Heterologous prime-boost vaccination drives early maturation of HIV broadly neutralizing antibody precursors in humanized mice,Science Translational Medicine

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Heterologous prime-boost vaccination drives early maturation of HIV broadly neutralizing antibody precursors in humanized mice
Science Translational Medicine ( IF 15.8 ) Pub Date : 2024-05-22 , DOI: 10.1126/scitranslmed.adn0223
Christopher A. Cottrell _{1,

2} , Xiaozhen Hu _{1,

2,

3,

4} , Jeong Hyun Lee _{1,

2,

3} , Patrick Skog _{1,

2,

3} , Sai Luo _{5,

6,

7} , Claudia T. Flynn _{1,

3} , Katherine R. McKenney ₃ , Jonathan Hurtado ₁ , Oleksandr Kalyuzhniy _{1,

2,

3} , Alessia Liguori _{1,

2,

3} , Jordan R. Willis _{1,

2,

3} , Elise Landais _{1,

3} , Sebastian Raemisch _{1,

2,

3} , Xuejun Chen ₈ , Sabyasachi Baboo ₉ , Sunny Himansu ₄ , Jolene K. Diedrich ₉ , Hongying Duan ₈ , Cheng Cheng ₈ , Torben Schiffner _{1,

2,

3} , Daniel L.V. Bader _{1,

2,

3} , Daniel W. Kulp _{1,

2,

3} , Ryan Tingle _{1,

2,

3} , Erik Georgeson _{1,

2,

3} , Saman Eskandarzadeh _{1,

2,

3} , Nushin Alavi _{1,

2,

3} , Danny Lu _{1,

2,

3} , Troy Sincomb _{1,

2,

3} , Michael Kubitz _{1,

2,

3} , Tina-Marie Mullen _{1,

2,

3} , John R. Yates ₉ , James C. Paulson ₉ , John R. Mascola ₈ , Frederick W. Alt _{5,

6,

7} , Bryan Briney _{1,

2,

3} , Devin Sok _{1,

2,

3} , William R. Schief _{1,

2,

3,

4,

10}

Affiliation

Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, CA 92037, USA.
Center for HIV/AIDS Vaccine Development, The Scripps Research Institute, La Jolla, CA 92037, USA.
IAVI Neutralizing Antibody Center, The Scripps Research Institute, La Jolla, CA 92037, USA.
Moderna Therapeutics, Cambridge, MA 02139, USA.
HHMI, Boston Children's Hospital, Boston, MA 02115, USA.
Program in Cellular and Molecular Medicine, Boston Children’s Hospital, Boston, MA 02115, USA.
Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.
Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
Department of Molecular Medicine, The Scripps Research Institute, La Jolla, CA 92037, USA.
The Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology and Harvard University, Cambridge, MA 02139, USA.

A protective HIV vaccine will likely need to induce broadly neutralizing antibodies (bnAbs). Vaccination with the germline-targeting immunogen eOD-GT8 60mer adjuvanted with AS01_B was found to induce VRC01-class bnAb precursors in 97% of vaccine recipients in the IAVI G001 phase 1 clinical trial; however, heterologous boost immunizations with antigens more similar to the native glycoprotein will be required to induce bnAbs. Therefore, we designed core-g28v2 60mer, a nanoparticle immunogen to be used as a first boost after eOD-GT8 60mer priming. We found, using a humanized mouse model approximating human conditions of VRC01-class precursor B cell diversity, affinity, and frequency, that both protein- and mRNA-based heterologous prime-boost regimens induced VRC01-class antibodies that gained key mutations and bound to near-native HIV envelope trimers lacking the N276 glycan. We further showed that VRC01-class antibodies induced by mRNA-based regimens could neutralize pseudoviruses lacking the N276 glycan. These results demonstrated that heterologous boosting can drive maturation toward VRC01-class bnAb development and supported the initiation of the IAVI G002 phase 1 trial testing mRNA-encoded nanoparticle prime-boost regimens.

中文翻译：

异源初免-加强疫苗接种促进人源化小鼠中 HIV 广泛中和抗体前体的早期成熟

保护性 HIV 疫苗可能需要诱导广泛中和抗体 (bnAb)。在 IAVI G001 1 期临床试验中，发现接种带有 AS01 _B 佐剂的种系靶向免疫原 eOD-GT8 60mer 疫苗可在 97% 的疫苗接受者中诱导 VRC01 类 bnAb 前体；然而，需要使用与天然糖蛋白更相似的抗原进行异源加强免疫来诱导 bnAb。因此，我们设计了 core-g28v2 60mer，这是一种纳米颗粒免疫原，用作 eOD-GT8 60mer 引发后的第一次加强。我们发现，使用接近人类 VRC01 类前体 B 细胞多样性、亲和力和频率条件的人源化小鼠模型，基于蛋白质和 mRNA 的异源初免加强方案均诱导 VRC01 类抗体获得关键突变并与缺乏 N276 聚糖的近天然 HIV 包膜三聚体。我们进一步表明，基于 mRNA 的方案诱导的 VRC01 类抗体可以中和缺乏 N276 聚糖的假病毒。这些结果表明，异源加强可以推动 VRC01 级 bnAb 开发的成熟，并支持启动 IAVI G002 1 期试验，测试 mRNA 编码的纳米颗粒初免加强方案。

更新日期：2024-05-22

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