Gain-of-Function Research Involving Potential Pandemic Pathogens

Potential Pandemic Pathogens

Potential pandemic pathogens (PPPs) are bacteria, viruses, and other microorganisms that are likely highly transmissible and capable of wide, uncontrollable spread in human populations and highly virulent, making them likely to cause significant morbidity and/or mortality in humans. Examples of pathogens that have the potential to cause human pandemics, or have caused a human pandemic, include the H5N1 or H7N9 influenza viruses(link is external), also referred to as bird or avian influenzas, SARS-CoV(link is external), which caused an epidemic in several countries in 2003, and SARS-CoV-2(link is external), also known as Severe Acute Respiratory Syndrome coronavirus 2, which causes COVID-19 disease. Genetic changes or mutations in pathogens, especially viruses that have ribonucleic acid as its genetic material, regularly occur in nature. Some mutations in nature can cause pathogens to gain new functions or enhance existing characteristics such as fitness or pathogenicity (ability to cause disease). We have seen many examples of that with SARS-CoV-2 since the beginning of the pandemic.

Gain-of-Function Research

The term gain-of-function (GOF) research describes a type of research that modifies a biological agent so that it confers new or enhanced activity to that agent. Some scientists use the term broadly to refer to any such modification. However, not all research described as GOF entails the same level of risk. For example, research that involves the modification of bacteria to allow production of human insulin, or the altering of the genetic program of immune cells in CAR-T cell therapy to treat cancer generally would be considered low risk. The subset of GOF research that is anticipated to enhance the transmissibility and/or virulence of potential pandemic pathogens, which are likely to make them more dangerous to humans, has been the subject of substantial scrutiny and deliberation. Such GOF approaches can sometimes be justified in laboratories with appropriate biosafety and biosecurity controls to help us understand the fundamental nature of human-pathogen interactions, assess the pandemic potential of emerging infectious agents, and inform public health and preparedness efforts, including surveillance and the development of vaccines and medical countermeasures. This research poses biosafety and biosecurity risks, and these risks must be carefully managed. When supported with NIH funds, this subset of GOF research may only be conducted in laboratories with stringent oversight and appropriate biosafety and biosecurity controls(link is external) to help protect researchers from infection and prevent the release of microorganisms into the environment.

U.S. Government Funding Pause

In 2014, the White House Office of Science and Technology Policy (OSTP), in coordination with agencies across the U.S. Government (USG), including the Department of Health and Human Services (HHS) and the National Institutes of Health (NIH), initiated a funding pause (link is external)on GOF research that was reasonably anticipated to confer attributes to influenza, Middle East Respiratory Syndrome (MERS), or SARS viruses such that the virus would have enhanced pathogenicity and/or transmissibility in mammals via the respiratory route.  

The pause allowed the USG, in partnership with the life sciences community and stakeholders, to conduct a public, deliberative process with the explicit goal of developing a new federal policy framework to guide future investments in this area of research. The deliberative process included multiple public meetings and two commissioned independent studies, including a comprehensive risk and benefit assessment of GOF research. As noted above, not all studies that may be considered GOF research pose the same level of risk. The deliberative process identified the subset of research that enhances a pathogen to make it likely highly transmissible and virulent in humans (enhanced PPP) as involving risks that warranted additional oversight. 

HHS P3CO Framework

At the conclusion of the deliberative process, HHS issued its Framework for Guiding Funding Decisions about Proposed Research Involving Enhanced Potential Pandemic Pathogens (HHS P3CO Framework)(link is external). This 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(link is external) issued by OSTP. The Framework guides HHS funding decisions on proposed research that is reasonably anticipated to create, transfer, or use PPPs resulting from the enhancement of a pathogen’s transmissibility and/or virulence in humans (enhanced PPP) and seeks to preserve the benefits of life sciences research involving enhanced PPPs while minimizing potential biosafety and biosecurity risks. Unlike the 2014 funding pause, the HHS P3CO Framework is not limited to certain pathogens. The HHS P3CO Review Group includes experts in scientific research, biosafety, biosecurity, medical countermeasures, law, ethics, public health preparedness and response, biodefense, select agent regulations, and public health policy. Research deemed acceptable under the HHS P3CO Framework must be conducted in an appropriate laboratory with stringent oversight and biosafety and biosecurity controls.

Once the HHS P3CO review and oversight process was in place, NIH announced in December 2017 that it was lifting the funding pause on NIH-supported research. Since that time, NIH has funded two projects(link is external) involving enhanced PPP research subsequent to review by the HHS P3CO Review Group. Both projects involved influenza virus. The HHS P3CO Review Group determined that for both research proposals, there were no feasible, equally effective alternative methods to address the same question in a manner that poses less risk, and that the research was acceptable for HHS funding. NIH makes all funded research publicly available on NIH RePORTER. Pre-funding information about unfunded individual proposals is not made public to preserve confidentiality and protect sensitive information, preliminary data, and intellectual property.

Research Within P3CO Scope

As an example, the University of Wisconsin-Madison research experiment on influenza that was reviewed in accordance with the HHS P3CO Framework was considered acceptable for HHS funding. The research project focused on H5N1 (an avian influenza virus that represents a serious pandemic threat) and was designed to improve understanding of the features and mechanisms that would enable avian influenza viruses to transmit to mammals. The leap from birds to humans (or from birds to another species such as pigs, then to humans) has been an important way that spillover has occurred in the past with influenza A virus. In this project, mutations associated with adaptation in mammals would be introduced into H5 avian influenza viruses. The project proposed that resulting viruses would be tested for their ability to transmit between ferrets, a common animal model for studying influenza A transmission that might be relevant to humans. In the ferret experiments, additional mutations then would be introduced to see if those changes made the viruses more transmissible between ferrets. The information generated from these ferret experiments provided a basis for assessing the potential risks to humans of circulating and emerging avian influenza viruses. Identification of specific mutations enables enhanced surveillance and response efforts, because finding these mutations in future avian influenza viruses could inform a public health response by identifying the need for development and use of protective vaccines and therapeutics.

Research Outside P3CO Scope

An example of a research project that some might describe as GOF research broadly but does not meet the criteria for review under the HHS P3CO Framework involves virus manipulation that results in the ability to generate higher vaccine yield. For background, egg-based influenza vaccine viruses are not always suitable for cell-cultured vaccine production due to potential issues with growth, protein yield, and antigenic stability (a substance that evokes an immune response). To increase cell-culture influenza vaccine production, a high-growth master influenza virus adapted to cells competent for vaccine production was needed. New mutations introduced in a mouse-adapted influenza virus (A/PR/8/1934) in cell culture resulted in a virus that had increased pathogenicity in mice and increased yield in cell culture which would advance vaccine development. Because the parental or primary virus was adapted in mice, it did not meet the definition of a PPP. This research is described in this Nature paper(link is external).

Timeline

December 19, 2017: NIH announces that it is lifting the funding pause.

December 19, 2017: HHS issues Framework for Guiding Funding Decisions about Proposed Research Involving Enhanced Potential Pandemic Pathogens(link is external).

January 9, 2017: U.S. Government issues Recommended Policy Guidance for Departmental Development of Review Mechanisms for Potential Pandemic Pathogen Care and Oversight (P3CO)(link is external).

May 2016: National Science Advisory Board for Biosecurity issues Recommendations for the Evaluation and Oversight of Proposed Gain-of-Function Research.

March 10-11, 2016: National Academies of Sciences, Engineering, and Medicine hosts 2^nd symposium on gain-of-function research (meeting summary(link is external)).

December 15-16, 2014: National Academies of Sciences, Engineering, and Medicine hosts symposium on potential risks and benefits of gain-of-function research (meeting summary(link is external)).

October 17, 2014: U.S. Government outlines the Gain-of-Function Deliberative Process and Research Funding Pause on Selected Gain-of-Function Research Involving Influenza, MERS, and SARS viruses(link is external).

October 16, 2014: NIH issues statement on U.S. Government funding pause on certain types of gain-of-function research.

Related Resources

NIH Gain-of-Function Research

HHS P3CO(link is external)