Dual Use Research of Concern and Bird Flu: Questions & Answers

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 viruses
• 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

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 Asian H5N1 and Asian 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 Asian H5N1 bird flu viruses might become more transmissible in mammals (1). The study assessed the ability of highly pathogenic Asian 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 Asian 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 these 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 certain 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 Asian H5N1 viruses include several that looked at how mutations to the surface proteins of the virus could affect the “receptor binding preference” of these viruses (3). The receptor binding preference determines the hosts that 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 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 these 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 specific H5N1 viruses (Asian lineage) to change so that they would be better suited to infecting and causing illness in people as opposed to birds (4). This study concluded that extensive evolution of existing H5N1 viruses at that time would need to occur before these they could become fully transmissible in humans. Other scientists have conducted gain-of-function research on Asian H5N1 viruses and identified molecular changes that increase the ability of those virusesto 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.