Heavy-chain CDR3-engineered B cells facilitate in vivo evaluation of HIV-1 vaccine candidates

Wenhui He; Tianling Ou; Nickolas Skamangas; Charles C Bailey; Naomi Bronkema; Yan Guo; Yiming Yin; Valerie Kobzarenko; Xia Zhang; Andi Pan; Xin Liu; Jinge Xu; Lizhou Zhang; Ava E Allwardt; Debasis Mitra; Brian Quinlan; Rogier W Sanders; Hyeryun Choe; Michael Farzan

doi:10.1016/j.immuni.2023.07.003

Heavy-chain CDR3-engineered B cells facilitate in vivo evaluation of HIV-1 vaccine candidates

Immunity. 2023 Oct 10;56(10):2408-2424.e6. doi: 10.1016/j.immuni.2023.07.003. Epub 2023 Aug 1.

Authors

Wenhui He¹, Tianling Ou¹, Nickolas Skamangas², Charles C Bailey³, Naomi Bronkema⁴, Yan Guo⁵, Yiming Yin⁶, Valerie Kobzarenko⁷, Xia Zhang⁵, Andi Pan⁴, Xin Liu⁸, Jinge Xu⁸, Lizhou Zhang², Ava E Allwardt⁶, Debasis Mitra⁷, Brian Quinlan⁵, Rogier W Sanders⁹, Hyeryun Choe⁶, Michael Farzan¹⁰

Affiliations

¹ Division of Infectious Disease, Boston Children's Hospital, Boston, MA 02115, USA; The Center for Integrated Solutions to Infectious Diseases, The Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA; Department of Immunology and Microbiology, UF Scripps Biomedical Research, Jupiter, FL 33458, USA.
² Division of Infectious Disease, Boston Children's Hospital, Boston, MA 02115, USA; Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA; Department of Immunology and Microbiology, UF Scripps Biomedical Research, Jupiter, FL 33458, USA.
³ The Center for Integrated Solutions to Infectious Diseases, The Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Immunology and Microbiology, UF Scripps Biomedical Research, Jupiter, FL 33458, USA.
⁴ Division of Infectious Disease, Boston Children's Hospital, Boston, MA 02115, USA; The Center for Integrated Solutions to Infectious Diseases, The Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Skaggs Graduate School, Scripps Research, La Jolla, CA 92037, USA.
⁵ Department of Immunology and Microbiology, UF Scripps Biomedical Research, Jupiter, FL 33458, USA.
⁶ Division of Infectious Disease, Boston Children's Hospital, Boston, MA 02115, USA; Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA.
⁷ Department of Computer Engineering and Sciences, Florida Institute of Technology, Melbourne, FL 32901, USA.
⁸ Division of Infectious Disease, Boston Children's Hospital, Boston, MA 02115, USA; The Center for Integrated Solutions to Infectious Diseases, The Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA.
⁹ Department of Medical Microbiology, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands.
¹⁰ Division of Infectious Disease, Boston Children's Hospital, Boston, MA 02115, USA; The Center for Integrated Solutions to Infectious Diseases, The Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA; Skaggs Graduate School, Scripps Research, La Jolla, CA 92037, USA. Electronic address: michael.farzan@childrens.harvard.edu.

PMID: 37531955
DOI: 10.1016/j.immuni.2023.07.003

Abstract

V2-glycan/apex broadly neutralizing antibodies (bnAbs) recognize a closed quaternary epitope of the HIV-1 envelope glycoprotein (Env). This closed structure is necessary to elicit apex antibodies and useful to guide the maturation of other bnAb classes. To compare antigens designed to maintain this conformation, we evaluated apex-specific responses in mice engrafted with a diverse repertoire of B cells expressing the HCDR3 of the apex bnAb VRC26.25. Engineered B cells affinity matured, guiding the improvement of VRC26.25 itself. We found that soluble Env (SOSIP) variants differed significantly in their ability to raise anti-apex responses. A transmembrane SOSIP (SOSIP-TM) delivered as an mRNA-lipid nanoparticle elicited more potent neutralizing responses than multimerized SOSIP proteins. Importantly, SOSIP-TM elicited neutralizing sera from B cells engineered with the predicted VRC26.25-HCDR3 progenitor, which also affinity matured. Our data show that HCDR3-edited B cells facilitate efficient in vivo comparisons of Env antigens and highlight the potential of an HCDR3-focused vaccine approach.

Keywords: B cell engineering; HCDR3; HIV-1 vaccine model; SOSIP; SOSIP-TM; affinity maturation; apex bnAb precursor; lipid nanoparticle; mRNA vaccine.

Publication types

Research Support, N.I.H., Extramural

MeSH terms

AIDS Vaccines*
Animals
Antibodies, Neutralizing
Antigens, Viral
Broadly Neutralizing Antibodies
HIV Antibodies
HIV Infections*
HIV-1*
Mice
Vaccines*
env Gene Products, Human Immunodeficiency Virus

Substances

HIV Antibodies
Antibodies, Neutralizing
Broadly Neutralizing Antibodies
Antigens, Viral
Vaccines
env Gene Products, Human Immunodeficiency Virus
AIDS Vaccines

Abstract

Publication types

MeSH terms

Substances

Grants and funding