nasal vaccines, new hope for scientists

A new generation of vaccines is on the way. Sprayed through the nose, they promise to prevent the spread of the virus in the body and block its transmission in the nasal cavity.

Two, three, soon four doses (immediately, for immunodeficiencies and those over 80) … And the more injections, most of the population wonders about their usefulness, especially when there is a less dangerous and more contagious variant that can be transmitted despite vaccination. In any case, it remains “a marvel of modern science,” according to Hans Henry Kluge, World Health Organization (WHO) regional director for Europe.

At the end of November, a study conducted by this institution in collaboration with the European Center for Disease Prevention and Control (ECDC) showed that vaccination itself saved the lives of nearly half a million people over 60. However, in the scientific world, as in the WHO itself, we know that “it is unlikely that a vaccination strategy based on multiplying booster doses of the vaccine in its original form will be adapted and sustainable. We need Covid-19 vaccines that, in addition to preventing severe disease and death, have a marked effect on infection prevention and transmission. It would be nice to have them sorted out. »

We need Covid-19 vaccines that, in addition to preventing serious forms of illness and death, have a marked impact on prevention and transmission.

In fact, the researchers did not wait for this instruction from the WHO, which was reported on January 11. Dozens of teams work for months try to develop these new vaccines. Among them, some have decided to neutralize the virus where it attacks us. Now everyone knows the gateway to Sars-CoV-2, its first place of spread: the upper respiratory tract, the throat and, above all, nose.

Thus, the nasal vaccine has become new grail. Twenty clinical trials have been started and are already in phase 3, with results that the labs believe promising. So Lovaltech, a biotech company established at the National Research Institute for Agriculture, Food and the Environment (Inrae) and the University of Tours, is working on a protein vaccine for nasal instillation. This cocktail of proteins encapsulated in nanoparticles based on starch and lipids, completely excreted by the body in a few hours and without any excipients, could enter the market at best by the end of 2023.

Among these proteins is the “spike”, the main target on which modern vaccines are based and which concentrates most of the mutations seen in variants. But other proteins that are not subject to mutations were added to the mixture. The function that gives hope that the vaccine will be effective against known variants. The Pasteur Institute, together with TheraVectys, is developing its own project for an intranasal vaccine against Covid-19. Here the principle is different. It is a “viral carrier” that carries the active principle (spike protein) to immune cells, which activate others to take revenge on the attacker.

Not enough and especially not good

The intranasal route of administration for respiratory infections theoretically has several advantages. First, and logically, a vaccine injected into the nose elicits an immune response in the nasal mucosa. There, therefore, where the virus enters the body. The idea is tothen offer sterilizing immunity, that is, which blocks the transmission of the virus in the nasal cavity, preventing its reproduction and then spread in the body. In animal models of the LovalTech project, the viral load in the nasal cavities of vaccinated golden hamsters was not detected – their symptoms of Sars-CoV-2 are very similar to those of humans. For one developed by Pasteur-TheraVectys, the viral load in mice was divided by a thousand. And in the golden hamster, the vaccine used as a booster intramuscular injection suppresses the development of lung lesions. Better: In mice, it not only protects the lungs but also the central nervous system.

In the golden hamster, the nasally vaccinated group transmits the virus one hundred times less than the intramuscular or unvaccinated group.© Getty

In short, in order to curb the contagion faster, it is therefore necessary produce antibodies in mucous membranes. However, “current vaccines do little in this area,” says Professor Peter Hellings, otorhinolaryngologist and maxillofacial surgeon at UZ Leuven. Not enough and especially not good ones. After intramuscular injections, which are used in all Covid-19 vaccines currently on the market, we certainly detect IgG antibodies present in the blood for some time. But their relatives, IgA, located in the mucous membranes of the nose and lungs, which are more sensitive and block the entry of the virus faster, are almost undetectable. However, these “IgA” type antibodies play a crucial role in the immune function of the mucous membranes. “They act locally and quickly to neutralize pathogens,” says Peter Hellings.

Nasal insertion also offers additional levels of protection. It stimulates the production of “memory B cells” that produce IgA or IgG. These memory cells, then specialized against that pathogen, persist in the airway mucosa even when the more ephemeral IgA disappears. And later, if the same virus reappears, infecting the mucous membranes of the nose or respiratory tract, they will be immediately reactivated and will carry out a specific and effective attack much faster, mobilizing their weapon, IgA antibodies.

Finally, intranasal vaccines mobilize another defense mechanism against an attacker: memory T cells, which are also found in the mucous membranes of the respiratory tract. These cells fight cells infected by the pathogen. They also have extended memory : they will be reactivated in the event of a new attack of the entire “coronavirus brood”, and not just its single spike protein.

Downshift

But the main hope with a virus as contagious as Sars-CoV-2 is to Rreduce transmission between people. “If we really want to break this cycle and live a normal life, now we really need to focus on reducing the transmission of the infection,” continues Yves Van Laethem, infectious disease specialist at CHU Saint-Pierre and inter-federal representative. RNA vaccines are very effective in controlling the virus, but they are not designed to control transmission. They do little, but that’s not their main goal. »

A study published in August 2021 in the journal Science Translational Medicine evaluated the AstraZeneca nasal vaccine in this way, which, like the intramuscular vaccine, is based on an adenoviral spike protein-enclosing vector. The researchers compared the two routes of administration in animals. “In golden hamsters, the nasally vaccinated group transmits the virus one hundred times less than the intramuscularly vaccinated or unvaccinated group,” the study concludes. This AstraZeneca vaccine is one of the most advanced intranasal candidate vaccines among the dozen listed by WHO that are currently undergoing clinical evaluation: human trials already started.

One of the problems with these vaccines
One of the challenges of these “late” vaccines will be to find volunteers willing to test their effectiveness, at a time when the share of the vaccinated population in the world is constantly increasing.© Getty

with nasal passage, precautionary measures however, are required. The mucous membrane is close to the brain and facial nerves, which prohibits the use of some components. For example, messenger RNA vaccines use polyethylene glycol and cannot be administered intranasally. “It is much more difficult to dose because the mucous membranes, unlike the blood, must provide tolerance,” notes Professor Peter Hellings. There are bacteria and viruses that play an essential role. The balance is very delicate. » In addition, over time, the nasal mucosa becomes capricious. “Being constantly exposed to viral or bacterial attacks, it cannot build up an immune memory against everything it encounters. »

Intranasal vaccines are more difficult to dose because mucous membranes, unlike blood, must be tolerated.

Another unknown remains the term of protection. It also remains to carry out repeated tests, measurements of IgG and IgA and, above all, to oppose the vaccine to Omicron and check its durability. There, one of the big problems of these “late” vaccines will be precisely the search for volunteers who are ready to test the effectiveness of the product, while the proportion of the vaccinated population in the world is constantly increasing and there are already very effective ones. So the idea is to offer them as reminders, as a “booster”. A person already vaccinated intramuscularly may benefit from a new dose of intranasal vaccine to support the mucosal immune response. “In a few months, in the fall, the concept of recall will still be just as important,” concludes Yves Van Laetem.

Therefore, this would be double action : against transmission and against serious forms. A pattern that could give hope, finally, for a return to pre-pandemic life. AT

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