One of the challenges we face is that all 3 EUR authorized vaccines in the U.S. churn out the spike protein. All of them will induce spike protein mediated immune responses and there is no way to specifically single out the spike protein versus any other antigen that these vaccines introduce.
So the PRR of these EUA authorized vaccines MUST be compared with other vaccines in the VAERS database to evaluate AEs that may be associated with the spike protein.
As we know, the spike glycoprotein binds the virus with the widespread receptor angiotensin-converting enzyme 2 and allows cell entry. The spike glycoprotein (along with the envelope protein, matrix protein, and nucleocapsid protein) is one of 4 structural proteins encoded by COVID-19.
Why aren't any of these other very important structural proteins manufactured in new vaccines?
Here is one bullshit (and now debunked) explanation: mRNA vaccines "prevent a disease-causing pathogen like COVID-19 from establishing an infection. Sterilizing immunity differs from effective immunity in that the latter can prevent illness but still lead to asymptomatic infection."
J&J uses an attenuated adenovirus (a double stranded DNA virus that must enter the nucleus for transcription) vector via clathrin-mediated endocytosis. Before this vaccine was developed, no adenoviral vector vaccines had demonstrated they can prevent disease in humans. One new worry is a J&J booster could unleash an antibody attack on the vaccine itself. No wonder experts are going to continue to promote its efficacy.
"Besides the mechanism of molecular mimicry, mRNA vaccines may give rise to a cascade of immunological events eventually leading to the aberrant activation of the innate and acquired immune system."
All vaccines have antigencity and side effects. Vaccine-associated autoimmunity is a well-known phenomenon attributed to either the cross-reactivity between antigens or the effect of adjuvant.
Recent scientific claims state that protective antibodies generated in response to an mRNA vaccine will be more targeted agains variants. "The neutralizing activity of vaccine-elicited antibodies was more targeted to the receptor-binding domain (RBD) of the SARS-CoV-2 spike protein compared to antibodies elicited by natural infection."
While this may be true, waning antibody levels to both infection and vaccine means we can expect yearly vaccines, while the more vulnerable (i.e. those people who might be prone to adverse effects) are expected to get boosters every 6 months.
Scientists have tried to assure us that corona viruses mutate more slowly than most other RNA viruses, probably because of a ‘proofreading’ enzyme that corrects potentially fatal copying mistakes. https://www.nature.com/articles/d41586-020-02544-6
Is the delta variant displaying genetic drift or shift?
"Delta does share mutations with other successful variants. Like all the identified variants in circulation, delta contains a spike mutation called D614G, sometimes known as “Doug,” which became ubiquitous last year.
Scientists think Doug increases the density of spike protein on the surface of viral particles and makes it easier for the virus to enter cells.
Delta also has a spike mutation called P681R, which closely resembles a mutation in the alpha variant that appears to produce higher viral loads in patients, Cooper said. People infected with delta have 1,000 times more virus in their respiratory tract, making them more likely to spread the virus when they sneeze, cough or talk.
The P681R mutation, also found in the kappa variant, is located at the beginning of a part of the genome called the furin cleavage site, Cooper said.
Furin is a naturally occurring human enzyme that gets hijacked by the coronavirus, which uses it to slice the spike protein into the optimal shape for entering the cell, Rasmussen said. The new mutation makes that sculpting more efficient, Rasmussen said.
Another delta mutation — also found in kappa and epsilon — is called L452R. Experiments suggest this mutation, which also affects the receptor-binding domain, acts to prevent antibodies from neutralizing the virus, Cooper said.
These mutations appear to be more formidable as a team than alone."
The problem I see is that vaccines in general, and not just these spike protein based vaccines, indiscriminately activate the immune system; that is what they are designed to do - either with PEG coated liposomes, or other adjuvants like aluminum based ones. Thus, the side effect profile will always be broad.
An example is the list of ADRs suffered by Japanese kids/teenagers after taking the HPV vaccine:
"The ADRs include complex, multi-system symptoms, such as seizures; disturbance of consciousness; systemic pain, including headache, myalgia, arthralgia, back pain and other pain; motor dysfunction, such as paralysis, muscular weakness, exhaustion and involuntary movements; numbness and sensory disturbances; autonomic symptoms, including dizziness, hypotension, tachycardia, nausea, vomiting and diarrhoea; respiratory dysfunction, including dyspnoea and asthma; endocrine disorders, such as menstrual disorder and hypermenorrhoea; hypersensitivity to light and sound; psychological symptoms, such as anxiety, frustration, hallucinations and overeating; higher brain dysfunction and cognitive impairments, including memory impairment, disorientation and loss of concentration; and sleep disorders, including hypersomnia and sudden sleep attacks. In some cases, these symptoms impair learning and result in extreme fatigue and decreased motivation, having a negative impact on everyday life (8, 9, 10, 11)."
Thus, using PRRs will show a dampened signal, whether one type of COVID-19 vaccine is compared to other COVID-19 vaccines, or to all other vaccines.
On the other hand, PRRs maybe useful - in conjunction with other methods-like epidemiological studies, etc (I'd like to really emphasize that!) - in determining any specific ADRs that stand out for one particular COVID-19 vaccine only - if any (myocarditis? thrombotic events?)
I didn't look at many of the comments on the first "Defining Away Vaccine Safety Signals" article, but I noticed the comment by Josh G (does Substack have a way of linking a specific comment?) suggesting that there is particular logic to why we might actually WANT the PRR to be scale-invariant (stimulated reporting).
I was expecting (and hoping) you'd provide a response to that comment in Part 2. Having a PRR that is insensitive to *the percentage of all AEs (reported and unreported) which are actually reported* IS highly desirable. The problem, it seems to me, is that that making it insensitive to stimulated reporting (by making it scale-invariant) weakens PRR as a signal. Another more practical response might be that there's no good reason to expect a higher percentage of Pfizer AEs to be reported than Moderna, for example.
I'd be surprised if you disagree that having a safety signal be insensitive to the percentage of AEs that get reported to VAERS is a good thing. If you do disagree, I'd like to know why. If you agree, then it seems like it might be useful for you to provide a clear explanation of the trade-off that's being made to achieve that insensitivity, and why, on balance, it might be a bad trade-off to make.
Should probably read "primum non nocere;" however, the more I think about it, a portmanteau of primum non nocere and prima noctum (primae noctis) seems pretty on message for the topic.
Thank you for showing how PRRs are calculated.
One of the challenges we face is that all 3 EUR authorized vaccines in the U.S. churn out the spike protein. All of them will induce spike protein mediated immune responses and there is no way to specifically single out the spike protein versus any other antigen that these vaccines introduce.
So the PRR of these EUA authorized vaccines MUST be compared with other vaccines in the VAERS database to evaluate AEs that may be associated with the spike protein.
As we know, the spike glycoprotein binds the virus with the widespread receptor angiotensin-converting enzyme 2 and allows cell entry. The spike glycoprotein (along with the envelope protein, matrix protein, and nucleocapsid protein) is one of 4 structural proteins encoded by COVID-19.
https://onlinelibrary.wiley.com/doi/10.1002/mds3.10140
Why aren't any of these other very important structural proteins manufactured in new vaccines?
Here is one bullshit (and now debunked) explanation: mRNA vaccines "prevent a disease-causing pathogen like COVID-19 from establishing an infection. Sterilizing immunity differs from effective immunity in that the latter can prevent illness but still lead to asymptomatic infection."
https://www.verywellhealth.com/covid-19-vaccines-and-sterilizing-immunity-5092148
You know, those asymptomatic (and mild) vaccine breakthrough cases the CDC doesn't care about. So, not so sterilizing mRNA vaccines.
The two mRNA vaccines (Pfizer and Moderna) enter human cells encapsulated in lipid nanoparticles.
https://www.cas.org/resource/blog/understanding-nanotechnology-covid-19-vaccines
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8032477/
J&J uses an attenuated adenovirus (a double stranded DNA virus that must enter the nucleus for transcription) vector via clathrin-mediated endocytosis. Before this vaccine was developed, no adenoviral vector vaccines had demonstrated they can prevent disease in humans. One new worry is a J&J booster could unleash an antibody attack on the vaccine itself. No wonder experts are going to continue to promote its efficacy.
https://www.ebsco.com/blogs/health-notes/adenovirus-vectored-vaccines-covid-19-how-do-they-work
https://cen.acs.org/pharmaceuticals/vaccines/Adenoviral-vectors-new-COVID-19/98/i19
https://abcnews.go.com/Health/experts-differ-johnson-johnson-covid-19-booster-shot/story?id=78632475
Concerns about how mRNA vaccines may cause dysregulation of the immune response have been raised for a while. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7833091/
"Besides the mechanism of molecular mimicry, mRNA vaccines may give rise to a cascade of immunological events eventually leading to the aberrant activation of the innate and acquired immune system."
All vaccines have antigencity and side effects. Vaccine-associated autoimmunity is a well-known phenomenon attributed to either the cross-reactivity between antigens or the effect of adjuvant.
Examples: Guillain-Barre, Immune Thrombocytopenic Purpura, myopericarditis
https://citeseerx.ist.psu.edu/viewdoc/download?doi=10.1.1.905.8384&rep=rep1&type=pdf
Recent scientific claims state that protective antibodies generated in response to an mRNA vaccine will be more targeted agains variants. "The neutralizing activity of vaccine-elicited antibodies was more targeted to the receptor-binding domain (RBD) of the SARS-CoV-2 spike protein compared to antibodies elicited by natural infection."
https://directorsblog.nih.gov/2021/06/22/how-immunity-generated-from-covid-19-vaccines-differs-from-an-infection/
While this may be true, waning antibody levels to both infection and vaccine means we can expect yearly vaccines, while the more vulnerable (i.e. those people who might be prone to adverse effects) are expected to get boosters every 6 months.
Scientists have tried to assure us that corona viruses mutate more slowly than most other RNA viruses, probably because of a ‘proofreading’ enzyme that corrects potentially fatal copying mistakes. https://www.nature.com/articles/d41586-020-02544-6
Is the delta variant displaying genetic drift or shift?
https://www.poynter.org/fact-checking/2021/how-some-mysterious-mutations-make-delta-the-most-transmissible-covid-virus-yet/
"Delta does share mutations with other successful variants. Like all the identified variants in circulation, delta contains a spike mutation called D614G, sometimes known as “Doug,” which became ubiquitous last year.
Scientists think Doug increases the density of spike protein on the surface of viral particles and makes it easier for the virus to enter cells.
Delta also has a spike mutation called P681R, which closely resembles a mutation in the alpha variant that appears to produce higher viral loads in patients, Cooper said. People infected with delta have 1,000 times more virus in their respiratory tract, making them more likely to spread the virus when they sneeze, cough or talk.
The P681R mutation, also found in the kappa variant, is located at the beginning of a part of the genome called the furin cleavage site, Cooper said.
Furin is a naturally occurring human enzyme that gets hijacked by the coronavirus, which uses it to slice the spike protein into the optimal shape for entering the cell, Rasmussen said. The new mutation makes that sculpting more efficient, Rasmussen said.
Another delta mutation — also found in kappa and epsilon — is called L452R. Experiments suggest this mutation, which also affects the receptor-binding domain, acts to prevent antibodies from neutralizing the virus, Cooper said.
These mutations appear to be more formidable as a team than alone."
I wish I was a fraction as good as you at slinging insults! You are a God! And again, Thank YOU for bring truth to light!
Those who have integrity need to start banding together in a coalition of new and actually truth-oriented institutions.
Thank you for the further clarification!
The problem I see is that vaccines in general, and not just these spike protein based vaccines, indiscriminately activate the immune system; that is what they are designed to do - either with PEG coated liposomes, or other adjuvants like aluminum based ones. Thus, the side effect profile will always be broad.
An example is the list of ADRs suffered by Japanese kids/teenagers after taking the HPV vaccine:
"The ADRs include complex, multi-system symptoms, such as seizures; disturbance of consciousness; systemic pain, including headache, myalgia, arthralgia, back pain and other pain; motor dysfunction, such as paralysis, muscular weakness, exhaustion and involuntary movements; numbness and sensory disturbances; autonomic symptoms, including dizziness, hypotension, tachycardia, nausea, vomiting and diarrhoea; respiratory dysfunction, including dyspnoea and asthma; endocrine disorders, such as menstrual disorder and hypermenorrhoea; hypersensitivity to light and sound; psychological symptoms, such as anxiety, frustration, hallucinations and overeating; higher brain dysfunction and cognitive impairments, including memory impairment, disorientation and loss of concentration; and sleep disorders, including hypersomnia and sudden sleep attacks. In some cases, these symptoms impair learning and result in extreme fatigue and decreased motivation, having a negative impact on everyday life (8, 9, 10, 11)."
Source: https://ijme.in/articles/lessons-learnt-in-japan-from-adverse-reactions-to-the-hpv-vaccine-a-medical-ethics-perspective/?galley=html
Thus, using PRRs will show a dampened signal, whether one type of COVID-19 vaccine is compared to other COVID-19 vaccines, or to all other vaccines.
On the other hand, PRRs maybe useful - in conjunction with other methods-like epidemiological studies, etc (I'd like to really emphasize that!) - in determining any specific ADRs that stand out for one particular COVID-19 vaccine only - if any (myocarditis? thrombotic events?)
I didn't look at many of the comments on the first "Defining Away Vaccine Safety Signals" article, but I noticed the comment by Josh G (does Substack have a way of linking a specific comment?) suggesting that there is particular logic to why we might actually WANT the PRR to be scale-invariant (stimulated reporting).
I was expecting (and hoping) you'd provide a response to that comment in Part 2. Having a PRR that is insensitive to *the percentage of all AEs (reported and unreported) which are actually reported* IS highly desirable. The problem, it seems to me, is that that making it insensitive to stimulated reporting (by making it scale-invariant) weakens PRR as a signal. Another more practical response might be that there's no good reason to expect a higher percentage of Pfizer AEs to be reported than Moderna, for example.
I'd be surprised if you disagree that having a safety signal be insensitive to the percentage of AEs that get reported to VAERS is a good thing. If you do disagree, I'd like to know why. If you agree, then it seems like it might be useful for you to provide a clear explanation of the trade-off that's being made to achieve that insensitivity, and why, on balance, it might be a bad trade-off to make.
> primum non noctum
Should probably read "primum non nocere;" however, the more I think about it, a portmanteau of primum non nocere and prima noctum (primae noctis) seems pretty on message for the topic.
are your classes still available? especially for conditional analysis and Bayes?
just add a third clause: ... *or* <number of AEs > >= 500. :)