Rare dizziness, syncope, loss of consciousness, seizure, and risk of falling after vaccination

1.   Introduction

Multiple vaccines have been associated with rare undesirable rare adverse events. Recent development of messenger ribonucleic acid (mRNA) and adenoviral vaccines for Severe Acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are associated with higher frequencies of adverse events than seen previously for all other vaccines combined [1]. A small subset of these adverse events affecting alertness, balance, vision, and consciousness have the potential for accidental injuries when they occur without warning. The etiology for these increased frequencies of adverse events associated with coronavirus disease 2019 (COVID-19) and other vaccines remain unknown.

Some vaccinees (vaccinated individuals) experience vasovagal reaction (VVR) shortly after vaccination. VVR can lead to dizziness, presyncope (near fainting), and reflex syncope (fainting/loss of consciousness). Immunization stress-response (ISRR) has been proposed by the World Health Organization (WHO) to include VVR. VVRs are reported to be more common in adolescents and young adults [2]. Syncope was the most common adverse event for 209215 vaccinees aged 6 through 17 [3]. Syncope was also the most common immediate adverse event reported by an Australian retrospective study [4]. Some cases of COVID-19 vaccine-associated syncope can occur after the typical 10–15 minutes waiting period [5],[6]. A study in Saudi Arabia reports adverse events per 10000 COVID-19 vaccine doses for dizziness (17.8), headache (9.7), nausea (7.1), and syncope (3.2) [7]. A case study of 20 million Malaysian reports a small increase risk of venous thromboembolism, arrhythmia, and convulsion/seizure for BNT162b2 vaccinees [8]. Seizures following SARS-CoV-2 vaccination are reported to occur as exceedingly rare events with 2.73 per million for mRNA-1273 (Moderna) and 1.02 per million for BNT162b2 (Pfizer-BioNTech) [9]. A retrospective study of 418 people with epilepsy reported a 6.2% increase in seizure frequency the month following vaccination [10]. Also, inclusion of varicella to the combination measles-mumps-rubella vaccine increases the risk of febrile seizure [11]; perhaps through increased reactogenicity due to combining these four vaccines.

The Vaccine Adverse Event Reporting System (VAERS) is the established database set up to monitor adverse events following vaccination in the United States. Herein, adverse events relevant to alertness, balance, vision, consciousness, falling, and head injury were characterized from VAERS reports from 1990 until Oct 21, 2022 for all vaccines with a focus on the vaccines with the highest reactogenicity levels. The majority of these adverse events occur within the first few days following vaccination, with the highest frequency within 24 hours of vaccination. This immediate onset timing pattern warrants additional studies. Individual vaccine subcomponents, including adjuvants, likely contribute to the reactogenicity level observed for each vaccine. Consistency of adverse event timing patterns and normalized frequency patterns of adverse events across unrelated vaccines support the hypothesis that reported reactogenicity adverse events are associated with and correlate with the level of innate immune responses to vaccination.

The VAERS database is a resource for researchers to detect patterns that warrant further study. VAERS is known to report and store co-occurring health events with no proof of causation. Mechanical incidents (e.g., car accident) may have no causality relationship with recent vaccination. An indirect relationship occurs when the mechanical operator experiences a vaccine associated adverse events negatively impacting consciousness or vision. Immediate onset patterns for rare adverse events affecting consciousness, ability to talk, vertigo, dizziness, vertigo, etc. are observed for vaccines with high reactogenicity levels. The inclusion of cautionary warnings may be warranted for driving, operating mechanical equipment, risk of falling, etc. for 24 to 48 hours post vaccination for high reactogenicity level vaccines. Syncope and consciousness adverse events are also known to be associated with elevated histamine levels [12],[13].

The observed immediate onset patterns of loss of consciousness/syncope and seizure all warrant additional study. Inclusion of cautionary warnings may be warranted. The immediate onset pattern possibly implicates elevated histamine levels and possibly additional molecules released by innate immune responses to vaccination.

2.   Materials and methods

2.1.   VAERS data mining

The VAERS database was data mined for data on the following reported adverse events: Altered state of consciousness, aphasia (loss of ability to understand or express speech), confusional state, depressed level of consciousness, dizziness, fall, head injury, hypotension, loss of consciousness, muscle twitching, pallor, presyncope, seizure, somnolence, syncope, tremor, unresponsive to stimuli, vertigo, vision blurred, and visual impairment; dizziness, pallor, vision blurred, and muscle twitching may precede syncope onset. The downloaded data include all adverse events reported from 1990 to Oct 21, 2022. The Ruby program, named vaers_slice.rb [1], was used to tally selected reported vaccine adverse events by vaccine and day of onset. The vaers_slice.rb program takes as input a list of one or more adverse events to characterize; these adverse events are summarized from 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). Microsoft Excel was used create figures.

3.   Results

All of the VAERS adverse events from 1990 to Oct 21, 2022 are summarized in the Supplemental data: Table S1 (all 20 adverse events combined), Table S2 (Altered state of consciousness), Table S3 (Aphasia), Table S4 (Confusional state), Table S5 (Depressed level of consciousness), Table S6 (Dizziness), Table S7 (Fall), Table S8 (Head Injury), Table S9 (Hypotension), Table S10 (Loss of consciousness), Table S11 (Muscle twitching), Table S12 (Pallor), Table S13 (Presyncope), Table S14 (Seizure), Table S15 (Somnolence), Table S16 (Syncope), Table S17 (Tremor), Table S18 (Unresponsive to stimuli), Table S19 (Vertigo), Table S20 (Vision blurred), and Table S21 (Visual impairment). Individual and combined symptoms reports from vaers_slice.rb are included in the Supplemental data (Tables S1–S21). The time to onset for selected adverse events are illustrated in Figures 1 and 2. The co-occurrences of pairs of examined adverse events is illustrated in Table 1. The gender ratio (female/male) of examined adverse events for COVID-19 vaccines is illustrated in Table 2. Vaccinees' age for presyncope and syncope adverse events are illustrated in Figures 3 and 4, respectively.

Figure 1.  Immediate onset of adverse events in VAERS (1990 to Oct. 21, 2022). Vaccines plotted include COVID-19 (Pfizer-BioNTech, Moderna, and Janssen), Human papillomavirus HPV (GARDASIL), Meningococcal conjugate (MENACTRA), and TDAP (tetanus, diphtheria, and pertussis) (BOOSTRIX).

DownLoad: Full-Size Img PowerPoint

Figure 2.  Immediate onset of adverse events in VAERS (1990 to Oct 21, 2022). Vaccines plotted include COVID-19 (Pfizer-BioNTech, Moderna, and Janssen), Human papillomavirus HPV (GARDASIL), Meningococcal conjugate (MENACTRA), and TDAP (tetanus, diphtheria, and pertussis) (BOOSTRIX).

DownLoad: Full-Size Img PowerPoint

Table 1.  Co-occurrences of pairs of examined adverse events reports from VAERS (1990 to Oct. 21, 2022); these represent counts of pairs of adverse events that are both reported by vaccinees.

Adverse event	Confusional state	Dizziness	Fall	Head injury	Hypotension	Loss of consciousness	Seizure	Syncope	Unresponsive to stimuli	Vertigo
Altered state of consciousness	74	368	131	20	73	148	178	189	80	36
Aphasia	476	760	176	24	61	215	201	154	172	114
Confusional state		3346	857	187	457	930	514	1256	662	389
Depressed level of consciousness	168	652	194	32	143	232	195	348	161	68
Dizziness	3346		4642	1267	3659	8308	1776	13735	2223	7575
Fall	857	4642		2886	524	4435	841	4490	835	545
Head injury	187	1267	2886		174	1992	299	2420	290	76
Hypotension	457	3659	524	174		1283	287	2528	612	239
Loss of consciousness	930	8308	4435	1992	1283		2413	6633	1299	588
Muscle twitching	154	1190	188	42	96	354	274	509	180	150
Pallor	424	6823	1256	345	1328	3486	622	4268	1545	175
Presyncope	156	3686	740	142	568	1413	302	1623	198	307
Seizure	514	1776	841	299	287	2413		2020	759	119
Somnolence	657	3346	394	99	311	765	390	822	451	355
Syncope	1256	13735	4490	2420	2528	6633	2020		3099	708
Tremor	1055	7688	1000	219	612	1812	1194	2320	882	711
Unresponsive to stimuli	662	2223	835	290	612	1299	759	3099		29
Vertigo	389	7575	545	76	239	588	119	708	29
Vision blurred	552	5796	364	86	270	659	229	975	100	816
Visual impairment	422	3875	347	71	248	603	232	834	197	546

---

 | Show Table

DownLoad: CSV

Table 2.  Gender ratio (female/male) of examined VAERS adverse events for COVID-19 vaccines.

Adverse event	COMIRNATY male	COMIRNATY female	SPIKEVAX male	SPIKEVAX female	AD26.COV2.S male	AD26.COV2.S female	COMIRNATY ratio	SPIKEVAX ratio	AD26.COV2.S ratio
Altered state of consciousness	393	566	158	154	16	23	1.44	0.97	1.44
Aphasia	802	1702	360	772	73	158	2.12	2.14	2.16
Confusional state	2595	3895	1511	2226	345	395	1.50	1.47	1.14
Depressed level of consciousness	606	1062	196	252	24	50	1.75	1.29	2.08
Dizziness	19257	52553	9905	27389	3704	6118	2.73	2.77	1.65
Fall	3738	4458	2115	2372	685	465	1.19	1.12	0.68
Head injury	883	895	396	524	222	127	1.01	1.32	0.57
Hypotension	2216	3604	998	1458	381	368	1.63	1.46	0.97
Loss of consciousness	5252	7569	2271	3599	1263	983	1.44	1.58	0.78
Muscle twitching	865	2148	310	861	111	200	2.48	2.78	1.80
Pallor	2514	3207	967	1014	706	376	1.28	1.05	0.53
Presyncope	1905	3718	762	1259	270	244	1.95	1.65	0.90
Seizure	3017	3968	1206	1559	514	381	1.32	1.29	0.74
Somnolence	2177	5370	1209	3031	297	513	2.47	2.51	1.73
Syncope	8288	13837	3163	5274	1869	1567	1.67	1.67	0.84
Tremor	3358	9284	2220	5563	781	1419	2.76	2.51	1.82
Unresponsive to stimuli	1576	1753	943	869	454	318	1.11	0.92	0.70
Vertigo	2621	7512	1247	3511	273	540	2.87	2.82	1.98
Vision blurred	2347	5611	1020	2561	461	854	2.39	2.51	1.85
Visual impairment	2057	4507	725	1676	281	446	2.19	2.31	1.59

---

 | Show Table

DownLoad: CSV

Figure 3.  Age of Vaccinees experiencing presyncope post COVID-19 vaccination.

DownLoad: Full-Size Img PowerPoint

Figure 4.  Age of Vaccinees experiencing syncope post COVID-19 vaccination.

DownLoad: Full-Size Img PowerPoint

4.   Discussion

All of the VAERS adverse events from 1990 to Oct 21, 2022 are summarized in the Supplemental data for combined adverse events (Table S1) and 20 individual adverse events (Tables S2–S21).

4.1.   Vasovagal reaction (VVR)

Some vaccinees experience VVR adverse events immediately post vaccination, typically within 15 minutes of vaccination. The highest frequency of examined adverse events (Figures 1 and 2) are highest within 24 hours with risks decreasing rapidly for the subsequent days. VVR adverse events are most common for adolescents and young adults [2]. For the examined COVID-19 post-vaccination adverse events, this risk appears to decay in an approximate linear relationship from ages 20 to 100 (Figures 3 and 4). While a subset of the post-vaccination adverse events may be caused by VVR, the time of onset and an age of vaccinees affected suggest that the majority of these adverse events are not caused by VVR.

4.2.   Immediate onset of adverse events

Immediate onset adverse events are observed for multiple high reactogenicity vaccines [1]. The highest levels of examined adverse events in VAERS are reported for the two COVID-19 mRNA vaccines (Pfizer-BioNTech and Moderna) and the COVID-19 adenovirus vaccine (Janssen) (Figures 1 and 2 and Supplemental data Tables S1–S21). The observed immediate onset pattern of these adverse events is also observed for some non-COVID-19 vaccines. Expressing the SARS-CoV-2 Spike mRNA in innate immune cells is a possible cause of the observed higher reactogenicity level of COVID-19 vaccines (Figures 1 and 2 and Supplemental data Tables S1–S21). The consistent onset pattern observed across unrelated vaccines (Figures 1 and 2 and Supplemental data Tables S1–S21) suggests that innate immune responses are the principal driver of the majority of these adverse events experienced by vaccinees. Innate immune responses release inflammatory molecules, including histamine, as part of the innate immune responses to vaccinations. Many of the post-vaccination symptoms overlap with those of mast cell activation (MCA) [14]. The observation of consistent onset data patterns across unrelated vaccines enables the exclusion of individual vaccine and adjuvant components (which drive reactogenicity level) with implication of immune responses to vaccinations. The immediate onset patterns of all of the examined adverse events also enables the exclusion of other possible etiology models (e.g., antibody responses can be excluded, etc.). The co-occurrences of these pairs of adverse events (Table 1) is suggestive of shared or overlapping etiology.

4.3.   Gender bias

The number of adverse event reports for some adverse events is generally higher for females, but can vary by vaccine type (mRNA versus adenoviral) (Table 2). Pearson correlations, r, of the gender ratios (female/male) are 0.95 for COMIRNATY versus SPIKEVAX, 0.81 for COMIRNATY versus AD26.COV2.S, and 0.71 for SPIKEVAX versus AD26.COV2.S. The mRNA vaccines are taken up by neutrophils and monocytes with modified monocytes migrating to lymph nodes. AD26.COV2.S infects muscle cells. These differences in gender ratios may be influenced the different vaccine type mechanisms for activating immune responses. The differences in gender bias ratios (female/male) (Table 2) may indicate more than one etiology for these adverse events.

4.4.   Granulocytes and mast cell mediators

Innate immune responses include activation of granulocytes and mast cells to release inflammatory molecules including histamine. The amount of inflammatory molecules released is predicted to correlate with the reactogenicity level of the vaccine. Cysteinyl leukotrienes are synthesized following degranulation of granulocytes and promote increased permeability of endothelium, enhancing vasodilation, and recruiting inflammatory cells; cysteinyl leukotrienes appear have higher potency than histamine with regard to their vascular effects (reviewed [15]). Histamine and platelet activating factor (PAF) can activate nitric oxide production resulting in dilation of blood vessels and dysfunction of the endothelial barrier (reviewed [15]). Histamine, cysteinyl leukotrienes, PAF, and additional inflammatory molecules are candidate drivers of the examined adverse events (Figures 1 and 2).

The majority of reactogenicity adverse events following vaccinations are predicted to be caused by elevated histamine levels [1] including menstrual adverse events [16], and cardiac adverse events including myocarditis and pericarditis [17]. The histamine tolerance level can vary by individual for multiple reasons including drugs [18], foods [13],[18], gastrointestinal microbiome [18], stage of menstrual cycle [13], and pregnancy; histamine intolerance may be associated with the rarity of the adverse events affecting consciousness level, etc.

4.5.   Loss of consciousness/syncope and seizure injury risks

The rare adverse events of loss of consciousness/syncope and seizure have rapid onset (Figure 1) with little or no advance warning; when they occur while driving a vehicle, operating heavy equipment, or in elevated locations, the risks for an accident or falling is significantly increased. Seizure can be associated with a syncopal episode. Figure 1 illustrates loss of consciousness, syncope, and seizure adverse events immediately post vaccinations with the greatest risk within the first 24 and 48 hours. These immediate onset patterns provide support for the addition of safety warnings to current high reactogenicity treatments, including COVID-19 mRNA and adenovirus vaccines. Vaccinees exercising caution and avoiding higher risk activities for a day or two will likely reduce falls, head injuries, and other rare accidents.

Elevated histamine has a potential role for a subset of the evaluated adverse events including hypotension, loss of consciousness, presyncope, syncope, etc. However, seizures may have a different etiology. Low levels of histamine are associated with convulsions and seizures [19]. It is suggested that H1 antagonists should not be administered to patients with febrile seizures to avoid disturbing the anticonvulsive central histaminergic system [20],[21].

5.   Conclusions

Vaccinations provide protection against potential pathogen infections. Rare adverse events impacting consciousness and risk of falling occur with immediate onset patterns. The majority of these adverse events are reported within the 48 hours of vaccination. Avoidance of activities like driving, operating heavy machinery, with increased risks of falling, etc. for 1 to 2 days post vaccination provide an opportunity to reduce the frequencies of falls, head injuries, and other rare accidents.