The current progress indicates the feasibility of therapeutic approaches for treatment of chronic HBV infection. There is a general agreement that a combination of antiviral treatment and immunomodulation is essential to achieve a sustained control of HBV infection. However, many scientific questions are still not answered. The question how HBV infection leads to defective immune responses to HBV proteins remains to be investigated. This issue is the key to a more rational design of new therapeutic approaches. Recently, HBV proteins were found to suppress host innate responses [188] . It has to be clarified whether an early blockage of innate immune responses may further negatively influence the priming of adaptive immune responses. In addition, different groups reported consistently that TLR2 and TLR4 signalling may be impaired in chronic HBV infection patients [189, 190] . Thus, it is worthy to test whether an enhancement of innate immune responses in chronic carriers is necessary for restoration of specific immune responses. With the increasing number of available vaccine formulation, a more crucial question raised recently: what is the optimal combination of these vaccines. Obviously, it is necessary to test the mutual influences of different types of vaccines to maximize their effects and avoid the negative interference between the vaccines. Finally, the future design of therapeutic vaccines needs to be considered in nonnaïve hosts since patients have undergone other infections. It is yet not possible to foresee how the pre-existing infections and immunological backgrounds will influence the effect of therapeutic vaccines. Understanding these issues will be helpful for the translation of recent progresses for clinical use of therapeutic vaccines. Human immunome, bioinformatic analyses using HLA supermotifs and the parasite genome, binding assays, studies of human T cell responses, and immunization of HLA-A*1101 transgenic mice including novel adjuvants provide a foundation for HLA-A03 restricted CD8(+)T cell epitope based, adjuvanted vaccine protective against Toxoplasma gondii BACKGROUND: Toxoplasmosis causes loss of life, cognitive and motor function, and sight. A vaccine is greatly needed to prevent this disease. The purpose of this study was to use an immmunosense approach to develop a foundation for development of vaccines to protect humans with the HLA-A03 supertype. Three peptides had been identified with high binding scores for HLA-A03 supertypes using bioinformatic algorhythms, high measured binding affinity for HLA-A03 supertype molecules, and ability to elicit IFN-γ production by human HLA-A03 supertype peripheral blood CD8(+ )T cells from seropositive but not seronegative persons. RESULTS: Herein, when these peptides were administered with the universal CD4(+)T cell epitope PADRE (AKFVAAWTLKAAA) and formulated as lipopeptides, or administered with GLA-SE either alone, or with Pam(2)Cys added, we found we successfully created preparations that induced IFN-γ and reduced parasite burden in HLA-A*1101(an HLA-A03 supertype allele) transgenic mice. GLA-SE is a novel emulsified synthetic TLR4 ligand that is known to facilitate development of T Helper 1 cell (TH1) responses. Then, so our peptides would include those expressed in tachyzoites, bradyzoites and sporozoites from both Type I and II parasites, we used our approaches which had identified the initial peptides. We identified additional peptides using bioinformatics, binding affinity assays, and study of responses of HLA-A03 human cells. Lastly, we found that immunization of HLA-A*1101 transgenic mice with all the pooled peptides administered with PADRE, GLA-SE, and Pam(2)Cys is an effective way to elicit IFN-γ producing CD8(+ )splenic T cells and protection. Immunizations included the following peptides together: KSFKDILPK (SAG1(224-232)); AMLTAFFLR (GRA6(164-172)); RSFKDLLKK (GRA7(134-142)); STFWPCLLR (SAG2C(13-21)); SSAYVFSVK((SPA250-258)); and AVVSLLRLLK(SPA(89-98)). This immunization elicited robust protection, measured as reduced parasite burden using a luciferase transfected parasite, luciferin, this novel, HLA transgenic mouse model, and imaging with a Xenogen camera. CONCLUSIONS: Toxoplasma gondii peptides elicit HLA-A03 restricted, IFN-γ producing, CD8(+ )T cells in humans and mice. These peptides administered with adjuvants reduce parasite burden in HLA-A*1101 transgenic mice. This work provides a foundation for immunosense based vaccines. It also defines novel adjuvants for newly identified peptides for vaccines to prevent toxoplasmosis in those with HLA-A03 supertype alleles. parasite burden using a luciferase transfected parasite, luciferin, this novel, HLA transgenic mouse model, and imaging with a Xenogen camera. Conclusions: Toxoplasma gondii peptides elicit HLA-A03 restricted, IFN-γ producing, CD8 + T cells in humans and mice. These peptides administered with adjuvants reduce parasite burden in HLA-A*1101 transgenic mice. This work provides a foundation for immunosense based vaccines. It also defines novel adjuvants for newly identified peptides for vaccines to prevent toxoplasmosis in those with HLA-A03 supertype alleles.