Points of View In response to the changes seen in R&D trends in vaccines for the prevention of infectious diseases

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

Introduction

(COVID-19) caused by a new coronavirus (SARS-CoV-2), which was first identified in China in December 2019, is still raging throughout the world, but the number of infected people worldwide is on a downward trend after peaking in January ²⁰²²¹⁾ and, once the pandemic is over, life 1) There are now signs that life after the pandemic is over may be possible.

Pharmaceutical companies in Japan and abroad are responding to this unprecedented situation by successfully commercializing COVID-19 therapeutics and vaccines more rapidly than ever before. In particular, the fact that a relatively small company was the first to create an unprecedented technology for an mRNA vaccine has attracted the attention of many people, not only those in the pharmaceutical industry.

The National Institute of Biomedical Innovation (NIBIO) has reported several times on the research and development trends of COVID-19 therapeutics and ^{vaccines2)-5)}. In addition, in the Policy Research Institute News No. 65, the author surveyed vaccines approved in Japan, the U.S., and Europe prior to the COVID-19 pandemic, and discussed collaboration with venture companies and others in the creation of such ^vaccines6). In this report, we survey the vaccine types and origins of R&D and marketed products of vaccines for the prevention of infectious diseases to understand the current status of global R&D of vaccines for the prevention of infectious diseases and changes from the past, as well as to provide perspectives for the creation of vaccines for the prevention of infectious diseases in the future.

Survey on R&D Products of Vaccines for Prevention of Infectious Diseases and Comparison with Marketed Products

Using EvaluatePharma, which collects information based on publicly available materials from pharmaceutical and biotech companies, we selected R&D and marketed products of vaccines for the prevention of infectious diseases worldwide as of May 2022 as the target products of this survey. Table 1 shows the number of products in each R&D and launch stage. For example, if the same product is being tested in clinical trials by different companies in multiple countries, it is counted as one product.

Table 2 shows the number of R&D items and the number of marketed items in the top 20 drug classes. Coronaviruses, including COVID-19, account for the largest number of R&D items, suggesting that R&D for a vaccine against COVID-19 is still being actively pursued. In addition, although there are no products on the market against the human immunodeficiency virus (HIV), Zika virus, and cytomegalovirus (CMV), there are many products in research and development, suggesting that the number of infectious diseases that can be addressed has increased compared to previous years due to advances in vaccine technology to date. In addition, all 16 marketed products for coronaviruses are COVID-19 prophylactic vaccines.

Figure 1 shows the percentage of vaccine types for developed and marketed vaccines for the prevention of infectious diseases. For the purposes of this paper, we define "new vaccine types" as those put into practical use in 2019 or later and those with no previous practical examples, and "existing vaccine types" as those with practical examples before 2018 (see Supplemental "Summary List of Vaccine Types"). Novel vaccine types include mRNA vaccines, DNA vaccines, viral vector vaccines, and peptide vaccines. In addition, items that are marketed or developed in one of the countries or regions of the world are defined as "Global Launched Products" and "Global Development Products," respectively.

The majority of globally marketed products are existing vaccine types, with inactivated vaccines accounting for less than 50% and attenuated live vaccines for less than 20%. On the other hand, globally developed products (Phase I to Filed) are characterized by a wide variety of vaccine types, including DNA vaccines, mRNA vaccines, viral vector vaccines, and other new vaccine types, and a lower percentage of inactivated vaccines and attenuated live vaccines compared to marketed products (Figure 1, upper row). (Figure 1, upper row).

Among globally marketed products and globally developed products, the percentages of vaccine types of products marketed or developed by Japanese companies are shown in the lower part of Fig. 1. For items related to Japanese companies, the proportion of existing vaccine types is also high for marketed products. On the other hand, the developed products show a variety of types including new vaccine types such as DNA vaccines and mRNA vaccines.

For example, mRNA vaccines do not require adjuvants, have no risk of contamination by cellular components, and are relatively easy to ^produce7).

Although there are no viral vector vaccines in ^Japan8), perhaps because Japan lags behind other countries in gene therapy research and development, Japanese companies have confirmed that viral vector vaccines are included in the R&D items for which they are the ^{originators9)}.

Figure 2 shows the percentage of vaccine types for the 258 global R&D items in the upper left of Figure 1, differentiated into coronavirus and other drug efficacy. A wide variety of vaccine types have been developed for both coronaviruses and other drug effects. For coronavirus vaccines, a higher proportion of DNA and mRNA vaccines and a lower proportion of recombinant protein vaccines were developed compared to other items, indicating that many new vaccine types have been developed in general. This difference in efficacy classification may be due in part to the fact that different vaccine types are suitable for different target pathogens.

In addition, using EvaluatePharma, we surveyed the originators of R&D and marketed products of vaccines for the prevention of infectious diseases, and classified the originators into four categories: pharmaceutical companies, venture companies, academia, and others. Ventures had the largest number of items, especially those in the research stage, such as pre-clinical and research project. The second largest number of items in the pharmaceutical companies after the venture companies are marketed products, and the number of items in the research stage is smaller than that of the venture companies.

DNA vaccine, mRNA vaccine, and viral vector vaccine were selected as new vaccine types, and inactivated vaccine and attenuated live attenuated vaccine were selected as existing vaccine types, and the ratio of Originator classification for each of these vaccine types was investigated for R&D products of vaccines to prevent infectious diseases. Figure 4 shows the results. Compared to existing vaccine types, a higher percentage of new vaccine types originated from venture companies.

In addition, ^Keyi4) and ^Takahashi8) reported that the proportion of items originating from Biotechnology companies including venture companies is higher for novel modalities such as gene therapy and cell therapy than for existing modalities such as small molecules. In both vaccines and pharmaceuticals, the contribution of venture companies has become indispensable in the R&D of new technologies.

Figure 5 shows the percentage of Originator categories in the top 10 countries in terms of the number of R&D products for vaccines to prevent infectious diseases, with the United States having the largest number of Originators in all categories (venture, pharmaceutical company, and academia), In terms of the percentage of Originator categories, most countries, including France and China, have the highest percentage of ventures. On the other hand, Japan and India have the largest share of pharmaceutical companies.

Inter-organizational Collaboration in R&D Products of Vaccines for Prevention of Infectious Diseases: A Survey by Deal

In order to understand the current status of inter-organizational collaboration in R&D products for vaccines to prevent infectious diseases, we conducted a Deal survey using EvaluatePharma.

Items for which R&D firms conduct R&D by collaborating with other companies through item in-licensing, joint R&D, acquisitions, and other deals are defined as "items including deals. In this survey, items are counted on an item-by-item basis. For example, if multiple companies collaborate on the same item, it is counted as one item, and thus the out-licensing of the same item is not double-counted. The percentage of R&D items including Deals by vaccine type is shown in Table 3. The percentage is higher for vaccine types compared to other types.

Figure 6 shows the number of deals and the percentage of deals classified by vaccine type (i.e., product introduction, joint R&D, technology introduction, and product acquisition through acquisition), indicating that the number of deals is high for DNA and mRNA vaccines. In addition, the ratio of deals for in-licensing and joint R&D is higher for new vaccine types (DNA, mRNA, and viral vectors) than for existing vaccine types. It can be inferred that while there are few companies that own new vaccine types and procure items from outside, there are many companies that own existing vaccine types, especially inactivated vaccines, and they tend to introduce peripheral technologies such as new manufacturing technologies, new administration technologies, and antigen screening technologies.

Figure 7 shows the number of Deals by R&D stage at the time the alliance was formed for the five selected vaccine types. Although the number of products in the research phase itself is large, the number of deals in the research project and pre-clinical research phases is larger than that in the development phase, and the breakdown of these deals is dominated by the introduction of products, joint R&D, and technology introduction. On the other hand, the proportion of deals acquired through acquisitions is mainly higher in the development stage from Phase I onward.

For the five selected vaccine types, we surveyed the status of partnerships in the top five countries with the largest number of Deals. The results are shown in Table 4, which shows that the percentage of items including Deals ranged from 20% to 40% in all countries, with the United Kingdom having the highest percentage at 40.9% and Japan at 23.1%, similar to the United States and South Korea. When the nationalities of the partners were categorized as either their own or other countries, the United States, the United Kingdom, and China showed 40-50% of deals with companies in other countries. In addition, in South Korea, all eight deals were with partners outside of South Korea. On the other hand, in Japan, the majority of deals were made in the country of origin.

Summary and Discussion

In this report, we surveyed the current status of global R&D on vaccines for the prevention of infectious diseases, including vaccine types and their originators, and the changes from the past.

Analysis of R&D products by efficacy category revealed that the number of products against coronaviruses, including COVID-19, was the largest by far, and it became clear once again that pharmaceutical companies are focusing their efforts on COVID-19 prophylactic vaccines in the wake of the pandemic. Furthermore, there are many R&D items for infectious diseases for which there are no products on the market, indicating that the range of infectious diseases that pharmaceutical companies are working on is expanding.

The survey on vaccine types of developed and marketed products revealed that the percentage of new vaccine types in both Japanese and global products was higher for developed products than for marketed products, indicating that a wide variety of vaccine types are being developed. As shown in Figure 1, although there were no viral vector vaccines developed by Japanese companies, the existence of viral vector vaccines was confirmed for R&D items in which Japanese companies were the originators. Especially for new types, technological innovation is expected to continue to progress at a dramatic pace in the future, triggered by the COVID-19 pandemic. In addition, research and development of peptide vaccines and other types that have not yet been put to practical use will be active throughout the world.

In March 2022, the Health Sciences Council of the Ministry of Health, Labour, and Welfare (MHLW) issued a new designation to accelerate research and development of vaccines for the prevention of infectious diseases. ¹⁰⁾ The Council decided on a tentative list of "priority infectious diseases" to be newly designated in order to accelerate research and development. We hope to see progress in the research and development of original new infectious disease vaccines for the priority infectious diseases and new modalities that can be converted to vaccine development through projects such as those launched by the Strategic Center for Advanced Research and Development (SCARDA), ¹¹⁾ utilizing basic research, which is one of Japan's strengths.

A survey of originators of vaccines for the prevention of infectious diseases revealed that, compared to marketed products, many R&D products, especially new vaccine-type products, originated from venture companies, indicating that the originators of vaccines are shifting from pharmaceutical companies to venture companies. In addition, a survey of the nationalities of the originators revealed that the proportion of items originating from venture companies was lower in Japan than in other major countries, while the proportion of items originating from pharmaceutical companies tended to be higher.

It has long been said that the number of ventures originating from academia is low in Japan, not only in vaccines but also in drug discovery and other industries, and that the lack of a bridge from academia to industry has resulted in a dearth of seeds from academia that reach the stage of practical application. In order to improve this situation, in the fields of vaccines and drug discovery, the Ministry of Economy, Trade and Industry has launched the "Drug Discovery Venture Ecosystem Enhancement Project," and as of May 2022, through the Japan Agency for Medical Research and Development (AMED), the number of drug discovery ventures that develop innovative technologies for the development of vaccines and therapeutic drugs for infectious diseases has been increasing. The company is currently in the process of accrediting venture capital (VC) suitable for supporting drug discovery ventures that develop innovative technologies for the development of vaccines and therapeutics for infectious ^diseases12). In the future, drug discovery ventures that receive hands-on support from certified VCs will be fostered.

The demand for this type of venture support is not limited to the pharmaceutical industry, but is spreading throughout Japan. For example, in March 2022, the Japan Business Federation (Keidanren) published its "Startup Breakthrough Vision: Toward 10X10X," in which it proposed the fundamental strengthening of the startup ecosystem as the most important issue for buoying the Japanese economy as a whole and regaining competitiveness. ¹³⁾ The report states that "the startup ecosystem is the most important issue to be addressed. In this context, it is expected that large companies will engage in full-scale M&A of startups and contribute to the diversification of exit methods other than initial public offering (IPO) of startups. In addition, at the "5th Conference on Realizing New Capitalism" held on April 12, 2022, Prime Minister Fumio Kishida mentioned the importance of open innovation between existing companies and start-ups, and stated that he would "review incentive measures and rules so that existing companies can invest in start-ups. ^14). Under these circumstances in which cooperation with venture companies is strongly demanded of industry, the pharmaceutical industry is charged with the role of commercializing the seeds of vaccines and other products created by drug discovery ventures through licensing agreements, acquisitions, etc. The pharmaceutical industry is expected to play an important role in the development of the Japanese economy. The pharmaceutical industry must play its part in the development of the Japanese economy.

Finally, the survey results on inter-organizational collaboration in R&D products for vaccines to prevent infectious diseases showed that the number of deals for novel vaccine types, such as DNA and mRNA vaccines, was higher than for other vaccine types. In addition, the breakdown of the number of Deals shows that the proportion of product introduction and joint R&D is high for new vaccine types, while the proportion of technology introduction is high for existing vaccine types. In addition, an analysis of the nationalities of the partners in the top countries in terms of the number of Deals shows that in the U.S. and other foreign countries, a high percentage of Deals were made with organizations in other countries, while in Japan, the majority of Deals were made with organizations in the home country.

Even in the U.S., where many ventures are created from the results of basic research in academia and venture-originated technologies are put to practical use as vaccines, nearly half of the ventures are in partnership with countries other than the U.S. Both China and South Korea are also showing a vigor to actively incorporate seeds and technologies from other countries into their own countries. While strengthening its domestic foundation for vaccine creation, Japan also needs to pay closer attention to trends in vaccine technologies outside of Japan. It is also essential to utilize the insights of those in the pharmaceutical industry who have been involved in drug discovery to date, and to work to incorporate the latest vaccine technologies available in other countries into Japan without delay.

In addition, to increase Japan's international competitiveness in drug discovery, it will be necessary to develop vaccines for the prevention of infectious diseases that are being researched and developed in Japan for use overseas. In fact, most of the COVID-19 prophylactic vaccines that have been commercialized have been deployed not only in Japan but also in many other countries. In March 2022, for example, Moderna announced its global public health ^strategy15) to further develop its mRNA vaccine technology, declaring that it will work to combat the threat of all infectious diseases not only in its own country, the United States, but also in low- and middle-income countries and other parts of the world. The strategy is designed to combat the threat of infectious diseases not only in the United States, but also in low- and middle-income countries. Japanese companies are also expected to establish a system to supply vaccines created using the world's most advanced technologies to people not only in Japan but also in the rest of the world.

In this report, we have surveyed and analyzed the current status of research and development of vaccines for the prevention of infectious diseases. However, in addition to research and development, there are many other issues that need to be addressed in Japan in order to make vaccines for the prevention of infectious diseases commercially available, including the expansion of production facilities, improvement of the clinical trial environment, and acceleration of the pharmaceutical approval process, Various initiatives are actually underway under the "Strategy for Strengthening Vaccine Development and Production System, "16) which was formulated by the government in June 2021.

The author believes that the most important point of view for the steady implementation of all of these strategies and the smooth progress of domestic vaccine development and production is to continue to gain public understanding, even after the COVID-19 pandemic. With the COVID-19 pandemic, the need for vaccines to prevent infectious diseases seems to have become widespread among the public. In response, domestic and foreign pharmaceutical companies are still devoting themselves to the research and development of vaccines, and it is necessary to advance preparations for other emerging infectious diseases that may occur in the future. I think the time has come to discuss what efforts should be made by the pharmaceutical industry from a long-term perspective in order to foster continuous understanding among the public. Finally, I would like to add that the key will be how to create a vaccine-friendly social climate through cooperation among various stakeholders, including the pharmaceutical industry.

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