Development of HBs-L based vaccine against Hepatitis B virus

• Project/Area Number: 19K16680
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 49060:Virology-related
• Research Institution: Tokyo Metropolitan Institute of Medical Science
• Principal Investigator: SANADA Takahiro 公益財団法人東京都医学総合研究所, 疾患制御研究分野, 主任研究員 (60721272)
• Project Period (FY): 2019-04-01 – 2023-03-31
• Project Status: Completed (Fiscal Year 2022)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2021: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2020: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2019: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
• Keywords: HBV / B型肝炎 / ワクチン / HBs-L / 経鼻免疫 / B型肝炎ウイルス / 経鼻接種 / 粘膜免疫 / ウイルス

Outline of Research at the Start

B型肝炎ウイルス（HBV）の外殻を形成する蛋白質HBsは長さによってHBs-S, HBs-M, HBs-Lの3種類に分けられる。現在、HBVに対するワクチンはHBs-Sが使われているが、多くのワクチン不応答者がいることやワクチンエスケープ変異体の出現など解決すべき問題点も多い。代表者らはHBs-L抗原を経鼻免疫することで、中和抗体を強力に誘導し、さらにIgA抗体やpreS1に対する抗体を誘導できることを見出した。本研究では、HBs-L抗原経鼻投与によって誘導される免疫応答を詳細に解析し、強い免疫応答をもたらす機序を明らかにする。これにより新たなるB型肝炎予防ワクチンの開発を試みる。

Outline of Final Research Achievements

To enhance the immunogenicity of HBs-L, HBs-L hybrid (HBs-Lh) protein composed of two genotypes was evaluated. Antibody level induced by HBs-Lh immunization showed high against not only S, but also pre-S1 and pre-S2 domians. Additionally, HBs-Lh immunization induced significantly stronger cross-reactive neutralizing antibodies compared to HBs-S or HBs-L of each genotype.These findings suggest that HBs-Lh could be a candidate of prophylactic HBV vaccine.

Academic Significance and Societal Importance of the Research Achievements

本研究によって、L抗原、さらにはLh抗原が現行ワクチンで使用されているS抗原よりも強い免疫原性を有していることが明らかとなった。特に、Lh抗原はいずれの遺伝子型に対しても強い中和抗体誘導能を示しており、本研究を進めることで、新規ワクチン開発へと繋がることが期待される。

Research Products

• [Journal Article] Characterization of innate immune response to hepatitis B virus genotype F acute infection in tree shrew (Tupaia belangeri) model (2022)
  • Author(s): Kayesh Mohammad Enamul Hoque、Hashem Md Abul、Sanada Takahiro、Kitab Bouchra、Rashid Md Haroon Or、Akter Lipi、Ezzikouri Sayeh、Murakami Shuko、Ogawa Shintaro、Tanaka Yasuhito、Kohara Michinori、Tsukiyama-Kohara Kyoko
  • Journal Title: Frontiers in Virology Volume: 2
  • DOI: 10.3389/fviro.2022.926831
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Intranasal therapeutic vaccine containing HBsAg and HBcAg for patients with chronic hepatitis B; 18?months follow‐up results of phase IIa clinical study (2022)
  • Author(s): Yoshida Osamu、Akbar Sheikh Mohammad Fazle、Imai Yusuke、Sanada Takahiro、Tsukiyama‐Kohara Kyoko、Miyazaki Takashi、Kamishita Taizou、Miyake Teruki、Tokumoto Yoshio、Hikita Hayato、Tsuge Masataka、Shimizu Masahito、Al Mahtab Mamun、Aguilar Julio Cesar、Guillen Gerardo、Kohara Michinori、Hiasa Yoichi
  • Journal Title: Hepatology Research Volume: 53 Issue: 3 Pages: 196-207
  • DOI: 10.1111/hepr.13851
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] HBs-S antigen-dependent enhancement of HBV infection (2022)
  • Author(s): Sanada Takahiro、Yoshida Osamu、Hiasa Yoichi、Kohara Michinori
  • Journal Title: bioRxiv Volume: -
  • DOI: 10.1101/2022.06.07.495222
  • Open Access
• [Journal Article] Tree Shrew as an Emerging Small Animal Model for Human Viral Infection: A Recent Overview (2021)
  • Author(s): Kayesh Mohammad Enamul Hoque、Sanada Takahiro、Kohara Michinori、Tsukiyama-Kohara Kyoko
  • Journal Title: Viruses Volume: 13 Issue: 8 Pages: 1641-1641
  • DOI: 10.3390/v13081641
  • Peer Reviewed / Open Access
• [Journal Article] Development and Characterization of a Highly Sensitive NanoLuciferase-Based Immunoprecipitation System for the Detection of Anti-Influenza Virus HA Antibodies. (2021)
  • Author(s): Honda T, Gomi S, Yamane D, Yasui F, Yamamoto T, Munakata T, Itoh Y, Ogasawara K, Sanada T, Yamaji K, Yasutomi Y, Tsukiyama-Kohara K, Kohara M.
  • Journal Title: mSphere Volume: 12 Issue: 3
  • DOI: 10.1128/msphere.01342-20
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Pathological and genetic aspects of spontaneous mammary gland tumor in Tupaia belangeri (Tree shrew) (2020)
  • Author(s): Chi Hai-Ying, Yuuki Tanaka, Tatsuro Hifumi, Ko-ichiro Shoji, Mohammad Enamu Hoque Kayesh, Md Abul Hashem, Bouchra Kitab, Takahiro Sanada, Tomoko Fujiyuki, Misako Yoneda, Hitoshi Hatai, Akira Yabuki, Noriaki Miyoshi, Chieko Kai, Michinori Kohara, Kyoko Tsukiyama-Kohara
  • Journal Title: PLoS One Volume: 15(5) Issue: 5 Pages: e0233232-e0233232
  • DOI: 10.1371/journal.pone.0233232
  • Peer Reviewed / Open Access
• [Journal Article] Intranasal vaccination with HBs and HBc protein combined with carboxyl vinyl polymer induces strong neutralizing antibody, anti-HBs IgA, and IFNG response (2019)
  • Author(s): Sanada Takahiro、Yamamoto Naoki、Kayesh Mohammad Enamul Hoque、Tsukiyama-Kohara Kyoko、Hasegawa Hideki、Miyazaki Takashi、Takano Jun-ichiro、Shiogama Yumiko、Yasutomi Yasuhiro、Goh Yasumasa、Yoshida Osamu、Hiasa Yoichi、Kohara Michinori
  • Journal Title: Biochemical and Biophysical Research Communications Volume: 520 Issue: 1 Pages: 86-92
  • DOI: 10.1016/j.bbrc.2019.09.072
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Construction of complete Tupaia belangeri transcriptome database by whole-genome and comprehensive RNA sequencing (2019)
  • Author(s): Sanada Takahiro、Tsukiyama-Kohara Kyoko、Shin-I Tadasu、Yamamoto Naoki、Kayesh Mohammad Enamul Hoque、Yamane Daisuke、Takano Jun-ichiro、Shiogama Yumiko、Yasutomi Yasuhiro、Ikeo Kazuho、Gojobori Takashi、Mizokami Masashi、Kohara Michinori
  • Journal Title: Scientific Reports Volume: 9 Issue: 1 Pages: 12372-12372
  • DOI: 10.1038/s41598-019-48867-x
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] HBs-large hybrid protein vaccination via intranasal route with carboxyl vinyl polymer rapidly induced strong neutralizing antibody and anti-HBs IgA. (2019)
  • Author(s): Sanada T, Kayesh MEH, Tsukiyama-Kohara K, Hasegawa H, Goh Y, Miyazaki T, Kohara M.
  • Organizer: 2019 AASLD THE LIVER MEETING.
  • Int'l Joint Research
• [Presentation] Construction of genomic and transcriptomic database of the tree shrew (Tupaia belangeri), which is a small animal model of HBV infection. (2019)
  • Author(s): Sanada T, Tsukiyama-Kohara K, Shin-I T, Yamamoto N, Kayesh MEH, Kohara M.
  • Organizer: 2019 International HBV Meeting: The Molecular Biology of Hepatitis B Viruses.
  • Int'l Joint Research
• [Presentation] Construction of genomic and transcriptomic database of the tree shrew (Tupaia belangeri), which is a small animal model of HBV infection. (2019)
  • Author(s): Sanada T, Tsukiyama-Kohara K, Shin-I T, Yamamoto N, Kayesh MEH, Kohara M.
  • Organizer: 第67回日本ウイルス学会学術集会
• [Remarks] 公益財団法人 東京都医学総合研究所 感染制御プロジェクト
  • URL: https://www.igakuken.or.jp/infectious/index.html
• [Remarks] 公益財団法人 東京都医学総合研究所 感染制御プロジェクト
  • URL: https://www.igakuken.or.jp/infectious/index.html
• [Remarks] 公益財団法人 東京都医学総合研究所 感染制御プロジェクト
  • URL: http://www.igakuken.or.jp/infectious/index.html