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ARRA Investments in 2009 H1N1 INFLUENZA

Public Health Burden
In the spring of 2009, a novel A (H1N1) influenza—2009 H1N1 Influenza A—emerged to cause the first pandemic in 41 years. On June 11, 2009 the World Health Organization (WHO) declared a pandemic, phase 6 of the global pandemic description, signifying that the virus had been identified on multiple continents with person-to-person transmission. At that time, more than 70 countries had reported cases of the Influenza A (strain H1N1), including all 50 states in the United States, the District of Columbia, Puerto Rico, and the U.S. Virgin Islands. As of October 4, 2009, globally more than 375,000 laboratory-confirmed cases and over 5,400 deaths were reported to the WHO. Although the Centers for Disease Control and Prevention kept individual case counts when the H1N1 virus first emerged, as the outbreak came to be more widespread, maintaining accurate counts of cases became increasingly more difficult and not representative of the true extent of the outbreak. The full public health burden is unfolding, but it is clear that the H1N1 will continue to be responsible for considerable morbidity and mortality.

NIH Supported Research in Response to 2009 H1N1 Influenza
Over the past several years, NIH has supported a major research program related to seasonal influenza in order to improve our preparedness for pandemic influenza. Since the outbreak of 2009 H1N1 influenza, NIH has intensified the implementation of a robust research agenda that includes the basic scientific research and clinical trials needed to develop and test pandemic influenza vaccines and therapies. ARRA funds are contributing to NIH’s much larger 2009 H1N1 influenza research agenda through the support of some very specific studies that are discussed here.

Influenza Evolution
NIH supports basic research to understand better how influenza viruses replicate, interact with their hosts, stimulate and evade immune responses, and evolve into new strains. Because virus evolution interferes with long lasting, natural, or vaccine-induced immunity, new vaccines must be reformulated yearly or with the emergence of each new strain. Furthermore, our understanding of the molecular mechanisms underlying influenza evolution in animals and humans is also still poorly understood. ARRA funds are supporting research on the 2009 H1N1 influenza A virus to:
  • Enhance understanding of how the virus eludes the immunity of the infected animal and or person (host), using an in vivo guinea pig transmission model1.
Disease Severity Modeling, Pathogenesis, and Transmission
A better understanding of the underlying features of highly pathogenic influenza strains and the development of cross-protective vaccines are needed to respond to the emergence of highly-lethal influenza viruses. Although the 2009 H1N1 influenza virus has caused relatively mild influenza symptoms for most people, we do not know how it will change in the future. Furthermore, epidemiologic data suggests that younger people between the ages of 10 and 24 seem to be at higher risk for significant complications for this flu. Non-human primates (NHP) have proven to be a useful model for studying several influenza A viruses. Conventional human and weak avian influenza viruses can cause fairly mild respiratory disease in NHPs. In contrast, NHPs infected with highly pathogenic avian influenza viruses develop severe pneumonia and can succumb to infection. Currently, it is not known which genetic changes would convert conventional avian or mammalian influenza viruses into more lethal viruses. This could easily result in an outbreak with pandemic potential, such as with the 2009 H1N1 influenza. ARRA funds are being used to explore the underlying features of highly pathogenic influenza strains.
  • One large study aims to: develop animal models, especially NHP, that mimic human disease; identify and characterize determinants of disease progression in these animal models; and develop and test the efficacy of cross-protective vaccines in the animal models.2
  • Another study seeks to inform our understanding of how the 2009 H1N1 influenza virus and other seasonal influenza strains cause wide-spread, global disease. Researchers are assessing the pathogenicity of the 2009 pandemic influenza virus using both experimental in vivo models and in vitro systems. These studies will map the virulence factors encoded by the novel virus and compare it to previous pandemic viruses (e.g. 1918 and 1957 pandemics). 3
Pre-Clinical and Clinical Vaccine Research
There are currently two types of licensed vaccines for prevention of influenza in the United States: (1) inactivated (chemically killed) vaccines and (2) live attenuated (weakened) vaccines engineered to express the two viral surface proteins. ARRA funds are supporting pre-clinical and clinical vaccine studies focusing on the 2009 H1N1 virus.
  • One study seeks to generate and evaluate candidate live attenuated vaccines against a range of influenza A viruses that have pandemic potential. The vaccine will contain genes encoding the surface proteins, from the 2009 H1N1 pandemic influenza virus, combined with attenuating genes from a donor virus. The process to develop this vaccine will mirror that used for seasonal flu. A follow-up clinical study will be performed to assess the immunogenicity of this new live attenuated vaccine against the pandemic influenza virus.5
  • The goal of another study is to evaluate the natural history of pandemic influenza virus infection in comparison to infection with seasonal influenza viruses in both immunocompromised and non-immunocompromised patients.6 The results of these studies will improve our understanding of why different strains of influenza viruses cause different levels of disease in humans and lead to insights into new treatments.
Patient-oriented Clinical Research
Initiating clinical trials in hospitalized adult and pediatric patients with the 2009 H1N1 Influenza virus in an expeditious manner is critically important. ARRA funds are being used to establish and support integrated patient-oriented clinical research that will inform treatment of patients with sever influenza and further public health policy and preparedness. Two trials7 to be supported through this contract include:
  • Clinical trial involving a single parenteral (administered through the skin or a vein) agent in adults and children with severe influenza of which the data elements will include safety, pharmacokinetics, and virology.
  • A comparative 3-arm trial of hyperimmune plasma versus regular IgG infusion versus placebo in hospitalized patients with severe H1N1 influenza.

  1. 1Z01AI001104-01 -- ARRA: H1N1 Influenza Virus Evolution In Vivo -- Bennink, Jack (MD)
  2. 1Z01AI001088-01 -- ARRA: H1N1 Influenza Disease Modeling and Transmission -- Feldmann, Heinrich (MD)
  3. 1Z01AI001114-01 -- ARRA -- H1N1 Influenza Comparative Pathogenesis -- Taubenberger, Jeffery (MD)
  4. 1Z01AI001109-01 -- ARRA -- Preclinical Studies of Vaccines for Pandemic H1N1 Influenza -- Subbarao, Kanta (MD)
  5. 1Z01AI001110-01 -- ARRA -- Clinical Studies of Vaccines for Pandemic H1N1 Influenza --Subbarao, Kanta (MD)
  6. 1Z01AI001113-01 -- ARRA --H1N1 Influenza Clinical Research -- Taubenberger, Jeffery (MD)
  7. 272200900001I-0-27200001-1 -- ARRA Anti-Viral and Immune Plasma Infrastructure Development -- Social and Scientific Systems (MD)

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