key: cord-0961207-ape6vqdz authors: Corey, Kristen B.; Koo, Grace; Phillips, Elizabeth J. title: Adverse Events and Safety of SARS-Cov2 Vaccines: What’s New and What’s Next date: 2022-05-10 journal: J Allergy Clin Immunol Pract DOI: 10.1016/j.jaip.2022.04.035 sha: 594faf95ffa0398c6d0224b230db878fc240ad36 doc_id: 961207 cord_uid: ape6vqdz Just over one year following rollout of the first vaccines for coronavirus disease 2019 (COVID-19), 572 million doses have been administered in the United States. Comparatively to the number of vaccines administered, adverse effects such as anaphylaxis have been rare, and seemingly, the more serious the effect, the rarer the occurrence. Despite these adverse effects, there are few, if any, true contraindications to COVID-19 vaccination and most individuals recover without further sequelae. This review provides guidance for the allergist/immunologist regarding appropriate next steps based on patient’s known allergy history or adverse reaction after receipt of COVID-19 vaccine in order to assist in safe global immunization. Immediate systemic reactions are those that can be described by acute onset (within 4 hours of 92 vaccination) of generalized symptoms such as rash, flushing, swelling, or difficulty breathing, among others; these 93 may also be referred to as immediate hypersensitivity reactions or immediate allergic-like reactions. Since the 94 emergency approval of the mRNA vaccines, immediate hypersensitivity reactions were initially described at rates 95 of 2.5 to 11.1 per one million vaccine doses administered.(16) Obtaining a true number of immediate systemic 96 reactions has been difficult due to the variation in reports, lack of physician confirmation and a standard definition 97 of "anaphylaxis," and ability for self-reporting, but the real-world data seems to suggest rates that are slightly 98 higher than the historical rates across all vaccines (about 1.3 per one million doses). (17, 18) The Centers for 99 Disease Control and Prevention (CDC) suggests rates between 2 and 5 per one million;(19) a large population-100 based study suggests a rate of 4.8 per one million;(20) and a recent meta-analysis describes a rate of 7.91 per one 101 million vaccine doses administered.(21) While the mechanism behind the high rate of immediate reactions 102 currently remains elusive, evidence to-date supports a non-IgE mechanism, as we can be reassured that, across 103 various studies, the majority of individuals with first-dose immediate reactions to an mRNA vaccine have either 104 J o u r n a l P r e -p r o o f tolerated subsequent doses without symptoms or had very mild symptoms not indicative of an IgE mechanism.(22-105 28) Further support comes from a meta-analysis encompassing over 1300 individuals with first-dose reactions 106 which demonstrated that, of these individuals, only 13% went on to develop reactions at second dose with less 107 than 0.5% being categorized as severe reactions.(29) Many conceivable mechanisms have been proposed including 108 direct mast cell activation, whether IgE or non-IgE mediated, complement activation, and contact system 109 activation by nucleic acids.(30) It is important to note that much of the data currently available lacks the laboratory 110 studies needed to discern mechanism of the reaction, and randomized double-blinded studies are ongoing in an 111 attempt to elucidate the mechanism of immediate reactions associated with mRNA vaccines. (17, 22, (30) (31) (32) The 112 construct or antigen that might be driving these immediate reactions, regardless of the mechanism, could be an 113 inactive component of the vaccine such as PEG2000 used to stabilize the lipid nanoparticle, an active component 114 of the vaccine such as the mRNA, or immune response to the translated spike protein itself. Individuals experiencing immediate reactions commonly reported symptoms of pruritus, flushing, rash, 116 difficulty breathing, and the sensation of throat tightness with onset of minutes after immunization; some 117 experienced disorientation and dizziness.(33) While IgE-mediated allergy and clinical anaphylaxis are the most 118 serious considerations given these symptoms, as mentioned, tolerance of second dose in the majority of 119 individuals is not consistent with this. Therefore, although the mechanism is unclear, the tolerance of second dose 120 makes an IgE mechanism much less likely in most patients, and other etiologies including complement activation, 121 paradoxical vocal cord motion (PVCM) or laryngospasm, anxiety or panic attacks, and vasovagal responses need to 122 be considered. (33, 34) 123 While likely very rare, true IgE mediated allergic reaction to mRNA based COVID vaccines is possible, 124 though seemingly unlikely based on the information we have gained in the last year. Previously, it was proposed 125 that the mechanism surrounded sensitization toward PEG present in the carrier of the mRNA in these vaccines. ( With initial reports of immediate systemic reactions to mRNA vaccines and the concern for PEG as a 156 possible inciting agent, it was recommended that high risk individuals have pre-vaccination screening with or role of skin testing is more limited than originally thought, with emphasis on history as an important guide for 159 vaccination, especially in individuals with first-dose reaction history.(21, 28) Studies have highlighted the inability 160 of skin testing to reliably predict clinical allergy to PEG and related excipients due to high rates of false positives 161 and the increasing idea that a non-IgE mediated mechanism is responsible for clinical reaction. In the first few months following the reports of anaphylaxis there was an abundance of caution in terms 173 of management of patients as it was not known whether these were IgE mediated or whether reactions could 174 worsen on subsequent doses. Currently, we know that most patients will tolerate subsequent doses, which 175 strongly suggests that the majority of immediate vaccine reactions are not IgE mediated. Additionally, many of the 176 patients who reacted on first dose have gone on to receive booster vaccination at least 6 months later, which 177 suggests that original thoughts of an IgE mechanism with refractory period of mast cell degranulation between first 178 and second doses is unlikely. Several papers have now been published supporting the safety of subsequent doses 179 even in the setting of anaphylaxis with the first dose. (23, 24, 26, 29) In addition, current guidelines support the 180 idea that excipient testing does not contribute to vaccine safety and could, in theory, delay vaccination in 70) A large real-world study highlights that true SARS-CoV-2 infection is associated with a 295 higher rate of myocarditis than in vaccination with a risk difference of 11 per 100,000 in those with COVID-19 296 infection,(6) and it is important to consider that infection-associated cases tend to be more severe in nature. Another comparison in the same study supports that myocarditis seems to be higher in the vaccinated versus the 298 unvaccinated general population with a risk difference of 2.7 events per 100,000.(6) Synthesis of this information 299 together supports that infection-associated myocarditis is more common than vaccine-associated myocarditis but 300 that vaccine-associated myocarditis does occur. It is also important to note the age and sex preference for The reported myocarditis cases indicate that young, generally healthy males seem to be at the greatest 305 risk for myocarditis, with a single case series reporting events in adolescents as young as 15 years of age. (72, 74) 306 Presenting symptoms include severe chest pain that can be associated with fever that occurs, on average, four 307 days after immunization and more commonly after the second or subsequent doses of mRNA vaccines; (74) Table 3 summarizes the features, diagnosis, and 365 therapeutics of VITT.(85, 88-90) While the incidence seems to be quite rare, the diagnosis is of particular concern 366 due to associated mortality rates, as high as 40%, secondary to complications from thrombosis; in CDC reports, this 367 has equated to a fatality rate of 0.6 per one million J&J vaccines administered (out of over 14 million total J&J With increasing experience, we know that most immediate reactions are unlikely to be IgE-mediated, and the vast 406 majority of individuals have gone on to safely tolerate subsequent doses. Largely, the response to the adverse 407 outcomes described above has been the question of how to safely move forward with widespread immunization . In an interim analysis of mRNA COVID-19 vaccines the incidence of specific serious outcomes was not higher 1 to (Table 1) . Thankfully, current data and the availability of 414 different types of COVID-19 vaccines has reassured us that it would be an exceptionally rare circumstance that an 415 adverse reaction to one COVID-19 vaccines precludes administration of any other, or even the same, COVID-19 416 vaccine with allergist guidance. Our knowledge of this concept is increasing, which is extremely important not only 417 for the COVID-19 vaccines but many other pathogens and diseases of global importance to follow that will benefit 418 from mRNA therapeutics. Individuals with an existing IgE mediated PEG allergy were previously advised against 419 receiving mRNA vaccines due to the PEG2000 lipid nanoparticle carrier; however, we now know that this may be 420 tolerated as in patients with PEG-asparaginase hypersensitivity,(39, 40) and, more recently, known PEG allergy.(38, In this mature phase of the pandemic, we can be reassured that the growing body of data supports the 461 continued safe and efficacious administration of COVID-19 vaccines, though there still exist many unanswered 462 questions (Table 4) . It is important for providers to become familiar with the presenting features of the major 463 vaccine reactions and take the appropriate steps for further evaluation and treatment in the rare circumstances 464 when it is needed. Immediate and cutaneous reactions, along with myopericarditis, have no long-term sequelae 465 that have been identified. Individuals with immediate and benign, delayed cutaneous reactions have additionally 466 gone on to safely tolerate further doses in the vaccine series after recovering from the acute adverse events, 467 oftentimes without the side effects experienced after the first dose. VITT/TTS is rarer than these events but is 468 associated with increased morbidity and mortality when compared to immediate, cutaneous, and myocardial side 469 effects, and the age and medical history of the individual seeking vaccination should be taken into consideration. It Table IV . Knowns and Unknowns -Examples of questions that have been answered and those that remain unanswered at this phase of the pandemic and vaccine rollout. • What is the mechanism? • Can these be prevented with pre-medication? • Are these rare IgE mediated and, if yes, what is the antigen? • Low incidence of recurrence upon repeat vaccination, suggesting mechanism other than IgE • Majority of individuals with negative skin testing to excipients, so unlikely to be the antigen • Small numbers of PEG-allergic individuals have tolerated mRNA vaccination • Important to consider diagnoses other than anaphylaxis Delayed Cutaneous and other Hypersensitivity reactions • What is the mechanism? • Can these be prevented with pre-medication? • Are there risk factors for recurrence? • In the absence of SCAR, not a barrier to repeat vaccination with same vaccine formulation • Resolves without intervention in majority of cases • Likely to be due to immune response generated by immunization • What is the mechanism and risk related to that mechanism? • What is the most appropriate management? • What is the risk of recurrence with subsequent vaccination and how should these be managed? • What are the long-term outcomes? • What is the incidence of subclinical myocarditis/pericarditis and how might this affect future vaccine doses? • Majority of cases mild in nature with no or brief hospitalization • Limited follow up data -available data suggest return to baseline cardiac function is expected • Higher index of suspicion for diagnosis in adolescent and young adult males • New insights into mechanisms and risk (specifically regarding the mechanism with specific adenoviral vectors vaccines)? • What is the risk of recurrence with subsequent vaccination even the same vaccine construct with a different virus? • Incidence of thrombotic events higher in individuals who contract true COVID-19 infection • Contraindication to further viral vector based COVID vaccine • Low incidence but high mortality, especially when not recognized early J o u r n a l P r e -p r o o f More Than 10.1 Billion Shots Given: Covid-479 A Phase 1 Study to Evaluate the Safety and Immunogenicity of eOD-482 GT8 60mer mRNA Vaccine (mRNA-1644) and Core-g28v2 60mer mRNA Vaccine ClinicalTirals.gov. Safety, Tolerability, and Immunogenicity of Zika Vaccine mRNA-1893 486 in Healthy Flavivirus Seropositive and Seronegative Adults Bethesda, MD2021 mRNA vaccine for cancer immunotherapy mRNA-based therapeutics--developing a new class of drugs Safety of the 493 BNT162b2 mRNA Covid-19 Vaccine in a Nationwide Setting Nanoparticle-Mediated Cytoplasmic Delivery of Messenger RNA Vaccines: 495 Challenges and Future Perspectives mRNA vaccines -a new era in vaccinology Safety and 499 Efficacy of the BNT162b2 mRNA Covid-19 Vaccine Efficacy and Safety of 501 the mRNA-1273 SARS-CoV-2 Vaccine Safety and 503 Efficacy of Single-Dose Ad26.COV2.S Vaccine against Covid-19 Developments in Viral Vector-Based Vaccines. Vaccines 506 (Basel) Viral vectors as vaccine 508 platforms: from immunogenicity to impact Mounting Evidence Suggests Sputnik COVID Vaccine is Safe and Effective. 510 Nature A global database 512 of COVID-19 vaccinations Acute Allergic Reactions to mRNA COVID-19 Vaccines Risk of 519 anaphylaxis after vaccination in children and adults mRNA Vaccines 565 to Prevent COVID-19 Disease and Reported Allergic Reactions: Current Evidence and Suggested 566 Approach Polyethylene glycol allergy and immediate-568 type hypersensivitity reaction to COVID-19 vaccination: case report Polyethylene glycol (PEG) is a 571 cause of anaphylaxis to the Pfizer/BioNTech mRNA COVID-19 vaccine 574 Tolerability of polysorbate 80 containing COVID-19 vaccines in confirmed PEG allergic patients Experience with 577 polyethylene glycol allergy-guided risk management for COVID-19 vaccine anaphylaxis mRNA 580 COVID-19 Vaccine Safety in Patients with Previous Immediate Hypersensitivity to Pegaspargase Safety of administration 583 of BNT162b2 mRNA (Pfizer-BioNTech) COVID-19 vaccine in youths and young adults with a 584 history of acute lymphoblastic leukemia and allergy to PEG-asparaginase Safety of COVID-19 587 vaccination in patients with polyethylene glycol allergy: A case series Graded 590 Administration of Second Dose of Moderna and Pfizer-BioNTech COVID-19 mRNA Vaccines Patients With Hypersensitivity to First Dose Successful administration of second dose of BNT162b2 COVID-19 593 vaccine in two patients with potential anaphylaxis to first dose Anti-PEG antibodies: Properties, formation, 595 testing and role in adverse immune reactions to PEGylated nano-biopharmaceuticals Complement activation-related pseudoallergy: a stress reaction in blood 598 triggered by nanomedicines and biologicals Immediate 600 Hypersensitivity to Polyethylene Glycols and Polysorbates: More Common Than We Have 601 Recognized Cutaneous 603 reactions reported after Moderna and Pfizer COVID-19 vaccination: A registry-based study of 604 414 cases Clinical and 606 pathologic correlation of cutaneous COVID-19 vaccine reactions including V-REPP: A registry-607 based study Incidence of 609 Cutaneous Reactions After Messenger RNA COVID-19 Vaccines Persistent maculopapular rash after 612 the first dose of Pfizer-BioNTech COVID-19 vaccine COVID-19 Vaccines and the Skin: The 615 Landscape of Cutaneous Vaccine Reactions Worldwide COVID-19 vaccine-induced Stevens-Johnson 617 syndrome Stevens-Johnson syndrome post second dose of Pfizer COVID-19 619 vaccine: a case report. Oral Surg Oral Med Oral Pathol Oral Radiol COVID-19 vaccine-induced acute generalized 621 exanthematous pustulosis A case of severe 623 cutaneous adverse reaction following administration of the Janssen Ad26.COV2.S COVID-19 624 vaccine Acute generalized exanthematous pustulosis induced by 626 Moderna COVID-19 messenger RNA vaccine Delayed Localized Hypersensitivity Reactions 628 to the Moderna COVID-19 Vaccine: A Case Series Delayed Large Local Reactions to mRNA-1273 Vaccine against SARS-CoV-2 Skin manifestations of the BNT162b2 mRNA COVID-19 634 vaccine in healthcare workers 637 International Consensus (ICON): allergic reactions to vaccines Skin tests in 640 urticaria/angioedema and flushing to Pfizer-BioNTech SARS-CoV-2 vaccine: Limits of 641 intradermal testing Risk of herpes zoster reactivation after 643 messenger RNA COVID-19 vaccination: A cohort study Herpes zoster following inactivated COVID-19 vaccine: A 645 coexistence or coincidence? Herpes zoster emergence following mRNA COVID-647 19 vaccine Ipsilateral herpes zoster after the first dose of BNT162b2 mRNA 649 COVID-19 vaccine Herpes zoster after ChAdOx1 nCoV-19 651 vaccine: a case series Reactivation of herpesvirus 653 infections after vaccinations? Oral angiotensin-converting 655 enzyme inhibitors for treatment of delayed inflammatory reaction to dermal hyaluronic acid 656 fillers following COVID-19 vaccination-a model for inhibition of angiotensin II-induced 657 cutaneous inflammation Myocarditis Cases Reported 659 After mRNA-Based COVID-19 Vaccination in the US From Between COVID-19 and Myocarditis Using Hospital-Based Administrative Data -United States Patients 665 With Acute Myocarditis Following mRNA COVID-19 Vaccination Acute Myocarditis in Seven Adolescents Following Pfizer-BioNTech COVID-19 Vaccination. 668 Pediatrics Myocarditis Following Immunization With mRNA COVID-19 Vaccines in Members of the US 671 Military Myocarditis Occurring After Immunization With 673 mRNA-Based COVID-19 Vaccines SARS-CoV-2 675 vaccination and myocarditis or myopericarditis: population based cohort study Epidemiology of myocarditis and pericarditis following mRNA vaccines in Ontario, 679 Canada: by vaccine product, schedule and interval Use of mRNA 681 COVID-19 Vaccine After Reports of Myocarditis Among Vaccine Recipients: Update from the 682 Advisory Committee on Immunization Practices -United States Recurrence of Acute Myocarditis Temporally 685 Associated with Receipt of the mRNA Coronavirus Disease 2019 (COVID-19) Vaccine in a Male 686 Adolescent Myopericarditis Following mRNA COVID-19 Vaccination in a Male Adolescent Myocarditis and 691 Pericarditis After Vaccination for COVID-19 COVID-19 693 and Cardiovascular Disease: From Bench to Bedside Thrombotic Adverse Events Reported for 695 COVID-19 Vaccines: Comparison of Occurrence and 696 Clinical Outcomes in the EudraVigilance Database. Vaccines (Basel) Use of the Janssen 698 (Johnson & Johnson) COVID-19 Vaccine: Updated Interim Recommendations from the Advisory 699 Committee on Immunization Practices -United States 702 Thrombosis and Thrombocytopenia after ChAdOx1 nCoV-19 Vaccination SARS-CoV-2 Vaccine-Induced Immune Thrombotic 708 Thrombocytopenia Thrombotic thrombocytopenia due to SARS-CoV-2 vaccination Vaccine-induced immune thrombotic thrombocytopenia and cerebral venous sinus 713 thrombosis post COVID-19 vaccination; a systematic review COVID-19 vaccine-associated immune 715 thrombosis and thrombocytopenia (VITT): Diagnostic and therapeutic recommendations for a 716 new syndrome Pabinger-Fasching I. Thrombosis with Thrombocytopenia Syndrome Thrombotic Thrombocytopenia) American Society of Hematology2021 720 Thrombotic Thrombocytopenia after Ad26.COV2.S 723 Vaccination -Response from the Manufacturer Updated 725 Recommendations from the Advisory Committee on Immunization Practices for Prevention CfDCa. Interim Clinical Considerations for Use fo COVID-19 Vaccines 730 Currently Approved or Authorized in the United States 2022 COVID-19 Vaccination-Related Lymphadenopathy: What To 741 Be Aware Of Lymphadenopathy Following 743 COVID-19 Vaccination: Imaging Findings Review Axillary 745 Adenopathy after COVID-19 Vaccine: No Reason to Delay Screening Mammogram Revised SBI Recommendations for the 749 Management of Axillary Adenopathy in Patients with Recent COVID-19 Vaccination 2022 750 Immune-mediated adverse 754 reactions to vaccines COVID-19 Incidence 756 and Death Rates Among Unvaccinated and Fully Vaccinated Adults with and Without Booster 757 Doses During Periods of Delta and Omicron Variant Emergence -25 Tixagevimab and Cilgavimab (Evusheld) for Pre-Exposure Prophylaxis of COVID-19 Administration USFaD. Coronavirus (COVID-19) Update: FDA Authorizes New Long-762 Acting Monoclonal Antibodies for Pre-exposure Prevention of COVID-19 in Certain Individuals