The overall U19 goal is to develop novel vaccines based on in vivo targeting human dendritic cells (DCs). The focus of the current competitive renewal application is on mucosal immunity. This project will carry out the in vivo immunogenicity and efficacy analysis of human vaccines in humanized mice. Our antibodies are directed against human DC receptors and thus, cannot be tested in regular mice. We have shown the validity of our model for vaccine testing. Thus, systemic and intranasal vaccination with live attenuated virus permits broad influenza virus-specific CD8+ T cell responses. Antigen-specific CD8+ T cells elicited by systemic vaccination can home to the lung. CD8+ T cell immunity can also be generated with recombinant FluM1 protein as well as fusion proteins composed of FluM1 and anti-DC receptor mAbs. Preliminary results indicate the actual targeting of FluM1 antigen to DCs via DCIR, the first demonstration of the targeting of human DCs in vivo. In parallel, we have also analyzed generation of antibody responses and found that vaccination via DCs can lead to generation of influenza-specific neutralizing T-cell dependent IgM that is protective in vivo. While the isotype switch remains a limiting factor in all current models of humanized mice, we are encouraged by our preliminary results which show generation of IgE in mice reconstituted with human stromal cells. Altogether, these results support our current hypothesis: Targeting DCs in vivo with combination of anti-DC mAb-flu antigens fusion proteins and DC activators will generate protective mucosal immunity in humanized mice.
AIM 1 will develop our preliminary results and determine the impact of DC activators on skin and mucosal DC activation and antigen internalization.
AIM 2 will select vaccines that generate polyfunctional Flu-specific CD8+ T cells with mucosa homing properties.
AIM 3 will select vaccines that generate neutralizing mucosal antibodies.
AIM 4 will demonstrate in vivo protection of mice vaccinated with polyvalent vaccines selected in vitro (Projects 1 &2). The final outcome will be protection in challenge experiments upon exposure of vaccinated mice to Flu infection. This project will select fusion proteins and adjuvant combinations that will be tested in the final stage of the project in non-human primates.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Program--Cooperative Agreements (U19)
Project #
Application #
Study Section
Special Emphasis Panel (ZAI1-KS-I)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Baylor Research Institute
United States
Zip Code
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:
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
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
Mathew, Anuja (2017) Humanized mouse models to study human cell-mediated and humoral responses to dengue virus. Curr Opin Virol 25:76-80
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
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
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
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

Showing the most recent 10 out of 129 publications