Publications

We thank Martin Furmanski for his interest in our article (1) concerning the unnatural origins of the 1977 H1N1 influenza virus strain. In his Letter to the Editor, he challenges our assertion that to date, there has been no real-world example of a laboratory accident that has led to a global epidemic, and he states that we ourselves concluded that the virus “originated in a microbiology laboratory and its release was unintentional,” to which he added that “which laboratory is responsible matters little in the GoF debate” (2). This is a mischaracterization of our findings.

The ongoing moratorium on gain-of-function (GOF) research with highly pathogenic avian influenza and SARS and MERS coronaviruses has drawn attention to the current debate on these research practices and the potential benefits and risks they present. While much of the discussion has been steered by members of the microbiology and policy communities, additional input from medical practitioners will be highly valuable toward developing a broadly inclusive policy that considers the relative value and harm of GOF research. This review attempts to serve as a primer on the topic for the clinical community by providing a historical context for GOF research, summarizing concerns about its risks, and surveying the medical products which it has yielded.

The U.S. government (USG) has taken steps intended to diminish the likelihood of misuse of research—in one recent action, declaring a funding moratorium on gain-of-function studies on influenza until a risk-benefit analysis can be conducted (1). The analysis is expected to examine biosafety concerns, the potential for such research to produce a biological weapons agent, and the possibility that publication may lower barriers to bioweapons development (1). To analyze the security risks of biological research, however, it is first necessary to determine the likelihood that bioweapons will threaten national security and to what degree legitimate research is at risk of misuse. This type of assessment is fraught with uncertainty.

The 1977-1978 influenza epidemic was probably not a natural event, as the genetic sequence of the virus was nearly identical to the sequences of decades-old strains. While there are several hypotheses that could explain its origin, the possibility that the 1977 epidemic resulted from a laboratory accident has recently gained popularity in discussions about the biosafety risks of gain-of-function (GOF) influenza virus research, as an argument for why this research should not be performed. There is now a moratorium in the United States on funding GOF research while the benefits and risks, including the potential for accident, are analyzed. Given the importance of this historical epidemic to ongoing policy debates, we revisit the evidence that the 1977 epidemic was not natural and examine three potential origins: a laboratory accident, a live-vaccine trial escape, or deliberate release as a biological weapon. Based on available evidence, the 1977 strain was indeed too closely matched to decades-old strains to likely be a natural occurrence. While the origin of the outbreak cannot be conclusively determined without additional evidence, there are very plausible alternatives to the laboratory accident hypothesis, diminishing the relevance of the 1977 experience to the modern GOF debate. 

Increasingly frequent and costly disasters in the US have prompted the need for greater collaboration at the local level among healthcare facilities, public health agencies, emergency medical services, and emergency management agencies. We conducted a multiphase, mixed-method, qualitative study to uncover the extent and quality of existing collaborations, identify what factors impede or facilitate the integration of the preparedness community, and propose measures to strengthen collaboration. Our study involved a comprehensive literature review, 55 semistructured key-informant interviews, and a working group meeting. Using thematic analysis, we identified 6 key findings that will inform the development of tools to help coalitions better assess and improve their own preparedness community integration.

This Synopsis provides summaries of key international treaties, agreements, instruments, guidelines, multilateral engagement mechanisms, and information resources intended to guide national approaches to biosafety in research, clinical, and industrial laboratories. It summarizes the benefits and limitations of each in promoting biosafety, and their individual contributions towards minimizing the global risk and consequences of laboratory accidents. Though the compilation of these arrangements, we have determined that there is an extensive array of existent governmental mechanisms related to biosafety. However, this work also exposed a major gap in international biosafety coverage related to the potential for high-consequence accidents: there remains a need for international norms for the biosafety and governance of those pathogens that have increased potential to spark a pandemic. 

Efforts by local health departments to screen recent immigrants for tuberculosis (TB) are an important component of broader TB control goals. Foreign-born individuals represent a significant source of new cases of active TB reported in the United States. In 2012, the incidence of TB was 11.5 times as great among foreign-born individuals in the United States than it was for individuals born in the United States. It has been estimated by the US Centers for Disease Control and Prevention (CDC) that 4 out of 5 active TB cases among foreign-born persons is attributable to reactivation of TB that was likely acquired prior to arrival in the United States.

This article assesses US government funding in 5 domains critical to strengthening health security: biodefense programs, radiological and nuclear programs, chemical programs, pandemic influenza and emerging infectious disease programs, and multiple-hazard and preparedness programs. This year's article also highlights the emergency funding appropriated in FY2015 to enable the international and domestic response to the Ebola outbreak in West Africa.

Leading experts have declared that the end of the age of antibiotics is imminent and that this development could undermine the foundation of much of modern medicine and public health., Since antibiotics were first introduced into clinical practice some 80 years ago, microbes have been evolving ways to resist these drugs, but in recent years this problem of antimicrobial resistance (AMR) has been rapidly getting worse.

In this article, we review the clinical management of deliberate infection with several pathogens of greatest bioweapons concern. On the basis of historical incidents coupled with information on ease of dissemination, contagiousness, mortality rates, public health impact, ability to engender panic, and the need for special preparedness,1-3 the Centers for Disease Control and Prevention (CDC) stratifies pathogens and toxins into three risk categories — A, B, and C — with category A meriting the highest level of concern and preparedness.4,5 In this review, we consider diseases that are caused by category A agents for which there are high-quality clinical data in the unclassified literature (see the Supplementary Appendix, available with the full text of this article at NEJM.org). The category A viral hemorrhagic fever viruses are beyond the scope of this review.

The White House recently called for a “robust and broad deliberative process” to assess the risks and benefits of select gain-of-function studies, pausing current experiments and further grants until new federal policy on research funding and oversight is developed. At issue is whether and under what conditions laboratory studies that enhance the transmissibility and/or virulence of potential pandemic pathogens such as the H5N1 avian influenza virus should go forward. To date, professionals from medicine, public health, and the life sciences have dominated the debate, and each side of the controversy has cited the public's well-being as the principal motivator for their position. A major stakeholder, the general public, has not yet actively and systematically weighed in on the matter. This commentary considers in what form and with what benefit public participation may materialize in the current debate regarding the governance of gain-of-function research.

For this second round of commentary, I focus on the grave risks of relying on nuclear weapons as a deterrent, and what is actually being done—and could be done—about those risks. While it can be imagined that a “safer” weapon could be switched out for nuclear weapons in our strategy of deterrence, in practice this will not happen. The myriad challenges of reducing nuclear weapons numbers across the globe would remain. In any case, governments need to do something to diminish the potential for armed nuclear conflict, for accidental launch, and for the increasing likelihood of nuclear-armed terrorist groups, which threatens to upend the strategic balance between nuclear armed and protected nations in ways that cannot be deterred. Adding another weapon of mass destruction to the mix does nothing to decrease this strategic risk.

A recent Bulletin column has suggested that non-contagious biological weapons may be a useful alternative to nuclear weapons as a deterrent, and could reduce the threat of nuclear devastation. While the United States may consider a variety of mechanisms toward a more stable deterrence strategy with fewer nuclear risks, biological weapons development will not be one of them. Doing so would violate US and international law and would be morally reprehensible. It would also leave the United States less secure.

Synthetic biology—often called “genetic engineering on steroids”— is on track to become an economically vibrant industry with national security implications. The rapidly expanding synthetic biology market is projected to grow to $16 billion by 2018.

While it is a relatively new field, synthetic biology has already been used to develop an antimalarial drug, make flu vaccines more rapidly, and to produce biofuels, detergents, adhesives, perfumes, tires, and specialized chemicals that formerly required the use of petrochemicals.

The US government has made sustained biodefense-related investments in basic and applied R&D aimed at producing anti-Ebola MCMs for more than a decade. Investments made by the National Institute of Allergy and Infectious Diseases (NIAID), through Biodefense and Emerging Infectious Diseases Program funding, and by the Department of Defense (DoD) Defense Threat Reduction Agency (DTRA), through the Chemical and Biological Defense Program (CBDP), have led to the development of a majority of the countermeasures in the pipeline. In addition, biodefense investments in building advanced development capabilities at the Biomedical Advanced Research and Development Authority (BARDA) and in building mechanisms for emergency clinical testing and emergency regulatory approval at the Food and Drug Administration (FDA) are now proving critical to current efforts to rapidly confirm safety and efficacy and ramp up production of countermeasures.

This article describes adoption by local health departments (LHDs) of federally recommended participatory approaches to public health emergency preparedness and LHD organizational characteristics associated with more intense community engagement in emergency preparedness, a top priority for US national health security.

Smallpox was one of the worst diseases that ever plagued humankind. From the time of the pharaohs until the 20^th century, it was a continuous scourge, killing 30 percent of those who were infected, and disfiguring most of the afflicted. The ability to vaccinate against it, and to use vaccine to diminish its spread, culminated in the eradication of smallpox. In 1980, the World Health Organization (WHO) declared that smallpox was no longer causing infections and that vaccinations could cease.

The UPMC Center for Health Security is grateful for the opportunity to provide comments on the ethical issues related to public health emergency response that have arisen as a result of the Ebola Virus epidemic in West Africa. The following comments reflect the collective views of several staff members of our organization but do not necessarily represent the views of all our staff and do not necessarily represent the official views of UPMC. We address each of the 7 issues posed in the Request for Comment.

Singapore is a critical security partner to the US in Southeast Asia. The US and Singapore share longstanding military relations, with American forces making use of Singapore’s Naval Base facilities, contributing to peace and stabilizing efforts throughout the region, offering humanitarian assistance, and acting as a deterrent to potential security threats.1 US-Singaporean security cooperation also extends to bilateral exercises, joint military training activities, and cargo screening efforts. The importance of Singapore to biosecurity in Southeast Asia continues to grow, due to its rapid biotechnology growth, its leadership in biosafety training within the region, its experience in containing the pandemic of severe acute respiratory syndrome (SARS), as well as ongoing preparedness efforts related to new, emerging diseases. 

Research on highly pathogenic organisms is crucial for medicine and public health, and we strongly support it. This work creates a foundation of new knowledge that provides critical insights around the world’s most deadly infectious diseases, and it can lay groundwork for the future development of new diagnostics, medicines, and vaccines. Almost all such research can be performed in ways that pose negligible or no risk of epidemic or global spread of a novel pathogen. However, research that aims to create new potential pandemic pathogens (PPP) (1)—novel microbes that combine likely human virulence with likely efficient transmission in humans—is an exception to that rule. While this research represents a tiny portion of the experimental work done in infectious disease research, it poses extraordinary potential risks to the public.