Induction of SARS CoV-2 neutralizing antibodies by anti-idiotype antibodies

• Project/Area Number: 21H02970
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Review Section: Basic Section 54030:Infectious disease medicine-related
• Research Institution: Kumamoto University
• Principal Investigator: MATSUSHITA Shuzo 熊本大学, ヒトレトロウイルス学共同研究センター, 特任教授 (00199788)
• Project Period (FY): 2021-04-01 – 2024-03-31
• Project Status: Completed (Fiscal Year 2023)
• Budget Amount: ¥17,420,000 (Direct Cost: ¥13,400,000、Indirect Cost: ¥4,020,000); Fiscal Year 2023: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000); Fiscal Year 2022: ¥5,850,000 (Direct Cost: ¥4,500,000、Indirect Cost: ¥1,350,000); Fiscal Year 2021: ¥6,500,000 (Direct Cost: ¥5,000,000、Indirect Cost: ¥1,500,000)
• Keywords: 新型コロナウイルス感染症（COVID-19） / SARS-CoV-2 / 中和抗体 / 抗イディオタイプ抗体 / 感染症 / 内科 / ウイルス

Outline of Research at the Start

新型コロナウイルス感染症（COVID-19）に対する有効なワクチン開発は世界的課題である。原因ウイルスであるSARS-CoV-2に対する中和抗体は、ウイルスの感染阻止に中心的役割を果たす。我々は、令和2年度までに、COVID-19の回復期症例から、SARS-CoV-2を低濃度で強力に中和する単クローン抗体（9-105、10-121）を樹立した（特願2020-143055）。我々は、また、中和抗体に対する抗イディオタイプ抗体を効率的に作成する方法を確立した。本研究では、SARS-CoV-2中和抗体に対する多様な抗イディオタイプ抗体を作成し、これらを用いた中和抗体誘導法の確立を目指す。

Outline of Final Research Achievements

Developing an effective vaccine against the COVID-19 is a global challenge. We generated an anti-idiotypic antibodies against a potent neutralizing monoclonal antibody (9-105) against SARS-CoV-2. However, in 2022, we entered a new era with the Omicron strain pandemic. Because 9-105had a limited activity against omicron variants, then we isolated a new neutralizing monoclonal antibody (4-66) with strong cross-neutralizing activity against the variety of Omicron variants. Now we are in the process of isolating an anti-idiotypic antibodies against it. We are currently planning to use single cell sorting to obtain B cells recognized by these anti-idiotypic antibodies from the peripheral blood of coronavirus breakthrough cases and examine the biological activity of the antibodies produced.

Academic Significance and Societal Importance of the Research Achievements

本研究の目的は、SARS-CoV-2中和抗体に対する抗イディオタイプ抗体パネルを作成し、特異的な中和抗体誘導の可能性を調べるところにある。現在、スパイク蛋白全長のmRNAワクチンが用いられているが、誘導できる抗体の大部分は非中和抗体である。一方、抗イディオタイプ抗体を用いる戦略は、強力な中和抗体のみを特異的に誘導する。特に、オミクロン株の抗原ドリフトに対応する広域中和抗体反応の誘導は、既存のワクチンでは困難と考えられる。現在もSARS-CoV-2は免疫逃避を繰り返しながら、コロナのパンデミックは続いている。抗イディオタイプ抗体ワクチンは効率よく交差中和抗体を誘導し、感染制御を可能にする。

Research Products

• [Journal Article] Differential Ability of Spike Protein of SARS-CoV-2 Variants to Downregulate ACE2 (2024)
  • Author(s): Maeda Yosuke、Toyoda Mako、Kuwata Takeo、Terasawa Hiromi、Tokugawa Umiru、Monde Kazuaki、Sawa Tomohiro、Ueno Takamasa、Matsushita Shuzo
  • Journal Title: International Journal of Molecular Sciences Volume: 25 Issue: 2 Pages: 1353-1353
  • DOI: 10.3390/ijms25021353
  • Peer Reviewed / Open Access
• [Journal Article] Longitudinal analysis of neutralization in sera from HCWs receiving 2 doses of Omicron BA.4/5-adapted bivalent vaccine. (2023)
  • Author(s): Amano M, Ichikawa Y, Matsumoto S, Matsushita S, Shimada S, Mitsuya H.
  • Journal Title: J Infect Volume: 87 Issue: 5 Pages: e79-e82
  • DOI: 10.1016/j.jinf.2023.08.012
  • Peer Reviewed
• [Journal Article] Neutralization against Omicron sublineages (BA.2/BA.5/BQ.1.1/XBB/XBB.1.5) in bivalent BNT162b2-vaccinated HCWs with or without risk factors, or following BT infection with Omicron. (2023)
  • Author(s): Amano M, Otsu S, Uemura Y, Ichikawa Y, Matsumoto S, Higashi-Kuwata N, Matsushita S, Shimada S, Mitsuya H.
  • Journal Title: Scientific Reports Volume: 13 Issue: 1 Pages: 17404-17404
  • DOI: 10.1038/s41598-023-44484-x
  • Peer Reviewed / Open Access
• [Journal Article] Evaluation of Neutralizing Activity against Omicron Subvariants in BA.5 Breakthrough Infection and Three-Dose Vaccination Using a Novel Chemiluminescence-Based, Virus-Mediated Cytopathic Assay (2023)
  • Author(s): Toyoda Mako、Tan Toong Seng、Motozono Chihiro、Barabona Godfrey、Yonekawa Akiko、Shimono Nobuyuki、Minami Rumi、Nagasaki Yoji、Miyashita Yusuke、Oshiumi Hiroyuki、Nakamura Kimitoshi、Matsushita Shuzo、Kuwata Takeo、Ueno Takamasa
  • Journal Title: Microbiology Spectrum Volume: 11 Issue: 4 Pages: 00660-23
  • DOI: 10.1128/spectrum.00660-23
  • Peer Reviewed / Open Access
• [Journal Article] Comparison of neutralization activity against Omicron BA.2/BA.5 in sera from HCWs receiving heterologous/homologous COVID-19 vaccines. (2023)
  • Author(s): Amano M, Ichikawa Y, Uemura Y, Matsumoto S, Maeda K, Matsushita S, Shimada S, Mitsuya H.
  • Journal Title: J Infect Volume: 86 Issue: 5 Pages: e130-e132
  • DOI: 10.1016/j.jinf.2023.01.038
  • Peer Reviewed / Open Access
• [Journal Article] Comparison of neutralization activity against Omicron BA.2/BA.5 in sera from HCWs receiving heterologous/homologous COVID-19 vaccines. (2023)
  • Author(s): Amano M, Ichikawa Y, Uemura Y, Matsumoto S, Maeda K,, Matsushita S, Shimada S, Mitsuya H.
  • Journal Title: Journal of Infection 2023 in press. Volume: -
  • Peer Reviewed
• [Journal Article] Characterization of a Novel CD4 Mimetic Compound YIR-821 against HIV-1 Clinical Isolates (2023)
  • Author(s): Matsumoto Kaho、Kuwata Takeo、Tolbert William D.、Richard Jonathan、Ding Shilei、Prevost Jeremie、Takahama Shokichi、Judicate George P.、Ueno Takamasa、Nakata Hirotomo、Kobayakawa Takuya、Tsuji Kohei、Tamamura Hirokazu、Smith Amos B.、Pazgier Marzena、Finzi Andres、Matsushita Shuzo
  • Journal Title: Journal of Virology Volume: 97 Issue: 1
  • DOI: 10.1128/jvi.01638-22
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Restoration of Neutralization Activity Against Omicron BA.2 and BA.5 in Older Adults and Individuals With Risk Factors Following the Fourth Dose of Severe Acute Respiratory Syndrome Coronavirus 2 BNT162b2 Vaccine. (2023)
  • Author(s): Amano M, Otsu S, Ichikawa Y, Higashi-Kuwata N, Matsushita S, Shimada S, Mitsuya H.
  • Journal Title: J Infect Dis. Volume: 227 Issue: 1 Pages: 161-163
  • DOI: 10.1093/infdis/jiac393
  • Peer Reviewed / Open Access
• [Journal Article] Sensitivity to a CD4 mimic of a consensus clone of monkey-adapted CCR5-tropic SHIV-MK38C (2023)
  • Author(s): Matsuura Kanako、Yamaura Mizuki、Sakawaki Hiromi、Himeno Ai、Pisil Yalcin、Kobayakawa Takuya、Tsuji Kohei、Tamamura Hirokazu、Matsushita Shuzo、Miura Tomoyuki
  • Journal Title: Virology Volume: 578 Pages: 171-179
  • DOI: 10.1016/j.virol.2022.12.004
  • Peer Reviewed
• [Journal Article] Development and characterization of a panel of anti-idiotype antibodies to 1C10 that cross-neutralize HIV-1 subtype B viruses (2022)
  • Author(s): Kaku Yu、Matsumoto Kaho、Kuwata Takeo、Zahid Hasan Md、Biswas Shashwata、Gorny Miroslaw K.、Matsushita Shuzo
  • Journal Title: Frontiers in Virology Volume: 2 Pages: 932187-932187
  • DOI: 10.3389/fviro.2022.932187
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Hybrids of small CD4 mimics and gp41-related peptides as dual-target HIV entry inhibitors (2022)
  • Author(s): Wang Rongyi、Tsuji Kohei、Kobayakawa Takuya、Liu Yishan、Yoshimura Kazuhisa、Matsushita Shuzo、Harada Shigeyoshi、Tamamura Hirokazu
  • Journal Title: Bioorganic & Medicinal Chemistry Volume: 76 Pages: 117083-117083
  • DOI: 10.1016/j.bmc.2022.117083
  • Peer Reviewed
• [Journal Article] Exploratory studies on soluble small molecule CD4 mimics as HIV entry inhibitors (2022)
  • Author(s): Tsuji Kohei、Kobayakawa Takuya、Konno Kiju、Masuda Ami、Takahashi Kohei、Ohashi Nami、Yoshimura Kazuhisa、Kuwata Takeo、Matsushita Shuzo、Harada Shigeyoshi、Tamamura Hirokazu
  • Journal Title: Bioorganic & Medicinal Chemistry Volume: 56 Pages: 116616-116616
  • DOI: 10.1016/j.bmc.2022.116616
  • Peer Reviewed / Open Access
• [Journal Article] Clonality of HIV-1 and HTLV-1 infected cells in naturally coinfected individuals (2021)
  • Author(s): Katsuya H, Cook L, Rowan AG, Melamed A, Turpin J, Ito J, Islam S, Miyazato P, Tan B, Matsuo M, Miyakawa T, Nakata H, Matsushita S, Taylor GP, Bangham CRM, Kimura S, Satou Y.
  • Journal Title: The Journal of Infectious Diseases Volume: 0 Issue: 2 Pages: 0-0
  • DOI: 10.1093/infdis/jiab202
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] A widely distributed HIV-1 provirus elimination assay to evaluate latency-reversing agents in vitro (2021)
  • Author(s): Matsuda K, Islam S, Takada T,Tsuchiya K, Tan BJY, Hattori S, Katsuya H, Kitagawa K, Kim KS, Matsuo M, Sugata K, Delino NS, Gatanaga H, Yoshimura K, Matsushita S, Mitsuya H, Iwami S, Satou Y, Maeda K
  • Journal Title: Cell Reports Methods Volume: 1 Issue: 8 Pages: 100122-100122
  • DOI: 10.1016/j.crmeth.2021.100122
  • Peer Reviewed / Open Access
• [Journal Article] Functional analysis of a monoclonal antibody reactive against the C1C2 of Env obtained from a patient infected with HIV-1 CRF02_AG (2021)
  • Author(s): Md Zahid H, Kuwata T, Takahama S, Kaku Y, Biswas S, Matsumoto K, Tamamura H, Matsushita S
  • Journal Title: Retrovirology Volume: 18 Issue: 1 Pages: 23-23
  • DOI: 10.1186/s12977-021-00568-y
  • Peer Reviewed / Open Access
• [Journal Article] Resistance of SARS-CoV-2 variants to neutralization by antibodies induced in convalescent patients with COVID-19 (2021)
  • Author(s): Kaku Y, Kuwata T, Zahid HM, Hashiguchi T, Noda T, Kuramoto N, Biswas S, Matsumoto K, Shimizu M, Kawanami Y, Shimura K, Onishi C, Muramoto Y, Suzuki T, Sasaki J, Nagasaki Y, Minami R, Motozono C, Toyoda M, Takahashi H, Kishi H, Fujii K, Tatsuke T, Ikeda T, Maeda Y, Ueno T, Koyanagi Y, Iwagoe H, Matsushita S.
  • Journal Title: Cell Reports Volume: 36 Issue: 2 Pages: 109385-109385
  • DOI: 10.1016/j.celrep.2021.109385
  • Peer Reviewed / Open Access
• [Journal Article] Phenotypic and Genotypic Co-receptor Tropism Testing in HIV-1 Epidemic Region of Tanzania Where Multiple Non-B Subtypes Co-circulate (2021)
  • Author(s): Judicate George P.、Barabona Godfrey、Kamori Doreen、Mahiti Macdonald、Tan Toong Seng、Ozono Seiya、Mgunya Amina Shaban、Kuwata Takeo、Matsushita Shuzo、Sunguya Bruno、Lyamuya Eligius、Tokunaga Kenzo、Ueno Takamasa
  • Journal Title: Frontiers in Microbiology Volume: 12 Pages: 703041-703041
  • DOI: 10.3389/fmicb.2021.703041
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] 抗体療法を目指した変異株に有効なSARS-CoV-2中和モノクローナル抗体の分離 (2021)
  • Author(s): 郭 悠、桑田岳夫、松下修三、
  • Journal Title: ウイルス Volume: 71
• [Presentation] SARS-CoV-2 Delta株ブレイクスルー感染例から分離した抗体の交差中和活性 (2023)
  • Author(s): 桑田岳夫、郭悠、清水美紀子、 Biswas Shashwata、松本佳穂、 Khairy Hamdy Edri Ahmed、松下修三
  • Organizer: 第37回日本エイズ学会学術集会・総会
• [Presentation] Isolation of monoclonal antibodies with neutralization and ADCC activities against SARS- CoV-2 variants (2023)
  • Author(s): Matsumoto K, Kuwata T, Kaku Y, Amano M, Shimizu M, Biswas S, Matsushita S
  • Organizer: 24th Kumamoto AIDS Seminar
• [Presentation] COVID-19回復者におけるSARS-CoV-2変異株を交差中和する抗体の誘導 (2023)
  • Author(s): 桑田岳夫、郭悠、清水美紀子、Shashwata Biswas、松本佳穂、松下修三
  • Organizer: 第１回新型コロナウイルス研究集会
• [Presentation] CD4類似化合物YIR-821の臨床株に対する有効性の検討 (2022)
  • Author(s): 松本佳穂, 桑田岳夫, 高濱正吉, Judicate GP, 上野貴将, 小早川拓也, 玉村啓和, 松下修三.
  • Organizer: 第30回抗ウイルス療法学会学術集会総会
• [Presentation] CD4 類似化合物YIR-821は多くのHIV-1臨床株に有効である (2022)
  • Author(s): 松本佳穂, 桑田岳夫, 高濱正吉 , Judicate GP, 上野貴将, 小早川拓也, 玉村啓和, 松下修三.
  • Organizer: 第36回日本エイズ学会学術集会総会
• [Presentation] The CD4 mimetic compound YIR-821 is broadly effective against HIV-1 clinical strains. (2022)
  • Author(s): Kaho Matsumoto, Takeo Kuwata, Shokichi Takahama, George P Judicate, Takamasa Ueno, Takuya Kobayakawa, Kohei Tsuji, Hirokazu Tamamura and Shuzo Matsushita.
  • Organizer: 24th Kumamoto AIDS Seminar
• [Presentation] Antibodies against CD4 induced epitope of HIV-1 evolve from B cells primed by gut microbiome (2022)
  • Author(s): Shashwata Biswas, Kyo Okazaki, Soichiro Yamauchi, Takeo Kuwata, Hiroshi Morioka and Shuzo Matsushita.
  • Organizer: 24th Kumamoto AIDS Seminar
• [Presentation] 抗イディオタイプ抗体を用いたHIV中和抗体誘導の為の段階的ワクチン戦略 (2021)
  • Author(s): 郭悠、Zahid Md H、Biswas S、松本佳穂、桑田岳夫、松下修三
  • Organizer: 第35回日本エイズ学会学術集会・総会
• [Presentation] COVID-19回復者で誘導された抗体に対するSARS-CoV-2変異株の中和抵抗性 (2021)
  • Author(s): 桑田岳夫、郭悠、清水美紀子、Zahid Md H、Biswas S、松本佳穂、松下修三
  • Organizer: 第35回日本エイズ学会学術集会・総会
• [Presentation] 回復患者より抽出したSARS-CoV-2中和抗体の検討 (2021)
  • Author(s): 郭悠、松本佳穂、Zahid Md H、Biswas S、桑田岳夫、松下修三
  • Organizer: 第35回日本エイズ学会学術集会・総会
• [Presentation] CD4類似化合物YIR-821によるサブタイプB HIV-1患者抗体の活性増強効果 (2021)
  • Author(s): 松本佳穂、桑田岳夫、Zahid Md H、郭悠、Biswas S、高濱正吉、玉村啓和、松下修三
  • Organizer: 第35回日本エイズ学会学術集会・総会
• [Presentation] Anti-Idiotype antibodies as sorting probes to isolate anti-CD4i antibodies (2021)
  • Author(s): Biswas S, Yamauchi S, Morioka H, Kaku Y, Kuwata T, Matsushita S
  • Organizer: 第35回日本エイズ学会学術集会・総会