title: Evaluation of a novel multi-immunogen vaccine strategy for targeting 4E10/10E8 neutralizing epitopes on HIV-1 gp41 membrane proximal external region.
abstract: The membrane proximal external region (MPER) of HIV-1 gp41 is targeted by broadly neutralizing antibodies (bnAbs) 4E10 and 10E8. In this proof-of-concept study, we evaluated a novel multi-immunogen vaccine strategy referred to as Incremental, Phased Antigenic Stimulation for Rapid Antibody Maturation (IPAS-RAM) to induce 4E10/10E8-like bnAbs. Rabbits were immunized sequentially, but in a phased manner, with three immunogens that are progressively more native (gp41-28×3, gp41-54CT, and rVV-gp160DH12). Although nAbs were not induced, epitope-mapping analyses indicated that IPAS-RAM vaccination was better able to target antibodies towards the 4E10/10E8 epitopes than homologous prime-boost immunization using gp41-28×3 alone. MPER-specific rabbit monoclonal antibodies were generated, including 9F6. Although it lacked neutralizing activity, the target epitope profile of 9F6 closely resembled those of 4E10 and 10E8 (671NWFDITNWLWYIK683). B-cell repertoire analyses suggested the importance of co-immunizations for maturation of 9F6, which warrants further evaluation of our IPAS-RAM vaccine strategy using an improved priming immunogen.
authors.affiliation: Department of Biomedical Sciences, Iowa State University, Ames, IA 50011, United States.
authors.forename: Saikat
authors.initials: S
authors.lastname: Banerjee
authors.affiliation: Department of Biomedical Sciences, Iowa State University, Ames, IA 50011, United States.
authors.forename: Heliang
authors.initials: H
authors.lastname: Shi
authors.affiliation: Department of Biomedical Sciences, Iowa State University, Ames, IA 50011, United States.
authors.forename: Marisa
authors.initials: M
authors.lastname: Banasik
authors.affiliation: Department of Biomedical Sciences, Iowa State University, Ames, IA 50011, United States.
authors.forename: Hojin
authors.initials: H
authors.lastname: Moon
authors.affiliation: Institute of Structural and Molecular Biology, Birkbeck College, University of London, UK.
authors.forename: William
authors.initials: W
authors.lastname: Lees
authors.affiliation: Department of Biomedical Sciences, Iowa State University, Ames, IA 50011, United States.
authors.forename: Yali
authors.initials: Y
authors.lastname: Qin
authors.affiliation: Department of Biomedical Sciences, Iowa State University, Ames, IA 50011, United States.
authors.forename: Andrew
authors.initials: A
authors.lastname: Harley
authors.affiliation: Institute of Structural and Molecular Biology, Birkbeck College, University of London, UK.
authors.forename: Adrian
authors.initials: A
authors.lastname: Shepherd
authors.affiliation: Department of Biomedical Sciences, Iowa State University, Ames, IA 50011, United States. Electronic address: mcho@iastate.edu.
authors.forename: Michael W
authors.initials: MW
authors.lastname: Cho
mesh_terms: D016915:AIDS Vaccines / Q000276:immunology*; D000595:Amino Acid Sequence; D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology*; D057134:Antibodies, Neutralizing / Q000276:immunology*; D001402:B-Lymphocytes / Q000276:immunology; D000080908:Broadly Neutralizing Antibodies; D002460:Cell Line; D018604:Epitope Mapping; D000939:Epitopes / Q000276:immunology*; D005260:Female; D057809:HEK293 Cells; D015483:HIV Antibodies / Q000276:immunology*; D015700:HIV Envelope Protein gp41 / Q000276:immunology*; D015497:HIV-1 / Q000276:immunology*; D006801:Humans; D011817:Rabbits; D014611:Vaccination
chemical_list: C558559:4E10 monoclonal antibody; D016915:AIDS Vaccines; D000911:Antibodies, Monoclonal; D057134:Antibodies, Neutralizing; D000080908:Broadly Neutralizing Antibodies; D000939:Epitopes; D015483:HIV Antibodies; D015700:HIV Envelope Protein gp41
keywords: Antibody maturation; HIV-1; MPER; NGS; Neutralizing antibody; Next-generation sequencing; Rabbit; Vaccine; gp41