Clinical Implications.
The second dose of Pfizer-BioNTech vaccine can be administered safely in children with a history of immediate and potentially allergic reactions to the first dose, as well as in children with a history of polyethylene glycol or polysorbate allergy.
Since their release in and subsequent approval for adult and pediatric patients, vaccines against SARS-CoV-2 have provided hope for ending the COVID-19 pandemic. However, reactions to mRNA vaccines early in the global vaccine rollout have hampered this effort not only by preventing the administration of a second dose but also by reducing compliance with the first dose. After clinical reports of allergic reactions were made concerning COVID-19 vaccinations, the US Centers for Disease Control and Prevention recommended that those who have an allergy to any component of the vaccine or who had an immediate allergic reaction (within 4 hours) to the first vaccine dose should not receive the second dose. Concerns were raised regarding the role of polyethylene glycol (PEG) or the chemically related polysorbate in immediate reactions given the presence of PEG 2000, an excipient used to stabilize the lipid nanoparticle in the mRNA vaccines. Since then, numerous reports have demonstrated the safety of administering the second dose of mRNA vaccine to adult patients who reacted to the first dose, as well as the safety of administering mRNA vaccine to adult patients with a history of PEG/polysorbate allergy.1, 2, 3, 4, 5 Despite administration of the Pfizer-BioNTech (New York, NY) SARS-CoV-2 mRNA vaccine to patients aged 5 years and older as of October 2021, there have been no reports evaluating safety in the pediatric population. In this study, we examine the safety of the second dose of this vaccine in children with an immediate or potential allergic reaction to the first dose as well as in children with documented PEG/polysorbate allergy.
A specialized vaccine clinic evaluated children referred for suspected immediate allergic reactions to the first dose of the Pfizer-BioNTech SARS-CoV-2 mRNA vaccine or suspected PEG/polysorbate allergy. All children were evaluated from May 2021 to February 2022; their families have provided consent for the publication of clinical data. Nine children were evaluated after experiencing an allergic reaction to the first dose (average age, 13 years; range, 8-17 years). Of the nine children evaluated, only two were female (22.2%). Seven children had a history of atopy (allergic rhinitis, food allergy, asthma, and penicillin allergy) and three reported a history of anaphylaxis to food or medicine. We evaluated the symptoms reported using the 2006 National Institute of Allergy and Infectious Disease and the Food Allergy and Anaphylaxis Network diagnostic criteria for anaphylaxis6 (see Table E1 in this article’s Online Repository at www.jaci-inpractice.org) as well as Brighton criteria for anaphylaxis7 (see Table E2 in this article’s Online Repository at www.jaci-inpractice.org).
Three children (33.3%) reported symptoms that met both National Institute of Allergy and Infectious Disease and Food Allergy as well as Anaphylaxis Network and Brighton criteria for anaphylaxis,7 whereas six children (66.6%) reported symptoms that were insufficient to meet the case definition. With parental consent, eight children went on to have an in-clinic observed second-dose administration of 0.3 mL Pfizer-BioNTech SARS-CoV-2 mRNA. One child (patient 8) received the second dose at a local pharmacy owing to scheduling constraints. The vaccine was administered as a single dose without premedications. All children successfully received the second vaccination with no or minimal symptoms (Table I ).
Table I.
Patient demographics, Pfizer-BioNTech mRNA COVID-19 dose 1 reaction history, and Pfizer-BioNTech mRNA COVID-19 dose 2 challenge result
| Patient ID | Age | Sex | Atopic history | Anaphylaxis (cause) | Onset after receipt, min | Signs and symptoms | Intervention | Time to symptoms resolution, h | Meet National Institute of Allergy and Infectious Disease and the Food Allergy and Anaphylaxis Network criteria | Brighton score | Symptoms after second dose |
|---|---|---|---|---|---|---|---|---|---|---|---|
| 1 | 16 | F | Allergic rhinitis, food allergy (shellfish) | No | <15 | Scratchy throat, tachycardia, elevated blood pressure, rash (face and torso), coughing | Diphenhydramine, lorazepam | 4 | Yes | 2 | None |
| 2 | 13 | M | Allergic rhinitis, asthma | No | <15 | Itchy throat | No intervention | 3 | INS | INS | None |
| 3 | 17 | M | Chronic urticarial and angioedema, idiopathic anaphylaxis | Yes (idiopathic) | 0.5 | Itching (arm and head), cough, difficulty swallowing, vomiting, rash (face and neck), stomach pain | Diphenhydramine, epinephrine, dexamethasone, famotidine | 2 | Yes | 2 | Mild pruritus (none after booster dose) |
| 4 | 15 | F | No | No | 10 | Rash (injection site, upper chest and neck) | Diphenhydramine | 1-2 | INS | INS | None |
| 5 | 12 | M | Food allergy (peanut, sesame, egg, hazelnut), penicillin allergy | Yes (peanut) | 5 | Raised itchy rash (generalized) | No intervention | Several | INS | INS | None |
| 6 | 8 | M | No | No | 10 | Throat hurt, closing up, dry heaving, gagging, nausea, difficulty breathing | Epinephrine, diphenhydramine, famotidine, steroids | Several | Yes | 2 | None |
| 7 | 10 | M | Allergic rhinitis | No | 120 | Itchy hives | Diphenhydramine, steroids | 6 | INS | INS | None |
| 8 | 8 | M | Allergic rhinitis | No | 120 | Facial swelling, swelling at injection site | No intervention | 2 | INS | INS | None |
| 9 | 10 | M | Allergic rhinitis, food allergy (tree nuts) | Yes (tree nuts) | <15 | Cough, throat itching | Diphenhydramine | 1 | INS | INS | None |
INS, insufficient information to meet case definition.
We also evaluated four children with clinical histories concerning for PEG/polysorbate allergy (Table II ). Two were female, average age 16 years (range, 15-17 years). Patients A, C, and D experienced reactions to PEG-asparaginase during treatment for leukemia, whereas patient B experienced a reaction to the polysorbate component of insulin as well as reported reactions to polysorbate in imitation whipped cream and pickles. Patient C also reported an anaphylactic episode to amphotericin B that had manifested as throat tingling, trouble breathing, and oxygen desaturations. Patient B had tested positive on skin testing to polysorbate 65 and 80 several years prior, but patients A, C, and D had never been skin tested for PEG or polysorbate. All four children tolerated PEG 3350 laxative with no issues. Patient A, B, and C elected to proceed with the vaccine challenge whereas patient D elected to receive Johnson & Johnson (New Brunswick, NJ) vaccine when he turned age 18 years, 3 months after evaluation. We elected not to perform skin testing to PEG/polysorbate before the vaccine challenge based on our review of data in adult patients2 and the recently published consensus recommendation.8 All three children tolerated both the first and second doses of the Pfizer-BioNTech SARS-CoV-2 vaccine given as a single dose, with no symptoms.
Table II.
Patient demographics and PEG/polysorbate reaction history
| Patient ID | Age | Sex | Initial reaction history (year) | Atopic history | Anaphylaxis (source) | Other medical conditions | Skin testing | Date Pfizer-BioNTech vaccine given | Symptoms after administration |
|---|---|---|---|---|---|---|---|---|---|
| A | 17 | F | Itching, rash, lip and ear swelling within minutes after PEG asparaginase (2013) | Allergic rhinitis, oral allergy syndrome | No | Pre-B-ALL on remission (6 y) | No | August 6, 2021; second dose on August 30, 2021 | None |
| B | 16 | F | Generalized pruritic rash, throat swelling, loss of consciousness after Lantus (Sanofi, Bridgewater, NJ) injection (2009) | Drug allergy (polysorbate 80) | Yes (insulin, imitation whipped cream, pickle) | Lymphopenia, neutropenia, type I diabetes status post pancreatic transplantation, hypogam-maglobulinemia | Positive to polysorbate 65 and 80 | August 6, 2021; second dose on August 30, 2021 | None |
| C | 15 | M | Facial swelling, hives, and blisters 60 min after PEG asparaginase (2016) | Drug allergy (PEG, trimethoprim/sulfamethoxazole, amphotericin B) | Yes (amphotericin B) | Pre-B-ALL on remission (3.5 y) | No | September 3, 2021; second dose on September 28, 2021; booster dose on April 1, 2022 | None |
| D | 17 | M | Generalized pruritic rash, hypotension, lip and periorbital swelling, nausea and vomiting 15 min after PEG asparaginase (2015) | Drug allergy (PEG) | Yes (PEG) | T-cell ALL on remission (4 y) | No | N/A; patient elected to receive Johnson & Johnson vaccine | N/A |
N/A, not applicable; PEG, polyethylene glycol; Pre-B-ALL, precursor B-cell acute lymphoblastic leukemia; T-cell ALL, T-cell acute lymphoblastic leukemia.
Currently, there is limited guidance regarding how to evaluate and proceed with the second dose in children with reactions to the first mRNA vaccine dose. Because identifying anaphylaxis in children can be especially challenging, children with potential anaphylaxis should undergo careful evaluation to weigh the benefits and risks of the second dose. This study presents a cohort of children who had immediate reactions to the first Pfizer-BioNTech SARS-CoV-2 vaccine dose and received a second dose with minimal side effects. We also presented three children with a history of PEG/polysorbate allergy, who tolerated both doses of Pfizer-BioNTech SARS-CoV-2 vaccine with no issues. Contrary to the published data on an immediate vaccine reaction in adults, which report a high prevalence of reactions in females (70.9% to 86%, depending on the study1 , 9), 77.7% of the children we evaluated were male. Consistent with the adult data, most children we evaluated experienced only mild reactions to the first dose, and only three patients (37.5%) fulfilled the Brighton criteria for anaphylaxis. Our experience argues that most of these initial reactions are not supportive of an IgE-mediated mechanism. Therefore, we elect to perform these challenges without premedication, because nonsedating antihistamines may not be necessary and will not prevent true IgE-mediated anaphylaxis.
Our report adds to the growing body of literature illustrating the safety of a second dose of mRNA COVID-19 vaccines in patients with mild to moderate immediate reactions to the first dose. This study was limited by a small sample size, referral bias, and the lack of objective diagnostic measurements such as serum tryptase after the initial vaccination. However, our results reaffirm similar studies performed in adults and provide additional assurance specific to the pediatric population.
Acknowledgment
S.P. Hartono was supported by the Intramural Research Program of the National Institutes of Health.
Footnotes
Conflicts of interest: The authors declare that they have no relevant conflicts of interest.
Online Repository
Table E1.
Anaphylaxis criteria according to 2006 National Institute of Allergy and Infectious Disease and Food Allergy and Anaphylaxis Network diagnostic criteria
Anaphylaxis is highly likely when any one of the following three criteria are fulfilled:
|
BP, blood pressure.
Low systolic blood pressure for children is defined as <70 mm Hg from 1 month to 1 year, less than (70 mm Hg + [2 × age]) from 1 to 10 years, and <90 mm Hg from 11 to 17 years.
Table E2.
Anaphylaxis criteria for sudden onset and rapid progression of signs and symptoms according to Brighton Collaboration case definition
| Diagnostic certainty level | Criteria |
|---|---|
| 1 | One or more major skin AND one or more major respiratory AND/OR one or more major cardiac criteria |
| 2 | One or more major skin AND one or more minor respiratory AND/OR one or more minor cardiac criteria |
| One or more major respiratory AND one or more major cardiac criteria | |
| One or more major respiratory AND one or more minor criteria from a different system | |
| One or more major cardiac AND one or more minor criteria from a different system | |
| 3 | One or more minor respiratory AND one or more minor criteria from two other different systems |
| One or more minor cardiac AND one or more minor criteria from two other different systems |
| Organ systems | Major | Minor |
|---|---|---|
| Skin | Generalized urticaria, generalized erythema, generalized pruritus with skin rash, generalized or localized angioedema | Generalized pruritus without skin rash, generalized prickle sensation, red and itchy eyes, localized injection site urticaria |
| Respiratory | Bronchospasm, stridor, upper airway swelling, respiratory distress defined by two or more of: tachypnea, use of accessory respiratory muscles, retraction, cyanosis, grunting | Persistent dry cough, hoarse voice, sensation of throat closure, difficulty breathing without wheeze or stridor, sneezing, rhinorrhea |
| Cardiac | Hypotension, uncompensated shock defined by three or more of: tachycardia, capillary refill time >3 s, decreased level of consciousness | Reduced peripheral circulation defined by two or more of: tachycardia, capillary refill time >3 s, decreased level of consciousness |
| Gastrointestinal | Diarrhea, abdominal pain, nausea, vomiting | |
| Laboratory | S-tryptase greater than upper normal level |
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