As of January 3, 2021, a total of 20,346,372 cases of coronavirus disease 2019 (COVID-19)
and 349,246 associated deaths have been reported in the United States. Long-term sequalae
of COVID-19 over the course of a lifetime currently are unknown; however, persistent
symptoms and serious complications are being reported among COVID-19 survivors, including
persons who initially experience a mild acute illness.* On December 11, 2020, the
Food and Drug Administration (FDA) issued an Emergency Use Authorization (EUA) for
Pfizer-BioNTech COVID-19 vaccine to prevent COVID-19, administered as 2 doses separated
by 21 days. On December 12, 2020, the Advisory Committee on Immunization Practices
(ACIP) issued an interim recommendation for use of Pfizer-BioNTech COVID-19 vaccine
(
1
); initial doses were recommended for health care personnel and long-term care facility
residents (
2
). As of December 23, 2020, a reported 1,893,360 first doses of Pfizer-BioNTech COVID-19
vaccine had been administered in the United States, and reports of 4,393 (0.2%) adverse
events after receipt of Pfizer BioNTech COVID-19 vaccine had been submitted to the
Vaccine Adverse Event Reporting System (VAERS). Among these, 175 case reports were
identified for further review as possible cases of severe allergic reaction, including
anaphylaxis. Anaphylaxis is a life-threatening allergic reaction that does occur rarely
after vaccination, with onset typically within minutes to hours (
3
). Twenty-one cases were determined to be anaphylaxis (a rate of 11.1 per million
doses administered), including 17 in persons with a documented history of allergies
or allergic reactions, seven of whom had a history of anaphylaxis. The median interval
from vaccine receipt to symptom onset was 13 minutes (range = 2–150 minutes). Among
20 persons with follow-up information available, all had recovered or been discharged
home. Of the remaining case reports that were determined not to be anaphylaxis, 86
were judged to be nonanaphylaxis allergic reactions, and 61 were considered nonallergic
adverse events. Seven case reports were still under investigation. This report summarizes
the clinical and epidemiologic characteristics of case reports of allergic reactions,
including anaphylaxis and nonanaphylaxis allergic reactions, after receipt of the
first dose of Pfizer-BioNTech COVID-19 vaccine during December 14–23, 2020, in the
United States. CDC has issued updated interim clinical considerations for use of mRNA
COVID-19 vaccines currently authorized in the United States (
4
) and interim considerations for preparing for the potential management of anaphylaxis
(
5
). In addition to screening for contraindications and precautions before administering
COVID-19 vaccines, vaccine locations should have the necessary supplies available
to manage anaphylaxis, should implement postvaccination observation periods, and should
immediately treat persons experiencing anaphylaxis signs and symptoms with intramuscular
injection of epinephrine (
4
,
5
).
CDC and FDA received notification of suspected anaphylaxis cases through multiple
channels, including direct outreach by health care providers and public health officials
and reports to VAERS, the national passive surveillance (spontaneous reporting) system
for adverse events after immunization, which is jointly operated by CDC and FDA (
6
). All notifications of suspected anaphylaxis that came to the attention of CDC or
FDA were also captured in VAERS. CDC physicians screened VAERS reports describing
suspected severe allergic reactions and anaphylaxis and applied Brighton Collaboration
case definition criteria (
7
), which use combinations of symptoms to define levels of diagnostic certainty to
identify cases with sufficient evidence to warrant further assessment for anaphylaxis.
Brighton level 1 represents the highest level of diagnostic certainty that a reported
case is indeed a case of anaphylaxis; levels 2 and 3 represent successively lower
levels of diagnostic certainty. Level 4 is a case reported as anaphylaxis but which
does not meet the Brighton Collaboration case definition. Level 5 is a case that was
neither reported as anaphylaxis nor meets the case definition. Reports with sufficient
evidence to suggest anaphylaxis were followed up by direct outreach, including telephoning
contacts listed in the VAERS report to gather additional clinical details (e.g., health
care facilities and treating health care providers, and, in some cases, vaccine recipients)
and collecting medical records. Physician reviewers also used their clinical judgment
to categorize reports that were considered not anaphylaxis as nonanaphylaxis allergic
reactions or nonallergic adverse events. Nonallergic adverse events, mostly vasovagal
or anxiety-related, were excluded from the analysis. Anaphylaxis and nonanaphylaxis
allergic reaction cases with symptom onset occurring later than the day after vaccination
(i.e., outside of the 0–1-day risk window) were also excluded because of the difficulty
in clearly attributing allergic reactions with onset later than this to vaccination.
†
CDC and FDA conducted joint review sessions to discuss and adjudicate cases. Because
the FDA EUA for the Moderna COVID-19 vaccine was received 1 week later than that for
the Pfizer-BioNTech vaccine (i.e., on December 18, 2020), and the Moderna vaccine
was only available beginning December 21, this report focuses on the Pfizer-BioNTech
COVID-19 vaccine. An assessment of adverse events reported after receipt of the Moderna
COVID-19 vaccine will be forthcoming.
During December 14–23, 2020, after administration of 1,893,360 first doses of Pfizer-BioNTech
COVID-19 vaccine (1,177,527 doses in females, 648,327 doses in males, and 67,506 doses
missing sex), reports of 4,393 (0.2%) adverse events after receipt of the vaccine
had been submitted to VAERS. Among these, 175 case reports were identified for further
review as possible cases of severe allergic reaction, including anaphylaxis, based
on descriptions of signs and symptoms; 21 of these reports met the Brighton Collaboration
case definition criteria for anaphylaxis, corresponding to an initial estimated rate
of 11.1 cases per million doses administered. All reports were Brighton levels 1 or
2 (Table 1). The median age of persons with anaphylaxis was 40 years (range = 27–60
years), and 19 (90%) cases occurred in females. The median interval from vaccine receipt
to symptom onset was 13 minutes (range = 2–150 minutes); 15 (71%) patients had onset
within 15 minutes, three (14%) within 15 to 30 minutes, and three (14%) after 30 minutes
(Figure). In 19 of 21 (90%) reports, patients were treated with epinephrine as part
of therapy; one patient received subcutaneous epinephrine and the remaining 18 were
confirmed or presumed to have received intramuscular epinephrine based on the report.
Four (19%) patients were hospitalized (including three in intensive care), and 17
(81%) were treated in an emergency department; 20 (95%) are known to have been discharged
home or had recovered at the time of report to VAERS. No deaths from anaphylaxis were
reported after receipt of Pfizer-BioNTech COVID-19 vaccine. Seventeen (81%) of 21
patients with anaphylaxis had a documented history of allergies or allergic reactions,
including to drugs or medical products, foods, and insect stings; seven (33%) patients
had experienced an episode of anaphylaxis in the past, including one after receipt
of a rabies vaccine and another after receipt of an influenza A(H1N1) vaccine (Table
2). No geographic clustering of anaphylaxis cases was observed, and the cases occurred
after receipt of doses from multiple vaccine lots. At the time of this report, investigators
have been unable to obtain sufficient information to confirm or rule out anaphylaxis
in seven cases despite follow-up efforts; these cases remain under investigation.
TABLE 1
Characteristics of reported cases of anaphylaxis (n = 21) after receipt of Pfizer-BioNTech
COVID-19 vaccine — Vaccine Adverse Events Reporting System (VAERS), United States,
December 14–23, 2020
Age (yrs)
Sex
Past history
Onset after receipt (mins)
Signs and symptoms
Treatment setting†
Epi received
Brighton level§
Outcome or disposition¶
Allergies or allergic reactions*
Anaphylaxis
27
F
Tropical fruit
No
2
Diffuse erythematous rash, sensation of throat closure
ED
Yes
2
Recovered at time of report
35
M
No
No
5
Diffuse erythematous rash, swollen tongue
ED
Yes
1
Discharged home
55
F
Rabies vaccine
Yes, rabies vaccine
5
Generalized urticaria, wheezing
Inpatient
Yes
1
Discharged home
52
F
Sulfa drugs
Yes, sulfa drugs
7
Wheezing, stridor, nausea
Inpatient
Yes
1
Discharged home
30
F
Bee sting
No
8
Generalized urticaria, wheezing
Inpatient
Yes
1
Recovered at time of report
32
F
No
No
10
Diffuse erythematous rash, difficulty breathing
Inpatient
Yes
2
Discharged home
60
F
Eggs, milk, sulfa drugs, jellyfish sting
Yes, jellyfish sting
10
Diffuse erythematous rash, hoarseness
ED
Yes
2
Recovered at time of report
29
F
Shellfish, eggs
No
10
Generalized urticaria, swollen lips and tongue
ED
Yes
1
Discharged home
52
F
Metoprolol, clarithromycin
No
10
Generalized urticaria, stridor, wheezing
ED
Yes
1
Recovered at time of report
49
F
Iodinated contrast media
No
13
Generalized urticaria, swollen throat
ED
Yes
1
Recovered at time of report
36
F
No
No
13
Generalized urticaria, nausea
ED
Yes
2
Not specified
40
F
Sulfa drugs, walnuts
Yes, walnuts
14
Generalized urticaria, nausea
ED
Yes
2
Discharged home
33
F
Wasp sting
No
15
Diffuse erythematous rash, swollen lip
ED
Yes
1
Recovered at time of report
41
F
Prochlorperazine
Yes, prochlorperazine
15
Diffuse erythematous rash, persistent dry cough
ED
No
2
Discharged home
57
F
Penicillin, azithromycin
Yes, unspecified
15
Diffuse pruritic rash, hoarseness
ED
Yes
2
Recovered at time of report
45
M
No
No
23
Generalized urticaria, swollen airway
ED
Yes
2
Discharged home
46
F
Hydrocodone, nuts
No
25
Diffuse erythematous rash, difficulty swallowing
ED
Yes
2
Discharged home
30
F
Cats, dogs
No
30
Generalized pruritis, wheezing
ED
No
2
Discharged home
44
F
Influenza A(H1N1) vaccine
Yes, influenza A(H1N1) vaccine
34
Generalized urticaria, swollen lips
ED
Yes
1
Discharged home
29
F
Sulfa drugs
No
54
Generalized urticaria, persistent cough
ED
Yes
2
Recovered at time of report
29
F
Steroids
No
150
Diffuse pruritic rash, swollen lip
ED
Yes
1
Discharged home
Abbreviations: COVID-19 = coronavirus disease 2019; ED = emergency department; epi
= epinephrine; F = female; M = male.
* As documented in the VAERS report or medical records, or through confirmation with
the treating health care provider or the patients themselves.
† Inpatient = inpatient hospitalization.
§ The Brighton Collaboration case definition uses combinations of symptoms to define
levels of diagnostic certainty. Brighton Level 1 represents the highest level of diagnostic
certainty that a reported case is indeed a case of anaphylaxis; Levels 2 and 3 are
successively lower levels of diagnostic certainty. Level 4 is a case reported as anaphylaxis
but that does not meet the Brighton Collaboration case definition. Level 5 is a case
that was neither reported as anaphylaxis nor meets the case definition (https://doi.org/10.1016/j.vaccine.2007.02.064).
¶ As documented in the description of the adverse event in the VAERS report in Box
18 or as document in recovery status in Box 20.
FIGURE
Interval (minutes) from vaccine receipt to onset of anaphylaxis (A)* and nonanaphylaxis
allergic reactions (B)
†
after receipt of Pfizer-BioNTech COVID-19 vaccine — Vaccine Adverse Events Reporting
System, United States, December 14–23, 2020
Abbreviation: COVID-19 = coronavirus disease 2019.
* The interval from vaccine receipt to symptom onset was >30 minutes for three anaphylaxis
cases (34, 54, and 150 minutes).
† The interval from vaccine receipt to symptom onset was >60 minutes for three nonanaphylaxis
patients who had a documented history of allergies or allergic reactions at 90, 96,
and 180 minutes and for three who did not have a documented history of allergies or
allergic reactions (105 minutes, 137 minutes, and 20 hours). Interval from vaccine
receipt to symptom onset was missing for four patients with a history of allergies
or allergic reactions and for seven without such history. Three cases of nonanaphylaxis
allergic reactions with symptom onset occurring later than the day after vaccination
(i.e., outside of the 0–1-day risk window) were excluded from the final analysis.
The figure is a histogram showing the interval (minutes) from vaccine receipt to onset
of anaphylaxis (A) and nonanaphylaxis allergic reactions (B) after receipt of Pfizer-BioNTech
COVID-19 vaccine, using data from the Vaccine Adverse Events Reporting System, in
the United States, during December 14–23, 2020.
TABLE 2
Characteristics of patients with report of anaphylaxis and nonanaphylaxis allergic
reactions after receipt of Pfizer-BioNTech COVID-19 vaccine — Vaccine Adverse Events
Reporting System (VAERS), United States, December 14–23, 2020
Characteristic
Type of reported reaction, no. (%)
Anaphylaxis (n = 21)
Nonanaphylaxis allergic reactions (n = 83)*
Median age, yrs (range)
40 (27–60)
43 (18–65)
Female
19 (90)
75 (90)
Mins to symptom onset, median (range)
13 (2–150)
12 (<1–1,200 [20 hrs])
Symptom onset ≤15 mins
15 (71)
44 (61)†
Symptom onset ≤30 mins
18 (86)
61 (85)†
Documented history of allergies or allergic reactions
17 (81)§
56 (67)
Abbreviation: COVID-19 = coronavirus disease 2019.
* Three of the initial 86 nonanaphylaxis allergic reaction reports were excluded from
the final analysis because symptom onset occurred later than the day after vaccination
(i.e., outside of the 0–1-day risk window).
† Eleven reports were missing information on time of symptom onset; percentage calculated
among 72 patients.
§ Seven anaphylaxis patients reported a history of a previous anaphylaxis episode,
including one after receipt of rabies vaccine and one after receipt of influenza A(H1N1)
vaccine.
During the same period, VAERS identified 83 cases of nonanaphylaxis allergic reaction
after Pfizer-BioNTech COVID-19 vaccination with symptom onset within the 0–1-day risk
window, 72 (87%) of which were classified as nonserious.
§
Commonly reported symptoms included pruritus, rash, itchy and scratchy sensations
in the throat, and mild respiratory symptoms. The median patient age was 43 years
(range = 18–65 years), and 75 (90%) reported reactions occurred in women. The median
interval from vaccine receipt to symptom onset was 12 minutes (range = <1 minute–20
hours); in 61 (85%) cases, onset occurred within 30 minutes, in 11 cases, onset occurred
after 30 minutes, and for 11 cases, time of onset was missing. For 56 (67%) case reports,
a past history of allergies or allergic reactions was documented (Table 2) (Figure).
Discussion
Early safety monitoring of the Pfizer-BioNTech COVID-19 vaccine has detected 21 cases
of anaphylaxis after reported administration of 1,893,360 first doses of Pfizer-BioNTech
COVID-19 vaccine (11.1 cases per million vaccine doses administered) as well as cases
of less severe nonanaphylaxis allergic reactions, based on U.S. data for December
14–23, 2020. Most (86%) anaphylaxis cases had symptom onset within 30 minutes of vaccination,
and most persons with anaphylaxis (81%) had a history of allergies or allergic reactions,
including some with previous anaphylaxis events; up to 30% of persons in the general
population might have some type of allergy or history of allergic reactions.
¶
Most (90%) reported anaphylaxis cases after receipt of Pfizer-BioNTech COVID-19 vaccine
occurred in women, although 64% of the vaccine doses administered with sex of recipient
recorded were given in women. Whereas a female predominance has been previously observed
in a review of immediate hypersensitivity reports to VAERS after influenza A(H1N1)
vaccine (
8
), the current finding could be impacted by the observation that more women than men
had received a first dose of Pfizer-BioNTech COVID-19 vaccine during the analytic
period. Anaphylaxis is potentially life-threatening and requires immediate treatment
(
5
). Based on early safety monitoring, anaphylaxis after the Pfizer-BioNTech COVID-19
vaccine appears to be a rare event; however, comparisons of anaphylaxis risk with
that associated with non-COVID-19 vaccines are constrained at this time by the limited
data available this early in the COVID-19 vaccination program. CDC and FDA will continue
enhanced monitoring for anaphylaxis among recipients of COVID-19 vaccines.
The findings in this report are subject to at least four limitations. First, the anaphylaxis
and nonanaphylaxis allergic reaction case reports were gathered through passive surveillance
based on spontaneous reports to VAERS. Spontaneous reporting is subject to reporting
biases (including underreporting); however, the reporting efficiency to VAERS for
clinically severe adverse events is believed to be high (
9
). A second potential source of bias arises from stimulated reporting related to increased
public and health care provider awareness of a potential safety concern. Thus, it
is possible that intense media attention around the national COVID-19 vaccination
program and heightened awareness of reports of anaphylaxis have affected vaccine recipient
and health care provider behavior and practices, including elevated concern and anxiety,
higher index of suspicion for anaphylaxis, and lower threshold for early treatment
of suspected cases, thereby resulting in an increase in diagnosis of suspected anaphylaxis
and corresponding stimulated above-baseline reporting to VAERS. Third, it is possible
that data lags and incomplete reporting of vaccine doses administered might underestimate
the denominator (doses administered) relative to the numerator (anaphylaxis cases).
If anaphylaxis cases after receipt of COVID-19 vaccine are identified and reported
faster than vaccine doses administered are reported, the anaphylaxis rate associated
with vaccination might be overestimated. Finally, the focus on the Pfizer-BioNTech
COVID-19 vaccine is a function of the timing of product availability and doses administered.
Data on the Moderna vaccine, which became available a week later, were limited. Vaccination
with Moderna COVID-19 vaccine commenced on December 21, 2020, and through December
23, 2020, an estimated 224,322 first doses of the vaccine had been administered; one
report that met the Brighton Collaboration case definition criteria for anaphylaxis
had been submitted to VAERS.
Mortality from COVID-19 in populations at high risk is substantial (
10
), and treatment options are limited. Widespread vaccination against COVID-19 with
highly effective vaccines represents an important tool in efforts to control the pandemic.
CDC and FDA will continue to monitor for adverse events, including anaphylaxis, after
receipt of COVID-19 vaccines and will regularly assess the benefits and risks of vaccination
in the context of the evolving epidemiology of the pandemic. Continued monitoring
in VAERS and additional monitoring in population-based surveillance systems, such
as the CDC’s Vaccine Safety Datalink (https://www.cdc.gov/vaccinesafety/ensuringsafety/monitoring/vsd/index.html),
will help to further characterize the risk for anaphylaxis after administration of
COVID-19 vaccines. CDC guidance on use of mRNA COVID-19 vaccines and management of
anaphylaxis is available (
4
,
5
). Specifically, vaccination locations should 1) ensure that necessary supplies are
available to manage anaphylaxis, especially sufficient quantities of epinephrine in
prefilled syringes or autoinjectors; 2) screen potential vaccine recipients to identify
persons with contraindications and precautions (
4
); 3) implement recommended postvaccination observation periods, either 15 or 30 minutes
depending on each patient’s previous history of allergic reactions; 4) ensure that
health care providers can recognize the signs and symptoms of anaphylaxis early; and
5) immediately treat suspected anaphylaxis with intramuscular epinephrine; because
of the acute, life-threatening nature of anaphylaxis, there are no contraindications
to epinephrine administration. Patients experiencing anaphylaxis should be transported
to facilities where they can receive appropriate medical care (
5
). All patients should be instructed to seek immediate medical care if they develop
signs or symptoms of an allergic reaction after their observation period ends and
they have left the vaccination location. Health care providers can play an important
role in vaccine safety by being vigilant in recognizing and reporting adverse events
after immunization to VAERS at https://vaers.hhs.gov/reportevent.html.
Summary
What is already known about this topic?
Anaphylaxis is a severe, life-threatening allergic reaction that occurs rarely after
vaccination.
What is added by this report?
During December 14–23, 2020, monitoring by the Vaccine Adverse Event Reporting System
detected 21 cases of anaphylaxis after administration of a reported 1,893,360 first
doses of the Pfizer-BioNTech COVID-19 vaccine (11.1 cases per million doses); 71%
of these occurred within 15 minutes of vaccination.
What are the implications for public health practice?
Locations administering COVID-19 vaccines should adhere to CDC guidance for use of
COVID-19 vaccines, including screening recipients for contraindications and precautions,
having the necessary supplies available to manage anaphylaxis, implementing the recommended
postvaccination observation periods, and immediately treating suspected cases of anaphylaxis
with intramuscular injection of epinephrine.