title: Comparison of Immunogenicity in Rhesus Macaques of Transmitted-Founder, HIV-1 Group M Consensus, and Trivalent Mosaic Envelope Vaccines Formulated as a DNA Prime, NYVAC, and Envelope Protein Boost.
abstract: An effective human immunodeficiency virus type 1 (HIV-1) vaccine must induce protective antibody responses, as well as CD4(+) and CD8(+) T cell responses, that can be effective despite extraordinary diversity of HIV-1. The consensus and mosaic immunogens are complete but artificial proteins, computationally designed to elicit immune responses with improved cross-reactive breadth, to attempt to overcome the challenge of global HIV diversity. In this study, we have compared the immunogenicity of a transmitted-founder (T/F) B clade Env (B.1059), a global group M consensus Env (Con-S), and a global trivalent mosaic Env protein in rhesus macaques. These antigens were delivered using a DNA prime-recombinant NYVAC (rNYVAC) vector and Env protein boost vaccination strategy. While Con-S Env was a single sequence, mosaic immunogens were a set of three Envs optimized to include the most common forms of potential T cell epitopes. Both Con-S and mosaic sequences retained common amino acids encompassed by both antibody and T cell epitopes and were central to globally circulating strains. Mosaics and Con-S Envs expressed as full-length proteins bound well to a number of neutralizing antibodies with discontinuous epitopes. Also, both consensus and mosaic immunogens induced significantly higher gamma interferon (IFN-γ) enzyme-linked immunosorbent spot assay (ELISpot) responses than B.1059 immunogen. Immunization with these proteins, particularly Con-S, also induced significantly higher neutralizing antibodies to viruses than B.1059 Env, primarily to tier 1 viruses. Both Con-S and mosaics stimulated more potent CD8-T cell responses against heterologous Envs than did B.1059. Both antibody and cellular data from this study strengthen the concept of using in silico-designed centralized immunogens for global HIV-1 vaccine development strategies.
  
  
  OBJECTIVE
  There is an increasing appreciation for the importance of vaccine-induced anti-Env antibody responses for preventing HIV-1 acquisition. This nonhuman primate study demonstrates that in silico-designed global HIV-1 immunogens, designed for a human clinical trial, are capable of eliciting not only T lymphocyte responses but also potent anti-Env antibody responses.
authors: Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA.
authors: Sandrine L
authors: SL
authors: Hulot
authors: Los Alamos National Laboratory, Los Alamos, New Mexico, USA.
authors: Bette
authors: B
authors: Korber
authors: Los Alamos National Laboratory, Los Alamos, New Mexico, USA.
authors: Elena E
authors: EE
authors: Giorgi
authors: Duke Human Vaccine Institute, Duke University Medical Center, Durham, North Carolina, USA.
authors: Nathan
authors: N
authors: Vandergrift
authors: Duke Human Vaccine Institute, Duke University Medical Center, Durham, North Carolina, USA.
authors: Kevin O
authors: KO
authors: Saunders
authors: Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA.
authors: Harikrishnan
authors: H
authors: Balachandran
authors: Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA.
authors: Linh V
authors: LV
authors: Mach
authors: Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA.
authors: Michelle A
authors: MA
authors: Lifton
authors: Centre Hospitalier Universitaire Vaudois (CHUV), Université de Lausanne, Lausanne, Switzerland.
authors: Giuseppe
authors: G
authors: Pantaleo
authors: Sanofi-Pasteur, Toronto, Canada.
authors: Jim
authors: J
authors: Tartaglia
authors: Sanofi-Pasteur, Toronto, Canada.
authors: Sanjay
authors: S
authors: Phogat
authors: Center for Infectious Diseases and Vaccinology, The Biodesign Institute, Arizona State University, Tempe, Arizona, USA.
authors: Bertram
authors: B
authors: Jacobs
authors: Center for Infectious Diseases and Vaccinology, The Biodesign Institute, Arizona State University, Tempe, Arizona, USA.
authors: Karen
authors: K
authors: Kibler
authors: Centro Nacional de Biotecnologia, Madrid, Spain.
authors: Beatriz
authors: B
authors: Perdiguero
authors: Centro Nacional de Biotecnologia, Madrid, Spain.
authors: Carmen E
authors: CE
authors: Gomez
authors: Centro Nacional de Biotecnologia, Madrid, Spain.
authors: Mariano
authors: M
authors: Esteban
authors: National Cancer Institute, Frederick, Maryland, USA.
authors: Margherita
authors: M
authors: Rosati
authors: National Cancer Institute, Frederick, Maryland, USA.
authors: Barbara K
authors: BK
authors: Felber
authors: National Cancer Institute, Frederick, Maryland, USA.
authors: George N
authors: GN
authors: Pavlakis
authors: Duke Human Vaccine Institute, Duke University Medical Center, Durham, North Carolina, USA.
authors: Robert
authors: R
authors: Parks
authors: Duke Human Vaccine Institute, Duke University Medical Center, Durham, North Carolina, USA.
authors: Krissey
authors: K
authors: Lloyd
authors: Duke Human Vaccine Institute, Duke University Medical Center, Durham, North Carolina, USA.
authors: Laura
authors: L
authors: Sutherland
authors: Duke Human Vaccine Institute, Duke University Medical Center, Durham, North Carolina, USA.
authors: Richard
authors: R
authors: Scearce
authors: Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA.
authors: Norman L
authors: NL
authors: Letvin
authors: Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA.
authors: Michael S
authors: MS
authors: Seaman
authors: Duke Human Vaccine Institute, Duke University Medical Center, Durham, North Carolina, USA.
authors: S Munir
authors: SM
authors: Alam
authors: Duke Human Vaccine Institute, Duke University Medical Center, Durham, North Carolina, USA.
authors: David
authors: D
authors: Montefiori
authors: Duke Human Vaccine Institute, Duke University Medical Center, Durham, North Carolina, USA.
authors: Hua-Xin
authors: HX
authors: Liao
authors: Duke Human Vaccine Institute, Duke University Medical Center, Durham, North Carolina, USA.
authors: Barton F
authors: BF
authors: Haynes
authors: Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA ssantra@bidmc.harvard.edu.
authors: Sampa
authors: S
authors: Santra
mesh_terms: D000818:Animals; D057134:Antibodies, Neutralizing / Q000097:blood; D000956:Antigens, Viral / Q000235:genetics / Q000276:immunology; D001219:Aspartate Aminotransferases; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D016384:Consensus Sequence; D058501:Enzyme-Linked Immunospot Assay; D015483:HIV Antibodies / Q000097:blood; D015497:HIV-1 / Q000235:genetics / Q000276:immunology*; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism; D008253:Macaca mulatta; D018449:SAIDS Vaccines / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology*; D014611:Vaccination / Q000379:methods*; D019444:Vaccines, DNA / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology*; D022223:Vaccines, Subunit / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology; D054299:env Gene Products, Human Immunodeficiency Virus / Q000235:genetics / Q000276:immunology
chemical_list: D057134:Antibodies, Neutralizing; D000956:Antigens, Viral; D015483:HIV Antibodies; D018449:SAIDS Vaccines; D019444:Vaccines, DNA; D022223:Vaccines, Subunit; D054299:env Gene Products, Human Immunodeficiency Virus; D007371:Interferon-gamma; D001219:Aspartate Aminotransferases