The first interview was conducted to Dr. Ken Ishii, Professor of Department of Microbiology and Immunology, The Institute of Medical Science, The University of Tokyo. When he had worked as a physician in ICU, Professor Ishii became aware of the importance of infectious diseases and immunology. He witnessed many patients after surgery for cardiac or gastrointestinal diseases died by postoperative multidrug-resistant infections not by the worsen primary disease in ICU. This motivated him to enter the world of immunology research. Basic research on malaria vaccines was his initial vaccine research subject at the Center for Biologics Evaluation and Research (CBER) in FDA. At that time, molecular biology was the mainstream in research, and vaccine, and adjuvant research were viewed as secondary. For that reason, Professor Ishii had a great deal of difficulties in research. Subsequently, the situation has been changed and research on innate immunity, self-purifying cells, and dendritic cells has become dominant in immunology. Professor Ishii has been begun to engage in adjuvant research around that time and he now leads the global vaccine and adjuvant research.
— Thank you for taking time for us today. The world's attention has been focused on the control of COVID-19 (new-type coronavirus disease) and we believe that makes you very busy. (Note: At the time of the 2020 interview, the world has begun to shake up with COVID-19.)
SARS-CoV-2 (causal virus of COVID-19) has become a very serious problem. Coronavirus is known as the causative viruses of flu. It often emerges in human world, through animals such as bats, as a new type of virus causes zoonotic infections. SARS (Severe Acute Respiratory Syndrome) and MERS (Middle East Respiratory Syndrome) are examples of coronaviruses. SARS attracted particular attention due to its higher mortality rate. After that, the possibility of a new epidemic of the new virus was pointed out, and MERS came out. Thus, we had experienced outbreaks of new viruses. The emergence of the newer virus, as we are experiencing currently, was anticipated. I think that pharmaceutical companies and researchers should have been prepared countermeasures for such cases. Actually, that industry and academia which experienced SARS are not in a fluster. Through various media, an impression is spread out that the public administration such as the government and local governments did not take prompt initiatives against SARS-CoV-2. That makes the whole society rather panicky.
— I think we are gradually identifying SARS-CoV-2. How the development of vaccines and therapeutic agents for SARS-CoV-2 are going?
As a cornerstone of countermeasures against infectious diseases, therapeutic drugs, such as antivirals or antimicrobials, and vaccines, are imperative. Since the issue of drug tolerance always associates with antivirals and antimicrobials, vaccines are better for long-term prevention of infections. However, no drugs or vaccines can be developed and ready to be clinically used soon after the infection emerges. Currently, no specific drugs with full efficacy is found, though anti-HIV drugs, anti-viral drugs, chloroquine (anti-malarial drugs), and asthma drugs are listed as drugs with promising efficacy. Existing drugs have been applied to SARS-CoV-2 with reference to research articles related to SARS. I heard anti-HIV drugs and Avigan is going into clinical trials. These drugs were used and had efficacy to control viral growth during an outbreak of SARS and Ebola virus disease. But risk of adverse reactions is anticipated and they cannot be used widely as influenza drugs. An anti-HIV drug which is told to be effective against SARS-CoV-2 have toxicity in long-term use of the drug, and their use against HIV was replaced by new generation drugs. If the efficacy against SARS-CoV-2 is confirmed, administration has to be limited for short term. Based on unofficial information, chloroquine, an ancient known drug for malaria, has been approved for the treatment of SLE (Systemic Lupus Erythematous), and it may become a dark horse.
— The word 'adverse reactions' reminds me HPV vaccine (vaccine of uterine cervical cancer). Public attention was focused on HPV vaccines at that time. How do you think about the risk and benefit of vaccine development?
I have been often asked about the HPV vaccine. Not only HPV vaccines, similar situations have been repeated for long time. Due to vaccination-induced adverse reactions, vaccination is discontinued and victim associations are established. This actually occurred with influenza vaccine, measles-rubella combination (MR) vaccine, and Japanese encephalitis vaccine. In general, I believe vaccines is far above superior in benefit in terms of risk and benefit balance. Unfortunately, the benefit of vaccine is difficult to realize. Because the benefit means not to be infected in the future. On the other hand, when adverse reactions occur, their risks are noticeable and easy to be criticized by the media. Similar cases occurred more than 200 years ago when Dr. Edward Jenner discovered the vaccine. In a case of administration of HPV vaccine, similar case could be expected. For this reason, I intended to have sounded an alarm to disseminate accurate information to the public. Unfortunately, the news of the adverse reactions induced confusions.
— It might be a difficult challenge to communicating its risks and benefits scientifically to general consumers and the media.
'Vaccine Hesitancy' is listed in "Ten Threats to Global Health in 2019" announced by the WHO (World Health Organization). Vaccine Hesitancy is the situation that we have effective vaccines but some people tend not to want to be administered. The most prominent case in Japan is that HPV vaccine. I try to explain that not getting the vaccine is the riskiest case, but it does not work that easy. Most people can understand that the risk of not getting vaccinated is more serious than the risk of getting vaccinated. But incorrect medical information is deluged in SNS, etc., then anti-vaccine people spread the incorrect information. The correct information is not perceived as correct by anti-vaccine people. There exists a scientific paper saying that even the counterevidence papers in scientific journals could not suppress the activity of the anti-vaccine…!
— The greatest risk is not to be vaccinated, but still some people refrain from vaccination. Then, is it necessary to develop legislations and enforce vaccination to some extent?
That's right. Vaccination, for example, is one of the essential tasks of public health in the United States. Children are not permitted to enter a primary school without designated vaccinations. However, there are always exceptions such as religions and beliefs. Unfortunately, a measles epidemic has occurred because children were exempted from vaccination by this exception. The situation is almost the same in the UK. As for Japan, there are relatively many people who do not trust vaccines. A past scientific paper published the ranking of anti-vaccine countries. France was the first anti-vaccine country, Bosnia Herzegovina was the second, and Japan was the third in 2016. The anti-vaccine situation in France seems to be gradually improving, but there is no sign of such improvement in Japan. Japan may now be the number one anti-vaccine country in the world. It might be rather exaggerating, but the incidence of uterine cervical cancer without vaccination is said to be increasing only in Japan and North Korea in the world. We aspire to find effective vaccine against SARS-CoV-2, but we have not found yet. On the other hand, we have already developed effective vaccine for uterine cervical cancer, but some people do not willing to receive it. It's quite ironic, isn't it? I believe there is no death case caused by the HPV vaccination directly, but about 3,000 young women die every year from uterine cervical cancer. Looking at this figure, the benefit of receiving the vaccine can be easily understood, but there is still a tendency to hesitate to receive the vaccination.
— How we evaluate the risks and benefits of vaccination scientifically and spread the information to the public…. I understand that there are challenges for both scientists and general consumers.
Scientists and healthcare professionals have to make the invisible benefits visible and appropriately communicate the risks and benefits to the public. It is very important to make efforts to disseminate correct information to the public. Consumers also have to collect and choose the information by themselves. They have to decide how to act at one's own risk without leaving the matter to the government or family doctors. We, Japanese are not good at judging by themselves, and tend to blame others, don't we? Trying to make decision by ourselves from childhood is very important to foster the ability to make scientific judgements. Recently, I have been contributing to this type of educational activities. For example, I am involved in the production of comics and cartoons on infectious diseases and immunity. Through these works, I would like to know the true significance of immunity, that is, how our body distinguishes 'self' from 'non-self'. I hope that this will lead us to learn how to live by identifying and selecting risks and benefits.
— We have asked about the background of vaccination. Now, I would like to ask about the methodology of vaccine development. In evaluating efficacy of vaccine and adjuvant in clinical trials, do the researchers compare future morbidity in vaccinated and non-vaccinated groups?
That's correct. Basic method is the same as developing medicines for general drugs such as diabetes and hypertension drugs. We compare the effectiveness (proportion of people who did not have the disease) of two sets of groups; the control (mock-up vaccine) group and the treatment group. If the benefits are recognized, the vaccine will be approved and marketed. That is a general flow. As you know, a common vaccine takes 15-20 years from its discovery to launch, so Japanese pharmaceutical companies tend to be less interested in developing vaccines. Not like small molecule drug discovery, which sometimes immediately benefit the company as blockbuster medicine, vaccines do not make immediate benefit. However, once the vaccines are marketed, rather steady profit is expected over a long period of time. Moreover, vaccination is essential for public health. Therefore, with implications of social contributions, global mega-pharmaceuticals are responsible for development, manufacturing, and marketing of vaccines. In Japan, a relatively small pharmaceutical companies were appointed by the government to develop and market vaccines. Around a decade ago, major pharmaceutical companies started to enter the vaccine market.
— I think if the season or region of pandemic is predicted, it is easier to plan development of vaccines. But it is not always the case. If we cannot predict them, do we just have to just wait for the occurrence of the incident?
Just as you pointed out, vaccine development is gradually progressing in the disease areas where its season, number of patients, or size of epidemic is possible to predict. In that case, pharmaceutical companies can calculate their cost and benefit. Recently marketed vaccines for herpes zoster and pneumococci for a group of elderly people are good examples. Pharmaceutical companies can expect benefit from a large market which reduces the barriers to enter vaccine development. Not limited to infectious diseases, vaccine discovery has begun in all areas of disease. A vaccine for smoking cessation is expected to be of great benefit in the future. In other words, pharmaceutical companies participate in and invest where they can easily predict development costs and greater financial benefit. On the other hand, pharmaceutical companies have not been actively engaged in the development of Emergency Infection Diseases, Emerging Infection Diseases, and Intractable Infection Diseases including SARS-CoV-2, dikaviruses, MERS, HIV, and malaria. That's because pharmaceutical companies know they cannot expect enough profit. The vaccine development for the mentioned infectious diseases is currently relying on funding from NGOs, so-called Global Fund.
— Public support for vaccine development is also necessary as for orphan drugs.
In the future, multi-product small-volume production such as prescription medicine will become the mainstream of vaccine development. Vaccines will be combined and produced based on individual differences like gene therapy for intractable diseases. We do not know to what extent pharmaceutical companies are committed to it, though. Japanese companies are working on developing vaccines for SARS-CoV-2, but I do not feel that they make much commitment as those of overseas companies.
— As diversity of vaccines and adjuvant developments, including the expansion of target disease areas, we believe that the regulation must also correspond to a variety of patterns. Do you think Japanese regulations are well-prepared?
From approximately a decade ago, vaccine discovery in Japan has been gradually changed. Since then, nonclinical and clinical guidelines for vaccine development have also been released. There are also pandemic and mock-up (mock-vaccine) guidelines, and the regulatory regime is gradually developing. Previously, vaccines have used attenuated pathogens, and thus methods for handling and cultivating pathogens were used as regulations. Now, however, the vaccine is becoming like an assembled car or rocket. In other words, there are cases that combinations of non-natural products are used to make vaccines. Past regulations cannot correspond to such developing methods. The regulations required for vaccine development is becoming closer to those of biological medicines, cell therapy, and gene therapy. In the areas of recombinant viruses, adjuvants, and drug delivery systems (DDS), it is increasing that we can share regulations of other medical fields. That makes the contributions from non-vaccine specialists essential.
— There is an image that a highly effective vaccine has a strong adverse reaction, but how do you think about this?
Adjuvants are key element which closely associated with the problem of adverse reactions. Adjuvants are strong immunoactive agents, and they are often pathogen derived. In a sense, they are toxicants. Lipopolysaccharide (LPS) is a good example. Such adjuvant is handled as a toxicant in regulations. Better adjuvants have stronger bioreactivity. I think how to use these somewhat toxic agents safely is the key of the regulations in vaccine development. In the past, an influenza vaccine developed in Japan was not approved because children experienced fever. The data indicated, however, that febrile children's immunity was more active and that showed the vaccine was effective. This does not mean vaccines do not work without fever. There are vaccines which work without fever, and do not work with fever. This is the point that the vaccine developer would show their sense and skills.
— Now diverse modalities becomes available, viewpoints for drug discovery is likely to expand infinitely. On the other hand, it would be difficult to decide where to start. For example, a target antigen, an adjuvant, or a DDS, and those combinations... Starting points seems limitless.
The existence of adjuvants has long been known, but the mechanisms, such as why they are effective and why they have side effects, have not been scientifically clarified. However, in the last two decades, studies on innate immunity and omics have been developed, and the mechanism of action of adjuvants has become revealed. Then, combinations can be surmised accordingly. In this sense, it is becoming possible to assemble specific parts together and devise a large number of similar concepts. Nevertheless, it is still unexplored fields. For example, what immunity must be induced, and which antigenic modalities and adjuvants should be chosen to induce that immunity to treat/prevent a specific target disease. In that regard, AI may be the key to explore the field. Recently, AI has been developed in mega pharmaceutical companies and Western consortia, and they utilize AI to drug discovery and vaccine development. I could say our research group lead in the field of adjuvants using AI. We are now in the process of making a paper, so please expect future evolution...!
— Many effective vaccines and drugs have been developed, so far. On the other hand, the mutations and antibiotic-resistance by antivirals and antimicrobials is being highlighted. In this context, how can we face viral and bacterial infections in the future?
First, I will talk about vaccines. As immunologist, I believe the vaccine has to be 'no two times.' In other words, once vaccinated, the vaccine is expected to prevent the plaque rest of the life. Such as influenza vaccine, which are given annually, are not fit my definition of vaccines. Since tens millions of people receive influenza vaccines each year, it is very successful as a business, but it needs to be greatly improved. Appearance of resistant bacteria against antiviral and antimicrobial agents is inevitable in a sense. AMR (Antimicrobial resistance) has become the most significant health issue in the world. If antibiotics are administered discontinued easily soon after the symptoms are improved, resistant strains may develop. AMR might be a cause of destruction of mankind. I heard there is a pharmaceutical company that is developing stronger antibiotics against the resistance strains. I definitely oppose that policy. Antibiotics were originally responsible for AMR. It is obvious that antibiotics should not be counteracted with stronger antibiotics. I look at drugs and vaccines as a "necessary evil." Public health is more important than medicines and vaccines, and hygiene is furthermore important. In short, it is important to return to hygiene, the foundation of social infrastructure, including not drinking dirty water, washing hands, and gargling. Media recently started to recommend washing hands and gargling against SARS-CoV-2. After all, we get back to hygiene. Moreover, agrochemicals and chemical fertilizers make larger vegetables and fruits, and chicken meat and eggs are improved at appearance. On the other hand, soil destruction is ongoing and microbiota diversity is losing, as in human gut bacteria. People used to live among microorganisms, including parasites but have been trying to eliminate them. It certainly comes back to bite. As the term 'One Health' has described, we are facing the fact that humans are destroying the ecosystems of animals and organisms as well as humans. I believe that it is more important to be aware of the fact and start discussions what we can do than to see news about antiviral drugs and vaccine production against SARS-CoV-2 in suspense. Current panic-like situation caused by SARS-CoV-2 is unusual. It is important to be scared based on the correct information.
— Being scared based on the correct information and thinking what we really need. Then, we will see future drug developments. I would like to bear in mind that. I still have a lot of things to ask, but time has passed quickly.
I hope this experience of SARS-CoV-2 and COVIC-19 will be a trigger for thinking about drug discovery and for human beings to grow significantly. Let's hope better developments will occur when we overcome this situation!
Through this interview, Professor Ishii conveyed his enthusiasm for vaccine research and the importance of appropriate judgment and vision formation based on correct information recognition. Not only in drug discovery research, but he motivated our attitudes facing our daily lives.
We will continue to conduct interviews to scientists who work in the front lines in irregular basis. If you have any comments or requests, please contact to Catalyst Unit. I look forward to hearing from you!
March 4, 2020