Updated guidance regarding the risk of allergic reactions to COVID-19 vaccines and recommended evaluation and management: A GRADE assessment and international consensus approach.

This guidance updates 2021 GRADE (Grading of Recommendations Assessment, Development and Evaluation) recommendations regarding immediate allergic reactions following coronavirus disease 2019 (COVID-19) vaccines and addresses revaccinating individuals with first-dose allergic reactions and allergy testing to determine revaccination outcomes. Recent meta-analyses assessed the incidence of severe allergic reactions to initial COVID-19 vaccination, risk of mRNA-COVID-19 revaccination after an initial reaction, and diagnostic accuracy of COVID-19 vaccine and vaccine excipient testing in predicting reactions. GRADE methods informed rating the certainty of evidence and strength of recommendations. A modified Delphi panel consisting of experts in allergy, anaphylaxis, vaccinology, infectious diseases, emergency medicine, and primary care from Australia, Canada, Europe, Japan, South Africa, the United Kingdom, and the United States formed the recommendations. We recommend vaccination for persons without COVID-19 vaccine excipient allergy and revaccination after a prior immediate allergic reaction. We suggest against >15-minute postvaccination observation. We recommend against mRNA vaccine or excipient skin testing to predict outcomes. We suggest revaccination of persons with an immediate allergic reaction to the mRNA vaccine or excipients be performed by a person with vaccine allergy expertise in a properly equipped setting. We suggest against premedication, split-dosing, or special precautions because of a comorbid allergic history.

Diagnostic accuracy of vaccine and vaccine excipient testing in the setting of allergic reactions to COVID-19 vaccines: A systematic review and meta-analysis.

For persons with immediate allergic reactions to mRNA COVID-19 vaccines, skin testing (ST) to the vaccine/excipients (polyethylene glycol[PEG] and polysorbate 80 [PS]) has been recommended, but has unknown accuracy. To assess vaccine/excipient ST accuracy in predicting all-severity immediate allergic reactions upon re-vaccination, systematic review was performed searching Medline, EMBASE, Web of Science, and the WHO global coronavirus database (inception-Oct 4, 2021) for studies addressing immediate (≤4 h post-vaccination) all-severity allergic reactions to 2nd mRNA COVID-19 vaccination in persons with 1st dose immediate allergic reactions. Cases evaluating delayed reactions, change of vaccine platform, or revaccination without vaccine/excipient ST were excluded. Meta-analysis of diagnostic testing accuracy was performed using Bayesian methods. The GRADE approach evaluated certainty of the evidence, and QUADAS-2 assessed risk of bias. Among 20 studies of mRNA COVID-19 first dose vaccine reactions, 317 individuals underwent 578 ST to any one or combination of vaccine, PEG, or PS, and were re-vaccinated with the same vaccine. Test sensitivity for either mRNA vaccine was 0.2 (95%CrI 0.01-0.52) and specificity 0.97 (95%CrI 0.9-1). PEG test sensitivity was 0.02 (95%CrI 0.00-0.07) and specificity 0.99 (95%CrI 0.96-1). PS test sensitivity was 0.03 (95%CrI 0.00-0.0.11) and specificity 0.97 (95%CrI 0.91-1). Combined for use of any of the 3 testing agents, sensitivity was 0.03 (95%CrI 0.00-0.08) and specificity was 0.98 (95%CrI 0.95-1.00). Certainty of evidence was moderate. ST has low sensitivity but high specificity in predicting all-severity repeat immediate allergic reactions to the same agent, among persons with 1st dose immediate allergic reactions to mRNA COVID-19 vaccines. mRNA COVID-19 vaccine or excipient ST has limited risk assessment utility.

Delayed systemic urticarial reactions following mRNA COVID-19 vaccination.

Background: As the vaccination campaign in response to the coronavirus disease 2019 (COVID-19) pandemic continues, concerns with regard to adverse reactions to the vaccine remain. Although immediate hypersensitivity reactions have received much attention, delayed systemic urticarial reactions after vaccination can occur. Objective: To describe the clinical presentation, vaccine excipient skin testing results, and outcomes of subsequent COVID-19 vaccination in patients who experienced delayed systemic urticarial reactions after messenger RNA (mRNA) COVID-19 vaccination. Methods: This was a retrospective case series of 12 patients referred to the Mayo Clinics in Rochester, Minnesota, and Jacksonville, Florida, between January 19, 2021, and April 30, 2021, for evaluation of delayed systemic urticarial reactions after mRNA COVID-19 vaccination. Demographics, medical and allergic history, reaction details, vaccine excipient skin testing results (when performed), and the outcome after subsequent vaccination were collected for each patient. Results: The mean age of the patients was 52 years, all were white, and 9 (75%) were women. Half of the patients had a history of drug allergy, and one had a history of chronic spontaneous urticaria. Seven patients reacted to the Pfizer-BioNTech vaccine and five reacted to the Moderna vaccine. Seven patients developed symptoms between 8 and 24 hours after vaccination. Nine patients required antihistamines for treatment. The median time to symptom resolution was 4 days. Nine patients underwent allergist-directed COVID-19 vaccine excipient skin testing, all of which were negative. Ten patients chose to receive their next mRNA COVID-19 vaccine dose, and four patients experienced recurrent delayed urticaria. Conclusion: Delayed systemic urticarial reactions after mRNA COVID-19 vaccination were not life-threatening, could be treated with antihistamines, and were not predicted with vaccine excipient skin testing. They were not a contraindication to subsequent vaccination, although patients should be counseled with regard to the possibility of recurrence.

Utility and futility of skin testing to address concerns surrounding messenger RNA coronavirus disease 2019 vaccine reactions.

BACKGROUND: The mechanism of coronavirus disease 2019 (COVID-19) vaccine hypersensitivity reactions is unknown. COVID-19 vaccine excipient skin testing has been used in evaluation of these reactions, but its utility in predicting subsequent COVID-19 vaccine tolerance is also unknown. OBJECTIVE: To evaluate the utility of COVID-19 vaccine and vaccine excipient skin testing in both patients with an allergic reaction to their first messenger RNA COVID-19 vaccine dose and patients with a history of polyethylene glycol allergy who have not yet received a COVID-19 vaccine dose. METHODS: In this multicenter, retrospective review, COVID-19 vaccine and vaccine excipient skin testing was performed in patients referred to 1 of 3 large tertiary academic institutions. Patient medical records were reviewed after skin testing to determine subsequent COVID-19 vaccine tolerance. RESULTS: A total of 129 patients underwent skin testing, in whom 12 patients (9.3%) had positive results. There were 101 patients who received a COVID-19 vaccine after the skin testing, which was tolerated in 90 patients (89.1%) with no allergic symptoms, including 5 of 6 patients with positive skin testing results who received a COVID-19 vaccine after the skin testing. The remaining 11 patients experienced minor allergic symptoms after COVID-19 vaccination, none of whom required treatment beyond antihistamines. CONCLUSION: The low positivity rate of COVID-19 vaccine excipient skin testing and high rate of subsequent COVID-19 vaccine tolerance suggest a low utility of this method in evaluation of COVID-19 vaccine hypersensitivity reactions. Focus should shift to the use of existing vaccine allergy practice parameters, with consideration of graded dosing when necessary. On the basis of these results, strict avoidance of subsequent COVID-19 vaccination should be discouraged.

Are the Allergic Reactions of COVID-19 Vaccines Caused by mRNA Constructs or Nanocarriers? Immunological Insights.

The Food and Drug Administration (FDA) has recently authorized the two messenger RNA (mRNA) vaccines BNT162b2 and mRNA-1273 for emergency use against the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causing the COVID-19 coronavirus disease. BNT162b2 and mRNA-1273 vaccines were developed by Pfizer-BioNTech and Moderna, respectively, in 2020. The United Kingdom, Bahrain, Canada, Mexico, United States, Singapore, Oman, Saudi Arabia, Kuwait, and European Union began their vaccination programs with the BNT162b2 vaccine, while the United States and Canada also started the mRNA-1273 vaccination program in mid December 2020. On 28th December 2020, studies reported severe allergic reactions in people who received the BNT162b2, and few people who received the mRNA-1273 vaccine. Authors of the letter thus attempt to explore possible causes of anaphylaxis following COVID-19 vaccination.

Adverse reactions to COVID-19 vaccines: A practical approach.

COVID-19-related mortality in high-risk individuals is substantial and current treatment options are limited. There is convincing evidence that the COVID-19 vaccines reduce the severity of infection and prevent deaths. Three COVID-19 vaccines are approved in the United Kingdom with many more in development. There are limited data on the triggers and mechanisms of anaphylaxis to these vaccines. We review the potential allergenic compounds in the COVID-19 vaccines and describe an innovative allergy support model for the vaccination hubs that allows most patients with severe allergy be immunized. Finally, we propose a practical algorithm for the investigations of anaphylaxis to these vaccines.

The effects of all-trans retinoic acid on immune cells and its formulation design for vaccines.

As one of the most important metabolites of vitamin A, all-trans retinoic acid (RA) plays a crucial role in regulating immune responses. RA has been shown to promote the differentiation of naïve T and B cells and perform diverse functions in the presence of different cytokines. RA also induces gut tropic lymphocytes through upregulating the expression of chemokine (C-C motif) receptor 9 (CCR9) and α4ß7 integrin. In addition, RA promotes the expression of the enzyme retinal dehydrogenase (RALDH) on dendritic cells, which in turn strengthens the ability to synthesize RA. Due to the insolubility of RA, proper formulation design can maximize its ability to improve immune responses for vaccines. Recent studies have developed some formulations co-loading RA and antigen, which can effectively imprint lymphocytes gut homing properties and induce intestine immune responses as well as systemic responses through parenteral administration, providing a promising direction for the protection against mucosal infections. Here, we review the mechanism and effects of RA on lymphocyte differentiation and gut homing, and recent progress of RA delivery systems to improve mucosal immune responses.

Three-percent sucrose acts as a thermostabilizer for cell-adapted foot-and-mouth disease virus without any negative effect on viral growth.

AIMS: As cell-adapted foot-and-mouth disease virus (FMDV) with H56R mutation in VP3 has reduced thermostability, this study aimed to investigate the effect of thermostabilizers on cell-adapted FMDV for vaccine production. METHODS AND RESULTS: We examined the effect of 3% sucrose, 10% (or 25%) glycerol or 10% FBS on cell-adapted FMDV O/SKR/JC/2014, containing H56R mutation in VP3, as vaccine seed virus at -80, 4, 25 or 37°C for 2, 4 or 7 days. The stabilizing effect of 3% sucrose on O/SKR/JC/2014 was observed at 25, 37°C, and after repeated freeze-thaw cycles. Additionally, we tested the effect of 3% sucrose on the growth of FMDV or cells and did not observe any decrease in either viral growth or cell viability. CONCLUSIONS: Our study showed the protective effect of 3% sucrose on FMDV infectivity at various temperatures; this virus stock in 3% sucrose could be used for infecting cells without the removal of sucrose. SIGNIFICANCE AND IMPACT OF THE STUDY: We suggest that 3% sucrose-containing medium could be beneficial for the stable storage and transport of cell-adapted FMDV.

Immune-mediated adverse reactions to vaccines.

Vaccination continues to be the single most important and successful public health intervention, due to its prevention of morbidity and mortality from prevalent infectious diseases. Severe immunologically mediated reactions are rare and less common with the vaccine than the true infection. However, these events can cause public fearfulness and loss of confidence in the safety of vaccination. In this paper, we perform a systematic literature search and narrative review of immune-mediated vaccine adverse events and their known and proposed mechanisms, and outline directions for future research. Improving our knowledge base of severe immunologically mediated vaccine reactions and their management drives better vaccine safety and efficacy outcomes.