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.

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