Avian Influenza (Bird Flu) Research

Why does CDC conduct research on bird flu viruses?

Although bird flu viruses mainly infect birds, these viruses can sometimes infect people and cause illness. Flu viruses constantly change (see antigenic drift and shift) and sometimes these changes result in the emergence of a novel (new) flu virus that can easily infect and spread between people. When this happens, a pandemic can occur. CDC Influenza Division is a World Health Organization (WHO) Collaborating Center. In this role, CDC conducts surveillance of circulating flu viruses to make informed decisions on the selection of viruses for use in creating vaccines against viruses with pandemic potential. Because of the possible threat bird flu viruses pose to human health, CDC also conducts research to learn more about these viruses, for example, where they spread, how they spread, and what kinds of disease they cause. This information can help scientists better understand the risk these viruses pose to human health and can help support development of tools and strategies for prevention and treatment.

In recent years, two bird flu viruses have caused the most human infections: highly pathogenic avian influenza (HPAI) H5N1 and low pathogenic H7N9 viruses (Note: the terms “highly pathogenic” and “low pathogenic” refer to the severity of disease that these viruses cause in birds). These two viruses have caused severe illness and death in humans.

For these reasons, CDC has focused considerable resources and time on monitoring human infections with and changes in these and other bird flu viruses, as well as developing vaccine viruses and testing antiviral drugs to prevent or treat human infections with them.

What is the purpose of this research?

CDC conducts laboratory research on bird flu viruses for important public health reasons, including but not limited to the following:

• to develop viruses for use in vaccines as part of pandemic preparedness efforts;
• to test to see if bird flu viruses are susceptible (sensitive) or resistant to existing flu antiviral drugs, and to monitor for ongoing changes that might indicate these viruses are becoming resistant;
• to develop diagnostic tests and test materials that can accurately and reliability detect infections with specific bird flu viruses, such as H5N1 and H7N9;
• to assess existing human immunity to circulating bird flu viruses and to determine whether people’s previous vaccinations or exposures to other flu viruses provides cross-protection against newer bird flu viruses.
• to better understand properties of bird flu viruses and changes in bird flu viruses, such as mutations, that could cause such viruses to infect humans more easily, cause more severe disease, or spread in a sustained and efficient manner among people or other mammals;
• to track globally where bird flu viruses are causing illness in people so that appropriate public health precautions and actions can be taken to minimize risks to human health in those areas.

What research does CDC conduct on bird flu viruses?

CDC conducts laboratory tests on bird flu viruses including, but not limited to the following: antigenic characterization, antiviral resistance, genetic characterization, serology and assessment of bird flu viruses’ ability to cause disease and spread in animal models. An explanation of this research and its public health purpose is provided below.

Antigenic Characterization

“Antigenic characterization” is the analysis of a flu virus’ surface features using antibodies. CDC researchers determine a flu virus’ antigenic (immune) properties to help assess how related different flu viruses are to each other. CDC flu laboratorians conduct antigenic characterization as part of global flu surveillance efforts to measure possible changes in circulating bird flu viruses. Antigenic characterization data help CDC experts determine if existing bird flu vaccines that have been stockpiled in the event of a pandemic would be expected to provide protection against circulating bird flu viruses or if new vaccine viruses should be developed. In some circumstances, CDC may prepare viruses in advance that vaccine manufacturers can use to produce a vaccine in the future, if needed. The main test used to conduct antigenic characterization is the Hemagglutination Inhibition Assay (HI Test). CDC primarily conducts antigenic characterization on bird flu H5, H7, and H9 viruses, but may test other types of bird flu viruses that pose a risk to humans. More information on antigenic characterization is available on CDC’s flu antigenic characterization page.

Antiviral Resistance Testing

Virus samples are tested to determine if they are resistant to any of the FDA-approved flu antiviral drugs. This information helps shape public health policy recommendations on the use of flu antiviral medications. CDC currently recommends use of the neuraminidase inhibitor class of antiviral drugs to prevent and treat flu illness in the United States. The neuraminidase inhibitors are drugs that are designed to bind to the neuraminidase protein on the surface of a flu virus to prevent the virus from replicating in the host. (More information about flu antiviral drugs is available at Treatment - Antiviral Drugs.) Antiviral resistance testing includes using a specific functional assay, the neuraminidase inhibition (NI) assay, to see whether virus replication is inhibited by the presence of the neuraminidase drugs.

Genetic Characterization

Genetic characterization – as it applies to bird flu research – is the study of the genes of a bird flu virus through a laboratory process known as “genome sequencing.” Through genome sequencing, researchers can determine the order and structure of the amino acids that bind together to form the proteins of a flu virus. Comparing the order of amino acids in one sequence to other sequences can reveal variations that might impact characteristics of the flu virus. For example, the ordering of these amino acids can affect factors such as how well a virus replicates during infection, how well it transmits between hosts, or its susceptibility to vaccines and antiviral drugs. Flu researchers use genetic characterization to better understand these markers and to assess the risk these viruses pose to public health.

Serology

Serology is the study of blood serum. Serum contains antibodies, which are proteins that are produced by the body in response to infection or vaccination. Antibodies play an essential role in protection against flu viruses. CDC’s flu serology research involves the study of antibodies in human populations to better understand whether people have any existing protection against bird flu viruses. These studies can tell public health officials whether people in the study population are susceptible to infection with a particular virus or if they have existing immune protection against infection. This information is important for determining a virus’ pandemic potential or ability to spread through a population. In addition, serology is used to determine whether vaccines developed against bird flu viruses are likely to offer adequate protection and whether this protection is likely to be effective against newly emerging bird flu viruses.

Animal testing

CDC conducts animal studies involving bird flu viruses to better understand these viruses, such as how transmissible they are in mammals, their disease severity and disease characteristics, and to test the efficacy of vaccines and other pharmaceutical interventions against them.

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How has CDC research helped to improve testing for bird flu viruses?

CDC research has strengthened the ability of the United States and foreign countries to detect bird flu viruses. In February 2006 and September 2008, the U.S. Food and Drug Administration (FDA) cleared laboratory tests researched and developed by CDC to presumptively identify H5 bird flu virus (Asian strain) in human respiratory specimens to aid in the diagnosis of suspected H5N1 cases. CDC has since expanded its test kits to detect other bird flu viruses, such as the H7N9 bird flu virus, which began causing human infections in China in March 2013. CDC’s bird flu test kits have been made available to state public health laboratories and have been shared globally with the Collaborating Centers of the World Health Organization and international influenza testing centers.

What is “dual use research of concern (DURC)”?

CDC only conducts bird flu research to benefit society. Some types of bird flu research that are beneficial to society also fall into a category called “dual use research of concern” (DURC). DURC is defined as life sciences research that, based on current understanding, can be reasonably anticipated to provide knowledge, information, products, or technologies that could be directly misapplied to pose a significant threat with broad potential consequences to public health and safety, agricultural crops and other plants, animals, the environment, materiel, or national security. DURC is a subset of research called “dual use research” (DUR). DUR is defined as research that is beneficial to society that could also pose risks to health or security if used malevolently.

What agents, toxins and categories of research experiments fall under the category of “DURC?”

There are 15 agents and toxins (known as “select agents”) and seven categories of experiments on these select agents that fall under the subset of research called DURC. These agents and toxins include the following:

• Highly pathogenic avian influenza virus
• Bacillus anthracis (anthrax),
• Botulinum neurotoxin,
• Burkholderia mallei,
• Burkholderia pseudomallei,
• Ebola virus,
• Foot-and-mouth disease virus,
• Francisella tularensis,
• Marburg virus,
• Reconstructed 1918 influenza virus,
• Rinderpest virus,
• Toxin-producing strains of clostridium botulinum,
• Variola major (smallpox)
• Variola minor viruses (smallpox),
• and Yersinia pestis.

The Select Agent Program regulates these agents under Federal law. Categories of research experiments that fall under DURC include those that do the following:

1. enhance the harmful consequences of the agent or toxin;
2. disrupt immunity or the effectiveness of an immunization against the agent or toxin without clinical and/or agricultural justification;
3. confer to the agent or toxin resistance to clinically and/or agricultural useful preventative or treatment interventions against that agent or toxin or facilitates their ability to evade methods of detection;
4. increase the stability, transmissibility, or the ability to disseminate the agent or toxin;
5. Alters the host range or tropism of the agent or toxin
6. enhance the susceptibility of a host population to the agent or toxin
7. generate or reconstitute an eradicated or extinct agent or one of the 15 DURC toxins or agents

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Why are highly pathogenic avian influenza (HPAI) viruses considered a select agent?

Select agents are biological agents and toxins that have been determined to have the potential to pose a severe threat to both human and animal health, to plant health, or to animal and plant products. Highly pathogenic avian influenza (HPAI) viruses are “agricultural select agents” because of the danger they pose to animal health, for example, U.S. poultry. HPAI viruses are not considered select agents because of the danger they pose to human health. Although human infections with certain HPAI viruses, such as H5N1 and H7N9, can lead to severe illness and death, human infections with these viruses are generally rare, and HPAI viruses currently do not spread easily from birds to humans or between humans.

Is CDC conducting any DURC research on bird flu viruses?

CDC is not currently conducting what is known as “dual-use research of concern” (DURC) with bird flu viruses. On January 20, 2012, a voluntary moratorium on laboratory research specific to the highly pathogenic H5N1 bird flu virus was announced in a letter signed by 39 international flu researchers. This moratorium, which was initially expected to last 60 days, was not lifted until a similar letter on January 23, 2013, due to the controversy surrounding the topic. This moratorium prompted the development of the U.S. Government’s DURC policy, which was launched in March 2012. While CDC is not conducting DURC studies on highly pathogenic avian influenza (HPAI) viruses, CDC does conduct transmissibility studies using naturally occurring (not altered) HPAI viruses in animal models to assess their transmissibility. This research informs CDC’s risk assessments of novel flu viruses.

What is “gain of function (GOF)” bird flu research?

Gain of function research is research that seeks to alter the functional characteristics of a virus. Examples of gain of function research include research that seeks to produce mutations in a virus that could allow it to become more transmissible, infect a wider range of hosts, increase its disease severity, or confer resistance to existing drugs, treatments or vaccines.

Does CDC currently conduct gain of function research on bird flu viruses?

CDC is not currently conducting “gain of function” research on bird flu viruses.

Has CDC done “gain of function” research on highly pathogenic avian influenza A (H5N1) in the past?

Yes. CDC has conducted “gain of function” research in the past on HPAI viruses as part of pandemic preparedness efforts. For example, in 2006 CDC conducted an experiment that sought to understand how H5N1 bird flu viruses might become more transmissible in mammals (1). The study assessed the ability of highly pathogenic H5N1 bird flu viruses to mix with human flu viruses through a process called “reassortment” that can occur in nature. Reassortment can result in the creation of new flu viruses with pandemic potential. This work was done in BSL-3 enhanced laboratory facilities. Although CDC researchers were able to successfully create new flu viruses that shared genes from both H5N1 bird flu and human flu viruses, the resulting viruses appeared to lack the molecular and biologic properties needed for efficient spread. The results suggested that H5N1 bird flu viruses required further genetic change to gain the properties needed to cause a human pandemic.

A similar study was conducted in 2009 that conducted a health risk assessment of the ability of human seasonal H3N2 flu viruses to mix with H5N1 bird flu viruses in a laboratory setting (2). This study concluded that continued exposure of humans and animals to both H5N1 bird flu viruses and H3N2 seasonal viruses increased the risk of producing new H5 viruses that could produce infectious secretions in the upper airways of mammals.

Other GOF CDC studies on H5N1 viruses include several that looked at how mutations to the H5N1 viruses’ surface proteins could affect the “receptor binding preference” of these viruses (3). The receptor binding preference determines which hosts a flu virus is best suited to infecting, such as birds as opposed to mammals. Results from this study found that mutations that changed the H5N1 viruses’ receptor binding preference from birds to humans also tended to reduce the virus’ ability to replicate (i.e., make copies of itself for the purpose of spreading infection.) The authors concluded that alternative molecular changes would be needed for H5N1 viruses to fully adapt to humans and be capable of causing a pandemic.

Another such study examined in a laboratory environment evolutionary changes that would need to occur for the receptor binding preference of H5N1 viruses to change so that they would be better suited to infecting and causing illness in humans as opposed to birds (4). This study concluded that extensive evolution of existing H5N1 viruses would need to occur before these H5N1 viruses could become fully transmissible in humans. Other scientists have conducted gain-of-function research on H5N1 viruses and identified molecular changes that increase the ability of the H5N1 virus to transmit in mammals via infectious respiratory droplets.

At this time, CDC has moratorium on gain of function research involving H5N1 bird flu viruses.

What “gain of function” studies on bird flu viruses have been conducted outside of CDC and what is the purpose of this research?

In gain of function research conducted outside of CDC in the past few years, researchers used knowledge of existing bird flu viruses to determine how many and what types of mutations were needed for H5N1 bird flu viruses to become easily transmissible through the air using test animals.

Typically, the purpose of this research is to identify dangerous mutations in existing viruses so that global surveillance efforts can monitor for these mutations in circulating flu viruses. These studies also have the potential to predict what dangerous viruses might emerge in nature before they actually emerge, which allows interventions such as vaccines and drugs to be developed before nature produces the next pandemic virus.

One of the biggest challenges of current flu vaccine development is the lag time between when a virus is first identified and when a vaccine can be manufactured and distributed to the public to protect against that virus. In the United States, the composition of the flu vaccine is decided in February, but due to technological and other limitations, the manufactured vaccine typically does not become available until July or later. Proponents of gain of function research hope to overcome the time constraints of vaccine production by preparing and manufacturing vaccines in advance to protect against flu viruses before they emerge in nature.

References

1. Maines TR, Chen LM, Matsuoka Y et al. Lack of transmission of H5N1 avian-human reassortant influenza viruses in a ferret model. PNAS. 2006. 103(32); 12121-12126.
2. Jackson S, Van Hoeven N, Chen LM et al. Reassortment between avian H5N1 and human H3N2 influenza viruses in fetters: a public health risk assessment. J. Virol. 2009. 83(16):8131-40.
3. Maines TR, Chen LM, Van Hoeven N, Tumpey TM, et al. Effect of receptor binding domain mutations on receptor binding and transmissibility of avian influenza H5N1 viruses. Virology 2011. 413:139-147.
4. Chen LM, Blixt O, Stevens J, Lipatov AS, Davis CT, Collins BE, Cox NJ, Paulson JC, Donis RO. 2012. In vitro evolution of H5N1 avian influenza virus toward human-type receptor specificity. Virology 422:105-113.

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