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Sunday, December 20, 2020

What is going on with Pfizer's mRNA COVID vaccine?

Are the anaphylactic reactions due to the nanoparticles or is the antigen too powerful?

N urse faints after receiving Covid vaccine: “I could feel it coming on. I felt a little disoriented but I feel fine now, and the pain in my arm is gone! Wait a minute . . . my arm! Where is my arm???!!!!!!!!

Okay, that last part is not what she said, exactly, but as of this writing there have been five incidents of acute anaphylactic reactions to Pfizer's mRNA Covid vaccine. What might be happening?

Pfizer says it is monitoring the reports and will update labeling language if needed. And it's worth stating that as reports of terrible neurological complications from Covid infection pour in, losing an arm or a leg would be well worth it.

The Pfizer/BioNTech vaccine BNT162b2 received an Emergency Use Authorization from the US FDA on Dec 11 2020. It consists of two doses of 30 μg of modified mRNA in a lipid nanoparticle formulation administered i.m. three weeks apart.[1]

There is speculation [2] that the allergic reaction may be triggered by polyethylene glycol. This might seem unlikely, as PEG has been used in drug formulations, both i.m. and i.v, for many years with few reported incidents. In our trial of an unrelated product, we gave PEG-400 as an infusion in elderly patients and had no incidence of any such adverse events. However, Pfizer is using PEG-2000 (which is much bigger) and more importantly they're not using ordinary everyday PEG-2000, but a lipidated form, which might conceivably result in immunoreactivity.

The authors[2] quote the UK's Medicines and Healthcare Products Regulatory Agency (MHRA)[3] (not to be confused with Methicillin-resistant staph aureus or MRSA, or Middle East Respiratory Syndrome or MERS) as saying the excipients include the following:

 Component    Function  
ALC-0315 = 4-hydroxybutyl) azanediyl)bis (hexane-6,1-diyl)bis(2-hexyldecanoate A lipid needed to make nanoparticles
ALC-0159 = 2-[(polyethylene glycol)-2000]-N,N-ditetradecylacetamide A lipidated form of polyethylene glycol
1,2-Distearoyl-sn-glycero-3-phosphocholine A lipid found in cells
Cholesterol A lipid found in cells
Potassium chloride Salt
Sodium chloride Salt
Potassium dihydrogen phosphate pH buffer
Disodium hydrogen phosphate dihydrate pH buffer
If viewing on a cell phone, drag table left or right to scroll.

The active ingredient is a highly purified, single stranded mRNA encoding the virus's spike protein, called S. The first four components in the table above are needed to make lipid nanoparticles. These are needed not only because unprotected mRNA is rapidly degraded, but also because mRNA by itself cannot get into the cell.

Structure of alc-0315

Structure of ALC-0315. Source: Strukturformel des Lipids ALC-0315 zur Herstellung von Lipid-Nanopartikeln. Creative Commons Attribution-Share Alike 4.0 International

The lipids might have scary names, but based on their structure they appear benign. For instance, ALC-0315 is shown at right. The other ingredient, ALC-0159, is merely a PEG with lipids attached.[4]

Using nanoparticles to get nucleic acids into the cell will permit drugs based on antisense oligonucleotides, ribozymes, DNAzymes, plasmids, immune protein-stimulating nucleic acids, aptamers, and microRNAs. It would enable a class of powerful new drugs. So we need to know whether nanoparticles are safe to use. Given the rapid mutation rate of the S protein on SARS-CoV-2, there are also questions about the wisdom of selecting S as an antigen.

I should mention that claims made by some bloggers that mRNA can be incorporated into your genome or that it can cause genetic problems are incorrect. An mRNA vaccine DOES NOT alter your DNA. The mRNA is translated in the cytosol to create spike proteins, which then travel to the surface of the muscle cells. This is quite different from a normal type of vaccination because it eliminates the need for adjuvants such as aluminum, squalene, and CpG 1018, whose purpose is to activate the immune system. Getting the cell to produce its own spike proteins is a clever way of introducing many more spike proteins than could ever be injected and it would produce a vigorous T cell response.

Here's how that works: the cell chews up foreign protein, creating small pieces, or peptides. The cell then automatically presents these peptides to the immune system on the surface of the cell. This is what a cell normally does all the time. The immune system has specialized cells that 'look' at these peptides and generate an immune response if necessary. That may include making antibodies and even killing the infected cell to stop the infection from spreading.

And that could be part of the problem. There are five types of antibodies: IgM, IgD, IgG, IgE, and IgA. Antibody production occurs as a sequence of different antibody serotypes, starting with IgM. Allergy and anaphylaxis are associated with IgE. IgE is produced by class switching, a type of DNA recom­bin­ation, that happens on a prior contact with an antigen. It is induced by—you guessed it—cytokines. It is not just food items: any virus infection can produce an IgE response, which can manifest as hives (urticaria) or allergic rhinitis. In fact, the runny nose (rhinorrhea), coughing, sore throat, and conges­tion we experience in a cold are not caused by the virus itself, but the body's immune response to it.

The serious and life-threatening version of an allergic reaction is a systemic response called anaphylaxis. Susceptibility to exaggerated IgE responses is genetic and GWAS (genome-wide association studies) showed that 40 different genes are responsible. Up to 40% of Westerners are predisposed to it. Despite much research, no common physical or chemical feature has yet been identified that determines whether something can be antigenic. So we can't rule out anything.

If a person has previously encountered some antigen, anaphylactic responses start within minutes of a second exposure. The hives and bronchial constriction are part of the early response, and occur when mast cells release large amounts of histamine. A late response, where the patient experiences edema or swelling, starts about six hours later.

There are other allergic diseases that involve IgG instead of IgE. These can happen when a noninfectious antigen triggers existing T cells. Drugs such as penicillin and cephalosporin can trigger drug-induced hypersensitivity reactions that destroy red blood cells, resulting in hemolytic anemia.

What does this tell us about Pfizer's vaccine? There are several possibilities: maybe the formulation is too potent, as with AstraZeneca's vaccine, and a lower dose might be safer and more effective. Or the choice of spike protein might be problematic. It could even be the excipient, as Cabanillas et al. suggested. We will need to wait and see if Pfizer investigates this question and releases the results. It is important to know the answer.

1 Oliver SE, Gargano JW, Marin M, Wallace M, Curran KG, Chamberland M, McClung N, Campos-Outcalt D, Morgan RL, Mbaeyi S, Romero JR, Talbot HK, Lee GM, Bell BP, Dooling K. The Advisory Committee on Immunization Practices' Interim Recommendation for Use of Pfizer-BioNTech COVID-19 Vaccine - United States, December 2020. MMWR Morb Mortal Wkly Rep. 2020 Dec 18;69(50):1922-1924. doi: 10.15585/mmwr.mm6950e2. PMID: 33332292.

2 Cabanillas B, Akdis C, Novak N. Allergic reactions to the first COVID-19 vaccine: a potential role of Polyethylene glycol? Allergy. 2020 Dec 15. doi: 10.1111/all.14711. PMID: 33320974.

3 Government of the United Kingdom. Health and social care https://www.gov.uk/government/publications/regulatory-approval-of-pfizer-biontech- vaccine-for-covid-19

4 Lipids and lipid nanoparticle formulations for delivery of nucleic acids. US Patent 9,738,593 S.M. Ansell and X. Du., Acuitas Therapeutics, Inc. August 22, 2017

dec 20 2020, 6:43 am. expanded jan 06 2021

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