Research Involving Enhanced 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 influenza viruses, also referred to as bird or avian influenza, SARS-CoV, which caused an epidemic in several countries in 2003, and SARS-CoV-2, 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) as has been seen with the many variants of SARS-CoV-2 since the beginning of the pandemic.

ePPP Research

On limited occasions, when justified by compelling public health need and conducted in very high biosecurity laboratories, NIH has supported certain research that may be reasonably anticipated to create, transfer or use potential pandemic pathogens resulting from the enhancement of a pathogen’s transmissibility and/or virulence in humans. The U.S. Government and the Department of Health and Human Services define such research as enhanced potential pandemic pathogen (ePPP) research. NIH-supported ePPP research requires strict oversight and may only be conducted with appropriate biosafety and biosecurity measures. This research can help us understand the fundamental nature of human-pathogen interactions, assess the pandemic potential of emerging infectious agents such as viruses and inform public health and preparedness efforts, including surveillance and the development of vaccines and medical countermeasures. While such research is inherently risky and requires strict oversight, the risk of not doing this type of research and not being prepared for the next pandemic is also high. While ePPP research is a type of so called “gain-of-function” (GOF) research, the vast majority of GOF research does not involve ePPP and falls outside the scope of oversight required for research involving ePPPs.


The HHS Framework for Guiding Funding Decisions about Proposed Research Involving Enhanced Potential Pandemic Pathogens (HHS P3CO Framework) was established in 2017 to guide funding decisions on proposed research that is reasonably anticipated to create, transfer or use potential pandemic pathogens resulting from the enhancement of a pathogen’s transmissibility and/or virulence in humans, called ePPP research. 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 by the White House Office of Science and Technology Policy. These policies were developed after a three-year deliberative process during which the U.S. government initiated a funding pause from 2014-2017 for select research that was reasonably anticipated to enhance pathogenicity and/or transmissibility of influenza, MERS or SARS viruses in mammals via the respiratory route.  

The Framework seeks to preserve the benefits of life sciences research involving ePPPs while minimizing potential biosafety and biosecurity risks. 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.

To date, only three projects involving ePPP research were reviewed by the HHS P3CO Review Group and proposed for funding by NIH. The HHS P3CO Review Group determined that for two of the research proposals, focused on influenza, 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. Those two projects have ended. For the third project, the HHS P3CO Review Group determined that a subset of the proposed research involving ePPPs was acceptable for funding with the implementation of additional risk mitigation measures. However, NIAID ultimately decided to redirect all funds under the award to support alternative approaches that do not involve ePPP research. 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.

HHS convened the NSABB on February 28, 2022, and the Senior Official performing the duties of the NIH Director, delivered a charge to the Board to thoroughly review the scope and effectiveness of the USG’s biosecurity policy frameworks governing research with ePPP and dual use research of concern. On January 27, 2023, the NSABB delivered its report, Proposed Biosecurity Oversight Framework For The Future of Science, which contains the findings and recommendations of two NSABB Working Groups aimed at ensuring U.S. biosecurity efforts are positioned to keep pace with an evolving scientific enterprise. The report was endorsed by the NSABB with minor modifications. In delivering the report, the NSABB fulfilled its charge. NIH, HHS, and its interagency partners, including the White House Office of Science and Technology Policy and the National Security Council, will consider the NSABB report as part of the USG review process for the oversight frameworks for P3CO and DURC, which aim to effectively balance science and security while safely enabling critical, lifesaving research. Following this process, the USG will announce the next steps in the review process. 

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This page last reviewed on June 5, 2023