Why have the Covid-19 vaccines arrived so quickly?

Updated:21/12/2020 13:44h


The virus SARS-CoV-2 it suddenly came into our lives, it spread throughout the planet very quickly causing havoc and we immediately heard: the solution is the vaccine, but it will take a long time until it arrives … But also quickly thousands of scientists got down to work, collaborating, sharing knowledge as it was produced and published.

As early as May, we knew that thousands of volunteers were being tested for the efficacy and safety of some vaccines. Before the end of the year, two RNA-based vaccines they are being administered to the most vulnerable population. How has it been possible?

Record-breaking vaccines

The development of traditional vaccines can lead 15 years or more. As indicated in the figure, it begins with a protracted discovery phase involving the design and performance of exploratory experiments.

This is followed by preclinical experiments and toxicology studies, as well as the development of production processes. During this process, an Investigational New Drug Application (IND) is submitted and Phase I, II, and III trials begin sequentially.

Upon completion of Phase III trials, and if predetermined end points have been met, a Biologics License Application (BLA) is submitted which is reviewed by regulatory agencies and ultimately authorized. After that point large-scale production begins.

Outline of the vaccine development process before and after the COVID-19 pandemic. Adapted and translated from Krammer (Nature, 2020) by Mercedes Jiménez.

But the pandemic, with all its consequences, has forced stepping on the gas without eliminating the steps that ensure efficiency, quality and safety. As we can see in the figure, the development of vaccines for SARS-CoV-2 has followed an accelerated time process for different reasons:

–Due to previous knowledge gained in the initial development of vaccines for SARS-CoV and MERS-CoV, the discovery phase was omitted.

–Existing processes were adapted and phase I / II trials started almost simultaneously.

–The phase III trials were started after the intermediate analysis of the results of the previous phases, keeping stages of clinical trials in parallel.

–Meanwhile, the large-scale production (at risk) of various vaccines began.

–The European Medicines Agency, EMA, has carried out a continuous evaluation of these vaccines.

Does a continuous review mean that it is not complete?

No. It means that the EMA Committee for Human Medicines (CHMP) reviews efficacy, safety and quality data as they become available from ongoing studies, even before a formal application is submitted. In this way, you can make your decision earlier on whether or not the vaccine should be authorized to expedite evaluation during a public health emergency.

What is RNA and what does it do?

It looks like we just discovered RNA, but this molecule was discovered in the 1950s by the distinguished scientist Severo Ochoa. In 1955 Severo Ochoa, together with Marianne Grunberg-Manago, published in a scientific article the discovery and isolation of an enzyme from a bacterial cell and named it polynucleotide-phosphorylase, later known as RNA-polymerase.

Using this enzyme, Severo Ochoa achieved RNA synthesis in the laboratory for the first time. Since that discovery until today, important research work has been carried out on RNA.

And what is RNA? Also know as ácido ribonucleico, is in the form of a single chain with three of the same letters (nitrogenous bases) as DNA (G, A, C) and a U instead of a T, and it is much more unstable and fragile.

RNA is involved in the expression and regulation processes of genes. It is responsible in the form of RNA- (m) messenger for carrying the information contained in the DNA from the nucleus to the cell cytoplasm to synthesize the proteins that our body needs, like a recipe from a cookbook that carries instructions.

Frozen RNA for Vaccination

RNA-based vaccines have been studied for several years, as they have several advantages over traditional ones, including those based on DNA.

One of the main challenges that scientists have faced during these years to obtain the clinical approval of mRNA vaccines was to obtain their intracellular administration, since this is very unstable under physiological conditions and “cannon fodder” of enzymes which are called ribonucleases.

These ribonucleases, when they see an RNA molecule, break it into smaller pieces, which is known as catalytic hydrolysis.

Therefore, unprotected mRNA administered by itself is not suitable and for that reason it was ignored by the pharmaceutical industry for a long time. It was not until a few years later that a way was found to stabilize the RNA in vivo using lipid nanocapsules, so that the RNA molecule is inside these nanocapsules completely safe from the attack of ribonucleases, and therefore managing to enter in the cell.

Scheme of the operation of mRNA vaccines encapsulated in lipid nanoparticles.  Adapted from Altounian (Science, 2020) by Nuria Campillo
Scheme of the operation of mRNA vaccines encapsulated in lipid nanoparticles. Adapted from Altounian (Science, 2020) by Nuria Campillo

And why do you have to keep these vaccines at such low temperatures?

As we have just seen, RNA is very unstable and much more likely to break down at high temperatures. What are the requirements for freezing? The Pfizer-BioNTech vaccine should be optimally stored at less than 70 ° C below zero and it degrades in about 5 days at temperatures above 0ºC.

The Moderna vaccine does not require that ultra-cold storage and remains stable between 2 y 8º C for 30 days. This difference in temperatures is probably due to the different characteristics of the lipid nanocapsules and to the different concentration of mRNA they contain. Moderna’s vaccine contains more mRNA and therefore lasts longer at less extreme temperatures.

What previous experience do Pfizer and Moderna have?

The two companies that develop the most advanced vaccines could not be more different. Founded in 1849, Pfizer is one of the largest pharmaceutical companies in the world and number 64 in the Fortune 500 ranking, which lists the 500 largest companies in the United States.

He has extensive experience producing vaccines. Two examples are the one that allowed the eradication of smallpox and that of the poliomyelitis, also on the verge of being eradicated.

On the other hand, Moderna is a company founded 10 years ago whose first product approved by a regulatory agency has been its vaccine against Covid-19. What do they have in common? The two bet very strongly on synthetic mRNA technology, a technology that, as we have said, had been in development for more than 30 years and that has built and destroyed scientific careers throughout those years.

The therapeutic potential of introducing mRNA into cells that codes for a specific protein had long been seen. The problem was that, when it was tried on animals, they immediately mounted an immune response to destroy it.

They were the Hungarian scientist Katalin Karikó and the american Drew Weissman who discovered that by modifying a nucleotide (one of the pieces that RNA is made of), the synthetic mRNA went unnoticed by the immune system.

In addition to Karikó and Weissman, two other scientists, Derrick Rossi and Ugur Sahin, they turned to this technology with their sights set on curing cancer. One of them would found the Moderna company, and the other BioNTech (Pfizer’s German ally in the production of the Covid-19 vaccine).

When the current pandemic emerged, the two immediately realized that this technology could be used to develop a vaccine. And they began a race against time that would lead to the fastest production in the history of a vaccine. But let’s not forget that the original investigations had started 30 years earlier!

We live accustomed to speed, to rushing, we accept new mobile models, new message applications, online shopping platforms.

Fortunately, vaccines are also developing rapidly. A generalized vaccination will allow us to achieve the desired immunity. Although there are months left, little by little we will breathe more calmly, although, for the moment, without taking off the mask.

María Mercedes Jiménez Sarmiento. CSIC scientist. Systems Biochemistry of the bacterial division. Scientific communicator, Margarita Salas Biological Research Center (CIB – CSIC)

Matilde Cañelles López. Scientific Researcher. Science, Technology and Society, Institute of Philosophy (IFS-CSIC)

Nuria Eugenia Campillo. Senior Scientist. Medicinal Chemistry, Margarita Salas Center for Biological Research (CIB – CSIC)

This article was originally published on The Conversation.

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