Table 1.

CEIRS network influenza response research framework

NIH roles and responsibilities for pandemic response a	Research questions applicable to the CEIRS network for an influenza response	Primary research activities for the CEIRS network that apply to the research questions
Goal 1: Provide technical and infrastructure resources to support USG and global efforts from international organizations to respond to the pandemic b
Prepare reference strains appropriate for vaccine manufacturing.	[Not applicable.]	Generate, amplify, and disseminate prototype virus stocks, including stocks of vaccine candidate viruses. (HP, RF) Generate panels of relevant virus clones. (MP, RF) Generate mouse‐adapted viral strains. (MP, RF) Clone gene segments into reverse genetics vectors and protein expression plasmids. (MP, RF) Create other key reagents (eg, monoclonal antibodies, assays, antisera, viral antigens, recombinant plasmids, proteins, and peptides). (HP, RF)
Goal 2: Provide scientific information to support the rapid development and use of medical countermeasures (eg, diagnostics, therapeutics, and vaccines) to mitigate the impact of an influenza pandemic a
Develop improved drugs against influenza.	Are investigational drugs safe and effective against the pandemic virus? Is the pandemic virus sensitive to existing antiviral agents? If the pandemic virus is sensitive to existing agents, is it likely to develop resistance to antiviral agents over time?	Conduct pre‐clinical evaluation of investigational drugs in animal models. (MP, RF) Determine antiviral susceptibility of pandemic strains to FDA‐approved and investigational drugs, using sequence and functional analyses. (HP, RF) Assess acquisition of antiviral resistance for pandemic strains over time. (MP, RF)
Evaluate the immune response to infection and vaccination	What is the innate immune response to the pandemic virus in animals and humans? What are the cell‐mediated and humoral immune responses to the pandemic virus in animals and humans? What is the baseline level of pre‐existing immunity to the pandemic virus in humans in different geographic areas and in different age groups? Do current influenza vaccines (including stockpiled vaccines) protect against infection with the pandemic virus? How does the immune response generated by the current seasonal vaccine relate to the pandemic strain? What are the immunologic responses to candidate vaccines in animals and humans?	Analyze innate and adaptive immune responses to the pandemic virus in animal models and in humans. (MP, RF) Assess baseline levels of pre‐existing immunity to the pandemic virus in humans using different markers. (HP, RF) Determine efficacy of current vaccines (including stockpiled vaccines) against the pandemic virus. (HP, NRF) Identify cross‐reactive antibodies and assess cross‐reactive immune responses to the pandemic virus. (MP, NRF) Determine the immunologic responses to candidate vaccines in animals and humans. (HP, RF [although somewhat time‐consuming])
Develop and clinically evaluate novel influenza vaccines and vaccination strategies (eg, adjuvants and delivery systems)	What are the growth and cytopathic effects of the pandemic virus in various cell lines and in eggs (for vaccine production)? What are the efficacies of candidate vaccines in pre‐clinical models? What are the safety, efficacy, and immunogenicity parameters of candidate vaccines in different human populations? What is the effect of prior exposure to seasonal viruses and seasonal vaccines on the efficacy of a pandemic vaccine?	Determine and improve the growth and cytopathic characteristics of the pandemic virus in cell lines and eggs. (HP, RF) Evaluate vaccine candidates. (HP, RF) Assess efficacy of candidate vaccines in pre‐clinical animal models. (HP, NRF) Assess immunogenicity, efficacy, and safety of candidate vaccines in different human populations. (MP, NRF) Determine the effect of prior exposure to seasonal viruses and seasonal vaccines on efficacy of pandemic candidate vaccines. (MP, NRF)
Develop sensitive, specific, and rapid diagnostic tests for influenza	What point‐of‐care diagnostic tests are the most sensitive and specific for rapid diagnosis of pandemic influenza?	Evaluate point‐of‐care diagnostic tests to enhance the use of antivirals. (MP, RF) Collect clinical specimens for future evaluation of diagnostic tests. (MP, RF)
Goal 3: Provide scientific information to aid in understanding the pandemic virus and assessing the potential severity of an influenza pandemic caused by the new virus a
Determine the molecular basis of virulence in humans and animals	What are the determinants of virulence for the pandemic virus? What is the pathogenicity of the pandemic virus in humans and animals? Does the pandemic virus have distinct phenotypic variants that are associated with virulence or pathogenicity? Are there virologic or host factors that predict disease severity? What are the changes in the pandemic virus over time, and do these changes affect disease severity?	Assess molecular signatures/markers that influence virulence of the pandemic virus. (HP, RF) Determine pathogenicity of the pandemic virus in animal species (eg, wild birds, poultry, ferrets, mice, macaques, swine, and guinea pigs). (HP, RF) Determine phenotype in primary cells and cell lines (eg, NHBE, HTBE, and MDCK cells). (HP, RF) Assess receptor binding specificity, cleavage, and membrane fusion properties of the pandemic virus. (HP, RF) Determine neuraminidase and polymerase activity of the pandemic virus. (HP, RF) Perform phenotypic characterization of the pandemic virus in various animal models. (HP, RF) Look for virologic and host factors that are markers or predictors of disease severity. (HP, NRF) Assess impact on virulence from mutations, reassortment with other avian influenza viruses, or changes in host tropism. (HP, NRF)
Support basic research, including structure/function studies of influenza virus proteins with the goal of identifying new therapeutic targets	What are the genetic characteristics of the pandemic virus? What are the antigenic characteristics of the pandemic virus?	Perform rapid genomic sequencing and full‐genotypic characterization of the pandemic virus. (HP, RF) Perform genotyping and phenotyping of variant viruses. (MP, RF) Perform antigenic cartography of pandemic strains. (MP, RF)
Goal 4: Provide scientific information to aid in understanding and limiting transmission of the pandemic virus a
Evaluate the molecular and/or environmental factors that influence the transmission of influenza viruses, including drug‐resistant strains	How transmissible is the pandemic virus in animal models? How well does the virus transmit to different animal hosts? How transmissible is the pandemic virus in humans? What are the features of the virus that make it transmissible between humans? What are the host determinants of transmission? What are the primary routes of transmission? What is the transmissibility of pandemic strains with drug‐resistant mutations? How effective would various intervention strategies be in controlling transmission?	Determine infectivity/transmissibility of the pandemic virus in different animal models, taking into consideration the limitations of extrapolating animal data to humans. (HP, RF) Determine transmission phenotypes of the virus and virus variants in animal models. (HP, RF) Determine viral tropism and replication in animal cell lines. (MP, RF) Determine viral tropism and replication in human nasal, tracheal, and lung epithelial cells. (MP, RF) Determine host factors involved in viral replication and release. (MP, NRF) Conduct epidemiologic studies to determine transmission dynamics in humans. (HP, NRF) Conduct modeling to determine transmission patterns in humans. (MP, RF) Determine transmissibility of antiviral‐resistant strains. (MP, NRF) Use computational modeling studies to predict the potential effectiveness of alternative control strategies (eg, school closures, other social distancing measures, and travel restrictions). (HP, NRF)
Study the evolution and emergence of influenza viruses, including the identification of factors that affect influenza host range and virulence	What is the likely origin (species, geographic location) of the virus? What is the relatedness of the pandemic virus to seasonal influenza viruses? What is the potential for reassortment of the pandemic virus with seasonal viruses? What are the rates of infection in various animal species? What are the rates of infection in various human populations in different geographic areas? Which human populations are at highest risk of increased morbidity and mortality? What are the predictions for global or regional disease spread based on epidemic models and simulations? What are the predictions for disease spread among high‐risk populations and healthcare providers based on epidemic models? Does the acquisition of antiviral resistance affect viral fitness?	Conduct phylogenetic analysis of the pandemic virus to elucidate virus origin and evolution. (MP, RF) Determine relatedness of the pandemic virus to current seasonal vaccine viruses. (HP, RF) Determine potential for reassortment of the pandemic virus with contemporary human seasonal viruses. (MP, NRF) Assess virus adaptation in various hosts. (MP, NRF) Conduct epidemiologic studies to determine disease burden in different populations, geographic spread, and disease severity. (HP, RF) Conduct computational modeling of the pandemic virus to determine emergence and spread over time and predict impact. (MP, RF)
Support virologic and serologic surveillance studies in animals of the distribution of influenza viruses with pandemic potential	What are the rates of infection in animal species of interest? What are the rates of infection in humans at the human‐animal interface? What is the viral ecology and environmental stability of the pandemic virus?	Conduct surveillance studies in animal populations of interest (eg, wild birds, poultry, and swine [domestic and wild]). (MP, RF) Conduct surveillance of animal‐to‐human and human‐to‐animal transmission. (HP, RF) Conduct environmental and ecological assessments of the pandemic virus. (MP, RF) Assess environmental stability of pandemic strains. (MP, RF)

Definitions:

HP: Highest priority; MP: medium priority.

HP: Provides critical scientific information or a critical service for the USG response to either an influenza pandemic or a pre‐pandemic situation and the information/service is urgently needed.

MP: Provides critical scientific information that will be useful for pandemic/pre‐pandemic response but the information is not urgently needed.

RF: Readily feasible; NRF: Not readily feasible or feasibility may not be clear.

RF: The activity can be completed in a timely fashion and will not require additional resources.

NRF: The activity will take longer, will require additional resources, or may not be feasible.

Abbreviations: FDA, US Food and Drug Administration; HTBE, human tracheobronchial epithelial cells; MDCK, Madin‐Darby canine kidney epithelial cells; NHBE, normal human bronchial epithelial cells.

^aAccording to the HHS Pandemic Influenza Plan (HHS 2005), the NIH directs these broad activities during an influenza pandemic. Some of these activities are central to the mission of the CEIRS network, while other activities are more peripheral to CEIRS, and CEIRS investigators may have a less substantial role (or a smaller supporting role) than other entities.

^bThese goals are specifically intended for response to an influenza pandemic, but are also applicable to emergence of a novel influenza strain with pandemic potential.