"A Fusion of Humanities & Sciences Research on the COVID-19 Pandemic: Prospects for a with-COVID-19 society" (Summary)

It will soon be three years since the outbreak of COVID-19. As the world is searching for ways to create a society based on the premise of living with COVID-19, it is essential to construct a new fusion of the life and social sciences which integrates the humanities and sciences. Kyoto University and RIETI have been collaborating since 2020 to develop research aimed at understanding the actual status of the progress of the disease. This is the first attempt in the world to conduct a large-scale epidemiological study integrating the medical and social fields using comprehensive human data including antibody tests. In this symposium, the characteristics of the spread of COVID-19 and the status of behavioral changes in people were introduced as part of the results of this research, and opinions were exchanged on the future vision for the utilization of health- and life-science data.

MINATO Nagahiro (President, Kyoto University)

The world is facing a number of major challenges such as global climate change, widening inequality, aging populations in developed countries, and the outbreak and spread of emerging infectious diseases, and these extremely complex issues cannot be solved by individual scientific fields. For this reason, in June 2020, the Basic Act on Science and Technology was revised to include social sciences in the Basic Act on Science and Technology Innovation, in order to create a growth strategy that integrates the various fields of modern science.

Although human biology research has made rapid progress in recent years, it is by no means sufficient to simply accumulate and meticulously analyze biological information. People are social animals, and their social and mental activities have a significant impact on their health. This globally-unparalleled joint research by Kyoto University and RIETI is very ambitious as a pioneering study in the new field of socio-life science in Japan, and I strongly hope that the research results will contribute to driving Japan's growth strategy.

Since 2020, Kyoto University’s Graduate School of Medicine and RIETI have conducted an international joint research project to determine the actual status of infection among local residents and healthcare workers using an antibody test kit developed by the Institut Pasteur in France. In order for a whole society to combat the spread of infectious diseases, it is essential to address not only medical efforts but also behavioral changes in people. In this study, antibody tests and a web-based questionnaire survey were conducted on approximately 1,100 participants of the ‶Nagahama Preliminary Prevention Cohort″, which is being established by Kyoto University in Nagahama City, Shiga Prefecture, in addition to medical workers at Kyoto University Hospital. By integrating and analyzing the actual situation of infection (including subclinical infection), the status of behavioral changes in people, and socioeconomic activities, we are developing a fusion of humanities & sciences research through the life and social sciences.

YAMAMOTO Masaki (Lecturer, Graduate School of Medicine Kyoto University)

Antibody testing for Kyoto University Hospital employees was conducted on 614 participants. The SARS-CoV-2 antibody testing assay using Luminex (MAGPIX) was developed at the Pasteur Institute, and this assay is capable of simultaneous testing for the five different proteins that make up the novel coronavirus (SARS-CoV-2).

These proteins are produced during infection with SARS CoV 2, but the spike protein (S) and its receptor binding domain (RBD) are produced both during infection and vaccination, whereas the envelope protein (E) and nucleocapsid protein (N) are not included in the m-RNA vaccine and are produced only upon infection.

When we measured each type of antibody (IgG, IgA, and IgM) using these characteristics, N- protein IgG antibodies were considered to be a relatively good indicator for determining the presence of infection (morbidity rate). As for antibodies to S-protein, we believe that RBD IgG antibodies and S-protein IgG antibodies are accurate test indicators, and we are planning to further investigate this in the future.

The N-protein IgG antibody retention rate rose to about 26%, but this may be a little too high, given to the fact that hospital-spread infection control measures had been implemented at Kyoto University Hospital, and we believe that further scrutiny is necessary. S-protein IgG antibodies were found to rise steadily with vaccination, with the retention rate of over 90% at the second and third surveys.

As for future challenges, since the analysis is based on a population that does not include many cases of clinical infection, we need to accumulate more data in order to conduct a more accurate test. As for S-protein, we have not been able to analyze whether RBD IgG antibodies and S-protein IgG antibodies are clinically useful, so we would also like to examine the correlation with neutralizing antibodies. In addition, since the types of vaccines are changing, we would like to focus on the effects of different vaccine types.

MATSUDA Fumihiko (Professor, Graduate School of Medicine Kyoto University)

In the second phase of the study (August-September 2022), we created a library of peripheral blood mononuclear cells (PBMCs) for all 1,101 participants in the Nagahama Cohort, and conducted antibody testing with these PBMCs. At the same time, a social science survey was conducted and participants were asked to self-report their infection history and other information.

The results of the investigation showed that the use of peripheral blood enabled the accurate measurement of the ratio of antibodies to S- and N-proteins.

173 of 1,101 participants of this study tested positive for anti-N-protein antibodies, which can only be obtained from viral infection. Of these, 62 were aware of infection and 111 were unaware, suggested the possibility that the virus may be spread through subclinical infection.

The majority of those who were infected without the vaccine did not acquire sufficient S1 and RBD antibodies to provide immunity after infection. There were also a small number of vaccinated individuals who did not acquire sufficient antibodies.

Now that we have created a library of peripheral blood from this study, we can determine which antibodies were produced in each person, and we are planning new analyses to determine what the cause of these infection situations may be.

The Pasteur Institute is developing a test reagent for the Omicron variant. This may also reveal whether or not the inoculated person is sufficiently producing Omicron antibodies, and we would like to proceed with experiments using such test reagents in the future.

I believe that a third antibody test should be conducted. This is because in Nagahama, there was only one test conducted on peripheral blood, so by obtaining data from two tests, we can analyze the acquisition of group immunity using a time series and determine how the number of infected people increases. I also think that people's sense of caution has relaxed considerably, and by comparing data through time series, we may be able to determine changes in awareness and behavior.

HIROTA Shigeru (Faculty Fellow, RIETI / Professor, Faculty of Economics, Kyoto Sangyo University)

We attempted to verify the relationship between people's behavioral changes and socioeconomic factors, and infection from the second web-based survey and antibody testing conducted on the "Nagahama Cohort" participants in August 2022.

The method for verification was to use data on behavioral change from the third dose of vaccine (administered since December 2021) to the fourth dose (administered since May 2022), since most of those infected were infected after the summer of 2022, and to regress the presence or absence of infection, including subclinical infection, on possible factors.

The results showed that, first of all, with regard to preventive actions, those who regularly measured their body temperature tended to be more susceptible to infection, but there was no significant correlation with other preventive actions, and no clear conclusion could be drawn as to which specific preventive actions were effective in preventing infection. Rather, those who were generally more risk averse tended to be less infected. In other words, overall behavioral prudence is clearly related to the presence or absence of infection. The results for temperature measurement may reflect a reverse causal relationship, as those who suspected infection due to poor physical condition were particularly cautious.

It was also found that those who live with preschool children may be more susceptible to infection probably because they have less freedom to avoid infection due to the necessity to care for their children and to bring them to daycare or nursery school. On the other hand, those who worked from home tended not to have been infected.

It is also important to note that the existence of a relationship between the evaluation of government policies and infection was discovered. Those who highly evaluated the country's policies in the first survey (2021) were more likely to be infected. A possible hypothesis for this is that those who valued the policy of easing restrictions and turning the economy around actively went out and became infected, or that those who questioned the effectiveness of the government's policy acted cautiously and avoided infection. In any case, it is extremely important to understand more clearly which specific policies were evaluated by respondents and how, and to use this information towards policymaking to control infection.

Panelists:

• Chris DAI (CEO, Recika Co., Ltd.)
• MATSUDA Fumihiko (Professor, Graduate School of Medicine, Kyoto University)
• YOSHIHARA Hiroyuki (Professor Emeritus, Kyoto University)

Moderator:

• YANO Makoto (President RIETI / Project Professor, Institute of Economic Research, Kyoto University / Professor, Professor by Special Appointment, Sophia University)

DAI:
Our company is a social implementer of Web 3.0 elemental technologies such as data management using blockchain technology, non-fungible tokens (NFT), and decentralized autonomous organization (DAO). In a joint project between Kyoto University and RIETI, our technology is being used in the data management of the project.

Conventional data management, especially for personal data, is very cumbersome, and the problems of information leakage and the cost of reusing data are extremely high. Therefore, we thought that a mechanism using blockchain would be optimal for assuring safety, by allowing individuals to have ownership of their data, at the same time needing to separate the method of identifying individuals from personal data.

The system we implemented uses the blockchain to allow participants to issue IDs and passwords by themselves and returns their data so that they can verify the data themselves. At that time, we developed a system that is safe and prevents the leakage of personal information by returning each individual's data encrypted with their private key without linking it to personal information.

The DAO elemental technology we are working on, based on distributed ledger technology, allows organizations themselves to make decisions without a specific leader, and to build a system in which the profits earned by the organization are returned to distributed individuals. I believe that the DAO system will lead to an increase in the number of new types of organizations in the digital world.

YOSHIHARA:
Millennial Medical Record is a data platform that enables the collection of medical information under real names. We, Life Data Initiative, the promoter of this project, have been certified as the first authorized anonymously processed medical information business operator based on the Next- Generation Medical Infrastructure Law.

Data needs to be aggregated to some extent and put into a common format. Therefore, in 2015, with the support of the Japan Agency for Medical Research and Development (AMED), we launched the Millennium Medical Record Project to establish a system for the collection of medical data on a national level, and with the implementation of the Next-Generation Law in 2019, secondary use of medical information became possible.

Currently, medical information from 35 facilities is collected, and by providing this data to researchers, we receive usage fees and operate the business. However, the data was not structured or standardized, making it difficult to incorporate into the database. Therefore, with the cooperation of the Cabinet Office, we are developing a data conversion service as a social infrastructure.

The problems we face are numerous. Under the current Next-Generation Law, there is no compulsion to provide data, and certified providers are responsible for the costs of operation. There is also the problem that data on missing or deceased persons cannot be used because use is based on the premise that individuals are notified of the data use. Linkage with administrative and school data is also an issue, and the development of medical and other IDs by the government is also anticipated. To solve these problems, we believe it is necessary to establish a quasi-public organization that specializes in drafting legislation and building the future system.

YANO:
What kind of research can be done and what kind of results have been achieved through secondary use of data?

YOSHIHARA:
Currently, 19 cases have been used. Most of them are pharmaceutical companies, but the content is very diverse, including post-marketing feasibility studies and construction of models for predicting the risk of rare disease incidence.

YANO:
Professor YOSHIHARA also mentioned the difficulty in getting patients to agree to share their data. For Professor MATSUDA, who constructs data more suited for experiments and research, are there any difficulties or challenges in getting subjects to agree to share their data?

MATSUDA:
One of the major projects I engage in is the "Intractable Disease Platform," and when we obtain consent from patients, we obtain their consent for secondary use, which is to provide the data to companies on a chargeable basis. I think it is important to have a contract with the company that clearly defines under what conditions the data will be released, and to set up restrictions on the use of the data.

I do not think it is necessary to go through an ethics committee when actually providing data that has received consent for secondary use, but the data is very important to the individual, so rules are needed to ensure that the ethical aspects of the data are properly followed.

Also, as is the case with the Nagahama Cohort, we cannot tell citizens which company obtained their data. This is because that company has competitors, and we must not reveal which company will use the data for what disease. We have to gain their trust in the area as well, and make sure that they understand we will provide the data based on a contract that has been thoroughly reviewed.

YANO:
Who do you think should conduct that review?

MATSUDA:
If it is to be coordinated by a corporate entity, I think a subcommittee should be set up to screen it thoroughly, and it would be good to have an organization that can say no when ill-informed companies request to provide the data. It is important to have an outside eye.

YOSHIHARA:
In our case, the process is a little different. Once the data has been collected and anonymized, it is no longer under the scope of the Act on the Protection of Personal Information but it is under the scope of Next-Generation Law. So, an external ethics committee conducts a unified ethical review. Therefore, the leading time to launch a research project is very short.

YANO:
For example, I think that a type of data collection of medical records like Professor Yoshihara's data construction would be a very large database, but can blockchain be used for such large data management?

DAI:
Until now, a centralized approach has inevitably led to a top-down design, and since all the detailed data standards have to be integrated, the overall system has become extremely complex, and the design has been difficult to finalize. However, with the decentralized approach, the first step is opt-in for a mass that can be easily integrated, and then the design is determined from the bottom up, so I believe that the decentralized approach will become mainstream in the future.

YANO:
I think the data sharing system that Professor YOSHIHARA is trying to build could be done using a DAO-like structure, but I think the amount of data would be too large.

DAI:
Therefore, I think it would be difficult to do this quickly. I think it would be good to keep a balance between top-down and bottom-up approaches.

YOSHIHARA:
Especially in the case of medical care, documents of various structures are generated on a daily basis, so I do not think a rigid system like a normal relational database would be a good fit. So, please additionally let us know what you think.

YANO:
What are some of the difficulties you face in protecting personal information?

DAI:
Although the blockchain is anonymized, research-wise, personal information may be necessary, so we look forward to the advancement of technologies that, for example, encrypt and computation of data.

YOSHIHARA:
Although it is quite difficult to balance ensuring privacy and secondary use, it will be necessary in the near future to incorporate technologies that can calculate patient information in a single step in a completely encrypted condition, for example, by using blockchain.

MATSUDA:
I am very troubled by the fact that the Act on the Protection of Personal Information has been revised and genome sequencing has become personal information. Another major challenge is linkable anonymization (ID), which is the process of adding new data to long-term data while protecting the personal information of the early stage of data, allowing a high degree of freedom in the research process.

YANO:
Thank you very much for the very productive discussion today.

YOSHIDA Yasuhiko (Vice Chairman, RIETI)

In the age of living with COVID-19, both the prevention of infectious diseases and continuation of economic activities are required. Neither medicine nor economics can reach that optimal solution alone. This research is truly the establishment of a new life-and-social science through a fusion of the social and natural sciences, and I would like to express my gratitude once again to all those involved in the project. RIETI and Kyoto University have long been engaged in research exchange. In addition to this joint research, we are currently promoting a wide range of collaborations, including a lunch seminar series on business portfolios and joint research with the Institute of Economic Research, Kyoto University, and we hope to continue to promote innovative research through these exchanges.