title: Potential To Streamline Heterologous DNA Prime and NYVAC/Protein Boost HIV Vaccine Regimens in Rhesus Macaques by Employing Improved Antigens.
abstract: In a follow-up to the modest efficacy observed in the RV144 trial, researchers in the HIV vaccine field seek to substantiate and extend the results by evaluating other poxvirus vectors and combinations with DNA and protein vaccines. Earlier clinical trials (EuroVacc trials 01 to 03) evaluated the immunogenicity of HIV-1 clade C GagPolNef and gp120 antigens delivered via the poxviral vector NYVAC. These showed that a vaccination regimen including DNA-C priming prior to a NYVAC-C boost considerably enhanced vaccine-elicited immune responses compared to those with NYVAC-C alone. Moreover, responses were improved by using three as opposed to two DNA-C primes. In the present study, we assessed in nonhuman primates whether such vaccination regimens can be streamlined further by using fewer and accelerated immunizations and employing a novel generation of improved DNA-C and NYVAC-C vaccine candidates designed for higher expression levels and more balanced immune responses. Three different DNA-C prime/NYVAC-C+ protein boost vaccination regimens were tested in rhesus macaques. All regimens elicited vigorous and well-balanced CD8(+)and CD4(+)T cell responses that were broad and polyfunctional. Very high IgG binding titers, substantial antibody-dependent cellular cytotoxicity (ADCC), and modest antibody-dependent cell-mediated virus inhibition (ADCVI), but very low neutralization activity, were measured after the final immunizations. Overall, immune responses elicited in all three groups were very similar and of greater magnitude, breadth, and quality than those of earlier EuroVacc vaccines. In conclusion, these findings indicate that vaccination schemes can be simplified by using improved antigens and regimens. This may offer a more practical and affordable means to elicit potentially protective immune responses upon vaccination, especially in resource-constrained settings.
  
  
  OBJECTIVE
  Within the EuroVacc clinical trials, we previously assessed the immunogenicity of HIV clade C antigens delivered in a DNA prime/NYVAC boost regimen. The trials showed that the DNA prime crucially improved the responses, and three DNA primes with a NYVAC boost appeared to be optimal. Nevertheless, T cell responses were primarily directed toward Env, and humoral responses were modest. The aim of this study was to assess improved antigens for the capacity to elicit more potent and balanced responses in rhesus macaques, even with various simpler immunization regimens. Our results showed that the novel antigens in fact elicited larger numbers of T cells with a polyfunctional profile and a good Env-GagPolNef balance, as well as high-titer and Fc-functional antibody responses. Finally, comparison of the different schedules indicates that a simpler regimen of only two DNA primes and one NYVAC boost in combination with protein may be very efficient, thus showing that the novel antigens allow for easier immunization protocols.
authors: Institute of Medical Microbiology and Hygiene, University of Regensburg, Regensburg, Germany.
authors: Benedikt
authors: B
authors: Asbach
authors: Institute of Medical Microbiology and Hygiene, University of Regensburg, Regensburg, Germany.
authors: Alexander
authors: A
authors: Kliche
authors: Institute of Clinical Microbiology and Hygiene, University of Regensburg, Regensburg, Germany.
authors: Josef
authors: J
authors: Köstler
authors: Department of Molecular and Cellular Biology, Centro Nacional de Biotecnología, Consejo Superior de Investigaciones Científicas (CSIC), Madrid, Spain.
authors: Beatriz
authors: B
authors: Perdiguero
authors: Department of Molecular and Cellular Biology, Centro Nacional de Biotecnología, Consejo Superior de Investigaciones Científicas (CSIC), Madrid, Spain.
authors: Mariano
authors: M
authors: Esteban
authors: Biodesign Institute, Arizona State University, Tempe, Arizona, USA.
authors: Bertram L
authors: BL
authors: Jacobs
authors: Duke University Medical Center, Durham, North Carolina, USA.
authors: David C
authors: DC
authors: Montefiori
authors: Duke University Medical Center, Durham, North Carolina, USA.
authors: Celia C
authors: CC
authors: LaBranche
authors: Duke University Medical Center, Durham, North Carolina, USA.
authors: Nicole L
authors: NL
authors: Yates
authors: Duke University Medical Center, Durham, North Carolina, USA.
authors: Georgia D
authors: GD
authors: Tomaras
authors: Duke University Medical Center, Durham, North Carolina, USA.
authors: Guido
authors: G
authors: Ferrari
authors: Vaccine Research Center, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, Maryland, USA.
authors: Kathryn E
authors: KE
authors: Foulds
authors: Vaccine Research Center, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, Maryland, USA.
authors: Mario
authors: M
authors: Roederer
authors: Division of Infectious Diseases, Department of Medicine, University of California, Irvine, School of Medicine, Irvine, California, USA.
authors: Gary
authors: G
authors: Landucci
authors: Division of Infectious Diseases, Department of Medicine, University of California, Irvine, School of Medicine, Irvine, California, USA.
authors: Donald N
authors: DN
authors: Forthal
authors: Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA.
authors: Michael S
authors: MS
authors: Seaman
authors: Statistical Center for HIV/AIDS Research and Prevention, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.
authors: Natalie
authors: N
authors: Hawkins
authors: Statistical Center for HIV/AIDS Research and Prevention, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.
authors: Steven G
authors: SG
authors: Self
authors: Statistical Center for HIV/AIDS Research and Prevention, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.
authors: Alicia
authors: A
authors: Sato
authors: Statistical Center for HIV/AIDS Research and Prevention, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.
authors: Raphael
authors: R
authors: Gottardo
authors: Sanofi Pasteur, Swiftwater, Pennsylvania, USA.
authors: Sanjay
authors: S
authors: Phogat
authors: Sanofi Pasteur, Swiftwater, Pennsylvania, USA.
authors: James
authors: J
authors: Tartaglia
authors: Novartis Vaccines and Diagnostics, Inc., Cambridge, Massachusetts, USA.
authors: Susan W
authors: SW
authors: Barnett
authors: Novartis Vaccines and Diagnostics, Inc., Cambridge, Massachusetts, USA.
authors: Brian
authors: B
authors: Burke
authors: Advanced BioScience Laboratories, Inc., Rockville, Maryland, USA.
authors: Anthony D
authors: AD
authors: Cristillo
authors: Advanced BioScience Laboratories, Inc., Rockville, Maryland, USA.
authors: Deborah E
authors: DE
authors: Weiss
authors: Advanced BioScience Laboratories, Inc., Rockville, Maryland, USA.
authors: Jesse
authors: J
authors: Francis
authors: Advanced BioScience Laboratories, Inc., Rockville, Maryland, USA.
authors: Lindsey
authors: L
authors: Galmin
authors: EuroVacc Foundation, Lausanne, Switzerland.
authors: Song
authors: S
authors: Ding
authors: Lab of Viral Zoonotics, Department of Veterinary Medicine, University of Cambridge, Cambridge, United Kingdom.
authors: Jonathan L
authors: JL
authors: Heeney
authors: Division of Immunology and Allergy, Department of Medicine, Centre Hospitalier Universitaire Vaudois, University of Lausanne, Lausanne, Switzerland.
authors: Giuseppe
authors: G
authors: Pantaleo
authors: Institute of Medical Microbiology and Hygiene, University of Regensburg, Regensburg, Germany ralf.wagner@klinik.uni-regensburg.de.
authors: Ralf
authors: R
authors: Wagner
mesh_terms: D016915:AIDS Vaccines / Q000235:genetics / Q000276:immunology*; D000818:Animals; D057134:Antibodies, Neutralizing / Q000276:immunology; D000920:Antibody-Dependent Cell Cytotoxicity; D017931:DNA Primers; D015483:HIV Antibodies / Q000276:immunology; D015488:HIV Antigens / Q000276:immunology; D015497:HIV-1 / Q000276:immunology*; D007371:Interferon-gamma / Q000096:biosynthesis; D008297:Male; D013601:T-Lymphocytes / Q000276:immunology; D014611:Vaccination / Q000379:methods; D019444:Vaccines, DNA / Q000235:genetics / Q000276:immunology*; D054301:gag Gene Products, Human Immunodeficiency Virus / Q000235:genetics / Q000276:immunology
chemical_list: D016915:AIDS Vaccines; D057134:Antibodies, Neutralizing; D017931:DNA Primers; D015483:HIV Antibodies; D015488:HIV Antigens; C572770:NYVAC-C vaccine; D019444:Vaccines, DNA; D054301:gag Gene Products, Human Immunodeficiency Virus; D007371:Interferon-gamma