Journal Pre-proof

mRNA Vaccines to Prevent COVID-19 Disease and Reported Allergic Reactions:

Current Evidence and Approach

Aleena Banerji, MD, Paige G. Wickner, MD, Rebeca Saff, MD, PhD, Cosby A. Stone,
Jr., MD, MPH, Lacey B. Robinson, MD, MPH, Aidan A. Long, MD, Anna R. Wolfson,
MD, Paul Williams, MD, David A. Khan, MD, Elizabeth Phillips, MD, Kimberly G.
Blumenthal, MD, MSc

PII: S2213-2198(20)31411-2
DOI: https://doi.org/10.1016/j.jaip.2020.12.047
Reference: JAIP 3355

To appear in: The Journal of Allergy and Clinical Immunology: In Practice

Received Date: 28 December 2020

Accepted Date: 28 December 2020

Please cite this article as: Banerji A, Wickner PG, Saff R, Stone CA Jr, Robinson LB, Long AA, Wolfson
AR, Williams P, Khan DA, Phillips E, Blumenthal KG, mRNA Vaccines to Prevent COVID-19 Disease
and Reported Allergic Reactions: Current Evidence and Approach, The Journal of Allergy and Clinical
Immunology: In Practice (2021), doi: https://doi.org/10.1016/j.jaip.2020.12.047.

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© 2020 Published by Elsevier Inc. on behalf of the American Academy of Allergy, Asthma & Immunology
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1 mRNA Vaccines to Prevent COVID-19 Disease and Reported Allergic Reactions: Current

2 Evidence and Approach

3 Aleena Banerji, MD1,2

4 Paige G. Wickner, MD1,3

5 Rebeca Saff, MD, PhD1,2

6 Cosby A Stone Jr, MD, MPH4

7 Lacey B. Robinson, MD, MPH1,2

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8 Aidan A. Long, MD1,2

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9 Anna R. Wolfson, MD1,2

10 Paul Williams, MD5

11 David A. Khan, MD6

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12 *Elizabeth Phillips, MD3
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13 *Kimberly G. Blumenthal, MD, MSc1,2,5

1
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Division of Rheumatology Allergy and Immunology, Department of Medicine, Massachusetts

15 General Hospital, Boston MA

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2
16 Harvard Medical School, Boston, MA
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3
17 Division of Allergy and Immunology, Department of Medicine, Brigham and Women’s

18 Hospital, Boston MA
4
19 Department of Medicine, Vanderbilt University Medical Center, Nashville, TN
3
20 Department of Internal Medicine, Division of Allergy & Immunology, University of Texas

21 Southwestern Medical Center, Dallas, TX

5
22 Allergy Division, University of Washington School of Medicine. Seattle, WA
6
23 Edward P. Lawrence Center for Quality and Safety, Massachusetts General Hospital, Boston

24 MA

25 *Denotes co-senior authorship

26
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27 Corresponding Author:

28 Aleena Banerji

29 Boston, Division of Rheumatology Allergy and Immunology, Department of Medicine,

30 Massachusetts General Hospital, Boston MA

31 UNITED STATES

32 617-726-3850

33 [email protected]

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34

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35 Manuscript Contents

36 Abstract Word Count: 195

37 Word Count: 3688

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38 Table: 6
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39 Figures: 6

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References: 33

41
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42 Key Words: mRNA, COVID-19, vaccine, drug allergy, allergic reactions, anaphylaxis,
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43 guidelines, risk stratification, polyethylene glycol, polysorbate

44

45 Abbreviations:

46 Coronavirus disease 19, COVID19

47 United States, US

48 Lipid nanoparticle, LNP

49 Food and Drug administration, FDA

50 Emergency Use Authorization, EUA

51 United Kingdom, UK

52 Centers for Disease Control and Prevention, CDC

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53 confidence interval, CI

54 polyethylene glycol, PEG

55 Funding

56 No funding was received for this work.

57

58 Disclosures

59 EJP reports grants from National Institutes of Health (P50GM115305, R01HG010863,

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60 R01AI152183, R21AI139021, U01AI154659) and from the National Health and Medical

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61 Research Council of Australia. She receives Royalties from Uptodate and consulting fees from

62 Janssen, Vertex and Biocryst. She is co-director of IIID Pty Ltd that holds a patent for HLA-

63
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B*57:01 testing for abacavir hypersensitivity, and has a patent pending for Detection of Human
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64 Leukocyte Antigen-A*32:01 in connection with Diagnosing Drug Reaction with Eosinophilia and
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65 Systemic Symptoms without any financial remuneration and not directly related to the submitted

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work. Funders played no role in any aspect of this Review.

67
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68 The other co-authors have no relevant conflicts of interest.

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69

70 Abstract

71 The recent Food and Drug Administration (FDA) approval of two highly effective COVID-19

72 vaccines from Pfizer-BioNtech and Moderna has brought hope to millions of American in the

73 midst of an ongoing global pandemic. The FDA Emergency Use Authorization guidance for both

74 vaccines is to not administer the vaccine to individuals with known history of a severe allergic

75 reaction (e.g., anaphylaxis) to any component of the COVID-19 vaccine. The Centers for

76 Diseases Control and Prevention (CDC) advises that all patients should be observed for 15

77 minutes after COVID-19 vaccination and staff must be able to identify and manage anaphylaxis.

78 Post-FDA approval, despite very strong safety signals in both phase 3 trials, reports of possible
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79 allergic reactions have raised public concern. To provide reassurance and support during

80 widespread vaccination across America, allergists must offer clear guidance to patients based on

81 the best information available, but also in accordance with the broader recommendations of our

82 US regulatory agencies. This review summarizes vaccine allergy epidemiology and proposes risk

83 stratification schema: (1) for individuals with different allergy histories to safely receive their first

84 COVID-19 vaccine and (2) for individuals who develop a reaction to their first dose of COVID-

85 19 vaccine.

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86 Introduction

87 Vaccination, one of the most effective public health interventions modern medicine can offer, has

88 become increasingly relevant as the global pandemic from Coronavirus Disease 2019 (COVID-

89 19) continues to worsen throughout the world. In the United States (US), the pandemic has risen

90 to crisis levels in every state, setting records with tens of thousands of new cases reported daily

91 and deaths mounting. As of December 2020, over 18 million people in the US have had

92 confirmed infections and more than 320,000 have died of COVID-19.1 Medical necessities are

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93 often in short supply, hospitals are overwhelmed, and healthcare workers are exhausted after

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94 months of fighting an uphill battle. At the time of writing this review, immediate allergic

95 reactions clinically compatible with anaphylaxis have occurred at a rate of 1.3 per 100,000 doses

96
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of the Pfizer-BioNTech mRNA vaccine. Currently the specific mechanism and the inciting
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97 antigen have not been identified. This review will summarize the current state of knowledge of
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98 immediate allergic reactions associated with the mRNA vaccines and a hypothesis regarding a

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potential relationship with the lipid-PEG2000 component of the lipid nanoparticle (LNP) mRNA

100 carrier system.

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101
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102 Clinical Trial Data

103 The US Food and Drug Administration’s (FDA) approval of two highly effective COVID19

104 vaccines in December 2020 was a landmark in the pandemic response for Americans. The Pfizer-

105 BioNTech two-dose COVID19 vaccine regimen given on day 0 and 21 showed a 95% efficacy at

106 preventing symptomatic COVID19 infection, measured forward from seven days after the second

107 dose was administered.2 The vaccine appeared equally protective across age groups as well as

108 racial and ethnic groups.2 The Moderna two-dose COVID19 vaccine regimen given on day 0 and

109 28 was 94% effective at preventing symptomatic COVID19, measured from 14 days after the

110 second dose onward.3 The efficacy of the Moderna vaccine appeared to be slightly lower in

111 people 65 years of age and older, but it was equally effective across different racial and ethnic
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112 groups.3 The safety of both vaccines over a median of 2 months was similar to that of other viral

113 vaccines. Severe systemic events were reported in less than 2% of Pfizer-BioNTech vaccine

114 recipients after either dose, except for 3.8% reporting fatigue and 2.0% reporting headache after

115 the second dose. The majority of adverse events after receiving the Moderna vaccine were mild or

116 moderate in severity. A small number of participants reported systemic reactions lasting longer

117 than 7 days, but there was no difference between vaccine and placebo groups. The Pfizer-

118 BioNTech Emergency Use Authorization (EUA) is for individuals age 16 and older while

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119 Moderna is for individuals age 18 and older.

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121 Prior to FDA EUA of a COVID-19 vaccine, the United Kingdom (UK) Commission on Human

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Medicines initiated their COVID-19 vaccination program using the Pfizer-BioNTech vaccine.
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123 Within 48 hours, there were two reports of severe allergic reactions in the UK that prompted
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124 treatment with epinephrine. These reported allergic reactions led to a closer review of the Pfizer-

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BioNTech clinical trial data by the FDA. The Pfizer-BioNTech and Moderna clinical trials

126 excluded patients with a prior history of severe adverse reactions associated with a vaccine, and
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127 the Pfizer-BioNTech trials further excluded severe allergic reaction (e.g., anaphylaxis) to any
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128 component of their COVID19 vaccine. Hypersensitivity-related adverse events were observed in

129 0.63% of Pfizer-BioNTech and 1.5% of Moderna vaccine clinical trial participants who received

130 the vaccine, compared to 0.51% and 1.1% respectively in the placebo groups. One case of

131 anaphylaxis and one drug hypersensitivity reaction were reported in the Pfizer-BioNTech trial,4

132 and two cases of delayed hypersensitivity reactions were reported in the Moderna trial.3 Only one

133 of the Moderna delayed allergic reactions was in the vaccine group, and, since it occurred several

134 months after vaccination, it was unlikely to be related to the vaccine. Also, in the Moderna trial,

135 there were three events of lip/face swelling 1-2 days after vaccination but exclusively in patients

136 with a history of dermal fillers but unclear from which manufacturer. There were no anaphylactic
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137 or severe hypersensitivity reactions reported with close temporal relation to administration of the

138 Moderna vaccine.

139

140 US Regulatory Approval and Guidance

141 The FDA EUA guidance for the Pfizer-BioNTech COVID19 vaccine specifies, “do not

142 administer Pfizer-BioNTech COVID19 vaccine to individuals with known history of a severe

143 allergic reaction (e.g., anaphylaxis) to any component of the Pfizer-BioNTech COVID19

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144 vaccine.” Given the reported reactions in healthcare workers, the US Centers for Disease Control

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145 and Prevention (CDC) subsequently advised that all patients – regardless of allergy history –

146 should be observed for 15 minutes after COVID19 vaccination and that vaccination staff must be

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trained to manage anaphylaxis. The CDC provided further recommendations, “that persons who
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148 have had a severe allergic reaction to any vaccine or injectable therapy (intramuscular,
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149 intravenous, or subcutaneous) discuss the risk of receiving the vaccine with their doctors and be

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monitored for 30 minutes afterward.” In addition, patients who have a severe allergic reaction

151 (e.g., anaphylaxis) to an mRNA COVID-19 vaccine should not receive a second dose. CDC
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152 precautions and contraindications for the Moderna vaccine under EUA were the same as the
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153 Pfizer-BioNTech vaccine for the purpose of “harmonization.”5

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155 US Post-Marketing Experience

156 Similar to the UK experience, within a few days of widespread vaccination of healthcare workers

157 in the US, several reports of presumed allergic reactions to the COVID19 vaccine emerged. At

158 the time of publication, there have been at least 10 reported allergic reactions to the Pfizer-

159 BioNTech vaccine across greater than 2 million doses administered in the United States and two

160 reports of a reaction to the Moderna vaccine. The most apparent reactions have occurred within

161 the CDC-recommended observation window, and patients have been treated immediately with
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162 complete resolution of symptoms. To date, there are no long-term sequelae or fatalities associated

163 with reported allergic reactions to any COVID19 vaccine.

164

165 Epidemiology and Etiology of Allergic Reactions to Vaccines

166 Allergic reactions to vaccines are generally described as occurring at a rate of 1.31 (95%

167 confidence interval (CI), 0.90-1.84) cases per million vaccine doses from a large population-

168 based study, with no fatalities reported.6 Rates remain similar when stratified by age and gender,

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169 although slightly higher frequencies have been observed in females.6 The incidence of allergic

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170 reaction by specific vaccine, however, is difficult to quantify in epidemiologic studies, as often

171 multiple vaccines are administered on the same day. The cases that followed administration of a

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single vaccine involved predominantly trivalent influenza vaccine, for which the rate of reaction
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173 was estimated to be 1.35 (95% CI, 0.65-2.47) per million vaccine doses.6 Of concern is that,
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174 while numerically rare, vaccine reactions can cause substantial fear and anxiety in the general

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population and may contribute to decreased willingness to receive a COVID19 vaccine.

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177 Confirmed allergic reactions to vaccines are not frequently attributed to the active ingredients but
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178 rather to the inactive ingredients, or excipients, including egg protein, gelatin, formaldehyde,

179 thimerosal, or neomycin. Excipients are necessary and added to a vaccine for specific purposes

180 such as stimulating a stronger immune response, preventing contamination by bacteria, or

181 stabilizing the potency of the vaccine during transportation and storage. Excipients represent the

182 major contributor to specific IgE-mediated and immediate reactions associated with vaccines.7

183 Efforts to specifically decrease well-known excipients like egg and gelatin in vaccines have been

184 highly successful in reducing subsequent allergic reactions.8,9 Other excipients, like polyethylene

185 glycol (PEG) and polysorbate (Figure 1), are used to improve water-solubility in drugs and

186 vaccines. PEG itself has not previously been used in a vaccine but polysorbate has been identified

187 as a rare cause of allergic reactions to vaccines. First dose reactions to vaccines containing
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188 polysorbates may have occurred due to prior sensitization from polysorbate 80.10 The recently

189 approved Pfizer-BioNTech and Moderna COVID19 mRNA vaccines are not formulated with any

190 food, drugs, or latex, but both contain the excipient PEG (Table 1, Table 2) for the purpose of

191 stabilizing the LNP containing the mRNA. The specific PEG in these vaccines is different from

192 the PEG used most commonly in other healthcare products, both in molecular weight and due to

193 its coformulation as a stabilizing portion of a liposome.10,11 The AstraZeneca and Johnson &

194 Johnson COVID19 vaccines currently under development do not contain PEG but instead contain

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195 the excipient polysorbate 80 (Table 2).

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197 Numerous FDA-approved and over-the-counter products contain PEG, including medications,
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198 skin creams and personal lubricants, as well as foods utilizing PEG as an anti-foaming agent
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199 (Table 3). Additionally, PEG3350 is the active ingredient in several medications prescribed for
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200 treating constipation (e.g., Miralax) and in bowel preps used prior to colonoscopy (e.g.,
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201 GoLytely). While considered to be safe and biologically inert, several reports have shown that up

202 to 70% of patients who have undergone treatment with PEGylated therapeutics will develop anti-
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203 PEG IgG antibodies.12 A more recent study in the general population showed that 5% to 9% of
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204 1721 serum samples tested were positive for anti-PEG IgG, 3% to 6% of 948 such samples tested

205 were positive for anti-PEG IgM, and 2 of 2091 (0.1%) samples tested were positive for anti-PEG

206 IgE.13 Also, reactions to PEG-containing products on the first exposure suggests previous

207 sensitization to PEG. However, a review of FDA voluntary reporting data from 2005 through

208 2017 identified an average of just four cases (range, two to eight cases) per year of PEG-

209 associated anaphylaxis during colonoscopy preparation or laxative use.10 Interestingly, more

210 subtle PEG allergies are usually discovered during allergist evaluation of patients being evaluated

211 for reactions to seemingly unrelated products, including injectable steroids, processed foods,

212 cosmetics, drugs, and other substances that contain PEG.14 Specific IgE directed against PEG has

213 recently been demonstrated in PEG allergic patients who reacted both to PEGs and, in one case,
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214 to a PEGylated liposomal product used as an echocardiogram contrast, by two independent

215 methods.10,11,13 In the earliest of these three reports, the binding of PEG specific IgG from PEG

216 anaphylaxis patients showed increased avidity as the molecular weight of the PEG assayed

217 increased from 1000 and above, with clinical tolerance of PEG300 upon challenge, suggesting

218 that not all PEGs are equally risky to cause reactions.10 Although an exact threshold of reactivity

219 based upon molecular weight of PEG is not known, tolerance of PEG with molecular weight

220 <400 has been described in those who have documented anaphylaxis to PEG3350.10

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222 Polysorbate, structurally similar to PEG with polyether domains with observed clinical cross-

223 reactivity (Figure 1), is also an excipient in a multitude of medical preparations (e.g., vitamin

224
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oils, vaccines, and anticancer agents), creams, ointments, lotions, and medication tablets (Table
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225 4).15 For example, at least 70% of injectable biological agents and monoclonal antibody
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226 treatments contain a polysorbate, most typically polysorbate 80.16 Unfortunately, polysorbate and

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its degradation products are known to be intrinsically anaphylactogenic, leading to a plausible

228 explanation for multiple reports of anaphylaxis in patients receiving polysorbate-containing

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229 biologics, vaccines, steroids, and chemotherapeutics, although there is limited in vivo and in vitro
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230 evidence to support this, and isolated sensitization through polysorbates appears rare and less

231 common than through higher molecular weight PEG.17-22 Attempts have been made to address

232 these issues by using safer alternatives to polysorbate, but the negative allergic outcomes are

233 often outweighed by the clinical benefit of improved drug performance. In the context of

234 evolving literature demonstrating PEG as an allergen, many allergists have hypothesized that any

235 cases of anaphylaxis during the rollout of the Pfizer/BioNTech and Moderna SARS-CoV2

236 vaccines, which utilize different liposomal delivery vehicles but contain PEG2000, could

237 potentially be due to preexisting PEG allergy.23 However, to date, confirmation that IgE-mediated

238 reactions to PEG are responsible for reported reactions to COVID-19 vaccines is lacking.

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240 In addition to considering excipients as the cause of IgE-mediated allergic reactions to the

241 currently approved COVID-19 vaccines, alternative non-IgE pathways for activating mast cells

242 and other inflammatory cells must also be considered, as they can lead to a similar clinical

243 presentation. For example, activation of the complement system leads to the generation of C3a,

244 C4, and C5a, which are potent activators of inflammation and are called anaphylatoxins due to

245 their ability to cause non-IgE-mediated mast cell degranulation. One of the first reports of acute

246 anaphylaxis associated with serum complement depletion was of a 45-year-old female

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247 experiencing anaphylaxis after receiving lidocaine. She developed faintness, flushing, pallor,

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248 dyspnea, and hypotension, but she did not have urticaria or bronchospasm. Complement levels

249 were markedly low (C1q, C3, C4, C5, and Factor B).24 Depletion of complement levels and

250
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production of C3a and C5a have been seen in both mouse models of anaphylaxis and in clinical
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251 studies. C5a is the most potent of the anaphylatoxins and can contribute to vascular permeability
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252 as well as activation and chemotaxis of neutrophils, basophils, and mast cells. Infection and

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tissue injury can lead to activation of the complement system resulting in the generation of C3a

254 and C5a, and these mediators can lead to anaphylaxis. PEG IgM and IgG can cause complement-
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255 activation-related pseudoallergy (CARPA),25 a nonspecific immune response to PEGylated,

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256 nanoparticle-based medicines.26 This pathway may be responsible for reactions to medications

257 such as liposomal doxorubicin27 and other drugs in clinical trials.26 Clearly, it is important to

258 consider both IgE and alternative mechanisms for the current reactions. Measurement of serum

259 tryptase, complement, and PEG antibodies may help elucidate the mechanism of the drug-induced

260 reactions in patients following COVID-19 vaccination.

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262 It is also important to note that other non-immunologic reactions may masquerade as allergic

263 reactions including anaphylaxis. Vasovagal reactions are a well-known cause of hypotension and

264 syncopal reactions associated with injections including vaccines. Panic or anxiety reactions can

265 also present with symptoms masquerading as allergic reactions such as flushing, shortness of
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266 breath, tachycardia and lightheadedness. Inducible laryngeal obstruction (i.e., vocal cord

267 dysfunction) may also masquerade as anaphylaxis with prominent symptoms of shortness of

268 breath and throat tightness but may also include flushing.

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270 Evaluation of Patients with a Severe Allergy Histories and Guidance for Initial

271 Administration of COVID19 Vaccine

272 Massive vaccination programs were initiated within a few days after the FDA EAU of the

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273 COVID-19 vaccines. However, many questions surrounded the safety of giving these vaccines to

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274 individuals with a prior allergy history. One approach is to risk stratify patients prior to COVID-

275 19 vaccination. The authors from Mass General Brigham (MGB, formerly Partners HealthCare;

276
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comprised of 16 healthcare institutions in the New England area and the largest employer in
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277 Massachusetts) and Vanderbilt University Medical Center developed a plan of care to risk-stratify
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278 employees to guide safe vaccination in patients with higher risk allergy histories (Figure 2). In

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order to ensure vaccination in as many individuals as quickly as possible, our guidance, in line

280 with FDA and CDC guidance, results in the rapid assessment of patients with concerning
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281 anaphylaxis histories but does not preclude large groups of individuals from receiving the
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282 COVID-19 vaccine per usual protocol with either 15 minute or 30 minute observation periods.

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284 Four screening questions are presented to patients prior to the initial vaccination assess risk:

285 1. Do you have a history of a severe allergic reaction to an injectable medication

286 (intravenous, intramuscular, or subcutaneous)?

287 2. Do you have a history of a severe allergic reaction to a prior vaccine?

288 3. Do you have a history of a severe allergic reaction to another allergen (e.g., food, venom,

289 or latex)?

290 4. Do you have a history of a severe allergic reaction to polyethylene glycol (PEG),

291 a polysorbate or polyoxyl 35 castor oil (e.g. paclitaxel) containing injectable or vaccine?
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292 The screening questions are accompanied by a “Frequently Asked Questions” document

293 explaining medical terminology, including descriptions of PEG and polysorbates (Table 5).

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295 If the answer is “no” to all four questions, the individual would be deemed “lower risk” and

296 receive the vaccine under usual conditions with 15-minute observation period. If the answer to

297 question #1, #2 or #3 is “yes,” the individual would be deemed “medium risk” and require a 30-

298 minute observation period. In addition, if “yes” for #1 and #2, specific investigation as to the

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299 specific injectable products and vaccines should be pursued to determine if these products could

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300 have contained high molecular weight PEG, polysorbate or polyoxyl 35 (e.g. paclitaxel). If the

301 answer to question #4 is “yes,” the individual would be deemed “higher risk,” prompting

302
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evaluation with an allergist for expanded skin testing using non-irritating skin testing
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303 concentrations (Figure 3, Figure 4).10 If skin testing to PEG is positive, under EUA, the
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304 individual is not a candidate for the Pfizer-BioNTech or Moderna COVID-19 vaccines, and the

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skin test result to polysorbate 20 and 80 become important with regards to the safety of future

306 SARS-CoV-2 vaccines in development. If skin testing to PEG is negative, vaccination with the
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307 Pfizer-BioNTech or Moderna COVID-19 vaccines could proceed with 30 minutes of observation.
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308

309 Evaluation and Management of Patients with Potential Reactions to the COVID-19

310 Vaccines

311 For patients presenting to the allergist with a possible reaction to the first dose of their COVID-19

312 vaccine, the primary concern will be the suggested action for the second dose (Figure 5).

313 Although the vaccines have good efficacy related to only one dose, both the Pfizer-BioNTech and

314 Moderna vaccines received EUA approval for efficacy that was evaluated with two doses. As

315 such, a crucial determination will be establishing whether or not an allergic reaction occurred. For

316 patients with a possible allergic reaction after their first dose that does meet criteria for

317 anaphylaxis (e.g. immediate urticaria), vaccination programs should prioritize follow-up with an
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318 allergist who can perform specialized skin testing and risk stratify the patient for future SARS-

319 CoV-2 vaccine administration (Figure 5). Antihistamines do not prevent anaphylaxis and could

320 mask cutaneous symptoms leading to a delay in treatment. As such, we do not recommend

321 antihistamine pretreatment at this time. If a patient develops anaphylaxis to the first dose, shared

322 decision making with an allergist including risk stratification and expanded skin testing must

323 occur before any consideration of vaccine rechallenge (Figure 5). There are no data on the safety

324 of the second vaccine after anaphylaxis to the first dose. For other vaccines for which there is

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325 much more allergy experience, split dose challenges (e.g. 10-25% of dose followed 30 minutes

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326 later by remaining 75-90% dose) have been used. For patients with convincing anaphylaxis

327 histories (e.g. objective documentation of hypotension, hypoxia), we recommend expanded skin

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testing (Figure 3) and if positive, avoidance of a second dose of the mRNA SARS-CoV-2
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329 vaccine from either Pfizer-BioNTech or Moderna (Figure 3, Figure 5). We do not
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330 recommend vaccine skin testing at this time due to limited vaccine supply, lack of
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331 information on sensitivity or specificity, and unclear safety of skin testing to these

332 vaccines
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333
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334 All patients with potentially allergic reactions should be reported through formal processes,

335 which include the CDC’s Vaccine Adverse Event Reporting System (clinician entry), and

336 patients should be encouraged to use V-Safe CDC application for second dose reminders and to

337 enter reaction information (patient entry).28

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339 Supporting Safe Vaccination and Addressing Public Concern: A Role for the Allergist

340 Allergists’ expertise in the diagnosis and treatment of allergic reactions is invaluable for the

341 screening of high-risk individuals, the training of clinic staff conducting vaccinations, and the

342 management of patients who experience potentially allergic reactions to a COVID-19 vaccine.
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343 To date, MGB screening methods prior to vaccination consist of self-reported answers to a

344 questionnaire followed by telemedicine visits with an allergy clinician for high-risk patients. This

345 allows for both determination of risk and reassurance to patients deemed low or medium risk, that

346 they can safely receive the vaccine. For reactions that happen onsite, vaccination clinics are

347 reliant on staff that do not regularly diagnose and treat anaphylaxis, but CDC guidance

348 emphasized a minimum of 15 minutes of observation after all doses and ready access to

349 appropriate medical treatment for allergic reactions. Those staffing the vaccination clinic should

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350 have education around anaphylaxis treatment guidelines. Anaphylaxis is a life-threatening

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351 hypersensitivity reaction where rapid, early administration of epinephrine is vital for recovery.

352 Along with the CDC educational and training videos, allergists can help reassure patients and

353 educate providers by addressing a few key issues:

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354 1) Education on the diagnosis of anaphylaxis. Allergists should include differentiating
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355 vasovagal and anxiety reactions from anaphylaxis and defining anaphylaxis with

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infographics (Table 6, Figure 6)

357 2) Education on the treatment of anaphylaxis. Allergists should review epinephrine use and
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358 anaphylaxis-kit contents. For example, prior to the roll-out of MGB employee
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359 vaccination, allergists provided education and replaced epinephrine vials with

360 epinephrine autoinjectors. A non-sedating antihistamine was added to the anaphylaxis

361 kits.

362 3) Providing at-the-elbow support to vaccination programs. Allergists may need to be on-

363 site or on-call during higher risk vaccination. This will ensure that vaccinated individuals

364 with possible reactions receive the best diagnostic evaluation and treatment plan, while

365 linking them to appropriate follow-up care prior to the second vaccine dose.

366 4) Providing support to individuals with benign symptoms after discharge. Up to 80% of

367 individuals in the vaccine clinical trials had local symptoms after vaccination. Large local

368 reactions with symptoms of pain, itching, burning, or swelling at the site of injection do
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369 not preclude an individual from getting the vaccine again. Non-steroidal anti-

370 inflammatory drugs used to treat fever or myalgias may precipitate urticaria that could be

371 misattributed to the vaccine. Allergists can provide assessments and reassurance and

372 encourage completion of vaccination.

373

374 Summary

375 Allergic reactions to vaccines occur and can be attributed to various vaccine components. In

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376 support of the COVID-19 vaccine rollout programs, allergists must offer clear recommendations

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377 based on the best available information to date, which includes the comprehensive ingredients in

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the vaccines, allergy contraindications from the FDA, and guidance on administration from the
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379 CDC.

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381 As the US prepares for massive COVID-19 vaccination, allergists must prepare for two main
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382 population health challenges: (1) ensuring that highly allergic individuals feel appropriately

383 informed and supported to receive the vaccine and (2) ensuring that rare patients who suffer from
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384 a potentially allergic reaction to the first dose of a SARS-CoV-2 vaccine have the requisite
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385 information and support needed to decide if and how to receive the second dose. While these

386 challenges require attention immediately during the current vaccination process, it is of equal

387 importance that we must also design and conduct adequately powered studies to investigate the

388 potential mechanistic etiology of these reactions. We need to understand the safety issues

389 surrounding these vaccines, because the success of this the mRNA vaccine platform is

390 foundational to the flexibility of the COVID-19 response and our response to other viruses with

391 similar vaccines in phase I and II trials.

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392 ACKNOWLEDGEMENTS

393 The authors thank the Mass General Brigham health system faculty and staff, including Dean

394 Hashimoto, MD, Tanya Laidlaw, MD, David Hong, MD, Anna Feldweg MD, Karen Ferreira,

395 Keisha Lewis, Barbara Schmidt, Nahal Beik, Adam Landman, MD, Erica S. Shenoy, MD, PhD,

396 and Rajesh Patel, MD, MPH. The authors thank Upeka Samarakoon, PhD, MPH, Allen Judd,

397 Christian Mancini, Amelia Cogan, and Aubree McMahon for their research assistance.

398

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399 Table 1. Ingredients of the Pfizer-BioNTech and Moderna COVID-19 Vaccines

400
Pfizer-BioNTech Moderna
Active Nucleoside-modified messenger Nucleoside-modified mRNA
RNA (modRNA) encoding the viral encoding the viral spike (S)
spike (S) glycoprotein of SARS- glycoprotein of SARS-CoV-
CoV-2. 2
Inactive - lipids (4- SM-102 (Proprietary to
hydroxybutyl)azanediyl)bis(hexane- Moderna)
6,1-diyl)bis(2-hexyldecanoate)
2[(polyethylene glycol [PEG])- Polyethylene glycol (PEG)
2000]-N,N-ditetradecylacetamide 2000 dimyristoyl glycerol
(DMG)

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1,2-distearoyl-sn-glycero-3- 1,2-distearoyl-sn-glycero-3-
phosphocholine phosphocholine
Cholesterol Cholesterol

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Inactive – salts, sugars, Potassium chloride, monobasic Tromethamin, Tromethamin
buffers potassium phosphate, sodium hydrocholoride, acetid acid,

dehydrate
-p
chloride, dibasic sodium phosphate sodium acetate
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Sugar (sucrose) Sugar (sucrose)
Diluent (Sodium Chloride) Diluent (None)
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 19

402 Table 2: Polysorbate and polyethylene glycol excipients in select vaccines30

403
404
Excipient Vaccine type Vaccine Amount per dose
Polysorbate 20 Influenza Flublok&Flublock quad <27.5 mcg (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 mcg (Tween 80)
Polysorbate 80 Influenza Fluad 1.175 mg
Polysorbate 80 Influenza Fluarix quad <0.0550 mg (Tween 80)
Polysorbate 80 Influenza Flucelvax quad <1500 mcg (Tween 80)
Polysorbate 80 Influenza Flulaval Quad <887 mcg
Polysorbate 80 HPV Gardasil and Gardasil - 50 mcg

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Polysorbate 80 Hepatitis B Heplisav-B 0.1 mg/ml

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Polysorbate 80 DTaP Infanrix <100 mcg (Tween 80)
Polysorbate 80 Japanese encephalitis JE-Vax <0.0007%
Polysorbate 80
Polysorbate 80
Polysorbate 80
DTaP + IPV
DTaP+HepB+IPV
Pneumococcal
-pKinrix
Pediarix
13- Prevnar 13
<100 mcg (Tween 80)
<100 mcg (Tween 80)
100 mcg
re
valent
Polysorbate 80 DTaP + IPV Quadracel 10 ppm
lP

Polysorbate 80 Rotavirus RotaTeq ?

Polysorbate 80 Zoster Shingrix 0.08 mg
Polysorbate 80 Meningococcal group Trumenba 0.018 mg
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B
Polysorbate 80 DTaP+IPV+HepB+Hib Vaxelis <0.0056%
Polysorbate 80* Sars-CoV-2
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(Astrazenica)
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Sars-CoV-2
(Johnson&Johnson)
PEG2000 Sars-CoV-2
(Moderna)

Sars-CoV-2
(Pfizer)
*Not approved at the time of publication
405
 20

406 Table 3: Common injectable medications containing polyethylene glycol31

407
Generic Name (Brand Molecular Weight General Description
Name)

Methylprednisolone acetate PEG 3350 An anti-inflammatory

(Depo-Medrol) glucocorticoid for
intramuscular, intra-articular,
soft tissue or intralesional
injection.
Methoxy Polyethylene 30 kD Methoxy polyethylene Used to treat anemia in adults
Glycol-Epoetin Beta glycol butanoic acid with chronic kidney disease

of
(Micera) (CKD)

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Pegfilgrastim (Neulasta) 20 kD Monomethoxy Used to help reduce the
polyethylene glycol chance of infection due to a
-p low white blood cell count, in
people with certain types of
cancer (non myeloid), who
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receive anti-cancer medicines
(chemotherapy) that can
lP

cause fever and low white

blood cell count
na

Medroxyprogesterone acetate PEG 3350 Contraceptive and adjunctive

(Depo-Provera) therapy and palliative
treatment of inoperable,
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recurrent, and metastatic

endometrial or renal
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carcinoma.
Brilliant Blue G Ophthalmic PEG 3350 Disclosing agent indicated to
Solution (TissueBlue) selectively stain the internal
limiting membrane (ILM)
Sulfur hexafluoride PEG 4000 Ultrasound contrast agent
(Lumason)
Biomatoprost implant PEG, unspecified Reduction of intraocular
(Durysta) pressure (IOP) in patients
with open angle glaucoma
(OAG) or ocular hypertension
(OHT)
Trastuzumab (Herceptin, PEG 3350 Adjuvant treatment of HER2
Herzuma, Kanjinti, Ogivri, overexpressing node positive
Ontruzant) or node negative breast cancer
 21

Rilonacept (Arcalyst) PEG 3350 Interleukin-1 blocker for

treatment of Cryopyrin-
Associated Periodic
Syndromes (CAPS)

Perflutren lipid microsphere PEG 5000 Contrast agent used to

(Definity) brighten and clarify images of
the heart during
echocardiograms

408

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409 Table 4: Common injectable medications containing polysorbate

410
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

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Antifungal Anidulafungin (Eraxis) Polysorbate 80

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Anti-inflammatory Interferon beta 1a (Avonex, Plegridy) Polysorbate 20
Omalizumab (Xolair) Polysorbate 20
Antineoplastic
-p
Ofatumumab (Kesimpta) Polysorbate 80
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Siltuximab (Sylvant) Polysorbate 80
Paliperidone palmitate (Invega Trinza,
Antipsychotic Polysorbate 20
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Invega Sustenna)
Aripiprazole lauroxil (Aristada) Polysorbate 20
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Antiretroviral Ibalizumab (Trogarzo) Polysorbate 80

Polysorbate 20
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(Imraldi) /
Antipsoriatic Adalimumab (Humira, Imraldi)
Polysorbate 80
(Humira)
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Golimumab (Simponi) Polysorbate 80

Guselkumab (Tremfya) Polysorbate 80
Infliximab - dyyb (Inflectra, Remicade,
Polysorbate 80
Renflexis)
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
 23

Daratumumab/hyaluronidase (Darzalex
Polysorbate 20
Faspro)
Denosumab (Prolia, Xgeva) Polysorbate 20
Dinutuximab (Unituxin) Polysorbate 20
Enfortumab (Padcev) Polysorbate 20
Olaratumab (Lartruvo) Polysorbate 20
Palifermin (Kepivance) Polysorbate 20
Pertuzumab/trastuzumab/hyaluronidase
Polysorbate 20
(Phesgo)
Polatuzumab vedotin (Polivy) Polysorbate 20

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Tafasitamab (Monjuvi) Polysorbate 20

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Trastuzumab (Herceptin, Herceptin
Hylecta, Herzuma, Kanjinti, Ontruzant, Polysorbate 20
Trazimera) -p
Belantamab (Blenrep) Polysorbate 80
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Brentuximab vedotin (Adcetris) Polysorbate 80
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Cemiplimab (Libtayo) Polysorbate 80

Docetaxel (Taxotere) Polysorbate 80
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Durvalumab (Imfinzi) Polysorbate 80

Elotuzumab (Empliciti) Polysorbate 80
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Etoposide (Toposar, VePesid) Polysorbate 80

Fam-trastuzumab deruxtecan (Enhertu) Polysorbate 80
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Fosaprepitant dimeglumine (EMEND,

Polysorbate 80
Fosaprepitant)
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
Ramucirumab (Cyramza) Polysorbate 80
Rituximab (Truxima, Rituxan, Ruxience) Polysorbate 80
 24

Rituximab and hyaluronidase (Rituxan

Polysorbate 80
Hycela)
Temsirolimus (Torisel) Polysorbate 80
Temozolomide (Temodar) Polysorbate 80
Medroxyprogesterone acetate (Depo-
Contraceptive Provera, Depo-Provera CI, Depo-subQ Polysorbate 80
provera 104)
Corticosteroid Methylprednisolone acetate (Depo-Medrol) Polysorbate 80
Triamcinolone acetonide (Aristocort Forte,
Aristospan, Kenalog-40, Kenalog-10,
Polysorbate 80
Protherix, Triesence, Triloan Suik, Triloan

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Diagnostic Sincalide (Kinevac) Polysorbate 20
Tuberculin purified protein derivative
Polysorbate 80

Disease-modifying
-p
(Aplisol, Tubersol)
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Anakinra (Kineret) Polysorbate 80
antirheumatic drug (DMARD)
Tocilizumab (Actemra) Polysorbate 80
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Enzyme Velaglucerase alfa (Vpriv) Polysorbate 20

Imiglucerase (Cerezyme) Polysorbate 80
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Taliglucerase alfa (Elelyso) Polysorbate 80

Erythoid maturation agent Luspatercept (Reblozyl) Polysorbate 80
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Coagulation factor Xa (recombinant),

Factor Xa inhibitor antidote Polysorbate 80
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inactivated-zhzo (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,
Polysorbate 20
Udenyca)
Romiplostim (Nplate) Polysorbate 20
Darbepoetin alfa (Aranesp) Polysorbate 80
Filgrastim (Neupogen, Nivestym, Granix,
Polysorbate 80
Zarxio)
Hepatitis B/ Hepatitis C agent Peginterferon (Pegasys Pegintron) Polysorbate 80
Hemostatic Vitamin K (Phytonadione) Polysorbate 80
 25

Hepatitis B Immune Globulin (HepaGam B,

Immune globulin Polysorbate 80
Nabi-HB)
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
Vedolizumab (Entyvio) Polysorbate 80
agent
Interleukin inhibitor Sarilumab (Kevzara) Polysorbate 20
Dupilumab (Dupixent) Polysorbate 80

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Secukinumab (Cosentyx) Polysorbate 80

Kallikrein inhibitor
-p
Tildrakizumab -asmn (Ilumya)
Lanadelumab (Takhzyro)
Polysorbate 80
Polysorbate 80
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Leptin analog Metreleptin (Myalept) Polysorbate 20
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Macular degeneration agent Aflibercept (Eylea) Polysorbate 20

Ranibizumab (Lucentis) Polysorbate 20
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Brolucizumab (Beovu) Polysorbate 80

Monoclonal antibody treatment Ocrelizumab (Ocrevus) Polysorbate 20
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Remdesivir (Veklury) Polysorbate 20

Romosozumab (Evenity) Polysorbate 20

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Teprotumumab (Tepezza) Polysorbate 20

Atoltivimab/maftivimab/odesivimab-ebgn
Polysorbate 80
(Inmazeb)
Bamlanivimab Polysorbate 80
Burosumab (Crysvita) Polysorbate 80
Canakinumab (Ilaris) Polysorbate 80
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
 26

Muscle relaxant Dantrolene sodium (Dantrium, Ryanodex) Polysorbate 80

P-selectin inhibitor Crizanlizumab (Adakveo) Polysorbate 80
Proprotein convertase subtilisin
Alirocumab (Praluent) Polysorbate 20
kexin type 9 (PCSK9) inhibitor
Evolocumab (Repatha) Polysorbate 80
Rheumatologic Belimumab (Benlysta) Polysorbate 80
Thrombolytic Tenecteplase (Tnkase) Polysorbate 20
Alteplase (Cathflo Activase) Polysorbate 80
Reteplase (Retavase) Polysorbate 80

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Vitamin infusion Calcitriol (Calcijex, Rocaltrol) Polysorbate 20
Doxercalciferol (Hectorol) Polysorbate 20

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Vitamins A, B1, B2, B6, C, D3, E, K
Polysorbate 80

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412 Table 5: Frequently Asked Questions (Patient Handout)

413
414 What is vaccine allergy?
415 Similar to medications or foods, people can be allergic to a vaccine. However, allergic reactions to vaccines
416 are very rare (about 1 in 1 million people will have an allergic reaction to a vaccine). Some reactions are mild, such as
417 hives as the only symptom, while others are more severe. A severe allergic reaction is called anaphylaxis. Symptoms
418 start very quickly (usually within minutes) and almost always within 4 hours of vaccination and typically include
419 multiple parts of the body: hives on the skin; swelling of mouth, lips, tongue or throat; shortness of breath, wheezing, or
420 chest tightness; or low blood pressure or loss of consciousness. About half of allergic reactions to vaccines happen
421 in the first 15 minutes after receiving the vaccination.
422
423 What about redness and swelling at the injection site- is that an allergic reaction?
424 Sometimes vaccines can cause large local reactions at the injection site, and these can begin hours after the vaccination
425 or even the next day. The skin at the site of vaccination can become sore, swollen, red, and painful. Sometimes
426 it can also become itchy. The symptoms can last several days. Although this type of reaction can be uncomfortable, if it
427 does not include the symptoms of allergic reactions listed above, it is not an allergic reaction to the vaccine, there is no
428 risk of an allergic reaction with the next vaccination, and an allergist consultation is not necessary.

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429
430 What is a severe allergic reaction?
431

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A severe allergic reaction is sometimes called anaphylaxis. Symptoms start very quickly (usually within minutes) and
432 almost always within 4 hours of vaccination and typically include hives; swelling of mouth, lips, tongue or throat;
433 shortness of breath, wheezing, or chest tightness; or low blood pressure or loss of consciousness.
434 -p
435 What are the ingredients in the Pfizer-BioNTech COVID-19 Vaccine?
436 1. mRNA.The active ingredient is a nucleoside-modified messenger RNA (modRNA) encoding the viral spike
re
437 (S) glycoprotein of SARS-CoV-2.
438 2. Inactive ingredients:
439 • Lipids ((4-hydroxybutyl)azanediyl)bis(hexane-6,1-diyl)bis(2-hexyldecanoate), [(polyethylene
lP

440 glycol [PEG])-2000]-N,N-ditetradecylacetamide, 1,2-distearoyl-sn-glycero-3-phosphocholine, and 0.2 mg

441 cholesterol),
442 • Electrolytes potassium chloride, monobasic potassium phosphate, sodium chloride, dibasic sodium
443 phosphate dihydrate, and
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444 • Sugar (sucrose)

445 • The diluent, added to the vaccine for administration, is saline (Sodium Chloride)
446
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447 What are the ingredients in the Moderna COVID Vaccine?

448 1. messenger ribonucleic acid (mRNA)
449 2. Inactive Ingredients:
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450 • lipids (SM-102, polyethylene glycol [PEG] 2000 dimyristoyl glycerol [DMG], cholesterol, and 1,2-
451 distearoyl-sn-glycero-3-phosphocholine [DSPC]),
452 • tromethamine,
453 • tromethamine hydrochloride,
454 • acetic acid,
455 • sodium acetate,
456 • Sugar (sucrose)
457
458 Which patients should speak to an allergist before receiving the vaccine?
459 In the vaccine trials, only patients with a history of severe allergic reaction associated with a vaccine and/or severe
460 allergic reaction to any component of the vaccine were excluded. If you are unsure about your vaccine or PEG allergy
461 history, an allergy consultation is recommended. In general, most patients allergic to one vaccine can receive other
462 vaccinations safely.
463
464 What is polyethylene glycol (PEG) and what are common products that contain PEG?
465 Polyethylene glycol (PEG) is a common, water-soluble ingredient in a wide variety of commercial products including
466 some vaccines and more than 1000 FDA approved medications. It is the primary ingredient in commonly used
467 colonoscopy preparations (Golytely) or constipation treatment (Miralax) as well as in IV medications such as
468 PEGylated medications. It is also in ultrasound gel and injectable steroid injections such as methylprednisolone
469 acetate. Reactions to polyethylene glycol are exceedingly rare but anaphylaxis has been reported.
470
 28

471 Table 6. Anaphylaxis compared to vasovagal reaction32

Signs and Symptoms Vasovagal Reaction Anaphylaxis
Within 30 minutes after
Sometimes before, usually
injection; the most severe
Interval (after injection) after a few seconds to a few
reactions begin within the first
minutes after the injection
15 minutes
Fainting sensation, dizziness, Anxiety, which may progress
Consciousness loss of consciousness in some into unconsciousness in severe
cases cases
Respiratory difficulties;
Slow, with a few seconds of
Breathing coughing, sneezing, wheezing,
apnea in some cases
stridor
Pulse Slow and weak, but regular Rapid, weak and irregular
• Warm skin, progressing to

of
clammy and pallor
Diaphoresis, clammy skin, • Pruritis and urticaria

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Skin
pallor (>90% of cases)
• Swelling of face and
-p tongue
Hypotension (systolic pressure
<90 mmHg), which may
re
Blood pressure Transient hypotension
progress to cardiovascular
collapse
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Nausea, vomiting, abdominal

Gastro-intestinal system Nausea, vomiting
pains, diarrhea
• Place client in a
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recumbent position and

elevate legs above head
(or have client sit with See Manitoba Health Protocol
ur

Treatment head between their knees) for Management of Suspected

• Ventilate the room well Anaphylaxis
•
Jo

Place cold, damp cloth on

face
• Give reassurance
Before vaccinating, ask if the
Do not vaccinate a standing person has ever had an
person. Before vaccinating, anaphylactic reaction to any
Prevention
ask if the person tends to faint; product; if yes, ask for the
if so ask patient to lie down name of the product and
decide accordingly
472

473
 29

474 FIGURE LEGENDS

475 Figure 1. Chemical structure and similarities between polyethylene glycol and polysorbate 80.

476 Figure 2. Risk stratification pathways with categories based on Mass General Brigham and

477 Vanderbilt allergy expert consensus prior to initial COVID-19 vaccination.

478 *If “yes” for questions 1 or 2, specific investigation as to the specific injectable products and

479 vaccines should be pursued to determine if these products could have contained high molecular

480 weight PEG, polysorbate or polyoxyl 35 castor oil (paclitaxel).

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¶
481 Current CDC guidance suggests 30 minutes of observation for patients with any history of

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482 anaphylaxis
§
483 See Figures 3 and 4 for expanded skin testing algorithm and non-irritating skin test

484 concentrations.
-p
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‡
485 If skin testing to PEG is positive, as of Dec 28th, 2020, Pfizer-BioNTech and Moderna are the
lP

486 only FDA approved vaccines and under EUA can not be given to an individual with a history of

487
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anaphylaxis to a component of the COVID-19 mRNA vaccine. The skin testing result to

488 polysorbate 20 and 80 become more important with regards to the safety of any future
ur

489 vaccination.
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490 Figure 3. Expanded Skin Testing Procedure. In patients with positive PEG skin testing, the result

491 of polysorbate 20 and 80 skin testing becomes important with regards to the safety of future

492 SARS-CoV-2 vaccines in development. Therefore, based on clinical history, skin testing to both

493 PEG and polysorbate during one clinic visit may be appropriate.

494 *Anaphylaxis with intradermal skin testing in PEG allergic patients has been described. We

495 recommend staff have anaphylaxis training and anaphylaxis kit available in close proximity.
¶
496 Tables 2, 3 and 4 contain a list of PEG/polysorbate containing vaccines and injectables that can

497 be shared with patients

498 Figure 4: Non-Irritating Skin Testing Concentrations for PEG3350 and Polysorbate
 30

499 *Methyl-prednisolone sodium succinate does not contain PEG or polysorbate 80 and can be used

500 as an additional control

¶
501 Refresh eye drops and Prevnar are an alternate source for polysorbate 80 skin testing
§
502 Some brands of methylprednisolone acetate contain polysorbate and PEG3350 while others only

503 have PEG3350; use methylprednisolone acetate containing PEG3350 only

‡
504 Non-irritating skin testing concentrations for Methyl-prednisolone Sodium Succinate and

505 Triamcinolone Acetonide include a range of 10-40 mg/mL for initial skin prick testing with

of
506 subsequent 10x dilutions.29 One author (EP) has extensive experience using 50 mg/mL as a non-

ro
507 irritating skin testing concentration for Methyl-prednisolone Sodium Succinate skin prick testing

508 with subsequent 10x dilutions.

509
-p
Figure 5. Risk stratification pathways with categories based on Mass General Brigham and
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510 Vanderbilt allergy expert consensus after allergic reaction to first dose of COVID19 vaccine.
lP

511 *Ideal laboratory assessment includes reaction serum tryptase within 2 hours and complement

512
na

activation by ELISA (C3a, C3b, C5a, C5b-9 ideally within one hour; send to National Jewish);

513 follow-up baseline serum tryptase is also useful

ur

¶
514 Shared decision making with allergist including risk stratification and expanded skin testing to
Jo

515 determine eligibility for second dose or future challenge with other SARS-CoV-2 vaccines. There

516 are no data on the safety of the second vaccine after anaphylaxis to the first dose. If decision

517 made to proceed with vaccination, consider 2-step graded challenge but no current safety or

518 efficacy data support this approach. Staff should have anaphylaxis training and anaphylaxis kit

519 needs to be available in close proximity.

§
520 See Figures 3 and 4 for expanded skin testing algorithm and non-irritating skin test

521 concentrations
‡
522 Consider 2-step graded challenge to the vaccine but no current safety or efficacy data support

523 this approach.

524 **Consider 15 or 30 minute observation based on clinical judgement.

 31

525 Figure 6: Graphic to assist in the recognition of anaphylaxis.33

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 32

526 REFERENCES

527 1. Adeline S, Jin CH, Hurt A, Wilburn T, Wood D, Talbot R. Coronavirus by

528 the numbers: Coronavirus is surging: How severe is your state's
529 outbreak? Washington DC: National Public Radio; 2020 (Updated December
530 24, 2020). Available at: https://www.npr.org/sections/health-
531 shots/2020/09/01/816707182/map-tracking-the-spread-of-the-coronavirus-in-the-
532 u-s. Accessed December 24, 2020.
533 2. Polack FP, Thomas SJ, Kitchin N, Absalon J, Gurtman A, Lockhart S, et al.
534 Safety and efficacy of the BNT162b2 mRNA Covid-19 vaccine. N Engl J Med. 2020. In
535 press. doi: 10.1056/NEJMoa2034577. PMID: 33301246; PMCID: PMC7745181.
536 3. Moderna COVID-19 vaccine [FDA briefing document]. Silver
537 Spring, MD: United States Food and Drug Administration, Vaccines and Related

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538 Biological Products Advisory
539 Committee; 2020. Available at: https://www.fda.gov/media/144434/download.

ro
540 Accessed December 24, 2020.
541 4. Pfizer-BioNTech COVID-19 vaccine (BNT162, PF-07302048) [FDA Briefing
542
543
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Document]. Silver Spring, MD: United States Food and Drug Administration, Vaccines
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re
544 Committee; 2020. Available at: https://www.fda.gov/media/144246/download. Acce
545 ssed December 24, 2020
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546 5. Interim clinical considerations for use of mRNA COVID-19 vaccines currently
547 authorized in the United States - Appendix B. Atlanta, GA: United States Centers for
548 Disease Control and Prevention; 2020 (Reviewed December 20, 2020).
na

549 Available at: https://www.cdc.gov/vaccines/covid-19/info-by-product/clinical-

550 considerations.html#Appendix-B. Accessed December 24, 2020.
551 6. McNeil MM, Weintraub ES, Duffy J, Sukumaran L, Jacobsen SJ, Klein NP, et al.
ur

552 Risk of anaphylaxis after vaccination in children and adults. J Allergy Clin
553 Immunol. 2016;137:868-78. doi: 10.1016/j.jaci.2015.07.048. PMID: 26452420;
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554 PMCID: PMC4783279.

555 7. Stone CA Jr, Rukasin CRF, Beachkofsky TM, Phillips EJ. Immune-mediated
556 adverse reactions to vaccines. Br J Clin Pharmacol. 2019;85:2694-706. doi:
557 10.1111/bcp.14112. PMID: 31472022; PMCID: PMC6955412.
558 8. Nakayama T, Aizawa C. Change in gelatin content of vaccines associated with
559 reduction in reports of allergic reactions. J Allergy Clin Immunol. 2000;106:591-2. doi:
560 10.1067/mai.2000.108433. PMID: 10984383.
561 9. Andersen DV, Jørgensen IM. MMR vaccination of children with egg allergy is
562 safe. Dan Med J. 2013;60:A4573. PMID: 23461988.
563 10. Stone CA Jr, Liu Y, Relling MV, Krantz MS, Pratt AL, Abreo A, et al.
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