Susceptibility and Protective Immunity to Noroviruses

Summary

Principal Investigator: Ralph Baric
Affiliation: University of North Carolina
Country: USA
Abstract: Norwalk-like viruses (NLV), a genus within the Caliciviridae, are the major cause of epidemic gastroenteritis in the US and a significant cause of severe diarrhea in young children. Based on their low infectious dose, high transmissibility and economic impact, NLVs have been classified as Bioterrorism Category B Priority Pathogens by the U.S. Centers for Disease Control and Prevention and the National Institute of Allergy and Infectious Diseases. The long-term goals of this proposal are to elucidate the molecular mechanisms governing human susceptibility to NLV infection. In this capacity, we will use human challenge models to test various hypotheses that specific human susceptibility alleles and acquired immune factors determine NLV infection outcomes and pathogenicity. It is anticipated that the identification of host factors and responses that influence NLV pathogenesis will reveal fundamental insights into the molecular biology of these viruses, simultaneously allowing for the development of NLV vaccine and therapeutic strategies. A second goal is to develop NLV vaccines using alphaviruses as heterologous vaccine vectors. Venezuelan equine encephalitis virus (VEE)-based vaccines elicit high levels of mucosal and systemic immunity against NLVs. We will test various hypotheses that VEE replicon particles (VRPs) encoding different genogroup I and II (GI and GII) NLV capsid genes elicit strong systemic, cellular and mucosal immune responses against homologous and heterologous NLVs and are superior to the current standards for NLV vaccine development (NLV recombinant virus-like particles (VLPs) and edible vaccines).
Funding Period: 2003-07-01 - 2007-12-31
more information: NIH RePORT

Top Publications

  1. pmc Chimeric GII.4 Norovirus Virus-Like-Particle-Based Vaccines Induce Broadly Blocking Immune Responses
    Kari Debbink
    Department of Microbiology and Immunology, University of North Carolina Chapel Hill, Chapel Hill, North Carolina, USA
    J Virol 88:7256-66. 2014
  2. pmc The effects of simvastatin or interferon-α on infectivity of human norovirus using a gnotobiotic pig model for the study of antivirals
    Kwonil Jung
    Food Animal Health Research Program, Ohio Agricultural Research and Development Center, Department of Veterinary Preventive Medicine, The Ohio State University, Wooster, Ohio, United States of America
    PLoS ONE 7:e41619. 2012
  3. pmc Emergence of a norovirus GII.4 strain correlates with changes in evolving blockade epitopes
    Lisa C Lindesmith
    Department of Epidemiology, University of North Carolina, Chapel Hill, North Carolina, USA
    J Virol 87:2803-13. 2013
  4. doi Specificity and kinetics of norovirus binding to magnetic bead-conjugated histo-blood group antigens
    P Tian
    Produce Safety and Microbiology Research Unit, Western Regional Research Center, Agricultural Research Service, United States Department of Agriculture, Albany, CA 94547 1105, USA
    J Appl Microbiol 109:1753-62. 2010
  5. pmc Prevalence of porcine noroviruses, molecular characterization of emerging porcine sapoviruses from finisher swine in the United States, and unified classification scheme for sapoviruses
    Kelly A Scheuer
    Food Animal Health Research Program, Ohio Agricultural Research and Development Center, The Ohio State University, Wooster, Ohio, USA
    J Clin Microbiol 51:2344-53. 2013
  6. pmc Emergence of new pandemic GII.4 Sydney norovirus strain correlates with escape from herd immunity
    Kari Debbink
    Department of Microbiology and Immunology
    J Infect Dis 208:1877-87. 2013
  7. doi Viral shape-shifting: norovirus evasion of the human immune system
    Eric F Donaldson
    University of North Carolina, Department of Epidemiology, Chapel Hill, North Carolina 27599, USA
    Nat Rev Microbiol 8:231-41. 2010
  8. pmc Characterization of blockade antibody responses in GII.2.1976 Snow Mountain virus-infected subjects
    Jesica Swanstrom
    Department of Epidemiology, University of North Carolina, Chapel Hill, North Carolina, USA
    J Virol 88:829-37. 2014
  9. pmc Human norovirus detection and production, quantification, and storage of virus-like particles
    Kari Debbink
    University of North Carolina, Chapel Hill, North Carolina
    Curr Protoc Microbiol 31:15K.1.1-15K.1.45. 2013
  10. pmc Alphavirus-adjuvanted norovirus-like particle vaccines: heterologous, humoral, and mucosal immune responses protect against murine norovirus challenge
    Anna D LoBue
    Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599 7435, USA
    J Virol 83:3212-27. 2009

Scientific Experts

  • Qiuhong Wang
  • Jennifer L Cannon
  • Ralph Baric
  • Lisa C Lindesmith
  • Kari Debbink
  • Eric F Donaldson
  • Jesica Swanstrom
  • Anna D LoBue
  • Jan Vinje
  • Lisa Lindesmith
  • Veronica Costantini
  • Christine L Moe
  • KAREN A CHACHU
  • Antonio Lanzavecchia
  • Davide Corti
  • Martina Beltramello
  • Linda J Saif
  • Kwonil Jung
  • Robert E Johnston
  • Kelly A Scheuer
  • Quan Shen
  • Zhenwen Zhang
  • Scot R Seitz
  • Sayaka Takanashi
  • Boyd Yount
  • P Tian
  • Peter F M Teunis
  • Herbert W Virgin
  • David W Strong
  • Joseph M Thompson
  • Jeffrey A Frelinger
  • Martin T Ferris
  • Wondwossen A Gebreyes
  • Armando E Hoet
  • Sudhakar Agnihothram
  • Tomoichiro Oka
  • Bayleyegn Z Molla
  • Kelly Scheuer
  • Kyeong Ok Chang
  • Yunjeong Kim
  • Marina L Fernandez
  • Ning Chen
  • Juan S Leon
  • Gwen Abdulhafid
  • Marisa McDaniels
  • Kellogg J Schwab
  • Masaru Yokoyama
  • G Marshall Lyon
  • Melissa Dowd
  • X Jiang
  • W Zhong
  • W Burkhardt
  • Juan Leon
  • David J Weber
  • Eric Donaldson
  • L Lindesmith
  • G Hartman
  • J W Woods
  • R Mandrell
  • D Yang
  • Rebecca L Calderon
  • Jacques Le Pendu
  • Christiane E Wobus
  • Pengbo Liu
  • Du Ping Zheng
  • Sara E Miller
  • Patrick R Harrington
  • John Treanor
  • Christine Moe
  • Jacques Lependu

Detail Information

Publications30

  1. pmc Chimeric GII.4 Norovirus Virus-Like-Particle-Based Vaccines Induce Broadly Blocking Immune Responses
    Kari Debbink
    Department of Microbiology and Immunology, University of North Carolina Chapel Hill, Chapel Hill, North Carolina, USA
    J Virol 88:7256-66. 2014
    ....
  2. pmc The effects of simvastatin or interferon-α on infectivity of human norovirus using a gnotobiotic pig model for the study of antivirals
    Kwonil Jung
    Food Animal Health Research Program, Ohio Agricultural Research and Development Center, Department of Veterinary Preventive Medicine, The Ohio State University, Wooster, Ohio, United States of America
    PLoS ONE 7:e41619. 2012
    ..Collectively, these findings indicate that Gn pigs are a useful model to test immunomodulators or efficacy of antivirals against HuNoV...
  3. pmc Emergence of a norovirus GII.4 strain correlates with changes in evolving blockade epitopes
    Lisa C Lindesmith
    Department of Epidemiology, University of North Carolina, Chapel Hill, North Carolina, USA
    J Virol 87:2803-13. 2013
    ....
  4. doi Specificity and kinetics of norovirus binding to magnetic bead-conjugated histo-blood group antigens
    P Tian
    Produce Safety and Microbiology Research Unit, Western Regional Research Center, Agricultural Research Service, United States Department of Agriculture, Albany, CA 94547 1105, USA
    J Appl Microbiol 109:1753-62. 2010
    ..To characterize the specificity and effect of pH and ionic strength on the kinetics of virus binding to histo-blood group antigens (HBGA)-conjugated magnetic beads...
  5. pmc Prevalence of porcine noroviruses, molecular characterization of emerging porcine sapoviruses from finisher swine in the United States, and unified classification scheme for sapoviruses
    Kelly A Scheuer
    Food Animal Health Research Program, Ohio Agricultural Research and Development Center, The Ohio State University, Wooster, Ohio, USA
    J Clin Microbiol 51:2344-53. 2013
    ..We tentatively classified SaVs into 14 genogroups based on the complete capsid protein VP1. In summary, porcine NoVs and highly divergent SaVs were present in North Carolina finisher pigs...
  6. pmc Emergence of new pandemic GII.4 Sydney norovirus strain correlates with escape from herd immunity
    Kari Debbink
    Department of Microbiology and Immunology
    J Infect Dis 208:1877-87. 2013
    ..A new pandemic isolate, GII.4 2012 Sydney, largely replaced previously circulating strains in late 2012. We compare the antigenic properties of GII.4 2012 Sydney with previously circulating strains...
  7. doi Viral shape-shifting: norovirus evasion of the human immune system
    Eric F Donaldson
    University of North Carolina, Department of Epidemiology, Chapel Hill, North Carolina 27599, USA
    Nat Rev Microbiol 8:231-41. 2010
    ..In this Review, we discuss the molecular and structural mechanisms that facilitate the persistence of noroviruses in human populations...
  8. pmc Characterization of blockade antibody responses in GII.2.1976 Snow Mountain virus-infected subjects
    Jesica Swanstrom
    Department of Epidemiology, University of North Carolina, Chapel Hill, North Carolina, USA
    J Virol 88:829-37. 2014
    ..4 strains, have undergone only a limited amount of evolution in blockade epitopes between 1976 and 2010 and indicate that the GII.2-protective component of a multivalent norovirus vaccine may not require frequent reformulation. ..
  9. pmc Human norovirus detection and production, quantification, and storage of virus-like particles
    Kari Debbink
    University of North Carolina, Chapel Hill, North Carolina
    Curr Protoc Microbiol 31:15K.1.1-15K.1.45. 2013
    ..Curr. Protoc. Microbiol. 31:15K.1.1-15K.1.45. © 2013 by John Wiley & Sons, Inc. ..
  10. pmc Alphavirus-adjuvanted norovirus-like particle vaccines: heterologous, humoral, and mucosal immune responses protect against murine norovirus challenge
    Anna D LoBue
    Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599 7435, USA
    J Virol 83:3212-27. 2009
    ..Together, these data suggest that humoral immunity induced by multivalent norovirus vaccines may protect against heterologous norovirus challenge...
  11. pmc Immune mechanisms responsible for vaccination against and clearance of mucosal and lymphatic norovirus infection
    KAREN A CHACHU
    Department of Pathology and Immunology, Washington University School of Medicine, St Louis, MO, USA
    PLoS Pathog 4:e1000236. 2008
    ....
  12. doi Norovirus pathogenesis: mechanisms of persistence and immune evasion in human populations
    Eric F Donaldson
    Department of Microbiology and Immunology, School of Medicine, University of North Carolina, Chapel Hill, NC 27599, USA
    Immunol Rev 225:190-211. 2008
    ..In this review, we discuss how evolution within the capsid drives receptor switching and allows escape from herd immunity...
  13. ncbi Norwalk virus: how infectious is it?
    Peter F M Teunis
    RIVM, Bilthoven, The Netherlands
    J Med Virol 80:1468-76. 2008
    ..Norwalk virus is a valuable model system to study virulence because genetic factors are known for both complete and partial protection; the latter can be quantitatively described as heterogeneity in dose response models...
  14. pmc Antibody is critical for the clearance of murine norovirus infection
    KAREN A CHACHU
    Department of Pathology and Immunology, Washington University School of Medicine, 660 S Euclid Avenue, St Louis, MO 63110, USA
    J Virol 82:6610-7. 2008
    ..Together, these data demonstrate that antibody plays an important role in the clearance of MNV and that immunoglobulin G anti-norovirus antibody can play an important role in clearing mucosal infection...
  15. pmc The state of norovirus vaccines
    Kari Debbink
    Department of Microbiology and Immunology
    Clin Infect Dis 58:1746-52. 2014
    ....
  16. pmc Within-Host Evolution Results in Antigenically Distinct GII.4 Noroviruses
    Kari Debbink
    Department of Microbiology and Immunology, University of North Carolina, Chapel Hill, North Carolina, USA
    J Virol 88:7244-55. 2014
    ....
  17. pmc Immunogenetic mechanisms driving norovirus GII.4 antigenic variation
    Lisa C Lindesmith
    Department of Epidemiology, University of North Carolina, Chapel Hill, North Carolina, United States of America
    PLoS Pathog 8:e1002705. 2012
    ..4 norovirus evolution is heavily influenced by antigenic variation of neutralizing epitopes and consequently, antibody-driven receptor switching; thus, protective herd immunity is a driving force in norovirus molecular evolution...
  18. pmc Genetic mapping of a highly variable norovirus GII.4 blockade epitope: potential role in escape from human herd immunity
    Kari Debbink
    Department of Epidemiology, University of North Carolina, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
    J Virol 86:1214-26. 2012
    ..4-1987 blockade response. Our data provide insights that help explain the emergence of new GII.4 epidemic strains over time, may aid development of norovirus therapeutics, and may help predict the emergence of future epidemic strains...
  19. pmc Monoclonal antibody-based antigenic mapping of norovirus GII.4-2002
    Lisa C Lindesmith
    Department of Epidemiology, University of North Carolina, Chapel Hill, North Carolina, USA
    J Virol 86:873-83. 2012
    ..4 norovirus evolution results in antigenic variation that allows the virus to escape from protective herd immunity, resulting in new epidemic strains...
  20. pmc Identification of cross-reactive norovirus CD4+ T cell epitopes
    Anna D LoBue
    Department of Microbiology and Immunology, School of Medicine University of North Carolina at Chapel Hill, North Carolina 27599 7435, USA
    J Virol 84:8530-8. 2010
    ....
  21. pmc Norovirus GII.4 strain antigenic variation
    Lisa C Lindesmith
    Department of Epidemiology, University of North Carolina Chapel Hill, Chapel Hill, NC 27599, USA
    J Virol 85:231-42. 2011
    ..As with influenza virus, HIV, and hepatitis C virus, norovirus antigenic variation will significantly influence the design of efficacious vaccines and immunotherapeutics against these important human pathogens...
  22. pmc Characterization and prevalence of a new porcine Calicivirus in Swine, United States
    Qiuhong Wang
    The Ohio State University, Wooster, Ohio, USA
    Emerg Infect Dis 17:1103-6. 2011
    ..One strain, NC-WGP93C, shares 89.3%-89.7% genomic nucleotide identity with Canadian strains. Whether these viruses cause disease in pigs or humans or are of food safety concern requires further investigation...
  23. pmc Characterization of emerging GII.g/GII.12 noroviruses from a gastroenteritis outbreak in the United States in 2010
    Sayaka Takanashi
    Food Animal Health Research Program, Ohio Agricultural Research and Development Center, The Ohio State University, 1680 Madison Ave, Wooster, OH 44691, USA
    J Clin Microbiol 49:3234-44. 2011
    ..We observed that this emerging GII.12 norovirus infected humans regardless of A/B/O blood type. The infection of pigs by strain HS206 suggests that interspecies transmission of this strain is possible under experimental conditions...
  24. pmc Norovirus infectivity in humans and persistence in water
    Scot R Seitz
    Hubert Department of Global Health, Rollins School of Public Health, Emory University, 1518 Clifton Road NE, Atlanta, GA 30322, USA
    Appl Environ Microbiol 77:6884-8. 2011
    ..This study demonstrates that Norwalk virus in groundwater can remain detectable for over 3 years and can remain infectious for at least 61 days. (ClinicalTrials.gov identifier NCT00313404.)...
  25. pmc Heterotypic humoral and cellular immune responses following Norwalk virus infection
    Lisa C Lindesmith
    Department of Epidemiology, University of North Carolina, Chapel Hill, North Carolina 27599, USA
    J Virol 84:1800-15. 2010
    ..1-1968-challenged individuals and highlight a potential complication in the design of efficacious norovirus vaccines...
  26. pmc Herd immunity to GII.4 noroviruses is supported by outbreak patient sera
    Jennifer L Cannon
    Centers for Disease Control and Prevention, Atlanta, Georgia 30333, USA
    J Virol 83:5363-74. 2009
    ..4 NoV. These results support the hypothesis that herd immunity is a driving force for GII.4 evolution in the U.S. population. The data also suggest that complex patterns of cross-protection may exist across NoV genotypes in humans...
  27. pmc Mechanisms of GII.4 norovirus persistence in human populations
    Lisa C Lindesmith
    University of North Carolina Chapel Hill, Chapel Hill, North Carolina, USA
    PLoS Med 5:e31. 2008
    ..4 strains is common in human populations. In this article, we analyze molecular mechanisms governing GII.4 epidemiology, susceptibility, and persistence in human populations...
  28. ncbi Multivalent norovirus vaccines induce strong mucosal and systemic blocking antibodies against multiple strains
    Anna D LoBue
    Department of Microbiology and Immunology, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599 7435, United States
    Vaccine 24:5220-34. 2006
    ..These data suggest that multivalent vaccination may provide better protection from a broader range of noroviruses than monovalent vaccination...
  29. pmc Cellular and humoral immunity following Snow Mountain virus challenge
    Lisa Lindesmith
    School of Public Health, University of North Carolina Chapel Hill, Chapel Hill, NC 27599, USA
    J Virol 79:2900-9. 2005
    ..To our knowledge, this is the first report characterizing T-cell and cytokine responses following live norovirus challenge...