Preventing Infections – The Research, Development, and Vision for Nasal Mucosal Vaccines

SNBL launched the Nasal Mucosal Vaccine Research and Development Center in the spring of 2023. The center is headed by Dr. Masaaki Miyazawa, professor emeritus at University and visiting professor at the School of Medicine, who is an authority on viral immunology, and is diligently promoting research and development of nasal mucosal vaccines with the aim of "preventing infection in the first place" under a comprehensive research system that encompasses immunologists, histostructural scientists, formulation engineers, and experts in animal experiments.

Please take a moment to read the discussion between Professor Miyazawa and our company president, Mr. Nagata.

Moderator:SNBL launched the Nasal Mucosal Vaccine Research and Development Center in April. At the top of the list was Dr. Masataka Miyazawa, an authority on viral infection immunology and former chief professor and dean of the Graduate School of Medicine at Kindai University School of Medicine, who has explained the new coronavirus in an easy-to-understand manner on NHK and various other media, and is currently a professor emeritus and visiting professor at Kindai University School of Medicine.
Today, President Nagata will explain the background and motivation forSNBL 's decision to establish the Nasal Mucosal Vaccine Research and Development Center, and after that, I would like to clarify the usefulness and future potential of the nasal mucosal vaccine in a dialogue between President Nagata and Dr. Miyazawa. Thank you very much.

President Nagata: First of all, I would like to talk about howSNBL established this Nasal Mucosal Vaccine Research and Development Center, and how and why they decided to develop a vaccine. We have been researching and developing nasal formulations of powders since 1997. Until now, nasal preparations were sprayed into the nasal mucosa with liquid, but we have continued to develop technology to administer the drug as a powder so that it can be effectively and efficiently absorbed from the nasal mucosa. Among them, some of the formulations are already in clinical trials.
The intranasal vaccine was previously researched when there were concerns about avian influenza entering Japan. However, obtaining influenza antigens was difficult, and adjuvant research had to be conducted simultaneously, presenting multiple hurdles, so the project was put on hold. However, with the outbreak of the new coronavirus infection, we decided to research the intranasal vaccine again, which led to the establishment of this Intranasal Vaccine Center.
I would like to ask Professor Miyazawa a few questions to proceed. First, could you explain what an intranasal mucosal vaccine is and how it differs from or what features it has compared to the vaccines we usually use via injection? I would appreciate it if you could explain.

Director Miyazawa: When discussing vaccines, we must first consider how vaccines work. The principle of vaccines utilizes the characteristics of the acquired immune response, commonly referred to as 'no second infection.' When first infected with a pathogen, the immune response occurs slowly, but upon the second invasion of the same pathogen, a 'faster and stronger' immune response occurs, eliminating the pathogen before symptoms appear.

This is because the 'memory cells' formed during the initial infection remain in the body for a long time and respond rapidly to the second invasion of the pathogen.
By getting vaccinated, similar memory against the pathogen is created, but for memory cells to activate, the pathogen must invade and stimulate the immune response. In other words, a 'second infection' triggers a 'faster immune response,' and the second time, symptoms may not appear, or one may not notice them. This is why many vaccines aim to prevent the onset of symptoms or severe illness. When explaining the COVID-19 vaccine, some people reacted by saying, 'If it only prevents severe illness but you still get infected, what's the point of the vaccine?' But that's essentially what vaccines are.
However, as I will discuss later, there are infections where, if contracted, the pathogen remains in the body for life and can cause severe illness over many years, or can be lethal upon initial invasion. For these, a vaccine that 'prevents infection in the first place' is ideal. Many pathogens enter through the mucous membranes of the respiratory, digestive, or reproductive systems, so it is necessary to prevent entry at the mucosal barriers. Our goal with the intranasal mucosal vaccine is to prevent infection from occurring in the first place (this is called 'blocking immunity').

President Nagata: Thank you. I now understand the difference between regular injectable vaccines and intranasal vaccines from your explanation.
So, What are the benefits of administering the intranasal vaccine, and in what disease areas can the intranasal vaccine be used? ,please tell me.

Director Miyazawa: Well, for example, in the case of viral infections, the pathogen, which is the virus, enters our body's living cells as 'wandering genes,' hijacking the cell's nucleic acid synthesis and protein synthesis functions to produce many copies of the virus. Therefore, to overcome a viral infection, it is necessary to eliminate the infected cells that have become virus copy factories from the body. This is the function of immune cells, but even though the infected cells have become virus copy factories, they were originally cells that made up our body. Eliminating them is essentially destroying a part of one's own body.

In fact, the symptoms of viral infections are not caused by the virus multiplying, but by immune cells attacking and destroying one's own cells that have been infected by the virus.
There is a disease called polio. The poliovirus infects the mucous membranes of the digestive tract and causes diarrhea symptoms. However, since the mucous membranes of the digestive tract naturally regenerate rapidly, replacing all cells within a few days, the mucous membranes recover even if the infected cells are destroyed. However, in rare cases, the virus infection can spread to the nervous system. When this happens, the immune system attacks the nerve cells infected by the virus. Since nerve cells do not regenerate, paralysis remains afterward.
The same applies to respiratory infections. An immune response occurs against the cells in the nose and throat infected by the virus, causing damage to the mucous membranes. However, since the cells in the nose and throat have a high regenerative capacity, they return to normal within a few days. However, if the infection spreads to the lungs, the lung cells are destroyed by the immune response. When the cells of the lung walls are destroyed, fluid from the blood vessels fills the lungs. Even if such lesions occur in part of the lungs, the lungs have a large reserve capacity, so it is not life-threatening. However, if the destruction of the lung walls exceeds a certain limit, it results in a state of "drowning on land," leading to death.

For such diseases, it is necessary to induce "blocking immunity," which prevents infection from occurring in the first place, rather than the conventional "suppression of onset" or "prevention of severe illness."
Similarly, once an infection is established, it becomes a persistent infection, and pathogens like herpesviruses and the AIDS virus, which can cause cancer and immunodeficiency over time, can only be prevented by blocking immunity to avoid infection altogether. Nasal mucosal vaccines are expected to be effective against these infections.

President Nagata: I understand well. Why have nasal mucosal vaccines, which have such wonderful benefits, not been developed or put into practical use until now? ？

Director Miyazawa: The cells that make up our bodies can only survive in the water known as body fluids. Viruses are also released from cells into the surrounding body fluids and emerge enveloped in these fluids.

Without being enveloped in water, the structure of virus particles cannot be maintained, nor can the three-dimensional structure of the proteins that function to attach to cells.
There are often people who say that naked virus particles fly from infected individuals (so masks can't prevent it), but this is a big mistake. Viruses always enter the body as droplets covered in water.
When droplets are absorbed into body fluids, the virus attaches to the surface of cells. The concept of 'blocking immunity' is to interfere with this using antibodies. For this, antibodies need to be present in the mucus of the nasal and throat mucosa, which serve as entry points.
However, antibodies (IgG) produced in the blood through typical intradermal, subcutaneous, or intramuscular vaccination do not directly appear in the mucus.
If the mucosa is damaged or infected, causing inflammation, antibodies in the blood may 'seep' into the mucus, but of course, by then it's too late. Conditions must be created where antibodies (IgA) are produced in the mucosa in advance and continue to be released into the mucus. This is the purpose of nasal mucosal vaccines.

Naturally, research on vaccines that secrete antibodies into mucus has been conducted for some time, but very few have been practically applied in humans. There are several reasons for this, one being that immunology research, including mucosal immunity, has primarily been conducted using mice.
The immune systems of humans and mice are fundamentally similar, but the structure of the mucosa is significantly different. Methods that worked well in mice do not necessarily apply directly to humans. Additionally, because mice are small, what was intended to be administered to the nose might actually flow into the lungs, leading to perceived effectiveness. The lack of thorough research methods for inducing 'immune responses that produce antibodies in the mucosa' is considered one of the reasons.
Moreover, the nose naturally inhales a variety of foreign substances, but immune responses generally do not occur against them. Hay fever and nasal allergies do not occur unless repeatedly exposed to the causative substances. In other words, the nasal mucosa is inherently a place where immune responses are difficult to trigger, and overcoming this is a challenge.

President Nagata: I see. I have a good understanding of the body's immune response. Then, how long will it take for the Nasal Vaccine Center to achieve its goals or to reach practical application? ？

Director Miyazawa: As President Nagata mentioned earlier, our company, TR Company, has been researching the delivery of drugs to the nasal cavity using our unique powder technology. By applying this technology, it is possible to concentrate the vaccine on the 'site suitable for inducing immune responses' within the human nasal cavity and ensure it adheres to the mucosa for a certain period. This is believed to induce immune responses in the mucosa more efficiently than liquid sprays.
Additionally, to produce antibodies secreted from the mucosa, it is necessary to provide the mucosal cells with an appropriate environment. Specifically, by using adjuvants, which are immune response-enhancing substances, including those with unique structures, specific cytokines (information transmission molecules between immune cells) are produced from the cells constituting the mucosa to promote antibody production.
We already possess the basic technology related to these, so we believe that within 2 to 3 years, we will be able to establish the groundwork for inducing strong antibody production in the mucosa. Ensuring safety is, of course, our company's specialty.
Naturally, we cannot develop the vaccines themselves, so our ultimate goal is to provide the nasal delivery-based mucosal antibody induction technology developed at the Nasal Vaccine Center to vaccine manufacturers and have it adopted as a platform for multiple mucosal immune vaccines in the future.

President Nagata: I'm looking forward to future developments. Then, how is the research and development system at the Nasal Vaccine Center? ？

Director Miyazawa: I took up my position at this Nasal Vaccine Center this April, but our company, TR Company, has been advancing research and development on absorbing drugs through the nasal cavity using our proprietary powder delivery system technology. In the process, we have naturally continued research on applying this to nasal vaccines, including studies on encapsulating vaccine antigens in nanoparticles. We also have unique achievements regarding the aforementioned immune response-enhancing substances.
With the establishment of the Nasal Mucosal Vaccine Research and Development Center, we reorganized these research groups and welcomed core members from my research group at Kinki University School of Medicine. We have created a comprehensive research system that includes immunologists, structural biologists, formulation technologists, and animal experiment specialists. Each group is led by an outstanding researcher at the level of a department head, with about two new master's level researchers under them.
The development of mucosal vaccines requires not only knowledge of cellular immunology in vitro but also pathological histology knowledge, including differences between humans and experimental animals. I am well-versed in human pathology as a former pathologist, and many of my collaborators are experts in respiratory diseases and human pathology, which is an advantage.
Additionally, since 2005, I have served as a science advisor for our company and as an external member of the Genetic Recombination Experiment Safety Committee, during which time I have built many connections with the headquarters' Safety Research Institute and others.
For the establishment of the Nasal Vaccine Center, we have also included members from the Safety Research Institute to concurrently serve, ensuring that we can effectively utilize the company's resources.

President Nagata: I am very relieved to hear your thoughts, Dr. Miyazawa.
Lastly, Dr. Miyazawa, you were born in Nagano, then went to Tohoku University, and after that, you were a professor at Kinki University School of Medicine for a long time. Now, you have come to the southern region of Kagoshima. How is life in Kagoshima? ？

Director Miyazawa: In fact, even before being invited to the Nasal Vaccine Center, I had a continuous connection with the company since 2005, having signed an advisory contract and served as an external member of the Genetic Recombination Experiment Safety Committee. I had opportunities for scientific discussions with members of various departments at the headquarters and visited Kagoshima almost every year, climbing Mount Kaimon and traveling to Yakushima, Koshikijima, and Amami Oshima with several people. Therefore, I was already captivated by Kagoshima's rich nature and delicious food.
This time, I moved to Kagoshima with my wife, and we are both already enjoying life here. In the Hanshin area, it takes about two hours to get out of the city if you want to go somewhere, but in Kagoshima, you can reach a small tourist spot in just 20 to 30 minutes by car from our home in Yoshino. The majestic view of Sakurajima is also wonderful.
Having grown up in the nature of Shinshu, life in Kagoshima feels more fitting than in Osaka. In fact, we lived for three and a half years in Montana, USA, a place where few Japanese have been. I think I'm good at getting used to new places, and I believe we will enjoy our time in Kagoshima very much.

President Nagata: That's great to hear. Thank you very much for today.