Development of a Recombinant Tetravalent Dengue Vaccine Based on a Subunit Envelo


Principal Investigator: Lynda G Tussey
Abstract: DESCRIPTION (provided by applicant): Dengue disease poses a significant threat to over 2.5 billion people worldwide and currently, no licensed vaccine is available. An effective and safe vaccine requires a balanced immune response to all four serotypes of dengue viruses (DENV-1 to -4) because sequential infection by different dengue virus serotypes can lead to life-threatening dengue hemorrhagic fever or dengue shock syndrome. Live attenuated or chimeric virus-based vaccines are promising but they struggle with inadequate attenuation or an imbalanced immune response due to interference. While interference can be overcome by a 12-month immunization schedule, this schedule renders the vaccine unsuitable for recipients requiring rapid development of immunity. Additionally, safety concerns associated with 17D may limit its use in immunocompromised individuals, children or elderly. We have developed a series of flavivirus vaccines based on our clinically proven vaccine platform in three formats, which differ in the site of antigen attachment to the flagellin (a TLR5 ligand). These vaccine candidates can be efficiently produced and elicit protective levels of neutralizing antibodies to both dengue serotypes. TLR signaling triggers an innate immune cascade that enhances antigen uptake and presentation, and facilitates induction of adaptive immune response, thereby eliminating the need for adjuvants typically used in subunit vaccines. Flagellin contains of four distinct domains (D0, D1, D2, and D3) where D1 contains the TLR5 binding site. Antigens can be fused to the C-terminus in the C-term format, in place of D3 in the R3 format, or to both positions in two copies in the R3.2x formats. Among the three, the R3.2x format was found to be the safest and the most immunogenic in Phase I trials of influenza vaccine. To develop flavivirus vaccines, we initially fused the domain III of the envelope (EIII) to the C-terminus of the flagellin. We have demonstrated that monovalent West Nile and DENV-2 vaccine candidates based on the flagellin-EIII fusion induce potent antibody responses and are efficacious in mouse challenge models. We have subsequently generated flagellin-EIII dengue vaccines in various formats, and have identified R3.2x as the lead format for use in a tetravalent vaccine candidate in mice and non-human primates (NHP). Based on recent findings of neutralizing epitopes of human polyclonal and monoclonal antibodies, we have generated backup subunit flagellin-E vaccines that include major neutralizing epitopes in the domains III and I of the E protein (EIEIII) as well as the EI/EII junction region. We here propose to optimize the lead TDV formulation (dose level and component ratio) in immunogenicity studies in mice, and then to optimize the fermentation conditions and purification process for those candidates. We will next evaluate the immunogenicity and efficacy of the lead TDV in NHP DENV challenge models, followed by evaluation of dose range using a well-established rabbit reactogenicity model as well as formulation development. We will demonstrate that the tetravalent vaccine induces durable, balanced immune responses that are capable of neutralizing a broad spectrum of strains and genotypes of each serotype, and provides protection against all four DENV serotypes in mouse and monkey models. Once the lead candidates are locked we will develop a liquid formulation suitable for 4 [unreadable]C storage for at least one year. Further, we will confirm a safe and effective window of the TDV candidate to guide the dose selection in the subsequent GLP rabbit toxicity study as well as dose escalating study in phase I trial. The positive outcome of this study will be a solid step towards the successful development of a safer, cheaper, and effective vaccine, which can be used to prevent DENV-associated diseases. Lastly, VaxInnate's rapid and low cost bacteria-based manufacturing can easily be transferred to endemic countries as demonstrated by a recent successful process transfer of the 2009 H1N1 pandemic vaccine.
Funding Period: 2013-04-01 - 2016-03-31
more information: NIH RePORT

Detail Information

Research Grants30

  1. Pacific NorthWest Regional Center of Excellence (PNWRCE)
    Jay A Nelson; Fiscal Year: 2013
    ..pseudomallei host pathogen response during both the septicemic as well as the intracellular phases of the disease. ..
  2. Optimization of HIV vaccines for the induction of cross-reactive antibodies
    Shan Lu; Fiscal Year: 2013
    ..RELEVANCE: To optimize the next generation polyvalent Env HIV vaccine formulations using the multi-gene, polyvalent DNA prime - protein boost technology platform. ..
    Rafi Ahmed; Fiscal Year: 2013
  4. Rocky Mountain Regional Center of Excellence or Biodefense and Emerging Infectiou
    John T Belisle; Fiscal Year: 2013
    ..abstract_text> ..
  5. Development of an H2O2-Inactivated Dengue Virus Vaccine
    Mark K Slifka; Fiscal Year: 2013
  6. Southeast Regional Centers of Excellence for Biodefense &Emerging Infectious Di
    Philip Frederick Sparling; Fiscal Year: 2013
    ..SERCEB brings new investigators to the biodefense effort through a combination of educational programs, support of innovative new projects, and the synergistic interactions among its world-class investigators. ..
  7. New England Regional Center of Excellence in Biodefense and Emerging Infectious D
    Dennis L Kasper; Fiscal Year: 2013
    ..NERCE will also continue its Developmental Projects program and Career Development in Biodefense program in an effort to initiate new research efforts and to attract new investigators to this field. ..
  8. Northeast Biodefense Center
    W Ian Lipkin; Fiscal Year: 2013
    ..As a Center based in a School of Public Health and a State Department of Health, the NBC has a firm commitment to and practical understanding of Emergency Preparedness. ..
  9. Pacific Southwest RCE for Biodefense &Emerging Infectious Diseases Research
    Alan G Barbour; Fiscal Year: 2013
    ..abstract_text> ..
  10. Optimizing HIV immunogen-BCR interactions for vaccine development
    LEONIDAS A STAMATATOS; Fiscal Year: 2013
  11. Harnessing Human DC Subsets for Improved Muscosal Vaccines
    Gerard Zurawski; Fiscal Year: 2013
    ..We propose four projects and two technical development components which will be supported by six cores. ..
  12. A Pan-Dengue Virus Immunotherapeutic for Prevention and Treatment
    LESLIE S JOHNSON; Fiscal Year: 2013
    ..Required studies will be performed under GLP conditions. This project aims to advance a collection of DV-neutralizing MAbs into a concise well-defined immunotherapeutic validated for initiation of clinical studies. ..
  13. Mucosal Immunity, Vaccines and Microbiota Interplay in Humans and Animal
    Marcelo B Sztein; Fiscal Year: 2013
    ..Given the shortcomings of available measures to successfully control this infection, and its bioterrorism potential, to develop a S. dysenteriae type 1 vaccine is of great importance. ..
  14. Development of a novel adjuvant for vaccine sparing
    Hao Shen; Fiscal Year: 2013
  15. DARE: Delaney AIDS Research Enterprise to find a cure.
    RAFICK PIERRE SEKALY; Fiscal Year: 2013