PEG in Pfizer’s COVID-19 Vaccine

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PEG in Pfizer’s COVID-19 Vaccine Apr 23, 2021 22:48:53 GMT

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Post by Admin on Apr 23, 2021 22:48:53 GMT

Severe allergy-like reactions in at least eight people who received the COVID-19 vaccine produced by Pfizer and BioNTech over the past 2 weeks may be due to a compound in the packaging of the messenger RNA (mRNA) that forms the vaccine’s main ingredient, scientists say. A similar mRNA vaccine developed by Moderna, which was authorized for emergency use in the United States on Friday, also contains the compound, polyethylene glycol (PEG).

PEG has never been used before in an approved vaccine, but it is found in many drugs that have occasionally triggered anaphylaxis—a potentially life-threatening reaction that can cause rashes, a plummeting blood pressure, shortness of breath, and a fast heartbeat. Some allergists and immunologists believe a small number of people previously exposed to PEG may have high levels of antibodies against PEG, putting them at risk of an anaphylactic reaction to the vaccine.

Others are skeptical of the link. Still, the U.S. National Institute of Allergy and Infectious Diseases (NIAID) was concerned enough to convene several meetings last week to discuss the allergic reactions with representatives of Pfizer and Moderna, independent scientists and physicians, and the Food and Drug Administration (FDA).

NIAID is also setting up a study in collaboration with FDA to analyze the response to the vaccine in people who have high levels of anti-PEG antibodies or have experienced severe allergic responses to drugs or vaccines before. “Until we know there is truly a PEG story, we need to be very careful in talking about that as a done deal,” says Alkis Togias, branch chief of allergy, asthma, and airway biology at NIAID.

Pfizer, too, says it is “actively seeking follow-up.” A statement emailed to Science noted it already recommends that “appropriate medical treatment and supervision should always be readily available” in case a vaccinee develops anaphylaxis.

Anaphylactic reactions can occur with any vaccine, but are usually extremely rare—about one per 1 million doses. As of 19 December, the United States had seen six cases of anaphylaxis among 272,001 people who received the COVID-19 vaccine, according to a recent presentation by Thomas Clark of the U.S. Centers for Disease Control and Prevention (CDC); the United Kingdom has recorded two. Because the Pfizer and Moderna mRNA vaccines use a new platform, the reactions call for careful scrutiny, says Elizabeth Phillips, a drug hypersensitivity researcher at Vanderbilt University Medical Center who attended an NIAID meeting on 16 December. “This is new.”

News reports about the allergic reactions have already created anxiety. “Patients with severe allergies in the US are getting nervous about the possibility that they may not be able to get vaccinated, at least with those two vaccines,” Togias wrote in an invitation to meeting participants. “Allergies in general are so common in the population that this could create a resistance against the vaccines in the population,” adds Janos Szebeni, an immunologist at Semmelweis University in Budapest, Hungary, who has long studied hypersensitivity reactions to PEG and who also attended the 16 December gathering.

Scientists who believe PEG may be the culprit stress that vaccination should continue. “We need to get vaccinated,” Phillips says. “We need to try and curtail this pandemic.” But more data are urgently needed, she adds: “These next couple of weeks in the U.S. are going to be extremely important for defining what to do next.”

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PEG in Pfizer’s COVID-19 Vaccine Apr 23, 2021 23:14:47 GMT

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Post by Admin on Apr 23, 2021 23:14:47 GMT

Toothpaste and shampoo
Pfizer’s and Moderna’s clinical trials of the vaccines, which involved tens of thousands of people, did not find serious adverse events caused by the vaccine. But both studies excluded people with a history of allergies to components of the COVID-19 vaccines; Pfizer also excluded those who previously had a severe adverse reaction from any vaccine. People with previous allergic reactions to food or drugs were not excluded, but may have been underrepresented.

The two vaccines both contain mRNA wrapped in lipid nanoparticles (LNPs) that help carry it to human cells but also act as an adjuvant, a vaccine ingredient that bolsters the immune response. The LNPs are “PEGylated”—chemically attached to PEG molecules that cover the outside of the particles and increase their stability and life span.

PEGs are also used in everyday products such as toothpaste and shampoo as thickeners, solvents, softeners, and moisture carriers, and they’ve been used as a laxative for decades. An increasing number of biopharmaceuticals include PEGylated compounds as well.

PEGs were long thought to be biologically inert, but a growing body of evidence suggests they are not. As much as 72% of people have at least some antibodies against PEGs, according to a 2016 study led by Samuel Lai, a pharmaco-engineer at the University of North Carolina, Chapel Hill, presumably as a result of exposure to cosmetics and pharmaceuticals. About 7% have a level that may be high enough to predispose them to anaphylactic reactions, he found. Other studies have also found antibodies against PEG, but at lower levels.

“Some companies have dropped PEGylated products from their pipeline as a result,” Lai says. But he notes that the safety record of many PEGylated drugs has persuaded others that “concerns about anti-PEG antibodies are overstated.”

Szebeni says the mechanism behind PEG-conjugated anaphylaxis is relatively unknown because it does not involve immunoglobulin E (IgE), the antibody type that causes classical allergic reactions. (That’s why he prefers to call them “anaphylactoid” reactions.) Instead, PEG triggers two other classes of antibodies, immunoglobulin M (IgM) and immunoglobulin G (IgG), involved in a branch of the body’s innate immunity called the complement system, which Szebeni has spent decades studying in a pig model he developed.

In 1999, while working at the Walter Reed Army Institute of Research, Szebeni described a new type of drug-induced reaction he dubbed complement activation-related pseudoallergy (CARPA), a nonspecific immune response to nanoparticle-based medicines, often PEGylated, that are mistakenly recognized by the immune system as viruses.

Szebeni believes CARPA explains the severe anaphylactoid reactions some PEGylated drugs are occasionally known to cause, including cancer blockbuster Doxil. A team assembled by Bruce Sullenger, a surgeon at Duke University, experienced similar issues with an experimental anticoagulant containing PEGylated RNA. The team had to halt a phase III trial in 2014 after about 0.6% of 1600 people who received the drug had severe allergic responses and one participant died. “That stopped the trial,” Sullenger says. The team found that every participant with an anaphylaxis had high levels of anti-PEG IgG. But some with no adverse reaction had high levels as well, Sullenger adds. “So, it is not sufficient to just have these antibodies.”

Until we know there is truly a PEG [polyethylene glycol] story, we need to be very careful in talking about that as a done deal.

Alkis Togias, National Institute of Allergy and Infectious Diseases
At the NIAID meeting, several attendees stressed that PEGylated nanoparticles may cause problems through a mechanism other than CARPA. Just last month, Phillips and scientists at FDA and other institutions published a paper showing patients who suffered an anaphylactic reaction to PEGylated drugs did have IgE antibodies to PEG after all, suggesting those may be involved, rather than IgG and IgM.

Other scientists, meanwhile, are not convinced PEG is involved at all. “There is a lot of exaggeration when it comes to the risk of PEGs and CARPA,” says Moein Moghimi, a nanomedicine researcher at Newcastle University who suspects a more conventional mechanism is causing the reactions. “You are technically delivering an adjuvant at the injection site to excite the local immune system. It happens that some people get too much excitement, because they have a relatively high number of local immune cells.”

Others note the amount of PEG in the mRNA vaccines is orders of magnitude lower than in most PEGylated drugs. And whereas those drugs are often given intravenously, the two COVID-19 vaccines are injected into a muscle, which leads to a delayed exposure and a much lower level of PEG in the blood, where most anti-PEG antibodies are.

Nevertheless, the companies were aware of the risk. In a stock market prospectus filed on 6 December 2018, Moderna acknowledged the possibility of “reactions to the PEG from some lipids or PEG otherwise associated with the LNP.” And in a September paper, BioNTech researchers proposed an alternative to PEG for therapeutic mRNA delivery, noting: “The PEGylation of nanoparticles can also have substantial disadvantages concerning activity and safety.’”

Katalin Karikó, a senior vice president at BioNTech who co-invented the mRNA technology underlying both vaccines, says she discussed with Szebeni whether PEG in the vaccine could be an issue. (The two know each other well; both are Hungarian and in the 1980s, Karikó taught Szebeni how to make liposomes in her lab.) They agreed that given the low amount of lipid and the intramuscular administration, the risk was negligible.

Karikó emphasizes that based on what we know so far, the risk is still low. “All vaccines carry some risk. But the benefit of the vaccine outweighs the risk,” she says.

Szebeni agrees, but says he hopes that’s also true in the long run. He notes that both mRNA vaccines require two shots, and he worries anti-PEG antibodies triggered by the first shot could increase the risk of an allergic reaction to the second or to PEGylated drugs.

Stay for 30 minutes.
To understand the risk, Phillips says, it’s crucial to unravel the mechanisms underlying the immune reactions and find out how often they are likely to occur. The known U.S. cases are currently under study, but key clues may have vanished: Anaphylactic reactions produce biomarkers that only remain in the blood for a few hours. At the NIAID meeting, participants discussed ways to ensure that blood samples from future cases are taken immediately and tested for those markers.

If PEG does turn out to be the culprit, the question is, what can be done? Screening millions of people for anti-PEG antibodies before they are vaccinated is not feasible. Instead, CDC guidelines recommend not giving the Pfizer or Moderna vaccines to anyone with a history of severe allergic reaction to any component of the vaccine. For people who have had a severe reaction to another vaccine or injectable medication, the risks and benefits of vaccination should be carefully weighed, CDC says. And people who might be at high risk of an anaphylactic reaction should stay at the vaccination site for 30 minutes after their shot so they can be treated if necessary.

“At least [anaphylaxis] is something that happens quickly,” Philips says. “So, it’s something that you can be very much alerted to, prepared to recognize early and be prepared to treat early.”

Last Edit: Apr 24, 2021 5:55:49 GMT by Admin

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PEG in Pfizer’s COVID-19 Vaccine Apr 24, 2021 5:52:38 GMT

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Post by Admin on Apr 24, 2021 5:52:38 GMT

If you are allergic to an ingredient in a COVID-19 vaccine
If you have had a severe allergic reaction or an immediate allergic reaction—even if it was not severe—to any ingredient in an mRNA COVID-19 vaccine, you should not get either of the currently available mRNA COVID-19 vaccines (Pfizer-BioNTech and Moderna).

If you have had a severe allergic reaction or an immediate allergic reaction to any ingredient in Johnson & Johnson’s Janssen (J&J/Janssen) COVID-19 vaccine, you should not get the J&J/Janssen vaccine.

If you aren’t able to get one type of COVID-19 vaccine because you are allergic to an ingredient in that vaccine, ask your doctor if you should get a different type of COVID-19 vaccine. Learn about the different types of COVID-19 vaccines.

If you had an allergic reaction to a previous shot of an mRNA vaccine
If you aren’t able to get the second shot of an mRNA vaccine because you had an allergic reaction to the first shot, ask your doctor if you should get a different type of COVID-19 vaccine. Learn about the different types of COVID-19 vaccines.

If you are allergic to polyethylene glycol (PEG) or polysorbate
PEG and polysorbate are closely related to each other. PEG is an ingredient in the mRNA vaccines, and polysorbate is an ingredient in the J&J/Janssen vaccine.

If you are allergic to PEG, you should not get an mRNA COVID-19 vaccine. Ask your doctor if you can get the J&J/Janssen vaccine.

If you are allergic to polysorbate, you should not get the J&J/Janssen COVID-19 vaccine. Ask your doctor if you can get an mRNA COVID-19 vaccine.

If you are allergic to other types of vaccines
If you have had an immediate allergic reaction—even if it was not severe—to a vaccine or injectable therapy for another disease, ask your doctor if you should get a COVID-19 vaccine. Your doctor will help you decide if it is safe for you to get vaccinated.

If you have allergies not related to vaccines
CDC recommends that people get vaccinated even if they have a history of severe allergic reactions not related to vaccines or injectable medications—such as food, pet, venom, environmental, or latex allergies. People with a history of allergies to oral medications or a family history of severe allergic reactions may also get vaccinated.

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PEG in Pfizer’s COVID-19 Vaccine Apr 24, 2021 19:46:15 GMT

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Post by Admin on Apr 24, 2021 19:46:15 GMT

Allergic reactions to vaccines are not common, but they are possible. To be on the safe side, when you get in line to receive your COVID-19 vaccine, you will be asked if you are allergic to any ingredients in the shot. While the ingredients in vaccines are safe, it is possible that someone might have sensitivities that could make them more likely to have an allergic reaction.

What's in the COVID-19 Vaccines?
With the COVID-19 vaccines, experts point to a specific ingredient that, although rare, can trigger an allergic reaction in people who are sensitive to it: polyethylene glycol (PEG).

What Is PEG?
PEG, also called macrogol, is a lipid compound that acts as a solvent, thickener, softener, and moisture carrier in many common products including medications, toothpaste, shampoo, skincare, and laxatives.

PEG is an additive in both the Moderna and Pfizer-BioNTech COVID-19 vaccines. It protects the mRNA as it is transferred into human cells.1

PEG in Vaccines
PEG, as well as another compound additive called polysorbate (which is used in the Johnson & Johnson vaccine), can trigger an immediate allergic reaction, though it is rare. The reaction may include anaphylactic symptoms including rashes, shortness of breath, rapid heartbeat, and a decrease in blood pressure.2

The creation of the COVID-19 vaccines is the first time PEG has been used as an additive in a widely used immunization platform. That means that we do not have any data confirming that vaccines containing PEG have caused any severe allergic reactions. However, PEG and polysorbate have been noted as suspected causes of anaphylactic reactions to the Moderna and Pfizer-BioNTech vaccines.2

What’s the Risk of Having a Severe Allergic Reaction to the COVID-19 Vaccine?
How Common is PEG Sensitivity?
A 2016 study published in Analytical Chemistry found that about 7% of people who have been exposed to PEG from various products have a level of antibodies to the compound that is high enough to cause an anaphylactic reaction.3

In a presentation at the American Academy of Allergy, Asthma, and Immunology Annual Meeting, John Kelso, MD, a practicing allergist in the Division of Allergy, Asthma, and Immunology at Scripps Clinic and voluntary health sciences clinical professor at the University of California San Diego School of Medicine, said that “Even in the rare patient who is PEG allergic, we still don’t know if there is enough PEG in the vaccine to actually cause a reaction. It is certainly possible, but remains a speculation to date.”4

Severe allergic reactions to the COVID-19 vaccines do not happen often. In his presentation, Kelso reported that since COVID vaccine distribution began, only about 5 in 1 million people have reported an anaphylactic reaction to the vaccine, which he says is “really quite rare.”

1. Garvey LH, Nasser S. Anaphylaxis to the first COVID-19 vaccine: is polyethylene glycol (PEG) the culprit? Br J Anaesth. 2021;126(3):e106-e108. doi:10.1016/j.bja.2020.12.020

2. Science. Suspicions grow that nanoparticles in Pfizer’s COVID-19 vaccine trigger rare allergic reactions. Updated December 21, 2020.

3. Yang Q, Jacobs TM, McCallen JD, et al. Analysis of pre-existing IgG and IgM antibodies against polyethylene glycol (PEG) in the general population. Anal Chem. 2016;88(23):11804-11812. doi:10.1021/acs.analchem.6b03437

Last Edit: Apr 24, 2021 19:47:27 GMT by Admin

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PEG in Pfizer’s COVID-19 Vaccine Apr 24, 2021 20:31:24 GMT

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Post by Admin on Apr 24, 2021 20:31:24 GMT

Anaphylaxis to the first COVID-19 vaccine: is polyethylene glycol (PEG) the culprit?
Lene H. Garvey
Shuaib Nasser

Published:December 17, 2020
DOI:https://doi.org/10.1016/j.bja.2020.12.020

Editor—The day after the world watched the first person receiving the coronavirus disease 2019 (COVID-19) vaccine on December 8, 2020, reports of three cases of suspected allergic reactions in connection with the vaccine emerged from the UK. Two were reports of anaphylaxis in healthcare workers, with onset within minutes of vaccination, responding well to treatment with epinephrine. Both recovered fully and were reported to have severe allergies to foods and drugs, respectively. The third case was less severe and did not require epinephrine.

Immediate-type life-threatening reactions to vaccines are exceedingly rare; they are reported to occur in 1.3 cases per million doses.1 Therefore, two cases of anaphylaxis on the second day of a vaccination campaign with a new vaccine require further scrutiny. The first important task is to confirm that these cases were indeed anaphylaxis. If anaphylaxis is proved likely, the cause of the reaction should be identified.

The active ingredient is rarely the cause, and the focus should be directed at the many excipients usually present in vaccines.2 A recent review of the literature showed that rare cases of immediate hypersensitivity reactions to excipients have been described for adjuvants/preservatives; antimicrobials; and a single case of a reaction to polysorbate 80, a polymer with structural similarities to polyethylene glycol (PEG).3,4 Hypersensitivity reactions to vaccines containing gelatin and egg had only been described in patients with previous known hypersensitivity to gelatin and egg. In fact, large studies have shown a very low risk of immediate reactions to ovalbumin in influenza vaccines in patients with allergy to eggs,5 and the recommendation to these patients is that the risk of anaphylaxis is no higher than for non-allergics.

The COVID-19 vaccine from Pfizer–BioNTech recently introduced in the UK, USA, and other countries is a messenger RNA (mRNA)-based vaccine (tozinameran, BNT-162b2) using lipid nanoparticles to facilitate the transport of mRNA into cells.6 The vaccine contains a number of excipients and lipids, one of them based on PEG-2000. This is currently the only excipient in the vaccine with recognised allergenic potential. The severity and rapid onset of the two reported reactions to the vaccine further increase suspicion towards PEG.

Allergy to excipients is often overlooked because of a lack of knowledge about their allergenic potential. However, allergy to PEG, also often called macrogol, has been reported with increasing frequency over recent years,7,8 Patients have usually had repeated systemic allergic reactions/anaphylaxis before diagnosis. A typical history is of severe allergic reactions to several classes of drugs, for example, penicillin, laxatives, injected corticosteroids, or antacids, all containing PEG. Symptoms are of rapid onset, usually within minutes, and typically result in severe generalised pruritus, urticaria, angioedema, hypotension, or difficulty in breathing. Reactions are more severe with higher doses and with higher-molecular-weight PEGs.

Polyethylene glycol is an ingredient in many laxatives, in about 30% of tablets and is used as a surfactant in many injectable formulations, where a prolonged effect is needed, such as in depot steroids. More recently, the technology of PEGylation has been introduced to enhance drug delivery in many areas of medicine. No reactions to PEG in vaccines have been reported, but PEG has not been a commonly used excipient in vaccines until now.

The mechanism of sensitisation to PEGs is unknown, but from the cases described in the literature7,8 and our personal experience with a total of 18 patients with PEG allergy, there is no reason to believe that existing inhalational or food allergies predispose to PEG allergy. However, PEG allergy may be suspected in patients with very severe reactions to drugs where the cause is unconfirmed, or patients with repeated immediate-type reactions to several structurally unrelated drugs or other products containing PEG.

The potential benefit of an effective COVID-19 vaccine is far reaching and a potential solution to a substantial threat to global health. The risk of hypersensitivity and ultimately anaphylaxis is present for all drugs, including vaccines, although usually low and is offset by the benefits of the drug. Randomised clinical trials of the Pfizer–BioNTech COVID-19 vaccine in >22 000 individuals receiving the active treatment were independently reviewed by the US Food and Drug Administration (FDA) and presented at an advisory committee meeting for emergency approval of the vaccine on December 10, 2020. The FDA found a small signal towards more hypersensitivity cases in the vaccine group, but none of the reactions were immediate, severe, or requiring epinephrine. Exclusion criteria for the clinical trials of the vaccine included individuals with known hypersensitivity to vaccines, or with a history of allergy, hypersensitivity, or intolerance to the COVID-19 vaccine or its excipients according to the registration of the trials on ClinicalTrials.gov. At the FDA advisory committee meeting, the cases of anaphylaxis in the UK were discussed at length. The advisory committee voted 17 to 4 in favour of granting Pfizer emergency approval for the vaccine, which was granted on December 11, 2020. The FDA requested that a warning be added to the product information that medication to treat immediate-type hypersensitivity reactions should be available where vaccinations take place. Also, the FDA advised that the vaccine should be contraindicated in patients with a severe allergic reaction to the first dose of vaccine, or with known hypersensitivity to any ingredient/component of the vaccine. Finally, a stringent surveillance system is to be initiated to monitor adverse effects of the vaccine with monthly reporting.

In the UK, based on the anaphylactic reactions reported, the present advice from the UK Medicines and Healthcare products Regulatory Agency (MHRA) is that ‘any person with a history of anaphylaxis to a vaccine, medicine or food should not receive the Pfizer/BioNTech COVID-19 vaccine’.9 This is very likely to be overly cautious, but understandable, to maintain public confidence in the vaccine until more detailed information about the reactions is available. The individuals who have had allergic reactions to the vaccine in the UK should be urgently investigated to determine the mechanisms behind the reactions and the potential involvement of PEG. The reported history of previous severe allergies should be scrutinised and their causes determined. Once details are available, it is very likely that more specific recommendations about at-risk groups can be made to modify the rather broad current MHRA recommendations. As a rule, allergy to foods, single drugs, or insect venom does not predispose to allergy to other drugs or vaccines.

Tryptase measurement taken 0.5–2 h after the reaction should help determine if this was indeed anaphylaxis.10 As in all allergic reactions occurring in a hospital setting, other potential allergens, such as disinfectants (e.g. chlorhexidine11) and latex, should be excluded. Investigations for allergy to PEG currently include skin testing,7,8 but in vitro tests may be in the pipeline.12 As systemic allergic reactions have been reported in connection with skin prick testing in PEG-allergic patients, the development of a reliable in vitro test is urgently needed.

In conclusion, allergic reactions to vaccines are exceedingly rare, and there is no reason to believe that this has changed. PEG has not been used previously as an excipient in vaccines with this potential for wide dissemination, but even if PEG is concluded to be the cause, allergy to this excipient is also very rare. As soon as a plausible explanation for the suspected vaccine reactions has been found, clear recommendations can be made for a safe vaccination strategy. At this stage, it is important that events such as these do not lead to misinterpretations and detract from global implementation of the vaccine.

The fact that these severe reactions have appeared early in the implementation of the vaccine should remind us all that anaphylaxis is a rare risk of drug administration, including vaccines. Anaphylaxis has a good prognosis when diagnosed and treated promptly and correctly.10 Vaccination centres should be made aware of the risk of anaphylaxis and have trained staff and equipment immediately available to treat anaphylaxis. If such precautionary measures are taken, combined with continued close surveillance of potential hypersensitivity reactions, then the benefits of the COVID-19 vaccine clearly outweigh the risks, and we can finally start hoping for an end to the COVID-19 pandemic.

Declarations of interest
The authors declare that they have no conflicts of interest.

Last Edit: Apr 24, 2021 20:32:00 GMT by Admin