title: An Enhanced Synthetic Multiclade DNA Prime Induces Improved Cross-Clade-Reactive Functional Antibodies when Combined with an Adjuvanted Protein Boost in Nonhuman Primates.
abstract: The search for an efficacious human immunodeficiency virus type 1 (HIV-1) vaccine remains a pressing need. The moderate success of the RV144 Thai clinical vaccine trial suggested that vaccine-induced HIV-1-specific antibodies can reduce the risk of HIV-1 infection. We have made several improvements to the DNA platform and have previously shown that improved DNA vaccines alone are capable of inducing both binding and neutralizing antibodies in small-animal models. In this study, we explored how an improved DNA prime and recombinant protein boost would impact HIV-specific vaccine immunogenicity in rhesus macaques (RhM). After DNA immunization with either a single HIV Env consensus sequence or multiple constructs expressing HIV subtype-specific Env consensus sequences, we detected both CD4(+) and CD8(+) T-cell responses to all vaccine immunogens. These T-cell responses were further increased after protein boosting to levels exceeding those of DNA-only or protein-only immunization. In addition, we observed antibodies that exhibited robust cross-clade binding and neutralizing and antibody-dependent cellular cytotoxicity (ADCC) activity after immunization with the DNA prime-protein boost regimen, with the multiple-Env formulation inducing a more robust and broader response than the single-Env formulation. The magnitude and functionality of these responses emphasize the strong priming effect improved DNA immunogens can induce, which are further expanded upon protein boost. These results support further study of an improved synthetic DNA prime together with a protein boost for enhancing anti-HIV immune responses.
  
  
  OBJECTIVE
  Even with effective antiretroviral drugs, HIV remains an enormous global health burden. Vaccine development has been problematic in part due to the high degree of diversity and poor immunogenicity of the HIV Env protein. Studies suggest that a relevant HIV vaccine will likely need to induce broad cellular and humoral responses from a simple vaccine regimen due to the resource-limited setting in which the HIV pandemic is most rampant. DNA vaccination lends itself well to increasing the amount of diversity included in a vaccine due to the ease of manufacturing multiple plasmids and formulating them as a single immunization. By increasing the number of Envs within a formulation, we were able to show an increased breadth of responses as well as improved functionality induced in a nonhuman primate model. This increased breadth could be built upon, leading to better coverage against circulating strains with broader vaccine-induced protection.
authors.affiliation: Department of Pathology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA.
authors.forename: Megan C
authors.initials: MC
authors.lastname: Wise
authors.affiliation: Department of Pathology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA.
authors.forename: Natalie A
authors.initials: NA
authors.lastname: Hutnick
authors.affiliation: Department of Surgery, Duke University, Durham, North Carolina, USA.
authors.forename: Justin
authors.initials: J
authors.lastname: Pollara
authors.affiliation: Department of Pathology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA.
authors.forename: Devin J F
authors.initials: DJ
authors.lastname: Myles
authors.affiliation: Department of Pathology, New York University Medical Center, New York, New York, USA.
authors.forename: Constance
authors.initials: C
authors.lastname: Williams
authors.affiliation: Inovio Pharmaceuticals, Plymouth Meeting, Pennsylvania, USA.
authors.forename: Jian
authors.initials: J
authors.lastname: Yan
authors.affiliation: Department of Surgery, Duke University, Durham, North Carolina, USA.
authors.forename: Celia C
authors.initials: CC
authors.lastname: LaBranche
authors.affiliation: Inovio Pharmaceuticals, Plymouth Meeting, Pennsylvania, USA.
authors.forename: Amir S
authors.initials: AS
authors.lastname: Khan
authors.affiliation: Inovio Pharmaceuticals, Plymouth Meeting, Pennsylvania, USA.
authors.forename: Niranjan Y
authors.initials: NY
authors.lastname: Sardesai
authors.affiliation: Department of Surgery, Duke University, Durham, North Carolina, USA.
authors.forename: David
authors.initials: D
authors.lastname: Montefiori
authors.affiliation: Novartis Vaccines and Diagnostics, Inc., Cambridge, Massachusetts, USA.
authors.forename: Susan W
authors.initials: SW
authors.lastname: Barnett
authors.affiliation: Department of Pathology, New York University Medical Center, New York, New York, USA Veterans Affairs Medical Center, New York, New York, USA.
authors.forename: Susan
authors.initials: S
authors.lastname: Zolla-Pazner
authors.affiliation: Department of Surgery, Duke University, Durham, North Carolina, USA.
authors.forename: Guido
authors.initials: G
authors.lastname: Ferrari
authors.affiliation: Department of Pathology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA dbweiner@mail.med.upenn.edu.
authors.forename: David B
authors.initials: DB
authors.lastname: Weiner
mesh_terms: D016915:AIDS Vaccines / Q000276:immunology / Q000494:pharmacology*; D000818:Animals; D003429:Cross Reactions / Q000276:immunology; D005260:Female; D015483:HIV Antibodies / Q000276:immunology*; D006801:Humans; D007117:Immunization, Secondary; D008253:Macaca mulatta; D008297:Male; D010957:Plasmids / Q000276:immunology / Q000494:pharmacology*; D019444:Vaccines, DNA / Q000276:immunology / Q000494:pharmacology*; D054299:env Gene Products, Human Immunodeficiency Virus / Q000276:immunology*
chemical_list: D016915:AIDS Vaccines; D015483:HIV Antibodies; D019444:Vaccines, DNA; D054299:env Gene Products, Human Immunodeficiency Virus