic individuals and the tracking details of AEs. For each specific AE, reporting biases would be the same for all vaccines to enable quantitative comparisons. 

5. Conclusion 

• The risks associated with developing neurological AEs following vaccinations might be reduced through the following measures: (i) Modifying the current vaccination schedule recommendations for infants, (ii) reducing the number of concomitant vaccinations, (iii) evaluation and removal of possible contaminants from the manufacturing process, (iv) modifying or removing vaccine excipients (e.g., replacing aluminum-containing adjuvant with an alternative adjuvant), and (v) modifying vaccine components (the AE profiles for closely related vaccines for the same target organism can have different AE profiles). Relevant documents (e.g., FDA package insert) should be adjusted as appropriate to ensure that informed consent requirements are met. 

Acknowledgements

• Funding :   None. 

• Conflict of interest  :   The author declares they have no competing interests. 

• Author contributions  :

  • • Conceptualization: Darrell O. Ricke 

    • Investigation: Darrell O. Ricke 

    • Methodology: Darrell O. Ricke 

    • Formal analysis: Darrell O. Ricke 

    • Visualization: Darrell O. Ricke 

    • Writing – original draft: Darrell O. Ricke 

    • Writing – review & editing: Darrell O. Ricke, Jessica Rose

Introduction

• In a small case series in 1998, Wakefield et al. published a study in the Lancet that indicated a possible association of ASD with the triple MMR vaccination. This article was retracted in 2010.1  Note that Thimerosal is not found in the MMR vaccine. In a retrospective study in Denmark, 263 of 440,655 vaccinated children (normalized frequency = 59.7)[1] developed ASD while 53 of 96,658 unvaccinated children (normalized frequency = 54.8) developed ASD.2 A time trend analysis observed increasing risks of ASD from 1988 to 1993 while the MMR vaccination rate remained consistent at over 95% for United Kingdom boys aged 2 to 5.3 A similar retrospective time trend analysis from California also showed increasing rates of ASD that were not associated with MMR vaccination.4 Based on multiple studies including,2–5 the current medical community consensus does not associate ASD onset with MMR immunization. In addition to exposure-associated AEs, individual genetics plays a role in ASD. A large number of genetic variants (copy number variations, duplications, deletions, translocations, inversions, and mutations) are associated with ASD6–9 including mutations in the genes chromodomain helicase DNA binding protein 8 (CHD8),10 neuronal voltage-gated sodium channel, type 2, alpha NaV1.2 (SCN2A),11,12 katanin catalytic subunit A1 like 2 (KATNAL2)13 and other genes.
• 3.4. Autism spectrum disorder (ASD) AEs
• The pattern of AEs for ASD is low from 1990 until 1997, increases from 1999 until 2010 and subsequently decreases after 2010 for multiple vaccines (Table S4). In the case of MMR, peaks in 2000 to 2003, 2007 and 2009 are observed. Altered reporting bias likely occurred after the 1998 Wakefield et al. Lancet article that associated ASD with MMR vaccination was published and since this article was retracted in 2010,1 the reporting bias appears to be altered again (Table S4). Twenty-five individual vaccines have enriched normalized frequencies for ASD compared to Influenza (Figure 4) for ASD AEs reported from 2011 to 2023; 12 of these 25 normalized frequencies are greater than 10-fold higher than that of Influenza (Figure 4). An estimate of ASD onset is 559.4 per 100,000 per year14; this yields an estimate of bASD = 559.4 per year/(365 days/year) = 1.53 which is 6 times lower than the normalized frequency for Influenza (adjusting P for children with no Influenza symptoms – 18.5/2 vs. 1.53). Summing the normalized ASD frequencies for the seven recommended vaccines for infants aged 0 and 1 (Table 1) yields 15,368 for two years; adjusting population size (P) for children with no symptoms yields a population frequency estimate (e.g., P=250,000 reduces estimate to 6,147/2 years or 3,073/year = 1 in 32 children/year) that aligns with current reports of 1 in 36.15
• (again) The annual population frequency for ASD is consistent with the sum of the normalized frequencies for recommended infant vaccines.
• 
  
• [1] Normalized frequency was calculated by dividing the total number of AEs by the number of vaccinated individuals and multiplying by 100,000 to obtain the rate of AE occurrence per 100,000 people vaccinated.
• Figure 4. Autism Spectrum Disorder day 0 onset; VAERS data from 2011 to November 3, 2023 and 1990 to November 3, 2023. VAERS vaccine names: DTAP: Diphtheria and Tetanus toxoids and acellular Pertussis, DTP: Diphtheria and Tetanus toxoids and Pertussis, HEPB: Hepatitis B, HIB: Haemophilus B conjugate, IPV: Poliovirus, inactivated, and Pneumo: Pneumococcal.
• Note that there is a differnece in Figure 4 for vaccines: Polio virus, MMR, and HIB. The yearly details for these three vaccines follow in Figure 5. Look at the differences between different vaccines in Figure 5.
• Figure 5. Autism Spectrum Disorder (ASD) yearly normalized frequencies for (A) Polio virus, inactivated; (B) Measles, Mumps, and Rubella (MMR); and, (C) Haemophilus B conjugate vaccine (HIB).  VAERS data from 1990 to November 3, 2023.
• Each bar in Figure 5 represents a different year. Major changes in formulations (or reduction of manufacturing contaminants, etc.) will show up as larger differences in the height of the bars.

Observations

• While excipients may vary between different individual vaccines for the same target pathogens, and can be modified over time, the results (Figure 5) might also be consistent with possible manufacturing contaminant(s) [e.g., endotoxins16] (with possible overlaps between unrelated vaccines) associated with AEs. See Substack posts by Dr.GeoffPain (https://substack.com/@geoffpain) on endotoxins in vaccines.
• Working Hypothesis: ASD associated with infant vaccines may be direct results of one or more manufacturing contaminants (e.g., endotoxins)!
• Suggestion: Rather than attacking messengers, perhaps a better strategy should be examining the data closely and examining potential causes of adverse events.
• Note: ASD also occurs independently of vaccine adverse events. This retrospective study only examines VAERS adverse event reports and normalizes them per 100,000 VAERS reports for each vaccine.

References

• 1.        Laura Eggertson. Lancet retracts 12-year-old article linking autism to MMR vaccines. CMAJ. 2010;182(4):E199. doi:10.1503/cmaj.109-3179
• 2.        Madsen KM, Hviid A, Vestergaard M, et al. A Population-Based Study of Measles, Mumps, and Rubella Vaccination and Autism. N Engl J Med. 2002;347(19):1477-1482. doi:10.1056/NEJMoa021134
• 3.        James A Kaye, Maria del Mar Melero-Montes, Hershel Jick. Mumps, measles, and rubella vaccine and the incidence of autism recorded by general practitioners: a time trend analysis. BMJ. 2001;322(7284):460. doi:10.1136/bmj.322.7284.460
• 4.        Dales L, Hammer SJ, Smith NJ. Time Trends in Autism and in MMR Immunization Coverage in California. JAMA. 2001;285(9):1183-1185. doi:10.1001/jama.285.9.1183
• 5.        Hviid A, Hansen JV, Frisch M, Melbye M. Measles, Mumps, Rubella Vaccination and Autism. Ann Intern Med. 2019;170(8):513-520. doi:10.7326/M18-2101
• 6.        De Rubeis S, He X, Goldberg AP, et al. Synaptic, transcriptional and chromatin genes disrupted in autism. Nature. 2014;515(7526):209-215. doi:10.1038/nature13772
• 7.        Fernandez BA, Scherer SW. Syndromic autism spectrum disorders: moving from a clinically defined to a molecularly defined approach. Dialogues Clin Neurosci. 2017;19(4):353-371. doi:10.31887/DCNS.2017.19.4/sscherer
• 8.        Turner TN, Hormozdiari F, Duyzend MH, et al. Genome Sequencing of Autism-Affected Families Reveals Disruption of Putative Noncoding Regulatory DNA. Am J Hum Genet. 2016;98(1):58-74. doi:10.1016/j.ajhg.2015.11.023
• 9.        Zhou X, Feliciano P, Shu C, et al. Integrating de novo and inherited variants in 42,607 autism cases identifies mutations in new moderate-risk genes. Nat Genet. 2022;54(9):1305-1319. doi:10.1038/s41588-022-01148-2
• 10.     Bernier R, Golzio C, Xiong B, et al. Disruptive CHD8 Mutations Define a Subtype of Autism Early in Development. Cell. 2014;158(2):263-276. doi:10.1016/j.cell.2014.06.017
• 11.     Sanders SJ, Murtha MT, Gupta AR, et al. De novo mutations revealed by whole-exome sequencing are strongly associated with autism. Nature. 2012;485(7397):237-241. doi:10.1038/nature10945
• 12.     Ben-Shalom R, Keeshen CM, Berrios KN, An JY, Sanders SJ, Bender KJ. Opposing Effects on NaV1.2 Function Underlie Differences Between SCN2A Variants Observed in Individuals With Autism Spectrum Disorder or Infantile Seizures. Biol Psychiatry. 2017;82(3):224-232. doi:10.1016/j.biopsych.2017.01.009
• 13.     Neale BM, Kou Y, Liu L, et al. Patterns and rates of exonic de novo mutations in autism spectrum disorders. Nature. 2012;485(7397):242-245. doi:10.1038/nature11011
• 14.     Roman-Urrestarazu A, Yang JC, van Kessel R, et al. Autism incidence and spatial analysis in more than 7 million pupils in English schools: a retrospective, longitudinal, school registry study. Lancet Child & Adolesc Health. 2022;6(12):857-868. doi:10.1016/S2352-4642(22)00247-4
• 15.     NIMH. Autism Spectrum Disorder (ASD). Published 2024. Accessed January 12, 2024. https://www.nimh.nih.gov/health/statistics/autism-spectrum-disorder-asd
• 16.     Geier M R, Stanbro H, Merril C R. Endotoxins in commercial vaccines. Applied and Environmental Microbiology. 1978;36(3):445-449. doi:10.1128/aem.36.3.445-449.1978