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 select agents and toxins 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.

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 human or 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 A(H5Nx) and A(H7Nx), 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.

What was the voluntary moratorium on laboratory research specific to the highly pathogenic A(H5N1) bird flu virus and what is the government’s current stance on this research?

On January 20, 2012, a voluntary moratorium on laboratory research specific to the highly pathogenic A(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 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. In October 2014, following publication of several controversial “gain of function” (GOF) studies as well as several high-profile incidents in U.S. biocontainment laboratories, the U.S. Government introduced another moratorium on all U.S. funded GOF research on certain “potential pandemic pathogens” (PPPs) [718 KB, 7 pages], including influenza viruses, severe acute respiratory syndrome (SARS) and Middle East Respiratory Syndrome (MERS) viruses.  On December 19, 2017, The U.S. Department of Health and Human Services (HHS) lifted this 3-year moratorium. The lifting of this moratorium allows certain types of U.S. government funded laboratory research studies involving these pathogens to resume. The types of studies that now can be conducted are governed by the HHS framework [718 KB, 7 pages] for guiding funding decisions about research involving enhanced potential pandemic pathogens, also known as the “HHS P3CO Framework,” which also was released on December 19, 2017.

What is the HHS P3CO Framework and what kinds of research does it provide guidance for?

On December 19, 2017, U.S. Health and Human Services (HHS) launched a new framework [718 KB, 7 pages] called the “Framework for Guiding Funding Decisions about Proposed Research Involving Enhanced Potential Pandemic Pathogens (PPP).”  HHS maintains a group of subject matter and policy experts for PPP care and oversight (P3CO). This framework is intended to guide HHS funding decisions on individual proposed research that is reasonably anticipated to create, transfer, or use enhanced PPPs [718 KB, 7 pages]. The HHS P3CO framework is responsive to and in accordance with the “Recommended Policy Guidance for Departmental Development of Review Mechanisms for Potential Pandemic Pathogen Care and Oversight” issued on January 9, 2017, and it supercedes a prior framework called the “Framework for Guiding Department of Health and Human Services Funding Decisions about Research Proposals with the Potential for Generating Highly Pathogenic Avian Influenza H5N1 viruses that are Transmissible among Mammals by Respiratory Droplets.” The HHS P3CO Framework ensures a multidisciplinary, department-level pre-funding review and evaluation of proposed research meeting the scope outlined in the document to help inform funding agency decisions. It strives to obtain the benefits of life sciences research while minimizing potential biosafety and biosecurity risks.

The HHS P3CO framework states that research involving PPPs is essential to protecting global health and security; however, it acknowledges that there are biosecurity risks associated with undertaking such research that must be adequately considered and appropriately mitigated in order to help safely realize the potential benefits.

The HHS P3CO Framework explains its scope and its definitions in an online PDF [718 KB, 7 pages].

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.

What is the public health justification for engaging in bird flu research that falls into the categories of DURC, GOF or enhanced PPP?

Knowledge gained from DURC, GOF, and enhanced PPP studies offers many benefits to the public. These studies support public health risk assessments that are essential to prioritize the development of infection control and intervention strategies such as antiviral drug treatment and vaccination and are essential to improve our readiness before nature produces the next pandemic virus.

A primary purpose of this type of research is to identify genetic sequences that exist or may emerge in flu viruses with the potential to cause a pandemic. Information from these studies is critical to the implementation of effective global surveillance strategies so that high-risk genetic signatures can be quickly identified in emerging viruses, providing early warning of a pandemic threat.

DURC, GOF, and enhanced PPP studies are also essential to identify and confirm that a given mutation confers a functional change to the flu virus. Understanding the functional mechanisms affected by key genetic sequences offers the opportunity to exploit viral processes for antiviral drug development. Flu viruses evolve quickly and have the potential to acquire resistance to currently available antiviral drugs, which would leave clinicians with limited options to treat patients.

The best way to control flu virus infections is by vaccination using safe and effective vaccines. Current flu vaccine development requires a substantial lag time between when a virus is first identified and when a vaccine can be manufactured and distributed to the public. Proponents of GOF research hope to overcome the time constraints of vaccine production by preparing and manufacturing flu vaccines in advance before they emerge in nature. GOF research is necessary to know which genetic characteristics to include in vaccines for optimal shelf life and effectiveness for prevention of infection and disease caused by the flu virus.

Is CDC conducting any DURC or enhanced PPP research on bird flu viruses?

During the period of the moratorium, CDC did not conduct DURC research on highly pathogenic avian influenza (HPAI) viruses. At this time, CDC is evaluating the need to conduct DURC and/or enhanced PPP studies on a case by case basis. Before CDC conducts studies on HPAI viruses, regardless of whether they fall into the DURC or enhanced PPP categories, a proposal for conducting the studies is first submitted to CDC’s Institutional Biosecurity Board (IBB). The IBB determines whether the study falls into the category of DURC or enhanced PPP or not. If the IBB determines that the proposed laboratory study falls into the category of DURC and potentially enhanced PPP, it will determine if additional HHS P3CO review is required before the study can be conducted. CDC’s research involving HPAI is conducted to inform risk assessments of novel flu viruses.

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

During the period of the moratorium, CDC did not conduct “gain of function” research on bird flu viruses.  Now that the moratorium has been lifted, CDC will determine whether to conduct “gain of function” research on bird flu viruses on a case by case basis. See the question entitled “Is CDC conducting any DURC or enhanced PPP research on bird flu viruses?” for a basic description of this process. Proposals for studies potentially involving “gain of function” research must first be approved by CDC’s internal IBB, which will determine if the studies warrant further review by the HHS P3CO framework [718 KB, 7 pages]. This review process will determine whether the research is safe to conduct, whether it should be conducted, and what biosafety precautions and practices are required to conduct the work.

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 A(H5N1) bird flu viruses might become more transmissible in mammals (1). The study assessed the ability of highly pathogenic Asian A(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 performed in BSL-3 enhanced laboratory facilities. Although CDC researchers were able to successfully create new flu viruses that shared genes from both Asian A(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 A(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 A(H3N2) flu viruses to mix with certain A(H5N1) bird flu viruses in a laboratory setting (2). This study concluded that continued exposure of humans and animals to both A(H5N1) bird flu viruses and A(H3N2) seasonal viruses increased the risk of producing new H5 viruses that could produce infectious secretions in the upper airways of mammals.

Other CDC GOF studies on Asian A(H5N1) viruses included looking 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 A(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 Asian A(H5N1) viruses 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 A(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 A(H5N1) viruses and identified molecular changes that increase the ability of those viruses to transmit in mammals via infectious respiratory droplets.

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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