5 Questions Fauci and FDA Need to Answer on Pfizer and Moderna COVID Vaccines

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Another day, another story about a healthcare worker suffering a “severe allergic reaction” after receiving Pfizer’s COVID vaccine — this time, in New York. The report follows the news Children’s Health Defense (CHD) has been covering about similar severe reactions, first in the UK, then in Alaska and Illinois.

In light of these events, and because CHD previously warned the U.S. Food and Drug Administration (FDA) officials and Dr. Anthony Fauci, director of the National Institute for Allergy and Infectious Diseases (NIAID), about the potential for the Pfizer and Moderna vaccines to cause anaphylactic reactions, we have some questions we’d like Fauci and the FDA to answer.

They are:

1. Why didn’t the FDA’s Center for Biological Evaluation and Research require Moderna and Pfizer-BioNTech to conduct immunogenicity testing on their COVID-19 vaccines for anti-drug antibodies as recommended in the agencies’ own guidelines for drug development during clinical trials?

In January 2019, the U.S. Department of Health and Human Services, FDA, Center for Drug Evaluation and Research, and Center for Biologics Evaluation and Research issued a document, “Immunogenicity Testing of Therapeutic Protein Products — Developing and Validating Assays for Anti-Drug Antibody (ADA) Detection: Guidance for Industry.”

The document, described as providing “recommendations to facilitate industry’s development and validation of essays for the assessment of the immunogenicity of therapeutic protein products during clinical trials,” clearly acknowledges the existence of anti-drug antibodies, such as polyethylene glycol (PEG), in humans. The document states:

• Immune responses to therapeutic protein products have the potential to affect product pharmacokinetics, pharmacodynamics, safety and efficacy.
• The clinical effects of immune responses in subjects are highly variable, ranging from no measurable effect to extremely harmful.
• Detection and analysis of ADA formation is a helpful tool in understanding potential immune responses.
• Information on immune responses observed during clinical trials, particularly the incidence of ADA induction or any implications of ADA responses affecting pharmacokinetics, pharmacodynamics, safet, or efficacy is crucial for any therapeutic protein product development program.
• Accordingly, such information, if applicable, should be included in the prescribing information as a subsection of the ADVERSE REACTIONS section entitled Immunogenicity.

However, despite the FDA’s own guidance recommending that information about immunogenicity be included on the vaccine package inserts, no such information is included on either the Pfizer-BioNTech or Moderna COVID-19 vaccine inserts.

Page six of the FDA document cites research that specifically addresses the need to “adequately understand the risk of anti-drug antibodies … in products with modifications such as pegylation.” But without that information provided on package inserts, vaccine recipients can’t understand those risks.

The rapidly developed and currently distributed mRNA vaccines rely on a new nanoparticle-based “carrier system” that utilizes PEG. The lipid nanoparticles (LNPs) carrier system used in the two COVID-19 vaccines to facilitate the delivery of the mRNA into the cell is pegylated — which means, coated with PEG. Coating the lipid nanoparticle with PEG keeps it from degrading.

An article published this year in Advanced Drug Delivery Reviews reported:

“Conjugation of polyethylene glycols (PEGs) to proteins or drug delivery nanosystems is a widely accepted method to increase the therapeutic index of complex nano-biopharmaceuticals. Nevertheless, these drugs and agents are often immunogenic, triggering the rise of anti-drug antibodies (ADAs). Among these ADAs, anti-PEG IgG and IgM were shown to account for efficacy loss due to accelerated blood clearance of the drug (ABC phenomenon) and hypersensitivity reactions (HSRs) entailing severe allergic symptoms with occasionally fatal anaphylaxis.”

It is mystifying how a never-before-utilized vaccine technology that contained a synthetic, nondegradable and increasingly controversial polymer (PEG) — known to be associated with adverse immune responses and the development of anti-drug antibodies — was allowed to bypass the bedrock of pharmaceutical development, which is immunological testing.

2. Why does the FDA seem surprised by the recent reports of life-threatening anaphylactic reactions after the agency approved emergency use of two mRNA COVID-19 vaccines that contain polyethylene glycol?

In a recent news article, FDA’s Marks told reporters the FDA was not certain what caused the reactions but that PEG “could be the culprit.” He added that the reaction some people have experienced “could be more common than once thought.”

A simple search of the U.S. National Library of Medicine PubMed database for anti-PEG antibodies resulted in 32,061 results. This information is readily available to anyone who has scientific curiosity about the use of this man-made polyether compound, derived from petroleum, which has  many applications, from industrial manufacturing to medicine.

Earlier this year, retired Lt. Col. Harold Gielow, a CHD member who suffers with life- threatening anaphylaxis from exposure to products that contain PEG, notified us about his concerns related to the use of PEG in Moderna’s COVID vaccine.

After we reviewed the extensive scientific literature on the subject, CHD notified the federal agencies responsible for oversight for COVID-19 vaccine development and clinical trials.

Through our research, we discovered that scientists who once assumed the polymer was largely “inert” are now questioning its biocompatibility and warning about the potential of PEGylated particles to promote tumor growth and trigger adverse immune responses that include “probably underdiagnosed” life-threatening anaphylaxis. Researchers reported that these undesirable responses have, on occasion, halted clinical trials. As a result, some argue that it is time to develop alternatives to replace PEG.

American and Dutch researchers declared in 2013: “…accumulating evidence documenting the detrimental effects of PEG on drug delivery make it imperative that scientists in this field break their dependence on PEGylation.”

Another article, “The Importance of Poly(ethylene glycol) Alternatives for Overcoming PEG Immunogenicity in Drug Delivery and Bioconjugation,” published in February 2020, reported that treating patients who have acquired anti-PEG antibodies with PEGylated drugs results in accelerated blood clearance, low drug efficacy, hypersensitivity and, in some cases, life-threatening side effects.

The authors of that article also acknowledged that anti-PEG antibodies are also found in patients who have never been treated with PEGylated drugs, but have consumed products containing PEG. This would explain why the woman in Alaska, who had no prior history of allergies, had to be hospitalized for at least two nights after going into anaphylactic shock upon receiving the Pfizer vaccine.

On Sept. 25, Robert F. Kennedy Jr., CHD chairman and chief legal counsel, sent a letter to FDA Director Steven Hahn and Peter Marks, director of the Center for Biological Evaluation and Research, with a copy to Dr. Anthony Fauci, director of the National Institute for Allergy and Infectious Diseases. In that letter, we voiced concerns about the use of PEG in the Moderna COVID vaccine trials, due to the development of anti-PEG antibodies and also because in recent years PEG has come under increasing scrutiny.

In the our letter to the FDA, CHD  recommended that additional steps must be taken to reduce the risk of exposing trial participants to a substance to which up to 72% of the U.S. population may have pre-existing antibodies.

The recommended steps included:

• Pre-screening trial participants for the presence and titers of anti-PEG antibodies.
• Using such data to characterize the potential association and impact of anti-PEG antibodies on adverse reactions in the trial.
• Identifying the level of anti-PEG antibody titers that precludes safe administration of the vaccine in the absence of secondary measures to address the anti-PEG immune response.
• Measuring the impact of the anti-PEG immune response on vaccine efficacy.

3. Why did FDA officials not acknowledge the valid and scientifically supported concerns regarding the use of PEG in COVID-19 vaccines when CHD first notified them in September? 

Despite the fact that the letter sent to FDA requested a timely review of our critical concerns — as time is of the essence in protecting those individuals with PEG antibodies from unnecessary exposure and harm — the FDA did not respond until December 2, more than 2 months later.

CHD has yet to receive a response from NAIAD’s Fauci. NIAID is a partner with Moderna on the development of its COVID-19 vaccine and has been in an oversight role for the clinical trials — that alone raises questions about conflicts of interest.

4. Why did the FDA abandon its regulatory authority to the pharmaceutical companies developing COVID-19 vaccines?

In the response CHD received from the FDA, we were instructed to reach out directly to the pharmaceutical company regarding our concerns about PEG. But we wonder if the FDA even read out letter? Here’s why.

In July, Gielow reached out to the COVID Prevention Network with concerns about the use of PEG in Moderna’s vaccines. He cited a 2016 study in Analytical Chemistry which reported detectable and sometimes high levels of anti-PEG antibodies (including first-line-of-defense IgM antibodies and later stage IgG antibodies) in approximately 72% of contemporary human samples and about 56% of historical specimens from the 1970s through the 1990s. Of the 72% with PEG IgG antibodies, 8% had anti-PEG IgG antibodies greater than 500ng/ml., which is considered extremely elevated.

The authors of that study concluded that  “…sensitive detection and precise quantitation of anti-PEG Ab levels in a clinical setting will be essential to ensuring the safe use of PEGylated drugs in all target patient populations going forward.”

In his letter to the COVID Prevention Network, Gielow cited the study’s conclusions regarding the need for anti-PEG antibody testing and asked the following question: “As Moderna’s mRNA-1273 candidate vaccine uses a PEGylated LNP vector, what procedures are included in the trial to mitigate this risk?”

Here’s how the network responded:

“Thank you so much for this scientific question. I consulted with several of the physician scientists working on the Moderna study, and they have provided me with this response to send on to you:

“Pre-existing antibody levels, along with various genetic polymorphisms, may impact the safety profile of a biomedical intervention in a variety of populations. If there are significant safety signals from the CoVPN clinical trials, all efforts will be made to understand the mechanisms that may have contributed to these signals. Pre-screening populations based on hypothesized biomarkers, such as anti-PEG antibodies, is not a strategy currently employed in our clinical trials.”

While the Moderna scientists allege that PEG antibody development is purely hypothetical, the scientific literature clearly documents that the immune system can and does form antibodies against PEG (anti-PEG Abs) in both animals and humans. The existence of anti-PEG antibodies threatens patient safety through possible anaphylaxis reactions, and re-exposure to PEG-containing drugs may greatly increase the chance for adverse effects due to B cell memory of anti-PEG Abs.

In addition, Moderna’s documents and publications indicate that the company was well aware of safety risks associated with PEG and other aspects of its mRNA technology. In the corporate prospectus supporting Moderna’s stock market launch in late 2018, the company was frank that its technical approach has numerous risks.

Specifically, Moderna acknowledged the potential for its proprietary lipid nanoparticles and PEG to produce “systemic side effects,” given the scientific literature’s documentation of these types of side effects for other LNPs. In comments not generally seen by the public, Moderna stated (p. 33):

“[T]here can be no assurance that our LNPs will not have undesired effects. Our LNPs could contribute, in whole or in part, to one or more of the following: immune reactions, infusion reactions, complement reactions, opsonation reactions, [links added] antibody reactions . . . or reactions to the PEG from some lipids or PEG otherwise associated with the LNP. Certain aspects of our investigational medicines may induce immune reactions from either the mRNA or the lipid as well as adverse reactions within liver pathways or degradation of the mRNA or the LNP, any of which could lead to significant adverse events in one or more of our clinical trials.”

Instead of expressing concern over clinical trial participants’ welfare, the prospectus concluded that any one of these problems “could materially harm [the company’s] business, financial conditions, and prospects.”

Such concerns stem from that fact that not only can vaccine recipients suffer a potentially severe allergic reaction, PEG-specific immune responses can actually reduce the efficacy of vaccines and increase the occurrence of adverse events.

The 2016 finding of 72% of individuals with anti-PEG antibodies is highly concerning when the data is extrapolated to the U.S. population of 330 million who may receive this vaccine.

Based on the numbers in that study, about 237.6 million people may experience reduced effectiveness of the vaccine. Of those,16.6 million who may have high antibody levels could be at risk for anaphylaxis. According to those numbers, we would see more severe allergic reactions to Pfizer’s PEG-containing vaccine than we’ve seen so far. That raises the question: Did the vaccine maker alter the PEG molecule to reduce the risk of an allergic reaction? If so, what process did they use, and was that process reviewed and approved?

Based on the growing number of news reports regarding the occurrences of allergic and anaphylactic reactions in individuals who have received the first dose of the vaccine, our concerns are justified. These serious and life-threatening reactions will continue and become even more common when the second round of vaccines are administered.

5. Will FDA and NIAID now require mRNA vaccine manufacturers to conduct assessments of the immunogenicity of the pegylated lipid nanoparticles used in their COVID-19 vaccines, and will they also consider pre-screening of all mRNA vaccine recipients for the presence and titers of anti-PEG antibodies? 

The fact that our federal agencies, responsible for assuring the public that the products they receive are safe and effective, have dropped the ball in their rush to develop COVID-19 vaccines is truly tragic. An important opportunity was missed.

According to Zhang, “screening and monitoring the anti-PEG abs in blood before and during the treatment with PEG-containing drugs are of particular importance to provide safety and maintain therapeutic efficacy. The generation of anti-PEG abs can accelerate the clearance of PEGylated therapeutics, thus reducing therapeutic efficacy. Moreover, the existence of anti-PEG abs threatened patient safety with anaphylaxis and other reactions. Re-exposure to PEG-containing drugs may greatly increase the chance for adverse effects due to B cell memory of anti-PEG abs.”

Due to the use of PEG in thousands of consumer products, including e-cigarettes and medications, it’s reasonable to assume that a growing number of people will develop anti-PEG antibodies.

If high-titer anti-PEG abs are present in blood, even people without known allergies may have severe hypersensitive reactions when receiving PEG containing therapeutics for the first time, studies show.

We urge federal agencies that such screening be recommended prior to administration of any vaccines that use PEG in their manufacturing process. Ideally, since anyone could unknowingly have anti-PEG antibodies, everyone should be screened before getting the Pfizer of Moderna vaccines. But at the very least, we recommend that anyone who has had an undiagnosed allergic reaction consult with their physicians and request testing for anti-PEG antibodies before taking any COVID vaccine.