Posted on 05/10/2021 9:39:58 PM PDT by Cathi
Re: Will covid-19 vaccines save lives? Current trials aren’t designed to tell us
Dear Editor: Peter Doshi’s nuanced article has opened up a rigorous and valuable discussion about the ongoing COVID-19 mRNA vaccine clinical trials, and I would like to home in on what is perhaps the most salient source of concern about their efficacy and safety, and a key step in building public confidence: the need for extensive data on the vaccines' cellular tropism and MHC Class I vs. MHC Class II-mediated antigen presentation, with attendant questions about potential seeding of autoimmunity.
The mRNA vaccines’ nucleic acid payload is ferried into human cells via complex lipid nanoparticles (LNPs) with a lipophilic formulation capable of traversing phospholipid bilayers, through endocytosis and other mechanisms [1]. While some LNP vehicles have been engineered with specific tropisms for target tissues, others have less selective tropisms (or are even potentially omnitropic), capable of entering diverse cell types [2]. From studies thus far, it remains unclear under which category the LNPs used in the COVID vaccine trials appear to fall, and this point is essential for gauging long-term safety and efficacy. If these LNPs have a broad cell tropism, then they would be capable of entering and expressing the SARS-CoV-2 viral spike protein within the parenchyma of vital organs and tissues, well beyond the tropism of wild-type coronavirus. The resulting non-self protein, presented to immune surveillance via MHC-I complexes, would trigger a cytotoxic (CD8-mediated) immune response to the expressing cells, which could with time engender clinically significant tissue damage.
To elaborate briefly on this concern, and the data which could alleviate it, we can roughly subdivide the standard pediatric and adult vaccine repertoires into two broad categories, on the basis of the cells that present the vaccine-mediated antigen to T-lymphocytes. Inactivated virus vaccines (such as Hepatitis A and IPV) and protein subunit vaccines (Hib, Hepatitis B, pertussis) involve primarily MHC-II-based presentation (“Type 1 vaccines” for this discussion). Their antigenic material is taken up principally via phagocytosis by antigen-presenting cells (APCs), particularly dendritic cells in visceral and peripheral tissues, which migrate to lymph nodes and present immunostimulatory epitopes in complex with MHC-II cell-surface molecules to CD4-expressing T-cells (T helper cells), which in turn help to initiate and coordinate the adaptive immune response to pathogens exhibiting the antigen. A cytotoxic response is not induced against the APCs utilizing the MHC-II pathway. Attenuated virus vaccines such as MMR (“Type 2”) enlist not only MHC-II-expressing APCs, but also the MHC-I antigen-presenting pathway present in almost all cell types which, through a standard cascade of events, triggers a cytotoxic response (mediated by CD8-expressing lymphocytes) against presenting cells and tissues, due to the presence of non-self epitopes. Thus attenuated virus (Type 2) vaccines like MMR do entail some cytotoxicity against infected cells, but still confined to the original tropism of the target virus, with an enhanced immunostimulatory effect.
LNP-containing mRNA vaccines represent a novel Type 3 in this classification: enlisting both MHC-II-mediated (through dendritic cells and other APCs) and cytotoxic MHC-I-mediated immunostimulation, but against a far broader array of MHC-I-presenting cells and tissues than the wild-type virus, particularly for LNPs with unselective tissue tropisms. There is potential for enhanced immunostimulatory impact through this process, but also elevated risk of cytotoxic, inflammatory, and autoimmune effects, even more so if the liposomal particles can traverse the blood-brain barrier to enter, for example, motor neurons or oligodendrocytes (the glial cells targeted in multiple sclerosis). These effects, in turn, depend critically on the organ and tissue profile of the cells that receive the LNPs, translate the mRNA payload, and dock the antigenic protein on MHC-I cell-surface molecules. This is doubly true in the case of COVID-19 in light of the still-evolving picture of SARS-CoV-2 immunology. Immune responses appear to be incremental and fleeting, both for natural and vaccine-mediated immunity, suggesting a likely need for multiple boosters after an initial inoculation. Therefore, if cytotoxic responses to integral tissues are transpiring through MHC-I-mediated presentation of SARS-CoV-2 spike protein, the effects may be at first subclinical, manifesting fully only after successive immunizations over months or years.
At present, relatively little has been reported on the tissue localization of the LNPs used to encase the SARS-CoV-2 spike protein-encoding messenger RNA, and it is vital to have more specific information on precisely where the liposomal nanoparticles are going after injection, both in concurrent animal studies and in the two ongoing mRNA vaccine human trials. This process can be commenced in straightforward fashion through cell culture and animal-based investigations, by supplying mRNA expressing a fluorophoric reporter gene (such as green fluorescent protein) delivered via the same LNP formulations as used in the two vaccine trials, and tracking its ingress into varied cells and tissues. The mRNA vaccines represent a remarkable and promising technology, with potential to expedite the development of immunization protocols for future epidemics, but this promise will evaporate if unanticipated safety issues and side effects emerge to weaken public trust in the new modality. Cellular and tissue localization data on the vaccines’ tissue tropisms, obtained and confirmed across multiple independent laboratories, would constitute a valuable step to reinforce public confidence in this regard.
References [1] doi: 10.1016/j.addr.2016.04.014. Mechanisms of transport of polymeric and lipidic nanoparticles across the intestinal barrier. Ana Beloqui, Anne des Rieux, Véronique Préat. Adv Drug Deliv Rev. 2016 Nov 15;106(Pt B):242-255. [2] doi: 10.1016/B978-0-12-391860-4.00012-4. Lipid nanoparticles for drug targeting to the brain. Maria Luisa Bondì , Roberto Di Gesù, and Emanuela Fabiola Craparo. Methods Enzymol. 2012;508:229-51.
Competing interests: No competing interests
21 December 2020 JW Ulm Physician-scientist (MD/PhD) Los Angeles, CA, USA
Thanks for posting this.
You looked up some of the links in the discussion below Derek Lowe’s blog article, didn’t you? /tease>
I recognized this author’s name.
Thanks!
Well, well, well…an article from December 2020 just when the big nation-wide “trials” of the authorized vaccines began. They sure as hell seem to be saving lives in Israel. They sure as hell seem to be saving lives in the US.
December 2020 articles posted in May 2021? That must mean the anti-vaxxers are reaching PEAK DESPERATION.
Ehh, that’s because you Branch Covidians still haven’t addressed the issues brought up back then, so we’re reminding people.
BTW I saw someone leaning towards pro-jab, posting from an article from 2003; the Figure he posted didn’t present anything like he thought it did, but two completely different variables.
Get that? A gene which produces a protein which cause problems.
And with the gene there is no way to get it out of the body.
Hey gas_dr, a fellow MD talking about long-neglected testing on the vaccines to see how much the spread through the body, including passing the blood-brain barrier. I think you missed the fun about an earlier discussion on that one.
Will COVID-19 vaccines save lives? Ask the Israelis. Read the ACTUAL news from Israel.
Yes....because.....that was....so...long ago. 🙄
Lets see.....when did the fake vaccines first roll out? Why, that would be Dec 2020!
That must mean the anti-vaxxers vax-holes are reaching PEAK DESPERATION.....to criticize the date of this important information, regarding the dangers of these gene therapy shots.
Fixed it.
You obviously posted without reading the article and are mindlessly spewing canned talking points again.
I’m a big fan of this scientist/physician. J. Wes Ulm, MD, PhD, is a physician-researcher, musician, and novelist originally hailing from Alexandria, Virginia, winning a National Merit Scholarship and graduating valedictorian of his class at T. C. Williams High School before earning a B.S. degree, summa cum laude, in chemistry and biochemistry at Duke University. At 22, on the cusp of starting medical school, he achieved five consecutive nights on the Jeopardy! TV quiz program and made the show’s Tournament of Champions.
He went on to earn a dual MD/PhD degree from Harvard Medical School and MIT, supported by an NIH Medical Scientist Training Program (MSTP) fellowship, publishing diversely in genetics, molecular biology, and pharmacology with a thesis focusing on the tissue targeting of retroviral gene therapy vectors.
He has since published news articles and a novel (Echoes of the Mystic Chords), started a popular alt-rock and 90s revival band (J. Wes Ulm and Kant’s Konundrum) with an award-winning music video (“A Hustler’s Tale”) and, most importantly for this interview, branched out into bioinformatics and therapeutic drug development, publishing recently on a rapidly flexible drug-repurposing system for the COVID 19 pandemic:
https://onlinelibrary.wiley.com/doi/epdf/10.1111/tbed.13710
Dr. Wes, as he’s known to fans and followers of his band and other creative pursuits, is here as part of the Heroes of the COVID Crisis series in relation to his ongoing efforts in the drug discovery and public health arena.
Noice!
Must be one of those rabid anti-vaxxers gas_dr keeps going on about.
January, 2021
“Even very recent related literature on trafficking other LNPs can’t answer this question for us, since again the different lipid recipes vary so much in their chemistries and in vivo localization that we won’t know which tissues the vaccines themselves are entering. We need to have precise information regarding where exactly *the vaccine manufacturers’ specific LNPs* are going, and where the SARS-CoV-2 S protein is expressed, since a non-selective tissue localization–especially if traversing the BBB–could lead to marked cytotoxic attack on MHC-I-spike protein complexes, and thus significant cumulative tissue damage, in a range of targets potentially well beyond the localization of the wild-type virus.
If anything, the wide population cohort of intended vaccine recipients, coupled with the compressed timeframe and lack of long-term efficacy and safety data, makes it all the more important to acquire such data instead of leaving such questions to chance. Even more so given the rate of adverse events and even deaths that are cropping up lately in the VAERS database logs.”
Peak Desperation!
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No, here are more facts.
“ The Lancet
May 05, 2021
Israel and the Covid19 Vaccine
4,777,977 total participants
3,816,911 “fully vaccinated”
961,066 unvaccinated
99.996% of the fully vaccinated DID NOT DIE
99.26% of unvaccinated DID NOT DIE
That is a 0.0073 reduction is deaths between the groups!.”
You do the math.....the facts bear out what has been known by us “ anti- vaccer’s”, the Covid flu currently has a 99.8 percent plus survival rate. No desperation, just common sense. “ We” simply do not buy into the fear campaign- if you do, go get your jab, then another and another....
| House Atreides wrote: |
Well, well, well…an article from December 2020 just when the big nation-wide “trials” of the authorized vaccines began. They sure as hell seem to be saving lives in Israel. They sure as hell seem to be saving lives in the US. December 2020 articles posted in May 2021? That must mean the anti-vaxxers are reaching PEAK DESPERATION. |
ransomnote: Prayers up for Israel. May God bless and protect the physicians and citizens working to get past the 'gatekeepers' and publish the truth about the vaccines.
It is understandable that many people equate Israel’s much improved case numbers strictly to the vaccine. But, that is highly unlikely to be accurate.
During the covid wave when vaccination began in full force Israel was totally locked down. They wouldn’t even let Israeli’s come back home.
And once the vax program began Israel experienced a huge jump in “all cause mortality” (4 times the rate of 2020.) Once vaccinating petered out when almost all willing Israeli’s had been vaccinated Israel’s “all cause mortality” dropped back down to normal rates comparable with the rest of Europe. Some people suggest Israel may have had high “after vax death” incidents like we did.
It is interesting to look at a UK covid graph. In the spring of 2020 daily new cases went up to over 5,000 a day. As the covid wave subsided (The UK was also totally locked down during this period) new cases went down to 500 per day.
There were no vaccines available at that time.
People seem to be giving full credit to vaxes when lockdown clearly was responsible for much of the improvement in both countries.
You know what some people say...”correlation is not causation”...:-)
“99.996% of the fully vaccinated DID NOT DIE
99.26% of unvaccinated DID NOT DIE
That is a 0.0073 reduction is deaths between the groups!.”
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I have no idea where you came up with your relative percentages and certainly do not if they have the slightest validity. But, addressing only your arithmetic…99.996% minus 99.26% leaves a difference of .736%. That’s a little less than a 1% reduction in deaths over a several months period.
If I was addressing a group of 1,000 people and told them “if we don’t do anything to prevent it, a random 7 or 8 of you will be dead over the next few months. But if we all take these vaccinations, those random 7 or 8 people won’t be dead. Let’s take a vote on whether to take the vaccine.”
What do you think will be the vote in that group of a thousand people?
No way Jose!
What do you think will be the vote in that group of a thousand people?
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Nice hypothetical situation. Guided totally by FEAR. Now the REALITY: using your scenario, they are told the facts: this virus is not a deadly killer, it has a 99.8 percent survival rate-do you think they would rush out to get an experimental MRNA jab knowing their have now been over 11,000 deaths ( and counting) recorded by the US and EU from the deadly jabs?
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