Following on Augusto’s efforts to get the Argentine state to look at what happened to him and others in the Pfizer Comirnaty Trial – See News Flash – over the next few weeks, this blog will show some trial results from the Buenos Aires site, which do point to issues that need to be clarified.
In preparation for presenting these data and questions, it seemed a good idea to lay out the basics of how the immune system and mRNA ‘vaccines’ work. I was originally going to call this post – mRNA for dummies. The dummy being me. I thought my first draft was reasonably sensible.
I availed of a possibility to interview Aditi Bhargava, a Professor of Molecular Biology at UCSF – the University of California San Francisco, who has made a delivery platform for RNA, DNA and small molecures. Turns out my original draft was pretty dumb in lots of ways. It is now hugely improved thanks to Aditi but of course I’ve fiddled with it since and added bits which she hasn’t had a chance to review, so all errors are mine but there are much less than there would once have been.
In The Beginning
Our naive immune system begins its training to differentiate between “self and non-self” soon after birth. It needs constant exposure to a multitude of non-self or foreign material to be better trained and develop robust immunity. Bacteria and viruses provide ample non-self-material.
One way is innate immunity – train some immune cells (T and B Cells) to remember these pathogens, which can then produce antibodies right away when they re-encounter the pathogen. Adapative immnity is another defence to these invading pathogens; this means having circulating less specific antibodies (IgA, IgE, IgG, and IgM a memory antibody) produced by B Cells.
Natural replicating viruses train immune cells to remember infections and produce antibodies to neutralize it on a repeat contact using both innate and adaptive arms of the immune system.
A dead virus inoculum (vaccine) generates a variety of antibodies to different parts of the virus but it doesn’t train immune cells to remember infection. Vaccination in that sense is less effective than natural immunity.
One advantage to the a dead virus inoculum is that it stays in the arm and relies on the local immune cells to do the job. Any inflammatory reactions generated are largely local to the arm.
To Infinity and Beyond
The new mRNA technologies utilize RNA, a messenger that shuttles between the nucleus and protein making areas of cells. RNA is very unstable. It can be degraded by various agents found in our sweat and hands. This can be solved by encasing it in a liposome/lipid nanoparticle (LNP) for stability. Freezing slows down the degradation of RNA molecules.
Encasing in a liposome/LNP, however, can create uncertainties about the dose:
- some liposomes are larger and others smaller and if several people are being injected from the same vial (6 injections per vial was standard in the Pfizer trial) some may get a substantially higher dose than others depending on liposomal size – unless there were steps to the standardize the size. it is not clear that there were such steps even though EMA enquired about this point.
- Freezing and Thawing liposomes is a way to crack them open and empty them.
- Any injector not wearing gloves and a mask risks degrading the mRNA, which is very susceptible to environmental contaminants.
- Handling mRNA in the lab needs inhibition of RNAses by special treatment of reagents, solutions and glassware, siliconized test-tubes (so that small amounts are not lost) and syringes. These steps may not always have been adhered to in clinical research or more general vaccination settings.
There are ways to control the dose, but it is not clear how good a job Pfizer did in this respect. They did add to sucrose to the mix which will help and may have added more sucrose or sorbitol when they changed the buffer to Tris when preparing a children’s version. All of a sudden, when running their children’s trials, they claimed there was no more need for freezing. This seemed very odd after all the fuss about the need for -80 C – but it may be trivial.
Do these variations in dose count?
Almost anything injected into an arm will generate immune (antibody) and inflammatory responses (cytokines). Even if the mRNA degrades, it will generate antibodies and a cytokine response.
The placebo in these trials may have generated antibodies unless it contained absolutely only saline. We know that with old style inactive vaccines (measles, HPV), tiny residues of other substances that get into saline that has the same adjuvants as are in the vaccine can lead to damaging immune responses.
An ideal trial design would have four arms:
- a sham treatment where nothing is actually injected (a retractable needle),
- a no-treatment arm to see if placebo/delivery vehicle itself has an effect,
- a random mRNA, It is possible that mRNA vaccines do demonstrate some benefit without having any specific effects.
- the therapeutic mRNA.
The antibodies generated by mRNA vaccines are largely IgM and IgG rather than IgA (mucosal antibodies found in the lining of lung and gut, which is where a virus is more likely to enter the body). IgA are most likely to be neutralizing antibodies generating a rapid defense against infection.
There may be IgE antibodies; these generate allergic responses.
The antibodies that count in terms of subsequent infection can act in various ways. In terms of COVID infections, the Spike protein binds to ACE-2 receptors (and perhaps several other receptors), through which it enters the cell. ACE-2 receptors have featured in lots of recent PSSD posts on RxISK – see Holy Grail and PSSD Research Fund.
A number of treatments that are proposed to help in combatting COVID, such as SSRI antidepressants, metformin and isotretinoin, destabilize ACE-2 receptors or other structurally related receptors and if they actually are antiviral in the case of COVID it may be through this action. See RxISK posts.
Naturally occurring Coronaviruses found to date are not known to enter cells through ACE-2 receptors. This is one pointer to the possible gain-of-function research that some believe played a part in the emergence of SARS-CoV-2.
The vaccine mRNA entering the cell comes in mRNA fragments wrapped in liposomes/LNP. CDC state ‘these fragments can generate harmless pieces of what is called the Spike protein’ CDC and vaccines
The CDC vision is very different to the apocalyptic vision of billions of bristling full scale Spikes travelling around the body and wreaking havoc that some of the literature on these issues can generate.
The fragments vary in size from 25 amino acids to the full 150 amino acids. No one knows exactly what is produced. The immune cells will make antibodies against any fragments they encounter, short or long. As a result, depending on a production of antibodies, after vaccination, can give the false impression that the mRNA vaccines produce a robust vaccine-induced immunity.
The data pointing to rapdily waning immunity – if the initial benefit is appropriately described as immunity – do not obviously support robuts immunity. On top of that, each injection given can potentially produce different responses.
While mRNA is injected into the arm, its encasement in liposomes/LNP means it is more likely to travel around the body than dead viruses are. This means it can lodge in various parts of the body.
If it lodges in heart cells that normally specialize in predominantly producing myosin for muscle, and if it then diverts even a small percentage of resources to producing Spike protein, quite aside from any risks from the Spike protein fragments, the diversion of cardiac muscle cell activity from what they should be producing can cause its own problems – less contractile muscle fibres available when exercising vigorously.
One of the upshots of all this is that traditional vaccines likely produce somewhere between 25 and 50 percent of the immunity we develop naturally on exposure to these agents. We just don’t know what if any immunity we get from mRNA agents and it is now widely conceded that these agents do not block transmission of the virus.
Has the Vaccine Worked?
Most people have had a Rapid Antigen test in the last two years. These are based on a polymerase chain reaction and are often called PCR tests as a result. They are sometimes called NAATs – nucleic acid amplification tests.
PCR tests for viral infection (asymptomatic or symptomatic). The various tests are patented often on the basis of detecting a different set of viral genomic sequences (nucleic acids) but all must target the wild type of the virus. They will typically aim at detecting Spike and nucleocapsid proteins (antigens) and ideally should also have a housekeeping control – a gene not part of the viral genome. They are usually engineered so that only the viral genome from the infection will trigger a positive response and not the viral genomic material in the vaccine.
Depending on the amplication threshold set, PCR tests can turn up a positive result even in those who are not infected. A low threshold is problematic. So people who need a confirmation they have been infected or are not now infected may be asked for serology tests (blood tests). These detect antibodies in blood. They are often referred to as N antibody tests (NABs).
NABs aim at detecting elements of the nucleocapsid protein marking prior infection rather than prior vaccination. N antibody tests for COVID in combination with RT-PCR tests are more specific than each of those tests in isolation. A positive RT-PCR or antibody test in absence of any symptoms is meaningless. RT-PCR cannot be used to confirm active infection whereas a NAB indicates past and/or present (active) infection but may not be specific as it can detect infection by a related pathogen/virus.
The view that mild infections only give rise to a weak NAB response is inadequate. Limited antibody responses in measles, COVID, and other conditions are often linked to significant immunity.
In the Comirnaty trial, the per protocol outcome measure was not clinical infection. The outcome that counted for Pfizer was PCR tests, of which volunteers had several – some conducted Centrally and some Locally.
The key outcome measure in the trial was the Central PCR Test. Central means a Pfizer laboratory in New York. The samples were couriered there from Buenos Aires, Ankara and Pretoria as well as Houston and Sacramento. We do not know what cycle thresholds were used as cutoffs or whether these thresholds were applied uniformly between vaccine and placebo groups or in the presence or absence of clinical symptoms – without which they are strictly speaking meaningless.
Volunteers also had to have a local test done – in Buenos Aires, Sao Paolo, Hamburg and Dallas – to check for treatment purposes in case of infection. We know there were regular mismatches between the Local and Central results. The trial protocol states that in the event of a mismatch the Central result prevails but it is not always clear that this was the case.
The N antibody tests were carried out in Houston. They were done at the start of the study to exclude people who had evidence of a prior infection. They were then repeated 5 weeks after Dose 2 to see whether anybody had had an infection in the period after Dose 1. But there was no NAB specific to the 5 weeks after Dose 2 – which is where the question of whether the vaccine worked or not arises. If there had been 3 tests, one taken with Dose 2, a positive NAB 5 weeks later might clarify if you got infected after Dose 2.
While almost universally done at the start, we know in many cases that follow-up NAB tests were not done. We also know that in many cases, NAB results were negative when the PCR was positive.
This might be explained by a NAB test not detecting ‘weak’ but effective immunity from a prior infection. Many sources view NAB results as less likely to give a false positive result than PCR results. We don’t know this for sure and we don’t know if the vaccine could interfere with the N antibody result.
At present the documents made public by Pfizer give a positive or negative or not done result for NAB tests in the trial for most subjects but we do not have documents giving the actual results, which might help reconcile the differences between NAB and PCR results.
Reconciling differences like this or the link between these tests and clinical infection is a matter of discretion. While PCR tests are the outcome measure, this is a surrogate for clinical infection. Deciding whether there has been an infection requires input from a review panel. There was a 3-person review panel – all Pfizer employees – who decided whether you had been infected post Dose 2 of the vaccine or placebo.
The adeno-associated viruses (AAV) (AstraZeneca and Johnson and Johnson) are DNA based vaccines.
These AAV vectors have the potential to integrate into our genomes. The mRNA therapies were touted as being unable to integrate with the genome. But recent evidence and the slide above suggests caution about this – protein replacement therapies is another way of saying Gene Therapy.
Our genome is 80% non-coding, 30-40% of which contains sequences left over from many thousands of years of viral infections. These serve as hotspots for a virus to integrate thereby protecting us from disrupting functioning of our essential genes.
The AAV agents were initially developed for gene therapy. The AAV vectors delivered genes that needed correction and provided for the expression of good genes in cells, leaving the bad copy in place in the genome. This therapy provides an additional copy of the gene that is free from mistakes and can code for missing (or defective) proteins which will cure a disease or ameliorate symptoms, allowing for a better quality of life.
This initially worked but the AAV vector instead of remaining episomal, integrated randomly in patients’ genome thereby and, in some cases, this produced lethal problems in other areas, leading to a moratorium on gene therapies.
Efforts were made to solve the problem by removing integrase enzymes from AAV vectors but these mutated AAV vectors can scavenge integrase from other adeno viruses already embedded in the genome from natural infection. Modified AAV vectors similar to those used in gene therapy are used in COVID vaccines, but there is no rigorous monitoring or follow-up being done for these vaccines.
If you want to know about these issues in more detail, Aditi has a wonderful walk through all of these subjects and more in the light of a trial that infected Healthy Volunteers with COVID. The slides in this post come from her article. It should be noted that all slides and points come from authoritative rather than alternative sources.
Drugs and Vaccines
A lot of other issues came up in my tutorial with Aditi.
Some of my key positions on psychotropic and other drugs are outlined in Shipwreck and in many of the interviews with Psychopharmacologists on the Shipwreck site – such as Peter Waldmeier, Solomon Snyder, Silvio Garattini and others, who played important roles in the discovery of receptors – the locks to which we think drugs and vaccines are the key.
Much of how we view health now hinges on ideas of specificity and Magic Bullets, which date back 130 years to ideas first put forward by Paul Ehrlich that hinge on antibodies and antigens. The idea was the True Bullet would only hit its target and nothing else.
Most of the best psychotropic and other drugs and vaccines we have, however, came from discoveries in the 1950s, 1960s and 1970s that arose from looking at the effects of these drugs in people – and in animals. While there can be ethical concerns about testing drugs on animals, it says something that many of our best drugs had clearly visible effects in animals.
In the 1980s, things changed. Pharmaceutical companies were handed new methods to screen thousands of compounds per day in automated receptor testing systems. They were able they thought to realize Ehrlich’s vision and produce real Magic Bullets. The idea of testing drugs in animals seemed antediluvian and was jettisoned. How could animal tests compete with being able to precisely target therapeutic keys to the locks of disease?
Receptor profiling didn’t work out. Company insiders made jokes about the company having great new treatments which they now had to find diseases to fit. Discoveries of chemicals that bind to receptors is a different matter to discovering new drugs or vaccines. Companies, now run by managers rather than scientists or doctors, got out of the business of discovering new drugs that really made a difference.
By the time it became clear we were not getting better drugs, the old way of discovering drugs – in animals and by building on the unexpected effects in people taking drugs – had been junked. This brought with it a company need to make sure no-one, especially doctors, would recognise or agree that unexpected (adverse) effects were happening – see Harmatology.
There is a very similar story with vaccines. From the 1990s, the older drugs were viewed as Dirty Drugs compared with modern Cruise Missiles. We think this way even though the hardest clinical trial evidence shows the Dirty Drugs (TCA antidepressants and clozapine for instance) work better.
The older dead virus vaccines similarly are viewed as Dirty and antedeluvian compared to the precision missiles that mRNA and DNA represent.
Except it now looks less than clear agents aren’t even Vaccines. The evidence that these agents inhibit transmission isn’t there. The evidence that these agents save lives or reduce hospitalizations isn’t there.
Forthcoming posts will give readers the chance to decide if the evidence claiming that the trials have showns that agents like Comirnaty have shown 95% efficacy is a conclusion they agree with.
For people more used to drugs than vaccines, I can bring this back to SSRIs and Withdrawal and PSSD. Paroxetine is the SSRI that has the tightest binding to the SSRI reuptake site. Paroxetine is the SSRI that causes the worst withdrawal and has very high rates of PSSD. Really tight binding from a precision missile appears to cause more damage than the less potent binding from Dirty Drugs.
One possibility is that tight binding is more likely to damage. Dirty Drugs touch on receptors enough to get a helpful effect. They then drop off the receptor allowing the system to recover. This is not what happens with precision missiles, which risk destroying rather than opening the lock.
With the pandemic, Blogs have been replaced by Substacks, which often note a subscription would help keep things going.
Published by Samizdat, Shipwreck of the Singular. Healthcare’s Castaways rolled out with the Vaccines. Its descriptions of a dystopian medical future seem all too present now.
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Samizdat aims at the middle ground in health, enabling conversations to happen. A copy of any of its books for you or a friend, in lieu of an hypnotic, might help us all find a way to wake up.