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Special Article

mRNA Vaccines to Prevent COVID-19 Disease and

Reported Allergic Reactions: Current Evidence and
Suggested Approach
Aleena Banerji, MDa,b, Paige G. Wickner, MD, MPHb,c, Rebecca Saff, MD, PhDa,b, Cosby A. Stone, Jr., MD, MPHd,
Lacey B. Robinson, MD, MPHa,b, Aidan A. Long, MDa,b, Anna R. Wolfson, MDa,b, Paul Williams, MDe, David A. Khan, MDf,
Elizabeth Phillips, MDd,*, and Kimberly G. Blumenthal, MD, MSca,b,g,* Boston, Mass; Nashville, Tenn; Seattle, Wash; and
Dallas, Texas

The U.S. Food and Drug Administration (FDA) has recently guidance of public health and regulatory authorities. The risk
issued an Emergency Use Authorization (EUA) for 2 highly stratification schema guide care for (1) individuals with different
effective coronavirus disease 2019 (COVID-19) vaccines from allergy histories to safely receive their first mRNA COVID-19
Pfizer-BioNTech and Moderna. This has brought hope to vaccine and (2) individuals who develop a reaction to their first
millions of Americans in the midst of an ongoing global dose of mRNA COVID-19 vaccine. Ó 2020 American Academy
pandemic. The FDA EUA guidance for both vaccines is to not of Allergy, Asthma & Immunology (J Allergy Clin Immunol
administer the vaccine to individuals with a known history of a Pract 2021;9:1423-37)
severe allergic reaction (eg, anaphylaxis) to any component of the
COVID-19 vaccine. The Centers for Disease Control and Key words: mRNA; COVID-19; Vaccine; Allergy; Allergic re-
Prevention (CDC) additionally advises individuals with a history actions; Anaphylaxis; Guidelines; Risk stratification; Poly-
of an immediate allergic reaction to a vaccine or injectable or any ethylene glycol; Polysorbate
history of anaphylaxis be observed for 30 minutes after COVID-
19 vaccination. All other individuals should be observed for 15
minutes after COVID-19 vaccination. Staff at vaccine clinics INTRODUCTION
must be able to identify and manage anaphylaxis. PosteFDA Vaccination, one of the most effective public health in-
EUA, despite very strong safety signals in both phase 3 trials, terventions modern medicine can offer, has become increasingly
reports of possible allergic reactions have raised public concern. relevant as the global pandemic from coronavirus disease 2019
To provide reassurance and support during widespread global (COVID-19) continues to worsen throughout the world. In the
vaccination, allergists must offer clear guidance to individuals United States, the pandemic has risen to crisis levels in every
based on the best information available, but also in accordance state, setting records with tens of thousands of new cases reported
with the broader recommendations of regulatory agencies. This daily and deaths mounting. As of January 9, 2021, more than 89
review summarizes vaccine allergy epidemiology and proposes million people globally have had confirmed infections and almost
drug and vaccine allergy expert opinion informed risk 2 million have died of COVID-19.1 Medical necessities are often
stratification for Allergy specialist use in conjunction with in short supply, hospitals are overwhelmed, and health care

a
Division of Rheumatology, Allergy and Immunology, Department of Medicine, Vertex, Regeneron, and Biocryst; is codirector of IIID Pty Ltd, which holds a
Massachusetts General Hospital, Boston, Mass patent for HLA-B*57:01 testing for abacavir hypersensitivity, and has a patent
b
Harvard Medical School, Boston, Mass pending for Detection of Human Leukocyte Antigen-A*32:01 in connection with
c
Division of Allergy and Immunology, Department of Medicine, Brigham and Diagnosing Drug Reaction with Eosinophilia and Systemic Symptoms without
Women’s Hospital, Boston, Mass any financial remuneration and not directly related to the submitted work. Funders
d
Department of Medicine, Vanderbilt University Medical Center, Nashville, Tenn played no role in any aspect of this review. The rest of the authors declare that they
e
Allergy Division, University of Washington School of Medicine, Seattle, Wash have no relevant conflicts of interest.
f
Division of Allergy & Immunology, Department of Internal Medicine, University of Received for publication December 28, 2020; accepted for publication December 28,
Texas Southwestern Medical Center, Dallas, Texas 2020.
g
Edward P. Lawrence Center for Quality and Safety, Massachusetts General Hos- Available online December 31, 2020.
pital, Boston, Mass Corresponding author: Aleena Banerji, MD, Division of Rheumatology, Allergy and
* Co-senior authors. Immunology, Department of Medicine, Massachusetts General Hospital, Cox 201,
No funding was received for this work. 100 Blossom Street, Boston, MA 02114. E-mail: [email protected].
Conflicts of interest: E. Phillips reports grants from the National Institutes of Health 2213-2198
(grant nos. P50GM115305, R01HG010863, R01AI152183, R21AI139021, and Ó 2020 American Academy of Allergy, Asthma & Immunology
U01AI154659) and from the National Health and Medical Research Council of https://doi.org/10.1016/j.jaip.2020.12.047
Australia; receives Royalties from Uptodate and consulting fees from Janssen,

1423
1424 BANERJI ET AL J ALLERGY CLIN IMMUNOL PRACT
APRIL 2021

and effectiveness of these vaccines in children under 16 years of

Abbreviations used age but studies are ongoing.
CDC- Centers for Disease Control and Prevention Before FDA EUA of a COVID-19 vaccine, the United
COVID-19- Coronavirus disease 2019 Kingdom Commission on Human Medicines initiated its
EUA- Emergency Use Authorization
COVID-19 vaccination program using the Pfizer-BioNTech
FDA- Food and Drug Administration
PEG- Polyethylene glycol
vaccine. Within 48 hours, there were 2 reports of severe
SARS-CoV-2- Severe acute respiratory syndrome coronavirus 2 allergic reactions in the United Kingdom that prompted treat-
VAERS- Vaccine adverse event reporting System ment with epinephrine. These reported allergic reactions led to a
closer review of the Pfizer-BioNTech clinical trial data by the
FDA. The Pfizer-BioNTech trial excluded patients with a pre-
vious history of severe adverse reactions associated with any
workers are exhausted after months of fighting an uphill battle. vaccine, and both the Pfizer-BioNTech and Moderna trials
Given the importance of the vaccine in fighting this public health further excluded severe allergic reaction (eg, anaphylaxis) to any
crisis, understanding the allergic reactions with the approved component of their COVID-19 vaccine. Hypersensitivity-related
mRNA COVID-19 vaccines is crucial. At the time of writing this adverse events were observed in 0.63% of Pfizer-BioNTech and
review, immediate reactions clinically compatible with anaphy- 1.5% of Moderna vaccine clinical trial participants who received
laxis have occurred at a rate of 11.1 per million doses of the the vaccine, compared with 0.51% and 1.1%, respectively, in the
Pfizer-BioNTech mRNA COVID-19 vaccine.2 Anaphylaxis has placebo groups. One case of anaphylaxis and 1 drug hypersen-
also been reported from the Moderna mRNA COVID-19 vac- sitivity reaction were reported in the Pfizer-BioNTech trial,6 and
cine. Currently, the specific mechanism of allergy and the 2 cases of delayed hypersensitivity reactions were reported in the
inciting antigen have not been identified. This review will Moderna trial.5 Only 1 of the Moderna delayed allergic reactions
summarize the current state of knowledge of immediate allergic was in the vaccine group, and, because it occurred several months
reactions associated with the mRNA vaccines and potential after vaccination, it was unlikely to be related to the vaccine.
mechanisms of hypersensitivity. We provide recommendations Also, in the Moderna trial, there were 3 events of lip/face
based on expert opinion using the currently available evidence to swelling 1 to 2 days after vaccination but exclusively in patients
facilitate safe vaccination based on updated epidemiology and with a history of dermal fillers but unclear from which manu-
guidance provided by the Centers for Disease Control and Pre- facturer. There were no anaphylactic or severe hypersensitivity
vention (CDC), US Food and Drug Administration (FDA) and reactions reported with close temporal relation to administration
other regulatory agencies. The information provided in this of the Moderna vaccine.
manuscript is intended as guidance and a framework for the
practicing Allergist based on the best available evidence at the
time. Although it is expected to have global relevance it does not US REGULATORY APPROVAL AND GUIDANCE
replace or override any guidance provided by public health or The FDA EUA guidance for the Pfizer-BioNTech COVID-
regulatory agencies.3 19 vaccine specifies “do not administer Pfizer-BioNTech
COVID-19 vaccine to individuals with known history of a se-
vere allergic reaction (eg, anaphylaxis) to any component of the
CLINICAL TRIAL DATA
Pfizer-BioNTech COVID-19 vaccine.” Given the reported re-
The US FDA’s Emergency Use Authorization (EUA) of 2
actions in health care workers, the US CDC subsequently
highly effective COVID-19 vaccines in December 2020 was a
advised that all patients—regardless of allergy history— should
landmark in the pandemic response for Americans. The Pfizer-
be observed for 15 minutes after COVID-19 vaccination and
BioNTech 2-dose COVID-19 vaccine regimen given on day
that vaccination staff must be trained to manage anaphylaxis.
0 and 21 showed a 95% efficacy at preventing symptomatic
The CDC provided further recommendations “that persons who
COVID-19 infection, measured forward from 7 days after the
have had an immediate allergic reaction of any severity to any
second dose was administered.4 The vaccine appeared equally
vaccine or injectable therapy (intramuscular, intravenous, or
protective across age groups as well as racial and ethnic groups.4
subcutaneous) discuss the risk of receiving the vaccine with their
The Moderna 2-dose COVID-19 vaccine regimen given on day
doctors and be monitored for 30 minutes afterward.” In addi-
0 and 28 was 94% effective at preventing symptomatic COVID-
tion, patients who have an immediate (within 4 hours) or severe
19, measured from 14 days after the second dose onward.5 The
allergic reaction (eg, anaphylaxis) to an mRNA COVID-19
efficacy of the Moderna vaccine appeared to be slightly lower in
vaccine should not receive a second dose. CDC precautions
people 65 years and older, but it was equally effective across
and contraindications for the Moderna vaccine under EUA were
different racial and ethnic groups.5 The safety of both vaccines
the same as for the Pfizer-BioNTech vaccine for the purpose of
over a median of 2 months was similar to that of other viral
“harmonization.”3
vaccines. Severe systemic events were reported in less than 2% of
Pfizer-BioNTech vaccine recipients after either dose, except for
3.8% reporting fatigue and 2.0% reporting headache after the US POSTMARKETING EXPERIENCE
second dose. Most adverse events reported after receiving the Similar to the UK experience, within a few days of widespread
Moderna vaccine were mild or moderate in severity. A small vaccination of health care workers in the United States, several
number of participants reported systemic reactions lasting longer reports of presumed allergic reactions to the COVID-19 vaccine
than 7 days, but there was no difference between vaccine and emerged. At the time of publication, there have been 21
placebo groups. The Pfizer-BioNTech EUA is for individuals 16 confirmed anaphylactic reactions to the Pfizer-BioNTech vaccine
years and older, whereas Moderna is for individuals 18 years and across almost 1.9 million doses administered in the United
older. There are currently insufficient data for efficacy, safety, States.2 Of note, while 175 severe allergic reactions to the Pfizer-
J ALLERGY CLIN IMMUNOL PRACT BANERJI ET AL 1425
VOLUME 9, NUMBER 4

FIGURE 1. Chemical structure and similarities between PEG and polysorbate 80.

TABLE I. Ingredients of the Pfizer-BioNTech and Moderna COVID-19 vaccines

Ingredients Pfizer-BioNTech Moderna
Active Nucleoside-modified mRNA encoding the viral spike Nucleoside-modified mRNA encoding the viral spike
glycoprotein of SARS-CoV-2 glycoprotein of SARS-CoV-2
Inactive—lipids (4-hydroxybutyl)azanediyl)bis(hexane-6,1-diyl)bis(2- SM-102 (proprietary to Moderna)
hexyldecanoate)
2[(PEG)-2000]-N,N-ditetradecylacetamide PEG 2000 dimyristoyl glycerol
1,2-Distearoyl-sn-glycero-3-phosphocholine 1,2-Distearoyl-sn-glycero-3-phosphocholine
Cholesterol Cholesterol
Inactive—salts, sugars, buffers Potassium chloride, monobasic potassium phosphate, Tromethamin, Tromethamin hydrocholoride, acetid acid,
sodium chloride, dibasic sodium phosphate dehydrate sodium acetate
Sugar (sucrose) Sugar (sucrose)
Diluent (sodium chloride) Diluent (none)

BioNTech were identified, upon further review, only 21 were rare, vaccine reactions can cause substantial fear and anxiety in
consistent with anaphylaxis. This highlights the critically the general population and may contribute to decreased will-
important role for allergists in clinical phenotyping of these re- ingness to receive a COVID-19 vaccine. Additionally, not all
actions with subsequent risk stratification rather than vaccine immediate reactions that occur in association with vaccines are
avoidance. The majority of CDC-confirmed anaphylactic re- true allergic reactions (eg, flushing, transient dyspnea) and careful
actions (86%, 18/21) occurred within a 30-minute observation clinical phenotyping is necessary to prevent large-scale COVID-
window, and patients were treated immediately with complete 19 vaccine avoidance. This is apparent in the recent CDC report
resolution of symptoms. While there are more epidemiologic demonstrating that of 175 possible severe allergic reactions, 86
data currently available for the Pfizer-BioNTech vaccine, the (49%) were nonanaphylactic allergic reactions.2
authors have personal knowledge through clinical care of at least Confirmed allergic reactions to vaccines are not frequently
3 possible anaphylactic reactions to the Moderna COVID-19 attributed to the active ingredients, but rather to the inactive in-
vaccine. To date, there are no fatalities associated with reported gredients, or excipients, including egg protein, gelatin, formalde-
allergic reactions to any COVID-19 mRNA vaccine. hyde, thimerosal, or neomycin. Excipients are necessary and added
to a vaccine for specific purposes such as stimulating a stronger
immune response, preventing contamination by bacteria, or sta-
EPIDEMIOLOGY AND ETIOLOGY OF ALLERGIC bilizing the potency of the vaccine during transportation and
REACTIONS TO VACCINES storage. Excipients represent the major contributor to specific IgE-
Allergic reactions to vaccines are generally described as mediated and immediate reactions associated with vaccines.8 Ef-
occurring at a rate of 1.31 (95% CI, 0.90-1.84) cases per million forts to specifically decrease well-known excipients such as egg and
vaccine doses from a large population-based study, with no fa- gelatin in vaccines have been highly successful in reducing subse-
talities reported.7 Rates remain similar when stratified by age and quent allergic reactions.9,10 Other excipients, such as polyethylene
sex, although slightly higher frequencies have been observed in glycol (PEG) and polysorbate (Figure 1), are used to improve water
females.7 The incidence of allergic reaction by specific vaccine, solubility in drugs and vaccines. PEG itself has not previously been
however, is difficult to quantify in epidemiologic studies, because used in a vaccine, but polysorbate has been identified as a rare cause
often multiple vaccines are administered on the same day. The of allergic reactions to vaccines. First-dose reactions to vaccines
cases that followed the administration of a single vaccine involved containing polysorbates may have occurred because of previous
predominantly trivalent influenza vaccine, for which the rate of sensitization from polysorbate 80.11 The recently approved Pfizer-
reaction was estimated to be 1.35 (95% CI, 0.65-2.47) per BioNTech and Moderna COVID-19 mRNA vaccines are not
million vaccine doses.7 Of concern is that, although numerically formulated with any food, drugs, or latex, but both contain the
1426 BANERJI ET AL J ALLERGY CLIN IMMUNOL PRACT
APRIL 2021

TABLE II. Polysorbate and PEG excipients in select vaccines12

Excipient Vaccine type Vaccine Amount per dose
Polysorbate 20 Influenza Flublok&Flublock quad
27.5 mg (Tween20)
Polysorbate 20 Hepatitis A Havrix 0.05 mg/mL
Polysorbate 20 Hepatitis A&B Twinrix Unknown
Polysorbate 20* SARS-CoV-2 (Sanofi)
Polysorbate 80 Tdap Boostrix
100 mg (Tween 80)
Polysorbate 80 Influenza Fluad 1.175 mg
Polysorbate 80 Influenza Fluarix quad
0.055 mg (Tween 80)
Polysorbate 80 Influenza Flucelvax quad
1500 mg (Tween 80)
Polysorbate 80 Influenza Flulaval Quad
887 mg
Polysorbate 80 HPV Gardasil and Gardasil -9 50 mg
Polysorbate 80 Hepatitis B Heplisav-B 0.1 mg/mL
Polysorbate 80 DTaP Infanrix
100 mg (Tween 80)
Polysorbate 80 Japanese encephalitis JE-Vax <0.0007%
Polysorbate 80 DTaP þ IPV Kinrix
100 mg (Tween 80)
Polysorbate 80 DTaP þ HepB þ IPV Pediarix
100 mg (Tween 80)
Polysorbate 80 Pneumococcal 13-valent Prevnar 13 100 mg
Polysorbate 80 DTaP þ IPV Quadracel 10 ppm
Polysorbate 80 Rotavirus RotaTeq ?
Polysorbate 80 Zoster Shingrix 0.08 mg
Polysorbate 80 Meningococcal group B Trumenba 0.018 mg
Polysorbate 80 DTaP þ IPV þ HepB þ Hib Vaxelis <0.0056%
Polysorbate 80* SARS-CoV-2 (AstraZeneca)
SARS-CoV-2 (Johnson & Johnson)
PEG2000 SARS-CoV-2 (Moderna)
SARS-CoV-2 (Pfizer)

*Not approved at the time of publication.

TABLE III. Common injectable medications containing PEG14

Generic name (brand name) Molecular weight General description
Methylprednisolone acetate (Depo- PEG 3350 An anti-inflammatory glucocorticoid for intramuscular, intra-articular, soft
Medrol) tissue or intralesional injection
Methoxy polyethylene glycol-epoetin 30-kD methoxy PEG Used to treat anemia in adults with chronic kidney disease
beta (Micera) butanoic acid
Pegfilgrastim (Neulasta) 20-kD Used to help reduce the chance of infection due to a low white blood cell count,
monomethoxy PEG in people with certain types of cancer (nonmyeloid), who receive anticancer
medicines (chemotherapy) that can cause fever and low white blood cell
count
Medroxyprogesterone acetate (Depo- PEG 3350 Contraceptive and adjunctive therapy and palliative treatment of inoperable,
Provera) recurrent, and metastatic endometrial or renal carcinoma
Brilliant Blue G Ophthalmic Solution PEG 3350 Disclosing agent indicated to selectively stain the internal limiting membrane
(TissueBlue)
Sulfur hexafluoride (Lumason) PEG 4000 Ultrasound contrast agent
Biomatoprost implant (Durysta) PEG, unspecified Reduction of intraocular pressure in patients with open-angle glaucoma or
ocular hypertension
Trastuzumab (Herceptin, Herzuma, PEG 3350 Adjuvant treatment of HER2 overexpressing node-positive or node-negative
Kanjinti, Ogivri, Ontruzant) breast cancer
Rilonacept (Arcalyst) PEG 3350 IL-1 blocker for treatment of cryopyrin-associated periodic syndromes
Perflutren lipid microsphere (Definity) PEG 5000 Contrast agent used to brighten and clarify images of the heart during
echocardiograms

excipient PEG (Tables I and II) for the purpose of stabilizing the AstraZeneca and Johnson & Johnson COVID-19 vaccines
lipid nanoparticle containing the mRNA. The specific PEG in currently under development do not contain PEG but instead
these vaccines is different from the PEG used most commonly in contain the excipient polysorbate 80 (Table II).
other health care products, both in molecular weight and due to its Numerous FDA-approved and over-the-counter products
coformulation as a stabilizing portion of a liposome.11,13 The contain PEG, including medications, skin creams, and personal
J ALLERGY CLIN IMMUNOL PRACT BANERJI ET AL 1427
VOLUME 9, NUMBER 4

TABLE IV. Common injectable medications containing polysorbate

Drug class Generic name (brand name) Polysorbate
Antiarrhythmic Amiodarone hydrochloride (generics only) Polysorbate 80
Antidiabetic Exenatide (Bydureon Bcise) Polysorbate 20
Insuline glargine (Lantus, Semglee) Polysorbate 20
Insuline glulisine (Apidra) Polysorbate 20
Dulaglutide (Trulicity) Polysorbate 80
Antidote Hyaluronidase (Hylenex Recombinant) Polysorbate 80
Antifungal Anidulafungin (Eraxis) Polysorbate 80
Anti-inflammatory Interferon beta 1a (Avonex, Plegridy) Polysorbate 20
Omalizumab (Xolair) Polysorbate 20
Antineoplastic Ofatumumab (Kesimpta) Polysorbate 80
Siltuximab (Sylvant) Polysorbate 80
Antipsychotic Paliperidone palmitate (Invega Trinza, Invega Sustenna) Polysorbate 20
Aripiprazole lauroxil (Aristada) Polysorbate 20
Antiretroviral Ibalizumab (Trogarzo) Polysorbate 80
Antipsoriatic Adalimumab (Humira, Imraldi) Polysorbate 20 (Imraldi)/
Polysorbate 80 (Humira)
Golimumab (Simponi) Polysorbate 80
Guselkumab (Tremfya) Polysorbate 80
Infliximab - dyyb (Inflectra, Remicade, Renflexis) Polysorbate 80
Ustekinumab (Stelara) Polysorbate 80
Antiviral Interferon alfa-2b (Intron A) Polysorbate 80
Biological response modifier Interferon gamma-1b (Actimmune) Polysorbate 20
Cancer treatment Ado-trastuzumab emtansine (Kadcyla) Polysorbate 20
Atezolizumab (Tecentriq) Polysorbate 20
Avelumab (Bavencio) Polysorbate 20
Bevacizumab (Avastin, Zirabev) Polysorbate 20
Daratumumab/hyaluronidase (Darzalex Faspro) Polysorbate 20
Denosumab (Prolia, Xgeva) Polysorbate 20
Dinutuximab (Unituxin) Polysorbate 20
Enfortumab (Padcev) Polysorbate 20
Olaratumab (Lartruvo) Polysorbate 20
Palifermin (Kepivance) Polysorbate 20
Pertuzumab/trastuzumab/hyaluronidase (Phesgo) Polysorbate 20
Polatuzumab vedotin (Polivy) Polysorbate 20
Tafasitamab (Monjuvi) Polysorbate 20
Trastuzumab (Herceptin, Herceptin Hylecta, Polysorbate 20
Herzuma, Kanjinti, Ontruzant, Trazimera)
Belantamab (Blenrep) Polysorbate 80
Brentuximab vedotin (Adcetris) Polysorbate 80
Cemiplimab (Libtayo) Polysorbate 80
Docetaxel (Taxotere) Polysorbate 80
Durvalumab (Imfinzi) Polysorbate 80
Elotuzumab (Empliciti) Polysorbate 80
Etoposide (Toposar, VePesid) Polysorbate 80
Fam-trastuzumab deruxtecan (Enhertu) Polysorbate 80
Fosaprepitant dimeglumine (EMEND, Fosaprepitant) Polysorbate 80
Inotuzumab ozogamicin (Besponsa) Polysorbate 80
Ipilimumab (Yervoy) Polysorbate 80
Isatuximab (Sarclisa) Polysorbate 80
Mogamulizumab (Poteligeo) Polysorbate 80
Moxetumomab pasudotox (Lumoxiti) Polysorbate 80
Nivolumab (Opdivo) Polysorbate 80
Ofatumumab (Arzerra) Polysorbate 80
Pembrolizumab (Keytruda) Polysorbate 80
(continued)
1428 BANERJI ET AL J ALLERGY CLIN IMMUNOL PRACT
APRIL 2021

TABLE IV. (Continued)

Drug class Generic name (brand name) Polysorbate
Ramucirumab (Cyramza) Polysorbate 80
Rituximab (Truxima, Rituxan, Ruxience) Polysorbate 80
Rituximab and hyaluronidase (Rituxan Hycela) Polysorbate 80
Temsirolimus (Torisel) Polysorbate 80
Temozolomide (Temodar) Polysorbate 80
Contraceptive Medroxyprogesterone acetate (Depo-Provera, Depo- Polysorbate 80
Provera CI, Depo-subQ provera 104)
Corticosteroid Methylprednisolone acetate (Depo-Medrol) Polysorbate 80
Triamcinolone acetonide (Aristocort Forte, Aristospan, Polysorbate 80
Kenalog-40, Kenalog-10, Protherix, Triesence,
Triloan Suik, Triloan II Suik, Zilretta)
Diagnostic Sincalide (Kinevac) Polysorbate 20
Tuberculin purified protein derivative (Aplisol, Polysorbate 80
Tubersol)
Disease-modifying antirheumatic drug Anakinra (Kineret) Polysorbate 80
Tocilizumab (Actemra) Polysorbate 80
Enzyme Velaglucerase alfa (Vpriv) Polysorbate 20
Imiglucerase (Cerezyme) Polysorbate 80
Taliglucerase alfa (Elelyso) Polysorbate 80
Erythoid maturation agent Luspatercept (Reblozyl) Polysorbate 80
Factor Xa inhibitor antidote Coagulation factor Xa (recombinant), inactivated-zhzo Polysorbate 80
(Andexxa)
Gonadotropin Follitropin (Menopur, Follistim) Polysorbate 20
Growth hormone analog Somatropin (Nutropin AQ Nuspin 5) Polysorbate 20
Hematopoietic growth factor Erythropoietin (Retacrit) Polysorbate 20
Pegfilgrastim (Fulphila, Neulasta, Nyvepria, Udenyca) Polysorbate 20
Romiplostim (Nplate) Polysorbate 20
Darbepoetin alfa (Aranesp) Polysorbate 80
Filgrastim (Neupogen, Nivestym, Granix, Zarxio) Polysorbate 80
Hepatitis B/Hepatitis C agent Peginterferon (Pegasys Pegintron) Polysorbate 80
Hemostatic Vitamin K (Phytonadione) Polysorbate 80
Immune globulin Hepatitis B immune globulin (HepaGam B, Nabi-HB) Polysorbate 80
Rho (d) immune globulin (WinRho) Polysorbate 80
Immunomodulator Interferon beta-1a (Avonex, Avonex Pen) Polysorbate 20
Emapalumab (Gamifant) Polysorbate 80
Immunosuppressant Mycophenolate mofetil (Cellcept IV) Polysorbate 80
Inflammatory bowel disease agent Vedolizumab (Entyvio) Polysorbate 80
Interleukin inhibitor Sarilumab (Kevzara) Polysorbate 20
Dupilumab (Dupixent) Polysorbate 80
Mepolizumab (Nucala) Polysorbate 80
Secukinumab (Cosentyx) Polysorbate 80
Tildrakizumab -asmn (Ilumya) Polysorbate 80
Kallikrein inhibitor Lanadelumab (Takhzyro) Polysorbate 80
Leptin analog Metreleptin (Myalept) Polysorbate 20
Macular degeneration agent Aflibercept (Eylea) Polysorbate 20
Ranibizumab (Lucentis) Polysorbate 20
Brolucizumab (Beovu) Polysorbate 80
mAb treatment Ocrelizumab (Ocrevus) Polysorbate 20
Remdesivir (Veklury) Polysorbate 20
Romosozumab (Evenity) Polysorbate 20
Teprotumumab (Tepezza) Polysorbate 20
Atoltivimab/maftivimab/odesivimab-ebgn (Inmazeb) Polysorbate 80
Bamlanivimab Polysorbate 80
Burosumab (Crysvita) Polysorbate 80
Canakinumab (Ilaris) Polysorbate 80

(continued)
J ALLERGY CLIN IMMUNOL PRACT BANERJI ET AL 1429
VOLUME 9, NUMBER 4

TABLE IV. (Continued)

Drug class Generic name (brand name) Polysorbate
Casirivimab/Imdevimab Polysorbate 80
Eptinezumab (Vyepti) Polysorbate 80
Fremanezumab (Ajovy) Polysorbate 80
Inebilizumab (Uplizna) Polysorbate 80
Raxibacumab Polysorbate 80
Multiple sclerosis treatment Natalizumab (Tysabri) Polysorbate 80
Muscle relaxant Dantrolene sodium (Dantrium, Ryanodex) Polysorbate 80
P-selectin inhibitor Crizanlizumab (Adakveo) Polysorbate 80
Proprotein convertase subtilisin kexin type 9 inhibitor Alirocumab (Praluent) Polysorbate 20
Evolocumab (Repatha) Polysorbate 80
Rheumatologic Belimumab (Benlysta) Polysorbate 80
Thrombolytic Tenecteplase (Tnkase) Polysorbate 20
Alteplase (Cathflo Activase) Polysorbate 80
Reteplase (Retavase) Polysorbate 80
Vitamin infusion Calcitriol (Calcijex, Rocaltrol) Polysorbate 20
Doxercalciferol (Hectorol) Polysorbate 20
Vitamins A, B1, B2, B6, C, D3, E, K (Infuvite) Polysorbate 80

lubricants, as well as foods using PEG as an antifoaming agent anaphylaxis to oral PEG has been postulated to be due to an
(Table III). In addition, PEG3350 is the active ingredient in impaired epithelial barrier, as PEG is normally used as an osmotic
several medications prescribed for treating constipation (eg, Mir- laxative due to its lack of absorption, anaphylaxis with serum IgE
alax) and in bowel preps used before colonoscopy (eg, GoLytely). detected to PEG has occurred in individuals without any apparent
Although considered to be safe and biologically inert, several re- defect.21
ports have shown that up to 70% of patients who have undergone Polysorbate, structurally similar to PEG with polyether do-
treatment with PEGylated therapeutics will develop anti-PEG IgG mains with observed clinical cross-reactivity (Figure 1), is also an
antibodies.15 A more recent study in the general population excipient in a multitude of medical preparations (eg, vitamin oils,
showed that 5% to 9% of 1721 serum samples tested were positive vaccines, and anticancer agents), creams, ointments, lotions, and
for anti-PEG IgG, 3% to 6% of 948 such samples tested were medication tablets (Table IV).22 For example, at least 70% of
positive for anti-PEG IgM, and 2 of 2091 (0.1%) samples tested injectable biological agents and mAb treatments contain a
were positive for anti-PEG IgE.16 Also, reactions to PEG- polysorbate, most typically polysorbate 80.23 Unfortunately,
containing products on the first exposure suggest previous sensi- polysorbate and its degradation products are known to be
tization to PEG. However, a review of FDA voluntary reporting intrinsically anaphylactogenic, leading to a plausible explanation
data from 2005 through 2017 identified an average of just 4 cases for multiple reports of anaphylaxis in patients receiving
(range, 2-8 cases) per year of PEG-associated anaphylaxis during polysorbate-containing biologics, vaccines, steroids, and chemo-
colonoscopy preparation or laxative use.11 Interestingly, more therapeutics, although there is limited in vivo and in vitro evi-
subtle PEG allergies are usually discovered during allergist evalu- dence to support this, and isolated sensitization through
ation of patients being evaluated for reactions to seemingly un- polysorbates appears rare and less common than through higher
related products, including injectable steroids, processed foods, molecular weight PEG.24-29 Attempts have been made to address
cosmetics, drugs, and other substances that contain PEG.17 Spe- these issues by using safer alternatives to polysorbate, but the
cific IgE directed against PEG, currently a research tool, has negative allergic outcomes are often outweighed by the clinical
recently been demonstrated in PEG-allergic patients who reacted benefit of improved drug performance. In the context of evolving
both to PEGs and, in 1 case, to a PEGylated liposomal product literature demonstrating PEG as an allergen, many allergists have
used as an echocardiogram contrast, by 2 independent hypothesized that any cases of anaphylaxis during the rollout of
methods.11,13,16 In the earliest of these 3 reports, the binding of the Pfizer/BioNTech and Moderna severe acute respiratory
PEG-specific IgG from patients with PEG anaphylaxis showed syndrome coronavirus 2 (SARS-CoV-2) vaccines, which use
increased avidity as the molecular weight of the PEG assayed different liposomal delivery vehicles but contain PEG2000,
increased from 1000 and above, with clinical tolerance of PEG300 could potentially be due to preexisting PEG allergy.30
upon challenge, suggesting that not all PEGs are equally risky to The positive and negative predictive values of skin testing to
cause reactions.11 Although an exact threshold of reactivity based PEG in the evaluation of potential allergy to the mRNA
on the molecular weight of PEG is not known, tolerance of PEG COVID-19 vaccines are not clear but has shown utility in the
with molecular weight less than 400 has been described in those evaluation of individuals with a history of anaphylaxis to
who have documented anaphylaxis to PEG3350.11 It has been PEG.11,18 Allergists have significant experience with skin testing,
reported that those who lose reactivity to lower molecular weight however drug skin testing relies on the use of nonirritating skin
PEG over time may still remain sensitized to very high molecular testing concentrations which are helpful when positive, but do
weight PEG.18 Additionally, there appears to be an increased not rule out allergy when negative. With the currently available
incidence of allergic reactions in patients who receive intravenous mRNA COVID-19 vaccines, PEG is the only component that
PEG compared to the intramuscular route.19,20 Although can be tested using skin prick and intradermal testing techniques.
1430 BANERJI ET AL J ALLERGY CLIN IMMUNOL PRACT
APRIL 2021

FIGURE 2. Risk stratification pathways with categories based on Mass General Brigham and Vanderbilt allergy expert consensus before
initial COVID-19 vaccination. *If “yes” for questions 1 or 2, specific investigation as to the specific injectable products and vaccines
should be pursued to determine whether these products could have contained high-molecular-weight PEG, polysorbate, or polyoxyl 35
castor oil (paclitaxel). See Tables II, III, and IV. {Current CDC guidance suggests 30 minutes of observation for patients with any history of
anaphylaxis. xSee Figures 3 and 4 for expanded skin testing procedures and non-irritating skin test concentrations. If skin testing to PEG is
positive, as of December 28, 2020, Pfizer-BioNTech and Moderna are the only FDA approved vaccines and under EUA can not be given to
an individual with a history of anaphylaxis to a component of the COVID-19 mRNA vaccine. Skin testing to polysorbate 20 and 80
become more important for patients with confirmed severe PEG allergy with regards to the safety of future vaccinations.

Thus, PEG skin testing could be considered in the evaluation of C3, C4, C5, and factor B).32 Depletion of complement levels
individuals with a history of IgE mediated allergy to a PEG and production of C3a and C5a have been seen in both mouse
containing injectable or a possible IgE mediated reaction to models of anaphylaxis and in clinical studies. C5a is the most
either of the currently available mRNA COVID-19 vaccines. We potent of the anaphylatoxins and can contribute to vascular
should remember, to date, that there is no confirmation IgE permeability as well as activation and chemotaxis of neutrophils,
mediated reactions to PEG are responsible for reported reactions basophils, and mast cells. Infection and tissue injury can lead to
to the mRNA COVID-19 vaccines. Polysorbate, which is cross- activation of the complement system resulting in the generation
reactive with PEG, is the excipient in both the AstraZeneca and of C3a and C5a, and these mediators can lead to anaphylaxis.
Johnson & Johnson COVID-19 vaccines (currently not FDA PEG IgM and IgG can cause complement-activationerelated
approved). Therefore, PEG and polysorbate skin testing may be pseudoallergy,33 a nonspecific immune response to PEGylated,
of value in shared decision making around future COVID-19 nanoparticle-based medicines.34 This pathway may be respon-
vaccination.31 sible for reactions to medications such as liposomal doxoru-
In addition to considering excipients as the cause of IgE- bicin35 and other drugs in clinical trials.34 Clearly, it is important
mediated allergic reactions to the currently approved COVID- to consider both IgE and alternative mechanisms for the current
19 vaccines, alternative non-IgE pathways for activating mast reactions. Measurement of serum tryptase and complement may
cells and other inflammatory cells must be considered, because help elucidate the mechanism of the drug-induced reactions in
they can lead to a similar clinical presentation. For example, patients following COVID-19 vaccination.
activation of the complement system leads to the generation of It is also important to note that other nonimmunologic re-
C3a, C4a, and C5a, which are potent activators of inflammation actions may masquerade as allergic reactions including anaphy-
and are called anaphylatoxins due to their ability to cause laxis. Vasovagal reactions are a well-known cause of hypotension
noneIgE-mediated mast cell degranulation. One of the first and syncopal reactions associated with injections including vac-
reports of acute anaphylaxis associated with serum complement cines. Panic or anxiety reactions can also present with symptoms
depletion was of a 45-year-old woman experiencing anaphylaxis masquerading as allergic reactions such as flushing, shortness of
after receiving lidocaine. She developed faintness, flushing, breath, tachycardia, and lightheadedness. Inducible laryngeal
pallor, dyspnea, and hypotension, but she did not have urticaria obstruction (ie, vocal cord dysfunction) may also masquerade as
or bronchospasm. Complement levels were markedly low (C1q, anaphylaxis, with prominent symptoms of shortness of breath
J ALLERGY CLIN IMMUNOL PRACT BANERJI ET AL 1431
VOLUME 9, NUMBER 4

TABLE V. Frequently asked questions (patient handout)

What is vaccine allergy?
Similar to medications or foods, people can be allergic to a vaccine. However, allergic reactions to vaccines are very rare (about 1 in 1 million people
will have an allergic reaction to a vaccine). Some reactions are mild, such as hives as the only symptom, whereas others are more severe. A severe
allergic reaction is called anaphylaxis. Symptoms start very quickly (usually within minutes) and almost always within 4 h of vaccination and
typically include multiple parts of the body: hives on the skin; swelling of mouth, lips, tongue, or throat; shortness of breath, wheezing, or chest
tightness; or low blood pressure or loss of consciousness. About half of allergic reactions to vaccines happen in the first 15 min after receiving the
vaccination. Rarely delayed reactions such as fever and local arm swelling can occur up to 2-3 weeks later. These reactions should not preclude a
second dose of the vaccine.
What about redness and swelling at the injection site—is that an allergic reaction?
Sometimes vaccines can cause large local reactions at the injection site, and these can begin hours after the vaccination or even the next day. The skin at
the site of vaccination can become sore, swollen, red, and painful. Sometimes it can also become itchy. The symptoms can last several days. Although
this type of reaction can be uncomfortable, if it does not include the symptoms of allergic reactions listed above, it is not an allergic reaction to the
vaccine, there is no risk of an allergic reaction with the next vaccination, and an allergist consultation is not necessary.
What is a severe allergic reaction?
A severe allergic reaction is sometimes called anaphylaxis. Symptoms start very quickly (usually within minutes) and almost always within 4 h of
vaccination and typically include hives; swelling of mouth, lips, tongue, or throat; shortness of breath, wheezing, or chest tightness; or low blood
pressure or loss of consciousness.
What are the ingredients in the Pfizer-BioNTech COVID-19 vaccine?
1. mRNA. The active ingredient is a nucleoside-modified mRNA encoding the viral spike glycoprotein of SARS-CoV-2
2. Inactive ingredients:
 Lipids ((4-hydroxybutyl)azanediyl)bis(hexane-6,1-diyl)bis(2-hexyldecanoate), [(PEG)-2000]-N,N-ditetradecylacetamide, 1,2-distearoyl-sn-glycero-
3-phosphocholine, and 0.2 mg cholesterol),
 Electrolytes potassium chloride, monobasic potassium phosphate, sodium chloride, dibasic sodium phosphate dihydrate, and
 Sugar (sucrose)
 The diluent, added to the vaccine for administration, is saline (sodium chloride)
What are the ingredients in the Moderna COVID vaccine?
1. mRNA
2. Inactive ingredients:
 lipids (SM-102, polyethylene glycol [PEG] 2000 dimyristoyl glycerol, cholesterol, and 1,2-distearoyl-sn-glycero-3-phosphocholine),
 tromethamine,
 tromethamine hydrochloride,
 acetic acid,
 sodium acetate,
 Sugar (sucrose)
Which patients should speak to an allergist before receiving the vaccine?
In the vaccine trials, only patients with a history of severe allergic reaction associated with a vaccine and/or severe allergic reaction to any component of
the vaccine were excluded. If you are unsure about your vaccine or PEG allergy history, an allergy consultation is recommended. In general, most
patients allergic to one vaccine can receive other vaccinations safely.
What is PEG and what are common products that contain PEG?
PEG is a common, water-soluble ingredient in a wide variety of commercial products including some vaccines and more than 1000 FDA-
approved medications. It is the primary ingredient in commonly used colonoscopy preparations (Golytely) or constipation treatment (Miralax) as well
as in intraveous medications such as PEGylated medications. It is also used in ultrasound gel and injectable steroid injections such as
methylprednisolone acetate. Reactions to PEG are exceedingly rare, but anaphylaxis has been reported.

and throat tightness but may also include flushing. Indeed, the vaccine had a prior allergy history and 33% (7/21) had a prior
most recent CDC report demonstrated that of 175 potential history of anaphylaxis.2 The CDC provides guidance with use of
severe allergic reactions, 61 (35%) were determined to be a recently developed pre-screening tool.36 A similar approach,
nonallergic after case review.2 commonly used in the allergy field, is to risk stratify patients
based on a clinical assessment. The authors from Mass General
EVALUATION OF PATIENTS WITH SEVERE Brigham (formerly Partners HealthCare; comprising 16 health
ALLERGY HISTORIES AND GUIDANCE FOR INITIAL care institutions in the New England area and the largest
ADMINISTRATION OF COVID-19 VACCINE employer in Massachusetts with 80,000 employees) and Van-
Massive vaccination programs were initiated within a few days derbilt University Medical Center developed a plan of care to risk
after the FDA EUA of the COVID-19 vaccines. However, many stratify employees and guide safe COVID-19 vaccination
questions surrounded the safety of giving these vaccines to in- (Figure 2). To ensure vaccination in as many individuals as
dividuals with a previous allergy history and further supported by quickly as possible, our guidance, in line with FDA and CDC
recent data showing that the majority (81%, 17/21) of patients guidance, results in the rapid identification of high risk in-
with confirmed anaphylaxis to the Pfizer-BioNTech mRNA dividuals needing Allergist assessment but does not preclude large
1432 BANERJI ET AL J ALLERGY CLIN IMMUNOL PRACT
APRIL 2021

FIGURE 3. Expanded skin testing procedure. *Recommended skin testing to evaluate only known potential IgE mechanism (PEG allergy).
{Skin testing for consideration to evaluate PEG and polysorbate allergy. In patients with positive PEG skin testing, the result of poly-
sorbate 20 and 80 skin testing becomes important with regards to the safety of future SARS-CoV-2 vaccines in development. Therefore,
based on clinical history, skin testing to both PEG and polysorbate during 1 clinic visit may be appropriate. xAnaphylaxis with intradermal
skin testing in PEG allergic patients has been described. We recommend staff have anaphylaxis training and anaphylaxis kit available in
close proximity. zTables II, III, and IV contain a list of PEG/polysorbate containing vaccines and injectables that can be shared with pa-
tients. **Recommended only after shared decision making between allergist and patient.

groups of individuals with lower risk allergy histories from paclitaxel). If the answer to question 4 is “yes,” the individual
receiving the COVID-19 vaccine per usual protocol with either would be deemed “higher risk,” prompting evaluation with an
15-minute or 30-minute observation periods. allergist for clinical phenotyping and consideration of
Four screening questions are presented to patients before the expanded skin testing if history is not consistent with
initial vaccination to assess risk: confirmed anaphylaxis using nonirritating skin test concen-
trations (Figures 3 and 4).11 If skin testing result to PEG is
1. Do you have a history of a severe allergic reaction to an positive, under EUA, the individual is not a candidate for the
injectable medication (intravenous, intramuscular, or Pfizer-BioNTech or Moderna COVID-19 vaccines, and the
subcutaneous)? skin test result to polysorbate 20 and 80 become important
2. Do you have a history of a severe allergic reaction to a previous with regard to the safety of future SARS-CoV-2 vaccines in
vaccine? development. If skin testing to PEG is negative, vaccination
3. Do you have a history of a severe allergic reaction to another with the Pfizer-BioNTech or Moderna COVID-19 vaccines
allergen (eg, food, venom, or latex)? could be considered in conjunction with shared decision
4. Do you have a history of an immediate or severe allergic re- making, informed consent, and would require 30 minutes of
action to PEG-, a polysorbate-, or polyoxyl 35 castor oil (eg, observation under Allergist supervision.
paclitaxel)-containing injectable or vaccine?

The screening questions address CDC guidelines and are EVALUATION AND MANAGEMENT OF PATIENTS
accompanied by a “Frequently Asked Questions” document WITH POTENTIAL REACTIONS TO THE COVID-19
explaining medical terminology, including descriptions of VACCINES
PEG and polysorbates (Table V). For patients presenting to the allergist with a possible reac-
If the answer is “no” to all 4 questions, the individual would tion to the first dose of their COVID-19 vaccine, the primary
be deemed “lower risk” and receive the vaccine under usual concern is the ability to safely receive the second dose
protocol with a 15-minute observation period. If the answer to (Figure 5). Although the vaccines have some efficacy related to
question 1, 2, or 3 is “yes,” the individual would be deemed only 1 dose, both the Pfizer-BioNTech and Moderna vaccines
“medium risk” and require a 30-minute observation period. In received EUA approval for efficacy, which was evaluated with 2
addition, if “yes” for 1 and 2, specific investigation as to the doses. As such, a crucial determination will be establishing
specific injectable products and vaccines should be pursued to whether or not an allergic reaction occurred. Recent CDC data
determine whether these products could have contained high- demonstrate that the vast majority, 84% (147/175) of reported
molecular-weight PEG, polysorbate, or polyoxyl 35 (eg, severe “allergic” reactions, were unconfirmed after case review.2
J ALLERGY CLIN IMMUNOL PRACT BANERJI ET AL 1433
VOLUME 9, NUMBER 4

FIGURE 4. Nonirritating skin testing concentrations for PEG3350 and polysorbate. *Methyl-prednisolone sodium succinate does not contain
PEG or polysorbate 80 and can be used as an additional control. {Refresh Optive Advanced Lubricant eye drops and Prevnar are an alternate
source for polysorbate 80 skin testing. xSome brands of methylprednisolone acetate contain polysorbate and PEG3350 while others only have
PEG3350; use methylprednisolone acetate containing PEG3350 only. zNonirritating skin testing concentrations for methyl-prednisolone so-
dium succinate and triamcinolone acetonide include a range of 10 to 40 mg/mL for initial skin prick testing with subsequent 10 dilutions.37
One author (E.P.) has extensive experience using 50 mg/mL as a non-irritating skin testing concentration for methyl-prednisolone sodium
succinate skin prick testing with subsequent 10 dilutions. **Dissolve 17 gram miralax packet in 100mL of sterile water for 1:1 solution (170
mg/mL).

Individuals with symptoms suggestive of a nonallergic reaction anaphylaxis to the first dose. For other vaccines for which there
(eg, transient dyspnea, tachycardia alone, metallic taste, flush- is much more allergy experience, split-dose challenges (eg, 10%-
ing, lip tingling) can proceed with a 15 or 30 minute obser- 25% of the dose followed 30 minutes later by the remaining
vation for the second dose. For patients with a potential allergic 75%-90% of the dose) have been used.38 Although some groups
reaction (eg, urticaria, angioedema) after their first dose that have indicated their intent to implement split dosing of the
does not meet criteria for anaphylaxis, vaccination programs mRNA vaccines, there are no supportive efficacy or safety data.
should prioritize follow-up with an allergist who can review the For both the Pfizer-BioNTech and Moderna vaccines, neither
clinical history and consider PEG skin testing if an IgE-medi- the stability of the vaccine diluted nor the safety and immu-
ated reaction is suspected to risk stratify the patient prior to a nogenicity at altered doses or concentration have been studied.
second COVID-19 vaccine dose (Figure 5). Antihistamines do It should be remembered that these are not simple protein
not prevent anaphylaxis and could mask cutaneous symptoms, vaccines but instead are mRNA vaccines and subject to degra-
leading to a delay in treatment. However, pretreatment with dation. The Pfizer-BioNTech vaccine indeed is only 0.3 mL and
fexofenadine 180-360 mg or cetirizine 10-20 mg 1-2 hours there are no data, to date, for either mRNA vaccine showing
prior to the second dose of COVID-19 vaccination can be split-dosing efficacy. We do not recommend vaccine skin testing
considered in individuals with mild allergic symptoms (ie, at this time because of limited vaccine supply, lack of infor-
pruritus or urticaria only), especially those that are delayed in mation on sensitivity or specificity, unclear safety of skin
onset. If a patient develops potential anaphylaxis to the first testing. At the time of publication, mRNA vaccines are under
vaccine dose, shared decision making with an allergist including EUA and remain unlicensed for skin testing.
risk stratification and expanded skin testing should occur before All patients with potential allergic reactions should be reported
any consideration of vaccine rechallenge (Figure 5). There are through formal processes, which include the Vaccine Adverse
no data on the safety of the second vaccine after confirmed Event Reporting System (VAERS; https://vaers.hhs.gov);
1434 BANERJI ET AL J ALLERGY CLIN IMMUNOL PRACT
APRIL 2021

FIGURE 5. Risk stratification pathways with categories based on Mass General Brigham and Vanderbilt allergy expert consensus after
allergic reaction to first dose of COVID19 vaccine. *Ideal laboratory assessment includes reaction serum tryptase within 2 hours and
complement activation by ELISA (C3a, C3b, C5a, C5b-9 ideally within 1 hour; send to National Jewish); follow-up baseline serum
tryptase is also useful. {Follow CDC guidance.3 xSee Figures 3 and 4 for expanded skin testing algorithm and nonirritating skin test
concentrations. zShared decision making with allergist considering eligibility for second dose or future challenge with other SARS-CoV-2
vaccines. There are no data on the safety of administering the second vaccine dose after potential anaphylaxis to the first dose and
limited anecdotal evidence from the authors’ clinical experience suggesting that some patients can safely receive the second dose after
more mild allergic type reactions to the first dose. If the decision is made to proceed with vaccination, staff should have anaphylaxis
training and anaphylaxis kit needs to be available in close proximity. **84% (147/175) of potential anaphylaxis cases reported to the
CDC were unconfirmed after their case review.2 {{PEG skin testing can be considered to assist in the evaluation of a potential IgE
mechanism but data confirming this mechanism is responsible for reported reactions to mRNA COVID-19 vaccines are lacking.
xxConsider 15 or 30 minute observation based on clinical judgment.

Patients should be encouraged to use V-Safe (https://vsafe.cdc. clinical phenotyping, risk stratification, and reassurance to pa-
gov), a CDC application for second-dose reminders and to tients deemed at lower risk to safely receive the vaccine. For
enter reaction information.39,40 reactions that happen onsite, vaccination clinics are reliant on
staff that do not regularly diagnose and treat anaphylaxis, but
CDC guidance emphasized a minimum of 15 minutes of
SUPPORTING SAFE VACCINATION AND observation after all doses and ready access to appropriate med-
ADDRESSING PUBLIC CONCERN: A ROLE FOR THE ical treatment for allergic reactions. Those staffing the vaccina-
ALLERGIST tion clinic should have education around anaphylaxis treatment
Allergists’ expertise in the diagnosis and treatment of allergic guidelines. Anaphylaxis is a life-threatening hypersensitivity re-
reactions is invaluable for the screening of high-risk individuals, action where rapid, early administration of epinephrine is vital
the training of clinic staff conducting vaccinations, and the for recovery. Along with the CDC educational and training
management of patients who experience potentially allergic re- videos,41 allergists can help reassure patients and educate pro-
actions to a COVID-19 vaccine. To date, Mass General Brigham viders by addressing a few key issues:
and Vanderbilt have instituted screening methods before and
after vaccination which consist of self-reported answers to a 1. Education on the diagnosis of anaphylaxis.42 Allergists should
questionnaire followed by telemedicine visits with an allergy include differentiating vasovagal and anxiety reactions from
clinician for high-risk patients prior to the first vaccine dose or anaphylaxis and defining anaphylaxis with infographics
after potential allergic reactions to the first dose. This allows for (Table VI and Figure 6).
J ALLERGY CLIN IMMUNOL PRACT BANERJI ET AL 1435
VOLUME 9, NUMBER 4

TABLE VI. Anaphylaxis compared with vasovagal reaction43

Signs and symptoms Vasovagal reaction Anaphylaxis
Interval (after injection) Sometimes before, usually after a few seconds to a few Within 30 min after injection; the most severe reactions begin
minutes after the injection within the first 15 min
Consciousness Fainting sensation, dizziness, loss of consciousness in Anxiety, which may progress into unconsciousness in severe
some cases cases
Breathing Slow, with a few seconds of apnea in some cases Respiratory difficulties; coughing, sneezing, wheezing, stridor
Pulse Slow and weak, but regular Rapid, weak and irregular
Skin Diaphoresis, clammy skin, pallor  Warm skin, progressing to clammy and pallor
 Pruritus and urticaria (>90% of cases)
 Swelling of face and tongue
Blood pressure Transient hypotension Hypotension (systolic pressure <90 mm Hg), which may
progress to cardiovascular collapse
Gastrointestinal system Nausea, vomiting Nausea, vomiting, abdominal pains, diarrhea
Treatment  Place client in a recumbent position and elevate legs See Manitoba Health Protocol for Management of Suspected
above head (or have client sit with head between their Anaphylaxis
knees)
 Ventilate the room well
 Place cold, damp cloth on face
 Give reassurance
Prevention Do not vaccinate a standing person. Before vaccinating, Before vaccinating, ask if the person has ever had an
ask if the person tends to faint; if so, ask patient to lie anaphylactic reaction to any product; if yes, ask for the name
down of the product and decide accordingly

2. Education on the treatment of anaphylaxis. Allergists autoinjectors. A nonsedating antihistamine was added to
should review epinephrine use and anaphylaxis-kit con- the anaphylaxis kits. It is necessary to recognize that some
tents. For example, before the rollout of Mass General medications in anaphylaxis kits contain PEG, and as such
Brigham employee vaccination, allergists provided educa- it is important for clinics to use epinephrine for suspected
tion and replaced epinephrine vials with epinephrine anaphylaxis cases.

FIGURE 6. Graphic to assist in the recognition of anaphylaxis.44 BP, Blood pressure; GI, gastrointestinal.
1436 BANERJI ET AL J ALLERGY CLIN IMMUNOL PRACT
APRIL 2021

3. Providing at-the-elbow support to vaccination programs. Al- decision models to achieve safe and effective outcomes. The
lergists may need to be on-site or on-call during higher risk potential life-saving benefit of vaccination in the setting of a
vaccination. This will ensure that vaccinated individuals with global pandemic makes it essential that we carefully evaluate
possible reactions receive the best diagnostic evaluation and every patient with a possible allergic reaction to prevent denying
treatment plan, while linking them to appropriate follow-up access to the vaccine unnecessarily. Our knowledge is rapidly
care before the second vaccine dose. evolving and future recommendations may change with addi-
4. Providing support to individuals with benign symptoms after tional data. Our intent is to provide updates on a regular basis as
discharge. Up to 80% of individuals in the vaccine clinical more information becomes available.
trials had local symptoms after vaccination. Large local re-
actions with symptoms of pain, itching, burning, or swelling
at the site of injection do not preclude an individual from
getting the vaccine again. Delayed local hypersensitivity re- Acknowledgments
actions, with onset after Day 8, have been observed specif- We thank the Mass General Brigham health system faculty
ically with Moderna's vaccine. Nonsteroidal anti- and staff, including Dean Hashimoto, MD, Tanya Laidlaw,
inflammatory drugs used to treat fever or myalgias may pre- MD, David Hong, MD, Anna Feldweg, MD, Karen Ferreira,
cipitate urticaria that could be misattributed to the vaccine. Kenisha Lewis, Barbara Schmidt, Nahal Beik, Adam Landman,
Allergists can provide assessments and reassurance and MD, Erica S. Shenoy, MD, PhD, and Rajesh Patel, MD, MPH.
encourage completion of vaccination. We thank Upeka Samarakoon, PhD, MPH, Allen Judd, Chris-
tian Mancini, Amelia Cogan, and Aubree McMahon for their
SUMMARY research assistance.
To date, allergic reactions to vaccines have been rare and often
attributed to various vaccine components. Current reports from REFERENCES
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