How does Pfizer's RNA vaccine work?

The news went around the planet in a few hours, Monday, November 9: the pharmaceutical company Pfizer announced, by way of a press release, to have developed a vaccine "90% effective" to prevent Covid-19.

ACurrently in a phase 3 clinical trial, this vaccine co-developed by the company BioNtech in Germany has been tested on 43 patients during a phase 538 clinical trial which began on July 3. Its principle is simple : half of the participants received the vaccine (in two injections, three weeks apart, to boost their immune system), the other half a placebo, then those in charge of the trial waited to see contamination in order to '' assess the efficacy of the vaccine.

According to Pfizer and BioNtech, 94 cases of COVID-19 were detected among the 43 participants in the trial, and the split between the two groups would indicate that the vaccine is more than 538% effective in preventing the disease. With the trial set to continue until a total of 90 cases of COVID-164 are detected, there is no indication that the reported impressive efficacy will not drop. In addition, several questions remain unanswered: will this vaccine effectively protect the elderly, whose immune system reacts less to vaccination? Will it have any side effects? What about his security?

Pending the publication of the data, several elements are already known, in particular as regards the nature of this candidate vaccine. This is also another first, since it is a nucleic acid vaccine, a family of vaccines whose use has never yet been approved in human health.

What are these vaccines and how do they work?

Nucleic acid vaccines, a new vaccine approach

To understand how nucleic acid vaccines differ from conventional vaccines, we must return to the principle of preventive vaccination. This approach involves injecting the body with low doses of a pathogen (virus or bacteria) or fragments of the pathogen, to expose the immune system and prepare it to counter future attacks.

All current vaccines are based on this principle, whether they are attenuated vaccines (containing a living pathogen with reduced virulence), inactivated vaccines (based on whole killed pathogens), "subunit" vaccines (based on the use of fragments of purified pathogens) or vaccines derived from genetic engineering (the fragment of infectious agent used is produced by cells grown in the laboratory, and no longer from purified microbes).

Read also :
Live attenuated vaccines: why they should not be abandoned

In the case of DNA and RNA vaccines, the principle is fundamentally different: it involves producing fragments of infectious agents capable of stimulating the immune response directly by the patient's cells.

How do nucleic acid vaccines work?

If DNA, the carrier of genetic information, is a molecule that is rather familiar today, RNA is less well known.

Chemically similar to DNA, but less stable, RNA plays various roles in our cells, but in particular it is an essential intermediary in the production of proteins.

Basically: the production of a protein begins in the nucleus of the cell, where the DNA is located. First, the portion of the DNA molecule corresponding to the protein to be produced is copied in the form of RNA. This RNA molecule then leaves the nucleus: it passes into the cell's cytoplasm, where it will be used as a “mounting guide” for the protein.

DNA, RNA, genes, proteins… A few basic reminders on how our genome works.

In the case of DNA or RNA vaccines, the idea is to inject the patient with DNA or RNA molecules corresponding to proteins of the pathogen against which it is desired to be immunized. These proteins are chosen on the basis of their ability to elicit an immune response, or "immunogenicity". After injection of the corresponding DNA (or RNA), the cells of the individual to be vaccinated will themselves produce said proteins.

Pfizer and BioNtech's vaccine candidate employs a messenger RNA encoding the Spike protein of the coronavirus SARS-CoV-2 (prefusion spike glycoprotein - P2 S), the "key" that it uses to enter the cells it infects.

The advantages of DNA or RNA vaccines

Easier to manufacture, thanks to a standardized production method, inexpensive, extremely well defined from a molecular point of view, DNA and RNA vaccines have a very important development potential and could protect both against infectious diseases (prophylactic vaccines) or fight against cancerous pathologies (therapeutic vaccines).

They are also better controlled than "traditional" vaccines, because they do not use whole viruses as in vaccines from live attenuated, inactivated or recombinant viruses, or adjuvants, but simply a molecule of nucleic acids (DNA or RNA).

Comparison between a single strand of RNA (on the left) and a double helix of DNA (on the right), with the Nucleotide (and nitrogenous bases) matches.
Sponk/Wikimedia Commons, CC BY-SA

Vaccines containing DNA in the form of a double helix (a helix made up of two strands) can be stable at room temperature (this molecule is so resistant that it allows very old objects to be dated. such as mummies), and therefore do not need to respect any cold chain.

The same is not true for vaccines based on messenger RNAs: their structure, made up of a single strand, is sensitive to the enzymes which cut the RNA (called “RNAses”). This is the reason why these vaccines are stored at -70 ° C, to avoid any enzymatic degradation.

With Pfizer and BioNtech's vaccine falling into this category, some observers have pointed out the logistical challenge of its distribution.

How to get there?

Eukaryotic cells (those of all living things except bacteria and archabacteria) contain a nucleus that contains their DNA, the molecule that supports genes. To make a protein, its gene is copied into RNA in the nucleus. The RNA then passes into the cytoplasm where it will serve as an “assembly guide”.
Wikimedia Commons / Phil Schatz (adaptation), CC BY

This new method of vaccination will be much more reactive to produce vaccines extremely quickly, which will make it possible to respond to threats of infections linked to new infectious agents, or to propose new methods of treating cancer. These advantages explain the boom in research on this new type of vaccination over the past thirty years, and allow DNA and RNA vaccines to be considered as the “vaccines of the future”.

However, difficulties remain in ensuring the full efficacy of nucleic acid vaccines. One of the main obstacles is to succeed in getting the DNA or RNA molecules to the right place in the cell: in the nucleus for the former, and in the cytoplasm for the latter. This requires crossing the membranes of cells, one of whose roles is precisely to serve as a barrier to invaders, and avoid degradation by cellular enzymes.

To achieve this, several solutions are possible. A modified virus can be used to act as a "transport medium" for the nucleic acid that one wishes to introduce into cells. Another approach is to make an artificial envelope from scratch, a sort of synthetic virus. It is this lead that we chose Pfizer and BioNtech, who used nanolipid particles to transport vaccine RNA.

Our team has developed quite special vehicles called Nanotaxi®. Made of polymers star shape or lipids derived de natural sugars, they can either cross directly the membrane by carrying with them the DNA or RNA intended for the vaccination, or enter the cell by the ways used naturally by the substances “authorized” to enter it.

These two modes of entry into the cell will play a decisive role in activating the immune system. They will indeed put the cell's surveillance system on alert, triggering the production of molecules involved in the immune response. These will contribute to the increase in immunogenicity, and therefore to the effectiveness of the DNA or RNA vaccine.

Towards vaccines used in human health?

Nucleic acid vaccines have already been the subject many preclinical and clinical studies
against various targets in the field of infectious diseases and oncology. All these tests have demonstrated the perfect tolerance of this type of vaccine.

Before the occurrence of the Covid-19 pandemic, four DNA vaccines had already received the regulatory authorizations necessary for their use in the animal. They are used, for example, to protect farmed salmon against infectious hematopoietic necrosis and pancreatic disease, chickens against avian influenza, or to treat dogs with oral melanoma.

But these promising results obtained in animals had not yet been reproduced in humans: the immunogenicity of these vaccines remained insufficient to provide patients with protection against the targeted pathogens. Marketing authorization still seemed a long way off.

The results announced by Pfizer, if confirmed, could be a game-changer and accelerate research on nucleic acid vaccines. The (near) future will tell us.

Bruno Pitard, Research Director, CRCINA, Inserm 1232, CNRS 6001, University of Nantes, Inserm

This article is republished from The Conversation under Creative Commons license. Read theoriginal article.

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