title: Characterization and Implementation of a Diverse Simian Immunodeficiency Virus SIVsm Envelope Panel in the Assessment of Neutralizing Antibody Breadth Elicited in Rhesus Macaques by Multimodal Vaccines Expressing the SIVmac239 Envelope.
abstract: Antibodies that can neutralize diverse viral strains are likely to be an important component of a protective human immunodeficiency virus type 1 (HIV-1) vaccine. To this end, preclinical simian immunodeficiency virus (SIV)-based nonhuman primate immunization regimens have been designed to evaluate and enhance antibody-mediated protection. However, these trials often rely on a limited selection of SIV strains with extreme neutralization phenotypes to assess vaccine-elicited antibody activity. To mirror the viral panels used to assess HIV-1 antibody breadth, we created and characterized a novel panel of 14 genetically and phenotypically diverse SIVsm envelope (Env) glycoproteins. To assess the utility of this panel, we characterized the neutralizing activity elicited by four SIVmac239 envelope-expressing DNA/modified vaccinia virus Ankara vector- and protein-based vaccination regimens that included the immunomodulatory adjuvants granulocyte-macrophage colony-stimulating factor, Toll-like receptor (TLR) ligands, and CD40 ligand. The SIVsm Env panel exhibited a spectrum of neutralization sensitivity to SIV-infected plasma pools and monoclonal antibodies, allowing categorization into three tiers. Pooled sera from 91 rhesus macaques immunized in the four trials consistently neutralized only the highly sensitive tier 1a SIVsm Envs, regardless of the immunization regimen. The inability of vaccine-mediated antibodies to neutralize the moderately resistant tier 1b and tier 2 SIVsm Envs defined here suggests that those antibodies were directed toward epitopes that are not accessible on most SIVsm Envs. To achieve a broader and more effective neutralization profile in preclinical vaccine studies that is relevant to known features of HIV-1 neutralization, more emphasis should be placed on optimizing the Env immunogen, as the neutralization profile achieved by the addition of adjuvants does not appear to supersede the neutralizing antibody profile determined by the immunogen.
  
  
  OBJECTIVE
  Many in the HIV/AIDS vaccine field believe that the ability to elicit broadly neutralizing antibodies capable of blocking genetically diverse HIV-1 variants is a critical component of a protective vaccine. Various SIV-based nonhuman primate vaccine studies have investigated ways to improve antibody-mediated protection against a heterologous SIV challenge, including administering adjuvants that might stimulate a greater neutralization breadth. Using a novel SIV neutralization panel and samples from four rhesus macaque vaccine trials designed for cross comparison, we show that different regimens expressing the same SIV envelope immunogen consistently elicit antibodies that neutralize only the very sensitive tier 1a SIV variants. The results argue that the neutralizing antibody profile elicited by a vaccine is primarily determined by the envelope immunogen and is not substantially broadened by including adjuvants, resulting in the conclusion that the envelope immunogen itself should be the primary consideration in efforts to elicit antibodies with greater neutralization breadth.
authors.affiliation: Yerkes National Primate Research Center, Emory University, Atlanta, Georgia, USA.
authors.forename: Katie M
authors.initials: KM
authors.lastname: Kilgore
authors.affiliation: Yerkes National Primate Research Center, Emory University, Atlanta, Georgia, USA.
authors.forename: Megan K
authors.initials: MK
authors.lastname: Murphy
authors.affiliation: Yerkes National Primate Research Center, Emory University, Atlanta, Georgia, USA.
authors.forename: Samantha L
authors.initials: SL
authors.lastname: Burton
authors.affiliation: Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA.
authors.forename: Katherine S
authors.initials: KS
authors.lastname: Wetzel
authors.affiliation: Yerkes National Primate Research Center, Emory University, Atlanta, Georgia, USA.
authors.forename: S Abigail
authors.initials: SA
authors.lastname: Smith
authors.affiliation: Yerkes National Primate Research Center, Emory University, Atlanta, Georgia, USA.
authors.forename: Peng
authors.initials: P
authors.lastname: Xiao
authors.affiliation: Yerkes National Primate Research Center, Emory University, Atlanta, Georgia, USA.
authors.forename: Sharmila
authors.initials: S
authors.lastname: Reddy
authors.affiliation: Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA.
authors.forename: Nicholas
authors.initials: N
authors.lastname: Francella
authors.affiliation: Seattle Biomedical Research Institute, Seattle, Washington, USA.
authors.forename: Donald L
authors.initials: DL
authors.lastname: Sodora
authors.affiliation: Yerkes National Primate Research Center, Emory University, Atlanta, Georgia, USA Emory Vaccine Center, Emory University, Atlanta, Georgia, USA Department of Pathology and Laboratory Medicine, Emory University, Atlanta, Georgia, USA.
authors.forename: Guido
authors.initials: G
authors.lastname: Silvestri
authors.affiliation: Department of Immunology, Center for Vaccine Research, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
authors.forename: Kelly S
authors.initials: KS
authors.lastname: Cole
authors.affiliation: Yerkes National Primate Research Center, Emory University, Atlanta, Georgia, USA Emory Vaccine Center, Emory University, Atlanta, Georgia, USA Department of Pathology and Laboratory Medicine, Emory University, Atlanta, Georgia, USA.
authors.forename: Francois
authors.initials: F
authors.lastname: Villinger
authors.affiliation: Department of Pediatrics, Tulane University Medical School, New Orleans, Louisiana, USA.
authors.forename: James E
authors.initials: JE
authors.lastname: Robinson
authors.affiliation: Yerkes National Primate Research Center, Emory University, Atlanta, Georgia, USA Emory Vaccine Center, Emory University, Atlanta, Georgia, USA Department of Pathology and Laboratory Medicine, Emory University, Atlanta, Georgia, USA.
authors.forename: Bali
authors.initials: B
authors.lastname: Pulendran
authors.affiliation: Yerkes National Primate Research Center, Emory University, Atlanta, Georgia, USA Emory Vaccine Center, Emory University, Atlanta, Georgia, USA Department of Pathology and Laboratory Medicine, Emory University, Atlanta, Georgia, USA.
authors.forename: Eric
authors.initials: E
authors.lastname: Hunter
authors.affiliation: Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA.
authors.forename: Ronald G
authors.initials: RG
authors.lastname: Collman
authors.affiliation: Yerkes National Primate Research Center, Emory University, Atlanta, Georgia, USA Emory Vaccine Center, Emory University, Atlanta, Georgia, USA Division of Microbiology and Immunology, Emory University, Atlanta, Georgia, USA.
authors.forename: Rama R
authors.initials: RR
authors.lastname: Amara
authors.affiliation: Yerkes National Primate Research Center, Emory University, Atlanta, Georgia, USA Emory Vaccine Center, Emory University, Atlanta, Georgia, USA Department of Pathology and Laboratory Medicine, Emory University, Atlanta, Georgia, USA cderdey@emory.edu.
authors.forename: Cynthia A
authors.initials: CA
authors.lastname: Derdeyn
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D057134:Antibodies, Neutralizing / Q000276:immunology*; D008253:Macaca mulatta; D008969:Molecular Sequence Data; D010802:Phylogeny; D017386:Sequence Homology, Amino Acid; D015302:Simian Immunodeficiency Virus / Q000145:classification / Q000378:metabolism*; D014759:Viral Envelope Proteins / Q000737:chemistry / Q000276:immunology / Q000378:metabolism*; D014765:Viral Vaccines / Q000276:immunology*
chemical_list: D057134:Antibodies, Neutralizing; D014759:Viral Envelope Proteins; D014765:Viral Vaccines