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Cross-serotypically conserved epitope recommendations for a universal T cell-based dengue vaccine.

ABSTRACT: Dengue virus (DENV)-associated disease is a growing threat to public health across the globe. Co-circulating as four different serotypes, DENV poses a unique challenge for vaccine design as immunity to one serotype predisposes a person to severe and potentially lethal disease upon infection from other serotypes. Recent experimental studies suggest that an effective vaccine against DENV should elicit a strong T cell response against all serotypes, which could be achieved by directing T cell responses toward cross-serotypically conserved epitopes while avoiding serotype-specific ones. Here, we used experimentally-determined DENV T cell epitopes and patient-derived DENV sequences to assess the cross-serotypic variability of the epitopes. We reveal a distinct near-binary pattern of epitope conservation across serotypes for a large number of DENV epitopes. Based on the conservation profile, we identify a set of 55 epitopes that are highly conserved in at least 3 serotypes. Most of the highly conserved epitopes lie in functionally important regions of DENV non-structural proteins. By considering the global distribution of human leukocyte antigen (HLA) alleles associated with these DENV epitopes, we identify a potentially robust subset of HLA class I and class II restricted epitopes that can serve as targets for a universal T cell-based vaccine against DENV while covering ~99% of the global population.

SUBMITTER: Ahmed SF

PROVIDER: S-EPMC7529213 | biostudies-literature | 2020 Sep

REPOSITORIES: biostudies-literature

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Cross-serotypically conserved epitope recommendations for a universal T cell-based dengue vaccine.

Ahmed Syed Faraz SF Quadeer Ahmed A AA Barton John P JP McKay Matthew R MR

PLoS neglected tropical diseases 20200921 9

Dengue virus (DENV)-associated disease is a growing threat to public health across the globe. Co-circulating as four different serotypes, DENV poses a unique challenge for vaccine design as immunity to one serotype predisposes a person to severe and potentially lethal disease upon infection from other serotypes. Recent experimental studies suggest that an effective vaccine against DENV should elicit a strong T cell response against all serotypes, which could be achieved by directing T cell respo ...[more]

PMID: 32956362

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Project description:Dengue poses a global health threat, which will persist without therapeutic intervention. Immunity induced by exposure to one serotype does not confer long-term protection against secondary infection with other serotypes and is potentially capable of enhancing this infection. Although vaccination is believed to induce durable and protective responses against all the dengue virus (DENV) serotypes in order to reduce the burden posed by this virus, the development of a safe and efficacious vaccine remains a challenge. Immunoinformatics and computational vaccinology have been utilized in studies of infectious diseases to provide insight into the host-pathogen interactions thus justifying their use in vaccine development. Since vaccination is the best bet to reduce the burden posed by DENV, this study is aimed at developing a multi-epitope based vaccines for dengue control. Combined approaches of reverse vaccinology and immunoinformatics were utilized to design multi-epitope based vaccine from the sequence of DENV. Specifically, BCPreds and IEDB servers were used to predict the B-cell and T-cell epitopes, respectively. Molecular docking was carried out using Schrödinger, PATCHDOCK and FIREDOCK. Codon optimization and in silico cloning were done using JCAT and SnapGene respectively. Finally, the efficiency and stability of the designed vaccines were assessed by an in silico immune simulation and molecular dynamic simulation, respectively. The predicted epitopes were prioritized using in-house criteria. Four candidate vaccines (DV-1-4) were designed using suitable adjuvant and linkers in addition to the shortlisted epitopes. The binding interactions of these vaccines against the receptors TLR-2, TLR-4, MHC-1 and MHC-2 show that these candidate vaccines perfectly fit into the binding domains of the receptors. In addition, DV-1 has a better binding energies of - 60.07, - 63.40, - 69.89 kcal/mol against MHC-1, TLR-2, and TLR-4, with respect to the other vaccines. All the designed vaccines were highly antigenic, soluble, non-allergenic, non-toxic, flexible, and topologically assessable. The immune simulation analysis showed that DV-1 may elicit specific immune response against dengue virus. Moreover, codon optimization and in silico cloning validated the expressions of all the designed vaccines in E. coli. Finally, the molecular dynamic study shows that DV-1 is stable with minimum RMSF against TLR4. Immunoinformatics tools are now applied to screen genomes of interest for possible vaccine target. The designed vaccine candidates may be further experimentally investigated as potential vaccines capable of providing definitive preventive measure against dengue virus infection.

Project description:Any potential dengue virus (DENV) vaccine needs to elicit protective immunity against strains from all four serotypes to avoid potential antibody-dependent enhancement (ADE). In this study, four independent DENV envelope (E) glycoproteins were generated using wild-type E sequences from viruses isolated between 1943 and 2006 using computationally optimized broadly reactive antigen (COBRA) methodology. COBRA and wild-type E antigens were expressed on the surface of subvirion viral particles (SVPs). Four separate wild-type E antigens were used for each serotype. Mice vaccinated with wild-type DENV SVPs had anti-E IgG antibodies that neutralized serotype-specific viruses. COBRA DENV SVPs elicited a broader breadth of antibodies that neutralized strains across all four serotypes. Two COBRA DENV vaccine candidates that elicited the broadest breadth of neutralizing antibodies in mice were used to vaccinate rhesus macaques (Macaca mulatta) that either were immunologically naive to any DENV serotype or had preexisting antibodies to DENV. Antibodies elicited by COBRA DENV E immunogens neutralized all 12 strains of DENV in vitro, which was comparable to antibodies elicited by a tetravalent wild-type E SVP vaccination mixture. Therefore, using a single DENV COBRA E protein can elicit neutralizing antibodies against strains representing all four serotypes of DENV in both naive and dengue virus-preimmune populations.IMPORTANCE Dengue virus infects millions of people living in tropical areas of the world. Dengue virus-induced diseases can range from mild to severe with death. An effective vaccine will need to neutralize viruses from all four serotypes of dengue virus without inducing enhanced disease. A dengue virus E vaccine candidate generated by computationally optimized broadly reactive antigen algorithms elicits broadly neutralizing protection for currently circulating strains from all four serotypes regardless of immune status. Most dengue vaccines in development formulate four separate components based on prM-E from a wild-type strain representing each serotype. Designing a monovalent vaccine that elicits protective immunity against all four serotypes is an effective and economical strategy.

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Cross-serotypically conserved epitope recommendations for a universal T cell-based dengue vaccine.

Publications

Cross-serotypically conserved epitope recommendations for a universal T cell-based dengue vaccine.

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