Tolerability of polysorbate 80-containing COVID-19 vaccines in confirmed polyethylene glycol-allergic patients.

Polyethylene glycol monoallergic patients identified through polyethylene glycol and polysorbate 80 skin testing can safely receive polysorbate 80–containing coronavirus disease 2019 vaccines.

During the worldwide coronavirus disease 2019 (COVID-19) vaccination campaign, a limited number of patients have experienced postvaccination anaphylaxis. The exact mechanisms remain unknown, yet specific excipients—such as polyethylene glycol (PEG) in the Pfizer/BioNTech and Moderna vaccines and polysorbate 80 (PS80) in the AstraZeneca and Johnson & Johnson vaccines—have been identified as causal allergens in a minority of cases.2, 3, 4, 5 Allergy to PEG and PS80 is considered exceedingly rare, although the exact prevalence remains unknown. Current guidelines recommend that patients with an allergy to PEG or PS80 should not be administered a COVID-19 vaccine with this excipient and should seek advice to identify a safe alternative. Both excipients are structurally similar, and cross-reactivity has been reported. , , As such, there is a theoretical risk of reactions to both PEG- and PS80-containing vaccines in patients with previous reactions to either component. Currently, the tolerability of COVID-19 vaccination in proven PEG- or PS80-allergic patients with an alternative, PS80- or PEG-containing vaccine, respectively, remains unexplored.

Within a prospective study on rare cases of anaphylaxis, tolerability to COVID-19 vaccines was evaluated in a cohort of patients with a skin test–confirmed PEG allergy. Medical record review and enquiry with the general practitioner and/or pharmacist served to identify inadvertent exposure to either PS80 and/or PEG after diagnosis. Those PEG-allergic patients with neither skin tests nor confirmed tolerated exposure to PS80 were recalled for additional skin testing (see Appendix 1 and Table E1; available in this article’s Online Repository at www.jaci-inpractice.org). All patients with negative PS80 skin tests and/or inadvertent exposure to PS80 since their PEG allergy diagnosis received a PS80-containing COVID-19 vaccine (Table I ). Patients with positive skin tests for both excipients were excluded from vaccination. Vaccines were administered either in a monitored hospital setting or in a routine setting in case of prior tolerance to the excipient. Tolerability was evaluated on-site and through telephone interview.

Table I

Study population characteristics and COVID-19 vaccination outcome

Patient no.	Sex	Age (y)	Index reaction	Index product	Positive skin tests	Post index PS80 exposure	Negative skin test for PS80	COVID-19 vaccine∗
1	M	53	ANA	PEG 3350	PEG: 3350, 4000, 6000	Yes	Not performed	J&J
2	M	67	ANA	PEG 4000	PEG: 4000	Yes	Not performed	J&J
3	F	73	ANA	PEG 4000	PEG: 4000	Yes	Not performed	J&J
4	F	54	U, AE	PEG 400	PEG: 400	Yes	Not performed	J&J
5	F	81	U	PEG 3350	PEG: 400, 4000	Yes	Not performed	AZ
6	M	70	Rash	PEG 3350	PEG: 3350, 4000	Yes	Not performed	AZ
7	F	21	U, AE	PEG 3350	PEG: 3350, 4000, 6000	Yes	Yes	J&J
8	M	39	ANA	PEG 3350	PEG: 3350,† 4000†	Yes	Yes	J&J
9	M	56	ANA	PEG 4000	PEG: 3350, 4000	No	Yes	J&J
10	F	60	ANA	PEG 3350	PEG: 3350,† 4000†	No	Yes	J&J
11	F	69	ANA	PEG 3350	PEG: 3350, 4000, 6000	No	Yes	J&J
12	M	33	ANA	PEG 3350	PEG: 1500, 3350, 4000; PS80	No	No	-
13	M	31	ANA	PEG 6000	PEG: 6000; PS80	No	No	-
14	F	34	ANA	PEG 4000	PS80‡	No	No	-

AE, Angioedema; ANA, anaphylaxis (defined as an immediate reaction involving > 1 organ system [World Allergy Organization]; AZ, AstraZeneca (Vaxzevria) COVID-19 vaccine; J&J, Johnson & Johnson (Janssen) COVID-19 vaccine; U, urticaria.

All COVID-19 vaccinations were tolerated.

Systemic reaction during skin testing without positive skin test.

Systemic reaction during skin testing with positive skin test.

Fourteen patients were identified with a skin test–proven primary PEG allergy (Table I). In 10 of 14 patients (71%), the index reaction was anaphylaxis. The culprit drug was PEG as a laxative in 3 of 14 patients (21%) and PEG in an extended-release steroid in 10 of 14 patients (71%). In 4 of 14 patients (29%), multiple events were noted. In 2 of 14 patients (14%), skin test–proven cross-reactivity between PEG and PS80 was observed. One patient (case 14) with a clinical history of multiple reactions to both PEG- and PS80-containing products developed a mild systemic reaction after a positive intradermal test with PS80 at the lowest concentration (Table E1). For safety reasons, no further skin testing with PEG was performed and the diagnosis of PS80 and PEG cross-reactivity was established on a clinical basis. All 11 patients with a monoallergy to PEG, based on negative PS80 skin tests and/or proven tolerance to PS80 after the initial allergy workup, tolerated a subsequent PS80-containing COVID-19 vaccine (Table I).

The COVID-19 pandemic has increased awareness of PEG and PS80 allergy. Nevertheless, PEG and PS80 remain rare causes of drug allergy with only 14 cases identified in our tertiary referral center over a 12-year period. Skin testing protocols for PEG and PS80 have evolved over time and a number of (unexplained) systemic reactions, especially upon intradermal testing, were the basis for the current drug-specific recommendations (outlined in Appendix 1). , Although sensitivity of PEG skin testing is estimated to be low (58.8%), specificity is high (99.5%). Cross-reactivity with PS80 was initially not systematically evaluated in our patients and was subsequently observed in 21%, in line with the 30% (3 of 10 cases) reported by Bruusgaard-Mouritsen et al, but lower than the 100% (2 of 2 cases) in Stone et al. Interestingly, 2 out of 3 patients with both PEG and PS80 allergy in our cohort experienced symptoms upon topical exposure to or manipulation of a PEG- containing drug and all had severe index reactions. The uneventful administration of PS80-containing vaccines to all patients with negative PS80 skin tests suggests an excellent negative predictive value of PS80 skin testing.

In addition, we demonstrate the potential of a noninvasive workup encompassing a thorough medical file search and contact with allied health care workers. Using this approach, we confirmed that half of our patients had already tolerated subsequent exposure to a parenteral drug containing PS80, in most cases in another vaccine. Combining both methods, the majority of PEG-allergic patients received a COVID-19 vaccine without incident and only a minority was excluded owing to cross-reactivity with PS80. Currently, there is no procedure for providing a COVID-19 vaccine in this subgroup because all available vaccines contain either PEG or PS80 and, to our knowledge, evidence on the safety and efficacy of (graded) vaccine challenges or desensitization procedures for PEG and PS80 is currently lacking. Theoretically, if the risk of not vaccinating significantly outweighs the (uncertain yet potential) risk of an allergic reaction to the vaccine, a challenge could be considered. If dose-splitting and/or dilution of current vaccine formulations for a graded challenge would impact vaccine integrity and/or immunogenicity, a single-dose challenge would be preferred. However, evidently, such an approach would require a process of shared decision making with extensive informed consent as well as the availability of a monitored setting with trained personnel.

In our cohort, we did not identify a previously known PS80 monoallergic patient, although a skin test–proven PS80 monoallergic patient, identified after anaphylaxis to rituximab and Vaxzevria, had negative PEG skin testing and safely received a second dose with a PEG-containing vaccine (Pfizer/BioNTech, data not shown). Although this case indicates that PS80 present in COVID-19 vaccines is sufficient to elicit an allergic reaction in certain patients monosensitized to PS80, it remains unknown whether this holds true for patients with a skin test–proven primary PEG allergy who subsequently also demonstrate skin test positivity to PS80.

In conclusion, our study emphasizes that an allergist-driven approach (Figure 1 ) can identify safe COVID-19 vaccine alternatives for those initially deemed ineligible for vaccination owing to a PEG or PS80 allergy and assists in further reducing barriers to vaccination.

Figure 1

Flowchart for the diagnostic evaluation prior to COVID-19 vaccination in patients with a history of PEG allergy. A careful review of the medical records in cooperation with allied health professionals can help identify patients with subsequent tolerated exposure to PS80, eligible for vaccination with a PS80-containing vaccine. If subsequent PS80 tolerability is absent or unclear, the patient should be referred to an allergist for further evaluation (skin testing with PEG and PS80 to identify a safe vaccine alternative can be considered). ∗In patients with double-negative skin tests despite a suggestive clinical history, a graded oral challenge to PEG can be considered on a case-by-case level, in a monitored setting. †In patients with positive skin tests to both PEG and PS80, no safe U.S. Food and Drug Administration– or European Medicines Agency-approved alternative is currently available. In selected cases in which the risk of not vaccinating would outweigh the potential risk of anaphylaxis, a (graded) vaccine challenge could be considered after informed consent or shared decision making and only in a monitored setting with personnel trained in the recognition and management of anaphylaxis.