V-920. Triple Combination Therapy is Highly Effective for Influenza A Infection
Session: Slide Session: Influenza
Sunday, October 26, 2008: 12:00 AM
Room: Room 202B
Background: Influenza A viruses are associated with mortality and morbidity in seasonal epidemics and pandemics. The biggest obstacles in the fight against influenza are poor efficacy and resistance. To date, only double combinations have been tested against influenza, and with variable success. We report in vitro and in vivo data of a triple combination of antivirals against influenza A, showing that the triple combination is synergistic and effective at reducing viral load and preventing resistance. Methods: Triple combinations composed of amantadine, ribavirin, and a neuraminidase inhibitor (zanamivir or oseltamivir) were tested against influenza A viruses from different subtypes in MDCK cells. The drugs were tested as single agents, and in double and triple combinations. For mouse challenge models, Balb/C mice were infected with a LD100 dose of influenza A. Infected animals were treated with each drug as a single agent or the triple combination at various times pre- and post-infection. Results: Triple combination therapy was highly synergistic, reducing the EC50 of the drugs by 10 to 100 fold compared to monotherapy. The synergy was seen against multiple influenza A subtypes. Furthermore, efficacy of the triple combination was superior to the double combinations and monotherapy. In an in vitro kinetic model of influenza infection, the triple combination was effective at reducing viral load and preventing the emergence of resistance. In mouse challenge models, the triple combination was superior to monotherapy in protection against mortality and weight loss in both prophylaxis and delayed treatment models. Conclusions: Our data provide evidence to support the development of triple combinations against influenza A infection. We have shown that the triple combination has a great advantage over double combinations and monotherapies in terms of efficacy and preventing resistance.
David Engelthaler, MS1, Donald Smee2, Elizabeth Driebe, MS3, Gregory Went, PhD4, Jack Nguyen, PhD5, Justin Hoopes, PhD2, Min-Hui Wong2, Paul Keim, PhD1 and  J. T. Nguyen,
Adamas Pharmaceuticals Role(s): Employee, Received: Salary., (1)The Translational Genomics Research Institute, (2)Utah State University, (3)Translational Genomics Research Institute, Flagstaff, AZ, (4)Adamas Pharmaceuticals, (5)Adamas Pharmaceuticals, Emeryville, CA

David M. Engelthaler is currently the Director of Programs and Operations at TGen North, a part of the Pathogen Genomics Division of TGen, the Translational Genomics Research Institute. TGen North is focused on advancing public health, clinical medicine and Biodefense through targeted microbial genomics. David oversaw the development of the TGen North Facility, established the TGen North strategic plan, directly coordinates the hiring of the technical staff, successfully brought in research grants and contracts, and oversees the research projects.
Under David’s leadership at TGen North, the research teams have developed several new surveillance diagnostic assays for infectious diseases and molecular analytical tools that can be translated to the public health, hospital, military and intelligence sectors. TGen North focuses on a variety of bacterial, fungal and viral pathogens, ranging from influenza to MRSA to Valley Fever.
David has fifteen years experience in public health and biodefense related research, including ten years with the Arizona Department of Health Services and three years with the Centers for Disease Control and Prevention. David was recently the Arizona State Epidemiologist and the Biodefense and Emergency Response Coordinator for the Arizona Department of Health Services.
• As the State Epidemiologist (2004-2006) he was responsible for coordinating disease outbreak investigation and response activities for the State of Arizona. Such outbreaks included West Nile, measles, salmonella and other food-borne, hospital outbreaks (MRSA, Acinetobacter, etc), rabies, plague, and reported cancer clusters. He acted as the lead public health scientist for the state providing briefings and consult to the state agency directors and the governor. He was also the spokesperson for the Arizona Department of Health Services during this time, providing media interviews and press conferences for local, state, and national media.
• As the State Biodefense Coordinator (2000-2004), David was responsible for developing and implementing a statewide system for training, response planning, exercises and drills and communication infrastructure for responding to and recovering from biological terrorism. He was also the lead health response official for suspect biothreat incidents in Arizona.
• As the Emergency Response Coordinator for the Arizona Department of Health Services (2000-2005), David was responsible for developing an emergency management system for the agency and acting as the lead health response official for several emergencies, including fires, vaccine shortages, and evacuees from Katrina.
• At the Centers for Disease Control and Prevention (1997-2000), David was a research biologist developing diagnostic and analytical tools to study diseases such as plague and tularemia.
He has briefed the Arizona legislature and has testified before Congress. He has worked closely with numerous state and federal agencies to help solve a variety of health and safety related problems.
David has published numerous papers in leading scientific journals related to epidemiology, disease ecology, genetics, and microbiology. He has a Master's Degree in Microbiology from Colorado State University, where he studied vector-pathogen-host dynamics associated with plague.

David M. Engelthaler is currently the Director of Programs and Operations at TGen North, a part of the Pathogen Genomics Division of TGen, the Translational Genomics Research Institute. TGen North is focused on advancing public health, clinical medicine and Biodefense through targeted microbial genomics. David oversaw the development of the TGen North Facility, established the TGen North strategic plan, directly coordinates the hiring of the technical staff, successfully brought in research grants and contracts, and oversees the research projects.
Under David’s leadership at TGen North, the research teams have developed several new surveillance diagnostic assays for infectious diseases and molecular analytical tools that can be translated to the public health, hospital, military and intelligence sectors. TGen North focuses on a variety of bacterial, fungal and viral pathogens, ranging from influenza to MRSA to Valley Fever.
David has fifteen years experience in public health and biodefense related research, including ten years with the Arizona Department of Health Services and three years with the Centers for Disease Control and Prevention. David was recently the Arizona State Epidemiologist and the Biodefense and Emergency Response Coordinator for the Arizona Department of Health Services.
• As the State Epidemiologist (2004-2006) he was responsible for coordinating disease outbreak investigation and response activities for the State of Arizona. Such outbreaks included West Nile, measles, salmonella and other food-borne, hospital outbreaks (MRSA, Acinetobacter, etc), rabies, plague, and reported cancer clusters. He acted as the lead public health scientist for the state providing briefings and consult to the state agency directors and the governor. He was also the spokesperson for the Arizona Department of Health Services during this time, providing media interviews and press conferences for local, state, and national media.
• As the State Biodefense Coordinator (2000-2004), David was responsible for developing and implementing a statewide system for training, response planning, exercises and drills and communication infrastructure for responding to and recovering from biological terrorism. He was also the lead health response official for suspect biothreat incidents in Arizona.
• As the Emergency Response Coordinator for the Arizona Department of Health Services (2000-2005), David was responsible for developing an emergency management system for the agency and acting as the lead health response official for several emergencies, including fires, vaccine shortages, and evacuees from Katrina.
• At the Centers for Disease Control and Prevention (1997-2000), David was a research biologist developing diagnostic and analytical tools to study diseases such as plague and tularemia.
He has briefed the Arizona legislature and has testified before Congress. He has worked closely with numerous state and federal agencies to help solve a variety of health and safety related problems.
David has published numerous papers in leading scientific journals related to epidemiology, disease ecology, genetics, and microbiology. He has a Master's Degree in Microbiology from Colorado State University, where he studied vector-pathogen-host dynamics associated with plague.

David M. Engelthaler is currently the Director of Programs and Operations at TGen North, a part of the Pathogen Genomics Division of TGen, the Translational Genomics Research Institute. TGen North is focused on advancing public health, clinical medicine and Biodefense through targeted microbial genomics. David oversaw the development of the TGen North Facility, established the TGen North strategic plan, directly coordinates the hiring of the technical staff, successfully brought in research grants and contracts, and oversees the research projects.
Under David’s leadership at TGen North, the research teams have developed several new surveillance diagnostic assays for infectious diseases and molecular analytical tools that can be translated to the public health, hospital, military and intelligence sectors. TGen North focuses on a variety of bacterial, fungal and viral pathogens, ranging from influenza to MRSA to Valley Fever.
David has fifteen years experience in public health and biodefense related research, including ten years with the Arizona Department of Health Services and three years with the Centers for Disease Control and Prevention. David was recently the Arizona State Epidemiologist and the Biodefense and Emergency Response Coordinator for the Arizona Department of Health Services.
• As the State Epidemiologist (2004-2006) he was responsible for coordinating disease outbreak investigation and response activities for the State of Arizona. Such outbreaks included West Nile, measles, salmonella and other food-borne, hospital outbreaks (MRSA, Acinetobacter, etc), rabies, plague, and reported cancer clusters. He acted as the lead public health scientist for the state providing briefings and consult to the state agency directors and the governor. He was also the spokesperson for the Arizona Department of Health Services during this time, providing media interviews and press conferences for local, state, and national media.
• As the State Biodefense Coordinator (2000-2004), David was responsible for developing and implementing a statewide system for training, response planning, exercises and drills and communication infrastructure for responding to and recovering from biological terrorism. He was also the lead health response official for suspect biothreat incidents in Arizona.
• As the Emergency Response Coordinator for the Arizona Department of Health Services (2000-2005), David was responsible for developing an emergency management system for the agency and acting as the lead health response official for several emergencies, including fires, vaccine shortages, and evacuees from Katrina.
• At the Centers for Disease Control and Prevention (1997-2000), David was a research biologist developing diagnostic and analytical tools to study diseases such as plague and tularemia.
He has briefed the Arizona legislature and has testified before Congress. He has worked closely with numerous state and federal agencies to help solve a variety of health and safety related problems.
David has published numerous papers in leading scientific journals related to epidemiology, disease ecology, genetics, and microbiology. He has a Master's Degree in Microbiology from Colorado State University, where he studied vector-pathogen-host dynamics associated with plague.



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