Points of View Creation of Vaccines for Prevention of Infectious Diseases

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Yuji Takasago, Senior Researcher, National Institute of Biomedical Innovation Policy

Introduction

Infectious diseases caused by the novel coronavirus (SARS-CoV-2) that broke out at the end of 2019 (COVID-19) have been spreading worldwide and still pose a major threat to health in Japan and around the world more than two years later. Under these circumstances, research and development of a vaccine to prevent COVID-19 is progressing at an unprecedented pace. In particular, the fact that an mRNA vaccine was developed in less than a year through co-creation by European and U.S. pharmaceutical companies and bio-ventures, which had been ongoing since before the COVID-19 pandemic, has not only stimulated the pharmaceutical industry but also the world in many other areas, and many people in Japan have benefited from this development. The development of a new bioventure in less than a year has been a global sensation not only in the pharmaceutical industry but also in many other fields.

In order to follow the lead of foreign-made COVID-19 prophylactic vaccines ^that have already been put into practical use, Japanese companies have been diligently promoting clinical development of several candidate products in collaboration with various stakeholders. However, in order to further accelerate research and development in the event of an epidemic of emerging infectious diseases1) , it is necessary to establish a solid foundation for the creation of prophylactic vaccines against infectious diseases caused by various viruses, bacteria, and other pathogens.

In the past, the National Institute of Biomedical Innovation Policy (NIBIO) has reported on trends in the pharmaceutical industry with regard to COVID-19 from various ^{perspectives2) - 4)}. In addition, the author reported on the research and development of a COVID-19 prophylactic vaccine using mRNA technology in Policy Research Institute News No. ⁶³⁵⁾. In this report, we review the research and development of vaccines for the prevention of infectious diseases prior to the COVID-19 pandemic by examining the market, development items, and approved items of vaccines for the prevention of infectious diseases, mainly in normal times. The report then discusses the collaboration among various stakeholders that is indispensable for the creation of such vaccines.

Global Infectious Disease Preventive Vaccine Market and Development Trends

Figure 1 shows the global market for vaccines for the prevention of infectious diseases and the share of the Japanese market. Also, looking at the global market by company in 2020, the top four global companies account for 82% of the total market share.

The global market has been continuously expanding since 2014, reaching approximately $23 billion in 2020. Looking at sales by drug class, influenza has the largest market share at $6.2 billion, and influenza has the highest sales growth rate from 2014 to 2020. After influenza, Streptococcus pneumoniae and varicella-zoster are the next largest generators in terms of sales. The Japanese market is growing at a slower pace than the global market, and its share has been declining in recent years, falling from over 10% in 2014 to below 8% in 2020.

Figure 2 shows the number of vaccines developed for the prevention of infectious diseases. The number of products developed by Japanese, U.S., and European companies has been on a continuous upward trend since 2005, but has been declining since then, peaking at 188 products in 2018. Of these, the number of products developed by Japanese companies increased gradually from only three in 2006 to 19 in 2019, accounting for about 10% of the total number of products developed by Japanese, U.S., and European companies. As of January 2022, there are 15 vaccines developed by Japanese companies for the prevention of infectious diseases other than COVID-19. Of these, 8 are being developed overseas by Japanese companies, including group companies, confirming that development has been active not only in Japan but also outside Japan in recent years.

Research and analysis of approved NMEs in Japan, the U.S., and Europe

Table 1 shows the number of approved items of vaccines for the prevention of infectious diseases, covering only New Molecular Entity (NME) in Japan, the U.S., and Europe. The survey period was 2005-2020. For Japan, vaccines for the prevention of infectious diseases that correspond to drugs containing new active ingredients listed in the "List of Approved New Drugs " ⁶⁾ on the website of the Pharmaceuticals and Medical Devices Agency (PMDA) were extracted. The U.S. was selected from the "BiologicalLicense Application The United States extracted vaccines for the prevention of infectious diseases from "BiologicalLicense Application Approvals" published on the Center for Biologics Evaluation and Research (CBER) website7) of the Food and Drug Administration (FDA). In Europe, vaccines for the prevention of infectious diseases approved by the European Medicines Agency (EMA) through the central review system and listed as "New active substances" in the "European Medicines Agency Annual Reports " ⁸⁾ were included. In Japan, the AMA approved ABILIFY in 1994.

In Japan, there were no new vaccines approved for prevention of infectious diseases for about 10 years after the hepatitis A vaccine was approved in 1994, but new vaccines for prevention of infectious diseases have been created continuously since 2005.

Figure 3 shows the efficacy classification (ATC classification managed by WHO) of vaccines for the prevention of infectious diseases approved in Japan, the U.S., and Europe during the period 2005-2020. According to Ikeda's ^report9), the efficacy classification of items launched between 1996 and 2006 was dominated by hepatitis vaccines and combination vaccines, but influenza was prominent in the current survey period. This may be due to the 2009-2010 pandemic of a new strain of influenza (H1N1) and the subsequent increase in the creation of prophylactic vaccines to prepare for the next influenza pandemic, which has contributed significantly to the expansion of the global infectious disease prophylactic vaccine market as shown in Figure 1. In addition, the global market for vaccines to prevent infectious diseases, as shown in Fig. 1, has been expanding. It should also be noted that vaccines against Ebola, another emerging infectious disease, have recently been approved in the U.S. and Europe.

Figure 4 shows the percentage of regions where infectious disease prevention vaccines approved by the PMDA, FDA, and EMA have been approved. In this survey (Figures 4 and 5), those approved before 2005 are counted as approved regions. On the other hand, more than half of the FDA- and EMA-approved items are approved in both the U.S. and Europe.

Of the 13 items approved in all three regions, 10 items for which the date of approval in each of the three regions could be confirmed were surveyed to determine their order of approval (Figure 5). The results show that most of the products were approved in the U.S. and Europe, followed by Japan in third place. Similar to previous Murakami reports on the order of launch of infectious disease prevention vaccines in eight major ^countries10), this survey also showed a delay in the development of new infectious disease prevention vaccines in Japan compared to the U.S. and European countries. In addition, 22 of the 24 FDA-approved products approved in both the U.S. and Europe have no information on development in Japan, indicating a vaccine gap between Japan and the U.S. and Europe.

Comparing these 22 products by drug category, the largest number of products approved only in Japan are for influenza. This is followed by meningococcal meningitis vaccine, which has few cases of infection in Japan, and third is a combination bacterial and viral vaccine that has increased the convenience of vaccination.

Furthermore, using Evaluate Pharma, we analyzed the Originator (the company or organization that created the product in question) of each approved vaccine for the prevention of infectious diseases. Figure 6 shows the percentage of originators by country of origin for each of the three regions (Japan, the U.S., and Europe). In addition, the percentage of products approved in both the U.S. and Europe was just under 40%. In addition, more than 40% of the FDA- and EMA-approved products were originated by U.S. companies. In addition, the fact that approved products in both Europe and the U.S. were originated by organizations in more diverse countries than in Japan suggests that research and development of vaccines to prevent infectious diseases is global in these regions.

Figure 7 shows the percentage of Originator nationalities for products approved by the PMDA, approximately every five years. It can be seen that the percentage of items with Japanese companies as the originators has been on a downward trend since 2005. There have been no vaccines for the prevention of infectious diseases originating from Japan since the approval of one product for the prevention of influenza in 2015. On the other hand, the "Vaccine Industry Vision " ¹¹⁾ published by the MHLW in March 2007 states that "there are growing expectations from various quarters, including the medical community, for the launch in Japan of products and other products used in other countries but not available in Japan. From this perspective, it is possible to view positively the situation in which vaccines for the prevention of infectious diseases of foreign origin are gradually becoming available in Japan as a result of globalization.

Figure 8 shows the percentage of vaccines approved by the FDA for the prevention of infectious diseases in the Originator classification, approximately every five years. The classification is divided into four categories: pharmaceutical companies, venture companies, academia, and others. The percentage of ventures has increased from 11% in 2005-2009 to 25% in 2015-2020, indicating their growing presence.

Figure 9 shows the originator classification and applicant classification of prophylactic vaccines approved in Japan, the U.S., and Europe. On the other hand, in Japan, although there are no venture-originated products, a variety of organizations, including academia, are originating vaccines for the prevention of infectious diseases.

In terms of the percentage of applicants, pharmaceutical companies account for a higher percentage than originators in all regions, indicating that while there is naturally collaboration among pharmaceutical companies, there are also a certain number of products for which approval was obtained after pharmaceutical companies acquired the candidate products created by non-pharmaceutical companies through licensing or corporate acquisition. However, there are a certain number of products that have been approved after pharmaceutical companies have acquired them through licensing, corporate acquisitions, etc.

According to information from EvaluatePharma, 30 of the 39 products actually approved by the FDA between 2005 and 2020 were the result of a total of 42 collaborations, including mergers, acquisitions, licensing, or technology introductions, between the originator's creation of the seeds for a vaccine to prevent infectious diseases and its approval. The survey confirmed that a total of 42 collaboration projects, such as mergers, acquisitions, licensing, or in-licensing, were involved between the Originator's creation of the seeds for a vaccine to prevent infectious diseases and its approval. It should be noted that in the U.S. and Europe, an environment had already been established prior to the COVID-19 pandemic where the venture companies themselves could work on the seeds and technologies of vaccines for the prevention of infectious diseases created by the venture companies up to their commercialization.

Collaboration with Various Stakeholders for the Creation of Vaccines to Prevent Infectious Diseases

As mentioned above, it was suggested that collaboration with various stakeholders is important for the creation of vaccines to prevent infectious diseases. Therefore, we further investigated how vaccines for the prevention of infectious diseases are being created through global collaboration.

There are two major patterns in the creation of vaccines to prevent infectious diseases through collaboration in the United States and Europe. One is that large megapharmaceutical companies have achieved regulatory approval through mergers and acquisitions, bringing in promising vaccine candidates and venture companies that possess the necessary technologies. On the other hand, a relatively small organization such as a venture company commercializes a vaccine through a licensing agreement to combine its own candidate product or technology with the technology of another party that has a high affinity for the candidate product or technology. Therefore, we first investigated this from the perspective of acquisitions and licensing.

Figure 10 shows the number of vaccines for the prevention of infectious diseases (excluding COVID-19 prophylactic vaccines) acquired through corporate and business acquisitions globally from 2005 to 2020.

During the study period, 753 products were acquired through acquisitions, of which 32%, or 238 products, were marketed. The collaboration through acquisitions shows that each company's strategy targets not only clinical products but also many marketed products: in 2006, Novartis acquired Chiron and Crucell acquired Berna Biotech, and in 2015, Novartis' vaccine business was acquired by GlaxoSmithKline, which acquired GlaxoSmithKline's vaccine business. In the years when there were major deals, mainly by megapharmaceutical companies, many items were acquired, but since 2016 only a few have been acquired.

Figure 11 shows the number of infectious disease prevention vaccine items in-licensed and the number of technology in-licensed. Similar to the number acquired through acquisitions in Figure 10, the number of licensing agreements has continued to decline since 2016. The above suggests that prior to the COVID-19 pandemic, the number of collaborations related to infectious disease prevention vaccines was on a gradual downward trend. The largest number of collaborations among the licenses are for item introductions, and in many cases, relatively small organizations are the source of item introductions. The most notable among these is the introduction of technology. The number of technology introductions accounts for more than 40% of the total number of licenses, including the number of vaccine item introductions and the number of technology introductions, and has a large weight compared to other modalities (Table 2).

Vaccines consist of a combination of various technologies, such as antigens to induce acquired immunity, platforms such as cells used to produce antigen proteins, adjuvants to activate innate immunity, and more recently, nucleic acids encoding antigen proteins and delivery systems such as lipid nanoparticles (LNPs) to transport them in vivo. The system consists of a combination of technologies. It is not realistic for a single company to own all of these technologies, especially for small companies, and opportunities to introduce technologies through licensing may naturally become increasingly important.

In addition to such technology-based collaboration, we will introduce one example of a venture-backed vaccine for the prevention of hepatitis B, Heplisav-B, in which the venture played a major role in the creation of a vaccine for the prevention of infectious diseases. ¹²⁾ Heplisav-B was developed by Dynavax Technologies, an American bio-venture company. Heplisav-B is a combination of Dynavax's CpG oligodeoxynucleotide nucleic acid immunoadjuvant technology and Berna Biotech's hepatitis B surface antigen creation technology, It is a novel vaccine for the prevention of infectious diseases created through collaboration between the two companies.

In 2007, during the Phase III study, Dynavax and Merck & Co. agreed to co-develop Heplisav-B, but announced the termination of this partnership about a year later. The drug was filed by Dynavax with the FDA in April 2012, but after protracted deliberations due to safety concerns and another Phase III trial, the drug was approved in November 2017 after a winding road. The existence of a partner to collaborate on development is extremely important for a small company like a venture, and it is assumed that the company faced many difficult situations in continuing its business, such as the dissolution of its alliance with Merck &Co.

How did Dynavax overcome these challenges? One reason may be that the company was able to raise funds from various sources. In fact, the company received support from the National Institutes of Health (NIH) for the development of the nucleic acid immunization vaccine adjuvant, as well as from several investors including venture capitalists. Another reason was the company's possession of useful technologies related to vaccine adjuvants. The CpG oligodeoxynucleotides produced by the company's technology are not only used as vaccine adjuvants, but are also being extensively researched and developed as anti-tumor and anti-allergy drugs due to their innate immune activation properties. This technology was licensed out to AstraZeneca, GlaxoSmithKline, and others, and R&D was continued over a long period of time to further expand the technology.

As described above, it can be seen that in the U.S. and Europe, not only pharmaceutical companies but also venture companies are sharing various technologies across national borders, and promising technologies are attracting funds and partners from all over the world for the creation of vaccines to prevent infectious diseases.

Summary

This report outlines the vaccine industry in normal times, prior to the COVID-19 pandemic, from the perspective of research and development.

While the global market for vaccines for the prevention of infectious diseases has continued to expand in recent years, the Japanese market has grown more slowly than other countries, and its share of the global market is shrinking. In addition, a study of the number of vaccines developed for the prevention of infectious diseases showed that globally, the number of such vaccines has been on a continuous upward trend since 2005, but has stagnated since 2017. Furthermore, a survey and analysis of the number of approved vaccines for the prevention of infectious diseases in Japan, the U.S., and Europe showed that less than half of all vaccines are approved only in Japan by domestic companies, which is a gap with those in the U.S. and European markets, and that the number of vaccine items of foreign origin has been increasing in Japan in recent years.

In addition, a survey of partnerships related to vaccines for the prevention of infectious diseases showed that corporate and business acquisitions are complex and actively conducted on a global basis, with multiple changes in the rights company for the same product due to acquisitions. On the other hand, we also found that the number of acquisitions and licenses has been on a downward trend since 2016, suggesting that the global infectious disease prevention vaccine industry had been in a declining trend in terms of R&D for the future, although the market had been expanding for about five years before the COVID-19 epidemic. COVID-19 arrived in such an industry context, and as is well known, COVID-19 vaccine development was instantly revitalized globally.

Finally, we introduced an example from the U.S., where a venture-backed vaccine for the prevention of infectious diseases was put into practical use by the venture itself. The existence of several approved items similar to this case suggests that in other countries, ventures had been nurtured and an environment enabling the creation of vaccines had been established even before the cases of Moderna and BioNTech, which commercialized the COVID-19 vaccine. Although no items originating from venture companies were identified in Japan in this survey, various measures to support venture companies are included in the "Strategy for Strengthening the Vaccine Development and Production System " ¹³⁾ approved by the Cabinet of the Japanese government. In addition, following the Cabinet decision on this strategy, the Ministry of Economy, Trade and Industry (METI) launched the "Drug Discovery Venture Ecosystem Enhancement Project (budgeted at 50.0 billion yen) ¹⁴⁾ in the supplementary budget for fiscal 2021, which was approved in December 2021. Looking at FDA-approved products that originated from ventures, it takes a short period of 10 years from the establishment of a venture to the approval of a vaccine, and a long period of about 30 years for a vaccine. For this reason, we believe that it is necessary to work on venture development from a long-term perspective in Japan as well. In addition, promising seeds and technologies that will become the origin of vaccines are constantly being created in Japan and abroad, regardless of national borders. Therefore, it would be effective to search for seeds and technologies not only in Japan but also overseas. In addition, it is also necessary to ensure that the focus on fostering venture companies that specialize in research and development of vaccines for infectious diseases does not lead to insufficient support for other fields. In Japan, more support for venture businesses in a wide range of fields, not just vaccines, is desirable.

This report focuses mainly on research and development of vaccines for the prevention of infectious diseases, but in order to revitalize efforts to create vaccines, not only research and development but also manufacturing facilities, clinical trials, regulatory affairs, and routine vaccination are all areas that need improvement, many of which are mentioned in the aforementioned government strategy. In addition, due to the nature of vaccines that are administered to healthy people, it is inevitable that measures must be taken to prevent so-called "vaccine evasion," in which people refuse to be vaccinated due to concerns about safety and other factors. It will be necessary to conduct activities to deepen understanding of vaccines among the public, the national government, government administrators, medical professionals, and industry, and to create an environment in which each individual can make his or her own judgment about the merits and demerits of vaccination.

As described above, in Europe and the United States, megapharmaceutical companies have been conducting research and development of vaccines to prevent infectious diseases across multiple countries since normal times, and in addition, an environment has been established for venture companies to create vaccines to prevent infectious diseases. These factors were one of the factors that made it possible to supply the vaccine against COVID-19 so quickly. In addition to mRNA vaccines, we must prepare for future emergencies by utilizing existing vaccine modalities.

Taking the opportunity of the COVID-19 pandemic, research and development of COVID-19 prophylactic vaccines is still being actively conducted not only in Japan but also around the world. Seeds and technologies for vaccines to prevent infectious diseases are continuously being created in all parts of the world. Pharmaceutical companies, especially Japanese companies, need to be more actively involved in the creation and development of seeds and technologies in cooperation with various stakeholders to dramatically increase their international competitiveness. We look forward to a future in which there are many Japanese companies that can skillfully combine these technologies to create vaccines to prevent infectious diseases for the maintenance of the health of people around the world.

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