이정현 (The Scripps Research Institute)

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The Scripps Research Institute

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Sci. Transl. Med., May 22 2024, | https://doi.org/10.1126/scitranslmed.adn0223 Heterologous prime-boost vaccination drives early maturation of HIV broadly neutralizing antibody precursors in humanized mice

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 Baboo⁹, Sunny Himansu ⁴, Jolene K. Diedrich⁹, 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 3rd ⁹, James C Paulson ⁹, John R. Mascola⁸, Frederick W. Alt ^5,6,7, Bryan Briney ^1,2,3, Devin Sok ^1,2,3, William R. Schief^1,2,3,4,10

¹Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, CA 92037, USA.

²Center for HIV/AIDS Vaccine Development, The Scripps Research Institute, La Jolla, CA 92037, USA.

³IAVI Neutralizing Antibody Center, The Scripps Research Institute, La Jolla, CA 92037, USA.

⁴Moderna Therapeutics, Cambridge, MA 02139, USA.

⁵HHMI, Boston Children's Hospital, Boston, MA 02115, USA.

⁶Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, MA 02115, USA.

⁷Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.

⁸Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.

⁹Department of Molecular Medicine, The Scripps Research Institute, La Jolla, CA 92037, USA.

¹⁰The Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology and Harvard University, Cambridge, MA 02139, USA.

^*Corresponding author; William R Schief

†These authors contributed equally to this work.

Abstract

A protective human immunodeficiency virus (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 following 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.

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형식Research article
게재일2024년 05월 (BRIC 등록일 2024-06-18)
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