title: Superiority in Rhesus Macaques of Targeting HIV-1 Env gp140 to CD40 versus LOX-1 in Combination with Replication-Competent NYVAC-KC for Induction of Env-Specific Antibody and T Cell Responses.
abstract: We compared the HIV-1-specific immune responses generated by targeting HIV-1 envelope protein (Env gp140) to either CD40 or LOX-1, two endocytic receptors on dendritic cells (DCs), in rhesus macaques primed with a poxvirus vector (NYVAC-KC) expressing Env gp140. The DC-targeting vaccines, humanized recombinant monoclonal antibodies fused to Env gp140, were administered as a boost with poly-ICLC adjuvant either alone or coadministered with the NYVAC-KC vector. All the DC-targeting vaccine administrations with poly-ICLC increased the low-level serum anti-Env IgG responses elicited by NYVAC-KC priming significantly more (up to aPvalue of 0.01) than in a group without poly-ICLC. The responses were robust and cross-reactive and contained antibodies specific to multiple epitopes within gp140, including the C1, C2, V1, V2, and V3, C4, C5, and gp41 immunodominant regions. The DC-targeting vaccines also elicited modest serum Env-specific IgA responses. All groups gave serum neutralization activity limited to tier 1 viruses and antibody-dependent cytotoxicity responses (ADCC) after DC-targeting boosts. Furthermore, CD4+and CD8+T cell responses specific to multiple Env epitopes were strongly boosted by the DC-targeting vaccines plus poly-ICLC. Together, these results indicate that prime-boost immunization via NYVAC-KC and either anti-CD40.Env gp140/poly-ICLC or anti-LOX-1.Env gp140/poly-ICLC induced balanced antibody and T cell responses against HIV-1 Env. Coadministration of NYVAC-KC with the DC-targeting vaccines increased T cell responses but had minimal effects on antibody responses except for suppressing serum IgA responses. Overall, targeting Env to CD40 gave more robust T cell and serum antibody responses with broader epitope representation and greater durability than with LOX-1.IMPORTANCEAn effective vaccine to prevent HIV-1 infection does not yet exist. An approach to elicit strong protective antibody development is to direct virus protein antigens specifically to dendritic cells, which are now known to be the key cell type for controlling immunity. In this study, we have tested in nonhuman primates two prototype vaccines engineered to direct the HIV-1 coat protein Env to dendritic cells. These vaccines bind to either CD40 or LOX-1, two dendritic cell surface receptors with different functions and tissue distributions. We tested the vaccines described above in combination with attenuated virus vectors that express Env. Both vaccines, but especially that delivered via CD40, raised robust immunity against HIV-1 as measured by monitoring potentially protective antibody and T cell responses in the blood. The safety and efficacy of the CD40-targeted vaccine justify further development for future human clinical trials.
authors.affiliation: Vaccine Research Institute, Université Paris-Est, Faculté de Médecine, INSERM U955, and Assistance Publique-Hôpitaux de Paris, Groupe Henri-Mondor Albert-Chenevier, service d'immunologie clinique, Créteil, France.|Baylor Institute for Immunology Research and INSERM U955, Dallas, Texas, USA.
authors.forename: Gerard
authors.initials: G
authors.lastname: Zurawski
authors.affiliation: Duke Human Vaccine Institute, Duke University Medical Center, Durham, North Carolina, USA.
authors.forename: Xiaoying
authors.initials: X
authors.lastname: Shen
authors.affiliation: Vaccine Research Institute, Université Paris-Est, Faculté de Médecine, INSERM U955, and Assistance Publique-Hôpitaux de Paris, Groupe Henri-Mondor Albert-Chenevier, service d'immunologie clinique, Créteil, France.|Baylor Institute for Immunology Research and INSERM U955, Dallas, Texas, USA.
authors.forename: Sandra
authors.initials: S
authors.lastname: Zurawski
authors.affiliation: Duke Human Vaccine Institute, Duke University Medical Center, Durham, North Carolina, USA.|Department of Surgery, Duke University Medical Center, Durham, North Carolina, USA.
authors.forename: Georgia D
authors.initials: GD
authors.lastname: Tomaras
authors.affiliation: Department of Surgery, Duke University Medical Center, Durham, North Carolina, USA.
authors.forename: David C
authors.initials: DC
authors.lastname: Montefiori
authors.affiliation: Vaccine Research Center, NIAID, NIH, Bethesda, Maryland, USA.
authors.forename: Mario
authors.initials: M
authors.lastname: Roederer
authors.affiliation: Department of Surgery, Duke University Medical Center, Durham, North Carolina, USA.
authors.forename: Guido
authors.initials: G
authors.lastname: Ferrari
authors.affiliation: Vaccine Research Institute, Université Paris-Est, Faculté de Médecine, INSERM U955, and Assistance Publique-Hôpitaux de Paris, Groupe Henri-Mondor Albert-Chenevier, service d'immunologie clinique, Créteil, France.
authors.forename: Christine
authors.initials: C
authors.lastname: Lacabaratz
authors.affiliation: Vaccine Research Institute, Université Paris-Est, Faculté de Médecine, INSERM U955, and Assistance Publique-Hôpitaux de Paris, Groupe Henri-Mondor Albert-Chenevier, service d'immunologie clinique, Créteil, France.|Baylor Institute for Immunology Research and INSERM U955, Dallas, Texas, USA.
authors.forename: Peter
authors.initials: P
authors.lastname: Klucar
authors.affiliation: Vaccine Research Institute, Université Paris-Est, Faculté de Médecine, INSERM U955, and Assistance Publique-Hôpitaux de Paris, Groupe Henri-Mondor Albert-Chenevier, service d'immunologie clinique, Créteil, France.|Baylor Institute for Immunology Research and INSERM U955, Dallas, Texas, USA.
authors.forename: Zhiqing
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Vaccine Research Center, NIAID, NIH, Bethesda, Maryland, USA.
authors.forename: Kathryn E
authors.initials: KE
authors.lastname: Foulds
authors.affiliation: Vaccine Research Center, NIAID, NIH, Bethesda, Maryland, USA.
authors.forename: Shing-Fen
authors.initials: SF
authors.lastname: Kao
authors.affiliation: Statistical Center for HIV/AIDS Research and Prevention, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.
authors.forename: Xuesong
authors.initials: X
authors.lastname: Yu
authors.affiliation: Statistical Center for HIV/AIDS Research and Prevention, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.
authors.forename: Alicia
authors.initials: A
authors.lastname: Sato
authors.affiliation: Duke Human Vaccine Institute, Duke University Medical Center, Durham, North Carolina, USA.
authors.forename: Nicole L
authors.initials: NL
authors.lastname: Yates
authors.affiliation: Department of Surgery, Duke University Medical Center, Durham, North Carolina, USA.
authors.forename: Celia
authors.initials: C
authors.lastname: LaBranche
authors.affiliation: Department of Surgery, Duke University Medical Center, Durham, North Carolina, USA.
authors.forename: Sherry
authors.initials: S
authors.lastname: Stanfield-Oakley
authors.affiliation: School of Life Sciences, Center for Infectious Diseases and Vaccinology, Arizona State University, Tempe, Arizona, USA.
authors.forename: Karen
authors.initials: K
authors.lastname: Kibler
authors.affiliation: School of Life Sciences, Center for Infectious Diseases and Vaccinology, Arizona State University, Tempe, Arizona, USA.
authors.forename: Bertram
authors.initials: B
authors.lastname: Jacobs
authors.affiliation: Oncovir, Washington, DC, USA.
authors.forename: Andres
authors.initials: A
authors.lastname: Salazar
authors.affiliation: Vaccine and Infectious Disease and Public Health Sciences Divisions, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.
authors.forename: Steve
authors.initials: S
authors.lastname: Self
authors.affiliation: Vaccine and Infectious Disease and Public Health Sciences Divisions, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.
authors.forename: William
authors.initials: W
authors.lastname: Fulp
authors.affiliation: Vaccine and Infectious Disease and Public Health Sciences Divisions, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.
authors.forename: Raphael
authors.initials: R
authors.lastname: Gottardo
authors.affiliation: Advanced BioScience Laboratories, Inc., Rockville, Maryland, USA.
authors.forename: Lindsey
authors.initials: L
authors.lastname: Galmin
authors.affiliation: Advanced BioScience Laboratories, Inc., Rockville, Maryland, USA.
authors.forename: Deborah
authors.initials: D
authors.lastname: Weiss
authors.affiliation: Advanced BioScience Laboratories, Inc., Rockville, Maryland, USA.
authors.forename: Anthony
authors.initials: A
authors.lastname: Cristillo
authors.affiliation: Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Pantaleo
authors.affiliation: Vaccine Research Institute, Université Paris-Est, Faculté de Médecine, INSERM U955, and Assistance Publique-Hôpitaux de Paris, Groupe Henri-Mondor Albert-Chenevier, service d'immunologie clinique, Créteil, France yves.levy@aphp.fr.
authors.forename: Yves
authors.initials: Y
authors.lastname: Levy
mesh_terms: D016915:AIDS Vaccines / Q000235:genetics / Q000276:immunology*; D000818:Animals; D057134:Antibodies, Neutralizing / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D019013:CD40 Antigens / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D016466:CHO Cells; D002266:Carboxymethylcellulose Sodium / Q000031:analogs & derivatives; D003412:Cricetulus; D003713:Dendritic Cells / Q000276:immunology; D015483:HIV Antibodies / Q000276:immunology*; D015497:HIV-1 / Q000276:immunology*; D007070:Immunoglobulin A / Q000276:immunology; D007074:Immunoglobulin G / Q000276:immunology; D008253:Macaca mulatta; D008297:Male; D011070:Poly I-C / Q000276:immunology; D011107:Polylysine / Q000031:analogs & derivatives / Q000276:immunology; D051127:Scavenger Receptors, Class E / Q000276:immunology*; D014611:Vaccination; D054299:env Gene Products, Human Immunodeficiency Virus / Q000276:immunology*
chemical_list: D016915:AIDS Vaccines; D057134:Antibodies, Neutralizing; D019013:CD40 Antigens; D015483:HIV Antibodies; D007070:Immunoglobulin A; D007074:Immunoglobulin G; C572770:NYVAC-C vaccine; C495137:OLR1 protein, human; D051127:Scavenger Receptors, Class E; D054299:env Gene Products, Human Immunodeficiency Virus; C097729:gp140 envelope protein, Human immunodeficiency virus 1; D011107:Polylysine; C019531:poly ICLC; D002266:Carboxymethylcellulose Sodium; D011070:Poly I-C
keywords: HIV-1; dendritic cells; vaccines