Clinical Translation Of Ivt Mrna
To enable the full potential of mRNA as a therapeutic modality to be realized, regulatory and scientific issues concerning clinical and product development require diligent consideration.
So far, clinical experience of IVT mRNA drugs is limited to immunotherapeutic applications. Of the clinical programmes in the field of vaccine development with IVT mRNA alone or IVT mRNA-transfected DCs, few are advanced enough to provide a sufficiently broad knowledge base for other applications. For each application, the well-established systematic exploration of the variables of treatment protocols, such as dosing, treatment schedule and route of administration, have to be delineated to identify the appropriate regimen.
Common objectives of early clinical trials are to explore pharmacokinetic characteristics of the drug and to conduct dose finding. However, the pharmacology of mRNA drugs is complex because the IVT mRNA is not the final pharmacologically active agent. So far, it has not been fully investigated whether the bioavailability of the protein it encodes can be robustly and precisely controlled under clinical conditions, which are particularly challenging because of high inter- and intra-individual variability. Accompanying medication also requires consideration, particularly when IVT mRNA therapies are combined with other drugs that affect mRNA metabolism and translation, such as certain antibiotics and anticancer drugs.
Left Out Of The Nobel Buzz
Malone is known in his field, and his work is often cited by the many, many others who’ve followed him to work further on mRNA vaccines and therapeutics. However, Malone is but one of a great many scientists who’ve made today’s mRNA vaccines possible.
What he did, in a nutshell, was show that messenger RNA a notoriously unstable and hard-to-work-with single-stranded molecule could be injected into mammals by using a lipid nanoparticle as its package. He worked on that ground-laying research in the late ’80s with scientists such as Philip Felgner, who is considered a contender for the Nobel Prize and who won Spain’s equivalent last year .
“There are many, many contributors to the field, and it’s really hard to distinguish and determine who brought more,” Ingmar Hoerr, the founder of the German biotechnology company CureVac, told Insider.
Pierre Meulien, a molecular biologist who runs the European Union’s Innovative Medicines Initiative, said that in 1993 he and his team were the first “to demonstrate that you could induce an immune response with mRNA.” But, like Malone’s experiments before, that research was in mice only.
“I don’t think there is one inventor of mRNA vaccines,” Meulien said. “It’s how science works. I mean, you add up the number of people who’ve published in this area over the last 30 years it is hundreds and hundreds of people.”
Missed Opportunities And Legal Exhaustion
Kay wasnt the only scientist who noticed MacLachlan and his teams work at the time.
In 2006, MacLachlans work caught the eye of a talented biochemist Katalin Karikó, a Hungarian scientist who is now a frontrunner for a Nobel Prize for her revolutionary work with mRNA.
Kariko has worked with BioNTech since 2013, but long before that, she proposed to MacLachlan that they partner to use her messenger RNA with his delivery system.
In an email to CTV News, Kariko explained that she asked him constantly in 2006 to consider using his LNP with mRNA.
I that he was formulating the siRNA, and I wanted him to try the mRNA as well, she said. Why did I want to formulate the mRNA with LNP? The mRNA product needed shelf-life. We need formulated mRNA that can be stored in the freezer for extended time.
However, MacLachlan was embroiled in legal conflicts over the technology, and so he declined Karikos idea.
We were a small company at the time, and very much focused on the siRNA drugs, as opposed to the mRNA drugs, he added.
The legal battles played a role, and after around a decade of legal wrangling over the ownership of , MacLachlan was drained.
He said as the company expanded and there were partners who werent necessarily very well behaved, leading to legal disputes with them over the ownership of the delivery system.
That was a very unfortunate distraction, and something that I didn’t want to spend the rest of my life having to deal with, MacLachlan said.
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Box : Patents And The Intellectual Property Landscape
The number of patent applications in the core field of mRNA-based therapeutics technology has been growing considerably in the past 10 years. The main mRNA-relevant intellectual property categories are composition of matter patents and applications related to the mRNA itself, applications covering formulations for mRNA delivery and patents claiming mRNA for certain applications. In contrast to the small interfering RNA field in which therapeutic use of the drug format itself is covered by fundamental patents, there are no basic patents limiting the broad industrial application of in vitro transcribed mRNA for therapy. The current patent landscape is characterized by low fragmentation. The highest currently visible patenting activity stems from the small group of biotechnology companies specialized in mRNA-based therapeutics. These patent portfolios document the anticipated systematic and strategic approach to develop each of these company’s own intellectual property estate as a basis for each company’s business model. An increasing number of patent applications are from academic groups featuring findings in preclinical studies and from industry for the use of IVT mRNA to replace defined disease targets.
As the field is young, many patent applications have not yet been granted.
Improving The Translation And Stability Of Mrna
The amount of IVT mRNA required for a therapeutic effect and the treatment duration depends on many factors. These include the intended biological function of the encoded protein and its mode of action, as well as the potency and the circulation half-life of the protein, which will vary by several orders of magnitude for different applications. Nanogram to microgram amounts of highly antigenic proteins may be sufficient for the efficient induction of immune responses in humans. By contrast, milligram or even gram amounts of proteins may be required for the delivery of systemically active growth factors, hormones or monoclonal antibodies. Through iterative optimization of the translational potency and intracellular stability of IVT mRNA, the protein amounts that can be generated per unit of mRNA have considerably increased.
Figure 3: Tuning mRNA drug dose pharmacokinetics.
a | Key structural elements of in vitro transcribed mRNA and strategies for their modifications. b | Depending on which elements or poly tails) are used alone or in combination, the duration and kinetic profile of expression of the protein product can be modulated and fine-tuned. eIF4E, eukaryotic translation initiation factor 4E IRES, internal ribosome entry site ORF, open reading frame.
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Dr Robert Malone Invented Mrna Vaccines
It is Dr. Katalin Karikó and her collaborator Dr. Drew Weissman who are more commonly credited with laying the groundwork for mRNA vaccines.
According to the Centers for Disease Control and Prevention, “mRNA vaccines teach our cells how to make a proteinor even just a piece of a proteinthat triggers an immune response inside our bodies.” mRNA vaccines are a new sort of vaccine the COVID-19 vaccines from Pfizer/BioNTech and Moderna were the first.
On his personal website, Twitter, and LinkedIn, Dr. Robert Malone has been promoting himself as the inventor of mRNA vaccines. This is misleading. In 1989, Malone published a paper titled “Cationic liposome-mediated RNA transfection.” While this paper is an example of his important contribution to the then-emerging field, it does not make him the inventor of mRNA vaccines.
According to Stat News, “for decades, scientists have dreamed about the seemingly endless possibilities of custom-made messenger RNA or mRNA.” According to the New York Times, “For her entire career, Dr. Kariko has focused on messenger RNA, or mRNA the genetic script that carries DNA instructions to each cells protein-making machinery. She was convinced mRNA could be used to instruct cells to make their own medicines, including vaccines.”
While Malone’s research may have been important, scientific breakthroughs don’t always boast a sole “inventor.” Instead, they come about through the work of many.
Reference links
What Does The Coronavirus Look Like
Like the other members of its viral family, SARS-CoV-2 the official name for the coronavirus is an RNA virus. Simply put, each individual virus is composed of single strands of genetic material protected by a fatty outer layer thats coated in spike proteins. Those spikes are what the virus uses to hijack our cells and use our molecular machinery to make more copies of itself.
The proteins allow the dendritic cells to alert two more key players in the immune system T cells and B cells that if they see those same spikes on any other cell, they should recognize them as a foreign invaders and either destroy them or generate antibodies to neutralize them immediately.
Theres a memory component of those cell populations, and that stays in your body over a long period of time, Sharp said. If a similar virus infects you, those memory cells are ready to go. They are all perfected to go out and kill that virus.
mRNA naturally degrades rapidly over time, so once it has served its purpose, it simply breaks down. The dendritic cells that expressed the spike protein eventually die and are replaced by new ones that continue to pick up that vaccine-delivered mRNA and repeat the process all over again in the course of about two weeks following immunization.
Its always, always much more risky to get the disease than it is to get the vaccine, Duprex said.
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There Are Reasons People Are Listening To Malone He’s An Expert Source And He’s Asking Interesting Questions About The Vaccines
Malone isn’t the raving propagandist that some might like to dismiss him as one who’s wrong about everything that comes out of his mouth. As easy as it can feel for a vaccinated person to say he’s full of it and lying about everything related to mRNA technology, the real story is far from that simple.
The mRNA vaccines we have are working to keep people from dying and staving off severe disease in many, many hundreds of millions of people around the world, but they’re not perfect. They don’t stop all infections, and it does seem like the immune protection they offer may fade more quickly than many would’ve hoped, especially now that new variants are at play.
They don’t promise to stop all transmission . What’s more, some people do have severe, painful, and rare vaccine side effects. While those are largely temporary, we don’t totally understand why they are triggered in some people and not others.
Malone has thrived in this space of the sometimes unanswerable and often complicated, frustrating lingering questions of the pandemic. He’s become an icon and a friend to people who feel not only left out and dismissed by the scientific community but also ignored and shamed by their exhausted vaccinated friends, colleagues, and family with the dismissive attitude of, “Get vaccinated already, morons, and stop questioning any of this.” He’s created a comfortable home base for those who feel just as disenfranchised as he does, and there’s a reason they’re listening to him.
What Does The Latest Mortality Data Tell Us
There is some evidence that the mRNA vaccine possibly reduces disease severity in some patients, but a) does not prevent infection, and b) does not prevent transmission. Indeed, there is increasing evidence that areas with the highest vaccination rates, also have the highest case rates, for example when comparing Maine with California.
Professor Norman Fenton in a presentation to the World Council for Health – General Assembly, very clearly points out concerns over the misclassification of data and how vaccine effectiveness has been badly assessed by Pfizer and subsequently by UK authorities .
He concludes his report making the following points:
1. Vaccine effectiveness studies are generally flawed.
2. The anomalies in the ONS report most easily explained by misclassification of some unvaccinated deaths as vaccinated.
3. After adjusting it appears that shortly after vaccination people may be exposed to an increased mortality risk.
4. The ONS data is both unreliable and misleading.
5. The ONS data provide no reliable evidence that the vaccines reduce all-cause mortality.
See – evidence for vaccine efficacy questionable
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Whistleblower Reports Falsified Data
According to The BMJ it now also appears that there were fundamental problems with the quality of the data produced by one of the contract research organisations hired by Pfizer to conduct the COVID-19 clinical trial . Reports include, “falsified data, unblinded patients, employed inadequately trained vaccinators”. See also – Whistleblower has revealed that the Pfizer pivotal COVID-19 vaccine trial was fundamentally compromised.
Where Mrna Stands Today
In the years since Weissman and Karikó made these breakthroughs, mRNA research has continued to march on. Weissman and his current colleagues have worked on a variety of mRNA vaccines, including a universal flu shot that could cover a majority of influenza viruses and has so far proven to be effective in animal trials.
Compared to traditional vaccine platforms that require a series of complex steps, like growing mammalian cells in massive quantities and a viral purification process that looks different depending on the pathogen youre working with, mRNA is now easy to manufacture at a fairly large scale.
Instead of needing to reinvent the wheel every time you make a new vaccine, Weissman said, with its the same reaction, and the only thing you have to do is plug in the new sequence for any virus, so that makes it very easy to produce a new vaccine.
Both Moderna and Pfizers vaccines generated above 90 percent protection after two doses during clinical trials that played out before new variants of the virus marginally reduced their efficacy. Even so, the two give recipients remarkably high levels of protection, particularly against severe disease and death.
The CDC recently released new research that found these vaccines reduce a fully vaccinated persons chance of getting infected with the coronavirus by 90 percent in real-world settings like the workplace.
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How Do Mrna Vaccines Work
Understanding the virus that causes COVID-19. Coronaviruses, like the one that causes COVID-19, are named for the crown-like spikes on their surface, called spike proteins. These spike proteins are ideal targets for vaccines.
What is mRNA? Messenger RNA, or mRNA, is genetic material that tells your body how to make proteins.
What is in the vaccine? The vaccine is made of mRNA wrapped in a coating that makes delivery easy and keeps the body from damaging it. The vaccine does not contain any virus, so it cannot give you COVID-19. It cannot change your DNA in any way.
How does the vaccine work? The mRNA in the vaccine teaches your cells how to make copies of the spike protein. If you are exposed to the real virus later, your body will recognize it and know how to fight it off. After the mRNA delivers the instruct-ions, your cells break it down and get rid of it.
Information courtesy of US Centers for Disease Control and Prevention
With this hurdle cleared, the clinical applications for synthetic mRNA seemed infinite. Custom-tailored mRNA, once injected into the body, could order cells to produce any desired sequence of proteins.
There were enormous possibilities, Weissman says. The scientists believed their technology had the potential to transform medicine, opening the door to countless new vaccines, therapeutic proteins, and gene therapies.
I told Kati our phones are going to ring off the hook, Weissman recalls. But nothing happened. We didnt get a single call.
The Beginnings Of Mrna
Malones experiments didnt come out of the blue. As far back as 1978, scientists had used fatty membrane structures called liposomes to transport mRNA into mouse and human cells to induce protein expression. The liposomes packaged and protected the mRNA and then fused with cell membranes to deliver the genetic material into cells. These experiments themselves built on years of work with liposomes and with mRNA both were discovered in the 1960s .
Nik Spencer/Nature Adapted from U. ahin et al. Nature Rev. Drug Discov.13, 759780 and X. Hou et al. Nature Rev. Mater. .
Back then, however, few researchers were thinking about mRNA as a medical product not least because there was not yet a way to manufacture the genetic material in a laboratory. Instead, they hoped to use it to interrogate basic molecular processes. Most scientists repurposed mRNA from rabbit blood, cultured mouse cells or some other animal source.
That changed in 1984, when Krieg and other members of a team led by developmental biologist Douglas Melton and molecular biologists Tom Maniatis and Michael Green at Harvard University in Cambridge, Massachusetts, used an RNA-synthesis enzyme and other tools to produce biologically active mRNA in the lab a method that, at its core, remains in use today. Krieg then injected the lab-made mRNA into frog eggs, and showed that it worked just like the real thing.
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Why Children Should Not Receive The Mrna Covid Vaccine:
Dr. Geert Vanden Bossche explains that the mRNA vaccine is likely to do more harm than good in children. The reasons, include original antigenic sin, and the observation that innate immunity can be trained such as to acquire memory and, therefore, improve the hosts innate immune defense upon future exposure to more infectious variants that may emerge during an epidemic or pandemic. The vaccines undermine innate immune system by, for example, hindering binding of innate, low affinity antibodies and by interfering with the normal training of a childs innate immune system.
unhampered capacity to naturally activate innate antibody mediated sterilizing immunity
It is important to note that Dr. Geert Vanden Bossche describes how it will be the unvaccinated children who will increasingly be able to handle future infection by new variants, compared to vaccinated children and vaccinated adults. This is because the unvaccinated have unhampered capacity to naturally activate innate antibody-mediated sterilizing immunity, whereas the vaccinated have compromised innate immunity and are prone to breakthrough infections . This situation and potentially predisposes people to Antibody-dependent enhancement of disease due to the presence of suboptimal vaccine induced antibodies.