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Galveston National Laboratory-Emerging Diseases- Jim LeDuc PhD

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The Galveston
     National
  Laboratory, a               The Galveston National Laboratory
national resource
  for emergi...

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What are the next emerging virus
  diseases to threaten the USA?
• Objectives for today:
  – Review some of virus diseases...

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GNL Mission
• The mission of the GNL is to assist
  the NIAID and the nation by
  conducting basic and applied
  research ...

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H1 N1 Flu 2009 Newsletter
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Galveston National Laboratory-Emerging Diseases- Jim LeDuc PhD

  1. 1. The Galveston National Laboratory, a The Galveston National Laboratory national resource for emerging diseases and bioterrorism threats Dr. Jim LeDuc Director Presented at the 41st Annual Symposium ―Global Movement of Infectious Pathogens and Improved Laboratory Detection‖ Eastern PA Branch-American Society for Microbiology November 17, 2011 Thomas Jefferson University, Philadelphia
  2. 2. What are the next emerging virus diseases to threaten the USA? • Objectives for today: – Review some of virus diseases of concern as potentially ―emerging‖ – Introduce the Galveston National Laboratory as a new national resource to address emerging infectious diseases – Provide examples of what’s already underway at the GNL to address EIDs
  3. 3. GNL Mission • The mission of the GNL is to assist the NIAID and the nation by conducting basic and applied research designed to improve the prevention, diagnosis and treatment of naturally emerging and purposefully disseminated infectious diseases.
  4. 4. Building Section Galveston National Laboratory BSL3 BSL2 BSL2 BSL2 ABSL3 Ike Surge BSL4
  5. 5. © Hedrich Blessing Photography 2009
  6. 6. Services Divisions Services available to researchers in biodefense and emerging infectious diseases:  Aerobiology  Assay Development  Experimental Pathology  Imaging  Immunology (currently inactive)  Insectaries Services  Preclinical Studies
  7. 7. Basic Product Development Research NIH R01 and other Funded Proof of Concept Research Concept Validation Pre-clinical/ GLP Studies Human Animal Rule Clinical Trials Phase I: FDA Safety Restricted Use Phase II: Approval GNL Expanded Safety Phase III: UTMB Efficacy FDA Licensure
  8. 8. West Nile Virus in the United States 1999-2008
  9. 9. Influenza A Viruses • Human, Avian, Equine, & Swine Influenza viruses • Influenza A, B and C – B & C viruses infect humans only • A viruses – ordinary flu & all pandemics – Subtyped by surface glycoproteins; change = Antigenic Shift – 16 hemagglutinins (HA) and 9 neuraminidases (NA) – Current human subtypes: H1N1, H3N2 NA HA www.pandemicflu.gov www.cdc.gov/flu
  10. 10. Emergence of Influenza A Viruses in Humans 1998 1999 *Avian H9* 2003 Influenza Viruses H5* 1997 2003- 2011 H7* 1980 1996 2002 2003 2004 H1 H3 H2 H1 1977 1915 1925 1935 1945 1955 1965 1975 1985 1995 200 1918 1957 1968 Spanish Asian Hong Flu H1N1 Flu H2N2 Kong Flu H3N2 www.pandemicflu.gov www.cdc.gov/flu
  11. 11. Cases of Avian influenza in People Year Strain Country No. No. confirmed confirmed human cases human deaths 1997 A/H5N1 Hong Kong 18 6 1999 A/H9N2* Hong Kong 2 0 2003 A/H5N1 Hong Kong 2 1 2003 A/H9N2* Hong Kong 1 0 2003 A/H7N3 Canada 2 0 2003 A/H7N7 Netherlands 84 1 2003- A/H5N1* Viet Nam, 569 334 (59%) 2011 Cambodia*, China, (Nov11) *WHO Bangladesh*, Thailand vaccine in Azerbaijan, Djibouti, Egypt**, Indonesia**, prep. Iraq, Myanmar, Thailand, Turkey, www.pandemicflu.gov www.cdc.gov/flu Nigeria, Pakistan, CDC, WHO,
  12. 12. Host and lineage origins for the gene segments of the 2009 A(H1N1) virus: PB2, polymerase basic 2; PB1, polymerase basic 1; PA, polymerase acidic; HA, hemagglutinin; NP, nucleoprotein; NA, neuraminidase; M, matrix gene; NS, nonstructural gene R. J. Garten et al., Science 325, 197 -201 (2009) Published by AAAS www.pandemicflu.gov www.cdc.gov/flu
  13. 13. Influenza activities at the GNL • Evaluation of candidate broadly cross protective vaccines • Testing of antiviral compounds for treatment of avian influenza • High through-put screening of clinical samples during H1N1 outbreak • Reagent production for WHO
  14. 14. Nipah virus disease • First recognized in 1998 during outbreak in pigs in Malaysia • Annual outbreaks in humans in Bangladesh • High mortality rate; serious sequelae • Potential for person-to-person transmission (so far not efficient) • Animal reservoir host (fruit bats)
  15. 15. Breaking the Chain in Bangladesh Science 4 March 2011: vol. 331 no. 6021 1128-1131
  16. 16. Pteropus Bats, suspect reservoir of Nipah virus
  17. 17. Nipah site in Bangladesh
  18. 18. Nipah investigations at GNL • Development and validation of NHP model for Nipah infection • Evaluation of monoclonal antibodies for treatment of Nipah infection • Basic replication studies • Vaccine efficacy studies in NHP
  19. 19. Rift Valley Fever History Kenya, Lake Naivasha 1910 Montgomery Kenya, Lake Naivasha 1930, 33 Daubney et al Uganda, Semliki Forest 1948 Smithburn et al South Africa 1950-1 Alexander & Dickson 1953 1955-56 South Africa 1975 Van Velden et al Egypt 1977 Meegan et al Mauritania 1987 Digoutte et al East Africa 1997-98 MMWR Arabian Peninsula 2000 MMWR; Madani et al East Africa 2006-07 MMWR, Bird et al, 2008 Madagascar 2008- Andriamandimby et al, South Africa 2008- 2009 NIV Bulletin, 2010 2010 2009
  20. 20. RVF Epizootiology/Epidemiology • Primary vector maintenance – Pool breeding Aedes spp. maintain via transovarial transmission (putative) – Can maintain in a silent manner during extended dry periods • Secondary vector species – Large populations during periodic/cyclic rainy seasons – Initial amplification in vertebrate hosts – High viremia levels in many species of vertebrate hosts overcome poor vector potential of secondary vectors
  21. 21. RVF Egypt 1977-1978 Governorate Sheep Cattle Humans Sharqiya 52 36 15 Asyut 40 27 19 Qena 38 21 5 Qalubiya 37 15 6 Aswan 33 57 6 Giza 24 19 3 Fayum 13 0 3 Minya 9 5 4 Daqahliya 3 0.4 1 Baheira 2 1 1 Kafr el Sheikh 0 0 3 Minufyia 0 0.8 2 Beni Suef 0 0 1
  22. 22. Summary of data implicating various animals and humans as amplifying hosts or reservoirs of RVF virus (Meegan, 1981) Host Viremia Viremia (peak (length in titer/ml) days) Sheep 1010 2-5 Cattle 109 2-5 Human 108 3-10 Goat 108 2-5 Rattus sp. < 103 <2 Arvicanthus sp. < 103 <2 Acomys sp. < 103 <2 Mus sp. < 103 <2 D EC 2010
  23. 23. Effect of Rainfall on RVF Outbreaks
  24. 24. Saudi Arabia Index Case Week 1 Week 2 Week 3 Week 4 Week 5 Jizan 0 25 50 Yemen kilometers
  25. 25. Hospitalized cases of Rift Valley Fever by week, Saudi Arabia, August 27, 2000 – November 18, 2000 100 N=678 80 60 Number of RVF Cases 40 20 0 0 1 2 3 4 5 6 7 8 9 10 11 12 Week of Onset
  26. 26. Entomological Investigations • Two major species identified –Aedes vexans arabiensis –Culex tritaeniorrhyncus • Virus isolates from both species • Transmission from both species • Some biting preference data –Human biting preference relatively high
  27. 27. Epidemic Curve (MMWR)
  28. 28. Adjoining Countries (WHO)
  29. 29. Vector Competence North American mosquitoes following Oral infection (Gargan et al, 1988;Turell et al, 1988) Species Infection (%) Transmission (%) Cu. tarsalis 88 36 Ae. canadensis 96 54 Ae. taeniorrhyncus 85 42 Ae. triseriatus 83 36 Ae. albopictus 89 12
  30. 30. Vaccines • Veterinary Vaccines – Smithburn neurotropic strain (SNS) – Killed products using formalin inactivated cell culture antigens – New generation: • MP12 • Strain 13 • Reverse genetics: NSS and NSM deletions • Human Vaccines (IND only) – Killed cell culture product (formalin)—USAMRIID –MP12—attenuated (mutagen passage) live product--USAMRIID
  31. 31. RVF studies at GNL • Advanced development of MP12 live, attenuated vaccine for RVF virus – Pilot lot production with commercial partner – Animal model development and standardization – Vaccine efficacy testing in animal models • Basic studies on viral replication and host cell targeting
  32. 32. Chikungunya Virus
  33. 33. 2007 2005 2008 before 1950`s 2004 2007 2007 2008 2005 Countries endemic for ECSA genotype Countries endemic for Asian genotype Countries endemic for WA genotype 2005 Regions invaded by CHIKV strains of IOL during 2004-2008 2006 Reconstructed movement of CHIKV during 2004-2008 outbreaks Introduction of progenitor of Asian Genotype before 1950`s
  34. 34. E1-226A E1-226V IOL E1-98A E1-98T ECSA Asian WA
  35. 35. Global destitution of Ae. albopictus Map showing the native habitat (blue) and recent spread (green) of the Aedes albopictus mosquito. Downloaded from http://afludiary.blogspot.com/2010/06/mmwr-travel-associated- dengue.html
  36. 36. Distribution of Ae. albopictus in the US. Ae. albopictus in USA as of 2001. Adapted form (Benedict et al., 2007)
  37. 37. Distribution of Ae. albopictus in Europe. Ae. albopictus in Europe per province, as of January 2007. Adapted form (Scholte and Schaffner, 2007)
  38. 38. CHIK in Yemen? Health Ministry warns of fatal illness spreading from Yemen Sunday, 20 March 2011 14:52 JEDDAH/SANAA: Many people who live on the Saudi-Yemen border fear that a fatal disease that has been responsible for dozens of deaths in Yemen’s western coastal area could cross into the Kingdom. At least 65 deaths were reported in Yemen’s western coastal province of Hodeidah. The disease is thought to be Chikungunya, though some medical officers dispute it. Symptoms of chikungunya include kidney failure, high temperature, diarrhea and vomiting. Dr. Abdul Hakim Al-Khohlaini, manager of the epidemiological surveillance department at the Yemeni Ministry of Health, said that samples sent to Cairo for tests showed that the disease is chikungunya. He added that local doctors have also found other diseases in the area. “Forty-five percent of the cases are Chikungunya, 10 percent malaria and the rest dengue fever,” he said.
  39. 39. •Tick-borne zoonosis; discovered 1944 in Crimean peninsula, isolated from over 30 countries •Causative agent Crimean-Congo hemorrhagic fever virus (CCHFV) •Hard ticks of the genus Hyalomma are the main vector •Severe hemorrhagic syndrome in humans; up to 70% mortality •ssRNA- , Bunyaviridae, Nairovirus (7 species, 34 strains) •Genome analysis indicated considerable evolution and high diversity of CCHFV strains (array of genotypes) •Different genotypes might cause different severities of disease •Experimental work with CCHFV requires a BSL-4 laboratory. •No vaccine, Ribavirin treatment uncertain efficiency •Outbreaks are usually sporadic with only a few cases but recent bigger outbreaks in Balkan and Southwest Asia demonstrated imminent public health threat
  40. 40. • Outbreaks are usually sporadic with only a few cases but recent bigger outbreaks in Balkan and Southwest Asia demonstrated imminent public health threat. • CCHFV first detected in Turkey in 2002; since then >4000 cases. • More here to come!
  41. 41. 1. To study the virulence of different CCHFV strains currently circulating in the Balkan, Caucasus and Turkey in in vitro an in vivo models. 2. To establish a tick in vivo feeding assay in which the host-tick-interface can be studied. 3. Use the in vitro feeding assay to study  the vector capacity of and North American tick species to CCHFV transmission  If viral attenuation is correlated with tick vector switch (Hyalomma spp. vs Rhipicephalus bursa)
  42. 42. Novel Bunyavirus in China  Designated SFTS virus (Severe Fever with Thrombocytopenia Syndrome)  First isolated from acutely ill patient  Found in rural areas of Hubei and Henan provinces; 96% of cases between May-July  Ages 39-83 y.o., 56% female, 97% working farmers  30% case fatality rate initially; 12% (21/171 confirmed cases) on further investigation  Genus Phlebovirus, perhaps new subgroup  35 RT-PCR confirmed cases all seroconverted  Suspect Tick transmission
  43. 43. Galveston National Laboratory
  44. 44. The disease is a severe hemorrhagic fever with very high fatality Clinical signs and symptoms • Fever • Leukopenia (low white blood cells) • Thrombocytopenia (low platelet count) • Gastrointestinal disorders (vomiting and diarrhea) • Hemorrhaging • Multiple organ failure • Death (on average 12% fatality rate and as high 30% in some areas) Galveston National Laboratory
  45. 45. Clinical Symptoms of Hospitalized Patients with Laboratory-Confirmed SFTS. Yu X et al. N Engl J Med 2011. DOI: 10.1056/NEJMoa1010095
  46. 46. The environment of a recovered patient is infested with ticks A farmer and his house The famer cultivated mushrooms Auricularia (Auricularia auricula) outside his house auricula The yard of the farmer Collecting ticks from a dog by the Collecting ticks from a dog by the house owner owner Galveston National Laboratory
  47. 47. Geographic Distribution of SFTS in China. Yu X et al. N Engl J Med 2011. DOI: 10.1056/NEJMoa1010095
  48. 48. Phylogenetic Analysis of SFTS Bunyavirus and Other Phleboviruses. Yu X et al. N Engl J Med 2011. DOI: 10.1056/NEJMoa1010095
  49. 49. The discovery of the severe fever with thrombocytopenia syndrome virus Xue-jie Yu, M.D., Ph.D. Patricia V. Aguilar, Ph.D. Professor Assistant Professor Department of Pathology Department of Pathology Center for Biodefence and Emerging Infectious Diseases Center for Biodefense and Emerging Infectious Diseases Sealy Center for Vaccine Development Institute for Human Infectious and Immunity Galveston National Laboratory
  50. 50. And Finally….A new Flavivirus from China ―Duck Egg-Drop Syndrome Caused by BYD virus, a New Tembusu-related Flavivirus‖ by J. Su et al. PLoS One, March 2011. • Infection completely eliminated duck reproduction on some farms; duck mortality 5-15%; • Baiyangdian (BYD) virus isolated from brain and ovary of affected ducks • Shown to be a flavivirus closely related to Tembusu and Sitiawan & Bagaza viruses, some known to cause disease in humans and animals.
  51. 51. In Conclusion • There’s no shortage of emerging virus diseases • Many are zoonoses, often vector-borne • Expanding sequence databases and improved techniques allow rapid recognition and characterization of new viruses • The GNL is available as a national resource to assist in basic and translational research on emerging viruses • www.UTMB.edu/gnl
  52. 52. Key Contacts Director: James W. LeDuc, Ph.D. Scientific Director: Scott C. Weaver, Ph.D. Associate Director for Research & Operations: Joan Nichols, Ph.D. Assistant Director: Andrew G. McNees, Ph.D. Director of Containment Operations: Thomas G. Ksiazek, D.V.M., Ph.D. Director of Strategic Initiatives: Galveston National Lab • Main: 409-266-6500 Alisha Prather www.utmb.edu/gnl Director of Information Technology: Bryan Fisher External Research Coordinator: Efthalia L. Bataki, Ph.D.

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