Science and Security: The Moratorium on H5N1 “Gain-of-Function” Experiments

The Highly Pathogenic Avian Influenza (HPAI) H5N1 virus poses a public health threat in many regions of the world. Approximately 600 human cases have been reported since 2003, with a laboratory-confirmed case fatality rate of up to 60% according to the World Health Organization (WHO). The recent death of a woman from southwest China, attributed to H5N1, has sparked concerns with public health officials that the strain can now be transmitted between humans. Typically, H5N1 is contracted by people in direct contact with poultry. Health authorities in Guiyang, Guizhou province concluded that two patients, including the woman who died, did not have contact with poultry before showing symptoms of the illness. Currently, the public health community remains cautious as H5N1 influenza viruses continue to evolve and potentially gain the ability to be transmitted efficiently to humans. One of the objectives for H5N1 research is to identify genetic changes that are linked to transmission or enhanced virulence in mammals. This information may lead to improved pandemic preparedness efforts such as development of better vaccines, antivirals, and diagnostics for H5N1 strains that have the potential to spread among humans.

Similar to other research experiments involving infectious pathogens, some H5N1 studies, due to their inherent dangers, are described as Dual Use Research of Concern (DURC). Biosafety risks include laboratory-acquired infections or accidental release of the virus, which are major threats for public health. In fact, last year, researchers around the world took the remarkable step of imposing a moratorium on “gain-of-function” experiments due to concerns about public health risks. The following provides answers to basic questions about the risks of this type of research, the status of the moratorium, and what steps are being taken to mitigate future public health risks.

What are “gain-of-function” experiments?

A “gain-of-function” experiment introduces or amplifies a gene product. This type of research is intended to increase the transmissibility, host range, or virulence of pathogens. Most “gain-of-function” experiments are used to examine the subtle complexities of biology. The gene products of the majority of these experiments result in cellular death or with phenotypes that are difficult or impossible to interpret. Specific to H5N1 influenza research, it is hoped that enhancing and analyzing the transmissibility of the pathogen could provide new information that could lead to improved vaccines to prevent an outbreak that may arise in the future. However, there is also risk that it could lead to an inadvertent release of a virus with enhanced transmissibility.

Why were they ceased?

The H5N1 influenza virus research was temporarily ceased in January 2012 due to the risks involved with disseminating experimental results that could be used for nefarious purposes. All research on H5N1 transmission was halted after laboratories at the University of Wisconsin and the Dutch Eramus Medical Center in Rotterdam, Netherlands created mutant forms that could be transmitted directly among ferrets. This was concerning because viruses that are easily transmissible between ferrets are often also easily transmissible between humans. Some experts argued that the benefits of this kind of H5N1 research to health and medicine were overhyped and not worth the risk of an accidental release that would expose the public to these mutant strains.

Bioterrorism, biosafety, and regulatory issues have also been brought to light since the initiation of the year-long voluntary moratorium. Many scientists fear that the scientific details on creating a potentially dangerous virus could be used for bioterrorism. Researchers claim that the experiments have the potential to lead to public health benefits but have also exposed regulation gaps on dual-use research. The public health benefits include: influenza surveillance that catches infectious strains early, better drugs, and improved vaccines. Yoshihiro Kawaoka of the University of Wisconsin and Ron Fouchier of Erasmus University in the Netherlands, both leading H5N1 researchers, argued the fears were overblown and surpassed by the potential public health preparedness their studies may lead to.

Has there ever been a similar moratorium before for other experiments?

This is not the first time that scientific research has been suspended due to security concerns. In July 1974, a call for a voluntary moratorium on research using emerging recombinant DNA (rDNA) technology stunned the scientific community. American scientists were concerned that unrestricted pursuit of this research might produce unanticipated and damaging consequences for human health and the ecosystem. Despite widespread apprehension, the moratorium was collectively observed worldwide. The 1975 Asilomar Conference on Recombinant DNA – named after the Asilomar Conference Center in California, where it was held – marked the beginning of a unique era for the public discussion of science policy. The major goal of the conference was to consider whether to lift the voluntary moratorium and, if so, under what circumstances could the research proceed safely. The moratorium was enacted by scientists and governments to protect laboratory personnel, the general public, and the environment from potential hazards that might be directly generated from rDNA experiments. During the conference, recommendations were established for how to safely conduct experiments using rDNA. The debate on potential biohazards was the primary focus of the conference, which is still a continued discussion in biotechnology today.

The conference also highlighted the fact that policy and regulations have both private and public stakeholders. Although the conference was primarily run by molecular biologists, the debate resulted in other scientists and non-scientists joining national and local review boards. Also resulting from the Asilomar Conference was membership expansion of the Recombinant DNA Advisory Committee (RAC) to 16 members in fields to include experts from: molecular biology, genetics, virology, microbiology, epidemiology, infectious diseases and the biology of enteric organisms. The purpose of the RAC was and is to promote transparency and access for all stakeholders, enabling public approval of critically important technology, and creating an environment in which scientific research can be performed in an informed, safe, and ethical manner.

How many researchers/countries are involved in “gain-of-function” experiments?

The letter that announced the voluntary moratorium on H5N1 transmission research, published in Science and Nature, was signed by 40 leading influenza researchers from the United States, China, Japan, Britain, the Netherlands, Hong Kong, Germany, Italy, and Canada. Everyone, in some way, may be affected by “gain-of-function” experiments. The “gain-of-function” experiments have a plethora of stakeholders within the international community. In December 2012, the United States hosted the “Gain-of-Function Research on Highly Pathogenic Avian Influenza H5N1 Viruses: An International Consultative Workshop.” This workshop integrated experts in various fields, including: influenza and other infectious diseases, bioethics, public health surveillance, biosafety, national and global public health, biosecurity, epidemiology, national security, agriculture and veterinary sciences, global public health law and those specifically involved with developing the WHO International Health Regulations and the Pandemic Influenza Preparedness Framework, and medical countermeasures to disease outbreak. While the purpose of the moratorium was primarily to take time to discuss risk/benefit analysis of gain-of-function experiments, another important consideration was how to educate the public and gain their acceptance for continued research.

What new steps are being taken to minimize the risk of H5N1 research to public health?

The RAC of the National Institutes of Health (NIH) has called for additional precautions on H5N1 “gain-of-function” experiments that are conducted strictly in biosafety level 3 (BSL-3) laboratories, which have been used in recent studies on H5N1 transmissibility. The committee has rejected the option of restricting research to facilities designated as BSL-4 – the highest level of biosafety laboratories – because only a few laboratories around the world would meet this standard. Limiting H5N1 research to only these labs would slow the pace of discovery. Additionally, many experts argue H5N1 experiments can safely be done in BSL-3 with enhanced safeguards. Existing BSL-3 laboratory requirements include: powered air purifying respirators (PAPRS), donning a protective suit, wrap-back disposable gowns, double gloving, shoe covers, and a shower before exiting the laboratory. The recommended steps are aimed at reducing the risk of laboratory-acquired infections and the accidental release of the dangerous pathogens. The additional requirements devised recently by the RAC include: increased personal protective equipment (PPE), a “buddy system” for all personnel, maintaining baseline serum samples, providing a licensed H5N1 vaccine, and requiring personnel to avoid contact with susceptible bird species for five days after working with the viruses. The RAC also recommended proper training of lab personnel would be essential and recommended that personnel be required to sign a statement confirming that they understand the safety and incident-reporting requirements. Additionally, the RAC recommended that all incidents that have the potential to be harmful to personnel and/or the public be reported to institutional authorities immediately and to public health officials within 24 hours.

What are the recommended next steps for the United States concerning the recent moratorium?

Although the H5N1 international research moratorium was lifted in January 2013, the United States has yet to resume research involving gain-of-function experiments on the H5N1 virus and is currently designing a framework for the Department of Health and Human Services (HHS) to make judgments about funding for this type of research. This framework will provide HHS’ funding agencies with guidance on how to classify potentially high-risk gain-of-function projects at the funding proposal stage and make determinations as to whether they are acceptable for HHS funding. For the proposals that are deemed acceptable for funding, the framework will also establish a basis for HHS’ funding agencies to designate any additional biosafety, biosecurity, and DURC risk mitigation measures that they will require of researchers.

With China’s February report of two new human cases of H5N1, the debate of moving forward with “gain-of-function” research remains of upmost importance for global public health. In light of the new cases, researchers are insistent to resume experimentation on the deadly virus in hopes to produce results for prevention or new countermeasures. But the dangerousness of the virus underscores the importance of prioritizing safety when carrying out this research, even if it means pausing for a moment to make sure experimentation does not inadvertently create more problems than it solves.

Malerie Briseno is a Biosecurity Intern at the Federation of American Scientists. She graduated from Georgetown University’s School of Medicine with a M.S. in Biohazardous Threat Agents and Emerging Infectious Diseases.

Christina England is currently a Masters Candidate from the University of Maryland School of Public Policy, specializing in International Security and Economic Policy.  She is serving as a biosecurity intern at the Federation of American Scientists, overseeing its Virtual Biosecurity Center.  She graduated from the United States Air Forces Academy as distinguished graduate, receiving her BS in Biochemistry.