Fig 1 above is obtained from the website @sciencemag.org
ALLERGY
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.
"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 U.S. National Institute of Allergy and Infectious Diseases (NIAID).
Pfizer, too, says it is “actively seeking follow-up.” A statement 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.”
“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.
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.”
CLINICAL TRIAL
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.
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.”
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.
RISK
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.”
Information on this page is provided for interest only on a "best efforts" basis and does not
constitute personal advice. Always discuss medical conditions and related matters with your doctor.
Reference: https://www.sciencemag.org/news/2020/12/suspicions-grow-nanoparticles-pfizer-s-covid-19-vaccine-trigger-rare-allergic-reactions
