Abstract

The overall purpose of this proposal is to determine the level of innate and adaptive immune activation (i.e., anti-viral Th1 cytokines, antibody and cellular immune responses) induced by cationic lipid-DNA (non-coding) complexes (CLDC) combined with whole-inactivated Simian Immunodeficiency Virus (SIV) virions (CLDC-SIVinact) in the Rhesus macaque monkey model. Evidence suggests that CLDC efficiently stimulate the innate and adaptive immune pathways by the presence of CpG and non-CpG motifs as well as other mechanisms yet to be determined. The current formulation of the product is effective at inducing systemic cytokine production as well as substantial humoral and cellular immune responses, particularly cytotoxic T lymphocyte (CTL) activity. The SIV-macaque model was chosen due to its immunological, virological, pathological and clinical similarities to Human Immunodeficiency Virus (HIV) infection in humans. A primary purpose of this proposal is to determine the effectiveness of CLDC adjuvant/immunostimulatory activity, which can subsequently be applied to specific virion, protein or peptide antigens of interest. ? ? The specific aims of this proposal are to: (1) characterize the innate immune activation induced in vitro by CLDC-SIVinact on Rhesus monkey PBMC, and (2) compare anti-SIV immune responses (i.e., innate and adaptive) in Rhesus macaques immunized with either CLDC-SIVinact or alum-SIVinact. Immunized monkeys will be analysed for innate immune cytokine responses as well as SIV-specific humoral and cellular immunity (i.e., antibody, T cell proliferation, CTL activity). ? ? Positive immunological results from the current study will provide the basis for a subsequent phase II proposal to evaluate the protection afforded by CLDC-SIVinact, in Rhesus macaques challenged with pathogenic SIV. The program will ultimately provide insight and knowledge toward the development of a novel immunostimulant/adjuvant for a prophylactic and/or therapeutic vaccine against HIV infection in humans. ? ?

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Small Business Innovation Research Grants (SBIR) - Phase I (R43)
Project #
5R43AI065289-02
Application #
7193458
Study Section
Special Emphasis Panel (ZRG1-VACC (01))
Program Officer
Butler, Robert C
Project Start
2006-03-15
Project End
2008-02-29
Budget Start
2007-03-01
Budget End
2008-02-29
Support Year
2
Fiscal Year
2007
Total Cost
$151,584
Indirect Cost

  Institution

Name
Juvaris Biotherapeutics, Inc.
Department
Type
DUNS #
144992067
City
Burlingame
State
CA
Country
United States
Zip Code
94010

  Publications

Schleiss, Mark R; Choi, K Yeon; Anderson, Jodi et al. (2014) Glycoprotein B (gB) vaccines adjuvanted with AS01 or AS02 protect female guinea pigs against cytomegalovirus (CMV) viremia and offspring mortality in a CMV-challenge model. Vaccine 32:2756-62
Fairman, Jeff; Moore, Joseph; Lemieux, Mathieu et al. (2009) Enhanced in vivo immunogenicity of SIV vaccine candidates with cationic liposome-DNA complexes in a rhesus macaque pilot study. Hum Vaccin 5:141-50
Schleiss, Mark R; Stroup, Greg; Pogorzelski, Kelly et al. (2006) Protection against congenital cytomegalovirus (CMV) disease, conferred by a replication-disabled, bacterial artificial chromosome (BAC)-based DNA vaccine. Vaccine 24:6175-86
Schleiss, Mark R; Bernstein, David I; McVoy, Michael A et al. (2005) The non-nucleoside antiviral, BAY 38-4766, protects against cytomegalovirus (CMV) disease and mortality in immunocompromised guinea pigs. Antiviral Res 65:35-43
Schleiss, Mark R (2005) Antiviral therapy of congenital cytomegalovirus infection. Semin Pediatr Infect Dis 16:50-9
Schleiss, Mark R; McVoy, Michael A (2004) Overview of congenitally and perinatally acquired cytomegalovirus infections: recent advances in antiviral therapy. Expert Rev Anti Infect Ther 2:389-403
McGregor, Alistair; Liu, Fenyong; Schleiss, Mark R (2004) Molecular, biological, and in vivo characterization of the guinea pig cytomegalovirus (CMV) homologs of the human CMV matrix proteins pp71 (UL82) and pp65 (UL83). J Virol 78:9872-89
Blackman, Samuel C; Lurain, Nell S; Witte, David P et al. (2004) Emergence and compartmentalization of fatal multi-drug-resistant cytomegalovirus infection in a patient with autosomal-recessive severe combined immune deficiency. J Pediatr Hematol Oncol 26:601-5
Schleiss, Mark R; Bourne, Nigel; Stroup, Greg et al. (2004) Protection against congenital cytomegalovirus infection and disease in guinea pigs, conferred by a purified recombinant glycoprotein B vaccine. J Infect Dis 189:1374-81
Schleiss, Mark R; Jensen, Nancy J (2003) Cloning and expression of the guinea pig cytomegalovirus glycoprotein B (gB) in a recombinant baculovirus: utility for vaccine studies for the prevention of experimental infection. J Virol Methods 108:59-65

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