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The pros and cons of the anti-COVID nasal vaccine

Contrary to what most people think, the main goal of current COVID-19 vaccines is only to protect against serious forms of the disease to reduce the risk of hospitalisation and death, not to stop the disease from spreading from one person to another. To do this, a “sterilising vaccination” would have to be the goal. Only then could the circle of infection be broken, putting an end to the pandemic.

How do you get to this level of effectiveness? In general, vaccination can trigger an immune response based on two types of cells: T lymphocytes, which can kill infected cells, and B lymphocytes, which make antibodies that can neutralise the virus (SARS-CoV-2 in the case of COVID) and stop it from multiplying and infecting new healthy cells.

Current vaccines, which include mRNA, are given through the muscle and are “systemic.” This means that they can activate a pool of immune cells that circulate through the blood and can then reach the infected organs.

As good as this systemic immunity is, it doesn’t allow for a high number of B and T lymphocytes to be sent to the nose and lungs to protect against the virus quickly and effectively, blocking it as soon as it arrives.

On the other hand, an intranasal vaccination not only causes a systemic immune response, but also a local immune response. This is right where SARS-CoV-2 enters the body. By turning on the immune cells in the nasal mucosa locally, it would be possible to beat the virus, which grows quickly in our respiratory system, and our systemic immune system (which need to be mobilised to the infected site).

In practise, this mucosal vaccination would quickly stop the virus, block its ability to spread and multiply in our bodies, and stop it from spreading and making us sick.

First of all, as we already said, only the nasal vaccination can directly stop the virus from getting in. But we should also say that the immune cells it wakes up there (T and B lymphocytes in the nose, mouth, and upper respiratory tract) are different from the immune cells that are woken up by the regular (systemic) intramuscular vaccination.

Also, the nasal route of vaccination causes B lymphocytes to make IgA (Type A immunoglobulins) antibodies, which are only very weakly caused by the intramuscular route, which mostly causes B cells to make IgG antibodies (Type G immunoglobulins).

Worst of all, IgAs are better than IgGs at “capturing” viruses and getting rid of them. Another benefit of IgAs is that they are more “versatile” than IgGs. This means that they can keep working well even if the virus changes in some way. Because of all of these things, “mucosal” vaccination would stop even mild forms of the disease and stop it from spreading from one person to another. This is called “sterilising immunity.”

The only intranasal vaccine approved for human use is FluMist (AMM). This flu vaccine is based on a weakened form of the virus that causes flu. It has been approved in the U.S. and Europe, and in young children, it works better than the intramuscular vaccine.

But adults are less likely to get better because they already have mucosal immunity from having had other infections. In fact, the vaccine, which is a weakened version of the virus, is quickly blocked by the existing immunity to the original virus. This makes it less likely that the vaccine will work well.

Our research team, led by Professor Isabelle Dimier-Poisson and based at the BioMAP laboratory of the Joint University-INRAE ISP 1282 research unit, has a lot of experience with immunology and mucosal vaccination. Based on our knowledge, we have come up with a new anti-COVID mucosal vaccine strategy to deal with its many unique features. Our candidate vaccine is based on three new ideas:

The antigen is what the virus wants, and it is the most important part of the vaccine. It is an original fusion protein that was made in our lab. It is made up of the well-known Spike (S) protein and another virus protein called nucleoprotein (N). This fusion strategy lets our vaccine keep working against different variants because it targets parts of the virus that stay the same no matter how the S protein changes.

To get the mucosal immune response going as well as possible, we wrap our antigen in “nano-carriers.” These nano-carriers are only made of sugar polymeric molecules. They can stick to the mucous membrane in a unique way, which makes it easier to deliver our protein. So, there is no need for an adjuvant, which is likely to cause inflammation. This lowers the chance of side effects.

Lastly, the last important part is a dedicated delivery system, such as a spray, that can put our vaccine in the nasal cavity, right where the mucosal immune cells are.

Other teams are using this kind of method to make anti-COVID vaccines that are given through the mucosa. But there are still not many vaccine candidates that can be used in people. China and India are two places where this happened recently (September 2022), though they don’t use the intranasal route in the strictest sense.

A first vaccine is being tested right now in China. It is given by breathing it in. Chinese health officials have given the CanSino Biologics vaccine the green light as a booster dose to protect against COVID-19 symptoms. Like the intradermal vaccine, it is made from a recombinant adenovirus that makes the S protein of SARS-CoV-2. It is given through the mouth with a nebuliser.

So, it needs a special medical device and, because it is a virus, even when it is weakened, it can cause side effects like inflammation of the lungs. The second vaccine has been approved by Indian health officials. It is called iNCOVACC and was made by Bharat Biotech. It is given in two doses through the nose.

This nasal vaccine also uses a modified and weaker version of the adenovirus to deliver the SARS-CoV-2 Spike protein. This vaccine was made by Michael S. Diamond and David T. Curiel at the University of Washington. It was recently written about in a paper that showed promising results from tests on chimpanzees. But this result doesn’t show what a “true” nasal vaccination would be like because it uses both intranasal and intrabronchial vaccination.

This way, the vaccine is given to the lungs, which could cause them to become inflamed. So, this preclinical result should not be taken too seriously. Also, it’s important to know that neither China nor India has yet released the results of human clinical studies that support their decision to approve these vaccines. No matter who is being considered, it is hard to make a vaccine formulation that works well when given through the nose.

In October, AstraZeneca announced that its first clinical trials of a nasal vaccine did not go as well as they had hoped. This vaccine, which was made with help from researchers at the University of Oxford and is given through the nose, showed only weak antibody responses in the nasal mucosa.

The reason would be that a lot of the deactivated virus in the vaccine didn’t get to where it was supposed to go and ended up in the digestive tract instead, before it could turn on the immune system in the mucous membranes. The spray system is very important, which is a point that the team working on this latest vaccine candidate makes a point to stress. Vaccinations given through the nose need to be thought about to make sure they work best where they are given.

In gold-standard preclinical models, our vaccine candidate worked very well against multiple versions of SARS-CoV-2, protecting against the disease and limiting its spread by a lot (mice and hamsters). Now, our goal is to show that it works in clinical trials on people, which are set to happen in 2023.

To move from preclinical studies to humans, the challenge is to get an effective immune response even though the vaccine is given in a different way. For example, in mouse and hamster models, the amount of vaccine used and how it is given with a micropipette in the nose causes immunisation not just in the nasal cavity but also in the upper part of the lungs.

But in humans, we want to stay at the level of the nasal cavity to reduce the risk of an uncontrolled immune response that can lead to an overly strong inflammatory reaction in the lungs (“cytokine storms”). The goal is to maximise stimulation of the nasal mucosal system only.

To do this, we want our vaccine to be completely deposited in the important parts of the nose, where the virus hides to infect and multiply and where the immune cells are that must respond to the vaccine (at the level of the NALT, or Nasal Associated Lymphoid Tissues, where IgA-producing B lymphocytes and T lymphocytes are concentrated).

A small difference: a vaccine spray is not the same as a traditional therapeutic spray that is used more than once. It must give the mucosal immune system a single, very accurate dose.

At the start of our project, we started working on these absolute requirements and set up research and development partnerships with two companies that specialise in intranasal delivery systems: Aptar pharma and Medspray. Two ways are used to figure out how well the spray systems might work:

In vitro, using an artificial model (nasal cast) that looks like the human nose and lets us see, with the help of a fluorescent dye, how our vaccine formulation gets into the different parts of the nose. This model lets us fix the spray so that it hits key immune system areas of the nasal mucosa in the best way.

In vivo, we compare the effectiveness of the different spray systems in rabbits, which are one of the best animal models, to see if they can get the best vaccine response in the nasal mucosa (in the context of regulatory toxicology tests).

Our goal is to choose the best intranasal delivery system in terms of how well it works in the body for future clinical trials (maximal vaccination efficacy despite a delivery restricted to the nasal cavity). With the idea of making a spray that can be used in low-income countries, we are also taking into account economic factors to make sure that it can be mass-produced at a lower cost.

In 2022, our team started the company LoValTech to support our candidate vaccine. This was done so that LoValTech could take over our academic research and follow its industrial development until it was ready to be sold.