Syncope after live attenuated influenza vaccine: Reports to the Vaccine Adverse Event Reporting System (2003–2024)

Abstract

Vasovagal syncope, or fainting, can be triggered by various stimuli, including medical procedures. Syncope after vaccination has been reported, most commonly among adolescents, and can result in injuries. Using the Vaccine Adverse Event Reporting System (VAERS), we reviewed and summarized reports of syncope after live attenuated influenza vaccine, intranasal (LAIV) administered as the sole vaccine (i.e., no concomitant injections). From June 17, 2003 (date of LAIV licensure in the US) through May 31, 2024, VAERS received 50 reports of syncope after LAIV. Nearly half (23; 46 %) pertained to individuals 10–19 years of age. While the vast majority of reports (35; 70 %) did not describe any injuries, 15 people (30 %) were injured, most commonly by falling and hitting their head or face. Twenty-two people (44 %) required evaluation in the emergency department or doctor’s office, including an individual who lost consciousness while he was driving home from the vaccination appointment. He did not report any injuries, but the car was severely damaged. Nearly three-quarters of people (37; 74 %) developed syncope within 15 min after vaccination, but fewer than half of reports (24; 48 %) stated that the patient had waited in the observation area for at 15 min. Based on approximately 111.9 million doses of LAIV distributed in the US during the same time period, the reporting rate is approximately 0.4 per million doses, suggesting that syncope following LAIV is rare. The information summarized here may enable clinicians, patients, and caregivers to make a more informed decision regarding preventing injuries that may occur following LAIV-related syncope.

1. Background

Vasovagal syncope, a transient loss of consciousness often described as “fainting,” “blacking out,” or “passing out,” can be triggered by various stimuli, including medical procedures [1-3]. Syncope after vaccination has been reported, most commonly among adolescents, and can result in injuries [2,4-6]. The Immunization Safety Review Committee of the National Academies of Sciences, Engineering, and Medicine (formerly known as the Institute of Medicine; IOM) concluded that the evidence convincingly supports a causal relationship between the injection of a vaccine and syncope [7].

Even in the absence of a needlestick, patients may be nervous or anxious. In a review of the Vaccine Safety Datalink (VSD), Daley et al. [8] evaluated the safety of live attenuated influenza vaccine (LAIV) among individuals 2–17 years of age, over 11 influenza seasons. In that review, syncope was rare (8.5 per million doses), and most cases occurred after patients received LAIV and a concomitant injection, but syncope also occurred following LAIV administration alone [8].

To reduce the risk of injury following post-vaccination syncope, the Advisory Committee on Immunization Practices (ACIP) states that “Vaccine providers should consider observing patients (with patients seated or lying down) for 15 minutes after vaccination to decrease the risk for injury should they faint” [9]. The American Academy of Pediatrics (AAP) states that, “A 15-minute observation period (with the patient sitting or lying down) is advised after all vaccine administration to avoid the risk of injury if syncope occurs” [10]. Although dizziness, lightheadedness, or weakness may precede syncope, the loss of consciousness can occur with no presyncopal symptoms [10].

On June 17, 2003, the Food and Drug Administration approved LAIV (FluMist) for active immunization for the prevention of influenza disease caused by influenza A subtype viruses and type B virus contained in the vaccine [11]. The quadrivalent formula (LAIV4), which added protection against a second type B virus, was approved on February 29, 2012 [12]. ACIP includes LAIV/LAIV4 in its annual recommendations regarding the prevention and control of influenza with vaccines [13].

To improve our understanding of syncope after LAIV/LAIV4, we reviewed and summarized reports received by the Vaccine Adverse Event Reporting System (VAERS).

2. Methods

VAERS is a national system for passive surveillance of adverse events following vaccination [14,15]. Established in 1990, VAERS is jointly managed by the U.S. Food and Drug Administration (FDA) and the Centers for Disease Control and Prevention (CDC). In 2023, VAERS received more than 106,000 US reports. Reports are submitted by health care providers, vaccine recipients or their parents or guardians, vaccine manufacturers, and other interested parties. FDA medical officers review all serious reports (7–14 % of all reports [14,15]), defined as events that are fatal, disabling, or life-threatening; require or prolong hospitalization; result in congenital anomalies; require medical intervention to prevent such outcomes; or are otherwise deemed to be other medically important conditions [16].

We searched VAERS for US reports of syncope that occurred on the same day of vaccination with LAIV or LAIV4 as the only vaccine listed on the report form (i.e., there were no concomitant injections, such as vaccination or Mantoux testing). We identified reports that were coded with any of the following Medical Dictionary for Regulatory (MedDRA) (https://www.meddra.org/) Preferred Terms (PTs): syncope vasovagal, syncope, hypotonic-hyporesponsive episode, altered state of consciousness, depressed level of consciousness, loss of consciousness, hyporesponsive to stimuli, presyncope, and/or unresponsive to stimuli. The search included all reports received June 17, 20,203 (date of US licensure) through May 31, 2024. We limited the search to US reports, and we included both serious [16] and non-serious reports. We manually reviewed each report and clinically assessed the narrative description of the event, time course, treatment, and any available medical records. We determined whether the event was consistent with vasovagal syncope and whether the person was injured. We calculated the onset interval from vaccination to syncope and assessed whether the person had waited in the facility for at least 15 min after vaccination. Duplicate reports were consolidated, and we clarified values whenever possible (e.g., the onset date and time were reported as “unknown,” but the event narrative stated the onset interval in minutes). Results were summarized with descriptive statistics using SAS Version 9.4 (SAS Institute, Cary, NC).

As part of routine safety surveillance, FDA applied Empirical Bayesian data mining [17] to identify disproportionality [18] of vaccine-adverse event pairs (based on MedDRA PT codes assigned to the reported adverse events), with adjustment for age, sex, and year in which the report was received.

Protection of human subjects: VAERS is a routine surveillance program conducted as a public health function and does not meet the definition of research. No interventional treatments, exposures, or procedures were performed. Therefore, this work was not subject to Institutional Review Board evaluation or informed consent requirements. Personal information provided to VAERS which identifies a person who received the vaccine(s) is not made available to the public.

3. Results

Among a total of 7643 VAERS reports after LAIV/LAIV4 given with no other vaccines, our search identified 73 reports of possible syncope, based on the original search terms. Manual review confirmed 50 cases of vasovagal syncope (Table 1). Affected individuals included children, adolescents, and adults of both sexes (Table 1).

Table 1.

Overview of reports of syncope ^a after live attenuated influenza vaccine (VAERS 2003–2024).

Demographic and Report Characteristics	n = 50
Age (years)
Median (range)	13 (2–41)
Mean (standard deviation)	15.7 (9.77)
Age 2–9	14 (28 %)
Age 10–19	23 (46 %)
Age ≥ 20	12 (24 %)
Age unknown	1 (2 %)
Sex
Male	28 (56 %)
Female	22 (44 %)
Seriousness b
Visit to emergency department or doctor’s office	22 (44 %)
Other medically important condition	4 (8 %)
Hospitalized	1 (2 %)
Recovered
Yes	43 (86 %)
Unknown	7 (14 %)
No	0
Onset interval of syncope (minutes)
Median (range)	10 (0–240)
Mean (standard deviation)	24.8 (48.71)
Onset ≤15 min	37 (74 %)
15 < Onset ≤30 min	3 (6 %)
30 < Onset ≤60 min	3 (6 %)
Onset >60 min	4 (8 %)
Onset unknown	3 (6 %)
Waited for at least 15 min after vaccination
Yes	24 (48 %)
Unknown	19 (38 %)
No	7 (14 %)

^aSyncope 0 days after LAIV/LAIV4 as the sole vaccine listed on the Vaccine Adverse Event Reporting System (VAERS) report.

^bCode of Federal Regulations. 21 15 600.80 [16]. “Other medically important condition” is a designation on reports from the vaccine manufacturer. Seriousness criteria are not mutually exclusive.

The vast majority of syncopal events (37; 74 %) occurred within 15 min post-vaccination, and almost all (43; 86 %) occurred within one hour (Table 1). Fewer than half of patients (24; 48 %) waited in the clinic or observation area for at least 15 min, although more than one-third of reports (19; 38 %) contained no information about waiting (Table 1). Of the 15 events that were associated with injury, 13 (87 %) occurred within 15 min of vaccination, and 12 (80 %) individuals were still in the vaccination facility or observation area (data not shown). Four people (8 %) had a history of syncope associated with vaccinations or injections, including an individual who had previously fainted following LAIV.

Fifteen people (30 %) were injured, most commonly by falling and hitting their head or face. There were no reports of death due to syncope-related injury. One person was hospitalized. Fifteen minutes after LAIV administration, a 13-year-old girl fell in the waiting room, hit her head, and was sent to the emergency department via ambulance. Physical examination revealed parietal tenderness but no laceration. Computerized tomography (CT) of the head revealed a hematoma of the parietal scalp, small contrecoup punctate subarachnoid temporoparietal hemorrhage, and trace edema, with no evidence of fracture, subdural or epidural hemorrhage, or shift. After being hospitalized overnight for observation, she recovered and was discharged home.

Twenty-one other people required a visit to the emergency department, including an individual who was in a motor vehicle accident. Five minutes after LAIV, a 28-year-old man experienced syncope while he was driving home from the vaccination appointment. He did not report any injuries, but the car was severely damaged (deemed a total loss by the insurance company). Four reports from the manufacturer of LAIV/LAIV4 described other medically important conditions [16], but only one described an injury: an adult fell, and her head struck the floor. She required medical attention, including head CT that did not reveal any acute findings.

Of the 50 reports of syncope, 43 stated that the person had recovered by the time the report was submitted, and 7 reports did not indicate recovery status. Treatment of syncope included observation, repositioning, and encouraging the person to eat or drink. Of the events that were not deemed to be vasovagal syncope, most were near-syncope, allergic reactions, seizures, or other conditions (e.g., migraine headache). Notably, near-syncope was sometimes associated with falls or other injuries, i.e., people who experienced vasovagal responses sometimes fell, even if they did not actually lose consciousness.

3.1. Data mining

Data mining for LAIV/LAIV4 did not identify disproportional reporting or elevated values [17,18] for syncope or related MedDRA Preferred Terms.

4. Discussion

Our review demonstrates that post-vaccination syncope is not necessarily related to an injection. Some individuals may experience a vasovagal reaction in response to the sensation of cold fluid on the nose or nervousness about a medical procedure—even one that is not expected to be painful. Our results suggest that syncope following LAIV/LAIV4 is uncommon, with a reporting rate of 0.4 per million doses, based on approximately 111.9 million doses of LAIV distributed in the US during the same time period (data shown with permission of Medlmmune).

Syncope following vaccination most commonly occurs within 15 min following vaccine administration [9]. ACIP [9] and AAP [10] recommend several steps for reducing the risk of injury related to post-vaccination syncope (Table 2). In our review, most cases of syncope after LAIV/LAIV4 occurred within 15 min of vaccination. Of the individuals who experienced syncope-related injury, most were still within the observation area. Our results suggest that adherence to the recommendations—particularly ensuring that people remain seated or lying down—may help to prevent injuries.

Table 2.

Recommendations for reducing the risk syncope-related injuries.^a,b

Providers should take appropriate measures to prevent injuries if weakness, dizziness, or loss of consciousness occurs. Patients should be seated or lying down during vaccination, since syncope can occur without any presyncopal symptoms or signs. CDCa: Vaccine providers should consider observing patients (with patients seated or lying down) for 15 min after vaccination to decrease the risk for injury should they faint. AAPb: A 15-min observation period (with the patient sitting or lying down) is advised after all vaccine administration to avoid the risk of injury if syncope occurs. If syncope occurs, patients should be observed until the symptoms resolve.

^aAdvisory Committee on Immunization Practices [9].

^bAmerican Academy of Pediatrics [10].

In order to evaluate a possible association with vasovagal reactions after LAIV/LAIV4, we restricted our review to include reports of syncope after LAIV/LAIV4 given as the sole vaccine. Based on an automated search covering the same time period, VAERS contains 152 reports of syncope 0 days after LAIV/LAIV4 with a concomitant vaccine/injection (data not shown). Although syncope may be attributed to the injection, it is also possible that LAIV/LAIV4 contributed to the development of symptoms. The manufacturer’s package insert lists syncope in the Postmarketing Experience section [19].

Strengths of VAERS include its national scope, timeliness, ability to detect events that were not observed during prelicensure trials, and surveillance among special populations [14]. However, passive surveillance systems such as VAERS are subject to many limitations, including underreporting, incomplete information, inadequate data regarding the numbers of doses administered, and lack of direct and unbiased comparison groups [14,15]. Because of these and other limitations, it is usually not possible to verify causal associations between vaccines and adverse events from spontaneous reports to VAERS. Nevertheless, VAERS data have been used to describe a range of potential vaccine adverse events and to look for unexpected patterns in demographics and clinical characteristics that might lead to hypotheses that can be tested with epidemiologic studies [20].

5. Conclusion

Vaccination remains the single best defense against influenza and its complications [13]. Routine postmarketing safety surveillance of LAIV/LAIV4 has not identified any unusual or unexpected safety signals. With more than 20 years’ worth of use in the general public, LAIV/LAIV4 is an important option for active immunization against influenza. Our review found that syncope after LAIV/LAIV4 is rare, and related injuries are even less common. Nevertheless, since syncope-related injuries are potentially preventable, we believe that the information summarized here may enable clinicians, patients, and caregivers to make a more informed decision regarding preventing injuries that may occur following LAIV-related syncope.

Data availability

A redacted version of the VAERS dataset is publicly available.