Anaphylaxis and Coronavirus Disease 2019 Vaccine: A Danger Relationship?

Luciana Kase Tanno; Mariana Castells; Marco Caminati; Gianenrico Senna; Pascal Demoly

Disclosures

Curr Opin Allergy Clin Immunol. 2021;21(5):411-417. 

In This Article

Review

The Truth Regarding Anaphylaxis due to Vaccines

Anaphylaxis, both immunoglobin E (IgE)- or non-IgE-mediated, is clinically known as a systemic hypersensitivity reaction characterized by rapid onset and the potential to endanger life through airway, breathing or circulatory involvement. It is usually, although not always, associated with skin and mucosal changes.[13] Its heterogeneous clinical presentation and sudden occurrence in virtually any setting without warning hampers the prompt recognition and treatment of this condition, increasing the risk of death. This multifaceted disease can occur at any age and in varying degrees of severity.[13] European data indicated incidence rates of all-cause anaphylaxis ranging from 0.3 to 7.9/105 people/year, with an estimate that 0.3% (95% confidence interval [CI] 0.1–0.5) of the population will suffer from anaphylaxis at some point in their life, known as the 'lifetime anaphylactic risk'.[14,15] The calculation made at the Montpellier University Hospital Center is 0.32/105 (95% CI 0.28–0.65).[15] Although it is a cause of death well known by physicians, anaphylaxis has never been properly monitored due to the difficulties of classification and coding in the different versions of the WHO International Classification of Diseases (ICD). For this reason, anaphylaxis has never been considered underlying cause of death in death certificates leading to under notification, until recently thanks to the construction and implementation of its 11th version, ICD-11 by the WHO Collaborating Center in Montpellier with the WHO governance for international classifications.[16,17] Strikingly however, it has been listed for a long time in vaccine safety surveillance programs.[18]

Although severe, anaphylaxis due to vaccine is extremely rare, estimated at 2.5–11/1 000 000, and specific cases should receive individualized investigation and care.[19–21] However, this data is based on passive reports and most of cases have not been deeply evaluated or validated by allergists. Also, difficulties in recognition anaphylaxis, in particular of less severe cases, can hamper the collection of accurate epidemiological data of reported cases.

The frequency of anaphylaxis[21] varies from vaccine to vaccine as follows: DPT (diphtheria, pertussis and tetanus) (0.36/100 000, usually due to the vaccine agent), influenza (0.08/100 000, exceptionally due to ovalbumin), MMR (measles, mumps and rubella) (0.18/100 000, less and less due to the porcine gelatin stabilizing it, never to the egg proteins it actually barely contains).

Anaphylaxis to mRNA-corona Virus Disease 2019 Vaccines: A Matter of its Components?

Allergic reactions to vaccines are generally due to adjuvants and other excipients/components in the vaccine such as preservatives and antibiotics, rather than to the active component itself.[10] Although the exact cause of vaccine-associated anaphylaxis with mRNA vaccines is still unknown, a polyethylene glycol (PEG)-conjugated lipid derivative in the lipid nanoparticles was immediately suspected to be the causative agent, a 'crime of dirty faces'.[22]

PEG, also known as macrogols, are a group of polyether compounds that are widely used in medicinal, cosmetic and household products (including creams and lotions, shampoo, hair dye, and dental hygiene products). They are formed via the polymerization of ethylene oxide, resulting in PEG polymers of variable chain length and thus molecular weight.[23]

In COVID-19 vaccines, the inclusion of pegylated nanoparticle encapsulating the mRNA impairs enzymatic degranulation of the mRNA, increases the water-solubility and, therefore, the bioavailability of the lipid nanoparticles. The Pfizer-BioNTech vaccine contains two novel lipid nanoparticles, one of which is 'pegylated' (polyethylene glycol of molecular weight 2000 Da, abbreviated to PEG-2000). The Moderna mRNA vaccine also includes a different pegylated lipid (also a PEG-2000).

PEG allergy is very uncommon, despite the widespread use in medicines, foods and household products. The majority of reports are due to high molecular weight PEG present as excipients in intra-articular corticosteroids or as active ingredients of laxative and bowel preparations.[23,24] The PEG-induced reactions publications appear to be at the more severe spectrum, most describing multiple episodes of anaphylaxis, often requiring multiple doses of epinephrine.[24]

The underlying mechanism of PEG-associated anaphylaxis is largely unknown, although IgE-dependent and IgE-independent mechanisms have been proposed. Recent report suggests that basophil activation tests to PEGylated liposomal drugs may be useful for the assessment of BNT162b2- (Pfizer-BioNTech COVID-19 vaccine) associated anaphylaxis.[24,25]

There is very little data to link the anaphylactic reactions to mRNA vaccines Pfizer and Moderna to the PEG that forms the nanoparticles for two reasons: we have not been able to do skin testing with vaccine products in large series and we have not been able to confirm positive PEG skin testing in the patients who have reacted, so that the allergenic components in the vaccines remain unknown and may be different for each patient.

Evidence-based Data: Coronavirus Disease 2019 Vaccine Surveillance

Monitoring and surveillance platforms are key to identify potential dangerous adverse effects to vaccines and trigger rapid and appropriate response accordingly. Data are produced and used in global, regional or national immunization programmes, regulatory authorities, ministries of health, partners and pharmacovigilance centers as well as vaccine manufacturers. Most of worldwide programs follow the WHO vaccine safety surveillance guidelines, but are adapted according to the needs and possibilities of national or regional levels.[26] The passive surveillance system supported by the CDC and the FDA in the United States is the Vaccine Adverse Event Reporting System (VAERS).[27,28] The European Medicines Agency (EudraVigilance), and the WHO (VigiBase) are as well robust international pharmacovigilance databases. Postmarketing safety trials will be essential to continue to increase knowledge about COVID-19 vaccine safety and efficacy, particularly in populations absent or underrepresented in preauthorization clinical vaccine trials, such as children and pregnant women.

Populational-based studies and national surveillance programs do not count with specific investigation to confirm (or not) allergies and understand the mechanisms involved. However, clinical complaints that arise immediately after the administration of a vaccine, whether or not compatible with an allergic reaction, have a significant impact on the public's perception of vaccines and their willingness to be vaccinated more.

Early safety monitoring of the Pfizer-BioNTech COVID-19 vaccine detected 21 cases of anaphylaxis after reported administration of 1 893 360 first doses of Pfizer-BioNTech COVID-19 vaccine (11.1 cases per million vaccine doses administered) as well as cases of less severe nonanaphylactic reactions, based on US data on 14–23December 2020.[29] Most (86%) anaphylactic cases developed symptoms within 30 min of vaccination, and 81% had a personal history of allergies or allergic reactions, including previous anaphylaxis. Most (90%) reported anaphylaxis cases after receipt of Pfizer-BioNTech COVID-19 vaccine occurred in women, although 64% of the vaccine doses administered were given in women.[2]

Since the initial UK reports, in which two cases of anaphylaxis after mRNA Pfizer/BioNTech COVID-19 vaccine, only one patient was confirmed to be allergic to PEG,[7] other reports have followed, without allergy work up so far. Therefore, the level of evidence that PEG-2000 is the culprit agent is so far null.

US CDC estimated that anaphylaxis to the mRNA COVID-19 vaccines would occur in 2.5–11.1 cases per million of doses, largely in individuals with a history of allergy with no indication of a confirmed role of PEG.[7] Blumenthal et al.[30] observed from all 64 900 subjects who received the first dose of mRNA COVID-19 vaccine, 16 developed self-reported anaphylaxis (0.025% [95% CI 0.014–0.040%]), 7 cases from the Pfizer/BioNTech vaccine (0.02% [95% CI 0.011–0.056%]) and 9 from Moderna vaccine (0.023% [95% CI 0.011–0.044%]), which dramatically raises the possible incidence to 30 (Pfizer) to 70 (Moderna) per million. Most of the vaccine recipients with anaphylaxis had allergy histories, with 31% having prior anaphylaxis. The main limitation of this study is that the data presented was based on self-reported reports and covered 81% of all vaccinated subjects in their area.

The last publication from the French National Agency for the Safety of Medicines and Health Products (ANSM), reports lower number of cases. From overall 13 610 000 doses in 8 April 2021, 9 889 000 were Pfizer/BioNTech vaccines, 994 000 were Moderna vaccine and 2 725 089 AstraZeneca vaccine. Sixty-seven severe hypersensitivity reactions were reported (0.0005% per application), 58 cases (5.86 per million) from Pfizer/BioNTech vaccine, four cases (4.02 per million) from Moderna vaccine and five cases (1.83 per million) from AstraZeneca vaccine.[20] Table 1 shows the current rate of anaphylaxis per million of doses according to the COVID-19 vaccine surveillance platforms and records.

Lessons From the Field

We are dealing with a new generation of vaccines, with innovative mechanisms and promising effects, but with potential adverse reactions, as for any drug. We still have limited data so far regarding the allergic or hypersensitivity effects associated with COVID-19 vaccines, but what is truly known are three facts that are novel and have never been reported before for any vaccination campaign:

There is a Predominance of Females who Present Hypersensitivity Reactions and Anaphylaxis (Over 90% of the Patients Reported in all Published Studies are Females)

One possible explanation for the sex imbalance is that sensitization to PEG (if confirmed the major culprit) is more common in women due to the relatively frequent exposure to PEG-containing products, such as cutaneous exposure to cosmetics or the use of medications such as contraceptives. Preexisting anti-PEG antibodies have been reported to be associated with severe allergic reactions upon administration of a PEGylated drug,[22,31] suggesting that prior exposure to the PEG-containing products may sensitize subjects and establish anti-PEG hypersensitivity. The female-biased severe allergic reaction against mRNA COVID-19 vaccines is partly supported by a higher prevalence of anti-PEG antibodies in women than in men.[22] Another possible explanation is the effect of hormones, such as estrogens, in allergic immunological responses. Hormonal status and the X-chromosome coded factors are deeply involved in the regulation of T-cell and B-cell responses, which may influence the sex differences noticed in allergic diseases.[32] Although the influence of hormones is not fully understood in anaphylaxis, the possible role of sex hormones is indirectly suggested through the rare phenotype of catamenial and breastfeeding anaphylaxis.[33,34] Estrogen and progesterone affect mast cells in vitro but in vivo effects are still unknown.[35,36] An animal model has demonstrated that anaphylaxis is more severe in female than male mice and that estrogens upregulate endothelial nitric oxide synthase and mast cell degranulation, resulting in increased vascular permeability and systemic manifestations.[37]

Sixty Percent of the Patients who Reacted had Previous Food Allergy, Drug Allergy, Hymenoptera Allergy or Reacted to Allergen Immunotherapy and/or Carry an Epinephrine Device

If we consider that about 30% of persons in the general population might have a personal history of some allergic condition, the data provided so far indicates that patients who experienced mRNA vaccine-related anaphylaxis reports two-fold more associated allergic or hypersensitivity conditions when compared to the general population. However, it is still not clear the reasons for this association. Even with this association, the formal recommendation is that people get vaccinated even if they have a history of severe allergic/hypersensitivity reactions not related to vaccines or injectable medications. Patients with a personal history of allergies to oral medications or familiar history of severe allergic/hypersensitivity reactions should also be vaccinated.[2]

Thirty Percent of the Patients who Reacted had Prior Anaphylaxis

In the context of new vaccines development and licensed at an unprecedented pace, there is additional pressure to properly distinguish symptoms directly related to mast cell degranulation from other mechanisms of action, to discern true immune-mediated allergic reactions within the larger context of adverse reactions. Overestimating anaphylaxis rates after COVID-19 vaccine injections is able to delay or deter vaccination programs. Public health bodies and healthcare professionals must apply the most accurate criteria to assign the diagnosis of anaphylaxis.

All cases of the personal history of anaphylaxis to the vaccine or a parenteral biological, an injected steroid, colonoscopy preparation, or laxatives and personal history of idiopathic anaphylaxis should receive individualized evaluation before receiving the mRNA vaccine.[11]

Relevance of Allergy in Patient Selection for Vaccination

Healthcare workers must follow local authorizations and policy in terms of indications and contra-indications for vaccines against COVID-19. Even with high number of guidance and recommendations from the allergy academies, all convey that the only recommendation should be addressed to patients who experienced prior allergic reaction to the vaccine in question or its components. These cases should be referred to allergists for risk stratification and allergy work-up to tailor the etiological diagnosis and recommendations. Allergists worldwide are currently testing these patients and documented case series will likely soon be published.

Potential risk factors should be controlled before the vaccination, such as asthma, as for any vaccine. Although patients with clonal mast cells disorders, including mastocytosis, are at risk for mast cells activation and anaphylaxis when exposed to certain drugs and procedures, there is no evidence of increased sensitization or reactivity to COVID-19 vaccine components. Patients with mast cells activation disorders may be good candidates for mRNA COVID-19 vaccines, with premedication, in an appropriate setting and under medical surveillance.[38–40]

Various diagnostic algorithms have emerged to investigate allergy to vaccine and PEG, however, the main concerns are: the choice of vaccine after anaphylaxis to a first vaccine dose and, the patients with proven PEG allergy, not to mention the potential cross-reactivity between PEG and polysorbates. Generally, subjects who developed a systemic allergic reaction to a vaccine, should not receive a second dose of the same type of vaccine, nor a vaccine with similar excipients without prior allergy work up.

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