Newcastle Disease Virus Vectored Vaccines for Norovirus Infection


Principal Investigator: Siba K Samal
Abstract: DESCRIPTION (provided by applicant): Human norovirus infection is the most common cause of viral gastroenteritis worldwide. Development of effective vaccines will be beneficial in reducing norovirus outbreaks and preventing the significant morbidity and potential mortality. However, vaccine development against norovirus infection has been hindered due to lack of cell culture and small animal model systems. Furthermore, existence of multiple genogroups and genotypes with the complex antigenic diversity and rapid evolution of these viruses have made it difficult to formulate broadly protective norovirus vaccines. Although use of norovirus-like particles (VLPs) has provided promising results for vaccine development, effective delivery and large-scale manufacture of VLP vaccines have been challenging. To overcome these obstacles, live vectored vaccine can be an attractive approach. Newcastle disease virus (NDV), an avian paramyxovirus, vectored vaccines have shown encouraging results for vaccinations against many human pathogens. In this project, we propose to engineer recombinant NDVs individually expressing the capsid proteins of human and murine noroviruses and to evaluate their protective immunity against murine norovirus in mice. We plan to express the capsid protein of genogroup II, genotype 4 (GII.4) norovirus, which is currently responsible for 70-80% of norovirus outbreaks worldwide. To enhance the immunogenicity and protective efficacy of our NDV vectored vaccine, we aim to optimize expression level of the capsid protein (VP1) by flanking its gene with untranslated regions (UTRs) of NDV or internal ribosome entry site (IRES) elements in the transcriptional unit. The characterization of the level of VP1 expression and their assembly into VLPs by different recombinant NDVs will enable us to identify the best construct in generating a NDV vectored norovirus vaccine. VLPs expressed by NDV will also be purified from infected allantoic fluids and Vero cells. Additionally, NDV expressing murine norovirus capsid protein and its purified VLPs from infected allantoic fluids will be included as homologous antigens for murine norovirus challenge in mice. VLPs purified from recombinant baculovirus will also be included for comparison purpose. Humoral, mucosal, and cellular immunity of live NDV vectored norovirus vaccines and of VLPs will be evaluated to identify the most effective antigen. The protective efficacy of these antigens will be evaluated in a mouse model with a murine norovirus. Determination of virus load in tissue samples, virus shedding, and clinical signs will be used as the criteria to evaluate the protective efficacy of our antigens. We expect that this study will allow us to evaluate whether live NDV vectored vaccines and purified VLPs expressed by NDVs can be a novel strategy in providing immunity and protection against human norovirus infection.
Funding Period: 2012-08-21 - 2014-07-31
more information: NIH RePORT

Detail Information

Research Grants32

  1. Rocky Mountain Regional Center of Excellence or Biodefense and Emerging Infectiou
    John T Belisle; Fiscal Year: 2013
    ..abstract_text> ..
  2. Design of HIV VLPs with Enhanced Immunogenicity
    Richard W Compans; Fiscal Year: 2013
    ..We will also focus on enhancing immune responses at mucosal surfaces, where most HIV infections are transmitted. ..
  3. 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. ..
  4. Novel Ad/MVA and Ad/Protein HIV-1 Vaccines
    Dan H Barouch; Fiscal Year: 2013
    ..To define the mechanism of blocking acquisition of stringent SIV challenges by conducting antigen formulation and adoptive transfer studies in rhesus monkeys. ..
  5. Optimizing Human B and T Cell Vaccines Against HIV Using Humanized BLT Mice
    Todd M Allen; Fiscal Year: 2013
    ..This model will also enable us to rapidly test iterative vaccine design approaches to further optimize cellular immune responses to HIV. ..
  6. 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. ..
  7. Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery
    Dennis R Burton; Fiscal Year: 2013
    ..The team will be sustained by five Scientific Research Support Components (SRSCs), including strong Operations and Management, that have been assembled to maximally accelerate progress toward the designated goals. ..
  8. Primary Immune Deficiency Treatment Consortium
    Morton Cowan; Fiscal Year: 2013
    ..These studies will resolve critical questions concerning HCT for these disorders and form the basis for future prospective clinical trials. ..
  9. Exploring HIV-Host Interactions in the Female Reproductive Tract
    Karen K Smith-McCune; Fiscal Year: 2013
    ..This work could also propel future efforts aimed at developing effective biomedical approaches to interdict male-to-female transmission of HIV. ..
  10. Epitope-targeted Vaccines for HIV-1 Prevention
    SUSAN B ZOLLA-PAZNER; Fiscal Year: 2013
  11. Attenuated RhCMV Delta 10 SIV Oral Vaccine Vectors Encoding TLR5 Ligand Sequences
    ELLEN ELIZABETH SPARGER; Fiscal Year: 2013
    ..Importantly, these studies will examine and develop a novel vaccine approach that is not previously tested in the SIVmac vaccine model, and carries the potential to significantly impact HIV vaccine design. ..
    Rafi Ahmed; Fiscal Year: 2013
  13. Optimizing HIV immunogen-BCR interactions for vaccine development
    LEONIDAS A STAMATATOS; Fiscal Year: 2013
  14. Role of innate immune responses in the activity of an Alphavirus based adjuvant.
    Robert E Johnston; Fiscal Year: 2013
    ..This potentiator could result in safer, more effective, and more easily-developed vaccines. We expect that our results will increase the knowledge of how our immune system responds to viruses and vaccines. ..
  15. Mechanism of alphavirus packaging: designing of pseudoinfectious viruses
    ILYA V FROLOV; Fiscal Year: 2013
    ..These viruses will be capable of inducing a balanced combination of cellular immune response and high levels of neutralizing antibodies. ..
  16. Oxidation in Inflammation and Cardiovascular Disease
    Stanley L Hazen; Fiscal Year: 2013
    ..It may also lead to important insights for atherosclerosis risk assessment, diagnosis and therapy. ..
  17. Newcastle disease virus vectored HIV vaccines
    Siba K Samal; Fiscal Year: 2013
    ..The optimal strategies will subsequently be moved into monkey studies. ..
  18. 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. ..
  19. 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. ..
  20. 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. ..
  21. 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. ..
  22. Novel vaccine against Norovirus
    Xi Jiang; Fiscal Year: 2013
    ..abstract_text> ..
  23. Center for the Study of Innate Immunity to HCV Infection
    Michael J Gale; Fiscal Year: 2013
    ..Our studies are linked with the U19 Clinical Core, and Projects 2 and 3 to feature translational approaches aimed at defining the virus-host interface that controls hepatic innate immunity and HCV infection. ..
  24. Pacific Southwest RCE for Biodefense &Emerging Infectious Diseases Research
    Alan G Barbour; Fiscal Year: 2013
    ..abstract_text> ..
  25. Recombinant Attenuated Bacterial Vaccines Against Biodefense Agents
    Roy Curtiss; Fiscal Year: 2013