Dr. Michael Yeadon is an Allergy & Respiratory Therapeutic Area expert with 23 years in the pharmaceutical industry and has published over 40 original research articles.
Arnold (AJ) Jameson February 6, 2021
Dr. Yeadon is the former VP and CSO (Chief Scientific Officer) of the big pharma giant Pfizer.
You can read his full bio here https://cv19news.wixsite.com/main/guests/dr.-mike-yeadon.
This post will be updated continually with new information and videos from and about Dr. Yeadon and his expert testimony on COVID 19, so make sure to check back from time to time for new information.
Be sure to visit our dedicated page for Dr. Yeadon to see all videos we have hosted for him at www.dryeadon.cv19news.ca.
Biography
Dr. Mike Yeadon is an Allergy & Respiratory Therapeutic Area expert, developed out of deep knowledge of biology & therapeutics and is an innovative drug discoverer with 23 years in the pharmaceutical industry. He trained as a biochemist and pharmacologist, obtaining his PhD from the University of Surrey (UK) in 1988 on the CNS and peripheral pharmacology of opioids on respiration. Dr Yeadon then worked at the Welcome Research Labs with Salvador Moncada with a research focus on airway hyper-responsiveness and effects of pollutants including ozone and working in drug discovery of 5-LO, COX, PAF, NO and lung inflammation. With colleagues, he was the first to detect exhaled NO in animals and later to induce NOS in lung via allergic triggers.
Joining Pfizer in 1995, he was responsible for the growth and portfolio delivery of the Allergy & Respiratory pipeline within the company. During his tenure at Pfizer, Dr Yeadon was responsible for target selection and the progress into humans of new molecules, leading teams of up to 200 staff across all disciplines and won an Achievement Award for productivity in 2008. Under his leadership the research unit invented oral and inhaled NCEs which delivered multiple positive clinical proofs of concept in asthma, allergic rhinitis and COPD. He led productive collaborations such as with Rigel Pharmaceuticals (SYK inhibitors) and was involved in the licensing of Spiriva® and acquisition of the Meridica (inhaler device) company.
Dr. Yeadon has published over 40 original research articles and now consults and partners with a number of biotechnology companies. Before working with Apellis, Dr. Yeadon was VP and Chief Scientific Officer (Allergy & Respiratory Research) with Pfizer. He left Pfizer in 2011 as Vice President & Chief Scientist for Allergy & Respiratory and eventually founded his own biotech company, Ziarco. In 2017 Dr. Yeadon sold Ziarco to Novartis, one of the world's largest pharmaceutical companies.
The original source article was here: https://twitter.com/MichaelYeadon3/status/1357255898348089345
I came across this lengthy 19 part post that Dr. Yeadon posted on Twitter on February 4, 2021. Fortunately I was smart enough to capture it all in a word document because, just 2 days later, this eminent scientist's Twitter account was de-platformed for the crime of exposing the truth about Covid19. I only wish I had grabbed much more of his brilliant content which is now lost to the digital dustbin courtesy of the criminal censors in silicon valley. No doubt he will reappear elsewhere on a censorship-free platform but, until then, enjoy this one article in its entirety.
I’ve been in touch with five U.K. university professors in departments which means they’re knowledgeable about immunology. All of us agree that the variants will not meaningfully alter immune recognition by our bodies of the virus. If you’ve been infected by the Wuhan sequence, you’re immune, not only to this original sequence but to all variants.
The reason is that the number of point changes (17 is the most in one variant) is irrelevantly small compared with the size of the entire virus, which is 10,000 amino acids long. The most mutated virus is 99.7% identical to the Wuhan sequence.
It is possible that much smaller changes in spike protein could alter infectiousness. But that’s not what I’m talking about here, which is immune recognition. That’s not going to change overall, because we don’t only recognise the part which has changed, but dozens, perhaps scores of parts of the virus. The vast majority of these parts are unchanged.
As a practical example, the original SARS virus from 2003 is around 80% identical to SARS-COV-2. Research has looked at immune recognition of various parts of SARS & found vigorous responses to multiple parts of SARS 17 years later. What’s also amazing is that these same people showed strong & unequivocal responses to SARS-COV-2, even though they’d never seen this new virus.
In other words, a virus which is as different as 20% from SARS was easily recognised as already known by an immune system which had memorised common sequences in an earlier virus to which it had been exposed. The 0.2% difference between the Wuhan sequence & any of the recent variants isn’t any kind of issue for our immune systems.
No question, if you choose to focus upon just one (of very many different) antibodies which are raised to the virus, then if the sequence that one type of antibody binds to has changed, that antibody may no longer bind well.
But that’s not what protects you from illness: it’s the multi-locus nature of the immune response that does that. And most of those loci have not changed. Recognising & defending a person against those variants will not be problematic. And this sole focus on the profile of antibodies also completely ignores the panoply of T-cell responses, which are also created against dozens or scores of parts of the virus.
It’s worth noting that variants arise normally by error-prone replication by viruses. It’s how they evolve. Apparently, around 40,000 different variants have already been identified, each a tiny amount different from the original sequence. Why we’ve decided to get over excited about a small subset of variants is inexplicable.
As argued above, it’s not necessary to “keep foreign mutants out of the county”. In any case, a negative PCR test eliminates people bringing in a copy of the virus (whatever it’s sequence). It’s a head scratcher why the idea has arisen that it’s necessary to keep out foreign mutants and why what amounts to a brief period of imprisonment is an appropriate method for doing it.
More important still, as mentioned already, variants are arising right now, within the U.K. Even with reduced daily cases, there’s a lot of replication going on in the U.K. and requiring inbound travellers to have a negative test would almost completely eliminate any possibility of importing an irrelevantly tiny number of imports compared with those forming spontaneously in the country anyway. Variants are not only inevitable (& have occurred in great profusion already) but are “way points” as the virus comes into equilibrium with its human host.
As respiratory viruses move through a population, there is selection pressure favouring variants which are more easily transmitted from the person to person (they out compete less transmissible variants). They’re especially favoured if they’ve less harmful to the infected host (because an ill person or a dead person is far worse at spreading the virus).
Over time, it’s therefore entirely normal & predictable that variants get selected for which are easier to transmit but less dangerous. That’s how this virus is highly likely to finish up being added to the existing four endemic coronaviruses which are causative agents in around a quarter of common colds. Indeed, it’s probably how those four got to their current status. There are probably other coronaviruses we’ve yet to characterise.
SARS-COV-2 mutates very slowly compared with influenza and so it’s highly unlikely that we’d need a new vaccine annually, as we do with ‘flu.
These university professors with deep knowledge of immunology are fearful these days even of talking about basic viral immunology. Apparently, they’re concerned they might end up in the bad books of the Welcome Trust, which is one of the top sources of research funding in U.K.
So I’m telling you instead. If you want, you can contort the science such that what you’re being told fits the narrative. But you’ll notice lots of things that are being said simply don’t fit & that’s because the tale they’re telling isn’t true. There’s a pattern. Lots of things that don’t make any sense. Why, I’ve no idea.
Rumble — November 23, 2020 (LifeSiteNews) – While Pfizer pharmaceutical made headlines announcing the imminent release of their COVID-19 vaccine, to much fanfare, a former Vice President and Chief Scientist for the company has flatly rejected the need for any vaccines to bring the COVID-19 pandemic to an end.
In a recent article, Dr. Michael Yeadon, who “spent over 30 years leading new [allergy and respiratory] medicines research in some of the world’s largest pharmaceutical companies,” and retired from Pfizer with “the most senior research position in this field,” wrote:
There is absolutely no need for vaccines to extinguish the pandemic. I’ve never heard such nonsense talked about vaccines. You do not vaccinate people who aren’t at risk from a disease. You also don’t set about planning to vaccinate millions of fit and healthy people with a vaccine that hasn’t been extensively tested on human subjects.
The British national’s comments come at the end of a comprehensive criticism of the Scientific Advisor Group for Emergencies (SAGE), a government agency of the U.K. tasked with advising the central government in emergencies. SAGE has played a predominant role in determining public lockdown policies in the U.K., including those recently implemented, as a response to the COVID-19 virus.
One last thing: Susan Mitchie, who is a psychologist in behavioral change and is a SAGE government advisor. She is also a member of the COMMUNIST PARTY of Great Britain! Think about that. Leon Trotsky said “Whoever controls the media, controls the mind”
Former Pfizer VP: ‘No need for vaccines,’ ‘the pandemic is effectively over’
Dr. Mike Yeadon, Pfizer's former Vice President and Chief Scientist for Allergy & Respiratory, states that the drive for a universal vaccine has 'the whiff of evil' which he 'will oppose … vigorously.'
November 23, 2020 (LifeSiteNews) – While Pfizer pharmaceutical made headlines announcing the imminent release of their COVID-19 vaccine, to much fanfare, a former Vice President and Chief Scientist for the company has flatly rejected the need for any vaccines to bring the COVID-19 pandemic to an end.
In a recent article, Dr. Michael Yeadon, who “spent over 30 years leading new [allergy and respiratory] medicines research in some of the world’s largest pharmaceutical companies,” and retired from Pfizer with “the most senior research position in this field,” wrote:
There is absolutely no need for vaccines to extinguish the pandemic. I’ve never heard such nonsense talked about vaccines. You do not vaccinate people who aren’t at risk from a disease. You also don’t set about planning to vaccinate millions of fit and healthy people with a vaccine that hasn’t been extensively tested on human subjects.
The British national’s comments come at the end of a comprehensive criticism of the Scientific Advisor Group for Emergencies (SAGE), a government agency of the U.K. tasked with advising the central government in emergencies. SAGE has played a predominant role in determining public lockdown policies in the U.K., including those recently implemented, as a response to the COVID-19 virus.
After pointing out that SAGE lacked essential expertise in the field they are addressing, with “no clinical immunologists” as members, Yeadon highlights two fundamental errors they have made in their presuppositions which cause their overall conclusions to go radically awry leading to the “torturing [of] the population for the last seven months or so.”
First Fundamental Error: “Ridiculous” presumption of 100% susceptibility
The first erroneous assumption SAGE makes is that “100% of the population was susceptible to the virus and that no pre-existing immunity existed.”
Yeadon states this notion is “ridiculous because while SARS-CoV-2 is indeed novel, coronaviruses are not. There’s no such thing as an ‘ancestor-less virus’.” Indeed, he points out, there are at least “four, endemic, common-cold inducing coronaviruses … [which] circulate freely in UK and elsewhere.” Those who have been infected by “one or more of these endemic, common-cold producing coronaviruses in the past, have a long-lived and robust [T-cell] immunity, not only to those viruses, but to closely related viruses. SARS-CoV-2 is one such closely-related virus.”
Striking once again at the competence of SAGE, Dr. Yeadon states, “To not expect such cross-over is … to demonstrate the lack of the requisite understanding to build a model reliable enough to use.”
Further, he states, that the common PCR test which is used for detecting COVID-19 “cases,” may come out positive when someone is infected with one of these common cold coronaviruses rendering this test that much less reliable. Of course, based on the final results of these tests, many thousands of individuals have been ordered to disrupt their lives and “self-quarantine” for up to 14 days.
Finally, drawing from the scientific data, Dr. Yeadon concludes that due to previous exposure to common-cold coronaviruses, “a significant proportion (30%) of the population went into 2020 armed with T-cells capable of defending them against SARS-CoV-2, even though they had never seen the virus… SAGE was naively wrong to assume ‘everyone was susceptible’.”
Second Fundamental Error: An “amateur underestimate” of the infection rate
SAGE’s second erroneous assumption is “The belief that the percentage of the population that has been infected can be determined by surveying what fraction of the population has antibodies” developed due to infection with COVID-19.
Because of this assumption, “SAGE believes that less than 10% of the population have so far been infected by SARS-CoV-2.”
However, Yeadon clarifies that it’s “well understood that not every person, infected by a respiratory virus, goes on to produce antibodies. And many people, having prior immunity, never get properly infected anyway.”
While almost all of those with significant symptoms, who were admitted to a hospital, produce antibodies, those with “milder responses to the virus” do not “all produce antibodies.”
Nevertheless, all of those infected have been shown to have “T-cells in their blood, capable of responding to SARS-CoV-2,” and thus they still develop immunity.
Drawing from two independent methods, which arrive at the same general conclusion, Yeadon demonstrates that the real infection rate is “in the mid-20s to low-30’s per cent,” and thus SAGE’s estimate of 7% “is a gross and amateur underestimate.”
Why it matters…“the pandemic is effectively over”
With a false presumption that 100% of the population is susceptible to the virus, along with only 7% having been infected, it is the view of SAGE, that “the pandemic has only just begun.” Yeadon clarifies, however, that this is “palpable nonsense.”
Since it is demonstrable that “around 30% of the population had prior immunity,” and if one includes some young children who are “resistant,” 40%, and while considering that the infection rate is “somewhere [in] the mid-20s to low-30s per cent,” this means that around 65 to 72% of the population currently has immunity to COVID-19.
And considering the reality of herd immunity, when susceptibility to a virus falls this low, at around 28 to 35%, “that population can no longer support an expanding outbreak of disease,” and thus the virus “wanes and disappears.”
Therefore, Yeadon concludes, “the pandemic is effectively over and can easily be handled by a properly functioning NHS (National Health Service). Accordingly, the country should immediately be permitted to get back to normal life.”
He further stipulates that he is “incandescent with rage at the damage” SAGE has “inflicted” on the U.K., charging that they have “either been irredeemably incompetent” or “dishonest,” and thus “they should be disbanded immediately and reconstituted,” as “they haven’t a grasp of even the basics required to build a model and because their models are often frighteningly useless.”
Concerns with Pfizer COVID-19 Vaccine: Severe complications
Despite an estimated 65% to 72% of the population now having immunity to COVID-19, a percentage which indicates a critical level of herd immunity, Operation Warp Speed in the United States appears intent to follow the globalist campaign advanced by Bill Gates and vaccinate all 328 million people in the nation with the Pfizer product or others emerging for approved distribution in the coming months.
Notwithstanding the fact that no vaccine has ever been successfully developed for any coronavirus, and such an endeavor would normally take years to safely and adequately complete, the Food and Drug Administration (FDA) has permitted the fast-tracking of this process skipping the standard stage of testing on animals to directly test these vaccines on humans.
Immediate results from some of these trials have included “severe” complications, involving headaches, fever, body aches and symptoms similar to a “severe hangover.” Further, as the New York Times emphasized, Pfizer’s initial claim that their vaccine was “more than 90 percent effective,” was “delivered in a news release, not a peer-reviewed medical journal. It is not conclusive evidence that the vaccine is safe and effective.”
Expected ‘high volume’ of adverse reactions
And given the enormous scale of the stated goal, of administering these chemicals to hundreds of millions of people, when there is normally some rate of severe complications to the use of vaccines, the negative results may be significant. For example, one study of influenza vaccines administered to adults over 65 years of age, found a rate of approximately 1% which experienced severe side effects. If a COVID-19 vaccine is merely similar for individuals in the same age bracket (54M in population), that would equate to 540,000 individuals in this age bracket alone who may need medical care in a hospital system which provides less than 925,000 total beds.
Curiously, there is evidence that at least the United Kingdom is preparing for a high number of adverse effects due to the COVID-19 vaccinations. That government’s Medicines & Healthcare products Regulatory Agency (MHRA), posted a bid request stating that “For reasons of extreme urgency,” they seek “an Artificial Intelligence (AI) software tool to process the expected high volume of Covid-19 vaccine Adverse Drug Reaction (ADRs).” It goes on to explain that “it is not possible to retrofit the MHRA’s legacy systems to handle the volume of ADRs that will be generated by a Covid-19 vaccine,” and that this “represents a direct threat to patient life and public health.”
New ‘unproven’ mRNA technology: 20% ‘serious injury rate’
Other concerns about the Pfizer vaccine is that it would be the first to use “an as-yet-unproven technology platform that relies on something called messenger RNA, usually shortened to mRNA.” Moderna, another corporation striving to develop a COVID-19 vaccine, is also venturing to utilize this mRNA platform. In May, Children’s Health Defense reported that clinical trials for Moderna’s vaccine had a 20% “serious injury rate” in its high-dose group.
Debi Vinnedge, executive director at Children of God for Life, a pro-life organization which specializes in the moral evaluation of vaccines, told LifeSiteNews, “[I]f Moderna and Pfizer are the ones supplying the first rounds of vaccines and they mandate it, that could be a disaster.
They are both using brand new technology with the mRNA that has never been used in a vaccine before and they are pushing this through in a matter of months of testing, rather than the typical 4-6 years of testing.”
Mandates and Public Distrust
With a push for vaccine mandates on the rise, and resistance for such invasive measures emerging in response, a recent study indicates a growing discomfort among Americans with vaccines overall.
A report from Civic Science (CS) indicates “a steady decline in the percentage of U.S. adults who say they’re ‘very’ comfortable with vaccines overall.” In fact, CS states, “the monthly percentage of those highly comfortable with vaccinations at large fell more than twenty percentage points since the start of 2020 (69% in January compared to October’s 47%).”
In addition, “only 22% percent of those surveyed say they would get the vaccine right away,” and CS concludes, “it’s clear that hesitancy to receive a future vaccine … is running rampant across the country” and this “sheds light on just how difficult it is for many to trust a future vaccine right now.”
Manipulation of the Public
Serving to counteract this trend, Yale University, in collaboration with the U.S. government, sponsored a study to determine the most effective means of persuading Americans to take the COVID-19 vaccine.
The study tests a variety of approaches, such as appeals to “Personal freedom,” “Economic benefit,” “Self-interest,” fears of “Guilt,” “Embarrassment,” and actually being a coward.
While several of the appeals are straightforward arguments, others hint at a willingness to use public shaming to elicit compliance.
One, for instance, “asks the participant to imagine the guilt they will feel if they don't get vaccinated and spread the disease,” with variants exchanging guilt with anger or embarrassment. Another suggests someone who refuses vaccination “doesn't understand how infections are spread or who ignores science.” Another declares that “those who choose not to get vaccinated against COVID-19 are not brave.”
The findings of this study will likely influence the messaging of state officials and academic institutions who have discussed mandating vaccination, as well as advertising campaigns surrounding a vaccine once it is completed.
Coercion of Black Communities and Children
Other strategies of coercion being developed include the “bundling” of vaccine mandates “with other safety net services,” for the poor, including “food security, rent assistance, and free clinic services” for “vulnerable populations,” with “Black and minority communities” receiving special mention.
And the District of Columbia (DC) is advancing a bill which circumvents parental consent when it comes to their minor children being given a vaccine. The “Minor Consent for Vaccinations Amendment Act of 2019,” states, “this bill permits a minor of any age to consent to receive a vaccine where the vaccination is recommended by the United States Advisory Committee on Immunization Practices. It also establishes that if a minor is able to comprehend the need for, the nature of, and any significant risks inherent in the medical care then informed consent is established.”
According to The Vaccine Reaction, “The bill would not only permit children aged 11 years and older to give consent for doctors and other vaccine administrators to give them vaccines without their parents’ knowledge or consent, but would also require insurance companies, vaccine administrators and schools to conceal from parents that the child has been vaccinated.”
The report clarifies, “If this bill passes, it is clear that minor children will be at risk of being pressured and coerced into getting a COVID-19 vaccine behind their parents’ back.”
Pfizer a “convicted serial felon”
Robert F. Kennedy, Jr., nephew of former U.S. president John F. Kennedy, environmental attorney, author, and founder of Children’s Health Defense, has been raising awareness about vaccines injuring children for decades. In addition to the organization’s firm opposition to the DC bill above, Kennedy has singled out Pfizer as one of several vaccine producers with a record of incurring criminal penalties for their products.
In a July debate, Kennedy emphasized that Pfizer, and three other leading developers of coronavirus vaccines, Glaxo, Sanofi, Merck, are “convicted serial felon[s].”
“In the past 10 years, just in the last decade, those companies have paid 35 billion dollars in criminal penalties, damages, fines, for lying to doctors, for defrauding science, for falsifying science, for killing hundreds of thousands of Americans knowingly,” Kennedy said during the debate.
“It requires a cognitive dissonance for people who understand the criminal corporate cultures of these four companies to believe that they’re doing this in every other product that they have, but they’re not doing it with vaccines.”
Following the announcement of Pfizer’s “90 percent effective” coronavirus vaccine, with the anticipation of imminent release, the firm’s stock price rose “15 per cent from $36.40 … to $41.94 per share,” at which point the company’s CEO and Chairman, Albert Bourla, sold 61.8 per cent of his shares in the company “for almost $5.6 million.” The Independent reports that in response to inquiries Pfizer replied that this transaction was an “automated process, set up earlier this year” where “shares are sold provided they go above a pre-agreed price.”
Yeadon: Vaccine proposals have ‘the whiff of evil’
While a government, media and corporate campaign prepares to “inoculate 300 million Americans by spring of 2021,” the voice of Michael Yeadon, along with those of tens of thousands of other medical scientists and practitioners remain suppressed and unheeded.
“Any such proposals” of universal inoculation, Yeadon writes, “are not only completely unnecessary but if done using any kind of coercion at all, illegal.”
“I would completely understand and would consider accepting early use of a vaccine only if done with fully informed consent and, even then, only if offered to the most vulnerable in our community. Other proposals have, to me, the whiff of evil about them and I will oppose them as vigorously as I have followed the pandemic so far,” he concluded.
RELATED:
Dr Yeadon’s (former Pfizer VP) Coronavirus Vaccine Safety Petition
POSTED ON DEC 4, 2020
Coronavirus vaccine safety concerns
On December 1, 2020, Dr. Michael Yeadon (former Vice President Respiratory & Chief Scientific Advisor, Pfizer) and Dr. Wolfgang Wodarg (lung specialist and former head of the public health department) filed an application with the EMA, the European Medicine Agency responsible for EU-wide drug approval, for the immediate suspension of all SARS CoV 2 vaccine studies, in particular the BioNtech/Pfizer study on BNT162b (EudraCT number 2020-002641-42).
Dr. Wodarg and Dr. Yeadon demand that the studies – for the protection of the life and health of the volunteers – should not be continued until a study design is available that is suitable to address the significant safety concerns expressed by an increasing number of renowned scientists against the vaccine and the study design.
On the one hand, the petitioners demand that, due to the known lack of accuracy of the PCR test in a serious study, a so-called Sanger sequencing must be used. This is the only way to make reliable statements on the effectiveness of a vaccine against Covid-19. On the basis of the many different PCR tests of highly varying quality, neither the risk of disease nor a possible vaccine benefit can be determined with the necessary certainty, which is why testing the vaccine on humans is unethical per se.
Furthermore, they demand that it must be excluded, e.g. by means of animal experiments, that risks already known from previous studies, which partly originate from the nature of the corona viruses, can be realized.
The concerns are directed in particular to the following points:
The formation of so-called “non-neutralizing antibodies” can lead to an exaggerated immune reaction, especially when the test person is confronted with the real, “wild” virus after vaccination. This so-called antibody-dependent amplification, ADA, has long been known from experiments with corona vaccines in cats, for example. In the course of these studies all cats that initially tolerated the vaccination well died after catching the wild virus.
The vaccinations are expected to produce antibodies against spike proteins of SARS-CoV-2. However, spike proteins also contain syncytin-homologous proteins, which are essential for the formation of the placenta in mammals such as humans. It must be absolutely ruled out that a vaccine against SARS-CoV-2 could trigger an immune reaction against syncytin-1, as otherwise infertility of indefinite duration could result in vaccinated women.
The mRNA vaccines from BioNTech/Pfizer contain polyethylene glycol (PEG). 70% of people develop antibodies against this substance – this means that many people can develop allergic, potentially fatal reactions to the vaccination.
The much too short duration of the study does not allow a realistic estimation of the late effects. As in the narcolepsy cases after the swine flu vaccination, millions of healthy people would be exposed to an unacceptable risk if an emergency approval were to be granted and the possibility of observing the late effects of the vaccination were to follow. Nevertheless, BioNTech/Pfizer apparently submitted an application for emergency approval on December 1, 2020.
DECEMBER 1, 2020
“There is no indication whether antibodies against spike proteins of SARS viruses would also act like anti-Syncytin-1 antibodies.
However, if this were to be the case this would then also prevent the formation of a placenta which would result in vaccinated women essentially becoming infertile.”
DR. MED. WOLFGANG WODARG & DR. MICHAEL YEADON Petition to European Medicine Agency
More Resources:
The full petition is below. Those with an even deep interest, the official UK Pfizer/BioNTech vaccine notes may be found here.
PETITIONER: December 1, 2020
Dr. med. Wolfgang Wodarg Germany
CO-PETITIONER:
Dr. Michael Yeadon
TO:
European Medicines Agency
Committee for human medicinal products (CHMP)
COVID-19 EMA pandemic Task Force (COVID-ETF) Domenico Scarlattilaan 6
1083 HS Amsterdam The Netherlands
!! URGENT !!
PETITION/MOTION FOR ADMINISTRATIVE/REGULATORY ACTION REGARDING
CONFIRMATION OF EFFICACY END POINTS AND USE OF DATA IN CONNECTION WITH THE FOLLOWING CLINICAL TRIAL(S):
PHASE III – EUDRACT NUMBER: 2020-002641-42 SPONSOR PROTOCOL NUMBER: C4591001 SPONSOR:
BIONTECH SE (SOCIETAS EUROPAEA), AN DER GOLDGRUBE 12, 55131 MAINZ, GERMANY
AND ANY OTHER ONGOING CLINICAL TRIALS OF VACCINE CANDIDATES DESIGNED TO STOP TRANSMISSION OF THE VIRUS FROM THE VACCINE RECIPIENT TO OTHERS AND/OR TO PREVENT COVID-19 OR MITIGATE SYMPTOMS OF COVID-19 FOR WHICH PCR RESULTS ARE THE PRIMARY EVIDENCE OF INFECTION
WITH SARS-COV-2 ADMINISTRATIVE/REGULATORY STAY OF ACTION
This petition for a stay of action is submitted by the undersigned (“Petitioner” or “Lead Petitioner”) to request the EMA a) stay the Phase III clinical trial(s) of BNT162b (EudraCT Number 2020-002641-42) in the EU (current protocol country: Germany) until study design is amended to conform with the requests in the “Action Requested” section (B.) below; and b) stay all other clinical trials of vaccine candidates designed to stop transmission of the virus from the vaccine recipient to others and/or prevent or mitigate symptoms of COVID-19 for which PCR results are the primary evidence of infection.
Because of the compelling need to ensure the safety and efficacy of any COVID-19 vaccine licensed by the EMA (and/or the German Paul-Ehrlich-Institut), and to allow Petitioner the opportunity to seek appropriate emergency judicial relief should the EMA deny its Petition, Petitioner respectfully requests that EMA act on the instant Petition immediately.
A. DECISIONS INVOLVED
I. Approval of trial design and/or decision to not challenge trial design for Phase III trial of BNT162 (EudraCT Number 2020-002641-42)
II. Approval of trial design and/or decision to not challenge trial design of all other clinical trials of vaccine candidates designed to stop transmission of the virus from the vaccine recipient to others and/or to prevent or mitigate symptoms of COVID-19 for which PCR results are the primary evidence of infection.
B. ACTION REQUESTED
I. Stay the Phase III trial of BNT162 in the protocol country Germany and in any other EU protocol countries (as applicable) until study design is amended to provide that:
Before an Emergency Authorization/Conditional Approval and/or Unrestricted Authorization is issued for the Pfizer/BioNTech vaccine, all “endpoints” or COVID-19 cases used to determine vaccine efficacy in the Phase 3 or 2/3 trials should have their infection status confirmed by appropriate Sanger sequencing (as described in section C. III. below), given a) the high cycle thresholds used in some trials; and b) design flaws of certain RT-qPCR tests identical to or modeled after what is sometimes called the “Drosten-Test”.
II. Stay the clinical trials of all vaccine candidates designed to stop transmission of the virus from the vaccine recipient to others and/or to prevent or mitigate symptoms of COVID-19 for which PCR results are the primary evidence of infection until study design is amended to provide that:
Before an Emergency Authorization/Conditional Approval and/or Unrestricted Authorization is issued for vaccine designed to stop transmission of the virus from the vaccine recipient to others and/or to prevent or mitigate symptoms of COVID-19, all “endpoints” or COVID-19 cases used to determine vaccine efficacy should have their infection status confirmed by appropriate Sanger sequencing (as described in section B. III. below), given a) the high cycle thresholds used in some trials; and b) design flaws of certain RT-qPCR tests identical to or modeled after what is sometimes called the “Drosten-Test”.
III. High cycle thresholds, or Ct values, in RT-qPCR test results have been widely acknowledged to lead to false positives. Also, a group of scientists and researchers have recently called for a retraction of the paper that describes the so called “Drosten-Test” (sometimes also being referred to as the “Corman-Drosten protocol” – a specific RT-qPCR assay described by Corman,Victor M., Drosten, Christian and others in “Detection of 2019 novel coronavirus (2019-nCoV) by real-time RT-PCR.” Euro Surveillance 2020;25(3):pii=2000045. https://doi.org/10.2807/1560-7917.ES.2020.25.3.2000045).
All RT-qPCR-positive test results used to categorize patient as “COVID-19 cases” in the trials and used to qualify the trial’s endpoints should be verified by Sanger sequencing to confirm that the tested samples in fact contain a unique SARS-CoV-2 genomic RNA. Congruent with FDA and EMA requirements for a confirmed diagnosis of human papillomavirus (HPV) using PCR, the sequencing electropherogram must show a minimum of 100 contiguous bases matching the reference sequence with an Expected Value (E Value) <10-30 for the specific SARS-CoV-2 gene sequence based on a BLAST search of the GenBank database (aka NCBI Nucleotide database).
C. STATEMENT OF GROUNDS
I. As detailed herein, (i) without the requested stay, the Petitioner and many EU residents/citizens will suffer irreparable harm, (ii) the request is not frivolous and is being pursued in good faith, (iii) the request demonstrates sound public policy, and (iv) the public interest favors granting a stay.
II. Petitioner deems the current study designs for the Phase II/III trials of BNT162b (“the Pfizer/BioNTech trial”) to be inadequate to accurately assess efficacy. Petitioner also deems the designs of clinical trials of vaccine candidates designed to stop transmission of the virus from the vaccine recipient to others and/or to prevent or mitigate symptoms of COVID-19 for which PCR results are the primary evidence of infection to be inadequate to accurately assess efficacy.
III. Petitioner and the public will suffer irreparable harm if the actions requested herein are not granted, because once the EMA (and other appropriate bodies in the various EU member states) approves the COVID-19 vaccines in question, both governments of EU member states and employers in the EU are most likely going to recommend them for widespread use. If the assignment of cases and non-cases during the course of the trials is not accurate, the vaccines will not have been properly tested. If the vaccines are not properly tested, important public policy decisions regarding its use will be based on misleading evidence. The medical and economic consequences to EU member states and their residents/citizens could hardly be higher.
IV. Furthermore, if the vaccines are approved without an appropriate and accurate review of efficacy, then any potential acceptance or mandate of these vaccines is likely to be based on inaccurate evidence regarding the vaccine, namely that it will stop transmission of the virus from the vaccine recipient to others and/or that it will reduce COVID-19 disease and deaths. The Pfizer/BioNTech trial protocol and other trial protocols are currently not designed to determine whether either of those objectives can be met; and even if it was, if cases cannot be reliably identified, neither objective could be reliably met.
V. The public interest also weighs strongly in favor of the requested relief because improving the accurate determination of primary endpoints (i) will comport with the best scientific practices, (ii) increase public confidence in the efficacy of a product likely to be mandated or intended for widespread use, and (iii) not doing so will have the opposite result and create uncertainties regarding the efficacy of and need for the COVID-19 vaccines.
VI. Petitioner hereby incorporates the grounds, facts, arguments and opinions stated in the “PETITION FOR ADMINISTRATIVE ACTION REGARDING CONFIRMATION OF EFFICACY END POINTS OF THE PHASE III CLINICAL TRIALS OF COVID-19 VACCINES” which has been submitted to the FDA by Dr. Sin Hang Lee via electronic filing on November 25, 2020 (Exhibit A – Docket No. FDA-2020-P-2225). Exhibit A attached hereto shall be incorporated herein and shall be understood to be a part hereof as though included in the body of this petition.
VII. Petitioner hereby also incorporates the grounds, facts, arguments and opinions stated in the external peer review of the “Drosten- Test” (Exhibit B). Design flaws of certain RT-qPCR tests that are identical to or modeled after what is sometimes called the “Drosten-Test” can lead to false-positive results in trials designed such that PCR results are the primary evidence of infection. Exhibit B attached hereto shall be incorporated herein and shall be understood to be a part hereof as though included in the body of this petition.
VIII. For a vaccine to work, our immune system needs to be stimulated to produce a neutralizing antibody, as opposed to a non-neutralizing antibody. A neutralizing antibody is one that can recognize and bind to some region (‘epitope’) of the virus, and that subsequently results in the virus either not entering or replicating in your cells. A non-neutralizing antibody is one that can bind to the virus, but for some reason, the antibody fails to neutralize the infectivity of the virus. In some viruses, if a person harbors a non-neutralizing antibody to the virus, a subsequent infection by the virus can cause that person to elicit a more severe reaction to the virus due to the presence of the non-neutralizing antibody. This is not true for all viruses, only particular ones. This is called Antibody Dependent Enhancement (ADE), and is a common problem with Dengue Virus, Ebola Virus, HIV, RSV, and the family of coronaviruses. In fact, this problem of ADE is a major reason why many previous vaccine trials for other coronaviruses failed. Major safety concerns were observed in animal models. If ADE occurs in an individual, their response to the virus can be worse than their response if they had never developed an antibody in the first place. This can cause a hyperinflammatory response, a cytokine storm, and a generally dysregulation of the immune system that allows the virus to cause more damage to our lungs and other organs of our body. In addition, new cell types throughout our body are now susceptible to viral infection due to the additional viral entry pathway. There are many studies that demonstrate that ADE is a persistent problem with coronaviruses in general, and in particular, with SARS-related viruses. ADE has proven to be a serious challenge with coronavirus vaccines, and this is the primary reason many of such vaccines have failed in early in-vitro or animal trials. For example, rhesus macaques who were vaccinated with the Spike protein of the SARS-CoV virus demonstrated severe acute lung injury when challenged with SARS-CoV, while monkeys who were not vaccinated did not. Similarly, mice who were immunized with one of four different SARS-CoV vaccines showed histopathological changes in the lungs with eosinophil infiltration after being challenged with SARS-CoV virus.
IX. There are some concerning issues with the trial designs, spelled out by Dr. Peter Doshi in the British Medical Journal. Dr. Doshi focuses on the two biggest issues. First, none of the leading vaccine candidate trials is designed to test if the vaccine can reduce severe COVID-19 symptoms, defined as: hospital admissions, ICU or death. And, second, the trials are not designed to test if the vaccine can interrupt transmission (https://www.bmj.com/content/bmj/371/bmj.m4037.full.pdf). If neither of these conditions is met, the vaccine in essence performs like a therapeutic drug, except a vaccine would be taken prophylactically, even by the perfectly healthy, and more than likely carries a higher risk of injury than a therapeutic drug. If this were to be true, then therapeutic drugs would be superior to any COVID vaccine.
X. In the Pfizer/BioNTech mRNA vaccine candidate, polyethylene glycol (PEG) is found in the fatty lipid nanoparticle coating around the mRNA.
70% of people make antibodies to PEG and most do not know it, creating a concerning situation where many could have allergic, potentially deadly, reactions to a PEG-containing vaccine. PEG antibodies may also reduce vaccine effectiveness.
Pfizer/BioNTech is also inserting an ingredient derived from a marine invertebrate, mNeonGreen, into its vaccine. The ingredient has bioluminescent qualities, making it attractive for medical imaging purposes, but it is unclear why an injected vaccine would need to have that quality. mNeonGreen has unknown antigenicity.
XI. Several vaccine candidates are expected to induce the formation of humoral antibodies against spike proteins of SARS-CoV-2. Syncytin-1 (see Gallaher, B., “Response to nCoV2019 Against Backdrop of Endogenous Retroviruses” – http://virological.org/t/response-to-ncov2019- against-backdrop-of-endogenous-retroviruses/396), which is derived from human endogenous retroviruses (HERV) and is responsible for the development of a placenta in mammals and humans and is therefore an essential prerequisite for a successful pregnancy, is also found in homologous form in the spike proteins of SARS viruses. There is no indication whether antibodies against spike proteins of SARS viruses would also act like anti-Syncytin-1 antibodies. However, if this were to be the case this would then also prevent the formation of a placenta which would result in vaccinated women essentially becoming infertile. To my knowledge, Pfizer/BioNTech has yet to release any samples of written materials provided to patients, so it is unclear what, if any, information regarding (potential) fertility-specific risks caused by antibodies is included.
According to section 10.4.2 of the Pfizer/BioNTech trial protocol, a woman of childbearing potential (WOCBP) is eligible to participate if she is not pregnant or breastfeeding, and is using an acceptable contraceptive method as described in the trial protocol during the intervention period (for a minimum of 28 days after the last dose of study intervention).
This means that it could take a relatively long time before a noticeable number of cases of post-vaccination infertility could be observed.
XII. It appears that Pfizer/BioNTech have not yet released any samples of written materials provided to patients, so it is unclear what, if any, instructions/information patients/subjects were given regarding ADE and PEG-related issues and (potential) fertility- or pregnancy-specific issues.
D. STAY URGENTLY REQUIRED
I. Petitioner and many EU residents/citizens will suffer irreparable harm because once the EMA approves the COVID- 19 vaccine(s) in question, both governments of EU member states and employers in the EU are most likely going to recommend them for widespread use, and hence without the EMA assuring proper safety trials of the vaccines now, the Petitioner and others will not have the opportunity to object to receiving the vaccine based on deficient clinical trials later.
II. Furthermore, if the vaccines are licensed without an appropriate efficacy review and without improving the accurate determination of primary endpoints, then any potential acceptance or mandate of these vaccines are likely to be based on inaccurate beliefs and data about the vaccines, namely that they will or might stop transmission of the virus from the vaccine recipient to others and/or that it will reduce severe COVID-19 disease and deaths. The trial protocols in question are not currently properly designed to determine whether either of those objectives can be met.
III. This petition is also not frivolous and is being pursued in good faith as it seeks to increase the scientific integrity and reliability of the trials of the COVID-19 vaccines.
IV. Finally, the public interest also weighs strongly in favor of the requested relief because improving the accurate determination of primary endpoints (i) will comport with the best scientific practices, (ii) increase public confidence in the efficacy of a vaccine expected to be mandated or strongly recommended for widespread use, and (iii) not doing so will have the opposite result in that it will create uncertainties regarding the efficacy of and need for the COVID-19 vaccines.
V. The Petitioner therefore respectfully urges that this request be granted
Respectfully submitted on my behalf and on behalf of Co-Petitioner Dr. Michael Yeadon:
_________________________
Dr. med. Wolfgang Wodarg
Exhibit A
Exhibit B
FOR EXHIBIT A, visit the source article and scroll to the bottom to expand the details.
The length of the exhibit caused me to exclude it within this post but it is well worth the read for those who like the extra details.
Exhibit B
External peer review of the RTPCR test to detect SARS-CoV-2 reveals 10 major scientific flaws at the molecular and methodological level: consequences for false positive results.
Pieter Borger(1 * ), Bobby Rajesh Malhotra(2) , Michael Yeadon(3) , Clare Craig(4) Kevin McKernan(5) , Klaus Steger(6) , Paul McSheehy(7) , Lidiya Angelova(8) Fabio Franchi(9), Thomas Binder(10), Henrik Ullrich(11) , Makoto Ohashi(12) Stefano Scoglio(13), Marjolein Doesburg−van Kleffens(14), Dorothea Gilbert(15) Rainer Klement(16), Ruth Schruefer(17), Berber W. Pieksma(18), Jan Bonte(19) Bruno H. Dalle Carbonare(20), Kevin P. Corbett(21), Ulrike Kämmerer(22) * Corresponding Author
ABSTRACT
“In the publication entitled “Detection of 2019 novel coronavirus (2019−nCoV) by real−time RT−PCR” (Eurosurveillance 25(8) 2020) the authors present a diagnostic workflow and RT−qPCR protocol for detection and diagnostics of 2019−nCoV (now known as SARS−CoV−2), which they claim to be validated, as well as being a robust diagnostic methodology for use in public−health laboratory settings.
In light of all the consequences resulting from this very publication for societies worldwide, a group of independent researchers performed a point−by−point review of the aforesaid publication in which
1) all components of the presented test design were cross checked, 2) the RT−qPCR protocol−recommendations were assessed with respect to good laboratory practice, and 3) parameters examined against relevant scientific literature covering the field.
The published RT−qPCR protocol for detection and diagnostics of 2019−nCoV and the manuscript suffer from numerous technical and scientific errors, including insufficient primer design, a problematic and insufficient RT−qPCR protocol, and the absence of an accurate test validation. Neither the presented test nor the manuscript itself fulfils the requirements for an acceptable scientific publication. Further, serious conflicts of interest of the authors are not mentioned. Finally, the very short timescale between submission and acceptance of the publication (24 hours) signifies that a systematic peer review process was either not performed here, or of problematic poor quality. We provide compelling evidence of several scientific inadequacies, errors and flaws. Considering the scientific and methodological blemishes presented here, we are confident that the editorial board of Eurosurveillance has no other choice but to retract the publication.” CONCISE REVIEW REPORT
This paper will show numerous serious flaws in the Corman−Drosten paper, the significance of which has led to worldwide misdiagnosis of infections attributed to SARS−CoV−2 and associated with the disease COVID−19. We are confronted with stringent lockdowns which have destroyed many people’s lives and livelihoods, limited access to education and these imposed restrictions by governments around the world are a direct attack on people’s basic rights and their personal freedoms, resulting in collateral damage for entire economies on a global scale. There are ten fatal problems with the Corman-Drosten paper which we will outline and explain in greater detail in the following sections. The first and major issue is that the novel Coronavirus SARS−CoV−2 (in the publication named 2019−nCoV and in February 2020 named SARS−CoV−2 by an international consortium of virus experts) is based on in silico (theoretical) sequences, supplied by a laboratory in China [1], because at the time neither control material of infectious (“live”) or inactivated SARS−CoV−2 nor isolated genomic RNA of the virus was available to the authors. To date no validation has been performed by the authorship based on isolated SARS−CoV−2 viruses or full length RNA thereof. According to Corman et al.:
“We aimed to develop and deploy robust diagnostic methodology for use in public health laboratory settings without having virus material available.” [1]
The focus here should be placed upon the two stated aims: a) development and b) deployment of a diagnostic test for use in public health laboratory settings. These aims are not achievable without having any actual virus material available (e.g. for determining the infectious viral load). In any case, only a protocol with maximal accuracy can be the mandatory and primary goal in any scenario−outcome of this magnitude. Critical viral load determination is mandatory information, and it is in Christian Drosten’s group responsibility to perform these experiments and provide the crucial data.
Nevertheless these in silico sequences were used to develop a RT−PCR test methodology to identify the aforesaid virus. This model was based on the assumption that the novel virus is very similar to SARS−CoV from 2003 as both are beta−coronaviruses.
The PCR test was therefore designed using the genomic sequence of SARS−CoV as a control material for the Sarbeco component; we know this from our personal email−communication with [2] one of the co−authors of the Corman−Drosten paper. This method to model SARS−CoV−2 was described in the Corman−Drosten paper as follows:
“the establishment and validation of a diagnostic workflow for 2019−nCoV screening and specific confirmation, designed in absence of available virus isolates or original patient specimens. Design and validation were enabled by the close genetic relatedness to the 2003 SARS−CoV, and aided by the use of synthetic nucleic acid technology.”
The Reverse Transcription−Polymerase Chain Reaction (RT−PCR) is an important biomolecular technology to rapidly detect rare RNA fragments, which are known in advance. In the first step, RNA molecules present in the sample are reverse transcribed to yield cDNA. The cDNA is then amplified in the polymerase chain reaction using a specific primer pair and a thermostable DNA polymerase enzyme. The technology is highly sensitive and its detection limit is theoretically 1 molecule of cDNA. The specificity of the PCR is highly influenced by biomolecular design errors. What is important when designing an RT-PCR Test and the quantitative RT-qPCR test described in the Corman-Drosten publication?
1. The primers and probes:
the concentration of primers and probes must be of optimal range (100−200 nM)
must be specific to the target−gene you want to amplify
must have an optimal percentage of GC content relative to the total nitrogenous bases (minimum 40%, maximum 60%)
for virus diagnostics at least 3 primer pairs must detect 3 viral genes (preferably as far apart as possible in the viral genome)
2. The temperature at which all reactions take place:
DNA melting temperature (>92˚)
DNA amplification temperature (TaqPol specific)
Tm; the annealing temperature (the temperature at which the primers and probes reach the target bindingƒdetachment, not to exceed 2 ̊C per primer pair). Tm heavily depends on GC content of the primers
3. The number of amplification cycles (less than 35; preferably 25-30 cycles); In case of virus detection, >35 cycles only detects signals which do not correlate with infectious virus as determined by isolation in cell culture [reviewed in 2]; if someone is tested by PCR as positive when a threshold of 35 cycles or higher is used (as is the case in most laboratories in Europe & the US), the probability that said person is actually infected is less than 3%, the probability that said result is a false positive is 97% [reviewed in 3] 4. Molecular biological validations; amplified PCR products must be validated either by running the products in a gel with a DNA ruler, or by direct DNA sequencing
5. Positive and negative controls should be specified to confirm/refute specific virus detection
6. There should be a Standard Operational Procedure (SOP) available
SOP unequivocally specifies the above parameters, so that all laboratories are able to set up the exact same test conditions. To have a validated universal SOP is essential, because it enables the comparison of data within and between countries. MINOR CONCERNS WITH THE CORMAN-DROSTEN PAPER
In Table 1 of the Corman−Drosten paper, different abbreviations are stated − “nM” is specified, “nm” isn’t. Further in regards to correct nomenclature, nm means “nanometer” therefore nm should read nM
It is the general consensus to write genetic sequences always in the 5’−3’ direction, including the reverse primers. It is highly unusual to do alignment with reverse complementary writing of the primer sequence as the authors did in figure 2 of the Corman−Drosten paper. Here, in addition, a wobble base is marked as “y” without description of the bases the Y stands
Two misleading pitfalls in the Corman−Drosten paper are that their Table 1 does not include Tm−values (annealing−temperature values), neither does it show GC−values (number of G and C in the sequences as %−value of total bases).
MAJOR CONCERNS WITH THE CORMAN-DROSTEN PAPER
A) BACKGROUND
The authors introduce the background for their scientific work as: “The ongoing outbreak of the recently emerged novel coronavirus (2019−nCoV) poses a challenge for public health laboratories as virus isolates are unavailable while there is growing evidence that the outbreak is more widespread than initially thought, and international spread through travelers does already occur”.
According to BBC News [4] and Google Statistics [5] there were 6 deaths world−wide on January 21st 2020 − the day when the manuscript was submitted. Why did the authors assume a challenge for public health laboratories while there was no substantial evidence at that time to indicate that the outbreak was more widespread than initially thought?
As an aim the authors declared to develop and deploy robust diagnostic methodology for use in public health laboratory settings without having virus material available. Further, they acknowledge that “The present study demonstrates the enormous response capacity achieved through coordination of academic and public laboratories in national and European research networks.”
B) METHODS AND RESULTS
1. Primer & Probe Design
1a) Erroneous primer concentrations
Reliable and accurate PCR−test protocols are normally designed using between 100 nM and 200 nM per primer [7]. In the Corman−Drosten paper, we observe unusually high and varying primer concentrations for several primers (table 1). For the RdRp_SARSr−F and RdRp_SARSr−R primer pairs, 600 nM and 800 nM are described, respectively. Similarly, for the N_Sarbeco_F and N_Sarbeco_R primer set, they advise 600 nM and 800 nM, respectively [1]. It should be clear that these concentrations are far too high to be optimal for specific amplifications of target genes. There exists no specified reason to use these extremely high concentrations of primers in this protocol. Rather, these concentrations lead to increased unspecific binding and PCR product amplification. Table1: Primers and probes (adapted from Corman−Drosten paper; erroneous primer concentrations are highlighted)
1b) Unspecified (“Wobbly”) primer and probe sequences
To obtain reproducible and comparable results, it is essential to distinctively define the primer pairs. In the Corman−Drosten paper we observed six unspecified positions, indicated by the letters R, W, M and S (Table 2). The letter W means that at this position there can be either an A or a T; R signifies there can be either a G or an A; M indicates that the position may either be an A or a C; the letter S indicates there can be either a G or a C on this position. This high number of variants not only is unusual, but it also is highly confusing for laboratories. These six unspecified positions could easily result in the design of several different alternative primer sequences which do not relate to SARS−CoV−2 (2 distinct RdRp_SARSr_F primers + 8 distinct RdRp_SARS_P1 probes + 4 distinct RdRp_SARSr_R). The design variations will inevitably lead to results that are not even SARS CoV−2 related.
Therefore, the confusing unspecific description in the Corman−Drosten paper is not suitable as a Standard Operational Protocol. These unspecified positions should have been designed unequivocally.
These wobbly sequences have already created a source of concern in the field and resulted in a Letter to the Editor authored by Pillonel et al. [8] regarding blatant errors in the described sequences. These errors are self−evident in the Corman et al. supplement as well.
Table 2: Primers and probes (adapted from Corman−Drosten paper; unspecified (“Wobbly”) nucleotides in the primers are highlighted)
The WHO−protocol (Figure 1), which directly derives from the Corman−Drosten paper, concludes that in order to confirm the presence of SARS−CoV−2, two control genes (the E−and the RdRp−genes) must be identified in the assay. It should be noted, that the RdPd−gene has one uncertain position (“wobbly”) in the forward−primer (R=GƒA), two uncertain positions in the reverse−primer (R=GƒA; S=GƒC) and it has three uncertain positions in the RdRp−probe (W=AƒT; R=GƒA; M=AƒC). So, two different forward primers, four different reverse primers, and eight distinct probes can be synthesized for the RdPd−gene. Together, there are 64 possible combinations of primers and probes! The Corman−Drosten paper further identifies a third gene which, according to the WHO protocol, was not further validated and deemed unnecessary: “Of note, the N gene assay also performed well but was not subjected to intensive further validation because it was slightly less sensitive.” This was an unfortunate omission as it would be best to use all three gene PCRs as confirmatory assays, and this would have resulted in an almost sufficient virus RNA detection diagnostic tool protocol. Three confirmatory assay−steps would at least minimize−out errors & uncertainties at every fold−step in regards to “Wobbly”−spots. (Nonetheless, the protocol would still fall short of any “good laboratory practice”, when factoring in all the other design−errors). As it stands, the N gene assay is regrettably neither proposed in the WHO−recommendation (Figure 1) as a mandatory and crucial third confirmatory step, nor is it emphasized in the Corman−Drosten paper as important optional reassurance “for a routine workflow” (Table 2). Consequently, in nearly all test procedures worldwide, merely 2 primer matches were used instead of all three. This oversight renders the entire test−protocol useless with regards to delivering accurate test−results of real significance in an ongoing pandemic.
Figure 1: The N−Gene confirmatory−assay is neither emphasized as necessary third step in the official WHO Drosten−Corman protocol−recommendation below [8] nor is it required as a crucial step for higher test−accuracy in the Eurosurveillance publication.
1c) Erroneous GC-content (discussed in 2c, together with annealing temperature (Tm)) 1d) Detection of viral genes RT−PCR is not recommended for primary diagnostics of infection. This is why the RT−PCR Test used in clinical routine for detection of COVID−19 is not indicated for COVID−19 diagnosis on a regulatory basis.
“Clinicians need to recognize the enhanced accuracy and speed of the molecular diagnostic techniques for the diagnosis of infections, but also to understand their limitations. Laboratory results should always be interpreted in the context of the clinical presentation of the patient, and appropriate site, quality, and timing of specimen collection are required for reliable test results”. [9]
However, it may be used to help the physician’s differential diagnosis when he or she has to discriminate between different infections of the lung (Flu, Covid−19 and SARS have very similar symptoms). For a confirmative diagnosis of a specific virus, at least 3 specific primer pairs must be applied to detect 3 virus−specific genes. Preferably, these target genes should be located with the greatest distance possible in the viral genome (opposite ends included).
Although the Corman−Drosten paper describes 3 primers, these primers only cover roughly half of the virus’ genome. This is another factor that decreases specificity for detection of intact COVID−19 virus RNA and increases the quote of false positive test results.
Therefore, even if we obtain three positive signals (i.e. the three primer pairs give 3 different amplification products) in a sample, this does not prove the presence of a virus. A better primer design would have terminal primers on both ends of the viral genome. This is because the whole viral genome would be covered and three positive signals can better discriminate between a complete (and thus potentially infectious) virus and fragmented viral genomes (without infectious potency). In order to infer anything of significance about the infectivity of the virus, the Orf1 gene, which encodes the essential replicase enzyme of SARS−CoV viruses, should have been included as a target (Figure 2). The positioning of the targets in the region of the viral genome that is most heavily and variably transcribed is another weakness of the protocol.
Kim et al. demonstrate a highly variable 3’ expression of subgenomic RNA in Sars−CoV−2 [23]. These RNAs are actively monitored as signatures for asymptomatic and non−infectious patients [10]. It is highly questionable to screen a population of asymptomatic people with qPCR primers that have 6 base pairs primer−dimer on the 3 prime end of a primer (Figure 3).
Apparently the WHO recommends these primers. We tested all the wobble derivatives from the Corman−Drosten paper with Thermofisher’s primer dimer web tool [11]. The RdRp forward primer has 6bp 3prime homology with Sarbeco E Reverse. At high primer concentrations this is enough to create inaccuracies.
Of note: There is a perfect match of one of the N primers to a clinical pathogen (Pantoea), found in immuno−compromised patients. The reverse primer hits Pantoea as well but not in the same region (Figure 3).
These are severe design errors, since the test cannot discriminate between the whole virus and viral fragments. The test cannot be used as a diagnostic for SARS−viruses. Figure 2: Relative positions of amplicon targets on the SARS coronavirus and the 2019 novel coronavirus genome. ORF: open reading frame; RdRp: RNA−dependent RNA polymerase. Numbers below amplicon are genome positions according to SARS−CoV, NC_004718 [1];
Figure 3: A test with Thermofischer’s primer dimer web tool reveals that the RdRp forward primer has a 6bp 3`prime homology with Sarbeco E Reverse (left box). Another test reveals that there is a perfect match for one of the N−primers to a clinical pathogen (Pantoea) found in immuno−compromised patients (right box).
2. Reaction temperature
2a) DNA melting temperature (>92˚).
Adequately addressed in the Corman−Drosten paper.
2b) DNA amplification temperature.
Adequately addressed in the Corman−Drosten paper.
2c) Erroneous GC−contents and Tm
The annealing−temperature determines at which temperature the primer attachesƒdetaches from the target sequence. For an efficient and specific amplification, GC content of primers should meet a minimum of 40% and a maximum of 60% amplification. As indicated in table 3, three of the primers described in the Corman−Drosten paper are not within the normal range for GC−content. Two primers (RdRp_SARSr_F and RdRp_SARSr_R) have unusual and very low GC−values of 28%−31% for all possible variants of wobble bases, whereas primer E_Sarbeco_F has a GC−value of 34.6% (Table 3 and second panel of Table 3).
It should be noted that the GC−content largely determines the binding to its specific target due to its three hydrogen bonds in base pairing. Thus, the lower the GC−content of the primer, the lower its binding−capability to its specific target gene sequence (i.e. the gene to be detected). This means for a target−sequence to be recognized we have to choose a temperature which is as close as possible to the actual annealing−temperature (best practise−value) for the primer not to detach again, while at the same time specifically selecting the target sequence.
If the Tm−value is very low, as observed for all wobbly−variants of the RdRp reverse primers, the primers can bind non−specifically to several targets, decreasing specificity and increasing potential false positive results.
The annealing temperature (Tm) is a crucial factor for the determination of the specificityƒaccuracy of the qPCR procedure and essential for evaluating the accuracy of qPCR−protocols. Best−practice recommendation: Both primers (forward and reverse) should have an almost similar value, preferably the identical value.
We used the freely available primer design software Primer−BLAST [12, 25] to evaluable the best−practise values for all primers used in the Corman−Drosten paper (Table 3). We attempted to find a Tm−value of 60˚ C, while similarly seeking the highest possible GC%−value for all primers. A maximal Tm difference of 2˚ C within primer pairs was considered acceptable. Testing the primer pairs specified in the Corman−Drosten paper, we observed a difference of 10˚ C with respect to the annealing temperature Tm for primer pair1 (RdRp_SARSr_F and RdRp_SARSr_R). This is a very serious error and makes the protocol useless as a specific diagnostic tool.
Additional testing demonstrated that only the primer pair designed to amplify the N−gene (N_Sarbeco_F and N_Sarbeco_R) reached the adequate standard to operate in a diagnostic test, since it has a sufficient GC−content and the Tm difference between the primers (N_Sarbeco_F and N_Sarbeco_R) is 1.85˚ C (below the crucial maximum of 2˚ C difference). Importantly, this is the gene which was neither tested in the virus samples (Table 2) nor emphasized as a confirmatory test. In addition to highly variable melting temperatures and degenerate sequences in these primers, there is another factor impacting specificity of the procedure: the dNTPs (0.4uM) are 2x higher than recommended for a highly specific amplification. There is additional magnesium sulphate added to the reaction as well. This procedure combined with a low annealing temperature can create non−specific amplifications. When additional magnesium is required for qPCR, specificity of the assay should be further scrutinized.
The design errors described here are so severe that it is highly unlikely that specific amplification of SARS−CoV−2 genetic material will occur using the protocol of the Corman−Drosten paper.
Table 3: GC−content of the primers and probes (adapted from Corman−Drosten paper; aberrations from optimized GC−contents are highlighted. Second Panel shows a table−listing of all Primer−BLAST best practices values for all primers and probes used in the Corman−Drosten paper by Prof. Dr. Ulrike Kämmerer & her team.
3. The number of amplification cycles
It should be noted that there is no mention anywhere in the Corman−Drosten paper of a test being positive or negative, or indeed what defines a positive or negative result. These types of virological diagnostic tests must be based on a SOP, including a validated and fixed number of PCR cycles (Ct value) after which a sample is deemed positive or negative. The maximum reasonably reliable Ct value is 30 cycles. Above a Ct of 35 cycles, rapidly increasing numbers of false positives must be expected .
PCR data evaluated as positive after a Ct value of 35 cycles are completely unreliable.
Citing Jaafar et al. 2020 [3]:
“At Ct = 35, the value we used to report a positive result for PCR, <3% of cultures are positive.”
In other words, there was no successful virus isolation of SARS−CoV−2 at those high Ct values. Further, scientific studies show that only non−infectious (dead) viruses are detected with Ct values of 35 [22].
Between 30 and 35 there is a grey area, where a positive test cannot be established with certainty. This area should be excluded. Of course, one could perform 45 PCR cycles, as recommended in the Corman−Drosten WHO−protocol (Figure 4), but then you also have to define a reasonable Ct−value (which should not exceed 30). But an analytical result with a Ct value of 45 is scientifically and diagnostically absolutely meaningless (a reasonable Ct−value should not exceed 30). All this should be communicated very clearly. It is a significant mistake that the Corman−Drosten paper does not mention the maximum Ct value at which a sample can be unambiguously considered as a positive or a negative test−result. This important cycle threshold limit is also not specified in any follow−up submissions to date.
Figure 4: RT−PCR Kit recommendation in the official Corman−Drosten WHO−protocol [8]. Only a “Cycler”−value (cycles) is to be found without corresponding and scientifically reasonable Ct (Cutoff−value). This or any other cycles−value is nowhere to be found in the actual Corman−Drosten paper.
4. Biomolecular validations
To determine whether the amplified products are indeed SARS−CoV−2 genes, biomolecular validation of amplified PCR products is essential. For a diagnostic test, this validation is an absolute must.
Validation of PCR products should be performed by either running the PCR product in a 1% agarose−EtBr gel together with a size indicator (DNA ruler or DNA ladder) so that the size of the product can be estimated. The size must correspond to the calculated size of the amplification product. But it is even better to sequence the amplification product. The latter will give 100% certainty about the identity of the amplification product. Without molecular validation one can not be sure about the identity of the amplified PCR products. Considering the severe design errors described earlier, the amplified PCR products can be anything.
Also not mentioned in the Corman−Drosten paper is the case of small fragments of qPCR (around 100bp): It could be either 1,5% agarose gel or even an acrylamide gel.
The fact that these PCR products have not been validated at molecular level is another striking error of the protocol, making any test based upon it useless as a specific diagnostic tool to identify the SARS−CoV−2 virus.
5. Positive and negative controls to confirm/refute specific virus detection.
The unconfirmed assumption described in the Corman−Drosten paper is that SARS−CoV−2 is the only virus from the SARS−like beta−coronavirus group that currently causes infections in humans. The sequences on which their PCR method is based are in silico sequences, supplied by a laboratory in China [23], because at the time of development of the PCR test no control material of infectious (“live”) or inactivated SARS−CoV−2 was available to the authors. The PCR test was therefore designed using the sequence of the known SARS−CoV as a control material for the Sarbeco component (Dr. Meijer, co−author Corman−Drosten paper in an email exchange with Dr. Peter Borger) [2].
All individuals testing positive with the RT−PCR test, as described in the Corman−Drosten paper, are assumed to be positive for SARS−CoV−2 infections. There are three severe flaws in their assumption. First, a positive test for the RNA molecules described in the Corman−Drosten paper cannot be equated to “infection with a virus”. A positive RT−PCR test merely indicates the presence of viral RNA molecules. As demonstrated under point 1d (above), the Corman−Drosten test was not designed to detect the full−length virus, but only a fragment of the virus. We already concluded that this classifies the test as unsuitable as a diagnostic test for SARS−virus infections.
Secondly and of major relevance, the functionality of the published RT−PCR Test was not demonstrated with the use of a positive control (isolated SARS−CoV−2 RNA) which is an essential scientific gold standard.
Third, the Corman−Drosten paper states:
“To show that the assays can detect other bat−associated SARS−related viruses, we used the E gene assay to test six bat−derived faecal samples available from Drexler et al. […] und Muth et al. […]. These virus−positive samples stemmed from European rhinolophid bats. Detection of these phylogenetic outliers within the SARS−related CoV clade suggests that all Asian viruses are likely to be detected. This would, theoretically, ensure broad sensitivity even in case of multiple independent acquisitions of variant viruses from an animal reservoir.”
This statement demonstrates that the E gene used in RT−PCR test, as described in the Corman−Drosten paper, is not specific to SARS−CoV−2.
The E gene primers also detect a broad spectrum of other SARS viruses.
The genome of the coronavirus is the largest of all RNA viruses that infect humans and they all have a very similar molecular structure. Still, SARS−CoV1 and SARS−CoV−2 have two highly specific genetic fingerprints, which set them apart from the other coronaviruses. First, a unique fingerprint−sequence (KTFPPTEPKKDKKKK) is present in the N−protein of SARS−CoV and SARS−CoV−2 [13,14,15]. Second, both SARS−CoV1 and SARS−CoV2 do not contain the HE protein, whereas all other coronaviruses possess this gene [13, 14]. So, in order to specifically detect a SARS−CoV1 and SARS−CoV−2 PCR product the above region in the N gene should have been chosen as the amplification target. A reliable diagnostic test should focus on this specific region in the N gene as a confirmatory test. The PCR for this N gene was not further validated nor recommended as a test gene by the Drosten−Corman paper, because of being “not so sensitive” with the SARS−CoV original probe [1].
Furthermore, the absence of the HE gene in both SARS−CoV1 and SARS−CoV−2 makes this gene the ideal negative control to exclude other coronaviruses. The Corman−Drosten paper does not contain this negative control, nor does it contain any other negative controls. The PCR test in the Corman−Drosten paper therefore contains neither a unique positive control nor a negative control to exclude the presence of other coronaviruses. This is another major design flaw which classifies the test as unsuitable for diagnosis.
6. Standard Operational Procedure (SOP) is not available
There should be a Standard Operational Procedure (SOP) available, which unequivocally specifies the above parameters, so that all laboratories are able to set up the identical same test conditions. To have a validated universal SOP is essential, because it facilitates data comparison within and between countries. It is very important to specify all primer parameters unequivocally. We note that this has not been done. Further, the Ct value to indicate when a sample should be considered positive or negative is not specified. It is also not specified when a sample is considered infected with SARS−CoV viruses. As shown above, the test cannot discern between virus and virus fragments, so the Ct value indicating positivity is crucially important. This Ct value should have been specified in the Standard Operational Procedure (SOP) and put on−line so that all laboratories carrying out this test have exactly the same boundary conditions. It points to flawed science that such an SOP does not exist. The laboratories are thus free to conduct the test as they consider appropriate, resulting in an enormous amount of variation. Laboratories all over Europe are left with a multitude of questions; which primers to order? which nucleotides to fill in the undefined places? which Tm value to choose? How many PCR cycles to run? At what Ct value is the sample positive? And when is it negative? And how many genes to test? Should all genes be tested, or just the E and RpRd gene as shown in Table 2 of the Corman−Drosten paper? Should the N gene be tested as well? And what is their negative control? What is their positive control?
The protocol as described is unfortunately very vague and erroneous in its design that one can go in dozens of different directions. There does not appear to be any standardization nor an SOP, so it is not clear how this test can be implemented.
7. Consequences of the errors described under 1-5: false positive results.
The RT−PCR test described in the Corman−Drosten paper contains so many molecular biological design errors (see 1−5) that it is not possible to obtain unambiguous results. It is inevitable that this test will generate a tremendous number of so−called “false positives”. The definition of false positives is a negative sample, which initially scores positive, but which is negative after retesting with the same test. False positives are erroneous positive test−results, i.e. negative samples that test positive. And this is indeed what is found in the Corman−Drosten paper. On page 6 of the manuscript PDF the authors demonstrate, that even under well−controlled laboratory conditions, a considerable percentage of false positives is generated with this test:
“In four individual test reactions, weak initial reactivity was seen however they were negative upon retesting with the same assay. These signals were not associated with any particular virus, and for each virus with which initial positive reactivity occurred, there were other samples that contained the same virus at a higher concentration but did not test positive.
Given the results from the extensive technical qualification described above, it was concluded that this initial reactivity was not due to chemical instability of real−time PCR probes and most probably to handling issues caused by the rapid introduction of new diagnostic tests and controls during this evaluation study.” [1] The first sentence of this excerpt is clear evidence that the PCR test described in the Corman−Drosten paper generates false positives. Even under the well−controlled conditions of the state−of−the−art Charité−laboratory, 4 out of 310 primary−tests are false positives per definition. Four negative samples initially tested positive, then were negative upon retesting. This is the classical example of a false positive. In this case the authors do not identify them as false positives, which is intellectually dishonest. Another telltale observation in the excerpt above is that the authors explain the false positives away as “handling issues caused by the rapid introduction of new diagnostic tests”. Imagine the laboratories that have to introduce the test without all the necessary information normally described in an SOP. 8. The Corman-Drosten paper was not peer-reviewed Before formal publication in a scholarly journal, scientific and medical articles are traditionally certified by “peer review.” In this process, the journal’s editors take advice from various experts (“referees”) who have assessed the paper and may identify weaknesses in its assumptions, methods, and conclusions. Typically a journal will only publish an article once the editors are satisfied that the authors have addressed referees’ concerns and that the data presented supports the conclusions drawn in the paper.” This process is as well described for Eurosurveillance [16]. The Corman−Drosten paper was submitted to Eurosurveillance on January 21st 2020 and accepted for publication on January 22nd 2020. On January 23rd 2020 the paper was online. On January 13th 2020 version 1−0 of the protocol was published at the official WHO website [17], updated on January 17th 2020 as document version 2−1 [18], even before the Corman−Drosten paper was published on January 23rd at Eurosurveillance. Normally, peer review is a time−consuming process since at least two experts from the field have to critically read and comment on the submitted paper. In our opinion, this paper was not peer−reviewed. Twenty−four hours are simply not enough to carry out a thorough peer review. Our conclusion is supported by the fact that a tremendous number of very serious design flaws were found by us, which make the PCR test completely unsuitable as a diagnostic tool to identify the SARS−CoV−2 virus. Any molecular biologist familiar with RT−PCR design would have easily observed the grave errors present in the Corman−Drosten paper before the actual review process. We asked Eurosurveillance on October 26th 2020 to send us a copy of the peer review report. To date, we have not received this report and in a letter dated November 18th 2020, the ECDC as host for Eurosurveillance declined to provide access without providing substantial scientific reasons for their decision. On the contrary, they write that “disclosure would undermine the purpose of scientific investigations.” [24]. 9. Authors as the editors A final point is one of major concern. It turns out that two authors of the Corman−Drosten paper, Christian Drosten and Chantal Reusken, are also members of the editorial board of this journal [19]. Hence there is a severe conflict of interest which strengthens suspicions that the paper was not peer−reviewed. It has the appearance that the rapid publication was possible simply because the authors were also part of the editorial board at Eurosurveillance. This practice is categorized as compromising scientific integrity.
SUMMARY CATALOGUE OF ERRORS FOUND IN THE PAPER
EXPAND
The Corman−Drosten paper contains the following specific errors:
There exists no specified reason to use these extremely high concentrations of primers in this protocol. The described concentrations lead to increased nonspecific bindings and PCR product amplifications, making the test unsuitable as a specific diagnostic tool to identify the SARS−CoV−2.
Six unspecified wobbly positions will introduce an enormous variability in the real world laboratory implementations of this test; the confusing nonspecific description in the Corman−Drosten paper is not suitable as a Standard Operational Protocol making the test unsuitable as a specific diagnostic tool to identify the SARS−CoV−2.
The test cannot discriminate between the whole virus and viral fragments. Therefore, the test cannot be used as a diagnostic for intact (infectious) viruses, making the test unsuitable as a specific diagnostic tool to identify the SARS−CoV−2 virus and make inferences about the presence of an infectious agent.
A difference of 10˚ C with respect to the annealing temperature Tm for primer pair1 (RdRp_SARSr_F and RdRp_SARSr_R) also makes the test unsuitable as a specific diagnostic tool to identify the SARS−CoV−2.
A severe error is the omission of a Ct value at which a sample is considered positive and negative. This Ct value is also not found in follow−up submissions making the test unsuitable as a specific diagnostic tool to identify the SARS−CoV−2.
The PCR products have not been validated at the molecular level. This fact makes the protocol useless as a specific diagnostic tool to identify the SARS−CoV−2.
The PCR test contains neither a unique positive control to evaluate its specificity for SARS−CoV−2 nor a negative control to exclude the presence of other coronaviruses, making the test unsuitable as a specific diagnostic tool to identify the SARS−CoV−2.
The test design in the Corman−Drosten paper is so vague and flawed that one can go in dozens of different directions; nothing is standardized and there is no SOP. This highly questions the scientific validity of the test and makes it unsuitable as a specific diagnostic tool to identify the SARS−CoV−2.
Most likely, the Corman−Drosten paper was not peer−reviewed making the test unsuitable as a specific diagnostic tool to identify the SARS−CoV−2.
We find severe conflicts of interest for at least four authors, in addition to the fact that two of the authors of the Corman−Drosten paper (Christian Drosten and Chantal Reusken) are members of the editorial board of Eurosurveillance. A conflict of interest was added on July 29 2020 (Olfert Landt is CEO of TIB−Molbiol; Marco Kaiser is senior researcher at GenExpress and serves as scientific advisor for TIB−Molbiol), that was not declared in the original version (and still is missing in the PubMed version); TIB−Molbiol is the company which was “the first” to produce PCR kits (Light Mix) based on the protocol published in the Corman−Drosten manuscript, and according to their own words, they distributed these PCR−test kits before the publication was even submitted [20]; further, Victor Corman & Christian Drosten failed to mention their second affiliation: the commercial test laboratory “Labor Berlin”. Both are responsible for the virus diagnostics there [21] and the company operates in the realm of real time PCR−testing.
In light of our re-examination of the test protocol to identify SARS-CoV-2 described in the Corman-Drosten paper we have identified concerning errors and inherent fallacies which render the SARS-CoV-2 PCR test useless. CONCLUSION The decision as to which test protocols are published and made widely available lies squarely in the hands of Eurosurveillance. A decision to recognize the errors apparent in the Corman−Drosten paper has the benefit to greatly minimize human cost and suffering going forward. Is it not in the best interest of Eurosurveillance to retract this paper? Our conclusion is clear. In the face of all the tremendous PCR−protocol design flaws and errors described here, we conclude: There is not much of a choice left in the framework of scientific integrity and responsibility.
More to come from Dr. Yeadon... check back again soon.
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