HIV/AIDS Vaccine Candidates Based on Replication-Competent Recombinant Poxvirus NYVAC-C-KC Expressing Trimeric gp140 and Gag-Derived Virus-Like Particles or Lacking the Viral Molecule B19 That Inhibits Type I Interferon Activate Relevant HIV-1-Specific B and T Cell Immune Functions in Nonhuman Primates.
The nonreplicating attenuated poxvirus vector NYVAC expressing clade C(CN54) HIV-1 Env(gp120) and Gag-Pol-Nef antigens (NYVAC-C) showed limited immunogenicity in phase I clinical trials. To enhance the capacity of the NYVAC vector to trigger broad humoral responses and a more balanced activation of CD4+and CD8+T cells, here we compared the HIV-1-specific immunogenicity elicited in nonhuman primates immunized with two replicating NYVAC vectors that have been modified by the insertion of theK1LandC7Lvaccinia virus host range genes and express the clade C(ZM96) trimeric HIV-1 gp140 protein or a Gag(ZM96)-Pol-Nef(CN54) polyprotein as Gag-derived virus-like particles (termed NYVAC-C-KC). Additionally, one NYVAC-C-KC vector was generated by deleting the viral geneB19R, an inhibitor of the type I interferon response (NYVAC-C-KC-ΔB19R). An immunization protocol mimicking that of the RV144 phase III clinical trial was used. Two groups of macaques received two doses of the corresponding NYVAC-C-KC vectors (weeks 0 and 4) and booster doses with NYVAC-C-KC vectors plus the clade C HIV-1 gp120 protein (weeks 12 and 24). The two replicating NYVAC-C-KC vectors induced enhanced and similar HIV-1-specific CD4+and CD8+T cell responses, similar levels of binding IgG antibodies, low levels of IgA antibodies, and high levels of antibody-dependent cellular cytotoxicity responses and HIV-1-neutralizing antibodies. Small differences within the NYVAC-C-KC-ΔB19R group were seen in the magnitude of CD4+and CD8+T cells, the induction of some cytokines, and the neutralization of some HIV-1 isolates. Thus, replication-competent NYVAC-C-KC vectors acquired relevant immunological properties as vaccine candidates against HIV/AIDS, and the viral B19 molecule exerts some control of immune functions.IMPORTANCEIt is of special importance to find a safe and effective HIV/AIDS vaccine that can induce strong and broad T cell and humoral immune responses correlating with HIV-1 protection. Here we developed novel replicating poxvirus NYVAC-based HIV/AIDS vaccine candidates expressing clade C HIV-1 antigens, with one of them lacking the vaccinia virus B19 protein, an inhibitor of the type I interferon response. Immunization of nonhuman primates with these novel NYVAC-C-KC vectors and the protein component gp120 elicited high levels of T cell and humoral immune responses, with the vector containing a deletion inB19Rinducing a trend toward a higher magnitude of CD4+and CD8+T cell responses and neutralization of some HIV-1 strains. These poxvirus vectors could be considered HIV/AIDS vaccine candidates based on their activation of potential immune correlates of protection.
Department of Molecular and Cellular Biology, Centro Nacional de Biotecnología, Consejo Superior de Investigaciones Científicas, Madrid, Spain.
Juan
J
García-Arriaza
Department of Molecular and Cellular Biology, Centro Nacional de Biotecnología, Consejo Superior de Investigaciones Científicas, Madrid, Spain.
Beatriz
B
Perdiguero
Department of Veterinary Medicine, University of Cambridge, Cambridge, United Kingdom.
Jonathan L
JL
Heeney
Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA.
Michael S
MS
Seaman
Duke University Medical Center, Durham, North Carolina, USA.
David C
DC
Montefiori
Duke University Medical Center, Durham, North Carolina, USA.
Nicole L
NL
Yates
Duke University Medical Center, Durham, North Carolina, USA.
Georgia D
GD
Tomaras
Duke University Medical Center, Durham, North Carolina, USA.
Guido
G
Ferrari
Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.
Kathryn E
KE
Foulds
Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.
Mario
M
Roederer
Statistical Center for HIV/AIDS Research and Prevention, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.
Steven G
SG
Self
Statistical Center for HIV/AIDS Research and Prevention, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.
Bhavesh
B
Borate
Statistical Center for HIV/AIDS Research and Prevention, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.
Raphael
R
Gottardo
Sanofi Pasteur, Swiftwater, Pennsylvania, USA.
Sanjay
S
Phogat
Sanofi Pasteur, Swiftwater, Pennsylvania, USA.
Jim
J
Tartaglia
Novartis Vaccines and Diagnostics, Inc., Cambridge, Massachusetts, USA.
Susan W
SW
Barnett
Novartis Vaccines and Diagnostics, Inc., Cambridge, Massachusetts, USA.
Brian
B
Burke
Advanced BioScience Laboratories, Inc., Rockville, Maryland, USA.
Anthony D
AD
Cristillo
Advanced BioScience Laboratories, Inc., Rockville, Maryland, USA.
Deborah E
DE
Weiss
Global Solutions on Infectious Diseases, South San Francisco, California, USA.
Carter
C
Lee
Biodesign Institute, Arizona State University, Tempe, Arizona, USA.
Karen V
KV
Kibler
Biodesign Institute, Arizona State University, Tempe, Arizona, USA.
Bertram L
BL
Jacobs
University of Regensburg, Regensburg, Germany.
Ralf
R
Wagner
EuroVacc Foundation, Lausanne, Switzerland.
Song
S
Ding
Division of Immunology and Allergy, Department of Medicine, Centre Hospitalier Universitaire Vaudois, University of Lausanne, Lausanne, Switzerland.
Giuseppe
G
Pantaleo
Department of Molecular and Cellular Biology, Centro Nacional de Biotecnología, Consejo Superior de Investigaciones Científicas, Madrid, Spain mesteban@cnb.csic.es.
Mariano
M
Esteban
D016915:AIDS Vaccines / Q000235:genetics / Q000276:immunology*; D000818:Animals; D057134:Antibodies, Neutralizing / Q000097:blood* / Q000276:immunology; D000920:Antibody-Dependent Cell Cytotoxicity / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D015483:HIV Antibodies / Q000097:blood* / Q000276:immunology; D015488:HIV Antigens / Q000276:immunology; D015699:HIV Envelope Protein gp120 / Q000276:immunology*; D015658:HIV Infections / Q000517:prevention & control; D007370:Interferon Type I / Q000235:genetics; D008253:Macaca mulatta; D008297:Male; D017471:Receptors, Interferon / Q000235:genetics / Q000276:immunology; D014611:Vaccination; D058425:Vaccines, Virus-Like Particle / Q000276:immunology*; D014616:Vaccinia virus / Q000235:genetics; D054299:env Gene Products, Human Immunodeficiency Virus / Q000235:genetics / Q000378:metabolism*
D016915:AIDS Vaccines; D057134:Antibodies, Neutralizing; D015483:HIV Antibodies; D015488:HIV Antigens; D015699:HIV Envelope Protein gp120; D007370:Interferon Type I; C572770:NYVAC-C vaccine; D017471:Receptors, Interferon; D058425:Vaccines, Virus-Like Particle; D054299:env Gene Products, Human Immunodeficiency Virus; C097729:gp140 envelope protein, Human immunodeficiency virus 1
B19R; HIV-1; NYVAC; cellular responses; humoral responses; immunogenicity; nonhuman primates; poxvirus