The Revolution Of Messenger RNA Vaccines

The coronavirus pandemic has been the key that has opened the door to a promising technology to combat other diseases in the not-so-distant future: messenger RNA . Despite being a tool that has been studied for decades to deal with other pathogens, such as influenza, HIV or Zika, this was the first time that an mRNA (messenger ribonucleic acid) vaccine has been tested.

The results of vaccines to deal with SARS-CoV-2, such as those developed by Pfizer-BioNTech and Moderna , are really promising, having shown a high percentage of efficacy. This has been the definitive leap to promote this type of vaccine.

What is its potential? What diseases could they be used for?
The potential for this technology for infectious diseases is promising ” since it only needs to have a nucleotide sequence, to be able to be put into a vehicle and injected . It may have potential for many other pathogens, from hepatitis C to malaria or other possible pathogens. viruses that could create pandemics in the future, “says Montserrat Plana, a researcher at Idibaps and a member of the AIDS and HIV infection group, 20 minutes away .

The flu could be the next candidate to apply this technology.
The next step might be to get a vaccine against the viruses that cause the flu that mutate each year. This is one of the most relevant scientific projects that some pharmaceutical companies such as Moderna are focusing on, which maintains an ongoing clinical trial for a vaccine against seasonal influenza ‘Mrna-1010’ in healthy adults.

“Many companies are making flu vaccines to see if they improve the traditional ones,” explains Sonia Zúñiga, a virologist and researcher at the CNB-CSIC , to 20 minutes . The current ones are based “on purified protein” and their main objective is “to prevent severe disease”. However, the immunity they generate “is short-lived.” Therefore, it seems very likely that this is the next pathogen to fight with mRNA.

“A giant step has been taken, now we have to see how it translates into other pathologies.”
But this technology could be applied to many viruses or bacteria that cause infectious diseases, “from the hepatitis C virus, through respiratory viruses and others that cause diseases for which there is no vaccine, ” adds Montserrat Plana.

The technology is revolutionary and has made incredible advances in a short time, but “you have to see how it behaves in the face of other diseases . Many analyzes indicate that the future will go this way, a giant step has been taken, now we have to see how all this translates into other pathologies “, points out Dr. Jaime Jesús Pérez, member of the Spanish Association of Vaccination (AEV) .

How does mRNA work?
The objective of any vaccine is for the immune system to react to the entry of a certain pathogen into the body by generating antibodies to defend itself. “Traditional vaccines have a single component of the pathogen and are based on proteins. When inoculated into the body accompanied by an adjuvant, it generates an immune response.

An example is influenza vaccines, which are based on a protein of the virus that changes every year “, explains Sonia Zúñiga, who is currently working on the CSIC’s intranasal vaccine against SARS-CoV-2 project . The main difference with mRNA vaccines is that “it is a nucleic acid molecule that encodes the protein.”

In mRNA vaccines “it is a nucleic acid molecule that encodes the protein.”
This nucleic acid is wrapped in a system so that it can be delivered, like a kind of capsule. It is inoculated and the cells recognize it. That’s when all the machinery is produced: they translate it to make an immune response. Therefore, what this mRNA does is give the cells the necessary instructions to develop the proteins that deal with the pathogen . And in the case of SARS-CoV-2 it is the S protein.

What are its advantages?
“Theoretically they are very safe and easy to approve because they are not integrated into cells. They are easy to produce and very versatile”, explains researcher Montserrat Plana. A versatility that can be verified in the current context of the pandemic in the face of the different variants of the original strain . “Once a sequence is designed, by varying it, you can reconvert the vaccine so that it goes against different variants of the virus itself,” he adds.

Another of the most relevant advantages is that “this RNA envelope system also functions as an adjuvant, that is, it helps the immune response”, adds Sonia Zúñiga. Likewise, it has the advantage of the speed of adaptation and “probably the manufacturing process can be faster than in traditional vaccines , for influenza for example, which could be better adapted to circulating strains”, emphasizes Dr. Jaime Jesús Pérez.

Vaccines against Covid-19 have become a key piece for the future of vaccinology. “Unlike conventional vaccines, mRNA vaccines are not grown in eggs or cells, a costly and time-consuming process. These vaccines are chemical substances catalyzed in a test tube, which makes them easier to develop quickly ” , highlights an article published in the journal ‘Journal of the American Medical Association (JAMA)’.

What obstacles do you face? Why had it never been used?
Despite current success, there are significant obstacles to the development of these vaccines against other pathogens, especially those capable of evading the response of the immune system. What happens then with diseases such as AIDS or cancer? “There are diseases in which it is not known what is needed to generate an immune response that will protect,” explains Sonia Zúñiga in this regard. This is what happens when trying to neutralize viruses such as HIV, which also attacks the immune system itself.

Malaria would be another of these complex cases . “It is not well known what is needed for protection and it is one of the problems for which today there is no good vaccine,” he adds. It is not only a question of knowing which proteins are encoded by that mRNA, but “how it is going to do it or what the envelope is going to be”. There are a multitude of factors to consider, despite the potential that has been shown to be “immense.”

Why has this great leap been made with Covid-19?
Montserrat Plana works in the Idibaps AIDS and HIV research group, which has been searching for therapeutic alternatives for several years. “We have been investigating possible therapeutic vaccines and for about 10 years we have been interested in mRNA vaccines because they seemed to us to be very novel, very safe and that they had demonstrated their good potential for efficacy in other treatments,” he details.

Now with the arrival of the pandemic and with all the previous knowledge they had about this technology, they considered “betting on an RNA vaccine against this pathogen” and the group, led by researcher Felipe García, is immersed in the development of a Spanish mRNA vaccine against coronavirus that offers long-term immune responses .

It had been studied for decades, but why has it been developed now in just 10 months? ” The fundamental reason is that this technology was not mature enough , ” explains the AEV spokesperson, in addition to the obstacles mentioned above. In fact, when the first vaccines against Covid began to be developed “there were serious doubts that it would be achieved due to stability problems,” he adds.

Also, “the logistical conditions are very special and at the beginning of the vaccination campaign there was talk of temperatures of -80 degrees to preserve the Pfizer vaccine.” Therefore, “a series of very special circumstances have arisen for the promotion of the first mRNA vaccines”.

In this sense, one of the aspects that is being improved thanks to vaccines against Covid is the problem of conservation. One of the causes has to do with the envelope of said mRNA “because it is very labile and lasts for a certain time “, Sonia Zúñiga emphasizes. It is, therefore, a great obstacle if vaccines are to be made on a large scale. “A problem that is being improved with wraps that allow them to be preserved, for example, at 4 degrees.”

From the first tests in 1990 to fighting malaria
A study published in 2018 in the journal ‘Nature’ assured that the future of mRNA vaccines represented “a promising alternative to conventional vaccine approaches due to its high potency, rapid development capacity, low-cost manufacturing potential and administration safe “. However, its application had been restricted until relatively recently by “instability and inefficient ‘in vivo’ delivery of mRNA.”

The first study on the use of ‘in vitro’ transcribed mRNA in animals was published in 1990.
These obstacles have influenced its development and for this reason its use in the current context has been so relevant. In fact, the first study on the use of transcribed mRNA ‘in vitro’ in animals was published in 1990 , when a team of researchers injected mRNA of the reporter gene into mice ‘in vivo’.

“Protein expression was easily detected in all cases and no special delivery system was required for these purposes,” they highlighted. However, the aforementioned instability problems prevented the investigation from being carried out.

The success of the Covid vaccines has been the necessary impetus for their research. In fact, BioNTech announced on July 26, 2021 the launch of a new project against malaria that aims to develop a “safe and highly effective mRNA vaccine with long-lasting protective immunity” to prevent the disease and its mortality.

The start of this clinical trial is scheduled for the end of 2022 and is an extension of efforts dedicated to mRNA research with the Covid-19 vaccine. For its part, Moderna , which was born with the spirit of fighting diseases such as cancer with this platform, also announced a few months ago that it would use this technology to design vaccines against the influenza virus or HIV .

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