Galveston National Laboratory-Emerging Diseases- Jim LeDuc PhD
The Galveston National Laboratory, a The Galveston National Laboratorynational 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
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
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.
Building Section Galveston National Laboratory BSL3 BSL2 BSL2 BSL2 ABSL3 IkeSurge BSL4
Services DivisionsServices available to researchers in biodefenseand emerging infectious diseases: Aerobiology Assay Development Experimental Pathology Imaging Immunology (currently inactive) Insectaries Services Preclinical Studies
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: ApprovalGNL Expanded Safety Phase III:UTMB Efficacy FDA Licensure
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
Cases of Avian influenza in PeopleYear Strain Country No. No. confirmed confirmed human cases human deaths1997 A/H5N1 Hong Kong 18 61999 A/H9N2* Hong Kong 2 02003 A/H5N1 Hong Kong 2 12003 A/H9N2* Hong Kong 1 02003 A/H7N3 Canada 2 02003 A/H7N7 Netherlands 84 12003- 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,
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
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
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)
Breaking the Chain in Bangladesh Science 4 March 2011: vol. 331 no. 6021 1128-1131
Pteropus Bats, suspect reservoir of Nipah virus
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
Rift Valley Fever HistoryKenya, Lake Naivasha 1910 MontgomeryKenya, Lake Naivasha 1930, 33 Daubney et alUganda, Semliki Forest 1948 Smithburn et alSouth Africa 1950-1 Alexander & Dickson 1953 1955-56South Africa 1975 Van Velden et alEgypt 1977 Meegan et alMauritania 1987 Digoutte et alEast Africa 1997-98 MMWRArabian Peninsula 2000 MMWR; Madani et alEast Africa 2006-07 MMWR, Bird et al, 2008Madagascar 2008- Andriamandimby et al,South Africa 2008- 2009 NIV Bulletin, 2010 2010 2009
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
Hospitalized cases of Rift Valley Fever by week, Saudi Arabia, August 27, 2000 – November 18, 2000 100 N=678 80 60Number ofRVF Cases 40 20 0 0 1 2 3 4 5 6 7 8 9 10 11 12 Week of Onset
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
Vector Competence North American mosquitoes following Oral infection (Gargan et al, 1988;Turell et al, 1988) Species Infection (%) Transmission (%)Cu. tarsalis 88 36Ae. canadensis 96 54Ae. taeniorrhyncus 85 42Ae. triseriatus 83 36Ae. albopictus 89 12
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
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
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
Global destitution of Ae. albopictusMap showing the native habitat (blue) and recent spread (green) of the Aedesalbopictus mosquito.Downloaded from http://afludiary.blogspot.com/2010/06/mmwr-travel-associated-dengue.html
Distribution of Ae. albopictus in the US.Ae. albopictus in USA as of 2001. Adapted form (Benedict et al., 2007)
Distribution of Ae. albopictus in Europe.Ae. albopictus in Europe per province, as of January 2007. Adapted form(Scholte and Schaffner, 2007)
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.
•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
• 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!
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)
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
The disease is a severe hemorrhagic fever withvery 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
Clinical Symptoms of Hospitalized Patients with Laboratory-Confirmed SFTS. Yu X et al. N Engl J Med 2011. DOI: 10.1056/NEJMoa1010095
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
Geographic Distribution of SFTS in China.Yu X et al. N Engl J Med 2011. DOI: 10.1056/NEJMoa1010095
Phylogenetic Analysis of SFTS Bunyavirus and Other Phleboviruses.Yu X et al. N Engl J Med 2011. DOI: 10.1056/NEJMoa1010095
The discovery of the severe fever with thrombocytopeniasyndrome 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
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.
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
Key ContactsDirector: 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/gnlDirector of Information Technology: Bryan FisherExternal Research Coordinator: Efthalia L. Bataki, Ph.D.