In the 1st U19, we established panels of high specificity and high affinity monoclonal antibodies against the following human DC receptors: LOX-1, BDCA-2, DC-SIGN/L, Dectin-1, CD1d, DC-ASGPR, Langerin, CLEC-6, MARCO, CD40 and DCIR. These human DC receptor reagents uncovered fundamental new biology and were used for development of prototype vaccines that target antigens directly to DCs. Based on extensive efficacy data in vitro, as well as preliminary studies in two in vivo models, the Humouse and Rhesus macaque, we hypothesize that the most potent antigen-targeting vaccines will deliver multiple antigens, engage two receptors simultaneously, and will be directly linked to adjuvants. We envision three areas for improvement that are the basis of Aims 1-3.
In Aim 1, we will construct polyvalent vaccines composed of influenza viral hemagglutinin (HA), nucleoprotein (NP), and matrix protein2 (M2). Triple vaccines will induce broad repertoires of both cellular and humoral immune responses.
In Aim 2, we will generate vaccines that target two DC receptors to enhance the immunogenicity of vaccines.
In Aim 3, adjuvant-linked DC-targeting vaccines will be produced. The vaccines generated herein will undergo analysis of DC binding, activation, and internalization through Aim 4, and then undergo further studies within Projects 1-4. Projects 1 and 2 serve, through in vitro analysis, to discover the most potent candidate vaccines - particularly those that will evoke mucosal immunity. The selected vaccines will be tested thoroughly in vivo via Projects 3 and 4.

Public Health Relevance

Vaccine platforms generated and validated in this study will be tested in Project 1-4. Technology obtained in this study will be applied for the generation of vaccines tested in Phase I clinical trials in the near future.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program--Cooperative Agreements (U19)
Project #
5U19AI057234-09
Application #
8377855
Study Section
Special Emphasis Panel (ZAI1-KS-I)
Project Start
Project End
Budget Start
2012-05-01
Budget End
2013-04-30
Support Year
9
Fiscal Year
2012
Total Cost
$345,379
Indirect Cost
$123,982
Name
Baylor Research Institute
Department
Type
DUNS #
145745022
City
Dallas
State
TX
Country
United States
Zip Code
75204
Todorova, Biliana; Salabert, Nina; Tricot, Sabine et al. (2017) Fibered Confocal Fluorescence Microscopy for the Noninvasive Imaging of Langerhans Cells in Macaques. Contrast Media Mol Imaging 2017:3127908
Athale, Shruti; Banchereau, Romain; Thompson-Snipes, LuAnn et al. (2017) Influenza vaccines differentially regulate the interferon response in human dendritic cell subsets. Sci Transl Med 9:
Mathew, Anuja (2017) Humanized mouse models to study human cell-mediated and humoral responses to dengue virus. Curr Opin Virol 25:76-80
Silvin, Aymeric; Yu, Chun I; Lahaye, Xavier et al. (2017) Constitutive resistance to viral infection in human CD141+ dendritic cells. Sci Immunol 2:
Yoshimatsu, Gumpei; Kunnathodi, Faisal; Saravanan, Prathab Balaji et al. (2017) Pancreatic ?-Cell-Derived IP-10/CXCL10 Isletokine Mediates Early Loss of Graft Function in Islet Cell Transplantation. Diabetes 66:2857-2867
Raymond, Donald D; Stewart, Shaun M; Lee, Jiwon et al. (2016) Influenza immunization elicits antibodies specific for an egg-adapted vaccine strain. Nat Med 22:1465-1469
Yin, Wenjie; Gorvel, Laurent; Zurawski, Sandra et al. (2016) Functional Specialty of CD40 and Dendritic Cell Surface Lectins for Exogenous Antigen Presentation to CD8(+) and CD4(+) T Cells. EBioMedicine 5:46-58
Blohmke, Christoph J; Darton, Thomas C; Jones, Claire et al. (2016) Interferon-driven alterations of the host's amino acid metabolism in the pathogenesis of typhoid fever. J Exp Med 213:1061-77
Schmitt, Nathalie; Liu, Yang; Bentebibel, Salah-Eddine et al. (2016) Molecular Mechanisms Regulating T Helper 1 versus T Follicular Helper Cell Differentiation in Humans. Cell Rep 16:1082-1095
Kovats, S; Turner, S; Simmons, A et al. (2016) West Nile virus-infected human dendritic cells fail to fully activate invariant natural killer T cells. Clin Exp Immunol 186:214-226

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