Letter to the Editor

Irritant skin test reactions to common vaccines

Intradermal skin test (IDT) with mRNA vaccines may represent a simple, reliable, and affordable tool to measure T cell response in immunocompromised patients who failed to mount serological responses following vaccination with mRNA covid-19 vaccines.

We compared anti-SARS-CoV-2 antibodies and cellular responses in vaccinated immunocompromised patients (n = 58), healthy seronegative naive controls (NC, n = 8), and healthy seropositive vaccinated controls (VC, n = 32) by Luminex, spike-induced IFN-γ Elispot and an IDT. A skin biopsy 24 h after IDT and single-cell RNAseq was performed in three vaccinated volunteers.

Twenty-five percent of seronegative NC had a positive Elispot (2/8) and IDT (1/4), compared to 95% (20/21) and 93% (28/30) in seropositive VC, respectively. Single-cell RNAseq data in the skin of VC showed a predominant mixed population of effector helper and cytotoxic T cells. The TCR repertoire revealed 18/1064 clonotypes with known specificities against SARS-CoV-2, among which six were spike-specific. Seronegative immunocompromised patients with positive Elispot and IDT were in 83% (5/6) treated with B cell-depleting reagents, while those with negative IDT were all transplant recipients.

Our results indicate that delayed local reaction to IDT reflects vaccine-induced T-cell immunity opening new perspectives to monitor seronegative patients and elderly populations with waning immunity.

Immediate hypersensitivity reactions to vaccines, the most severe of which is anaphylaxis, are uncommon events occurring in fewer than 1 in a million doses administered. These reactions are infrequently immunoglobulin E–mediated. Because they are unlikely to recur, a reaction to a single dose of a vaccine is rarely a contraindication to redosing. This narrative review article contextualizes the recent knowledge we have gained from the coronavirus 2019 (COVID-19) pandemic rollout of the new mRNA platform with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines within the much broader context of what is known about immediate reactions to other vaccinations of routine and global importance. We focus on what is known about evidence-based approaches to diagnosis and management and what is new in our understanding of mechanisms of immediate vaccine reactions. Specifically, we review the epidemiology of immediate hypersensitivity vaccine reactions, differential diagnosis for immune-mediated and nonimmune reaction clinical phenotypes, including how to recognize immunization stress–related responses. In addition, we highlight what is known about mechanisms and review the rare but important contribution of excipient allergies and specifically when to consider testing for them as well as other key features that contribute to safe evaluation and management.

Anaphylaxis is an acute, potentially life-threatening, systemic allergic reaction usually affecting multiple organ systems. The diagnosis of anaphylaxis is clinical and requires assessment of a variety of symptoms and signs. A thorough history detailing the reaction and events surrounding anaphylaxis is critical in diagnosis and treatment, and in determining the trigger with the goal of avoiding future reactions. Differential diagnosis of several conditions mimicking anaphylaxis must be considered. The most common triggers for anaphylaxis are food, drugs, and hymenoptera sting. In the United States, peanut, tree nuts, milk, egg, wheat, soy, fish, shellfish, and sesame are major causes of immunoglobulin E-mediated food reactions. More delayed hypersensitivity reactions to foods are observed in α-gal sensitivity. In adults, drugs and hymenoptera stings are more common causes of anaphylaxis than foods. In cases of idiopathic anaphylaxis, a clear trigger is not identified. Following appropriate diagnosis and treatment of acute anaphylaxis, referral to an allergist is an important next step to determine whether further workup with skin testing, laboratory assays, or graded challenges should be considered.

The development and widespread use of vaccination over the past centuries has been the single most impactful intervention in public health, by effectively preventing morbidity and mortality from infectious diseases. Vaccination is generally well tolerated in the vast majority of the population, and the benefits of vaccination largely outweigh the risk of severe adverse events in the majority of patients. Vaccine hesitancy can be a significant concern and lead to infectious disease outbreaks. All health care providers play an important role in maintaining public confidence in vaccines because their attitude and knowledge is often critical in facilitating acceptance of a vaccine. The purpose of this review is to first, provide an understanding of the basic concepts that are relevant to vaccine pharmacovigilance, and secondly, to provide an overview and discuss management of both immune and nonimmune adverse events after vaccination.

Reports about cases of anaphylaxis to mRNA vaccines have created anxiety in the community and could increase vaccine hesitancy in the population. There are no standardized protocols for allergy testing to mRNA vaccines. PEG is currently the only excipient in both vaccines with recognized allergenic potential. Allergy to PEG has been reported with increasing frequency over recent years, often in patients who had repeated systemic allergic reactions/anaphylaxis to several classes of drugs before diagnosis. Proposed protocols are based on current knowledge about potential mechanisms of anaphylaxis associated with the mRNA vaccines, and the assumption that polyethylene glycol (PEG) is the most likely culprit. Allergy testing to PEGs and mRNA vaccines is complex and carries the risk of anaphylaxis and should be conducted in a specialist drug allergy center. Appropriate PEG-free emergency medical treatment and supervision should be readily available.

This Review updates the scientific evidence assessing possible causal associations of adverse events following immunisation (AEFI) compiled in the 2012 report from the Institute of Medicine and the 2014 report from the Agency for Healthcare Research and Quality. For 12 of 46 AEFI examined, a causal relationship has been established with at least one vaccine currently routinely recommended to the general USA population: anaphylaxis, arthralgia or arthritis (mild, acute, and transient, not chronic), deltoid bursitis (when vaccine is administered improperly), disseminated varicella infection (in immune deficient individuals for whom the varicella vaccine is contraindicated), encephalitis, febrile seizures, Guillain-Barré syndrome, hepatitis (in immune deficient individuals for whom the varicella vaccine is contraindicated), herpes zoster, immune thrombocytopenic purpura, meningitis, and syncope. Other than mild acute and transient arthralgia or arthritis, which is very common in adult women after rubella vaccine, these adverse reactions are rare or very rare. Vaccines have an excellent safety profile overall and provide protection against infectious diseases to individuals and the general population.