Beyond gain of function: strengthening oversight of research with potential pandemic pathogens

ABSTRACT

In 2017, the Department of Health and Human Services adopted a policy, known as the P3CO Framework, to govern proposed research that could enhance the lethality or transmissibility of a potential pandemic pathogen. The prospect of a human-made virus with artificially enhanced lethality and transmissibility has raised serious biosafety and biosecurity concerns. The COVID-19 pandemic has generated new concerns about the risks posed by such research. Even if the origins of the pandemic are presumed or proven to be the result of a natural zoonotic spillover event, the pandemic has placed greater scrutiny on research that could generate pandemic-capable viruses and dramatically illustrated the consequences if such a virus were released from a laboratory. This article assesses the strengths and weaknesses of the P3CO Framework and provides recommendations for strengthening oversight of research with potential pandemic pathogens. The P3CO Framework should be replaced by a national policy that would apply to all relevant research, regardless of the source of funding and be implemented by a new national agency for biorisk management. This new policy would need to be accompanied by a comprehensive analysis of potential pandemic pathogen risks, clear guidance on how to identify research that falls within the scope of the policy, a rigorous process for reviewing the risks and benefits of such research, and criteria for determining the appropriate measures needed to conduct such research safely, securely, and responsibly.

KEYWORDS:

• Biosafety
• biosecurity
• pandemic
• dual-use research
• risk assessment

Disclosure statement

No potential conflict of interest was reported by the author(s).

Notes

¹ Department of Health and Human Services (HHS). Framework for Guiding Funding Decisions about Proposed Research Involving Enhanced Potential Pandemic Pathogens. 2017. cited January 11, 2023. https://www.phe.gov/s3/dualuse/documents/p3co.pdf.

² Jocelyn Kaiser, ‘Grants funding virus research the United States defines as risky have ended,’ Science, November 4, 2021, https://www.science.org/content/article/united-states-has-stopped-funding-virus-research-it-defines-risky

³ United States Government (2012). United States Government Policy for Oversight of Life Sciences Dual Use Research of Concern. Available at: https://www.phe.gov/s3/dualuse/Documents/us-policy-durc-032812.pdf [cited June 7, 2022].

⁴ National Research Council. Biotechnology Research in an Age of Terrorism. National Academies Press, 2004.

⁵ United States Government (2014). United States Government Policy for Institutional Oversight of Life Sciences Dual Use Research of Concern. Available at: https://www.phe.gov/s3/dualuse/Documents/durc-policy.pdf

⁶ Fouchier RA, Garcia-Sastre A, Kawaoka Y. Pause on avian flu transmission studies. Nature. 2012;481(7382):443. Fouchier RA, Garcia-Sastre A, Kawaoka Y. H5N1 virus: transmission studies resume for avian flu. Nature. 2013;493(7434):609.

⁷ HHS. A Framework for Guiding U.S. 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. February 21, 2013. [cited 2023 August 1]. http://www.phe.gov/s3/dualuse/Documents/funding-hpai-h5n1.pdf

⁸ Harold Jaffe, Amy P. Patterson, and Nicole Lurie, ‘Extra Oversight for H7N9 Experiments,’ Science, Vol 341, Issue 6147 (16 Aug 2013): 713–714.

⁹ National Academies of Sciences, Engineering, and Medicine. Potential risks and benefits of gain-of-function research: summary of a workshop. Washington, DC: National Academies Press; 2015; and National Academies of Sciences, Engineering, and Medicine. Gain-of-function research: summary of the second symposium, March 10–11, 2016. Washington, DC: National Academies Press; 2016.

¹⁰ Gryphon Scientific. Assessing the Risks and Benefits of Conducting Research on Pathogens of Pandemic Potential. April 2016. [cited 2023 Aug 1]. http://www.gryphonscientific.com/wp-content/uploads/2016/04/Risk-and-Benefit-Analysis-of-Gain-of-Function-Research-Final-Report.pdf

¹¹ Selgelid MJ. Gain-of-Function Research: Ethical Analysis. Sci Eng Ethics. 2016 Aug;22(4):923–964. Epub 2016 Aug 8. PMID: 27502512; PMCID: PMC4996883.

¹² National Science Advisory Board for Biosecurity (NSABB), Recommendations for the Evaluation and Oversight of Proposed Gain-of-Function Research, May 2016. [cited 2023 Jan 11]. https://osp.od.nih.gov/wp-content/uploads/2016/06/NSABB_Final_Report_Recommendations_Evaluation_Oversight_Proposed_Gain_of_Function_Research.pdf

¹³ Office of Science Technology and Policy (OSTP). Recommended Policy Guidance for Departmental Development of Review Mechanisms for Potential Pandemic Pathogen Care and Oversight (P3CO). January 9, 2017. [cited 2023 Jan 11]. https://www.phe.gov/s3/dualuse/documents/p3co-finalguidancestatement.pdf

¹⁴ Email communication from Gerald Epstein, Former Assistant Director of OSTP for Biosecurity and Emerging Technologies, September 6, 2023.

¹⁵ Department of Health and Human Services (HHS). Framework for Guiding Funding Decisions.

about Proposed Research Involving Enhanced Potential Pandemic Pathogens. 2017. [cited 2023 Jan 11]. https://www.phe.gov/s3/dualuse/documents/p3co.pdf.

¹⁶ Wolinetz CD. Charge to the National Science Advisory Board for Biosecurity (NSABB). January 23, 2020: Bethesda, MD. [cited 2023 Jan 11]. https://osp.od.nih.gov/wp-content/uploads/Wolinetz-NSABB_Charge.pdf

¹⁷ Tabak LA , Jorgenson LA. 2022 Charge to the NSABB. February 28, 2022: Bethesda, MD. [cited 2023 Jan 11]. https://osp.od.nih.gov/wp-content/uploads/2022/06/Tabak_and_Jorgenson-2022_Charge_to_the_NSABB.pdf

¹⁸ Reardon S. Stricter US guidelines for ‘gain-of-function’ research are on the way – maybe. Nature. January 27, 2023. [cited 2023 Feb 1]. https://www.nature.com/articles/d41586-023-00257-0#correction-1

¹⁹ Section 2315 of the Consolidated Appropriations Act of 2023. [cited 2023 Jan 11]. https://www.congress.gov/117/bills/hr2617/BILLS-117hr2617enr.pdf

²⁰ Romm T. House GOP to embark on sweeping probe of covid origin, U.S. response. Washington Post. January 9, 2023. [cited 2023 Feb 1]. https://www.washingtonpost.com/us-policy/2023/01/09/house-covid-origin-investigation/

²¹ Matt Field, ‘Woke virology? Ron DeSantis finds another thing to ban in Florida,’ Bulletin of the Atomic Scientists, May 12, 2023. [cited 2023 Aug 1]. https://thebulletin.org/2023/05/woke-virology-ron-desantis-finds-another-thing-to-ban-in-florida/

²² Klotz LC, Koblentz, GD. New Pathogen Research Rules: Gain of Function, Loss of Clarity. Bulletin of the Atomic Scientists. February 26, 2018. [cited 2023 Feb 15]. https://thebulletin.org/2018/02/new-pathogen-research-rules-gain-of-function-loss-of-clarity/

²³ National Research Council. Biotechnology Research in an Age of Terrorism. National Academies Press, 2004.

²⁴ NSABB), Recommendations for the Evaluation and Oversight of Proposed Gain-of-Function Research.

²⁵ National Research Council. Biotechnology Research in an Age of Terrorism, 113–114.

²⁶ Kuiken T. Global Pandemics: Gain-of-Function Research of Concern. Congressional Research Service, November 21, 2022. [cited 2023 Sep 6]. https://crsreports.congress.gov/product/pdf/IF/IF12021

²⁷ Lerner S, Hibbett M. Leaked grant proposal details high-risk coronavirus research. The Intercept. September 23, 2021. [cited 2023 Jan 11]. https://theintercept.com/2021/09/23/coronavirus-research-grant-darpa/

²⁸ Sandbrink J, Ahuja J, Swett J, Koblentz G, Standley C. Mitigating biosecurity challenges of wildlife virus discovery. Social Sciences Research Network. September 7, 2022. [cited 2023 Jan 11]. http://dx.doi.org/10.2139/ssrn.4035760

²⁹ USAID. Notice of Funding Opportunity: Discovery & Exploration of Emerging Pathogens – Viral Zoonoses (DEEP VZN), May 13, 2021, 26. [cited 2023 Sep 6]. https://indiabioscience.org/media/articles/7200AA21RFA00005-NOFO-DEEP-VZN-signed.pdf

³⁰ David Willman, ‘The US Quietly Terminates a Controversial $125 m Wildlife Virus Hunting Programme Amid Safety Fears,’ BMJ 2023; 382: p2002.

³¹ HHS. Framework for Guiding Funding Decisions about Proposed Research Involving Enhanced Potential Pandemic Pathogens, 1.

³² Lentzos F, Koblentz GD. Have Hybrid Coronaviruses Already Been Made? We Simply Don’t Know for Sure, and That’s a Problem. The Conversation. February 21, 2022. [cited 2023 Feb 15]. https://theconversation.com/have-hybrid-coronaviruses-already-been-made-we-simply-dont-know-for-sure-and-thats-a-problem-176077

³³ Chen D, Kenney D, Chin CV, et al. Role of spike in the pathogenic and antigenic behavior of SARS-CoV-2 BA.1 Omicron. bioRxiv. October 14, 2022. https://doi.org/10.1101/2022.10.13.512134

³⁴ NEIDL researchers refute UK article about COVID strain. The Brink. October 18, 2022. cited January 11, 2023. https://www.bu.edu/articles/2022/neidl-researchers-refute-uk-article-about-covid-strain/

³⁵ Branswell H. Boston University researchers’ testing of lab-made version of Covid virus draws government scrutiny. Stat News. October 17, 2022. [cited 2023 Jan 11]. https://www.statnews.com/2022/10/17/boston-university-researchers-testing-of-lab-made-version-of-covid-virus-draws-government-scrutiny/

³⁶ Kaiser J. Was a study that created a hybrid COVID-19 virus too risky? Science. October 18, 2022.

³⁷ Koblentz GD. The evolving global biosecurity landscape. Prepared statement before the Bipartisan Commission on Biodefense, The Biological Threat Expanse: Current and Future Challenges to National Biodefense; March 22, 2033; Washington, DC.

³⁸ Koblentz GD. A critical analysis of the scientific and commercial rationales for the synthesis of horsepox virus. mSphere. 2018;3(2): 1–10. https://doi.org/10.1128/mSphere.00040–18

³⁹ NEIDL researchers refute UK article about COVID strain. The Brink. October 18, 2022. cited January 11, 2023. https://www.bu.edu/articles/2022/neidl-researchers-refute-uk-article-about-covid-strain/

⁴⁰ NSABB. Recommendations for the Evaluation and Oversight of Proposed Gain-of-Function Research.

⁴¹ OSTP, Recommended Policy Guidance for Departmental Development of Review Mechanisms for Potential Pandemic Pathogen Care and Oversight (P3CO).

⁴² National Science Advisory Board for Biosecurity. Proposed Biosecurity Oversight Framework for the Future of Science. March 2023. [cited 2023 May 1]. https://osp.od.nih.gov/wp-content/uploads/2023/03/NSABB-Final-Report-Proposed-Biosecurity-Oversight-Framework-for-the-Future-of-Science.pdf

⁴³ HHS. Framework for Guiding Funding Decisions about Proposed Research Involving Enhanced Potential Pandemic Pathogens.

⁴⁴ NSABB. Recommendations for the Evaluation and Oversight of Proposed Gain-of-Function Research. 59.

⁴⁵ Government Accountability Office (GAO). Public Health Preparedness: HHS Could Improve Oversight of Research Involving Enhanced Potential Pandemic Pathogens. GAO-23-105455. Washington, D.C.: GAO; January 2023. cited February 1, 2023. https://www.gao.gov/assets/gao-23–105455.pdf

⁴⁶ Godbold GD, Hewitt FC, Kappell AD, Scholz MB, Agar SL, Treangen TJ, Ternus KL, Sandbrink JB, Koblentz GD. Improved understanding of biorisk for research involving microbial modification using annotated sequences of concern. Front Bioeng Biotechnol. 2023 Apr 25;11:1124100. PMID: 37180048; PMCID: PMC10167326.

⁴⁷ Mullbacher A, Lobigs M. Creation of killer poxvirus could have been predicted. J. Virol. 2001;75(18) (2001): 8353–8355.

⁴⁸ Karim SSA, Karim QA. Omicron SARS-CoV-2 variant: a new chapter in the COVID-19 pandemic. Lancet. 2021; 398(10317): 2126–2128.

⁴⁹ NSABB. Recommendations for the Evaluation and Oversight of Proposed Gain-of-Function Research. 59–60.

⁵⁰ OSTP. Recommended Policy Guidance for Departmental Development of Review Mechanisms for Potential Pandemic Pathogen Care and Oversight (P3CO). 5.

⁵¹ HHS. Framework for Guiding Funding Decisions about Proposed Research Involving Enhanced Potential Pandemic Pathogens. 6.

⁵² GAO. Public Health Preparedness: HHS Could Improve Oversight of Research Involving Enhanced Potential Pandemic Pathogens. January 2023, 17–20.

⁵³ NSABB. Proposed Biosecurity Oversight Framework for the Future of Science. March 2023. cited May 1, 2023. https://osp.od.nih.gov/wp-content/uploads/2023/03/NSABB-Final-Report-Proposed-Biosecurity-Oversight-Framework-for-the-Future-of-Science.pdf

⁵⁴ National Institutes of Health (NIH). Research involving enhanced potential pandemic pathogens. Reviewed February 28, 2022. [cited 2023 Jan 11]. https://www.nih.gov/news-events/research-involving-potential-pandemic-pathogens

⁵⁵ GAO. Public Health Preparedness: HHS Could Improve Oversight of Research Involving Enhanced Potential Pandemic Pathogens. 16.

⁵⁶ Collins, F. Letter to Senator Charles Grassley. July 28, 2021. [cited 2023 Jan 11]. https://www.grassley.senate.gov/imo/media/doc/national_institutes_of_health_to_grassley_-_covid_origins_grant_oversight.pdf

⁵⁷ NIH. Tools for the Identification, Assessment, Management, and Responsible Communication of Dual Use Research of Concern. Bethesda, MD; NIH; 2014. [cited 2023 Jan 11]. https://www.phe.gov/s3/dualuse/Documents/durc-companion-guide.pdf

⁵⁸ NIH. Implementation of the USG Policy for Institutional Oversight of Life Sciences DURC: Illustrative Case Studies. Bethesda, MD; NIH; 2014. [cited 2023 Jan 11]. https://www.phe.gov/s3/dualuse/Documents/12-case-studies-durc.pdf

⁵⁹ Willman D, Muller M. A science in the shadows. Washington Post. August 26, 2021. cited January 11, 2023. https://www.washingtonpost.com/nation/interactive/2021/a-science-in-the-shadows/

⁶⁰ Mark Lipsitch, ‘Closing Keynote,’ Pathogens Project Conference, April 20, 2023, https://www.youtube.com/watch?v=ijOG74syzXA

⁶¹ NIH. Research involving enhanced potential pandemic pathogens.

⁶² United States Government Policy for Institutional Oversight of Life Sciences Dual Use Research of Concern, 8.

⁶³ NSABB. Proposed Biosecurity Oversight Framework for the Future of Science.

⁶⁴ Gerald L. Epstein, ‘Private-sector research could pose a pandemic risk. Here’s what to do about it,’ Bulletin of the Atomic Scientists, February 16, 2023, https://thebulletin.org/2023/02/private-sector-research-could-pose-a-pandemic-risk-heres-what-to-do-about-it/

⁶⁵ Ritterson R, Kingston L, Fleming AEJ, Lauer E, Dettmann RA, Casagrande R. A call for a national agency for biorisk management. Health Secur. 2022;20(2): 1–5.

⁶⁶ Dettmann, RA, Ritterson, R, Lauer, E and Casagrande, R. Concepts to bolster biorisk management. Health Secur. 2022;20(5). https://doi.org/10.1089/hs.2022.0074

⁶⁷ Amesh A. Adalja, Matthew Watson, Eric S. Toner, Anita Cicero, and Thomas V. Inglesby, The Characteristics of Pandemic Pathogens: Improving Pandemic Preparedness by Identifying the Attributes of Microorganisms Most Likely to Cause a Global Catastrophic Biological Event (Baltimore, MD: Johns Hopkins Center for Health Security, 2018), https://centerforhealthsecurity.org/sites/default/files/2022–12/180510-pandemic-pathogens-report.pdf

⁶⁸ Anice C. Lowen, Arturo Casadevall, James C. Alwine, Lynn W. Enquist, Felicia D. Goodrum, Michael J. Imperiale, Seema S. Lakdawala, ‘Oversight of Pathogen Research Must Be Carefully Calibrated and Clearly Defined,’ Journal of Virology 97(3), February 27, 2023, https://doi.org/10.1128/jvi.00176–23

⁶⁹ Jacobsen KX, Mattison K, Heisz M, Fry S. Biosecurity in emerging life sciences technologies, a Canadian public health perspective. Front Public Health. 2014;2(198). Public Health Canada. Centre for Biosafety and Biosecurity. Updated December 8, 2022. [cited 2023 Jan 11]. https://www.canada.ca/en/services/health/biosafety-biosecurity.html

⁷⁰ Biden J. National Biodefense Strategy. Washington, DC; White House; 2022. viii.

⁷¹ Lentzos F, Koblentz GD, Rodgers J. The urgent need for an overhaul of global biorisk management. CTC Sentinel. 2022;15(4): 23–29.

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The author(s) reported there is no funding associated with the work featured in this article.