TOKYO, JAPAN - Media OutReach^[1] - 17 September 2021 - A joint clinical trial confirmed that continuous intake of Kirin Holdings Company, Limited's (Kirin Holdings) Lactococcus lactis strain Plasma (LC-Plasma)*¹ for two months significantly reduced the cumulative number of days of fever, muscle pain, joint pain, and pain behind the eyes, which are known to be the main symptoms of dengue fever. LC-Plasma is the same functional ingredient in Kirin Holdings' stable of IMMUSE material that help maintain the immune system. The study was conducted by The Kirin Central Research Institute in collaboration with Professor Dr. Sazaly Abu Bakar, Director of the Tropical Infectious Diseases Research & Education Centre (TIDREC) at the University of Malaya.

*1: Lactococcus lactis subsp. lactis JCM 5805 is owned by the RIKEN BioResource Research Center^[2].

• No Cure, No Vaccine... But Hope Against Symptoms Arises – In Food!

There is still no definitive cure or vaccine for dengue fever. However, the study results show there is hope for dealing with symptoms. The results of a clinical trial have confirmed the suppression of dengue fever-like symptoms through a food that is safe and does not rely on medical infrastructure, reflecting a groundbreaking achievement that has the potential to provide a solution to the global social issue of dengue fever. The results of this research were presented at the 25th Annual Meeting of the Japanese Society of Travel and Health^[3] on August 22.

Since LC-Plasma activates the command center of antiviral immunity, it has been shown to contribute to the prevention of a wide range of viral infections other than the dengue fever virus*^[4]2. Moving forward, Kirin Holdings and the University of Malaya will accelerate joint research aiming to verify the antiviral effects ofLC-Plasmaon tropical disease viruses other than the dengue virus.

*2: Lactococcus lactis strain Plasma Research Report https://health.kirin.co.jp/ps/index.html^[5]

Kirin Holdings has reported that LC-Plasma has shown immunostimulatory effects in the body's defense against viral infections through activation of plasmacytoid dendritic cells*³ in non-clinical and clinical trials, and that LC-Plasma can reduce the incidence of influenza*⁴ in clinical trials. In collaboration with TIDREC, a WHO Collaborating Centre for Arbovirus Reference and Research^[6], our collaboration will continue to verify the effects of LC-Plasma on other tropical infectious diseases, which are expected to expand further due to global warming. In tandem, Kirin Holdings will make LC-Plasma more accessible to more people in Southeast Asia through alliances and business expansion, providing a solution to a major social issue.

*3: Jounai et al., PLoS One (2012) / Sugimura et al., Clin. Immunol (2013)^[7][8]

*4: Sakata et al., Health (2017)^[9]

[Attachments]

1.Dengue Fever Joint Research Results Summary (1 page)

ATTACHMENT

DENGUE FEVER JOINT RESEARCH RESULTS SUMMARY

Clinical trial

According to the previous research outcomes performed by Kirin Holdings Company Limited^*5, the Kirin Central Research Institute at Kirin Holdings Company Limited and the Tropical Infectious Diseases Research and Education Center (TIDREC) at the University of Malaya collaborated on a joint research project on Lactococcus lactis strain Plasma (LC-Plasma) against dengue fever from December 2019 to February 2020. During this time, approximately 100 healthy adults of Malaysian nationality living in dengue infection cluster areas near Kuala Lumpur, Malaysia, were asked to take a tablet containing LC-Plasma (approximately 100 billion cells) or a placebo for 8 weeks, and symptoms were measured. The results showed that LC-Plasma significantly reduced the cumulative number of days with dengue fever-like symptoms such as headache, joint pain, and pain behind the eyes (Figures 1-3). These results suggest that LC-Plasma, a food product, can help alleviate the symptoms and prevent the severity of the disease, while the only other option currently available for dengue fever is coping therapy.

Figs. 1-3 Comparison of the cumulative number of days of occurrence of symptoms specific to tropical diseases such as dengue fever（Representative symptoms）

*5: Tsuji et al., Antiviral Res (2018) / Suzuki et al., Int J Mol Med. (2019)^[10][11]

Outline of Collaborative Research

• Location: Laboratory for Immuno-Regulation Studies, Tropical Infectious Disease Research and Education Centre (TIDREC), University of Malaya
• Visiting Fellow: One Research Fellow appointed as visiting professor from Kirin Holdings Company, Limited.
• Research Period: From the end of 2021 to December 2023 (thereafter, the period will be extended as the project and research progress)
• Research Topics: Conduct immunological research on tropical infectious diseases in order to , to contribute to public health in the region and accelerate the overseas business development of Kirin Holdings' health science business by:

References

1. ^{^} Media OutReach (www.media-outreach.com)
2. ^{^} RIKEN BioResource Research Center (web.brc.riken.jp)
3. ^{^} 25th Annual Meeting of the Japanese Society of Travel and Health (www.pco-prime.com)
4. ^{^} other than the dengue fever virus* (health.kirin.co.jp)
5. ^{^} https://health.kirin.co.jp/ps/index.html (health.kirin.co.jp)
6. ^{^} WHO Collaborating Centre for Arbovirus Reference and Research (www.tidrec.com)
7. ^{^} Jounai et al., PLoS One (2012) (pubmed.ncbi.nlm.nih.gov)
8. ^{^} Sugimura et al., Clin. Immunol (2013) (pubmed.ncbi.nlm.nih.gov)
9. ^{^} Sakata et al., Health (2017) (www.scirp.org)
10. ^{^} Tsuji et al., Antiviral Res (2018) (pubmed.ncbi.nlm.nih.gov)
11. ^{^} Suzuki et al., Int J Mol Med. (2019) (pubmed.ncbi.nlm.nih.gov)