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HHS Pandemic Influenza Plan

 

Home: HHS Pandemic Influenza Plan

Visit PandemicFlu.gov for one-stop access to U.S. Government avian and pandemic flu information. HHS is responsible for Pandemic Influenza Planning, outlined below.

PandemicFlu.gov

Table of Contents

I. Introduction

II. U.S. pandemic influenza: Research activities and needs

A. Basic virology and molecular biology
B. Animal surveillance
C. Human surveillance and epidemiology
D. Immune response parameters
E. Diagnostic development
F. Antiviral drug development
G. Vaccine development
H. Research resources and training
I. Research priorities during a pandemic
J. Research priorities after a pandemic

I.  INTRODUCTION

Influenza is not a disease that can be eradicated. Wild birds and domestic animals harbor influenza A viruses, which have the potential for direct transmission to man and for genetic recombination with human influenza A strains. As a result, animal reservoirs present opportunities for the emergence of influenza A viruses that are antigenically novel to the human immune system. The emergence of such a virus that develops the ability for person-to-person transmission could lead to an influenza pandemic. Although exactly when and where the next influenza pandemic will occur is unknown, it is possible that the outcome will vary from serious to catastrophic. Expanding research on influenza before the next pandemic occurs will promote a better understanding of influenza and will lead to new strategies and products that could improve the effectiveness of a pandemic response and prevent disease and death.

Research on influenza is conducted by several HHS and other U.S. government agencies such as the Department of Defense, Department of Veteran’s Affairs, and the Department of Agriculture. The largest proportion of influenza research is supported by the National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), primarily through investigator-initiated grants and contracts. These agreements support both basic and applied research on influenza virus biology, epidemiology, pathogenesis, and immunology, as well as the development of new and improved influenza diagnostics, antiviral drugs, and vaccines. Other influenza research is supported through the intramural program at NIH, including the Laboratory of Infectious Diseases (LID), which also has a strong focus in new vaccine development.

The Centers for Disease Control and Prevention (CDC), through the National Center for Infectious Diseases and the National Immunization Program, supports a broad intramural and collaborative influenza research portfolio including studies on influenza epidemiology, immunology, vaccines, and vaccination programs.

The Food and Drug Administration's (FDA) Center for Biologics Evaluation and Research (CBER) and Center for Drug Evaluation and Research (CDER), conduct and/or advise on research on influenza vaccines and antivirals, respectively.

The Agency for Healthcare Research and Quality (AHRQ) supports research on surge capacity, the use of information systems for bed-tracking and syndromic surveillance in emergency departments, and primary care.

In April 2005, the Institute of Medicine (IOM) convened The John R LaMontagne Memorial Symposium on Pandemic Influenza Research to address the current state of the research and outline future priorities of scientific research for pandemic influenza. HHS will consider these recommendations, as well as other outside expert opinion, as the basis for scientific research in influenza in the near future. The combined efforts of HHS agencies including NIH, CDC, and FDA, as well as the private sector, will be needed to develop and implement this research agenda.

Research has provided the underpinning of many of the tools HHS currently has to combat influenza and will be the basis of those that are developed in the future. This document will summarize critical HHS influenza research activities. As much of the research on influenza A is applicable to both interpandemic (H3N2 & H1N1) and pandemic influenza, this document will cover both.

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A. Critical basic research foundation
Basic research on influenza facilitates new ways of detecting and rapidly characterizing these viruses as they emerge. Most Federal funds currently available for influenza research are provided through NIH in the form of grant support for scientists to study fundamental issues related to basic biology, virology, immunology, pathogenesis, and the development of new diagnostics, antiviral agents, and vaccines. In addition, NIAID supports centralized research resources such as contracts to screen new drugs, develop new animal models, and establish a reagent repository. These resources are available to research scientists around the world and contribute to pandemic preparedness.

Basic research on the virus and its structure, the factors that contribute to its virulence, and its ability to evade the immune system, and an understanding of the genetic changes that permit an influenza virus to suddenly acquire the ability to transmit between species, provide important information for fighting pandemic influenza. The development of new systems for manipulating influenza genes to create strains (referred to as “reverse genetics”) provides researchers with the opportunity to systematically uncover the function and interactions of each gene in the influenza virus genome. The application of this technology has already begun to expand understanding of virus-host range restriction, viral replication, and pathogenicity in order to speed the production of inactivated and live-viral vaccine candidates.

An increasing number of materials and reagents are being made available through the NIAID Influenza Reference Repository, the CDC WHO Collaborating Center, and FDA/CBER, including antibodies and reference antigens to a number of avian influenza viruses considered to be of high pandemic potential. Updating the reagents in this library and making them available to research scientists around the world remains an area of high priority.

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B. The transition to applied research
The plasticity of the influenza genome facilitates the virus’s adaptability and its ability to escape the specific host immune responses, leading to the need for annual vaccination with updated vaccine. Through NIH and private sector-supported applied research programs, new vaccine candidates are being developed and clinically tested. One successful public-private partnership has been the government’s long-standing involvement in the development of the live-attenuated influenza virus vaccine, which was licensed by the FDA in 2003.

Efforts are also underway to enhance the immunogenicity of inactivated influenza vaccines (especially for very young and very old individuals) by administering them using new delivery systems, providing them in higher doses, or by combining them with adjuvants or supplemental proteins. Vaccines that contain common protein epitopes from influenza viruses may provide generic protection against a wide range of influenza viruses and are being aggressively pursued. While the exact subtype of influenza virus that will cause the next pandemic is not known, producing prototypic vaccine reference strains that can be used in developing vaccine candidates is essential for preparedness and is being supported by the CDC, FDA, the NIH, and other international laboratories. Production and clinical testing of investigational lots of vaccines made with these reference strains should be supported as they become available.

In addition to vaccine-related research, the NIH supports several programs on the development of new antiviral agents against influenza. These programs range from target identification to the support of clinical trials. In vivo and in vitro screening programs to identify promising drug candidates provided by private sector companies and academic laboratories are also ongoing.

The NIAID Biodefense Partnership and Challenge Grant Programs provide support to private sector companies to develop new vaccines against influenza, including non-egg based vaccine platforms, new antiviral drugs against influenza, and genomics-based diagnostic assays against a number of acute respiratory viruses, including influenza.

Applied research also leads to the development of tools and to refinement of strategies that are critical to effective surveillance and pandemic response programs. Improved influenza rapid diagnostic tests, development of more sensitive and rapid laboratory assays for detecting and subtyping influenza viruses, and new high capacity methods to test influenza virus strains for susceptibility to antiviral drugs—and their implementation at CDC, public health, and hospital laboratories—all are key to identifying and tracking disease before and during a pandemic, and to providing public health and health care providers the information needed to make optimal decisions.

Another component of applied research relates to the AHRQ support for research on health system preparedness. This work has focused on the use of real-time information systems to track hospital bed capacity, including emergency department and ventilator beds. In addition, a mass prophylaxis and vaccination program is currently part of the Cities’ Readiness Initiative and the Strategic National Stockpile training activities.

In addition, epidemiological, programmatic, and behavioral research results lead to new understanding of influenza infections including their consequences and who is at risk, strategies to improve vaccination delivery and help eliminate racial and ethnic disparities, and effective communications messages and tools that will be vital to a pandemic response.

This appendix identifies ongoing HHS research activities for influenza, as well as highlights future research priorities that will allow the U.S. to prepare, respond, and reduce the overall morbidity and mortality associated with pandemic influenza.

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II. U.S. PANDEMIC INFLUENZA: RESEARCH ACTIVITIES AND NEEDS

A. Basic virology and molecular biology
Influenza viruses, members of the family Orthomyxoviridae, are classified into three types: A, B, and C, with influenza A causing the most severe disease in humans and the most likely to trigger a pandemic. While a number of structural proteins have been identified in influenza A viruses, the two surface proteins, the hemagglutinin (HA) and neuraminidase (NA), play key roles in the pathogenesis of the virus and the host’s immune response. Although only two influenza A subtypes currently co-circulate globally in humans (H1N1 and H3N2), at least 16 distinct antigenic subtypes of HAs (H1 to H16) and nine NAs (N1 to N9) have been identified in wild aquatic birds. In spite of the severity of influenza disease, little is known about the role of the viral proteins in the virus’ pathogenicity or transmission.

Goals:

Ongoing HHS activities:

Future priorities:

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B. Animal surveillance
Animal surveillance of influenza is important for several reasons. Previous epidemics of human infection with influenza in 1957 and 1968 were preceded by circulation of these viruses in animals. This was likely true in 1918 also, though the specific source is not clear. In addition, outbreaks in animals can be associated with considerable economic costs due to culling of infected animals and reduction in trade.

Recent outbreaks in domestic poultry in Asia associated with cases of human disease highlight the importance of coordinating surveillance activities. Surveillance for influenza A viruses in poultry in the U.S. has increased since the outbreak of highly pathogenic avian influenza (HPAI) in Pennsylvania and surrounding states in 1983 and 1984. Investigations may be conducted by state animal health officials, USDA-accredited veterinarians, university personnel, or members of the poultry industry. Samples from affected flocks are routinely submitted to state laboratories for diagnosis. If importation of HPAI is suspected, a Foreign Animal Disease Diagnostician will conduct an investigation and submit samples directly to the National Veterinary Services Laboratories (NVSL) in Ames, Iowa.

Most birds submitted for entry into the United States must be quarantined in USDA-approved quarantine facilities. During quarantine, avian influenza virus isolation is attempted on samples collected from all dead birds and some live birds.

Surveillance in the U.S. for influenza A viruses in swine and horses is currently less systematic than in poultry. While no requirement exists for USDA notification when cases or outbreaks of influenza occur in these animals, considerable interest exists in understanding the viruses that are circulating among them. In general, only outbreaks in swine of unusual severity or duration are likely to be investigated and reported. On the other hand, surveillance for influenza viruses causing disease in horses has practical utility because data generated from analysis of equine influenza viruses can be used to guide equine influenza vaccine formulation.

Goal:

Ongoing HHS activities:

In addition to the HHS activities, other agencies are also conducting animal research.

Future priorities:

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C. Human surveillance and epidemiology
The information regarding circulating influenza strains is used to monitor global influenza activity and to update the formulation of annual influenza vaccines. It is also used to detect novel influenza strains (i.e., influenza A subtypes that have not recently circulated among people) that infect humans, leading to the implementation of control measures and providing early warning of a possible pandemic.

CDC conducts and coordinates influenza surveillance in the United States. Surveillance focuses on collecting influenza viral isolates for testing, monitoring morbidity and mortality, and identifying unusual or severe influenza outbreaks (see Part 2, Supplement 1). The U.S. national influenza surveillance system includes: laboratory surveillance, outpatient influenza-like illness (ILI) surveillance, pneumonia and influenza (P&I) related mortality surveillance, and an assessment of influenza activity at the state level. Traditionally, U.S. influenza surveillance has been conducted from October through mid-May, but is now being conducted year-round. Year-round influenza surveillance provides information on the baseline level of influenza activity during the summer, and these data have the potential to become an important component of early detection for a pandemic.

Goals:

Ongoing HHS activities:

In addition, the World Health Organization (WHO) supports an international laboratory-based surveillance network for influenza to detect the emergence and spread of new antigenic variants of influenza.

Future priorities:

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D. Immune response parameters
Historical experience with influenza vaccines suggests that two doses of inactivated vaccine will be needed to induce adequate levels of immunity to a pandemic strain of influenza. Enhancing the immunogenicity of a pandemic vaccine so that a one dose course could be used could ultimately reduce the time and cost required to protect the population. This may require inclusion of an adjuvant—a substance included in vaccines to increase the strength of the immune response—in the formulation of a pandemic vaccine. Further investigation needs to be done to understand whether adjuvants will be useful in a pandemic situation.

Goals:

Ongoing HHS activities:

Future priorities:

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E. Diagnostic tools development
Early detection of new influenza outbreaks is critical to limit the spread of infection and control its impact on human health. The influenza diagnostic tests that are currently available have limited sensitivity and specificity and are not able to discriminate between viral subtypes. Novel diagnostic tools are needed in the detection of newly emerging influenza strains and to discriminate between different influenza subtypes.

The ability to test new diagnostic technologies in public health laboratory settings is also being enhanced through the distribution of standardized protocols for lab methods by introducing new techniques, such as multiplex PCR, and by expanding the role for use of molecular techniques to rapidly diagnose respiratory agents, including influenza types and subtypes.

Goal:

Ongoing HHS activities:

Future priorities:

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F. Antiviral drug development
In the event of a pandemic, antiviral drugs will be the first line of defense before a vaccine is available and could delay the spread of the pandemic, particularly if the strain is not efficiently transmitted between humans. There are currently two classes of antiviral drugs against influenza: the neuraminidase inhibitors and the M2-ion channel blockers known as adamantanes. Studies have shown that neuraminidase inhibitors, in addition to being active against influenza A and B, may reduce complications of influenza in some individuals. H5N1 viruses isolated from poultry and humans in Asia in 2004 are known to be resistant to the adamantanes. The development of new anti-influenza drugs with broad activity and diminished risks of resistance emergence is of great importance.

Goals:

Ongoing HHS activities:

Future priorities:

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G. Vaccine development
When the next influenza pandemic emerges, it will likely be caused by a type of influenza virus to which humans have little to no previous exposure. Vaccination offers one of the most effective measures for minimizing the morbidity and mortality of influenza. Inactivated influenza vaccines were developed more than 50 years ago, and since that time, annual vaccination with the inactivated vaccine has been the primary method by which the disease burden of influenza has been reduced. While influenza vaccines work well in the majority of people, they often do not work as well in the very young, the very old, or in patients with a compromised immune system. A live, attenuated vaccine against influenza was licensed in 2003 for use in individuals 5 to 49 years of age. During a pandemic with a novel influenza virus, public health officials will be confronted with making critical decisions about the vaccine dosage level and immunization regimen for various populations.

Vaccines produced in the event of the emergence and spread of a new pandemic influenza strain must be safe, able to be produced in large quantities and delivered quickly, and protect the largest number of individuals possible. Currently available influenza vaccines are produced by growing influenza viruses in embryonated chicken eggs, and take from 6 to 9 months to prepare. The rapid production and clinical evaluation of investigational lots of pandemic vaccines is an urgent global public health priority.

Goals:

Ongoing HHS activities:

Future priorities:

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H. Research resources and training
Supporting the availability of research resources is essential to facilitate advances in basic and translational research on influenza. These resources include providing research reagents and access to genomic and immunologic databases, animal models for preclinical drug and vaccine development, and biocontainment laboratories.

Goals:

Ongoing HHS activities:

Future priorities:

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I. Research priorities during a pandemic
In the face of novel infections including novel influenza viruses, the optimal treatment and public health management is not clear. In the absence of clinical trials evaluating a pandemic strain, anecdotal experience is often extrapolated to mandates on standards of care, even if the intervention has no proven utility and may be harmful. Performing clinical research during a pandemic offers a unique opportunity for gaining critical information about novel influenza infections. The information gained may help minimize the impact of future epidemics.

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Future priorities:

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J. Research priorities after a pandemic
Since influenza is a global infection affecting multiple species, it is unlikely that influenza can ever be eradicated. It is likely that future pandemics that occur will continue to affect people. Therefore, critical examination of plans, responses, and outcomes of the pandemic may afford information that could affect planning and minimize impact of future pandemics.

Goal:

Future priorities:

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