Messenger RNA (mRNA) - not just for Coronavirus vaccines

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On December 23, as part of a publicity push to encourage people to get vaccinated against covid-19, the University of Pennsylvania released footage of two researchers who developed the science behind the shots, Katalin Karikó and Drew Weissman, getting their inoculations. The vaccines, icy concoctions of fatty spheres and genetic instructions, used a previously unproven technology based on messenger RNA and had been built and tested in under a year, thanks to discoveries the pair made starting 20 years earlier.

In the silent promotional clip, neither one speaks or smiles as a nurse inserts the hypodermic into their arms. I later asked Weissman, who has been a physician and working scientist since 1987, what he was thinking in that moment. “I always wanted to develop something that helps people,” he told me. “When they stuck that needle in my arm, I said, ‘I think I’ve finally done it.’”
https://www.technologyreview.com/2021/02/05/1017366/messenger-rna-vaccines-covid-hiv/
I would expect Katalin Karikó and Drew Weissman to be awarded the Noble Prize in Physiology or Medicine.
Unlike traditional vaccines, which use live viruses, dead ones, or bits of the shells that viruses come cloaked into train the body’s immune system, the new shots use messenger RNA—the short-lived middleman molecule that, in our cells, conveys copies of genes to where they can guide the making of proteins.
The technology may be applied to other viruses.

In the near future, researchers believe, shots that deliver temporary instructions into cells could lead to vaccines against herpes and malaria, better flu vaccines, and, if the Covid-19 germ keeps mutating, updated Coronavirus vaccinations, too.

But researchers also see a future well beyond vaccines. They think the technology will permit cheap gene fixes for cancer, sickle-cell disease, and maybe even HIV.
 
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Ygggdrasil
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A few of the key papers from Kariko and Weissman toward the development of mRNA vaccines:

Suppression of RNA recognition by Toll-like receptors: the impact of nucleoside modification and the evolutionary origin of RNA
Kariko et al. Immunity 23:165 (2005)
https://pubmed.ncbi.nlm.nih.gov/16111635/

Naturally occurring nucleoside modifications suppress the immunostimulatory activity of RNA: implication for therapeutic RNA development
Kariko & Weissman. Curr Opin Drug Discov Devel. 10:523 (2007)
https://pubmed.ncbi.nlm.nih.gov/17786850/

Incorporation of pseudouridine into mRNA yields superior nonimmunogenic vector with increased translational capacity and biological stability
Kariko et al. Mol Ther. 16:1833 (2008)
https://pubmed.ncbi.nlm.nih.gov/18797453/

Zika virus protection by a single low dose nucleoside modified mRNA vaccination
Pardi et al. Nature 543: 248 (2017)
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5344708/

Here's a similar early paper from Moderna's efforts to develop mRNA vaccines:

Preclinical and Clinical Demonstration of Immunogenicity by mRNA Vaccines against H10N8 and H7N9 Influenza Viruses
Bahl et al. Mol Ther 25:1316 (2017)
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5475249/

Attempts to deliver mRNAs into cells as a means to get them to produce protein on demand dates back to the 1990s:

Direct gene transfer into mouse muscle in vivo
Wolff et al. Science 247: 1465 (1990)
https://science.sciencemag.org/content/247/4949/1465

Reversal of diabetes insipidus in Brattleboro rats: intrahypothalamic injection of vasopressin mRNA
Jirikowski et al. Science 255: 996 (1992)
https://science.sciencemag.org/content/255/5047/996

Other good articles with more history on the development of mRNA vaccine technology:
https://www.statnews.com/2020/11/10...leading-technology-in-the-covid-vaccine-race/
https://www.nature.com/news/business-the-billion-dollar-biotech-1.17674
 
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  • #3
Ygggdrasil
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Other important basic research leading to the successful creation of the COVID-19 vaccines was work done studying the structure of Coronavirus spike glycoproteins, which is the target of nearly all of the vaccines. In particular, most of the vaccines (including all three of the ones with EUAs in the US, Pfizer-BioNTech, Moderna, and Johnson and Johnson) use a mutant version of the spike protein that stabilizes the protein in the pre-fusion state developed by Jason McLellan's lab. Here are some of the key papers from his lab:

Pre-fusion structure of a human Coronavirus spike protein
Kirchdoefer et al. Nature 531:118 (2016)
https://pubmed.ncbi.nlm.nih.gov/26935699/

Immunogenicity and structures of a rationally designed prefusion MERS-CoV spike antigen
Pallesen et al. Proc Natl Acad Sci USA 114: E7348 (2017)
https://pubmed.ncbi.nlm.nih.gov/28807998/

Cryo-EM structure of the 2019-nCoV spike in the prefusion conformation
Wrapp et al. Science 367: 1260 (2020)
https://pubmed.ncbi.nlm.nih.gov/32075877/

SARS-CoV-2 mRNA Vaccine Design Enabled by Prototype Pathogen Preparedness
Corbett et al. Nature 586:567 (2020)
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7581537/
 
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  • #5
Ygggdrasil
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Here's a nice piece from C&EN about the McClellan lab's work on Coronavirus spike proteins: https://cen.acs.org/pharmaceuticals/vaccines/tiny-tweak-behind-COVID-19/98/i38

C&EN also has a nice feature on the development of the lipid nanoparticles that are used to deliver the mRNA vaccines: https://cen.acs.org/pharmaceuticals/drug-delivery/Without-lipid-shells-mRNA-vaccines/99/i8

Unlike the work from Weissman et al on the development of the mRNA modifications for mRNA deliver and the work by McClellan et al on the spike protein, a lot of the research and development for the LNP components was done in industry at various companies (Provita, Acuitas, Alnylam, etc).
 
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I would expect Katalin Karikó and Drew Weissman to be awarded the Noble Prize in Physiology or Medicine.

Kariko and Weissman were awarded the 2021 Breakthrough Prize in Life Sciences:
September 9, 2021 – San Francisco – The Breakthrough Prize Foundation and its founding sponsors – Sergey Brin, Priscilla Chan and Mark Zuckerberg, Yuri and Julia Milner, and Anne Wojcicki – today announced the winners of the 10th annual Breakthrough Prizes, awarding a total of $15.75 million to an esteemed group of laureates and early-career scientists.

The Breakthrough Prize recognizes groundbreaking discoveries in Fundamental Physics, Life Sciences and Mathematics. The world’s largest science prize, each of the five main Breakthrough Prizes is $3 million. Traditionally celebrated during a live, televised awards ceremony that honors the laureates, this year’s program is postponed until 2022 due to the pandemic.

The scientific and medical response to Covid-19 has been unprecedented, and two of this year’s prizes are for breakthroughs that played a significant role in that response. The innovative vaccines developed by Pfizer/BioNTech and Moderna that have proven effective against the virus rely on decades of work by Katalin Karikó and Drew Weissman. Convinced of the promise of mRNA therapies despite widespread skepticism, they created a technology that is not only vital in the fight against the Coronavirus today, but holds vast promise for future vaccines and treatments for a wide range of diseases including HIV, cancer, autoimmune and genetic diseases.
https://breakthroughprize.org/News/65

See also: https://www.nature.com/articles/d41586-021-02449-y

Perhaps we'll see another award for the duo announced in about a month.
 
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  • #7
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Karikó and Weissman were awarded the 2021 Lasker~DeBakey Clinical Medical Research Award:
https://laskerfoundation.org/winners/modified-mrna-vaccines/

See also: https://www.cell.com/cell/fulltext/S0092-8674(21)00993-4

Many Lasker prize winners go on to later win a Nobel Prize. Because the Nobel Prize can honor up to 3 individuals, I hope that Jason McClellan also gets awarded alongside Karikó and Weissman for his work on the structural biology of Coronavirus spike proteins (including devising a critical mutation on the spike protein that stabilizes the protein in the pre-fusion state; this mutation is used in all the mRNA vaccines).
 
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  • #8
atyy
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Many Lasker prize winners go on to later win a Nobel Prize. Because the Nobel Prize can honor up to 3 individuals, I hope that Jason McClellan also gets awarded alongside Karikó and Weissman for his work on the structural biology of Coronavirus spike proteins (including devising a critical mutation on the spike protein that stabilizes the protein in the pre-fusion state; this mutation is used in all the mRNA vaccines).
Me too. But we probably have different biases. I was at Texas where McClellan is (no, I didn't know him), whereas I'm guessing it's because he's in your field.
 
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The mRNA technology might also be used as an "anti-vaccine" (to treat autoimmune diseases).

https://pubmed.ncbi.nlm.nih.gov/33414215/
A noninflammatory mRNA vaccine for treatment of experimental autoimmune encephalomyelitis.
Krienke C, Kolb L, Diken E, Streuber M, Kirchhoff S, Bukur T, Akilli-Öztürk Ö, Kranz LM, Berger H, Petschenka J, Diken M, Kreiter S, Yogev N, Waisman A, Karikó K, Türeci Ö, Sahin U.
Science. 2021 Jan 8;371(6525):145-153. doi: 10.1126/science.aay3638.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7875549/
Roberto Furhan's easy reading summary of the paper.
 
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An interesting development, mRNA with a twist.
https://www.science.org/content/art...st-it-copies-itself-protects-against-covid-19

"A third messenger RNA (mRNA) vaccine appears to have proved its worth against COVID-19. And although it is more than a year behind the Moderna and Pfizer-BioNTech vaccines now seen as gold standards, the new vaccine may come with significant advantages: easier storage, along with lower cost because its “self-amplifying” design allows for smaller doses."

Developers site:
https://ir.arcturusrx.com/news-rele...nounces-self-amplifying-covid-19-mrna-vaccine
 
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(at this point they seem to be looking for folks to buy their stock)
That's a fair statement, I can't find any instances to cite altruism as the motivation to do this type of development. It does appear that saRNA / mRNA is going to be popular with Vaccine manufacturers, judging by the interest I'm seeing. I might be wrong but the Arcturus vaccine, from what I find is a combination of self-amplifying RNA and mRNA, for some reason that was problematic until recently.
From: https://www.science.org/content/art...st-it-copies-itself-protects-against-covid-19
"Some researchers have cautioned that self-amplifying vaccines cannot use an mRNA modification that is key to the Moderna and Pfizer-BioNTech vaccines: the replacement of the natural RNA building block uridine with pseudouridine... "

An early "update" over one year old.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7911542/

From July 2021.
https://www.imperial.ac.uk/news/222553/self-amplifying-rna-covid-19-vaccine-technology-safe/
The word "Safe" leads to this,
AZ invests in saRNA.
https://www.reuters.com/business/he...ng-rna-technology-with-eye-future-2021-09-23/
https://www.imperial.ac.uk/news/230554/imperial-rna-technology-developed-vaxequity-with/

Where there's money, there are always lawyers involved.
https://www.reuters.com/legal/gover...tole-covid-19-vaccine-secrets-ipo-2022-03-22/
"HDT said in the lawsuit that is developing a self-amplyifing RNA (saRNA) vaccine for COVID-19. According to HDT, saRNA improves on existing mRNA vaccine technology by reducing the risk of side effects like myocarditis and allowing for shots to be given with lower dosages and kept in standard refrigerators."

This follows the usual pattern, https://www.reuters.com/business/he...ent-lawsuit-over-covid-19-vaccine-2022-03-18/

There is some interesting information linked throughout these sites, way more than just the Covid angle.

Conclusion: This wouldn't be a bad bet as far as stock futures go.
 
  • #13
atyy
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From: https://www.science.org/content/art...st-it-copies-itself-protects-against-covid-19
"Some researchers have cautioned that self-amplifying vaccines cannot use an mRNA modification that is key to the Moderna and Pfizer-BioNTech vaccines: the replacement of the natural RNA building block uridine with pseudouridine... "
It's very interesting that an mRNA vaccine can be made without this. If I understand correctly (not sure), this was the key contribution of Kariko and Weissman.

https://doi.org/10.1016/j.immuni.2005.06.008
Suppression of RNA Recognition by Toll-like Receptors: The Impact of Nucleoside Modification and the Evolutionary Origin of RNA.
Karikó K, Buckstein M, Ni H, Weissman D.
Immunity. 2005 Aug;23(2):165-75. doi: 10.1016/j.immuni.2005.06.008.
 
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I might be wrong but the Arcturus vaccine, from what I find is a combination of self-amplifying RNA and mRNA, for some reason that was problematic until recently.
From: https://www.science.org/content/art...st-it-copies-itself-protects-against-covid-19
"Some researchers have cautioned that self-amplifying vaccines cannot use an mRNA modification that is key to the Moderna and Pfizer-BioNTech vaccines: the replacement of the natural RNA building block uridine with pseudouridine... "

It's very interesting that an mRNA vaccine can be made without this. If I understand correctly (not sure), this was the key contribution of Kariko and Weissman.

https://doi.org/10.1016/j.immuni.2005.06.008
Suppression of RNA Recognition by Toll-like Receptors: The Impact of Nucleoside Modification and the Evolutionary Origin of RNA.
Karikó K, Buckstein M, Ni H, Weissman D.
Immunity. 2005 Aug;23(2):165-75. doi: 10.1016/j.immuni.2005.06.008.

It's worth noting that CureVac developed an mRNA vaccine that does not use the modified nucleoside (N1-methylpseudouridine) used in the Moderna and Pfizer vaccines. Unfortunately, their Phase 3 trials of the vaccines showed that it is much less effective (only ~47% efficacy against COVID-19 disease of any severity) than the other mRNA vaccines, so including the modified nucleosides does appear to be important for mRNA vaccine technology.

Popular press summaries:
https://blogs.sciencemag.org/pipeline/archives/2021/06/17/curevac-comes-up-short
https://www.nature.com/articles/d41586-021-01661-0

Previous PF post on: https://www.physicsforums.com/threads/coronovirus-vaccine-progress.992484/post-6505108
 
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