Advanced Neurology
ORIGINAL RESEARCH ARTICLE
*Corresponding author:
Darrell O. Ricke
(doricke@molecularbioinsights.com)
Citation: Ricke DO, Rose J, 2024,
Signatures of neurological adverse
events after vaccination. Adv Neuro.
https://doi.org/10.36922/an.2258
Received: November 16, 2023
Accepted: February 15, 2024
Published Online: March 12, 2024
Copyright: © 2024 Author(s).
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Volume X Issue X (2024)
Signatures of neurological adverse events after
vaccination
Darrell O. Ricke1* and Jessica Rose2
Department of Research, Molecular BioInsights, Winchester, Massachusetts, United States of
1
America
2
Independent Researcher, Ontario, Canada
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.
Keywords: Neurological diseases; Vaccines; COVID-19 vaccines; Febrile convulsion;
Seizure; Syncope; Autism spectrum disorder
1. Introduction
Serious adverse events (SAEs), including neurological AEs, occur in some individuals
following vaccination.1 In any given population, a background rate of neurological
AE reporting can therefore be established based on an expected calculated number of
people that develop these AEs. Thus, observed neurological AEs post-vaccination will be
a combination of background AEs and vaccine-induced AEs.
Vaccines provide protection against multiple infectious organisms but risks of AEs
need to be considered in the context of benefits for each vaccine. Neurological AEs
following vaccinations previously reported include syncope,2,3 seizures (including
Dravet syndrome4) and febrile seizures,5 aphasia,6 and more. Genetic studies have
identified genetic variants associated with subsets of these AEs. Neurological AEs
such as febrile convulsions, encephalitis/encephalopathy, and infantile spasms
are known to be associated with the measles, and pertussis7 vaccines. Seizures
are known to be associated with diphtheria and tetanus toxoids and whole-cell
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Advanced Neurology
pertussis (DTP),8,9 measles,9 and measles, mumps and
rubella (MMR) vaccines.8 Neurological AEs following
vaccinations10-12 and COVID-19 immunization have also
been reviewed.13-16
Vaccine excipients have been considered in the
context of possible associations with neurological AEs.
In a precautionary measure to decrease overall exposure
to mercury in young children, the United States Food
and Drug Administration (FDA) removed thimerosal
from all childhood vaccines in 2001 with the exception of
inactivated influenza vaccine in multi-dose vials. A meta-
analysis concluded that exposure to thimerosal-containing
vaccines is associated with AEs, including autism spectrum
disorder (ASD) and speech disorders.17 A retrospective
study of VAERS data from 1998 through 2000 found that
the vaccines for hepatitis B (HepB), diphtheria, tetanus
toxoids, and acellular pertussis (DTaP/DTAP) which
contained thimerosal were associated with an increased
risk ratio for the incidence of ASD.18 It is important to
note that VAERS19 data represents only a small fraction of
AEs experienced by vaccinees due to well-known under
reporting.20
Wakefield et al. published a small case series in the
Lancet in 1998, indicating a possible association of ASD
with the triple MMR vaccination, but this article was
retracted in 2010.21 It should be noted 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.22 A time trend analysis
observed increasing risks of ASD from 1988 to 1993
while the MMR vaccination rate remained consistent at
over 95% for boys aged 2 to 5 in the United Kingdom.23 A
similar retrospective time trend analysis from California,
U.S.A., also showed increasing rates of ASD that were not
associated with MMR vaccination.24 Based on multiple
studies including,22-25 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 ASD,26-29 including mutations in the
genes chromodomain helicase DNA binding protein
8 (CHD8),30 neuronal voltage-gated sodium channel,
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.
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Neurological adverse events post-vaccination
type 2, alpha NaV1.2 (SCN2A),31,32 and katanin catalytic
subunit A1 like 2 (KATNAL2).33
Multiple diseases with a genetic component have
been found to be triggered by vaccinations, and
several pathological events and diseases, such as the
overrepresentation of HLA-DR2 antigen in multiple
sclerosis following vaccination34 (overviewed by Pordeus
et al.35), Dravet syndrome with SCN1A4,36 and multiple
autoimmune diseases have been reported.37 Children
with Dravet syndrome, also known as severe myoclonic
epilepsy of infancy, present with their first seizure following
vaccination. Mutations in the sodium channel protein
type 1 subunit alpha (SCN1A) gene are frequently found
in these children.4,36 Furthermore, 18 additional genes
associated with neurological AEs have been identified by
sequencing post-vaccination.38
Both febrile and afebrile seizures that occur within
14 days after immunization are regarded as vaccine-
proximate seizures.39 The vaccine-proximate seizure
risk interval (days after vaccination) has been observed
to be 5 – 14 days for live-attenuated MMR and measles,
mumps, rubella, and varicella vaccines and 0 – 2 days for
three inactivated vaccines.39 Duffy et al.40 observed that
the risk for febrile seizures increased with concomitant
administration of influenza trivalent (IIV3) vaccine
with either pneumococcal (PCV) or DTAP and further
increased with concomitant administration of IIV3,
PCV, and DTAP. In a Danish study of children aged 15
– 17 months, the cumulative incidence rate for febrile
seizures per 1,000 children was 2.46 for MMR-vaccinated
children and 0.90 for unvaccinated children.41 Comparable
results to the Danish study were observed in a systematic
review and meta-analysis.42 Febrile seizures attributed to
DTP and MMR vaccines has been estimated to be 6 to 9
and 25 – 34/100,000 children, respectively.8 A small subset
of these events and all other AEs are passively collected in
the VAERS database.19
The VAERS database is designed to collect voluntary
submissions of AEs and SAEs post-immunization. Ideally,
the subset of AEs reported in VAERS is representative of
AEs experienced by all vaccinees. As the time between
the onset of symptoms of AEs post-immunization
increases, the likelihood of reporting decreases, this
is referred to as reporting bias. Within a population,
AEs can occur randomly and these are referred to as
background events. Each vaccine dose represents a single
immunization event. AEs reported post-immunization
were compared against control populations (who
received no immunization) for a window of time (days).
Signals that are temporally associated with immunization
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Advanced Neurology
can be lost against background frequencies of AEs as
the number of days considered increases. The observed
highest reports of neurological AEs on day 0 may
simply reflect reporting bias. The observed frequencies
of AEs for each vaccine should represent background
frequencies with expected random variations. Higher
associated frequencies of AEs likely represent potential
safety signals worthy of further investigations such
as proportional reporting ratio, Bayesian, or causality
assessments. Performing surveillance on VAERS can
help discover safety signals not detected in pre-market
testing that warrant further investigations. Therefore,
in this study, neurological AEs within VAERS were
examined retrospectively. Neurological AEs reported
following immunization were compared across multiple
vaccines. Normalized neurological AE frequencies,
both by the age group and also by onset within 24 h of
immunization, were examined. Findings from this study
can help formulate strategies to reduce reporting bias
and background events.
2. Materials and methods
2.1. Materials
The VAERS database19 was retrospectively examined for
the neurological AEs designated by the following Medical
Dictionary for Regulatory Activities (MedDRA)43 codes:
Abnormal behavior, antisocial behavior, aphasia, autism or
ASD (combined), cognitive disorder, convulsion or seizure
(combined), coordination abnormal, delirium, depression,
encephalopathy, encephalitis, febrile convulsion, meningitis,
mental disorder, mental impairment, mental status changes,
metabolic encephalopathy, nervous system disorder,
neurodevelopmental disorder, psychomotor hyperactivity,
speech disorder, staring, and tinnitus. Within the VAERS
data records, usage of “convulsion” was transitioned to
“seizure,” and “autism” to “ASD.” Syncope was also included
for comparisons with seizure. The downloaded VAERS data
includes all AEs reported from 1990 to November 3, 2023.
The Ruby program named vaers_slice4.rb44 was used to tally
selected reported vaccine AEs by vaccine, day of onset, year,
and age. The vaers_slice4.rb program takes a list of one or more
AE names as input, and characterizing them with the VAERS
data files. The output from vaers_slice4.rb consists of multiple
reports: summaries by vaccine, summary by year, summaries
by vaccine age, summaries by day of onset of symptoms by
(i) dose and sex and (ii) vaccine type, and two summaries of
additional symptoms reported (selected symptoms and all
other symptoms). The output from vaers_matrix.rb consists
of multiple reports: summary by vaccine and dose, summary
by vaccine and year, summary by vaccine and AEs, summary
by vaccine and day of onset, and summary by vaccine and age.
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Neurological adverse events post-vaccination
2.2. Adverse events following immunization
Adverse events following immunization can be represented
by the following equation for a population subset
X
immunized (P), AE (X), (n) days, reporting bias ( ri ) for
the i day post-immunization, vaccine-associated AEs
th
reported on the ith day post-immunization (viX ), and daily
background rate of AE (bX) (Equation I).
n days
Adverse event ( X ) = P * [ Σr
X
i * (viX + b X ) ] (I)
i=0
Day 0 (the first 24 h) following immunization can be
examined to solve for the term v X (Equation II):
0
Adverse event ( X within 24 h ) = AE0X = P * r0X * (v0X + b X )
(II)
Immunization-associated AEs (X) are detectable when
v0X > 0 (when the number of AEs exceeds the background
rate within 24 h of immunization).
When there is no immunization-associated AE (X), the
number of AEs is the background AEs (Equation III).
Background adverse events
( X within 24 h ) = AE0X = P * r0X * b X (III)
The VAERS reports represent only a subset of the
population vaccinated with one or more symptoms
a
( P1+ symptoms ) with the true population size for a vaccine
represented in Equation IV.
Population size (P) for vaccine (a):
P a = P1a+ symptoms + PNo
a
symptoms (IV)
Comparisons between different vaccines (a and b) for
the same AE are represented by Equation V.
Adverse events comparison between vaccines
P1a+ * r0X * (v0a:X + b X )
(a,b : X within 24 h) = (V)
P1b+ * r0X * (v0b:X + b X )
Notethatwhen P1a+ >> P1b+ ,theratiosbetweenmultipleAEs(X,
Y, Z, etc.) will appear similar reflecting the ratio P1a+ / P1b+ . In
general, when AE0a:X >> AE0b:X , then v0a:X >> v0b:X .
3. Results
3.1. Day 0 onset safety signals
The VAERS database was data mined with vaers_slice4.
rb44 for selected neurological AEs and vaers_matrix.
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Advanced Neurology
rb44 for summary totals by vaccine. To minimize the
impact of reporting bias, the normalized frequencies
of multiple neurological AEs arising within 24 h of
immunization were compared across multiple vaccines;
AEs were normalized to 100,000 VAERS reports for
each vaccine, as shown in Figure 1 and Table S1 for 13
vaccines. Syncope (loss of consciousness) is a known AE
that can occur following immunization.45 For human
papillomavirus quadrivalent (HPV4), the normalized
frequency of syncope is considerably higher than for other
vaccines (Figure 1 and Table S1). For the vaccine DTP, the
normalized frequency of seizures is three times that of
DTAP vaccine, and nine times that of influenza (FLU3)
(Table S1). Increased reactogenicity for DTP compared
to DTAP has been previously reported.46 For abnormal
behavior, PNC13 has the highest normalized frequency
(Table S1). ASD has the highest normalized frequencies
for MMR and Haemophilus B conjugate vaccine (HIBV or
HIB) (Table S1). This is further examined in the following
section. The normalized frequencies for febrile convulsions
and syncope are high for meningococcal group B, rDNA
absorbed (MENB) vaccine followed by DTP (Figure 1
and Table S1). For the AE Staring, pneumococcal
(PNC) vaccine is associated with the highest normalized
frequency (Table S1).
3.2. COVID-19 and influenza vaccines safety signals
The COVID-19 vaccines were widely administered in the
United States and comprised both the modified mRNA
and adenoviral SARS-CoV-2 spike protein vaccines. The
frequencies of neurological AEs per 100,000 COVID-
Figure 1. Day 0 adverse events frequencies per 100,000 vaccinations with
symptoms.
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Neurological adverse events post-vaccination
19 immunizations with symptoms varied by age and
AE (Figure 2 and Table S2). Differences in normalized
frequencies of neurological AEs were observed between
the COVID-19 and influenza (FLU3) vaccines by age group
(Figures 2 and 3, Tables S2 and S3). For both influenza and
COVID-19, the normalized frequencies increased with age
(>60 years old) for AEs: abnormal behavior (>70 years),
aphasia (>70 years), cognitive disorder (>80 years),
encephalopathy (>80 years), seizure (>80 years), and speech
disorder (>80 years) (Tables S2 and S3); and for COVID-
19 alone, the normalized frequencies increased with age
for delirium (>70 years), and metabolic encephalopathy
(>70 years) (Table S2).
3.3. Infants (aged 0 – 2) safety signals
For infants aged 0, 1, and 2, neurological AEs per
100,000 shots with symptoms are summarized in Table 1
for 10 vaccines. The highest number of reports for all
neurological AEs had onset within the first 24 h, followed
in decreasing order by 48 h and 72 h. The Centers for
Disease Control and Prevention has provided vaccination
recommendations based on age.47 It has been observed that
seizure episodes occurring on the day of vaccination are
most likely vasovagal syncopal episodes.48 For infants aged
0 – 1, syncope normalized frequencies are higher than for
those aged 1 – 2 and 2 – 3 (Table 1). Assuming no reporting
bias between identification of syncope and seizure, the
increase in reported seizure AEs associated with the
DTP vaccine for infants aged 1 and 2 likely represents a
vaccine-specific association (Table 1). In comparison,
the normalized frequencies for abnormal behavior are
relatively low for DTP in comparison to MMR and other
vaccines (Table 1). The normalized frequencies for febrile
convulsions and syncope are high for the MENB vaccine
(Table 1). The normalized frequencies for MMR are also
Figure 2. Influenza (FLU3) neurological adverse events by age per
100,000 vaccinations with symptoms.
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Advanced Neurology
Figure 3. COVID-19 neurological adverse events by age per 100,000
vaccinations with symptoms.
higher for aphasia, ASD, and speech disorder (also higher
for HEP vaccine) (Table 1).
3.4. Adverse effect incidence for ASD
The incidence of AEs for ASD remained low from 1990
to 1997, increased from 1999 to 2010, and subsequently
decreased 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 1998.
When an article associating ASD with MMR vaccination
by Wakefield et al. published in the Lancet was retracted
in 2010,21 the reporting bias appeared to be altered again
(Table S4). Twenty-five individual vaccines have enriched
the 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 559.4/100,000/year;49 this yields an estimate
of bASD = 559.4/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 2 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 36.50
The three vaccines (HIB [No Brand Name], Polio Virus,
inactive [No Brand Name], and MMR II) exhibit differences
in normalized frequencies when comparing frequency in
2011 – 2023 with that in 1990 – 2023 (Figure 4). The yearly
normalized frequencies for these vaccines by individual
vaccine are illustrated in Figure 5 whereby yearly
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Neurological adverse events post-vaccination
Figure 4. Normalized frequency of autism spectrum disorder on day 0
onset based on VAERS data from 2011 to November 3, 2023, and 1990 to
November 3, 2023.
Abbreviations: VAERS vaccine codes: DTAP: Diphtheria and tetanus
toxoids and acellular pertussis; DTP: Diphtheria and tetanus toxoids and
pertussis; HEPB: Hepatitis B; HIB: Haemophilus B conjugate; IPV: Polio
virus, inactive; Pneumo: Pneumococcal.
variability is observed. The ASD normalized frequency
for measles+mumps+rubella+varicella (PROQUAD) after
2014 is relatively low compared to MMR II. Likewise,
the normalized frequency of yearly Polio Virus, inactive
(IPOL) is lower than those of Polio Virus, inactive (No
Brand Name) and POLIOVAX. Likewise, recent HIB
(ACTHIB) and (PEDVAXHIB) normalized frequencies
are lower than HIB (No Brand Name). Some of the larger
variations between years for the same vaccine are not
consistent with being associated with expected random
variations.
3.5. Observations
The retrospective results enable the comparisons of AEs
across all vaccines. Some key observations include:
• The HEP vaccine has the highest normalized frequencies
for infants aged 1 and 2 for neurological AE.
• The HPV4 vaccine is associated with the highest
normalized frequency for syncope within 24 h of
vaccination.
• The MENB vaccine is associated with high normalized
frequencies for febrile convulsions and syncope.
• The PNC vaccine is associated with the highest
normalized frequency for staring.
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Advanced Neurology Neurological adverse events post-vaccination

Table 1. Neurological adverse events per 100,000 vaccinations with symptoms in infants aged 0 – 2 years

Adverse events Age DTAP DTP FLU3 HEP HIBV IPV MENB MMR PNC PNC13
(AEs) (year)
Recommended 0 2, 4, and 6 See DTAP 6 mo. Birth and 2 and 4 mo. 2, 4, and 2, 4, and 2, 4, and 6 mo.
dosing mo. 1 – 2 mo. 6 – 18 mo. 6 mo.
1 15 – 18 mo. See DTAP 24 mo. 6 – 18 mo. 12 – 15 mo. 6 – 18 mo. 12 – 15 mo. 12 – 15 mo. 12 – 15 mo.
VAERS shots 0 14,496 13,133 1,859 14,616 31,980 13,316 1,687 980 15,681 14,579
with symptoms 1 13,940 4,351 3,166 2,884 17,024 4,398 621 30,890 8,069 6,421
2 2,557 761 1,016 802 1,858 809 252 2,208 1,023 844
Pyrexia (fever) 0 27,794 42,382 26,573 27,107 31,482 29,716 37,759 26,939 29,144 22,388
1 28,615 64,054 26,374 38,592 39,433 34,538 42,351 41,489 32,606 30,649
2 19,398 56,636 17,028 25,935 29,279 24,475 34,921 33,877 24,536 18,009
Abnormal 0 938 198 646 691 722 698 711 2,143 797 1,008
behavior 1 1,083 345 1,011 1,942 999 1,023 483 1,984 868 1,090
2 1,291 394 984 2,244 1,346 742 397 2,174 684 1,777
Aphasia 0 248 61 108 151 125 120 <59 1,633 83 158
1 574 437 632 589 693 455 322 1,172 359 716
2 391 131 98 499 646 124 <397 1,132 196 237
Autism spectrum 0 911 343 538 937 416 623 119 5,102 332 316
disorder 1 1,198 1,402 600 2,774 1,416 1,342 322 3,373 1,115 716
2 1,212 657 197 3,616 1,507 1,607 <397 4,982 978 711
Coordination 0 124 69 <54 103 59 75 59 612 38 48
abnormal 1 323 735 158 728 435 477 <161 702 359 140
2 117 394 492 873 431 371 <397 272 293 237
Encephalopathy 0 373 449 108 356 288 345 178 306 293 192
1 201 253 190 416 241 227 161 282 211 187
2 117 394 98 499 54 247 <397 272 <98 355
Encephalitis 0 366 297 108 322 266 368 296 612 166 254
1 158 161 126 277 282 227 161 450 335 265
2 274 263 197 499 161 494 397 136 293 <118
Febrile 0 1,462 1,432 4,034 1,368 1,401 1,675 9,959 2,959 1,422 1,907
convulsion 1 4,340 6,964 7,960 4,161 5,645 5,070 16,264 5,442 4,722 5,996
2 1,643 2,760 3,543 2,244 2,799 2,843 17,460 3,125 1,369 3,791
Meningitis 0 724 777 54 472 810 691 830 306 784 357
1 136 322 32 208 499 250 322 207 273 234
2 156 263 98 <125 1,722 <124 397 136 587 118
Nervous system 0 345 168 215 397 219 293 <59 1,327 249 144
disorder 1 222 161 95 1,110 229 250 <161 223 186 93
2 235 <131 98 1,372 215 124 <397 91 391 <118
Seizure 0 8,471 9,564 7,208 7,198 7,364 8,073 7,469 4,388 6,875 5,563
1 6,227 16,617 6,822 8,599 9,034 7,071 7,246 7,595 6,556 5,669
2 3,324 14,060 4,429 4,988 6,512 4,326 5,556 6,612 3,617 3,673
Speech disorder 0 531 442 108 684 313 421 <59 2,143 230 219
1 710 712 221 1,144 746 750 161 1,437 632 327
2 548 526 394 1,372 969 494 1,587 1,630 196 829
Staring 0 1,794 129 753 718 1,001 1,540 1,304 816 1,786 1,571
1 832 92 758 728 717 955 483 903 1,029 1,028
2 665 <131 295 249 538 1,112 397 725 880 474
Syncope 0 1,621 921 699 1,232 1,185 1,975 5,453 1,122 1,817 1,687
1 725 850 442 832 723 1,364 4,026 864 768 1,168
2 548 1,183 1,181 998 646 742 2,778 951 782 592
Note: Neurological AE frequency greater than 1,000 are in bold. Abbreviation: mo.: Months.

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Advanced Neurology
A B
Figure 5. Autism spectrum disorder yearly normalized frequencies for (A) polio virus, inactivated; (B) measles, mumps, and rubella; and (C) Haemophilus
B conjugate vaccine. The charts were developed based on Vaccine Adverse Events Reporting System data from 1990 to November 3, 2023.
• Compared to influenza, the ASD day 0 normalized
frequency is enriched for 25 vaccines; some
immunizations may act like a trigger event for ASD,
similar to that for Dravet syndrome, for vaccinees
with preexisting genetic risk factors.
• The current population ASD frequency can be aligned
with the combined frequencies reported to VAERS for
recommended infant vaccines.
• For infants less than 12 months of age, delaying MMR
immunization until the recommended age of 12 –
15 months is predicted to reduce AEs in aphasia, ASD,
neurological disorder, and speech disorder.
• 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., endotoxins51) (with possible
overlaps between unrelated vaccines) associated with
AEs.
• Seizure AEs have higher normalized frequencies
across all of the vaccines summarized herein.
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Neurological adverse events post-vaccination
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 neurological
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Advanced Neurology
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
X
reporting bias ( ri ) 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.
Volume X Issue X (2024)
Neurological adverse events post-vaccination
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.
Acknowledgments
None.
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
8 https://doi.org/10.36922/an.2258
Advanced Neurology
Ethics approval and consent to participate
Not applicable.
Consent for publication
Not applicable.
Availability of data
The vaers_slice4.rb and vaers_matrix.rb reports are
available at https://doi.org/10.7910/DVN/CFSVIU.44
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