HIV-1 Neutralizing Antibody Signatures and Application to Epitope-Targeted Vaccine Design

Christine A Bricault; Karina Yusim; Michael S Seaman; Hyejin Yoon; James Theiler; Elena E Giorgi; Kshitij Wagh; Maxwell Theiler; Peter Hraber; Jennifer P Macke; Edward F Kreider; Gerald H Learn; Beatrice H Hahn; Johannes F Scheid; James M Kovacs; Jennifer L Shields; Christy L Lavine; Fadi Ghantous; Michael Rist; Madeleine G Bayne; George H Neubauer; Katherine McMahan; Hanqin Peng; Coraline Chéneau; Jennifer J Jones; Jie Zeng; Christina Ochsenbauer; Joseph P Nkolola; Kathryn E Stephenson; Bing Chen; S Gnanakaran; Mattia Bonsignori; LaTonya D Williams; Barton F Haynes; Nicole Doria-Rose; John R Mascola; David C Montefiori; Dan H Barouch; Bette Korber

doi:10.1016/j.chom.2018.12.001

HIV-1 Neutralizing Antibody Signatures and Application to Epitope-Targeted Vaccine Design

Cell Host Microbe. 2019 Jan 9;25(1):59-72.e8. doi: 10.1016/j.chom.2018.12.001.

Authors

Christine A Bricault¹, Karina Yusim², Michael S Seaman¹, Hyejin Yoon³, James Theiler², Elena E Giorgi², Kshitij Wagh², Maxwell Theiler³, Peter Hraber³, Jennifer P Macke³, Edward F Kreider⁴, Gerald H Learn⁴, Beatrice H Hahn⁴, Johannes F Scheid⁵, James M Kovacs⁶, Jennifer L Shields¹, Christy L Lavine¹, Fadi Ghantous¹, Michael Rist¹, Madeleine G Bayne¹, George H Neubauer¹, Katherine McMahan¹, Hanqin Peng⁷, Coraline Chéneau¹, Jennifer J Jones⁸, Jie Zeng⁸, Christina Ochsenbauer⁸, Joseph P Nkolola¹, Kathryn E Stephenson⁹, Bing Chen⁷, S Gnanakaran², Mattia Bonsignori¹⁰, LaTonya D Williams¹¹, Barton F Haynes¹², Nicole Doria-Rose¹³, John R Mascola¹³, David C Montefiori¹⁴, Dan H Barouch¹⁵, Bette Korber¹⁶

Affiliations

¹ Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Boston, MA 02215, USA.
² Los Alamos National Laboratory, Los Alamos, NM 87545, USA; New Mexico Consortium, Los Alamos, NM 87545, USA.
³ Los Alamos National Laboratory, Los Alamos, NM 87545, USA.
⁴ Departments of Medicine and Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
⁵ Massachusetts General Hospital, Boston, MA 02114, USA; Harvard Medical School, Boston, MA 02114, USA.
⁶ Division of Molecular Medicine, Children's Hospital, Boston, MA 02115, USA; Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA; Departments of Chemistry and Biochemistry, University of Colorado, Colorado Springs, CO 80918, USA.
⁷ Division of Molecular Medicine, Children's Hospital, Boston, MA 02115, USA; Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA.
⁸ Department of Medicine and CFAR, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
⁹ Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Boston, MA 02215, USA; Ragon Institute of Massachusetts General Hospital, MIT, and Harvard, Boston, MA 02114, USA.
¹⁰ Duke Human Vaccine Institute, Duke University School of Medicine, Durham, NC 27710, USA; Department of Medicine, Duke University School of Medicine, Durham, NC 27710, USA.
¹¹ Duke Human Vaccine Institute, Duke University School of Medicine, Durham, NC 27710, USA.
¹² Duke Human Vaccine Institute, Duke University School of Medicine, Durham, NC 27710, USA; Department of Medicine, Duke University School of Medicine, Durham, NC 27710, USA; Department of Immunology, Duke University School of Medicine, Durham, NC 27710, USA.
¹³ Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20814, USA.
¹⁴ Duke Human Vaccine Institute, Duke University School of Medicine, Durham, NC 27710, USA; Department of Surgery, Duke University School of Medicine, Durham, NC 27710, USA.
¹⁵ Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Boston, MA 02215, USA; Ragon Institute of Massachusetts General Hospital, MIT, and Harvard, Boston, MA 02114, USA. Electronic address: [email protected].
¹⁶ Los Alamos National Laboratory, Los Alamos, NM 87545, USA; New Mexico Consortium, Los Alamos, NM 87545, USA. Electronic address: [email protected].

Abstract

Eliciting HIV-1-specific broadly neutralizing antibodies (bNAbs) remains a challenge for vaccine development, and the potential of passively delivered bNAbs for prophylaxis and therapeutics is being explored. We used neutralization data from four large virus panels to comprehensively map viral signatures associated with bNAb sensitivity, including amino acids, hypervariable region characteristics, and clade effects across four different classes of bNAbs. The bNAb signatures defined for the variable loop 2 (V2) epitope region of HIV-1 Env were then employed to inform immunogen design in a proof-of-concept exploration of signature-based epitope targeted (SET) vaccines. V2 bNAb signature-guided mutations were introduced into Env 459C to create a trivalent vaccine, and immunization of guinea pigs with V2-SET vaccines resulted in increased breadth of NAb responses compared with Env 459C alone. These data demonstrate that bNAb signatures can be utilized to engineer HIV-1 Env vaccine immunogens capable of eliciting antibody responses with greater neutralization breadth.

Keywords: HIV-1; V2-apex antibodies; broadly neutralizing antibodies; hypervariable regions; machine learning; signature analysis; vaccine design.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Amino Acid Sequence
Animals
Antibodies, Neutralizing / immunology*
Antibodies, Neutralizing / therapeutic use
Antibody Formation
Disease Models, Animal
Epitopes / genetics
Epitopes / immunology*
Female
Guinea Pigs
HEK293 Cells
HIV Antibodies / immunology*
HIV Envelope Protein gp120 / immunology
HIV Infections / immunology*
HIV Infections / prevention & control*
HIV Infections / virology
HIV-1 / genetics
Humans
Immunization
Inhibitory Concentration 50
Models, Molecular
Mutation
Peptide Fragments / immunology
Protein Binding
Vaccination
Vaccines*
env Gene Products, Human Immunodeficiency Virus / genetics
env Gene Products, Human Immunodeficiency Virus / immunology

Substances

Antibodies, Neutralizing
Epitopes
HIV Antibodies
HIV Envelope Protein gp120
HIV envelope protein gp120 (305-321)
Peptide Fragments
Vaccines
env Gene Products, Human Immunodeficiency Virus

Abstract

Publication types

MeSH terms

Substances

Grants and funding