Risk Estimation for Allergic Reactions to Covid-19 mRNA Vaccines
An official guideline for managing the serious allergy concerns in the present pandemic.
Incidents of serious allergic reactions — called anaphylaxis — have occurred within a few minutes of receiving the mRNA vaccines for Covid-19 in the U.S. and U.K. Anaphylaxis is life-threatening if untreated, and usually occur within minutes of allergen exposure. Symptoms include hives; swelling of the mouth, lips, tongue, or throat; breathlessness, wheezing, or chest tightness; or low blood pressure or consciousness loss.
Fortunately, vaccine anaphylaxis is incredibly rare. Historically, only 33 anaphylaxis cases have been documented out of 25 million vaccine doses. In the U.S., there were 21 anaphylaxis cases from the 1,893,360 million first doses of Pfizer-BioNTech mRNA vaccine administered. While the anaphylaxis rate is higher with the mRNA vaccine than regular vaccines — at about 11.1 vs. 1.3 in 1,000,000 doses — it’s assuring that there were no deaths or long-term side effects from the anaphylaxis cases.
Nevertheless, understanding who is at risk for vaccine anaphylaxis would prevent any unnecessary mishaps. In that light, researchers at the Division of Rheumatology Allergy and Immunology in Massachusetts General Hospital have done an extensive review on this topic and advised guidelines. Their review, “mRNA Vaccines to Prevent COVID-19 Disease and Reported Allergic Reactions: Current Evidence and Suggested Approach,” was published in the Journal of Allergy and Clinical Immunology: In Practice recently.
Herein, the authors across over 15 healthcare institutions detailed a risk stratification plan, wherein four screening questions are asked:
1. Do you have a history of a severe allergic reaction to an injectable medication (intravenous, intramuscular, or subcutaneous)?
2. Do you have a history of a severe allergic reaction to a prior vaccine?
3. Do you have a history of a severe allergic reaction to another allergen (e.g., food, venom, or latex)?
4. Do you have a history of an immediate or severe allergic reaction to PEG-, a polysorbate-, or polyoxyl 35 castor oil (eg, paclitaxel)-containing injectable or vaccine?
Based on ‘yes’ or ‘no’ answer:
- If ‘no’ to all questions, the person is at low risk and should be observed for 15 minutes after vaccination.
- If ‘yes’ to #1, #2, or #3, the person is at medium risk and should be observed for 30 minutes after vaccination.
- If ‘yes’ to #1 or #2, it should be investigated if the injectables could have contained high-molecular-weight PEG, polysorbate, or polyoxyl 35.
- If ‘yes’ to #4, the person is at high risk and should be examined for an allergic skin test.
- If mild allergic reactions appeared on the first dose, allergic skin testing should be done before taking the second shot. If the skin test is positive, then the second shot should be avoided.
- If severe anaphylaxis occurred from the first dose, then the second dose of mRNA vaccine should be avoided.
What are PEG and polysorbate?
Polyethylene glycol (PEG) and polysorbate are excipients that enhance the efficacy of medications or vaccines. In vaccines, such excipients increase the water-solubility and stability during transport and storage while preventing bacterial contamination.
Allergic reactions or anaphylaxis to PEG and polysorbate in medications (e.g., penicillin, injected corticosteroids, cancer drugs, antivirals, etc.), healthcare products (e.g., laxatives, skin creams, and lubricants), or vaccines have happened before. However, the clinical benefits of PEG and polysorbate (in boosting drug performance) often outweigh its rare allergic concerns.
Thus, the PEG and polysorbate in the Covid-19 mRNA vaccine are suspected to be responsible for the anaphylaxis incidents. Notably, the PEG used in the mRNA vaccine is different from other healthcare products as the PEG was specifically designed to stabilize the lipid nanoparticle that delivers the mRNA into the human cell. So, it remains unclear if the PEG in Covid-19 mRNA vaccine is as allergenic as other medications or healthcare products.
Intriguingly, in the screening question, polyoxyl 35 castor oil (e.g., paclitaxel) is mentioned, but the authors did not elaborate further. Probing further, paclitaxel is an anti-cancer chemotherapy drug, and one of its side effects are allergic reactions that can occur within 10 minutes of injection. Although rare, allergic reactions to cosmetics or injections containing castor oil have also been documented.
What is allergic skin testing?
First, the person’s skin is pricked with a potential allergen — such as diluted PEG3350, methylprednisolone acetate containing PEG3350, triamcinolone acetate containing polysorbate 80, or hepatitis A vaccine containing polysorbate 20. If this skin prick elicits an allergic reaction, then the person is ineligible for PEG/polysorbate containing vaccines or other injectables.
If this skin prick elicited no reactions, another skin test into the intradermal — shallow injection into the skin dermis — should be done with the allergen. Staff should be on alert as anaphylaxis can occur at this stage. If an allergic reaction happens, the person is ineligible for the injectables containing PEG/polysorbate. If this test produced no reactions, the person can take the Covid-19 mRNA vaccine and be monitored for 30 minutes.
Why not use the mRNA vaccine itself as skin testing? But this isn’t advised. “We do not recommend vaccine skin testing at this time because of limited vaccine supply, lack of information on sensitivity or specificity, unclear safety of skin testing,” the review authors wrote. “At the time of publication, mRNA vaccines are under EUA and remain unlicensed for skin testing.”
Pre-treatment with antihistamines — commonly used to relieve allergic symptoms — is not recommended as it may mask the skin manifestation of allergic reactions, delaying proper treatment. When anaphylaxis occurs after vaccination, immediate and quick epinephrine administration — such as through auto-injectors — can resolve the problem. If a mild allergic reaction occurred on the first dose, fexofenadine or cetirizine pre-treatment of 1–2 hours before the second dose could be considered.
According to the CDC, about 84% — 147 out of 175 — of reported allergic reactions after the mRNA vaccine were not anaphylaxis. So, proper diagnosis of anaphylaxis is also important since anaphylaxis can get confused with other similar conditions:
- Vasovagal reactions occur when a person overreacts to a trigger — such as seeing blood, injections, or emotional shock— wherein the blood pressure and heart rate drops, and the person might faint. Vasovagal reactions are harmless unless the person fell and got injured.
- Anxiety reactions — such as flushing, breathlessness, fast heartbeat, and lightheadedness — may also get mistaken for anaphylaxis.
- Pain, swelling, itching, or burning at the injection site is typical, and does not mean anaphylaxis.
- Non-steroidal anti-inflammatory drugs that treat fever and myalgia may lead to urticaria — also known as skin hives that can appear suddenly — which may be mistaken as vaccine anaphylaxis.
In response to the rare anaphylaxis cases from the Pfizer-BioNTech mRNA vaccine for Covid-19, guidelines for risk stratification and management have been developed. Now, healthcare providers know what to expect and do in the coming vaccination programs. Such guidelines also help the public to understand anaphylaxis and its level of threat better. Overall, “The potential benefit of an effective Covid-19 vaccine is far-reaching and a potential solution to a substantial threat to global health,” stated Lene H. Garvey, MD, Ph.D., head of the Danish Anaesthesia Allergy Centre, and a co-worker. “The risk of hypersensitivity and ultimately anaphylaxis is present for all drugs, including vaccines, although usually low and is offset by the benefits of the drug.”