For the 98th HGPI Seminar, entitled “Rebuilding the Vaccine Research and Development Pipeline to Support Public Health and National Security,” we hosted Dr.Ken Ishii, a professor in the Division of Vaccine Science at the University of Tokyo Institute of Medical Science. Dr. Ishii spoke about the background of Coronavirus Disease 2019 (COVID-19) vaccine development and current issues and future prospects for Japan’s vaccine R&D pipeline.

To prevent the potential spread of COVID-19, this seminar was held online.

 

Key points of the lecture

– When the COVID-19 pandemic began, each country entered the race to develop vaccines. Historic and disruptive innovation in vaccine production and supply on a global scale took place in about one year, an extremely short period for vaccine R&D.

– Two successes led to that innovation: (1) development was shortened significantly because each stage of the development process, from basic research to production and supply, was advanced simultaneously, and (2) new types of vaccines with different mechanisms of action from conventional vaccines were successfully put to real-world use.

– The COVID-19 pandemic reminded us of the importance of vaccines from various perspectives including foreign policy and national security. Japan’s current issues include insufficient investments in vaccine development during non-emergencies and the absence of a coordinating organization to function as a control tower for research.

– Future vaccine development will require efforts in a broad range of fields. These include establishing a central research organization which can incorporate international perspectives, promoting R&D using the latest technologies and scientific knowledge, systematically implementing education on vaccines and infectious disease control at medical schools, and undertaking activities to disseminate and build awareness for accurate vaccine information among the public, especially children.

 

■ The Historic and Disruptive Innovation that Occurred During COVID-19 Vaccine Development

The outbreak of COVID-19 in 2019 once again highlighted the importance and urgency of vaccine development. Each country entered the race to develop vaccines, kicking off work on over 100 different types. Pharmaceutical companies and research institutes in certain countries like the U.S. and the U.K. succeeded in developing vaccines, which are now being supplied in many countries. While R&D for COVID-19 vaccines is also underway in Japan, as of August 2021, those efforts have yet to produce success.

Vaccine development usually requires more than a decade to complete. However, historic and disruptive innovation occurred during the development of COVID-19 vaccines, which led to the rapid production and supply of vaccines on a global scale within one year. There are two reasons there are two reasons why this occurred: each step of the development process, from basic research to production and supply, was advanced simultaneously, which significantly shortened the time required to complete development and because new types of vaccines with different mechanisms of action from conventional vaccines were successfully put to real-world use.[1]

■ Shortened development times through simultaneous progress on each step of the development process, from basic research to production and supply

The stages of developing and supplying a vaccine are basic research; non-clinical trials; clinical trials (in Phases 1, 2, and 3); regulatory application, review, and approval; production system development; and production and supply. Normally, the stages of this development process are carried out one at a time, in order. For example, development moves onto Phase 2 trials after Phase 1 trials are completed. However, during COVID-19 vaccine development, these stages overlapped so later trials were carried out before previous trails were completed. For example, regulatory application and approval processes were initiated while clinical trials were still underway. In addition, some countries prepared systems to manufacture more doses than needed for their own populations before development was complete. This allowed them to provide vaccines to countries around the world very rapidly after successful development. In this manner, different stages of the development process were carried out in parallel instead of in a series, like usual, which significantly reduced development time.

There is now an initiative for further accelerating development called the 100 Days Mission. It aims to reduce the time required to produce and supply COVID-19 vaccines from the current period of approximately 300 days to approximately 100 days. The 100 Days Mission was backed by G7 leaders at the June 2021 G7 meeting chaired by the U.K. It was also endorsed by the COVAX Facility (COVID-19 Vaccine Global Access Facility), the Coalition for Epidemic Preparedness Innovations (CEPI), and the Bill & Melinda Gates Foundation. The Government of Japan also endorsed the 100 Days Mission, so we must now search for methods of shortening vaccine development time to 100 days.

■ The practical implementation of new types of vaccines with different mechanisms of action from conventional vaccines

Another factor that contributed to the rapid development of COVID-19 vaccines was the real-world implementation of new types of vaccines with different mechanisms of action from conventional vaccines. Specifically, there are the mRNA vaccines and viral vector vaccines,　which, upon approval, may also be joined by DNA vaccines.

The modalities of these vaccines are not exactly new; a base research paper on the use of mRNA was published about 30 years ago, in the 1990s. Since then, research to develop vaccines and pharmaceuticals applying this concept has advanced. Due to their tendency to cause significant inflammatory responses and their instability, it was difficult to put mRNA molecules to practical use. However, a method for administering mRNA while suppressing the inflammatory response was discovered with the publication of a research paper by Katalin Carrico, Michael Buckstein, Houping Ni, and Drew Weissman in 2005. This was a major step forward for vaccine? research. Improvements in drug delivery systems (DDS)[2] also contributed to the successful implementation of mRNA-based vaccines.

Compared to conventional vaccines such as live vaccines and inactivated vaccines, mRNA vaccines can be produced more rapidly and provide the same immune responses as live vaccines (e.g. the production of antibodies and cellular immunity). While the safety of conventional vaccines has become clear over their long history of usage, in many cases, the long-term safety of mRNA vaccines is not yet clear because it is still a new technology. Evidence for their safety must be established in the future.

■ Factors that led to the successful development of vaccines in the U.S. and the U.K.

The main reason COVID-19 vaccine development succeeded in the U.S. and the U.K. was because vaccine development was taken as an emergency measure. Rather than responding in a manner suitable to normal times, both countries responded as if faced with a war or a disaster. They also recognized vaccines as a key element of public health that affects both national security and foreign policy. As such, advance investments in regulatory science[3] and mRNA vaccine technology development had already been made, which also contributed to the successful development of COVID-19 vaccines.

Vaccines have a broad impact on society in areas like foreign policy, national security, economy, and industry. This is especially the case during emergencies like the ongoing COVID-19 pandemic. As such, making progress on vaccine policy requires policy discussions that cut across ministries and agencies in addition to discussions with healthcare specialists and healthcare-related ministries. However, cooperation among ministries and agencies is insufficient in Japan. The lack of cross-ministerial policy discussions must be addressed.

Including the points raised above, the reasons behind the successful development of vaccines in the U.K. and the U.S. can be summarized as follows.

• There was support for basic research that contributed to continuous infectious disease research and vaccine development. (Compared to Japan, research investments were 20 times greater in the U.S. and 5 times greater in the U.K.)
• Vaccines were positioned as a key item for security (including bioterrorism) as well as for foreign policy.
• Development received nationwide support (including budgets, human resources, and resources).
• Infrastructure and resources necessary for large-scale clinical trials were in place.
• Budgets were prepared and regulations were relaxed to enable the simultaneous advancements of development stages.
• Thorough steps were taken for sharing, transparency, and visibility of data and information.
• In both countries, there was support for start-up companies, vast human resources, positive attitudes toward attempting challenges, and a cultural tolerance for failure.

■ The current situation in Japan and issues for domestic vaccine R&D and policy

Vaccines are one of the most successful medical technologies. As of August 2021, 27 diseases including smallpox and polio have been designated as Vaccine Preventable Diseases (VPDs),　and their vaccines protect many people. Beyond the field of infectious disease, vaccines are currently being developed for a wide range of non-infectious diseases such as neurological diseases, cardiovascular diseases, aging, and obesity. However, there are also issues unique to vaccine policy, such as addressing certain diseases that are difficult to control with vaccines alone. There are also times when people find it difficult to appreciate the value of vaccines because how they control infectious diseases may be difficult to visualize or understand.

Other topics in vaccine R&D include the need for research into the development or manufacture of antigens, in vivo delivery systems, and adjuvants,[4] as well as the need to draw expertise from various academic fields including regulatory science, health economics, and ethics. Vaccine R&D requires large-scale vaccine R&D teams (or consortiums) that include specialists from various fields, so steps must be taken to establish such teams in Japan. Another issue that has been raised is the deterioration and degradation of the research environment, which needs urgent improvements. Finally, vaccines are an important strategic commodity from the perspectives of foreign policy and national security. While taking steps for domestic vaccine development and production, it will be necessary to adopt a global perspective and build cooperative ties with other countries in all aspects of vaccine development and production, from active pharmaceutical ingredients to production lines and distribution.

Given the above, we see that successful vaccine R&D will require us to consider a broad variety of complex issues in a comprehensive manner. Foreign countries such as the U.S. and the U.K. have established organizations that serve as central control towers to coordinate collaborative efforts, but Japan has yet to establish such an organization that can operate on a global scale.

In recognition of these issues, the Headquarters for Healthcare and Medical Strategy Promotion Pharmaceutical Development Council of the Prime Minister’s Office issued a proposal on the need for a global research center for vaccine R&D. Then, on June 1, 2021, the Cabinet approved the Strategy for Strengthening the Vaccine Development and Production System to promote cross-ministerial measures to reinforce the vaccine R&D pipeline. On June 15, 2021, HGPI also issued recommendations for vaccine policy in “A Life Course Approach to Immunization and Vaccination Policy – Five Perspectives and Recommended Actions.” (For details, please click here.)

■ Steps for advancing vaccine R&D after COVID-19

To promote vaccine R&D post-COVID-19, we believe the first step will be improving education at medical schools. There are three key aspects to infectious disease control: 1) medicine; 2) public health, including epidemiological surveys, biostatistics, and hygiene activities conducted by public health organizations; and 3) hygiene, which includes health maintenance and prevention activities implemented at the individual and community levels, such as masking, hand washing, and ventilation. Of these three topics, public health and hygiene are often neglected during medical school education, and people studying these fields in Japan lack opportunities to study vaccine-related fields, such as immunology and microbiology, in an integrated manner. Vaccine R&D requires a wide range of expertise, so we must renew our understanding of the importance of education on vaccines in medical schools.

Future vaccine development will require innovations that simplify and speed up the complicated development process. To achieve that, we are advancing an initiative called “Establishing a Vaccine Research Infrastructure for a New Dimension in the Post-COVID-19 Era.” This initiative aims to develop technologies based on past research results that will enable higher-resolution profiling of the various human immune responses and the modularization[5] of antigen systems, adjuvants, and delivery systems suitable to those immune responses. We expect such innovations will enable the development of vaccines that can be used to produce immunity in a rapid and accurate manner during pandemics.

Vaccine hesitancy, which occurs due to people’s concerns regarding vaccine safety, is another topic that requires attention when thinking about vaccine R&D. Many factors can contribute to vaccine hesitancy and there are signs that vaccine hesitancy is particularly strong in Japan and France.

Accurate information is of the utmost importance in discussions on vaccine hesitancy. Efforts are needed to convey accurate information based on scientific evidence, especially during educational opportunities for children.

 

[1] During the R&D process for COVID-19 vaccines, vaccines of different modalities utilizing different immune responses and scientific technologies emerged. These ranged from those produced using conventional methods to those made using the latest techniques, including (1) viral vector vaccines, (2) mRNA vaccines, (3) plasmid-based DNA vaccines, (4) recombinant protein vaccines, (5) recombinant virus-like particle (VLP) vaccines, and (6) inactivated vaccines.
[2] Drug delivery systems: Techniques and technologies that aim to provide the minimum amounts of pharmaceutical compounds to target sites (organs, tissues, etc.) at the necessary times (for both timing and duration) to maximize therapeutic effects.
[3] Regulatory science: A branch of science for transforming the results of scientific technology into the forms that are most suitable to people and to society that also involves conducting evidence-based, accurate predictions, assessments, and judgments with the ultimate goal of making said results useful to people and society. (Reference: Pharmaceuticals and Medical Devices Agency (PMDA))
[4] “Adjuvant” is derived from “adjuvare,” a Latin word which means “to help.” Adjuvants are substances administered with vaccines that increase vaccine effectiveness (specifically, immunogenicity). Adjuvants are only meant to enhance vaccine effectiveness and administering them alone does not produce immunity. Vaccines with purified antigen components are generally less effective and therefore must be administered together with adjuvants. Furthermore, in recent years, vaccine R&D has expanded beyond infectious diseases to also include cancer and other non-infectious diseases, but the targets of such vaccines do not induce immune responses and have low therapeutic effectiveness. This has created high expectations for adjuvants that can induce strong immune responses and serve as the key to future vaccine R&D and treatment. (Reference: Ken Ishii Research Laboratory, Division of Vaccine Science, Department of Microbiology and Immunology, The Institute of Medical Science, The University of Tokyo.)
[5] Modularize: The act of splitting a complex product or system into functionally independent parts (or modules) during the design process or other processes. Also refers to efforts to promote the standardization of constituent elements (or parts) to reduce the amount of work required for fitting operations during design or manufacture.

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■ Profile:
Dr. Ken J. Ishii (Professor, Division of Vaccine Science, The Institute of Medical Science, The University of Tokyo)

Dr. Ken J. Ishii is currently Director for International Vaccine Design Center, and Professor of Vaccine Science Division at Institute of Medical Science, University of Tokyo. Until 2018, he was Director of Center for Vaccine and Adjuvant Research at National Institute of Biomedical Innovation, Health and Nutrition. Prof. Ishii obtained M.D. and a Ph.D. from the School of Medicine, Yokohama City University, Kanagawa, Japan. He is further qualified with his years of experience in vaccine research supported by numerous books and over 200 periodical publications and 20,000 citations since 1998 including 7 years as a IND reviewer at US Food and Drug Administration (FDA), two years as Managing Director at Japan Agency for Medical Research and Development (AMED), and over 20 years as an immunologist and vaccinologist.

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