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NEJM reviews: Safety of COVID-19 vaccines
NEJM reviews: Safety of COVID-19 vaccines. “New England Journal of Medicine” review: the safety of the COVID-19 vaccines.
In the next few months, millions or even billions of people will be vaccinated against the COVID-19 vaccine, and several cases of severe allergic reactions after the mass vaccination of mRNA vaccines have caused serious public concern. Ensuring the effectiveness and safety of vaccines to the utmost extent is the top priority for countries all over the world after issuing emergency vaccine authorizations.
Last Wednesday (December 30, 2020), the “New England Journal of Medicine” (NEJM) published a review “Ensuring the Safety of SARS-Cov-2 Vaccine”, detailing the most likely serious allergic reactions related to mRNA vaccines currently reported Allergens and their sensitization mechanisms, public health and individual response measures, and questions still to be answered.
The authors of this review are two immunologists specializing in drug allergy from Harvard Medical School and Vanderbilt University Medical Center. While calling for long-term and systematic monitoring of vaccine-related adverse events, they also pointed out that vaccine-related “severe allergic reactions can be cured without permanent damage” (Anaphylaxis is a treatable condition with no permanent effects).
So far, the development of mRNA vaccines to prevent SARS-CoV-2 infection has been successful, and no serious problems occurred during the phase 3 clinical trials that are still ongoing . The proportion of minor local side effects such as pain, redness and swelling in the vaccine group was higher than that in the placebo group. The incidence of systemic symptoms such as fever, fatigue, headache, muscle and joint pain is also slightly higher in the vaccine group than in the placebo group, and most symptoms appear within 24 to 48 hours after vaccination .
The mRNA vaccines jointly developed by Pfizer-BioNTech and Moderna (Moderna) have excluded potential participants with a history of allergies to any component of the vaccine in Phase 1-3 clinical trials. The vaccine study at Pfizer-BioNTech also excluded participants with a history of severe allergies to any vaccine (for complete exclusion criteria, please refer to the research protocols of these two trials. The research protocol and the full text of this article are available at NEJM.org) [1,2 ]. In these two trials, the incidence of allergic adverse events was the same in the placebo (normal saline) and vaccine groups .
The British Medicines and Healthcare Products Regulatory Agency (MHRA) was the first to grant Pfizer-BioNTech mRNA vaccine emergency use permit. On December 8, 2020, the United Kingdom reported two suspicious cases of severe allergic reactions within 24 hours after the launch of the mass vaccination program for medical staff and the elderly: they were 40 and 49-year-old women, both of whom were sensitive to food and drugs. Have a known history of allergies and carry an epinephrine auto-injector with you.
On December 11, the U.S. Food and Drug Administration (FDA) granted Pfizer-BioNTech mRNA vaccine emergency use authorization (EUA), and on December 14 (Monday), the general vaccination of medical staff began. On December 15, a vaccinator with a known history of allergies in Alaska developed a severe allergic reaction within 10 minutes of the first dose of the vaccine. For the three earliest reported severe allergic reactions, if the participants with these reactions initially participated in the mRNA vaccine clinical trial, the researchers would not exclude them based on their medical history [1,2].
Since the first severe allergic reaction occurred in Alaska, several cases of severe allergic reactions related to the vaccine have been reported after nearly 2 million medical staff in the United States received the Pfizer mRNA vaccine. The incidence of severe allergic reactions related to the Pfizer SARS-CoV-2 mRNA vaccine seems to be about 10 times the incidence reported by various vaccines before, the former is about one in 100,000 and the latter is about one in a million ( The known stable incidence of other vaccine-related severe allergic reactions).
The EUA for the Moderna mRNA vaccine was promulgated on December 18. It is still too early to clarify whether the vaccine will cause similar severe allergic reactions; however, a few suspicious cases of severe allergic reactions have been reported, including December 24 in Boston A severe allergic reaction occurred in a medical worker; the medical worker was allergic to shellfish and was carrying an epinephrine auto-injector.
In response to two cases of severe allergic reactions in the UK, MHRA suspended the Pfizer-BioNTech SARS-CoV-2 mRNA vaccine for people with a history of severe allergic reactions to any food, medicine or vaccine. The US Centers for Disease Control and Prevention (CDC) has issued recommendations for the first or second dose of Pfizer-BioNTech or Moderna mRNA vaccines. They recommend that any vaccine component (including polyethylene glycol [PEG] and polysorbate Anyone with a history of severe or immediate allergic reactions (within 4 hours) should not be vaccinated with this type of vaccine .
Severe allergic reaction is a serious multi-system reaction, with rapid onset, and patients can die from asphyxia, cardiovascular failure and other complications . A rapid diagnosis and adrenaline therapy are required to block the rapid progression of life-threatening symptoms.
The mechanism of severe allergic reaction is the combination of antigen and IgE and cross-linking, thereby activating mast cells; mast cells release inflammatory mediators such as histamine, proteases, prostaglandins, and leukotrienes, causing tissue reactions, resulting in flushing, urticaria, Symptoms such as laryngeal edema, wheezing, nausea, vomiting, tachycardia, hypotension and cardiovascular failure.
The patient became an IgE sensitized physique due to exposure to the antigen. Formerly called allergic-like reactions, reactions that have similar symptoms and signs to severe allergic reactions are now called non-IgE-mediated reactions because they have not been found to involve IgE. The reaction is the same as the clinical manifestations of a severe allergic reaction, and the reaction to epinephrine is also the same. But its mechanism is to directly activate mast cells and basophils, complement activation or other pathways, and it can occur when exposed to the antigen for the first time.
The blood trypsin level usually increases when IgE-mediated severe allergic reactions and non-IgE-mediated mast cell activation (a small increase) occur. This feature can be used to determine that mast cells are the source of inflammatory mediators.
Skin prick tests and intradermal tests as well as serum IgE testing can be used to determine the specific drug causing the reaction, but the negative predictive value of these testing methods is not 100% . The clinical manifestations of the two cases in the United Kingdom and one in the United States in the previous article are consistent with severe allergic reactions: the onset of illness within a few minutes after the injection, the symptoms are typical, and the adrenaline therapy is effective. The reaction at the first exposure is not a typical IgE-mediated reaction; however, pre-sensitization to a component of the vaccine may be the cause of this result .
Severe allergic reactions can be cured without permanent damage. However, the news of these adverse reactions has raised concerns about the risks of the new vaccine. These cases of severe allergic reactions raise more questions than the answers given; however, such safety signals are almost inevitable when a vaccination program involving millions of people is initiated; they highlight the need for a firm, proactive “Safety roadmap” to clarify the pathogenesis, identify people at risk of such reactions, and adopt strategies that help treatment and prevention (Figure 1) .
Figure 1. Evaluation of vaccine response
SARS-CoV-2 mRNA vaccines are based on the same lipid nanoparticle drug delivery technology; however, the lipid composition of the Pfizer-BioNTech vaccine is different from that of the Moderna vaccine. “Operation Warp Speed” enabled us to respond at an unprecedented speed, conducting safety and effectiveness studies on new vaccines that have never been used in humans, and after clarifying the SARS-CoV-2 virus sequence, less than one Vaccines have been developed and approved for marketing.
Several such vaccines may be approved in the next few months, and inevitably, there will also be adverse events that have not been observed in the clinical trials required to obtain the EUA. Ensuring vaccine safety requires us to take the initiative to take measures to ensure public confidence and reduce hesitation towards vaccination. These measures not only include vigilance and careful response, record adverse events and clarify their characteristics in order to discover and clarify their mechanisms, but also include adopting appropriate methods to predict, prevent and treat adverse events. The first step in adopting a systematic approach to vaccine adverse reactions is to make a clinical diagnosis and give appropriate initial treatment, and then a detailed medical history and causality assessment.
Non-immune-mediated rapid reactions (such as vasovagal reactions) are more common, usually manifesting as sweating, nausea, vomiting, pale complexion, and bradycardia; on the contrary, severe allergic reactions are manifested as flushing, itching, urticaria, and blood vessels Sexual edema, tachycardia and laryngeal edema. The clinical evaluation after the vaccine reaction should be done by an allergy-immunologist, including skin testing of the vaccine components, which may be beneficial. The results of other laboratory tests may help clinical and mechanism evaluations, and guide future vaccine and drug safety evaluations and treatments, such as provocation testing with other vaccines when re-vaccinations are needed.
The website for searching drug and vaccine excipient information is: https://dailymed.nlm.nih.gov/dailymed/. The excipient information for the approved vaccine is: https://www.cdc.gov/vaccines/pubs/pinkbook/downloads/appendices/b/excipient-table-2.pdf.
We can rest assured that for most known vaccines, vaccine-related severe allergic reactions are extremely rare, with an incidence of only one in a million . Acute allergic reactions after vaccination may be caused by vaccine antigens, residual non-human proteins, or preservatives and stabilizers (also called excipients) in the vaccine formulation . Although local reactions may be mostly related to the active antigen in the vaccine, IgE-mediated reactions or severe allergic reactions have traditionally been more related to inactive ingredients or substances in the vaccine production process, such as eggs, gelatin or latex .
The mRNA vaccines developed by Pfizer-BioNtech and Moderna both use lipid nanoparticle drug delivery systems, which can prevent the rapid degradation of mRNA by enzymes and facilitate the delivery of the vaccine in vivo [1,2,7]. This lipid nanoparticle drug delivery system is conjugated with polyethylene glycol (PEG) 2000 lipid; PEG lipids further enhance the stability of the drug delivery system, provide a hydrophilic layer for it, and extend the half-life.
Although mRNA vaccines are not a new technology, there is currently no licensed mRNA vaccine. Pfizer-BioNtech and Moderna’s vaccines were the first two mRNA vaccines to obtain EUA. Therefore, we do not have any experience to refer to the possible incidence or mechanism of allergic reactions related to mRNA vaccines. There may be such a situation: some people have a higher risk of non-IgE-mediated mast cell activation or complement activation, which is related to vaccine lipids or PEG lipid components.
For comparison, up to 40% of patients will experience infusion reactions after infusion of polyethylene glycol liposomal doxorubicin and other preparations; it is currently speculated that the cause of infusion reactions is that the patients have not been exposed to such drugs, the first Complement is activated after the first injection of drugs, and the reaction can be reduced after the second and subsequent injections of such drugs .
As an excipient in drugs, PEG is considered to be a rare “hidden hazard” leading to IgE-mediated reactions and recurring severe allergic reactions . The mRNA vaccine contains the lipid PEG 2000, so there is concern that this component may be related to severe allergic reactions. So far, no other vaccines with PEG as an excipient have been widely used. The sensitization risk of injections containing high molecular weight PEG seems to be higher; there have been case reports of severe allergic reactions after intestinal preparation with drugs containing PEG 3350 to PEG 4000 [9,10].
The case report included a patient who had a severe allergic reaction after receiving PEG 3350 bowel preparation; after that, the patient was first exposed to polyethylene glycol liposomal microbubbles (ie PEGLip 5000 perfluoropropane echocardiography contrast agent [Definity]) A severe allergic reaction occurred again; the label of the contrast agent was marked with a warning of immediate hypersensitivity . It seems that for drugs containing PEG 3350, such as methylprednisolone acetate and medroxyprogesterone for injection, PEG components are more likely to cause severe allergic reactions than active drugs [9,12].
Patients with a history of severe allergic reactions to Pfizer-BioNTech’s SARS-CoV-2 mRNA vaccine should be vaccinated with Moderna’s SARS-CoV-2 mRNA vaccine (this vaccine also uses a PEG 2000-based delivery system, but the lipid The mixture is different [see Table 1]), and the risk of severe allergic reactions is unclear.
Table 1. SARS-CoV-2 vaccines that have received emergency use authorization (EUA) or are in late stages of research
SARS-CoV-2 vaccines constructed with adenovirus vectors and protein subunits usually use polysorbate 80 (a non-ionic surfactant and emulsifier with a structure similar to PEG) as an excipient. The impact of the application is also unknown [6,13]. According to the current recommendations of the US CDC, people who have a history of severe allergic reactions to any component of the SARS-Cov-2 mRNA vaccine should not receive such vaccines. The current recommendation also requires that people with a history of PEG-related immediate reactions should not receive such vaccines. .
In addition, the recommendation also requires that patients with severe allergic reactions after being vaccinated with BioNTech-Pfizer or Moderna vaccines should avoid vaccinating various mRNA vaccines with PEG 2000 as an excipient, and avoid contact with various PEG-containing and injections The product of polysorbate 80 will not be decided until further research and more information is obtained.
We are entering a critical stage of rapid and phased vaccination for all priority groups. In response to the severe allergic reaction cases related to the Pfizer-BioNTech vaccine in the United Kingdom and the several severe allergic reaction cases currently occurring in the United States, the US CDC’s recommendation only requires people who are known to be allergic to any component of the vaccine not to receive such vaccines. A comprehensive study of existing hypersensitivity cases and all new cases will ensure that our strategy not only guarantees the safety of current vaccines, but also guarantees future mRNA vaccines and SARS-CoV-2 with the same or similar components as current vaccines The safety of the vaccine (Figure 1 and Table 1) .
In the next few months alone, the United States may market at least five new vaccines, and several more vaccines are under development (Table 1) . Ensuring public confidence is essential to alleviate their hesitation about vaccination [14,15]. Similar to all EUA-obtained projects, we expect that there will be adverse events not observed in clinical trials. In addition, the participating groups in clinical trials may not fully reflect the susceptibility of other groups to adverse events .
Regardless of the speed of development, all drugs, vaccines and medical products are expected to trigger certain adverse events. Fortunately, immune-mediated adverse events are relatively rare. We are entering a new phase. In the next few months, millions or even billions of people worldwide will receive new vaccines. Therefore, we must develop strategies to maximize the effectiveness and safety of vaccines at the individual and group levels.
It is also extremely important to develop systematic evidence-based strategies for safe vaccination. These strategies will be intertwined with our understanding of vaccine effectiveness and the need for re-vaccinations. When a higher incidence of rare side effects is observed in the general population (for example, Pfizer-BioNTech’s vaccine group reported 4 cases of Bell’s palsy), we still need to clarify whether these side effects are really related to the vaccine .
If someone is allergic to one SARS-CoV-2 vaccine, how safe is it to get another SARS-CoV-2 vaccine? In addition, what safety issues may completely terminate the future vaccination of the allergic person? In fact, mRNA vaccines are a promising new technology, which proves that its safety is of great significance for the development of several other viral vaccines of global importance and many cancer vaccines .
In the future while the epidemic will continue to spread, the focus of our work should be to carry out large-scale vaccination through safe and efficient methods. However, in the future, these new vaccines may mark the beginning of the era of individualized vaccinology, which means that we can tailor the safest and most effective vaccines for individuals and groups .
In addition, the monitoring and recording work after vaccination also brings us challenges. At the public health level, the Vaccine Adverse Event Reporting System (VAERS; https://vaers.hhs.gov) is a national reporting system in the United States that aims to detect early safety issues of approved vaccines, but the system will be used in the Covid-19 vaccine After obtaining the EUA, it will perform the same function. At the individual level, a system that can track the specific SARS-CoV-2 vaccine vaccinated and monitor potential long-term adverse events related to the vaccine is critical to individual safety and effectiveness.
The smartphone app V-safe (https://cdc.gov/coronavirus/2019-ncov/vaccines/safety/vsafe.html) can remind patients to receive the second dose of vaccine as needed, and track and manage Covid-19 vaccine related Side effects.
There are still many unsolved mysteries in the field of Covid-19 and its vaccine. What are the relevant parameters of protective immunity after natural infection or vaccination? How long can immunity last? Can large-scale herd immunity limit the spread of the virus in the population? Which components of the vaccine can cause allergic reactions? Are some vaccines less likely to cause IgE and non-IgE-mediated reactions than others? We need to carry out long-term close monitoring of vaccine safety, and also need to clarify the mechanism of adverse events of different types of SARS-CoV-2 vaccines, so as to develop a strategic and comprehensive solution to vaccine safety.
(source:internet, reference only)