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Id Subject Object Predicate Lexical cue
T1 0-43 Sentence denotes Maintaining Safety with SARS-CoV-2 Vaccines
T2 45-424 Sentence denotes To date, the development of mRNA vaccines for the prevention of infection with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been a success story, with no serious concerns identified in the ongoing phase 3 clinical trials.1 Minor local side effects such as pain, redness, and swelling have been observed more frequently with the vaccines than with placebo.
T3 425-842 Sentence denotes Systemic symptoms such as fever, fatigue, headache, and muscle and joint pain have also been somewhat more common with the vaccines than with placebo, and most have occurred during the first 24 to 48 hours after vaccination.1 In the phase 1–3 clinical trials of the Pfizer–BioNTech and Moderna mRNA vaccines, potential participants with a history of an allergic reaction to any component of the vaccine were excluded.
T4 843-1211 Sentence denotes The Pfizer–BioNTech studies also excluded participants with a history of severe allergy associated with any vaccine (see the protocols of the two trials, available with the full text of the articles at NEJM.org, for full exclusion criteria).1,2 Hypersensitivity adverse events were equally represented in the placebo (normal saline) and vaccine groups in both trials.1
T5 1212-1374 Sentence denotes The Medicines and Healthcare Products Regulatory Agency (MHRA) in the United Kingdom was the first to authorize emergency use of the Pfizer–BioNTech mRNA vaccine.
T6 1375-1682 Sentence denotes On December 8, 2020, within 24 hours after the start of the U.K. mass vaccination program for health care workers and elderly adults, the program reported probable cases of anaphylaxis in two women, 40 and 49 years of age, who had known food and drug allergies and were carrying auto-injectable epinephrine.
T7 1683-1902 Sentence denotes On December 11, the Food and Drug Administration (FDA) issued an emergency use authorization (EUA) for the Pfizer–BioNTech mRNA vaccine, and general vaccination of health care workers was started on Monday, December 14.
T8 1903-2100 Sentence denotes On December 15, a 32-year-old female health care worker in Alaska who had no known allergies presented with an anaphylactic reaction within 10 minutes after receiving the first dose of the vaccine.
T9 2101-2803 Sentence denotes The participants who had these initial three reported cases of anaphylaxis would not have been excluded on the basis of their histories from the mRNA vaccine clinical trials.1,2 Since the index case in Alaska, several more cases of anaphylaxis associated with the Pfizer mRNA vaccine have been reported in the United States after vaccination of almost 2 million health care workers, and the incidence of anaphylaxis associated with the Pfizer SARS-CoV-2 mRNA vaccine appears to be approximately 10 times as high as the incidence reported with all previous vaccines, at approximately 1 in 100,000, as compared 1 in 1,000,000, the known and stable incidence of anaphylaxis associated with other vaccines.
T10 2804-3211 Sentence denotes The EUA for the Moderna mRNA vaccine was issued on December 18, and it is currently too soon to know whether a similar signal for anaphylaxis will be associated with that vaccine; however, at this time a small number of potential cases of anaphylaxis have been reported, including one case on December 24 in Boston in a health care worker with shellfish allergy who was carrying auto-injectable epinephrine.
T11 3212-3460 Sentence denotes In response to the two cases of anaphylaxis in the United Kingdom, the MHRA issued a pause on vaccination with the Pfizer–BioNTech SARS-CoV-2 mRNA vaccine, to exclude any person with a history of anaphylactic reaction to any food, drug, or vaccine.
T12 3461-3888 Sentence denotes The Centers for Disease Control and Prevention (CDC) has issued advice pertaining to administration of either the first or the second dose of the Pfizer–BioNTech or Moderna mRNA vaccine, recommending exclusion of any person who has a history of a severe or immediate (within 4 hours) allergic reaction associated with any of the vaccine components, including polyethylene glycol (PEG) and PEG derivatives such as polysorbates.3
T13 3889-4163 Sentence denotes Anaphylaxis is a serious multisystem reaction with rapid onset and can lead to death by asphyxiation, cardiovascular collapse, and other complications.4 It requires prompt recognition and treatment with epinephrine to halt the rapid progression of life-threatening symptoms.
T14 4164-4556 Sentence denotes The cause of anaphylactic reactions is the activation of mast cells through antigen binding and cross-linking of IgE; the symptoms result from the tissue response to the release of mediators such as histamine, proteases, prostaglandins, and leukotrienes and typically include flushing, hives, laryngeal edema, wheezing, nausea, vomiting, tachycardia, hypotension, and cardiovascular collapse.
T15 4557-4621 Sentence denotes Patients become IgE-sensitized by previous exposure to antigens.
T16 4622-4821 Sentence denotes Reactions that resemble the clinical signs and symptoms of anaphylaxis, previously known as anaphylactoid reactions, are now referred to as non-IgE–mediated reactions because they do not involve IgE.
T17 4822-5030 Sentence denotes They manifest the same clinical features and response to epinephrine, but they occur by direct activation of mast cells and basophils, complement activation, or other pathways and can occur on first exposure.
T18 5031-5244 Sentence denotes Tryptase is typically elevated in blood in IgE-mediated anaphylaxis and, to a lesser extent, in non–IgE-mediated mast-cell activation, a feature that identifies mast cells as the sources of inflammatory mediators.
T19 5245-5644 Sentence denotes Prick and intradermal skin testing and analysis of blood samples for serum IgE are used to identify the specific drug culprit, although the tests lack 100% negative predictive value.5 The clinical manifestations of the two U.K. cases and the one U.S. case fit the description of anaphylaxis: they occurred within minutes after the injections, symptoms were typical, and all responded to epinephrine.
T20 5645-5821 Sentence denotes The occurrence on first exposure is not typical of IgE-mediated reactions; however, preexisting sensitization to a component of the vaccine could account for this observation.4
T21 5822-5885 Sentence denotes Anaphylaxis is a treatable condition with no permanent effects.
T22 5886-5988 Sentence denotes Nevertheless, news of these reactions has raised fear about the risks of a new vaccine in a community.
T23 5989-6391 Sentence denotes These cases of anaphylaxis raise more questions than they answer; however, such safety signals are almost inevitable as we embark on vaccination of millions of people, and they highlight the need for a robust and proactive “safety roadmap” to define causal mechanisms, identify populations at risk for such reactions, and implement strategies that will facilitate management and prevention (Figure 1).6
T24 6392-7021 Sentence denotes We can be reassured that vaccine-associated anaphylaxis has been a rare event, at one case per million injections, for most known vaccines.6 Acute allergic reactions after vaccination might be caused by the vaccine antigen, residual nonhuman protein, or preservatives and stabilizers in the vaccine formulation, also known as excipients.6 Although local reactions may be commonly associated with the active antigen in the vaccine, IgE-mediated reactions or anaphylaxis have historically been more typically associated with the inactive components or products of the vaccine manufacturing process, such as egg, gelatin, or latex.6
T25 7022-7395 Sentence denotes The mRNA vaccines developed by Pfizer–BioNtech and Moderna use a lipid-based nanoparticle carrier system that prevents the rapid enzymatic degradation of mRNA and facilitates in vivo delivery.1,2,7 This lipid-based nanoparticle carrier system is further stabilized by a polyethylene glycol (PEG) 2000 lipid conjugate that provides a hydrophilic layer, prolonging half-life.
T26 7396-7567 Sentence denotes Although the technology behind mRNA vaccines is not new, there are no licensed mRNA vaccines, and the Pfizer–BioNtech and Moderna vaccines are the first to receive an EUA.
T27 7568-7713 Sentence denotes There is therefore no prior experience that informs the likelihood or explains the mechanism of allergic reactions associated with mRNA vaccines.
T28 7714-7907 Sentence denotes It is possible that some populations are at higher risk for non–IgE-mediated mast-cell activation or complement activation related to either the lipid or the PEG-lipid component of the vaccine.
T29 7908-8241 Sentence denotes By comparison, formulations such as pegylated liposomal doxorubicin are associated with infusion reactions in up to 40% of recipients; the reactions are presumed to be caused by complement activation that occurs on first infusion, without previous exposure to the drug, and they are attenuated with second and subsequent injections.8
T30 8242-8555 Sentence denotes PEG is a compound used as an excipient in medications and has been implicated as a rare, “hidden danger” cause of IgE-mediated reactions and recurrent anaphylaxis.9 The presence of lipid PEG 2000 in the mRNA vaccines has led to concern about the possibility that this component could be implicated in anaphylaxis.
T31 8556-8638 Sentence denotes To date, no other vaccine that has PEG as an excipient has been in widespread use.
T32 8639-9698 Sentence denotes The risk of sensitization appears to be higher with injectable drugs with higher-molecular-weight PEG; anaphylaxis associated with bowel preparations containing PEG 3350 to PEG 4000 has been noted in case reports.9,10 The reports include anaphylaxis after a patient was exposed to a PEG 3350 bowel preparation; anaphylaxis subsequently developed on the patient’s first exposure to a pegylated liposome microbubble, PEGLip 5000 perflutren echocardiography contrast (Definity), which is labeled with a warning about immediate hypersensitivity reactions.11 For drugs such as methylprednisolone acetate and injectable medroxyprogesterone that contain PEG 3350, it now appears that the PEG component is more likely than the active drug to be the cause of anaphylaxis.9,12 For patients with a history of an anaphylactic reaction to the SARS-CoV-2 Pfizer–BioNTech mRNA vaccine, the risk of anaphylaxis with the Moderna SARS-CoV-2 mRNA vaccine — whose delivery system is also based on PEG 2000, but with different respective lipid mixtures (see Table 1) — is unknown.
T33 9699-10253 Sentence denotes The implications for future use of SARS-CoV-2 vaccines with an adenovirus carrier and protein subunit, which are commonly formulated with polysorbate 80, a nonionic surfactant and emulsifier that has a structure similar to PEG, are also currently unknown.6,13 According to the current CDC recommendations, all persons with a history of an anaphylactic reaction to any component of the mRNA SARS-Cov-2 vaccines should avoid these vaccines, and this recommendation would currently exclude patients with a history of immediate reactions associated with PEG.
T34 10254-10577 Sentence denotes It would also currently exclude patients with a history of anaphylaxis after receiving either the BioNTech–Pfizer or the Moderna vaccine, who should avoid all PEG 2000–formulated mRNA vaccines, and all PEG and injectable polysorbate 80 products, until further investigations are performed and more information is available.
T35 10578-10725 Sentence denotes We are now entering a critical period during which we will move rapidly through phased vaccination of various priority subgroups of the population.
T36 10726-11015 Sentence denotes In response to the cases of anaphylaxis associated with the Pfizer–BioNTech vaccine in the United Kingdom and now several cases of anaphylaxis in the United States, the CDC has recommended that only persons with a known allergy to any component of the vaccine be excluded from vaccination.
T37 11016-11273 Sentence denotes A systematic approach to the existing hypersensitivity cases and any new ones will ensure that our strategy will maintain safety not only for this vaccine but for future mRNA and SARS-CoV-2 vaccines with shared or similar components (Figure 1 and Table 1).6
T38 11274-11599 Sentence denotes The next few months alone are likely to see at least five new vaccines on the U.S. market, with several more in development (Table 1).13 Maintaining public confidence to minimize vaccine hesitancy will be crucial.14,15 As in any post-EUA program, adverse events that were not identified in clinical trials are to be expected.
T39 11600-11885 Sentence denotes In addition, populations that have been studied in clinical trials may not reflect a predisposition to adverse events that may exist in other populations.16 Regardless of the speed of development, some adverse events are to be expected with all drugs, vaccines, and medicinal products.
T40 11886-11939 Sentence denotes Fortunately, immune-mediated adverse events are rare.
T41 11940-12215 Sentence denotes Because we are now entering a period during which millions if not billions of people globally will be exposed to new vaccines over the next several months, we must be prepared to develop strategies to maximize effectiveness and safety at an individual and a population level.
T42 12216-12429 Sentence denotes The development of systematic and evidence-based approaches to vaccination safety will also be crucial, and the approaches will intersect with our knowledge of vaccine effectiveness and the need for revaccination.
T43 12430-12686 Sentence denotes When uncommon side effects that are prevalent in the general population are observed (e.g., the four cases of Bell’s palsy reported in the Pfizer–BioNTech vaccine trial group), the question whether they were truly vaccine-related remains to be determined.1
T44 12687-12833 Sentence denotes If a person has a reaction to one SARS-CoV-2 vaccine, what are the implications for the safety of vaccination with a different SARS-CoV-2 vaccine?
T45 12834-12909 Sentence denotes Furthermore, what safety issues may preclude future vaccination altogether?
T46 12910-13276 Sentence denotes Indeed, mRNA vaccines are a promising new technology, and demonstration of their safety is relevant to the development of vaccines against several other viruses of global importance and many cancers.7 For the immediate future, during a pandemic that is still increasing, it is critical that we focus on safe and efficient approaches to implementing mass vaccination.
T47 13277-13566 Sentence denotes In the future, however, these new vaccines may mark the beginning of an era of personalized vaccinology in which we can tailor the safest and most effective vaccine on an individual and a population level.17 Moreover, postvaccination surveillance and documentation may present a challenge.
T48 13567-13869 Sentence denotes On a public health level, the Vaccine Adverse Event Reporting System (VAERS; https://vaers.hhs.gov) is a national reporting system designed to detect early safety problems for licensed vaccines, but in the case of Covid-19 vaccines, the system will serve the same function after an EUA has been issued.
T49 13870-14106 Sentence denotes On an individual level, a system that will keep track of the specific SARS-CoV-2 vaccine received and will provide a means to monitor potential long-term vaccine-related adverse events will be critical to individual safety and efficacy.
T50 14107-14333 Sentence denotes V-safe (https://cdc.gov/coronavirus/2019-ncov/vaccines/safety/vsafe.html) is a smartphone application designed to remind patients to obtain a second dose as needed and to track and manage Covid-19 vaccine–related side effects.
T51 14334-14395 Sentence denotes In the world of Covid-19 and vaccines, many questions remain.
T52 14396-14482 Sentence denotes What are the correlates of protective immunity after natural infection or vaccination?
T53 14483-14511 Sentence denotes How long will immunity last?
T54 14512-14585 Sentence denotes Will widespread immunity limit the spread of the virus in the population?
T55 14586-14655 Sentence denotes Which component of the vaccine is responsible for allergic reactions?
T56 14656-14743 Sentence denotes Are some vaccines less likely than others to cause IgE- and non-IgE–mediated reactions?
T57 14744-14973 Sentence denotes Careful vaccine-safety surveillance over time, paired with elucidation of mechanisms of adverse events across different SARS-CoV-2 vaccine platforms, will be needed to inform a strategic and systematic approach to vaccine safety.
T58 14975-15077 Sentence denotes Disclosure forms provided by the authors are available with the full text of this article at NEJM.org.
T59 15079-15140 Sentence denotes This article was published on December 30, 2020, at NEJM.org.
T60 15142-15158 Sentence denotes Disclosure Forms
T61 15159-15195 Sentence denotes Click here for additional data file.
T62 15197-15239 Sentence denotes Figure 1 Assessing Reactions to Vaccines.
T63 15240-15433 Sentence denotes SARS-CoV-2 mRNA vaccines are built on the same lipid-based nanoparticle carrier technology; however, the lipid component of the Pfizer-BioNTech vaccine differs from that of the Moderna vaccine.
T64 15434-15727 Sentence denotes Operation Warp Speed has led to an unprecedented response to the study of the safety and effectiveness of new vaccine platforms never before used in humans and to the development of vaccines that have been authorized for use less than a year after the SARS-CoV-2 viral sequence was discovered.
T65 15728-15957 Sentence denotes The next few months could see the authorization of several such vaccines, and inevitably, adverse drug events will be recognized in the coming months that were not seen in the studies conducted before emergency use authorization.
T66 15958-16077 Sentence denotes Maintenance of vaccine safety requires a proactive approach to maintain public confidence and reduce vaccine hesitancy.
T67 16078-16329 Sentence denotes This approach involves not only vigilance but also meticulous response, documentation, and characterization of these events to heighten recognition and allow definition of mechanisms and appropriate approaches to prediction, prevention, and treatment.
T68 16330-16511 Sentence denotes A systematic approach to an adverse reaction to any vaccine requires clinical recognition and appropriate initial treatment, followed by a detailed history and causality assessment.
T69 16512-16779 Sentence denotes Nonimmune immediate reactions such as vasovagal reactions are common and typically manifest with diaphoresis, nausea, vomiting, pallor, and bradycardia, in contrast to the flush, pruritus, urticaria, angioedema, tachycardia, and laryngeal edema seen with anaphylaxis.
T70 16780-16926 Sentence denotes Post-reaction clinical assessment by an allergist–immunologist that includes skin testing for allergy to components of the vaccine can be helpful.
T71 16927-17144 Sentence denotes Use of other laboratory information may aid in clinical and mechanistic assessment and guide future vaccine and drug safety as well as management, such as rechallenge with alternative vaccines if redosing is required.
T72 17145-17256 Sentence denotes A useful resource for searching the excipients of drugs and vaccines is https://dailymed.nlm.nih.gov/dailymed/.
T73 17257-17402 Sentence denotes A useful resource for excipients in licensed vaccines is https://www.cdc.gov/vaccines/pubs/pinkbook/downloads/appendices/b/excipient-table-2.pdf.
T74 17403-17497 Sentence denotes Table 1 SARS-CoV-2 Vaccines under Emergency Use Authorization (EUA) or in Late-Phase Studies.
T75 17498-17627 Sentence denotes Vaccine Platform Type of Vaccine and Immunogen Developer(Name of Vaccine) Dose Scheduleand Administration Phase* Excipients†
T76 17628-17736 Sentence denotes RNA-based vaccine mRNA encoding spike protein (30 μg) BioNTech–Pfizer(BNT162b2) Two doses (day 0, day 21)
T77 17737-18133 Sentence denotes Intramuscular Post-EUA 0.43 mg ((4-hydroxybutyl)azanediyl)bis(hexane-6,1-diyl)bis(2-hexyldecanoate), 0.05 mg2[(polyethylene glycol)-2000]-N,N-ditetradecylacetamide, 0.09 mg 1,2-distearoyl-sn-glycero-3-phosphocholine, and 0.2 mg cholesterol, 0.01 mg potassium chloride, 0.01 mg monobasic potassium phosphate, 0.36 mg sodium chloride, 0.07 mg dibasic sodium phosphate dihydrate, and 6 mg sucrose.
T78 18134-18237 Sentence denotes The diluent (0.9% sodium chloride Injection) contributes an additional 2.16 mg sodium chloride per dose
T79 18238-18340 Sentence denotes RNA-based vaccine mRNA encoding spike protein (100 μg) Moderna(mRNA-1273) Two doses (day 0, day 28)
T80 18341-18611 Sentence denotes Intramuscular Post-EUA Lipids (SM-102; 1,2-dimyristoyl-rac-glycero-3-methoxypolyethylene glycol-2000 [PEG 2000-DMG]; cholesterol; and 1,2-distearoyl-sn-glycero-3-phosphocholine [DSPC]), tromethamine, tromethamine hydrochloride, acetic acid, sodium acetate, and sucrose
T81 18612-18665 Sentence denotes Adenovirus vector (nonreplicating) ChAdOx1-Sn Cov-19
T82 18666-18810 Sentence denotes Nonreplicating chimpanzee AdV5 expressing spike protein AstraZeneca and University of Oxford(AZD1222) One (day 0) or two (day 0, day 28) doses
T83 18811-18997 Sentence denotes Intramuscular Phase 3 10 mM histidine, 7.5% (w/v) sucrose,35 mM sodium chloride, 1 mM magnesiumchloride, 0.1% (w/v) polysorbate 80,0.1 mM edetate disodium, 0.5% (w/v)ethanol, at pH 6.6
T84 18998-19044 Sentence denotes Adenovirus vector(nonreplicating) Ad26.COV2.S
T85 19045-19160 Sentence denotes Adenovirus 26 vectored vaccine using AdVac and PER.C6 technology Janssen One (day 0) or two (day 0, day 56) doses
T86 19161-19318 Sentence denotes Intramuscular Phase 3 Sodium chloride, citric acid monohydrate, polysorbate 80, 2 hydroxypropyl-B-cyclodextrin (HBCD), ethanol (absolute), sodium hydroxide
T87 19319-19419 Sentence denotes Protein subunit Full-length recombinant SARS-CoV-2 glycoprotein nanoparticle with Matrix M adjuvant
T88 19420-19479 Sentence denotes Spike prefusion protein Novavax Two doses (day 0, day 21)
T89 19480-19609 Sentence denotes Intramuscular Phase 3 Matrix M1 adjuvantFull-length spike protein formulated in polysorbate 80 detergent and Matrix M1 adjuvant
T90 19610-19708 Sentence denotes Protein subunit SARS-CoV-2 vaccine formulation with adjuvant (S-protein) (Baculovirus production)
T91 19709-19773 Sentence denotes Spike protein Sanofi Pasteur and GSK Two doses (day 0, day 21)
T92 19774-19977 Sentence denotes Intramuscular Phase 1–2 Sodium phosphate monobasic monohydrate, sodium phosphate dibasic, sodium chloride polysorbate 20, disodium hydrogen phosphate, potassium dihydrogen phosphate, potassium chloride
T93 19978-20035 Sentence denotes * Phase information was current as of December 21, 2020.
T94 20036-20080 Sentence denotes In all cases, the placebo was normal saline.
T95 20081-20235 Sentence denotes † Bold entries are excipients potentially related to vaccine reaction that may be cross-reactive to other excipients (e.g., PEG 2000 and polysorbate 80).
T96 20236-20313 Sentence denotes SM-102, a component of the Moderna vaccine, is a proprietary ionizable lipid.