The long term goal is to develop a vaccine that prevents toxoplasmosis, including transmission from mother to child and reduction or elimination of organisms during initial acute infection. Work toward this goal will be accomplished using a rational approach based on understanding and using only epitopes that induce a protective immune response, without extraneous epitopes that may be harmful, and optimizing adjuvants.
Specific aims are: 1. Identify optimal adjuvants and delivery, characterizing and optimizing peroral bilosome delivery systems for DMA vaccines;2.Characterize protective effect, and when there is protection, immune responses produced by SAG1 or ROP2 or GRA2 or 3 or 6 or 7 or a bradyzoite antigen (BLKAg), and for oocyst challenge a sporozoite antigen (SpAg) vaccination. HLA A2.1, HLA A3/11 and HLA B7 mice, will be vaccinated with DMA constructs containing parasite antigens, with and without adjuvant(s) or bilosomes or MVA for boost;3. Create multiepitope vaccines based on epitopes identified from those proteins which confer protection;4. In later studies, test the most promising constructs in (a) peroral bradyzoite or oocyst challenges, (b) challenges with hypervirulent, recombinant and a Brazilian strain of T. gondii, and (c) in congenital and ocular models. Studies initially will define the best adjuvant(s) of 6 cytokine eliciting or cytokine encoding constructs or delivery with bilosomes or MVA boost construct using T. gondii SAG1. These will be used to vaccinate HLA A2 transgenic mice with DNA from clonal type 1 or II parasites and challenge with the homologous clonal type of parasite. Adjuvants that will be tested include DNA constructs which encode each of the following separately: IL -1Beta,-2,-12,-15,and -18;delivery within an attenuated vaccinia construct following an injection within the DNA construct;and delivery in bilosomes. Then, vaccines will be tested with DNA encoding T. gondii proteins that are candidates for protection with the best adjuvant(s) or means of delivery in HLA supermotif transgenic B7, and A*201 and A3/11 mice (HLA supermotifs present in ~90% of humans). Proteins were selected based on data available about peptides that enter MHC Class I pathways and confer protection in inbred strains of mice, including SAG1, ROP2, GRA2, GRA3, GRA6, GRA7, BLKAG, and SpAg. When protective proteins in each HLA supertype mouse are identified, epitope-encoding constructs will be designed following the principles of vaccine optimization defined by the Sette/Alexander group. This work will provide a foundation to develop a vaccine protective against toxoplasmosis for humans as well as a paradigm for vaccines to protect against other pathogens.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project--Cooperative Agreements (U01)
Project #
5U01AI077887-05
Application #
8290398
Study Section
Special Emphasis Panel (ZAI1-TP-M (J1))
Program Officer
MO, Annie X Y
Project Start
2008-07-24
Project End
2014-06-30
Budget Start
2012-07-01
Budget End
2014-06-30
Support Year
5
Fiscal Year
2012
Total Cost
$810,759
Indirect Cost
$77,272
Name
University of Chicago
Department
Ophthalmology
Type
Schools of Medicine
DUNS #
005421136
City
Chicago
State
IL
Country
United States
Zip Code
60637
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El Bissati, Kamal; Zhou, Ying; Dasgupta, Debleena et al. (2014) Effectiveness of a novel immunogenic nanoparticle platform for Toxoplasma peptide vaccine in HLA transgenic mice. Vaccine 32:3243-8
Sa, Qila; Woodward, Jerold; Suzuki, Yasuhiro (2013) IL-2 produced by CD8+ immune T cells can augment their IFN-ýý production independently from their proliferation in the secondary response to an intracellular pathogen. J Immunol 190:2199-207
Sullivan, Adam M; Zhao, Xiaopeng; Suzuki, Yasuhiro et al. (2013) Evidence for finely-regulated asynchronous growth of Toxoplasma gondii cysts based on data-driven model selection. PLoS Comput Biol 9:e1003283
Dubey, J P; Ferreira, L R; Martins, J et al. (2012) Oral oocyst-induced mouse model of toxoplasmosis: effect of infection with Toxoplasma gondii strains of different genotypes, dose, and mouse strains (transgenic, out-bred, in-bred) on pathogenesis and mortality. Parasitology 139:1-13
Cong, Hua; Mui, Ernest J; Witola, William H et al. (2012) Toxoplasma gondii HLA-B*0702-restricted GRA7(20-28) peptide with adjuvants and a universal helper T cell epitope elicits CD8(+) T cells producing interferon-ýý and reduces parasite burden in HLA-B*0702 mice. Hum Immunol 73:1-10
Cong, Hua; Mui, Ernest J; Witola, William H et al. (2011) Towards an immunosense vaccine to prevent toxoplasmosis: protective Toxoplasma gondii epitopes restricted by HLA-A*0201. Vaccine 29:754-62
Suzuki, Yasuhiro; Sa, Qila; Gehman, Marie et al. (2011) Interferon-gamma- and perforin-mediated immune responses for resistance against Toxoplasma gondii in the brain. Expert Rev Mol Med 13:e31
Caetano, Braulia C; Biswas, Amlan; Lima Jr, Djalma S et al. (2011) Intrinsic expression of Nod2 in CD4+ T lymphocytes is not necessary for the development of cell-mediated immunity and host resistance to Toxoplasma gondii. Eur J Immunol 41:3627-31
Wen, Xiangshu; Kudo, Tomoya; Payne, Laura et al. (2010) Predominant interferon-?-mediated expression of CXCL9, CXCL10, and CCL5 proteins in the brain during chronic infection with Toxoplasma gondii in BALB/c mice resistant to development of toxoplasmic encephalitis. J Interferon Cytokine Res 30:653-60

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