A Framework for Tomorrow’s Pathogen Research

International standards and guidance set overarching global benchmarks, and there are many with relevance to biorisk assessment.

The contemporary governance space for research with potential pandemic pathogens.

Recently, WHO developed a Global guidance framework for the responsible use of the life sciences, which, among other things, lays out a set of values and principles for responsible science. Published in 2022 and fundamentally anchored in a clear commitment to use the knowledge, material, and skills of basic and applied life sciences for the common good, the framework’s overarching aim is to make life better for humans and other animals, and to protect and promote the planet’s biodiversity, ecosystems, and environments. Promoting health, safety, and security, should, in turn, contribute to peace. In practice, this means using appropriate biosafety and biosecurity measures to prevent life sciences knowledge from causing harm, and it means preserving biodiversity where possible, to promote health, safety, and security and as an intrinsic value.

Of critical importance to the pursuit of health, safety, and security is a commitment to responsible stewardship of science. As detailed in WHO’s guidance framework, this entails a commitment to rigorous, evidence-based life science, to exercising caution to minimize risks, and to identifying and managing the reasonably foreseeable, potentially harmful consequences of life sciences research that could result from accidental, inadvertent, or intentional actions. Of particular relevance to research with pandemic risks, the responsible stewardship of science also involves a commitment to identify whether risks are proportionate to the potential benefits of the research, whether less-risky forms of research could be equally beneficial, and whether modifying the research design or the dissemination and publication plans as the research proceeds or after the research has been completed is advisable.

Other prominent international standards and guidance with relevance to biorisk assessment include the International Organization for Standardization’s ISO 35001: Biorisk management for laboratories and other related organisations, which outlines a process to identify, assess, control, and monitor the risks associated with hazardous biological materials, and the World Organisation for Animal Health (WOAH) Guidelines for responsible conduct in veterinary research, which provides advice to the veterinary community on identifying, assessing, and managing dual-use research.

Additionally, there are several international organizations and networks that support strengthening biorisk management (e.g., the International Federation of Biosafety Associations (IFBA), the American Biological Safety Association (ABSA) International, and the Association for Assessment and Accreditation of Laboratory Animal Care (AAALAC) International). Professional accreditation and certification in biosafety and biosecurity-related activities are critical to ensuring that practitioners and researchers are proficient and up-to-date on international biosafety and biosecurity standards.

While research regarding medical countermeasures and surveillance of known and potential pandemic pathogens may be an international priority, ensuring that this research occurs at the appropriate biosafety level is critical. The European Research Infrastructure on Highly Pathogenic Agents (ERINHA), for example, provides maximum containment support for research that has undergone a comprehensive application process to ensure scientific feasibility and meets ethical standards and the organization’s research priorities.

Ensuring that known and potential pandemic pathogens are secured and that research is monitored is a key function of international biorisk oversight. The WHO’s Advisory Committee on Variola Virus Research (ACVVR) is a prime example of the role of international research oversight and laboratory inspections to ensure that previously pandemic pathogens do not re-emerge while allowing approved research plans to fill critical knowledge gaps on orthopoxviruses. AAALAC International conducts on-site visits as part of its laboratory accreditation process, which includes an assessment of transportation and arrangements when new animals are introduced to an existing herd as well as laboratory physical security.

Capacity-building and knowledge-sharing also form a crucial part of strengthening international biorisk management. The Global Health Security Agenda partnership of more than 70 countries and non-governmental organizations focuses its biosafety and biosecurity work on community-building, information-sharing, and resource hub functions. The primary focus of the group is providing expertise and resources for addressing country-level gaps identified in WHO assessments of country capacities to prevent, detect, and respond rapidly to public health risks (WHO n.d.b). The International Experts Group of Biosafety and Biosecurity Regulators (IEGBBR) is a group of biosafety and biosecurity regulatory representatives from 11 member countries who share practical knowledge on developing national-level oversight and regulatory standards for biorisk management, encouraging a global complementary approach to developing a regulatory framework. The Biosafety Level 4 Zoonotic Laboratory Network (BSL4ZNet) provides training opportunities and workshops for laboratory workers, focused primarily on the care and handling of animals in a maximum-containment laboratory environment.

At the national level, a mix of legislation, regulations, policies, and guidelines aimed at assessing and managing biological risks apply to researchers and their institutions. Widely recognized and adapted to a broad range of national contexts, gold standards for working safely with biological agents include: (1) the US Centers for Disease Control and Prevention’s Biosafety in Microbiological and Biomedical Laboratories (BMBL); (2) the US National Institutes of Health’s Guidelines for Research Involving Recombinant or Synthetic Nucleic Acid Molecules; (3) the United Kingdom’s health and safety laws and guidance on biological agents including the Advisory Committee on Dangerous Pathogen’s Management and operation of microbiological containment laboratories; and (4) the European Union’s legislation on the contained use and deliberate release of genetically modified organisms.

There is limited guidance, internationally or nationally, focused specifically on review and oversight of potential pandemic pathogens. The US policies for oversight of dual-use research of concern and the potential pandemic pathogen care and oversight (P3CO) policy framework are the leading standards. But each nation needs to consider resource availability, sensitivities, and public health priorities in creating policies that are appropriate for the local context.

In the US policies, dual-use research of concern is defined as “life sciences research that, based on current understanding, can be reasonably anticipated to provide knowledge information, products, or technologies that could be directly misapplied to pose a significant threat with broad potential consequences to public health and safety, agricultural crops and other plants, animals, the environment, materiel, or national security (US Government 2012; Fink 2004).” Review is limited to research involving one or more of the 15 listed agents considered to pose the greatest risk of intentional misuse with most significant potential for mass casualties or devastating effects to the economy, critical infrastructure, or public confidence. Review is further limited to research with the listed categories that aims to produce, or is reasonably anticipated to produce, one or more of the following effects:

• Enhance the harmful consequences of the agent.
• Disrupt immunity or the effectiveness of an immunization against the agent without clinical or agricultural justification.
• Confer resistance to the agent to clinically or agriculturally useful prophylactic or therapeutic interventions or facilitates its ability to evade detection methodologies.
• Increase the stability, transmissibility, or the ability to disseminate the agent.
• Alter the host range.
• Enhance susceptibility of a host population to the agent.
• Generate or reconstitute an eradicated or extinct agent.

The US potential pandemic pathogen care and oversight framework (HHS 2017) outlines a review and reporting process aimed at limiting the possibility of accidental, inadvertent, or intentional release of a pathogen capable of causing widespread harm to public health from US federally funded research. It provides a list of criteria for guiding funding decisions by the Department of Health and Human Services on proposed research that involves, or is reasonably anticipated to involve, the creation, transfer, or use of enhanced potential pandemic pathogens. Included in the list is a requirement that researchers demonstrate “… [t]here are no feasible, equally efficacious alternative methods to address the same question in a manner that poses less risk ... .” Since the policy’s implementation in 2017, the federal agency has reviewed three research projects, all of which were approved, though one project was ultimately modified so that it did not involve potential pandemic pathogens (NIH n.d.). The department has not released details on its process for deciding whether research projects should undergo review, nor has it specified the nature of the review or the deliberations leading to the approval of these projects. Many have criticized this lack of transparency, and the framework is currently under review (Inglesby et al. 2023).

In March 2023, the National Science Advisory Board on Biosecurity (NSABB), a US federal advisory committee that addresses issues related to biosecurity and dual-use research, published its recommendations on how to develop a more comprehensive and integrated framework for oversight of pathogen research that may pose significant biosafety or biosecurity risks (NSABB 2023). The US Government issued a request for information on potential changes to the dual-use research of concern and potential pandemic pathogen care and oversight policies in September 2023.

In summary: Effective legislation, regulations, policies, and guidelines specifically regulating research with pandemic risks will strengthen the scientific enterprise and should be put in place without delay. Greater clarity about work that does not require special oversight would reduce uncertainty among researchers and streamline the research process.

In the meantime, informal governance through professional norms, codes of ethics, standard operating procedures, and other practices associated with self-governance should be harnessed to provide norm-setting standards and raise awareness of the need for enhanced harm–benefit assessments for this kind of research. At present, it is broadly accepted that science should be conducted in a way that avoids subjecting populations, human research participants, or laboratory workers to undue risks or causing unnecessary suffering to experimental animals. It should become a similar article of scientific ethos that exceptional public health benefits unachievable by safer means are necessary to justify any undertaking that could increase the risk of an accidental, inadvertent, or intentional pandemic.

Education and training are also important components of informal governance. They not only raise awareness but can provide important how-to tools for assessing and documenting biorisks in a way that is accessible to co-workers and to internal and external auditors as well as tools to identify and implement measures and practices to minimize the impact of biorisks. We should aspire towards a state in which concern for minimizing population-level risks of accidental pathogen releases or misuse of research results is as automatic and universal to researchers as current norms about ensuring proper treatment of human research participants and reducing, replacing, and refining the use of nonhuman animals in research.

Stanford University’s The Biorisk Management Casebook: Insights Into Contemporary Practices provides a series of concrete examples of how biorisk frameworks from around the world have been implemented in practice (Greene et al. 2023). These case studies, and others like them, can enable scientists and their institutions to learn from one another about what works and under which circumstances.

Key to the success of more informal tools and mechanisms is that they are properly and sustainably resourced and institutionally recognized, valued, incentivized, and rewarded.