Despite more than two decades of extensive research, the development of an effective vaccine for HlV-1 remains elusive. A significant critical hurdle that compounds this challenge in vaccine development includes a lack of knowledge in defining the key correlate of protection against infection with HIV-1. Emerging evidence in various preclinical and clinical studies suggest a key role for HIV-1 specific neutralizing antibody responses present in high levels both systemic and at mucosal surfaces, as well as a role for polyfunctional T cell responses that can control the spread of the virus. It is now well documented that innate immunity plays a central role in shaping the quality and longevity of adaptive immune responses. Rational approaches that mediate robust activation of innate immunity and deliver HlV-1 specific antigens to key innate immune cells such as dendritic cells (DCs) could significantly enhance the magnitude, quality and persistence of ensuing humoral and T cell immunity against the HIV-1 virus. Recent studies have demonstrated that select combinations of ligands for toll like receptors (TLRs) can mediate such robust activation of DCs. Our proposal is driven by the hypothesis that such synergistic increases in DC activation would translate into synergistic enhancement in frequencies and quality of antigen specific B and T cells. Our studies in mice using a variety of protein antigens and combination of ligands for TLR-4 (MPL) and TLR-7 (R837) delivered in novel synthetic nanoparticle formulations indicate synergistic increases in antigen specific memory B cell, CD4 and CDS T cell responses, which persist for almost the life time of the animal. Furthermore, our best adjuvant chosen from mice studies when tested in non human primates with a whole inactivated 2009 H1N1 flu virus mediated robust neutralization antibody responses even with a single immunization. Collectively, these data strongly support our hypothesis that the combination of ligands for TLR-4 and TLR-7/8 could significantly enhance the quality of B cell and T cell responses against SIV antigens. Here we propose to evaluate SIV virus like particle (VLP) antigens adjuvanted with toll like receptor (TLR) ligands encapsulated in biodegradable nanoparticles in mediating protective immunity against the SIV virus in non human primates.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program--Cooperative Agreements (U19)
Project #
5U19AI096187-03
Application #
8516866
Study Section
Special Emphasis Panel (ZAI1-LR-A)
Project Start
2013-07-01
Project End
2016-06-30
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
3
Fiscal Year
2013
Total Cost
$546,375
Indirect Cost
$228,578
Name
Emory University
Department
Type
DUNS #
066469933
City
Atlanta
State
GA
Country
United States
Zip Code
30322
Chamcha, Venkateswarlu; Kannanganat, Sunil; Gangadhara, Sailaja et al. (2016) Strong, but Age-Dependent, Protection Elicited by a Deoxyribonucleic Acid/Modified Vaccinia Ankara Simian Immunodeficiency Virus Vaccine. Open Forum Infect Dis 3:ofw034
Smith, S Abigail; Kilgore, Katie M; Kasturi, Sudhir Pai et al. (2016) Signatures in Simian Immunodeficiency Virus SIVsmE660 Envelope gp120 Are Associated with Mucosal Transmission but Not Vaccination Breakthrough in Rhesus Macaques. J Virol 90:1880-7
Locci, Michela; Wu, Jennifer E; Arumemi, Fortuna et al. (2016) Activin A programs the differentiation of human TFH cells. Nat Immunol 17:976-84
Kannanganat, Sunil; Wyatt, Linda S; Gangadhara, Sailaja et al. (2016) High Doses of GM-CSF Inhibit Antibody Responses in Rectal Secretions and Diminish Modified Vaccinia Ankara/Simian Immunodeficiency Virus Vaccine Protection in TRIM5α-Restrictive Macaques. J Immunol 197:3586-3596
Cho, Alice; Wrammert, Jens (2016) Implications of broadly neutralizing antibodies in the development of a universal influenza vaccine. Curr Opin Virol 17:110-5
Yu, Cuiling; Liu, Yanling; Chan, Justin Tze Ho et al. (2016) Identification of human plasma cells with a lamprey monoclonal antibody. JCI Insight 1:
Havenar-Daughton, Colin; Reiss, Samantha M; Carnathan, Diane G et al. (2016) Cytokine-Independent Detection of Antigen-Specific Germinal Center T Follicular Helper Cells in Immunized Nonhuman Primates Using a Live Cell Activation-Induced Marker Technique. J Immunol 197:994-1002
Kilgore, Katie M; Murphy, Megan K; Burton, Samantha L et al. (2015) 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. J Virol 89:8130-51
Chamcha, Venkateswarlu; Jones, Andrew; Quigley, Bernard R et al. (2015) Oral Immunization with a Recombinant Lactococcus lactis-Expressing HIV-1 Antigen on Group A Streptococcus Pilus Induces Strong Mucosal Immunity in the Gut. J Immunol 195:5025-34
Kwa, Suefen; Sadagopal, Shanmugalakshmi; Shen, Xiaoying et al. (2015) CD40L-adjuvanted DNA/modified vaccinia virus Ankara simian immunodeficiency virus (SIV) vaccine enhances protection against neutralization-resistant mucosal SIV infection. J Virol 89:4690-5

Showing the most recent 10 out of 48 publications