T lymphocyte responses to heterologous secondary dengue virus infections.
ABSTRACT The available evidence suggests that plasma leakage in dengue hemorrhagic fever is caused by the action of circulating mediators on the vascular endothelium, and that the host immune response is a critical determinant of this response. We have been exploring the role of dengue virus-specific T lymphocytes in the immunopathogenesis of plasma leakage. Memory dengue virus-specific T cells induced during a primary dengue virus infection are reactivated by the heterologous viral serotype during a secondary infection to expand to high levels and produce a skewed cytokine profile. Investigations are underway to identify the immunologic profiles associated with increased or decreased risk for severe disease.
SourceAvailable from: Narayan Gyawali[Show abstract] [Hide abstract]
ABSTRACT: Dengue is a mosquito-borne viral disease of humans that is a major public health concern in tropical and sub-tropical regions of the world. The increasing mortality and morbidity rates caused by infection in recent years are attributable partly to a lack of availability of effective antiviral therapies and vaccines. In a concerted attempt to arrest this global expansion, several dengue vaccine candidates have progressed from pre-clinical testing into clinical trials. However, the advancement of vaccine development has manifest challenges to be overcome. A principal tenet underpinning dengue vaccine design is balanced immunity to all five recognised virus serotypes, but difficulties in achieving optimal attenuation of each virus and interference between individual attenuated viruses are significant hurdles to successful implementation. Currently, the most advanced vaccine candidate, the recombinant, live-attenuated ChimeriVax-DEN1-4 preparation developed by Sanofi Pasteur, is likely to achieve licensure at the completion of phase III trials and undergo population safety surveillance. Subunit and DNA vaccines are also in various stages of clinical evaluation. The intrinsic rationale is to produce a safe, efficacious and cost-effective vaccine. While this remains an achievable goal, progress is limited by an incomplete understanding of dengue viral pathogenesis, together with a lack of suitable animal models for fundamental pre-clinical development. This editorial highlights current approaches and future directions for vaccine strategies to combat the global expansion of this infectious disease.
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ABSTRACT: Dengue viruses (DENVs) cause approximately 390 million cases of DENV infections annually and over 3 billion people worldwide are at risk of infection. No dengue vaccine is currently available nor is there an antiviral therapy for DENV infections. We have developed a tetravalent live-attenuated DENV vaccine tetravalent dengue vaccine (TDV) that consists of a molecularly characterized attenuated DENV-2 strain (TDV-2) and three chimeric viruses containing the pre-membrane and envelope genes of DENV-1, -3, and -4 expressed in the context of the TDV-2 genome. To impact dengue vaccine delivery in endemic areas and immunize travelers, a simple and rapid immunization strategy (RIS) is preferred. We investigated RIS consisting of two full vaccine doses being administered subcutaneously or intradermally on the initial vaccination visit (day 0) at two different anatomical locations with a needle-free disposable syringe jet injection delivery devices (PharmaJet) in non-human primates. This vaccination strategy resulted in efficient priming and induction of neutralizing antibody responses to all four DENV serotypes comparable to those elicited by the traditional prime and boost (2 months later) vaccination schedule. In addition, the vaccine induced CD4(+) and CD8(+) T cells producing IFN-γ, IL-2, and TNF-α, and targeting the DENV-2 NS1, NS3, and NS5 proteins. Moreover, vaccine-specific T cells were cross-reactive with the non-structural NS3 and NS5 proteins of DENV-4. When animals were challenged with DENV-2 they were protected with no detectable viremia, and exhibited sterilizing immunity (no increase of neutralizing titers post-challenge). RIS could decrease vaccination visits and provide quick immune response to all four DENV serotypes. This strategy could increase vaccination compliance and would be especially advantageous for travelers into endemic areas.Frontiers in Immunology 06/2014; 5:263. DOI:10.3389/fimmu.2014.00263
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ABSTRACT: Closely related peptide epitopes can be recognized by the same T cells and contribute to the immune response against pathogens encoding those epitopes, but sometimes cross-reactive epitopes share little homology. The degree of structural homology required for such disparate ligands to be recognized by cross-reactive TCRs remains unclear. In this study, we examined the mechanistic basis for cross-reactive T cell responses between epitopes from unrelated and pathogenic viruses, lymphocytic choriomeningitis virus (LCMV) and vaccinia virus. Our results show that the LCMV cross-reactive T cell response toward vaccinia virus is dominated by a shared asparagine residue, together with other shared structural elements conserved in the crystal structures of K(b)-VV-A11R and K(b)-LCMV-gp34. Based on analysis of the crystal structures and the specificity determinants for the cross-reactive T cell response, we were able to manipulate the degree of cross-reactivity of the T cell response, and to predict and generate a LCMV cross-reactive response toward a variant of a null OVA-derived peptide. These results indicate that protective heterologous immune responses can occur for disparate epitopes from unrelated viruses.The Journal of Immunology 10/2013; 191(10). DOI:10.4049/jimmunol.1300852 · 5.36 Impact Factor