Part 4 of 10- The pre-pandemic LNP history vaccine developers likely won't want you to see. LNP (and mRNA) developer studies dating back 20 years tell a different story than "safe and effective"

Katalin Kariko, Drew Weissman, and Peter Cullis mRNA and LNP development studies: Lipid and LNP adverse reactions are more than allergy and anaphylaxis. Why weren't we told? These are The LNP Files...

Below is part 4 of 10 of the Executive Summary on Sars-CoV-2 mRNA Vaccine Lipid Nanoparticles (LNPs). The studies utilized, referenced, and quoted in this series include medical studies and articles mainly written or co-written by the developers of the COVID-19 mRNA vaccine LNPs and mRNA technology. These studies date back twenty years. The drug manufacturer data and studies are included along with Pfizer’s internal white paper, which is relevant to the LNPs and lipid development. * Parts one, two, and three of this series are found in my SubStack. * References are found on the last page/article in this series of Ten Articles. *Please credit my work and link to this source if you repost any part of my work. Thank You

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Heather Hudson May 2023 - Part 4 of 10

H: The Importance of Warnings, Testing, Administration Instructions, and Labeling for Drugs: 2007 FDA guidelines are added in this document for the numerous reasons above, and also due to the similarity of the lipids in the lipid shell of both drugs (Pfizer Covid-19 mRNA-LNP vaccine and Onpattro) --pointed out by Pfizer-- and because these lipid drug component reactions can be fatal, severe, or life-altering, we will first look at the FDA guidelines that show us the recommendations surrounding drug labeling when similar drugs have adverse events and/or “usage is associated with a clinically significant risk or hazard” (FDA), and “whether the adverse event is known to be caused by related drugs” (FDA). Please see the 2020 FDA EUA similar guidelines below.

Regarding Similar Drug Warnings: Re-stated for context in this section, according to the July 2018 Onpattro EMA assessment [3] (regarding Onpattro drug class and the “liposomal formulation” (LNP)), it states, “… may lead to adverse effects related to immune stimulation, activation of C’ alternative pathway and inhibition of the coagulation cascade, as well as tissue accumulation in the liver, kidneys, spleen and lymph nodes.” According to the EMA assessment, Patisiran “toxicity” is related to the liposomal formulation and not to the siRNA itself. [3]

1.      Specifically, the reactions known to Onpattro lipid shell LNPs and similar lipids shell drugs were not included in the FDA EUA Warnings and Precautions for the Covid-19 mRNA therapies/vaccines. Onpattro and the other similar lipid shell drug adverse events (and other pertinent Onpattro lipid and LNP findings) were not disclosed in the labeling or sections of Pfizer mRNA Covid-19 therapies/vaccines. They also were not included in the Covid-19 mRNA therapeutics/vaccines rates of reactions. Pfizer based the reaction rates for allergy on traditional “vaccines” and not the similar lipid shell or LNP findings in similar drugs and the drugs that use similar lipids in LNP carrier therapeutics. [25][26]

2.      Especially as this is a novel therapeutic and the lipids (or platform) are associated with similar lipids per Pfizer, the adverse events known to the similar lipids should be included in the Covid-19 mRNA therapeutics/vaccines FDA EUA (and future) labeling to warn consumers of the facts surrounding each of the known relevant lipid, liposomal and LNP adverse reactions. The next several sections below detail the specific areas in which FDA guidelines and recommendations for labeling/warning consumers apply to the Covid-19 mRNA therapies/vaccines. References as follows:

a)      In the above Onpattro EMA assessment, the pre-clinical toxicity, they say, is “related to” the liposomal formulation (LNP). [3]

b)      When looking at myocarditis, Pfizer stated in their internal White Paper,“ Lipid components in the LNP may also activate host immune responses following systemic or local administration (Hou et al, 2021). For example, PEG-lipids may stimulate the complement system. … Although the immune responses to these lipids has not yet been fully understood.” [1][2]

c)      According to the Onpattro EMA approval data, the EMA states, “Based on the preclinical findings, it seems that the observed preclinical toxicology after administration of patisiran LNP is linked to the LNP and not the siRNA.”[3][Note: preclinical findings are animal studies.] One study states, “Hepatotoxicity signs in both rats and cynomolgus monkeys were hepatocyte single-cell necrosis, vacuolation, and liver inflammation/infiltration. Based on studies using a sham-LNP (dssiRNA against insect luciferase), the observed toxicities are to a large degree likely due to the LNP part of Patisiran-LNP.” [3] [Patisiran is also known as Onpattro. EMA = European Medicines Agency (similar to our FDA).]

3.      Per the 2020 FDA EUA “IV. Nonclinical Data –Considerations, “A. General Considerations - The purpose of nonclinical studies of a COVID-19 vaccine candidate is to define its immunogenicity and safety characteristics through in vitro and in vivo testing. Nonclinical studies in animal models… help identify potential vaccine related safety risks and guide the selection of dose, dosing regimen, and route of administration to be used in clinical studies. The extent of nonclinical data required to support proceeding to first in human (FIH) clinical trials depends on the vaccine construct, the supportive data available for the construct, and data from closely related vaccines.” [78]

4.      Similar 2007 FDA guidelines for DNA vaccine approval, state, “Biodistribution studies will still be necessary for DNA vaccines utilizing novel vectors, formulations, methods of delivery, routes of administration, or any other modifications expected to significantly impact cellular uptake and/or biodistribution.” [64]  Biodistribution, kinetics, and pharmacokinetics studies are used to show potential adverse reactions and more. For reference, in chemistry, according to Merriam-Webster, “Kinetics” “is the mechanism by which a physical or chemical change is effected.”

5.      Knowing this, please see biodistribution sections where it is shown that PEGylated lipids (LNPs) and their circulation time in the body are associated with adverse reactions. [65][72] Then note that in the “Expression Kinetics” study [Section C and D], we are shown that the depth of the injection can alter the amount of time that the LNP (lipids) remain in the body. [58]

This illustrative figure shows the different structures of nanomedicines and their approximate sizes. For comparison, the sizes of biological nanostructures are shown at the top of the figure. Diagram found on The article, “What is nanomedicine” The British Society of Nanomedicine https://www.britishsocietynanomedicine.org/what-is-nanomedicine/

I: Nano lipids and Nanomedicine were a Narrow Field of Medicine before the Covid-19 mRNA Vaccines –for a reason--: It should be kept in mind that lipid nano particles and RNA therapy was a narrow field of medicine pre-pandemic. More than twenty-five peer-reviewed pre-pandemic articles in this document on PEG, CARPA, and the use of nanomedicines in human drugs point out the adverse reactions and warn on the use of these lipids in drugs, and many describe these safety issues as factors that prevented this gene therapy technology from becoming a mainstream therapy in medicine.

In 2018, a University of North Carolina study called “Physician Awareness of Immune Responses to Polyethylene Glycol‐Drug Conjugates” found that of the physicians polled, “Only 22% of physicians who prescribe PEGylated therapeutics are aware of APA. Only 35% of physicians who prescribe PEGylated drugs know that PEG is a part of that drug compound.” [note APA is Anti Peg Antibodies] The study continues on to say “These findings underline a need for improved awareness of APA. Physicians who prescribe PEGylated therapeutics should undergo targeted education. Given the low levels of awareness, it may be important to quantitate the efficacy of knowledge transfer from the research community to clinicians, especially on topics of patient safety. Finally, as the use of PEG in medicine becomes more prevalent, providers should closely monitor potential polypharmacy issues.” [93]

What is most notable about this study is the low number of physicians that were familiar with PEG antibodies, but most alarming is that in this study on awareness of PEGylated drugs adverse events it did not mention CARPA (known to PEGylated drugs). This intelligent study was attributed in part to physicians in Microbiology and immunology, Biomedical Engineering, Pharmacoengineering, and Molecular Pharmaceutics, as seen in the study. It provides numerous vital points on PEG ADAs (Anti-Drug Antibodies), and it highlights the lack of knowledge in the medical field on the issues surrounding PEGylated drugs and their adverse reactions.

These issues were known pre-pandemic by those who worked in this industry. However, due to this narrow field of science and medicine (detailed herein), only the physicians in this field, the makers of these drug components, the executives (that spoke and wrote on these issues in science, medical and financial documents), and their investors have had a vested interest in the safety of the use of nano lipids in drugs—that is until Covid-19 mRNA vaccines with LNP shells were made available to mass consumers in the market- upon this event.

It was then that the consumers of these vaccines had a vital interest in these findings, but they were not a party to, nor were they privy to, the pre-pandemic findings on the dangers known in the medical use of these components.

According to their experts in their writings, these reactions that are known in the liposomal and LNP drugs are said to be related to the LNPs/lipid components as follows:

• “Most likely,” says Pfizer on myocarditis [1][2]

• “Common underlying cause” says Szebeni et al. (on anti-PEG Ab-induced complement (C) activation) [93] (Ab = antibody. (C) activation is complement activation.)

• “Presumed” to be a representation of a reaction to the lipids as shown in the DOXIL FDA warning label. [14]

• “Non-clinical studies have shown that the toxicity primarily is related to the liposomal formulation” Onpattro FDA consumer information. [3] (Remember Pfizer states that the Onpattro lipids are “relevant lipids” and “similar lipids” to the Pfizer COVID-19 vaccine lipids in their internal white paper. [2])

To be clear, current Covid-19 mRNA vaccines adverse reactions and the same or similar nano lipid-hypersensitivity reactions (HSRs), or Complement Activated Pseudo Allergy (CARPA), are reported in the pre-pandemic medical literature. Medical literature written after the roll-out of the Covid-19 mRNA vaccines also shows us that these reactions are seen after the Covid-19 mRNA-LNP vaccines are administered to the public. [1][2][6][28][24]

In December 2020, within days of the Covid-19 mRNA vaccine roll-out, when several cases of Anaphylaxis reactions produced a safety signal that alerted the National Institute of Allergy and Infectious Diseases (NIAID) to the reactions seen in the Covid-19 mRNA vaccines, the lipids were again in question. Specifically, PEG and the PEGylated lipid were questioned as the cause of these reactions. According to Science magazine, in 2020, “Szebeni believes CARPA explains the severe anaphylactoid reactions some PEGylated drugs are occasionally known to cause, including cancer blockbuster Doxil.”[6]

This article also states, “If PEG [PEGylated lipids] does turn out to be the culprit [of these reactions], 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.” [6][25][26] Several vital and life-saving factors are not spoken of above; however, they are presented below:

1.      Known life-threatening immune mechanism of components are not detectible with an allergy test: The CDC suggestion to refrain from vaccination if the consumer is “allergic” does not address the consumers who will have CARPA and Complement anaphylactoid reactions that can take place upon first exposure; these are reactions that do not warn, they are not an allergy, they are called a “pseudo allergy.” Equally important, the referenced studies inform that the immune mechanisms of the components and properties of the nano lipids (LNPs) and nano component size, shape, and curvature, and the way nanoparticles and nanomedicines move around in the body can all take part in eliciting these reactions (that can be fatal) these factors are not detectible with a PEG allergen test. [29][28][3] These are key issues to these reactions (discussed in the referenced medical literature in this document). These reactions were also known pre-pandemic, as found in the previously highly specified nano lipid, nanotechnology, and nanomedicine industry.

2.      Consumers Should Have Been Warned: What is also not said in the quote from the Science magazine article is that PEG and the nano lipids produce the “sometimes deadly” reaction CARPA, known as a “pseudo allergy.” Consumers should have been warned on the consumer label by the manufacturer or distributor (and upon administration) of this industry-known possibility that left the consumer misled and innocent to the fact that CARPA (and the related potential dysregulated complement immune mechanisms) cannot be known ahead of time in order to be “refrained from,” “tested for,” or “waited out” for 30 minutes, the claims that these countermeasures protect consumers from known CARPA reactions are not possibilities for CARPA, according to the literature. The medical studies also show that the LNP components and their properties are known to bring about these reactions outside of the above PEG recommendations, and some who took part in the development and testing of these lipids, liposomes, and LNPs. [3][5][16]

3.      Delayed Reactions: Something that is not said in the above recommendations but that is crucial is the warning that these PEGylated drug/nano lipid reactions can take place days or weeks after administration (delayed reactions) of the nano lipid drugs. These reactions do not take place only within 30 minutes, as stated in the vaccine patient data and other publications as seen here where this 2021 article titled, “General determination of causation between Covid-19 vaccines and possible adverse events,” states, “Others have advised that late expression of adverse vaccine reactions should also be considered, as well as “potential safety problems that may be identified only after widespread use… Failure to undertake rapid, credible assessments of such potential safety problems risks missing a true safety concern…” [18]. Reiterated for context, please see here where this 2020 MDPI  Special Issue “The Role of the Complement System in Chronic Inflammation” article states, “Complement has a role to play in both the immediate and time-delayed reactions of type I hypersensitivity. Via the production of the anaphylatoxins C3a and C5a, complement is involved in the recruitment of inflammatory cells…”[42]

4.      Pseudo Allergy was a Known Reaction in Nano Medicines: Pseudo allergy, complement, CARPA, and nanomedicine reactions were known reactions to PEGylated lipids and nano lipids, so much so that in similar drugs, they require assessment and/or pre-treatment before administration of the drug/treatment in instances of similar PEGylated lipid infused nanomedicine delivery drugs. [24][25][26][42] Repeated here for context Knowing in 2020, Pfizer introduced Onpattro lipids (DLin-MC3-DMA and PEG2000-C-DMG) (with their known pre-pandemic established anaphylactoid, connective tissue, and other adverse events) as similar lipids to the Pfizer Covid-19 mRNA-LNP vaccine in their internal documents. Of importance, it should be known that pre-pandemic, in 2015, the “similar lipids” (DLin-MC3-DMA and PEG2000-C-DMG) were also described as similar lipids to the lipids in the mRNA-LNP “Expression Kinetics” study co-authored by Pfizer senior VP Katalin Kariko, Pfizer mRNA developer Peter Weissman, and four Acuitas Therapeutics scientists. [58]

5.      CARPA Cannot be easily Predicted in the General Population: The above statement that suggests that “allergy testing millions for PEG is not feasible” seems to infer that if one had an allergy test to PEG that it would alert them to the potential danger of the CARPA reactions brought on by PEG. This, in turn, might indicate that a lack of positive allergy tests would render the individual free from the potential harm of PEG in the vaccines. This is not the case with CARPA, as seen in medical literature. See section FF for details on testing for CARPA.

6.      Unpredictability and the Need for Premedication: This 2018 article, “Roadmap and strategy for overcoming infusion reactions to nanomedicines” by Szebeni et al. states, “Despite decades of research suggesting that the incidence of IRs depends on both pharmacodynamics and pharmacogenetics, it is largely unknown why some patients develop these reactions while others do not. The lack of uniform terminology and classification of the reactions further complicates the issue. As such, acute IRs cause substantial stress among patients and their families as well as care providers and regulatory agencies… Therefore, IRs in patients are currently managed by systemic administration of immunosuppressive, anti-pyretic, and anti-inflammatory medications before the infusion, during administration, or both…”[9] Note: IRs or Infusion Reactions are included as lipid drugs with PEGylated lipids (or similar lipids) that have attributed the reactions to the lipids.

7.      Anti-Drug Antibodies ADAs, PEG and PEGylated Lipids: This 2021 ACS Nano article on Polyethylene Glycol Immunogenicity is repeated for context in this section, it addresses the known long term potential PEG and PEGylated lipid antibody issues that are also a possibility with each PEGylated LNP administration in the body, it states: “The elephant in the PEG room is the widespread use of SARS-CoV-2 RNA vaccines. Important questions remain to be answered, including how many people receiving BNT162b or mRNA-1273 develop antibodies against PEG, how long induced anti-PEG antibodies remain in the circulation, and whether memory B cell responses are generated.” [82] The article continues below, to similarly warn (that as in the Biomolecular Corona studies) that safety and efficacy of the lipid drugs may change, in this 2021 article, PEG antibodies are pointed out, however each study that presents the safety and efficacy variables in PEGylated drug outcomes, present a similar warning that an alternative to PEG or PEGylated lipids are suggested as seen below:

8.      It is critical that Physicians are aware of PEG safety and efficacy issues: This 2021 article titled, “Theoretical, Clinical, and Practical Aspects of Anti-Polyethylene Glycol Antibodies,” states, “It is critical that physicians are made aware that the safety and efficacy of previously safe PEGylated medicines may change, especially if booster vaccinations of SARS-CoV-2 RNA vaccines are necessary, which seems increasingly likely as more SARS-CoV-2 variants emerge… At a minimum, more testing for anti-PEG antibodies before administration of PEGylated drugs may be warranted. Widespread use of RNA vaccines may accelerate development of PEG alternatives...” [82] Also see the ABC phenomenon in sections “T” and “U” for further information on PEG and safety and efficacy changes with repeat doses of PEGylated drugs.

J: Lipid Nano – The Little Known and Unknown Science-- and the Need to Classify and Clarify Adverse Events and Reaction Rates in Nano Drugs: Szebeni et al. 2018 article, “Roadmap and Strategy for Overcoming Infusion Reactions to Nanomedicines,” states, “The nanomedicine community must clarify the role of the complement, cytokines, macrophages, platelets, and other mechanisms in the context of the physicochemical attributes of the nanoparticles.”[9] In fact, several medical journal articles call for a similar clarification on the elusive nature of the pharmacokinetics, physiochemical attributes, biodistribution, and bioavailability which determines the extent a substance or drug becomes completely available to its intended biological destination(s). Classification of the specific adverse reactions is also called for –as this information has been known mainly to a highly specified field of scientists and physicians that work closely with these nanoparticles and nanomedicines.

1.      Of importance, there are laws on nanotechnology and how it is utilized, administered, and more, as seen here in this 2022 article titled “Development of Pharmaceutical Nanomedicines: From the Bench to the Market,” where it states, “Due to the debate on the adequacy of current regulatory frameworks and procedures, wider concerns have been raised about the inherent risks of nanotechnology and products containing nanoparticles, including nanoparticle toxicity, the unintended effects of nanoparticles’ ability to cross the BBB [Blood Brain Barrier], and the long-term effects of nanoparticles... Accordingly, the FDA has issued one draft and five final guidance documents discussing the use of nanotechnology in FDA-regulated products, including nanomedicines. All six guidelines encourage manufacturers to consult the company before marketing their products.” [10] Were these guidelines followed when marketing Covid-19 mRNA vaccines?

2.      When the Covid-19 mRNA vaccines were approved under the Emergency Use Authorization (EUA), the consumer could not have known about these highly specific areas of nanomedicine and nanotechnology. The LNPs are lipid nano drugs/technology. Their studies and development had been a little-known or niche area of science and medicine that was struggling to find its footing, funding, and success in treatment (largely due to safety issues (as seen in several peer-reviewed articles herein )). It was mainly used as the carrier lipid in cancer drugs and had little recognition, as seen here, in this Cell Magazine article in which  Acuitas labs co-founder and Covid-19 mRNA-LNP vaccine LNP co-developer,  Peter Cullis is interviewed, in 2022, and states, “Then in November [2020] … lipid nanoparticles became really popular. Nobody had ever heard of a lipid nanoparticle before, but in the last year and a half, they certainly have.”[11] More information can be found on the illusive nature of the use of pre-pandemic nanomedicine here in the references [12] and [23], and more can be found within the quoted material herein.

3.      Here again, we see evidence of the little-known nature of these lipid nano reactions. In the 2020 Science magazine article, just after the Covid-19 mRNA vaccines saw at least eight people develop severe allergy-like reactions, it states, “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…”[6]

4.      In this 2021 article in the European Journal of Allergy and Clinical Immunology, it states, “Possible sensitization to PEG by previous use of cosmetics or drugs containing PEG is conceivable. Little is known about the prevalence of anti-PEG antibodies in the population. Certain reports state that as much as 72% of the population have at least some IgG or IgM antibodies against PEG,… while others report high levels in healthy people and even in those without documented treatment with PEGylated products…. However, there is no evidence for allergy or anaphylaxis depending on IgG in man. Evidence for a possible role of IgE in triggering PEG-induced hypersensitivity is also being discussed…Allergic reactions following the use of PEG as an excipient in a variety of products have been described. This is also referred to as a “hidden” allergen. [48]

5.      Lipid delivery drugs have been discontinued in trials due to toxicity, for instance, CALAA-01, a PEGylated siRNA drug, discontinued in the clinical trials in part due to infusion-related innate immune responses. [105] More information on withdrawn/discontinued lipid drugs can be seen here, from the December 2020 Science magazine article, “ Suspicions grow that nanoparticles in Pfizer's COVID-19 vaccine trigger rare allergic reactions” where it states, 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." [6]

K. Duty to Warn, obscured frequency of reactions statements --in non-pre-treated individuals administered PEGylated lipids, lipid nanomedicines, and nanomedicines-- and missing warnings for countermeasures/pre-treatment premedication in similar lipids for Covid-19 mRNA vaccine labeling:

1.      There are many forms of “hypersensitivity” reactions, and one issue seen in the labeling, warnings, and articles for these nano medicine pseudo allergy complement activated reactions is that they are often simply listed or referred to as an “allergy,” “hypersensitivity” or “anaphylaxis,” which can be problematic as they are not an allergy and the literature tells us that these reactions need their own category as sometimes they do not respond to treatment in the way that the more commonly understood allergies, hypersensitivity reactions and anaphylaxis reactions do. This issue spills over into the labeling of drugs, as seen below.

2.      “Frequency of reactions” warnings are placed on drugs, such as the Covid-19 mRNA-LNP vaccine, which states, “there is a remote chance of an allergic reaction” [pg. 4 Pfizer recipient and caregiver fact sheet [25]]. Did these statements take into account the FDA medical literature seen for similar lipid and LNP carrier drugs and their reactions? Did they take into account the rates of reactions from premedicated consumers of similar lipid carrier drugs?

3.      When manufacturers develop the labels for medications/drugs and reactions are seen/known in similar drugs, the FDA guidelines provide information on listing those adverse reactions when  a warning is recommended “whether the adverse event is known to be caused by related drugs.” This warning label is addressed in the FDA guidelines discussed below and found under item A-7 in the 2007 FDA “Warnings And Precautions Section” (§ 201.57(c)(6))

4.      The 2020 FDA EUA for Covid-19 vaccines provides similar guidelines regarding data on similar drugs, as discussed in “Non-Clinical Data, Animal studies and biodistribution sections “N”,”O”, “P”, “Q” “S” and “U” of this Executive Summary. We also see in the FDA EUA requirements that this non-clinical data “help identify potential vaccine related safety risks and guide the selection of dose, dosing regimen, and route of administration to be used in clinical studies.” [78]

5.      Also see all of section [DD all] for more information on warnings, labeling and adverse events, including the 2020 FDA EUA guidelines for Covid-19 vaccines, the WHO guidelines and comparisons of the Covid-19 mRNA-LNP vaccines to traditional vaccines.

6.      Lipid/liposomal PEGylated doxorubicin – Doxil CARPA warnings, premedication in use, and associated clarification of frequency ratings as seen in the DOXIL FDA label: The Doxil FDA patient information sheet provides an example of the reduced rate of reaction due to premedication vs. non-premedication for CARPA can be seen here, “The use of Doxil has been implicated in acute infusion reactions in up to 45% of the cancer patients who receive the drug without premedication with steroids and antihistamines, while 4–7.1% in pre-medicated patients ...[7][14]. The black box warning for Doxil shows specific wording for the reaction name, “Acute infusion-related reactions, sometimes reversible upon terminating or slowing infusion, occurred in up to 10% of patients. Serious and sometimes fatal allergic/anaphylactoid-like infusion reactions have been reported. Medications/emergency equipment to treat such reactions should be available for immediate use ...” [14] Onpattro wording is as follows: All patients should receive premedication prior to Onpattro (patisiran) administration to reduce the risk of infusion-related reactions (IRRs). [3]

7.      The wording above is important as it not only shows that a little-known area of medicine showed a reaction that has occurred at (what we see in the medical literature) a common frequency in these drugs, but also an “acute” reaction occurred at a “common” frequency. The wording also listed specified reactions, “allergic/anaphylactoid-like infusion reactions”(Doxil) and “infusion-related reactions” (Onpattro) were used in the warnings as opposed to simplified wording such as “allergy,” “anaphylaxis” or “Hypersensitivity” which do not describe the pseudo allergy or anaphylactoid reactions known to CARPA. Other similar nano intravenous lipids/liposomal administered & LNP delivery drug’s FDA and EMA patient fact sheets, list these CARPA (AKA Pseudo allergy) adverse reactions as anaphylactoid, IR (or IRR) reactions. They are not an allergy and cannot be listed as an allergy. [24][25][26]

8.      Again, the medical literature surrounding these lipid carriers or nano lipid drugs tells us, “The lack of uniform terminology and classification of the reactions further complicates the issue. As such, acute IRs cause substantial stress among patients and their families as well as care providers and regulatory agencies… Therefore, IRs in patients are currently managed by systemic administration of immunosuppressive, anti-pyretic, and anti-inflammatory medications before the infusion, during administration, or both…”[9]

9.      Pfizer and Moderna’s information on adverse events in the Covid-19 mRNA therapies/vaccines did not in 2020 and does not now in 2023 include CARPA (and/or non-allergic, or pseudo allergy/ anaphylaxis, HSR, or complement activated events) reactions or their rates in their labeling and warnings. If it is argued that CARPA is included under the blanket statement along with “allergic reactions” (seen just below for Pfizer), this statement cannot alert consumers as CARPA is not an allergy, it is a pseudo allergy and it is called this to help consumers and providers with identification and treatment of the reaction. In addition the wording “allergic reactions” did not and does not clarify between medicated and non-medicated CARPA reactions, nor does it specify an accurate frequency of CARPA reactions which is 19% in the Onpattro drug that Pfizer informs as having similar lipids in Pfizer’s internal “White Paper” document obtained by project veritas.[2] [Note: 19% is not a “remote chance,” See [99] Onpattro Adverse Events Table in section Y. ]

10.  The Covid-19 mRNA-LNP vaccine FDA EUA fact sheet warn the consumer only of traditional/ general allergies, as seen here where it states, “There is a remote chance that the vaccine could cause a severe allergic reaction.” [25 pg. 4] Again, CARPA is not an allergy, it is a pseudo allergy with a “4–7.1% “ reaction rate for the pre-treated population in the similar lipid shell Doxil drug and a 19% rate of reaction in the pre-treated population in the Onpattro drug that Pfizer informed the lipids were similar to the Pfizer Covid-19 mRNA-LNP Vaccine LNPs. [2][14] Of note: The listed nonclinical toxicity or adverse events in both drugs is attributed to the lipids, per the FDA and EMA labels for these drugs, and they are not listed in the Pfizer Covid-19 mRNA Vaccine FDA EUA fact sheet for the similar lipid drug Onpattro (at minimum).[3][14][31]

11.  It should also be noted that on the Pfizer FDA EUA fact sheet [25 pg. 5] it states, “Side effects that have been reported with Pfizer-BioNTech COVID-19 Vaccine, Bivalent, Pfizer-BioNTech COVID-19 Vaccine, or COMIRNATY (COVID-19 Vaccine, mRNA) include: • Severe allergic reactions • Non-severe allergic reactions such as rash, itching, hives, or swelling of the face…” This list continues, but again there is no mention of CARPA pseudo allergy or autoimmune reaction, even though Pfizer scientists have shared their findings of autoimmune and immune mediated reactions from “vaccines” and the lipids in their internal document [2]) and Pfizer scientists have acknowledged reactions in relation to the mRNA-LNP vaccines [2][6], but of equal importance, these reactions were seen in the drug with similar lipids that Pfizer points out and also names as “relevant” in their internal documents meant for their own experts, [2] and they also compared these same lipids as they studied them in 2015 [58], but they were not shared with the consumer or their providers.

12.   The Importance of reporting accurate Rates of Reaction on the FDA fact sheets for consumers and providers: In learning about these pseudo allergy complement activated reactions, this 2019 Journal of Controlled Release article, informs, “The increasing use in the last decade of PEGylated nanodrugs such as Doxil has seen a rise in the number of associated occurrences of hypersensitivity reactions (HSRs). These reactions (also called infusion reactions or IR) can range from harmless symptoms to life-threatening reactions. Current means to prevent IR include the prophylactic use of antihistamines and steroids, but they cannot ensure total prevention.”[17]

L. Of importance, for percentages and frequency of reactions reported in the literature and on the FDA and manufacturer warnings for adverse reactions, to the similar lipid drugs: Please see the ADR chart below for reference. The FDA guidelines for warnings are found in FDA “Warnings and Precautions” (§ 201.57(c)(6)) guidelines. Also, see FDA guidelines and anticipated adverse events detailed above and discussed further below.)

1. Adverse Drug Reaction (ADR) frequencies are designated by the following table/guide, as seen here. According to the “Standard categories of ADR frequency recommended by CIOMS and commonly used in SmPCs: [13]

ADR frequency categories:

·         Very common ≥10 %

·         Common         ≥1% and <10%

·         Uncommon     ≥0.1% and <1%

·         (Very) rare     <0.1% ”

2. Repeat for context: The earlier liposomal and LNP drug manufacturers of Doxil and the similar LNP carrier drug Onpattro learned of these CARPA reactions attributed to the lipids or lipid carriers in these drugs, and the warning and adverse reaction labeling sections on their FDA Fact sheets reflect these adverse reactions. [3][14]

a)      These liposomal and lipid nanocarrier drugs saw measures taken to prevent (pre-treat) the “sometimes deadly [14]” severe and mild CARPA or CARPA-like reactions. In this, we see that the reactions are made less frequent, as was the purpose of the premedication and assessment countermeasures. These rates of reaction were listed on their FDA consumer labels, and they also indicate that the patients are premedicated.

b)      In further looking at Doxil’s FDA label, we see that Doxil has a black box warning that shares similar reactions (such as Myocardial damage and Anaphylactoid Adverse Reactions) to what is being seen in the mRNA Covid-19 vaccines [14]. [Note, on the label only the Anaphylactoid reaction are attributed to the LNP. However, in Pfizer’s internal White Paper, Pfizer looks towards the lipids in elucidating the cause of the myocarditis reactions seen in the Pfizer Covid-19 vaccines.]

c)      For Doxil, we also learn that “Acute infusion-related reactions, sometimes reversible upon terminating or slowing infusion, occurred in up to 10% of patients. Serious and sometimes fatal allergic/anaphylactoid-like infusion reactions have been reported. Medications/emergency equipment to treat such reactions should be available for immediate use (5.2)”.[14]

d)      In using the chart above, this percentage falls into the “very common” rate of reaction [13]; this does not fall into the “rare,” “low,” or “occasional” rates of reactions. It correlates to “very common.” Remember that these intravenous lipid drugs (including the LNP drug Onpattro, below) are administered in supervised settings, and the majority of patients are premedicated to avoid these reactions (seen in the peer-reviewed references herein [3])). [Section Y table 1 Onpattro adverse reactions.]

e)      Of note, in some instances, you will see the literature refer to the reactions as rare, and some will say they are alarmingly frequent. Clarification should be used in these LNP medicines by the manufacturers and responsible parties to not only warn of  CARPA (brought on by nano lipids) but to separate and designate the reaction rates of CARPA pseudo allergy reactions from the larger subset of more generalized “allergy” and “hypersensitivity” reactions when accounting for --and referring to-- the frequency of pseudo allergy reactions in a drug or product with similar components and a known potential to produce the CARPA pseudo allergy reactions.

3. Pre-pandemic LNPs and adverse reactions labeling Onpattro:  Of importance, when the LNP shell delivery system (as opposed to liposomes) was finally approved, we are told in the literature that significant issues with the lipids remain in the form of adverse reactions, as seen here, in the Chemical and Engineering News article,  “In 2018, patisiran became the first approved siRNA drug and the first approved therapy delivered via LNPs. But the drug requires an 80 min infusion every 3 weeks and pretreatment with multiple anti-inflammatory drugs to minimize reactions to the nanoparticle.”[12] In a controlled clinical study, 19% of Onpattro-treated patients experienced IRRs, compared to 9% of placebo-treated patients.” [15]

a)      Observing the frequency rate chart above [13], this reaction rate in the administration of nano lipids is not a “rare” or “low” occurrence, this isn’t a “remote chance” of adverse reaction to the lipids (that we have seen in some instances), according to the FDA and EMA data and literature-- this rate, 19% for this lipid delivery drug falls above the “very common” rate as seen above.

b)     Remember, we are told in the medical literature that IRRs are a similar or same reaction to CARPA. These reactions can take place unpredictably and at a significant rate with PEGylated lipids, nano lipid, and LNP delivery drugs (as seen in Onpattro). [See section Y Table 1 for Onpattro adverse events rates of reactions]

c)      More information on these reactions are seen here, “In addition, the PEGylated liposomal formulations, including Doxil, Ambisome, Abelect, and Amphocyl showed acute immune toxicity represented in non-IgE mediated hypersensitivity reactions (CARPA) in a small percentage of individuals treated for the first time in the absence of pre-medication...”[28].

d)     Perhaps some of the confusion lies here as the acute rate represents a small percentage, however, these reactions “can range from harmless symptoms to life-threatening reactions” [17], the overall reaction rates of 10% Doxil and 19% Onpattro include all the reactions, not just severe.

e)      The reaction rate in the administration of the similar lipids to the Covid-19 Pfizer vaccines (Onpattro) do not represent a “small percentage” as we see these reactions referred to in some of the literature, but, closer to the roll-out of the Covid-19 mRNA vaccines or post-pandemic, these reactions are often referred to as “rare” or as having a “low” occurrence or as having a “remote chance” of adverse reaction to the lipids, but the FDA and EMA fact sheets, and the patient literature are clear, the Onpattro table of adverse events in the FDA patient Fact sheet, shows the rate of reaction for CARPA like IR (infusion reactions) pseudo allergy-HSR reactions as “very common,” to this day. [Section Y table 1.]

f)       It should also be known that according to the 2006 FDA guidelines for warnings and labeling, a “common” rate or “uncommon” [rare] rate of adverse reaction should be reported when the reactions are severe or can produce (significant), life-long, or lengthy illness, as found in the FDA guidelines for labeling.[31][19]

g)      Further, this 2016 article on Anti-Peg antibodies also discusses the need for studies, as seen here, where it states, “…also we highlight the in vitro, animal and human data attesting to anti-PEG Ab-induced complement (C) activation as common underlying cause of both adverse effects. A main message is that correct measurement of anti-PEG Abs and individual proneness for C activation might predict the rise of adverse immune reactions to PEGylated drugs and thereby increase their efficacy and safety.”[93]

h)     Many articles, pre-pandemic, also warned of the need for further development of nano drugs that omitted the use of PEG in their components; others warned of the dangers of PEGylated drugs. As seen here again for importance, this 2021 ACS Nano article on Polyethylene Glycol Immunogenicity addresses the known PEG and PEGylated lipid issues in the future as PEG antibodies become more prevalent and can bring about these health issues in a larger population. It states:

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“The elephant in the PEG room is the widespread use of SARS-CoV-2 RNA vaccines. Important questions remain to be answered, including how many people receiving BNT162b or mRNA-1273 develop antibodies against PEG, how long induced anti-PEG antibodies remain in the circulation, and whether memory B cell responses are generated. It is critical that physicians are made aware that the safety and efficacy of previously safe PEGylated medicines may change, especially if booster vaccinations of SARS-CoV-2 RNA vaccines are necessary, which seems increasingly likely as more SARS-CoV-2 variants emerge…At a minimum, more testing for anti-PEG antibodies before administration of PEGylated drugs may be warranted. Widespread use of RNA vaccines may accelerate development of PEG alternatives...” [82]…

But PEG and PEG antibodies are only the tip of the iceberg with lipids and LNPs… so we have an elephant and an iceberg. Next sections coming soon:

M- Before the COVID-19 vaccines are administered to the Public: Were the COVID-19 vaccine consumers or the FDA warned of this “common” rate of CARPA (and complement-activated) reactions? If not, why not? Were they warned after these vaccines were administered?

N- After The mRNA Vaccines Were Approved and “Anaphylaxis” Adverse Reactions Were Seen, What Did The Pfizer LNP Experts Say? What Can be Found in the Animal and Medical Studies?:

O- Animal studies - Pfizer Covid-19 mRNA-LNP vaccine and “similar lipid” mRNA-LNP Pfizer scientists LNP development co-authored studies:

P- Pfizer pre-clinical animal studies did not reveal the adverse events seen after the vaccine was approved; what did they show?    

Q- After learning about the pre-clinical studies and learning of the adverse events seen after the Covid-19 mRNA-LNP vaccines were approved, these factors and questions remain and should be considered:

R- Despite the “Low dose” and “intramuscular injection” “negligible risk” (Kariko) – adverse events persist- other scientists warned of many LNP adverse events pre-pandemic.

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*This Executive Summary is modified for SubStack and published in a series (The LNP Files); the next sections (part 5 of 10 (M through Q)) will be published later in the week. *The references and citations will be posted on the last page of the series. *Please credit my work and link to this source if you repost any part of my work. Thank You

Heather Hudson 2023

About the author: Many may know me from my SubStack, media appearances, or testimony. I am the mother of Cody Hudson, who has a published medical case study and was significantly vaccine-injured at age 21.  My research on the COVID-19 vaccine LNP has been published and is used in investigations into the COVID-19 mRNA vaccines. I write to bring awareness to these issues as I care for Cody.  Please consider contributing to support my work or to help with his medical and educational expenses. Thank you.

 

The writer is not a doctor, and even though guest writers may be medical professionals, the information in this document and this publication is not a substitution for personal or individual medical care, treatment, medical advice, or diagnosis. Always contact your own medical care provider for individual care and consultation. This document does not diagnose medical conditions, treat illnesses, or prescribe medicine or drugs. Any information contained in this document, related links, or attachments is not a substitute for seeking adequate medical care, diagnosis, and/or treatment from your own medical doctor.