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In the 1990s and for most of the 2000s, nearly every vaccine company that considered working on mRNA opted to invest its resources elsewhere. The conventional wisdom held that mRNA was too prone to degradation, and its production too expensive. “It was a continuous struggle,” says Peter Liljeström, a virologist at the Karolinska Institute in Stockholm, who 30 years ago pioneered a type of ‘self-amplifying’ RNA vaccine.

“RNA was so hard to work with,” says Matt Winkler, who founded one of the first RNA-focused lab supplies companies, Ambion, in Austin, Texas, in 1989. “If you had asked me back [then] if you could inject RNA into somebody for a vaccine, I would have laughed in your face.”

The mRNA vaccine idea had a more favourable reception in oncology circles, albeit as a therapeutic agent, rather than to prevent disease. Beginning with the work of gene therapist [Dr. David Terry Curiel (born 1956)], several academic scientists and start-up companies explored whether mRNA could be used to combat cancer. If mRNA encoded proteins expressed by cancer cells, the thinking went, then injecting it into the body might train the immune system to attack those cells.

[Dr. David Terry Curiel (born 1956)], now at the Washington University School of Medicine in St Louis, Missouri, had some success in mice10. But when he approached Ambion about commercialization opportunities, he says, the firm told him: “We don’t see any economic potential in this technology.”

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With vaccines being distributed across the country, it seems like there will be an end to the coronavirus pandemic.

And for that, we have to thank, in part, a Missouri man. Dr. David Curiel and his team at Washington University in St. Louis have been researching mRNA vaccines since 1995. He’s been called the “father” of the Covid-19 vaccine, and technology he worked on has allowed the vaccine to be developed in just a year, instead of several. The two approved vaccines, from Pfizer and Moderna, both work via a genetic molecule called mRNA that’s naturally found in human cells. That mRNA instructs the body to produce a coronavirus protein, called spike. Even though your own body made the spike, it’s recognized as a foreign invader, triggering the body’s infection-fighting antibodies.

Right now, the two approved vaccines both require two shots, spaced weeks apart. But Dr. Curiel is hopeful for another breakthrough, achieved by introducing the mRNA vaccine through the nose. It’s not only less invasive than a needle, but it could be faster-acting and more effective, since the immune response will be in the most-likely site of infection.

We chatted with Dr. Curiel about his work.

How does nasal delivery differ from a shot?

In addition to giving you protective immunity from the infection, it specifically enhances the immunity of the upper respiratory tract.  And that may be important to limiting what we call lateral transmission, that is person-to-person transmission.  The virus is naturally a respiratory pathogen. So by stimulating immunity at the portal where it normally infects, there is a logical way to accomplish the optimal immune response.

Are there any side effects that the nasal vaccine has?

We haven’t done big enough studies to capture every possible side effect; but, in the limited studies that we’ve done, there have been minimal side effects.  So it may be that this is a way to reduce side effects as well.

What happens to the protein the body makes in response to the vaccine?

There’s a process called antigen processing. So the certain cells in your body take that protein and break it down, and they present it to the immune system in a way the immune system can see it. So the protein is consumed as if it were in the process of developing the immune response. It can’t cause an infection or even a pathology based on the one gene.

Does this vaccine protect just you or others as well?

Because it eradicates and sterilizes the upper airway and gets rid of anything that’s there, it should limit your ability to transmit it and protect you from getting the infection.

How does the mRNA intranasal vaccine differ in terms of storage and distribution?

For the Moderna and the Pfizer vaccines, which are mRNA vaccines, the storage requirements are much more stringent than for the adenovirus vaccines. The nasal vaccine is with adenovirus, and no matter how good the mRNA gets, it’s probably not going to be something we can give to as many body sites as we can the adenovirus, which is very stable and very effective.

Will the Covid vaccine be similar to the flu vaccine?  Will one have to be vaccinated every year?

It will probably be very analogous because the way the flu vaccine works is through epidemiology and screening.  We can anticipate months in advance what will be the makeup of the influenza strain; and, based on that, there’s adequate time to design a vaccine and implement it.  So, it’s probably going to be very analogous to that for the SARS-COV-2 virus.

How does the body know to create and fight the protein that is placed in the body?

The body sees the spike protein as if the spike protein were part of the virus. So, it develops antibodies, and some of those antibodies block the portion of the spike protein that is critical for anchoring to the host cells.

When will this vaccine become available?

We started making the virus at the end of February, and our collaborators in India have started a human trial this week. So we’ve gone from an idea to a trial in humans in less than a year. And, their trial will have data, we hope, by the end of March. Based on that data, we’ll be able to do much larger trials to prove the efficacy of the agent.

These two lines of dialogue could sum up the beginning of many of the most important scientific discoveries in history. They also sum up the beginning of the discovery that has made it possible for billions of people to be immune to covid-19 without having to go through the disease. This is only possible thanks to vaccines, of course. And, of all the vaccines being administered around the world, the ones from Pfizer and Moderna stand out because they are made with a technology based on a type of molecule called messenger RNA. Developing it was not easy.

RNA is a fundamental molecule for life. In fact, many scientists think that the history of life on Earth began with these molecules. Inside every nucleus of every cell of everyone who reads this is the genetic material (DNA) with the instructions to make the proteins that shape and function your body. The mission of messenger RNA is to become a copy of the information stored in the DNA in the nucleus and carry it to the parts of the cell where the corresponding proteins are made. This very fundamental function quickly raised suspicions in the scientific community: if there is a disease caused by a lack of a protein, instead of dealing directly with the protein, which is technically difficult, you can deal with the messenger RNA that makes the body's cells create the protein.

Reasons for doubt

South African biologist Sydney Brenner discovered RNA in 1961, but it wasn't until the early 1990s that technology made it possible to use it as a therapeutic tool. In 1992, a group of scientists at Scripps Research Institute in the United States used this molecule in laboratory rats to temporarily reverse diabetes insipidus, a disease that causes excess urination due to a lack of antidiuretic hormone. The idea was simple: inject messenger RNA into the rats so that their cells would produce the missing hormone. In 1995, a group of researchers led by David Curiel of the University of Alabama-Birmingham, also in the United States, were the first to develop a vaccine based on messenger RNA. They tested it in mice with the aim of generating an immune system response against tumour cells. They published a proof of concept, but were unable to continue the research due to lack of funding. Beyond the experts working directly with it, almost nobody saw a future for it at the time.

There were a few reasons for investors' doubts. First, messenger RNA is a very delicate molecule that must be kept at temperatures several tens of degrees below zero, which complicates its storage and distribution. With a little heat, the components fall apart. In addition, laboratory experiments indicated that in many cases the vaccines did not produce enough protein to achieve the therapeutic goal. This suggested that the messenger RNA did not reach the inside of the cells correctly. Another major problem was that, when injected, the immune system identified it as a foreign substance and generated inflammation to attack and destroy it.

A lot of stubbornness and some luck

In the early 1990s, a Hungarian researcher, who had received her PhD in biochemistry from the University of Szeged, was a postdoctoral fellow at Temple University in Philadelphia and was convinced that the technology had a chance. It was just a matter of having the money to do the research and finding a way to solve the problems. That is why Katalin Karikó asked for funding again and again. She received so many refusals that, after ten years of insisting, she even thought about giving up research. As a result of the lack of success in obtaining funding, the University of Pennsylvania demoted her from her job. And then, as has happened so many times throughout the history of science, chance intervened in a memorable way to turn Karikó's stubbornness into scientific results.

A chance encounter in the early 2000s led Karikó to begin working with researcher Drew Weissman on an AIDS vaccine. The approach, of course, was to make it from messenger RNA. With funding, the results were soon forthcoming. In 2005 they found the solution to two major problems with the technology. Weissman and Karikó's discovery is comparable to that of a carpenter who polishes a door so that it doesn't rub against the floor or a sculptor who, with a single stroke of a scarp, has just given personality to a bust. RNA molecules are chains of smaller molecules called nucleotides. Researchers realised that if they replaced one of these molecules, uridine, with a slightly different molecule, pseudouridine, the messenger RNA would not attract the attention of the immune system and could enter cells to produce more proteins than before.

Entrepreneurs with a vision

Once the discovery was made, the scientists patented the system to produce the messenger RNA, but the University of Pennsylvania sold it to the company CellScript for $300,000. Soon, two scientists saw potential in the discovery. The first, Derrick Rossi, was a postdoc in stem cells at Stanford University and began using the techniques developed by Weissman and Karikó to reprogramme any cells into embryonic stem cells. The technology worked so well that in 2010 Rossi partnered with other researchers and investors to found the company Moderna. Although the company's initial interests were stem cells, it developed a platform for producing messenger RNA that it would use in the early 2020s to design the covid-19 vaccine.

In parallel, a couple of German scientists of Turkish origin, Ugur Sahin and Özlem Türeci, who were researching cancer immunotherapy, saw in messenger RNA technology the possibility of developing personalised therapeutic vaccines that would generate immune activity to destroy cancer cells. In 2008 they had founded the biotech company BioNTech and after learning of Weissman and Karikó's discoveries they acquired some patents. In 2013 they signed Karikó, who today is vice president of the company. In early 2020 BioNTech would team up with the pharmaceutical company Pfizer to produce the covid-19 vaccine.

The envelope is also important

However, to develop covid-19 vaccines, there is still one more discovery to be made. This time Karikó made it in 2015, as a researcher at Philadelphia University together with Norbert Pardi, a Hungarian biochemist who was born in the same city as her. Although the pseudouridine-modified RNA produced more protein than the previous version, it wasn't enough. To get the molecule to better access to the inside of cells, Karikó and Pardi used nanotechnology techniques to wrap it in a tiny sphere of fat called a lipid nanoparticle. Problem solved.

A technology of the future

"RNA vaccines are not new, but have been investigated for some time, especially in relation to cancer treatment", explains Jorge Carrillo, main investigator of the immunology group at IrsiCaixa. In fact, he points out, "there have been phase 2 trials that have shown that they are safe and that they generate an immune response". Idibaps AIDS researcher Montserrat Plana hopes that "from now on there will be more investment in this technology and that Catalonia will choose to have an RNA platform focused on new pathogens. Plana considers that, "although we still have to work on conservation to make these vaccines more manageable, it is a line that cannot be lost".

A fast, simple and versatile technology

The production of RNA is simpler and faster than that of traditional vaccine components because, among other things, it does not require cell cultures that take months of work. In fact, on 10 January, 2020, the coronavirus genome was published, and in April Moderna began the first vaccine trials with volunteers. This also means that if a virus mutates significantly, the vaccine can be adapted in a short time. Another interesting feature of these vaccines is that RNA is a substance that degrades very easily. Therefore, once inside the body it does not last long, which makes it a safe technology. RNA, moreover, cannot enter the nucleus of the cell and modify the DNA. On the other hand, these are vaccines that produce a very robust immune response, and they can be produced in a scalable and relatively inexpensive way.

A clean immune response

Messenger RNA vaccines generate an immune response that scientists call clean. Vaccines that use the envelopes of other viruses to encapsulate the genetic material of the pathogen they immunise against generate unnecessary immune responses. Because the structure of these other viruses contains proteins, the immune system also generates defenses against them. Something similar happens with protein vaccines: as there is always some impurity in the final preparation, proteins from the pathogen are introduced along with other proteins that also generate an immune response that would not be necessary. This does not happen with messenger RNA vaccines. The RNA only contains instructions for a protein to be produced, which will give rise to a specific immune response. In the case of covid-19 vaccines, this is the S protein that the virus uses to gain access to the inside of cells and infect them.

ST. LOUIS — The science behind India’s new nasal vaccine for COVID-19 has its roots in St. Louis.

India-based drug company Bharat Biotech announced Tuesday that its nasal vaccine had received emergency approval. The vaccine technology was licensed from Washington University.

[Dr. Michael S. Diamond (born 1964)], a Washington University professor and viral immunologist, said he began working on the vaccine in the spring of 2020 with fellow Washington University professor Dr. David Curiel. The world’s scientific community was just mobilizing on its massive, urgent search for methods to treat and prevent the new coronavirus.

Diamond and Curiel knew many other researchers were racing to develop vaccines, but they didn’t see anyone else pursuing oral or nasal vaccines.

Their work is now making its public debut nearly two years after the injectable products made by Pfizer, Moderna and others. But it could become a strong tool in the fight against COVID-19. In an interview in 2020, Curiel recalled Albert Sabin’s oral polio vaccine, which came several years after Jonas Salk’s injectable vaccine but proved to be safer and more effective.

The new vaccine doesn’t require the ultra-cold storage needed for Pfizer’s shot. It is stored between 36 and 46 degrees Fahrenheit. And because it is administered through the nose, it doesn’t produce the biohazard waste of needles and syringes.

The nasal vaccine may also have an advantage when it comes to reducing spread, Diamond said: It hasn’t been proven in humans, but researchers theorize the nasal vaccines could actually reduce infection in the upper airway, leading to shorter infections and less transmission.

Unlike the mRNA-based vaccines from Pfizer and Moderna, the nasal vaccine is made from a deactivated cold virus — “basically like a dummy virus particle,” Diamond said. Scientists deleted the genes that allow the cold virus to replicate, then inserted the spike gene from the virus that causes COVID-19. When administered as a vaccine, it triggers an immune response that protects the recipient against COVID-19.

The Washington University researchers tested the vaccines in mice, hamsters and primates. Bharat Biotech formulated the vaccine for humans, put it into nasal drops and tested the vaccine in a Phase 3 trial of about 3,100 participants.

Bharat Biotech has not released the data from that trial.

Researchers at multiple universities in the U.S. and abroad are studying similar COVID-19 vaccine candidates. On Sunday, CanSino Biologics announced that an inhaled version of the company’s COVID-19 vaccine had been approved for use in China. Iran and Russia have also approved nasal and oral vaccines, according to Nature.

Nasal vaccines aren’t a new concept. The nasal flu vaccine, FluMist, has been used in the U.S. since 2003. But they still aren’t common.

In the future, Diamond said, researchers could look to develop nasal vaccines for any number of rhinoviruses and coronaviruses as well as common “nuisance” upper respiratory infections. A clear candidate would be respiratory syncytial virus, or RSV, which can cause serious illness in infants and older adults.

“You could think about any number of respiratory viruses,” he said. “RSV is obviously a big target.”

The nasal vaccine’s approval comes as the U.S. rolls out doses of the updated COVID-19 vaccines from Pfizer and Moderna, which have been modified to specifically target the most recent variants of the virus.

And a similar update for the nasal vaccines may already be on the way.

“We’ve already done it,” Diamond said. “We’re testing them now.”