key: cord-1012457-0ds8a6h1
authors: Banerji, Aleena; Norton, Allison E.; Blumenthal, Kimberly G.; Stone, Cosby A.; Phillips, Elizabeth
title: Rapid Progress in Our Understanding of Covid-19 Vaccine Allergy: A Cause for Optimism, not Hesitancy
date: 2022-04-07
journal: J Allergy Clin Immunol
DOI: 10.1016/j.jaci.2022.03.023
sha: eb1e764ff0655864f6ea76ca7b34bc1bca5d5af5
doc_id: 1012457
cord_uid: 0ds8a6h1

Anaphylaxis is a life-threatening condition and when associated with vaccination, leads to vaccine hesitancy. The concerns around vaccine related anaphylaxis have become even more important during the COVID-19 pandemic where the COVID-19 vaccines remain one of our most important tools. While rates of anaphylaxis to COVID-19 vaccines are not significantly different from other vaccines, CDC guidance recommends avoidance of the same COVID-19 vaccine in individuals who had an allergic reaction or are allergic to a COVID-19 vaccine component. Fortunately, our understanding of COVID-19 vaccine allergic reactions has improved dramatically in the past year in large part due to significant research efforts from individuals in the allergy community. Initially, researchers published algorithmic approaches using risk stratification and excipient skin testing. However, as our experience and knowledge improved with ongoing research, we have better data showing safety of repeat vaccination despite an initial reaction. We review our progress starting in December 2020 when the FDA approved the first COVID-19 vaccine in the United States through early 2022 highlighting our success in understanding COVID-19 vaccine reactions.

confirmed by positive skin testing. 6 Conversely, there are now multiple reports of individuals 89 previously known to have PEG anaphylaxis; skin tests positive to both PEG and polysorbate 80 90 who have tolerated the mRNA or adenoviral vector 8 In addition, there are 91 reports of patients with histories of immediate reactions to pegylated drugs (i.e., pegaspargase) or 92 those containing PEG-derivatives (i.e., paclitaxel) who tolerated the mRNA vaccines. [9] [10] [11] [12] Current 93 evidence suggests that those with presumed anaphylaxis to the first dose of the COVID-19 mRNA 94 vaccines largely tolerate second and booster doses, which favors a non-IgE-mediated 95 mechanism. 13,15 Many immediate reactions were experienced without objective hypersensitivity 96 symptoms documented were ultimately vasovagal, sympathetic stress reaction, reactogenic, or 97 syncopal rather than allergic. 3 Recent reports suggest that PEG skin testing after an mRNA 98 COVID19 vaccine reaction is not needed and may delay completion of vaccination. Many 99 individuals with immediate allergic and in some cases anaphylactic reactions have tolerated 100 subsequent doses of mRNA vaccines, although overwhelmingly with allergist oversight. 101

There is an ongoing crucial need to decrease COVID-19 vaccine hesitancy despite an 102 allergy history. First, for viral variants of concern such as Delta and Omicron, reduction in disease 103 severity is dependent on boosting the primary mRNA vaccination. 16 

Beyond IgE-mediated reactions which appear to occur only rarely, there is some theoretical 115 evidence that non-IgE mediated mechanisms such as complement activation-related pseudo 116 allergy (CARPA) could be caused by PEG IgM and IgG in vaccine reactors. 17 However, given that 117 5-10% of the population have preexisting IgM and/or IgG to PEG, this test is unlikely to be useful 118 in predicting reactions to mRNA vaccines. 18 It is also possible that some individuals might have 119 reactogenic symptoms associated with the active components of the vaccine that unmask an 120 underlying tendency to non-IgE mediated mast cell activation. There may also be diverse triggers 121 of non-allergic symptoms including underlying anxiety around vaccination. Exacerbation of 122 urticaria and the occurrence of chronic urticaria following both natural infection with and COVID-19 vaccination have been described. 19, 20 Although new insights on mechanism will 124 come from studies currently in progress, it is now clear that the vast majority of individuals with 125 a history of PEG allergy or COVID19 vaccine reactions can safely receive subsequent doses of 126 the mRNA vaccines. 127

True immediate and anaphylactic reactions to PEG are fortunately very rare. 21 Unlike 130 reactions to the mRNA vaccines that are predominantly in females, PEG anaphylaxis appears to 131 be more equal amongst males and females. 21, 22 Current reports are reassuring that many patients 132 with histories of PEG anaphylaxis and positive skin tests to PEG3350 or higher tolerate mRNA 133 J o u r n a l P r e -p r o o f Banerji, 8 vaccines. 7 At this time, it is still prudent to manage these rare cases carefully and consider skin 134 prick testing to PEG and the mRNA vaccines with physician-observed vaccination ( Figure 2) . 135

Although it appears that the vast majority of those with anaphylaxis to PEG will tolerate COVID-136 19 mRNA vaccines, these individuals are still at risk and likely to have potentially fatal 137 anaphylaxis to the higher molecule weight PEG (e.g. PEG3350) products to which they initially 138 reacted. All individuals with a history of PEG anaphylaxis regardless of whether they have 139 tolerated an mRNA vaccine should still be worked up comprehensively by an allergist to determine 140 the future safety of PEG-containing drug and products. 23 141 142

The approach to the COVID-19 pandemic has and will continue to require a global effort 144 that should see its eventual retreat into endemicity. The rollout of COVID-19 vaccines has been a 145 remarkable global safety success story because of exceptional clinical dedication and care, 146 collaboration, and research efforts. While patients are still seeking "exemption" from the first or 147 subsequent COVID-19 vaccine doses for a variety of reasons, data suggest that allergy is almost 148 never a reason for COVID-19 vaccine "exemption". We can be reassured one year following the 149 COVID-19 vaccine rollout that there is no history of allergy, including to foods, drugs, vaccines, 150 or other substances that is a contraindication to receipt of any COVID-19 vaccine. With 151 anaphylaxis or another adverse event to any dose of a COVID-19 vaccine, shared decision making 152

is key although reassuringly patients appear to tolerate subsequent COVID-19 mRNA vaccination. 153

The greatest contribution from the Allergy & Immunology community, in this challenging period 154

where we continue to strive towards achieving universal global COVID-19 vaccination, is 155 consultation for vaccine counseling, which may enable the vaccine-hesitant or resistant patient to 156 J o u r n a l P r e -p r o o f Banerji, 9 get immunized. The experience of rolling out a global immunization effort against SARS-CoV2 157 has been novel and challenging, and amongst those challenges was the need to adequately 158 immunize patients who had experienced immediate vaccine reactions. In a matter of months, 159 research from around the world improved our understanding of COVID-19 vaccine allergy and 160 allowed large-scale vaccination efforts to succeed. 

Reports of Anaphylaxis After Receipt of mRNA 182

COVID-19 Vaccines in the US

Acute Allergic Reactions to mRNA COVID-19 Vaccines

Maintaining Safety with SARS-CoV-2 Vaccines

Vaccination in Patients with Reported Allergic Reactions: Updated Evidence and 191

mRNA COVID-19 Vaccine Allergic Reactions: Limited Role for Excipient Skin Testing

Anaphylaxis to Pfizer/BioNTech 196 mRNA COVID-19 vaccine in a patient with clinically confirmed PEG allergy

COVID-19 vaccination in patients with polyethylene glycol allergy: A case series

COVID-19 vaccine tolerated in 10 patients with confirmed 203 polyethylene glycol allergy

mRNA COVID-19 vaccine safety in patients with previous immediate hypersensitivity to 206 pegaspargase

SARS-CoV-2 vaccines in persons with a known history of pegaspargase allergy: A single 209 institution experience

Safety of administration 211 of BNT162b2 mRNA (Pfizer-BioNTech) COVID-19 vaccine in youths and young adults 212 with a history of acute lymphoblastic leukemia and allergy to PEG-asparaginase

COVID-19 vaccines tolerated in patients with paclitaxel and docetaxel allergy

Anaphylaxis to the first dose of mRNA SARS-CoV-2 vaccines: Don't give up on the 219 second dose

Evaluation of the Second Dose of Messenger RNA COVID-19 Vaccines in Patients With 222

Immediate Reactions to the First Dose

incidence, severity, and risk factors associated with treated acute-onset COVID-19

mRNA vaccination-associated hypersensitivity reactions

Vaccination Neutralization of SARS-CoV-2 Omicron Infection

Potential mechanisms of anaphylaxis to COVID-19 mRNA vaccines

IgE in anaphylaxis associated with polyethylene glycol

After COVID-19 Vaccine

COVID-19 Disease Leading 239 to Chronic Spontaneous Urticaria Exacerbation: A Romanian Retrospective Study

Hypersensitivity to Polyethylene Glycols and Polysorbates: More Common Than We 243

Have Recognized

Anaphylaxis to PEGylated liposomal 245 echocardiogram contrast in a patient with IgE-mediated macrogol allergy