The Zika virus outbreak is spreading in the U.S., according to local public health authorities and the federal Centers for Disease Control (CDC); international Zika virus cases are also increasing. Infection occurs because of a mosquito bite that transmits the virus, and most public health interventions to date concentrate on limiting exposure to the mosquito (Aedes aegypti). As of yet, there is no vaccine or specific treatment for the Zika virus. The discovery that Zika virus infection in pregnant women can lead to birth defects, including microcephaly, raised the alarm about the spread of the virus in this population (see earlier post here). To date, there are about 1400 reported cases in the U.S; there are about 400 cases of Zika infection in pregnant women. Most cases in the U.S. are traced to individuals traveling outside the country, returning with the infection; Puerto Rico, Brazil and other Caribbean and Latin American countries are some of the hotspots of transmission. Now, however, there appear to be are several cases of local transmission of the Zika virus in Florida, which means that the virus is gaining a foothold in the U.S. itself. As in most public health crises, the government is tasked with providing increased support to local authorities, funding for treatment developments, and other activities. Congress has been in a stalemate over emergency Zika virus funding over the last month. President Obama sought $1.9 billion in new dedicated funding; the House of Representatives approved $1.1 billion. On to the Senate, where several provisions inserted into the funding bill encountered opposition; most notably, an explicit ban on Planned Parenthood as the recipient of any new funds. As discussed in an earlier post, because of the risk that Zika virus infection poses to pregnant women, who are at risk to give birth to babies with developmental disorders (and not all are known at this point), access to contraception and other reproductive services would appear to be a key ingredient in minimizing the birth of Zika-affected babies. That’s where the usual political conflict over reproductive and family planning funding entered the Zika funding legislation, and created an impasse. So to date, the Senate has not approved the funding that the House approved, and Congress has taken its usual lengthy summer break without acting on emergency funding for Zika virus research and support. The 7-week hiatus in the Zika funding battle has dismayed federal public health officials. The American Medical Association (AMA) faulted Congress:
At a time when concerns continue to mount about the nation's readiness to protect the public from the Zika virus, the AMA is disappointed by Congress' failure to pass legislation before adjourning for summer recess that would provide the resources necessary for our country to respond to this looming public health crisis. Without ensuring there are sufficient resources available for research, prevention, control and treatment of illnesses associated with the Zika virus, the United States will be ill-equipped to deploy the kind of public health response needed to keep our citizens safe and healthy—especially since the spread of mosquito-borne illness is accelerated during the summer months.
Editorials in some of the hardest hit areas of the country noted how the impasse would adversely affect their regions; here is the Palm Beach Post from Florida on the local impact:
Congress has left the building. And in its dysfunctional wake, it leaves yet another failed effort at passing crucial emergency funding to fight the spread of the dreaded Zika virus. For at least the next seven weeks, Florida — which has distinguished itself as ground zero for cases of the mosquito-borne virus — will just have to hope that the worst part of the rainy storm season doesn’t translate into more infections. (Palm Beach County has seen about 12 cases of travel-related Zika.) It may be a long, hot summer. Mosquitoes that carry the Zika virus breed year-round here, and the number of infections in the continental United States is mounting. On Monday, the state Health Department reported 13 new cases of the Zika virus in Florida - the most reported cases of the virus in a single day. Moreover, federal officials say they will have to postpone a slew of anti-Zika actions. For example, the U.S. Centers for Disease Control and Prevention will have “limited capacity” to help with efforts to counter mosquito populations in the continental U.S. and territories.
Yes, it should be noted that the CDC is now dispersing about 60 million dollars currently to localities to augment public health efforts, but these are “stopgap” awards that will not approach the scale of the demand. Congress returns on September 6th.
In the ongoing outbreak of Zika virus infection across parts of North and South America, there are several developments which signal increasing concern over the exact impact and geographic reach of the virus (the first death in the U.S. linked to the virus has been reported). At least 55 countries report Zika outbreaks, according to the World Health Organization. The virus is spread by mosquitos, specifically the Aedes aegypti. In the U.S., 426 cases of Zika-infected individuals have been reported. Although a course of infection may be mild and easily resolved in most individuals, Zika has become a high-profile infectious disease because viral infection in pregnant women has been linked to an increased risk of microcephaly in offspring. There are suspicions that more developmental risks to the child of an infected mother may exist, possibly unknown and only seen as development unfolds. In general, the mosquito thrives in warm and tropical climates, but seasonal weather patterns can shift the field of exposure. NASA scientists and other colleagues have published an Aedes aegypti risk map of the U.S., showing that a wide swath of the eastern U.S. is potentially susceptible to mosquito (and thus virus) spread, especially in the upcoming summer of 2016; the potential spread goes north as far as New York City. A commercially available test for detection of the Zika virus received an Emergency Use Authorization (EUA) from the FDA (the Quest Diagnostics Zika RT-PCR test). A current legislative battle over possible increased funding for public health responses to Zika reached a stalemate before Congress adjourned. One bill calls for $1.6 billion in supplemental funding for dedicated Zika virus research and public health capabilities, but is encountering Republican opposition. Some of the political infighting over a federal response to the Zika outbreak recalls earlier conflicts during the Ebola virus crisis. However, the Zika virus is already in the U.S., cases are officially documented, and the upcoming summer portends more infections, not less. The 2016 Summer Olympics in Brazil this summer have already caused concern among attending athletes; the current understanding of transmission suggests that Zika virus cases in the U.S. are largely explained by travel to countries with high risk of infection; that fact will also impact the Olympics participation. No effective treatment or vaccine for the Zika virus is yet developed; increased NIH funding would certainly allow research to expand. Another target for intervention is to reduce the Aedes aegypti mosquito population; already, a British biotechnology has produced a genetically engineered (GE) mosquito that is reproductively crippled and is hoping to conduct trials in the U.S. An upcoming post will examine that option in more detail.
The Ebola virus disease crisis continues in western Africa. To date, in the hardest-hit countries of Liberia, Guinea and Sierra Leone, at least 23,913 cases are reported by the World Health Organization (WHO), with 9,714 deaths. At the height of the Ebola outbreaks on several continents last fall, the experimental biotech drug, ZMapp, made by Mapp Biopharmaceutical of San Diego, and comprised of several humanized monoclonal antibodies, was given to several U.S. health care workers who had contracted the virus while working in western Africa, with positive results. Although no drug had received formal approval for treating Ebola virus disease, WHO assembled an expert panel to consider the ethical implications of using non-approved, but potentially promising drugs (including ZMapp) during the expanding Ebola crisis; a summary of their consultation stated:
In the particular circumstances of this outbreak, and provided certain conditions are met, the panel reached consensus that it is ethical to offer unproven interventions with as yet unknown efficacy and adverse effects, as potential treatment or prevention.
Now, the first formal clinical trial for ZMapp has been announced by the National Institute of Allergy and Infectious Disease (NIAID):
In partnership with the Liberian government, the National Institute of Allergy and Infectious Diseases (NIAID) today launched a clinical trial to obtain safety and efficacy data on the investigational drug ZMapp as a treatment for Ebola virus disease. The study, which will be conducted in Liberia and the United States, is a randomized controlled trial enrolling adults and children with known Ebola virus infection.
“Although ZMapp has been used to treat several Ebola-infected patients in recent months, we cannot determine if the drug actually benefitted those patients because it was not administered within the context of a clinical trial,” said Anthony S. Fauci, M.D., director of the NIAID, at the National Institutes of Health (NIH). “This clinical trial will help us determine if ZMapp and other treatments are safe and effective for use in the current devastating outbreak in West Africa as well as in future outbreaks.
ZMapp, developed by Mapp Biopharmaceutical Inc., based in San Diego, is composed of three different proteins called monoclonal antibodies. ZMapp is designed to prevent the progression of Ebola virus disease within the body by targeting the main surface protein of the Ebola virus. The antibodies comprising ZMapp are produced in tobacco plants specially bioengineered to produce large quantities of these proteins. Studies in nonhuman primates demonstrated that ZMapp has strong antiviral activity and rescued the animals from death as late as five days after infection with Zaire ebola virus. The drug has not yet been tested in human clinical trials, but was administered under emergency use authorization to nine infected patients in Africa, the United States, and Western Europe.
The current picture for containing Ebola virus is mixed; while western Africa is still a focus of public health and relief efforts, there are warnings regarding the possibility that other countries with poor public health infrastructure could be susceptible to future outbreaks. Furthermore, there is still no vaccine available, although some promising candidates are in development. From the U.S. perspective, the American troops committed to public health assistance in western Africa are being withdrawn. The Ebola "czar" has now finished his term, and has called for improving the WHO response capacity, decreasing reliance on overburdened NGOs and establishing a formal international public health responder force ready to be deployed in similar crises. The Ebola crisis illustrates a paradox of modern public health management: specific therapeutic options may originate in cutting-edge biotechnology, but the overall containment of any infectious disease crisis is equally dependent on the availability of basic, old-fashioned public health infrastructure.
Over the last year, reports of biosafety lapses in federal laboratories conducting research on anthrax, smallpox and Ebola virus elicited strong reactions in the scientific community and generated official responses to reduce the likelihood of similar events (see here for overview of CDC, NIH and FDA incidents). As the nation's signature public health agency, the incidents at the CDC laboratories were especially troublesome. In general, laboratories conducting microbiological research are designed to accommodate the safety requirements attendant to the threat of the pathogen itself. The safety evaluation will mandate the appropriate facilities, procedures and trained personnel based on the level of risk Laboratories are classified in a tier of biosafety levels (BSL1-4), with a BSL-4 designation describing the highest level containment environment:
Biosafety Level 4 is required for work with dangerous and exotic agents that pose a high individual risk of aerosol-transmitted laboratory infections and life-threatening disease that is frequently fatal, for which there are no vaccines or treatments, or a related agent with unknown risk of transmission. Agents with a close or identical antigenic relationship to agents requiring BSL-4 containment must be handled at this level until sufficient data are obtained either to confirm continued work at this level, or re-designate the level. Laboratory staff must have specific and thorough training in handling extremely hazardous infectious agents. Laboratory staff must understand the primary and secondary containment functions of standard and special practices, containment equipment, and laboratory design characteristics. All laboratory staff and supervisors must be competent in handling agents and procedures requiring BSL-4 containment.
Now, the CDC has issued its internal report on the December, 2014 Ebola incident in which a lab worker was possibly exposed to live Ebola virus. The report is detailed,
and it is clear that human error explains the incident where Ebola virus may have been unintentionally transferred from a BSL-4 lab to a BSL-2 lab, which would lack the same degree of protection for potentially exposed workers. An earlier internal CDC report on the June, 2014 anthrax incident, involving transfer of a biological sample from a BSL-3 to a BSL-2 lab also identified personnel errors, as well as gaps in the overall containment protocols. In August, 2014, as a result of the pattern of safety lapses, the White House ordered a stand-down for federal laboratories to pause and review their biocontainment policies and practices, as well as perform an audit of pathogens and select agents. Reports now issued by the CDC and NIH detail the result of the stand-down,
detailing the scale and site of research with the most dangerous pathogens, and identifying instances where undocumented biological samples have been left behind from earlier investigations. Overall, the stand-down produced a real-time status report on pathogen storage and handling in the leading federal labs; it is clear from the specific incidents reports, however, that human error can still override the most carefully planned containment measures.
The urgency of calls for reliable and scaled public health responses to the magnitude of the international Ebola virus disease (EVD) outbreak is increasing; a media frenzy over the apparent emergence of Ebola in Dallas, TX is underway. At the present time, over 7,000 cases and over 3,300 deaths are attributed to the outbreak concentrated in West Africa, where the virus emerged earlier this year. The crisis requires a combination of public health resources (personnel, facilities, diagnostic capabilities) and effective countermeasures (vaccines, drugs). To date, the most effective drug against the virus appears to be ZMapp, an antibody-based treatment developed by Mapp Biotherapeutical. However, ZMapp supplies are limited, and efforts to scale up production, while necessary, will still not produce enough to meet demand. An expert consultation called by the World Health Organization this week to review vaccine candidates has identified two Ebola vaccines that are ready for Phase I clinical trials. Scheduled milestones for the testing and evaluation of these potential vaccines are now published. Even in a best case scenario, in which a vaccine candidate performs well enough to justify scaleup and distribution, WHO does not anticipate that a significant number of vaccines to be ready before around March, 2015. The WHO meeting participants noted the unprecedented severity and spread of this viral disease relative to other public health crises:
Participants also drew heavily on lessons learned, in the African setting, during trials for candidate malaria, HIV/AIDS, cholera, epidemic meningitis, hepatitis B, and other vaccines. As some experts noted, never again can the international community allow what boils down to “market failure” to create such catastrophic suffering for humanity in any country, in any region of the world. The sense of urgency and need for speed, without compromising the integrity of studies or the quality of their data, are fully justified by the dire situation in affected countries and the risk that other countries may soon experience their first imported cases. The Ebola outbreak currently ravaging parts of West Africa is the most severe acute public health emergency in modern times. Never before in recent history has a biosafety level 4 pathogen infected so many people so quickly, over such a wide geographical area, for so long.
The CDC has already estimated that 1.4 million cases of EVD could emerge by January next year. Case projections from WHO are smaller, but both agencies point out that a near-term ability to reverse the course of EVD will depend on successful public health efforts, including patient isolation and contact avoidance measures. Drugs and vaccines will not be produced fast enough in the short term to meet demand, but the efforts described above are good starts. More generally, as the WHO acknowledged with its reference to “market failure,” it is clear that government expenditures for research on countermeasures need to continue, but the development of a true pipeline from lab to clinic is still lacking. That is a translational failure here: the emergence of rare but deadly outbreaks of diseases like Ebola are not met with stockpiles of drugs. The U.S. Strategic National Stockpile maintains supplies of drugs for use in viral epidemics, but these are directed to the more familiar diseases such as influenza and anthrax. The current Ebola outbreak illustrates the consequences of focusing national resources too narrowly on the usual suspects in bioterrorism or pandemic crises, with the consequence that new or remote pathogens emerging in the U.S. are not met immediately with effective countermeasures that would contain disease outbreaks.
Ebola virus disease (EVD) has appeared in several West African nations over the last several months, and is now spreading with increasing speed. The international public health response has involved World Health Organization (WHO), Centers for Disease Control (CDC), Doctors Without Borders (MSF), and local public health authorities, among others. WHO has now formulated an Ebola response roadmap for the crisis.The history of Ebola virus outbreaks shows the first recognition of the pathogen in 1976, followed by several decades of periodic outbreaks with various virus subtypes. Dr. Anthony Fauci, director of the National Institute of Allergy and Infectious Disease (NIAID), placed the current EVD outbreak in historical context:
In most instances, the virus emerged in geographically restricted, rural regions, and outbreaks were contained through routine public health measures such as case identification, contact tracing, patient isolation, and quarantine to break the chain of virus transmission. In early 2014, EVD emerged in a remote region of Guinea near its borders with Sierra Leone and Liberia. Since then, the epidemic has grown dramatically, fueled by several factors. First, Guinea, Sierra Leone, and Liberia are resource-poor countries already coping with major health challenges, such as malaria and other endemic diseases, some of which may be confused with EVD. Next, their borders are porous, and movement between countries is constant. Health care infrastructure is inadequate, and health workers and essential supplies including personal protective equipment are scarce. Traditional practices, such as bathing of corpses before burial, have facilitated transmission. The epidemic has spread to cities, which complicates tracing of contacts. Finally, decades of conflict have left the populations distrustful of governing officials and authority figures such as health professionals. Add to these problems a rapidly spreading virus with a high mortality rate, and the scope of the challenge becomes clear.
To date, at least 3,000 cases and over 1800 deaths have been reported in the West Africa nations of Sierra Leone, Guinea, and Liberia, with numbers rising. Isolated cases are also observed in Nigeria and Senegal. To date, the case fatality rate is estimated at around 60%. No vaccine or effective antiviral is currently available against the virus. An unapproved cocktail of monoclonal antibodies produced by Mapp Biopharmaceutical of San Diego, called ZMapp, was administered to several health workers from the U.S.; their recovery may be partially explained by the use of this drug (although their access raises ethical questions regarding how to allocate scarce countermeasures). That drug essentially transfers an immune response to the patient (passive immunity). The other modalities for EVD treatment and prevention are the more commonly known avenues of vaccines that elicit the patient’s own immune response and/or antiviral drugs which interfere with virus replication. The availability of vaccines and antivirals for “emerging or reemerging diseases” illustrates the deficiencies in matching market realities to public health demands. The research that led to ZMapp was partially funded by the U.S. government as part of its program to establish medical countermeasures against a bioterrorist attack (resources that greatly expanded after 9/11). The supply of ZMapp is limited; HHS is now funding expanded production and formal clinical trials of the drug. In addition, several Ebola vaccines will enter clinical trials soon. But the availability of countermeasures, while necessary, is not the only determinant of how soon the outbreak (not yet called a pandemic) will be contained. The international public health infrastructure, ideally coordinated by WHO, is dependent on funding from national governments, and mandated funding has declined over the years, undercutting WHO's capabilities. WHO did not declare a public health emergency until August, despite the fact that cases began to spread in March. While more vaccines and antivirals can make a difference in any viral disease outbreak, the spread of EBV could have been managed with a more robust public health emergency response earlier this year. MSF has called for countries with biological disaster response teams (e.g., U.S.) to send these personnel to the regions to augment field hospitals, diagnostic laboratories, and other facilities needed to manage the crisis.
In a climate where concerns over experiments that create new potentially dangerous pathogens are now amplified due to recent biosafety lapses in high-profile labs, a new group of scientists, Scientists for Science (SFS), emerged this week to assert that research on dangerous pathogens can be (and generally is) conducted safely, that it is adequately regulated, and that such work is critical for public health (the current Ebola virus public health crisis contributes to public attention on these issues). This statement and organization contrasts with and follows the recent statement from the recently formed Cambridge Working Group (CWG) (see here) that called for curtailing certain high-risk pathogen experiments until a thorough cost-benefit analysis is conducted by the scientific community, along the lines of work done by the 1975 Asilomar conference on the risks of recombinant DNA research. The SFS rejects the Asilomar comparison and does not call for limiting such experiments now, but it does call for a more formal review of risks and benefits conducted by an outside expert body, such as the National Academy of Sciences (NAS). From the SFS statement:
Scientists for Science are confident that biomedical research on potentially dangerous pathogens can be performed safely and is essential for a comprehensive understanding of microbial disease pathogenesis, prevention and treatment. The results of such research are often unanticipated and accrue over time; therefore, risk-benefit analyses are difficult to assess accurately.
If we expect to continue to improve our understanding of how microorganisms cause disease we cannot avoid working with potentially dangerous pathogens. In recognition of this need, significant resources have been invested globally to build and operate BSL-3 and BSL-4 facilities, and to mitigate risk in a variety of ways, involving regulatory requirements, facility engineering and training. Ensuring that these facilities operate safely and are staffed effectively so that risk is minimized is our most important line of defense, as opposed to limiting the types of experiments that are done.
In contrast to recombinant DNA research at the time of Asilomar in 1975, studies on dangerous pathogens are already subject to extensive regulations. In addition to regulations associated with Select Agent research, experimental plans on other pathogens are peer reviewed by scientists and funding agencies, and the associated risk assessments are considered by biosafety experts and safety committees. Risk mitigation plans are proposed and then considered and either approved or improved by safety committees.
If there is going to be further discussion about these issues, we must have input from outside experts with the background and skills to conduct actual risk assessments based on specific experiments and existing laboratories. Such conversations are best facilitated under the auspices of a neutral party, such as the International Union of Microbiological Societies or the American Society for Microbiology, or national academies, such as the National Academy of Sciences, USA. We suggest they should organize a meeting to discuss these issues.
The CWG and SFS clearly do not agree on the need to halt certain experiments while a more thorough review of cost-benefit parameters for high-risk pathogen research is conducted. However, a consensus is clearly emerging on both sides that public confidence in the need for such experiments as well as continued funding support does require more thorough, expert assessment from outside experts. Neither statement references the National Science Advisory Board for Biosecurity (NSABB), the federal advisory committee that most recently was called on during to assess the publication of gain-of function influenza H5N1 research in 2011. That panel has been recently reshuffled by NIH. A high-level study by the NAS on these issues, therefore, appears welcome to all sides of the current debate. The NAS (through its National Research Council) did undertake a general review of bioterrorism research post-9/11, entitled Biotechnology Research in an Age of Terrorism: Confronting the Dual Use Dilemma (2004) (the Fink Report), which called for the establishment of the NSABB, so there is a certain circularity here.
Recent developments regarding the biosafety practices in several government laboratories have raised concerns about the containment of potentially dangerous pathogens in scientific research. In the past month, a series of separate incidents exposed weaknesses in the oversight and management of dangerous pathogens. These included the accidental exposure of CDC scientists to anthrax in CDC labs, the discovery of forgotten vials of viable smallpox virus in an FDA lab housed at the NIH, and an unintentional cross-contamination of a benign influenza strain with a dangerous H5N1 influenza and its subsequent transfer. All of these events involve naturally occurring pathogens, but these events also occur at a time when public debate continues over the deliberate creation of potentially dangerous pathogens in the field of dual-use research of concern (DURC). With scientists reporting the creation of new pathogens in order to define what genetic changes correlate with pathogenicity or transmissibility, concerns emerged as to how such scientific detail should be publicly shared, and how such pathogens were to be safely contained in the laboratory environment. Most of the attention focused on the publication of genetic detail, evidencing concerns that the pathogens could be reconstructed for malicious intent. However, an equally serious concern related to the possibility that the newly designed pathogens could be released inadvertently, due to laboratory or personnel errors. This recent series of safety lapses now amplify the concerns over the general state of biosafety practices in laboratories handling the most dangerous pathogens, whether natural or engineered. Although the standards for the containment of dangerous pathogens in laboratories are well-known and generally followed, one untoward release of a high-risk infectious agent could be catastrophic. In general, there are established biosafety protocols which define the type of required facilities, procedures and personnel based on the level of risk that a particular pathogen poses to public health and/or the environment. The guidelines assign a biosafety level (BSL) based on that analysis; the high-containment BSL-3 and BSL-4 labs are required for work with the most dangerous pathogens. In addition, the transport of such pathogens is also managed with protocols that establish safe transfer. The CDC director, Dr. Thomas Frieden, conceded the pattern of biosafety lapses in a press conference and at a Congressional hearing yesterday. Dr. Frieden has shut down several labs and instituted a moratorium on some shipments of pathogens. The Government Accountability Office (GAO) has conducted several studies on laboratory safety in high-containment laboratories (private or public), specifically noting the absence of any overarching federal body to oversee these laboratories, particularly in view of their proliferation in the years since 9/11 (the anthrax incidents), as bioterror-related research has increased (note recent controversy over a BSL-4 lab established in Boston). The GAO was represented at yesterday’s hearing, and it reminded Congress of their previous investigations and recommendations on laboratory safety; the recent incidents may cause Congress to revisit this work and act accordingly.
The public health campaign to eradicate smallpox, a highly contagious viral disease with significant mortality, was one of the public health success stories of the 20th century. Following decades of vaccination against the variola major virus, the causative agent of smallpox, the World Health Organization (WHO) declared the eradication of smallpox in 1980 (the last case in the U.S. occurred in 1949, and the last global case was in Somalia in 1977). With this goal achieved, a long-standing concern for international public health authorities has been how to limit and manage the remaining stocks of the smallpox virus. With eradication achieved, should variola virus be retained in laboratories, in view of its characterization as a dual-use microbe – a source of legitimate research interest as a viral pathogen as well as a potential bioweapon? In 1983, by international agreement, a decision was made to retain variola virus stocks at two WHO Collaborating Center laboratories: the State Research Centre for Virology and Biotechnology in Koltsovo, Russia, and in the U.S. at the Centers for Disease Control and Prevention in Atlanta, Georgia. Speculation has continued, however, over whether unaccounted virus stocks exist in other places. The World Health Assembly (WHA), the decision-making conference of the WHO, supported the policy of setting limits on access to variola virus, and, by 1994, endorsed the eventual destruction of the remaining virus stocks. Over the years, WHO surveyed whether consensus research goals required continued maintenance of virus stocks. In 2011, the WHA reaffirmed the eventual destruction of the virus stocks, but deferred the setting of an actual date to the WHA conference in May of this year. Within WHO, the two advisory committees that considered the issue reached different conclusions. At this recent conference, it was decided that the virus stocks will continue to be maintained, because research goals dependent on access to the virus remain unfinished. These goals include the further development of antivirals (smallpox vaccines exist and are maintained in national and international stockpiles). Dissension among the WHO advisory committees contributed to the decision to delay the setting of a date for destruction of the stocks. Not surprisingly, a divergence of views on the merits of retaining variola virus stocks exists in the scientific community (support for maintaining virus stocks for future research versus calls for destroying the virus stocks) as well as among the WHO member states (with U.S. favoring retention while less-developed countries have favored destruction). A further wrinkle in the debate is the emergence of new technical capabilities (e.g., synthetic biology techniques) that could allow artificial reconstruction of the smallpox genome; such a possibility focuses policy concerns away from access to viral stocks and instead on access to genomic and technical information (actual publication). Of course, concerns about informational access have surfaced recently with research reporting the development of highly pathogenic H5N1 influenza viruses (see here and here). The still-unresolved smallpox (variola) virus retention issue illustrates how dual-use research concerns can originate from existing natural pathogens, as well as newly engineered or synthesized pathogens.
A declaration of intent to conduct “gain-of function” experiments on the novel avian influenza A(H7N9) virus has been published by scientists who wish to alter the genetic composition of the viruses to determine what genetic changes/mutations correlate with altered function. Gain of function (GOF) experiments on pathogens alter existing properties and can result in the creation of more dangerous pathogens; the goal is to gain insights into the relationship between genetics (structure) and function. The H7N9 virus emerged earlier this year in China, and to date the World Health Organization reports 135 human cases, with 44 fatalities. This new effort to study H7N9 is proposed by a consortium of scientists, including Ron Fouchier and Yoshihiro Kawaoka, who were the principal investigators for the experiments on HPAI H5N1 viruses that produced viruses with potentially increased human to human transmissibility. Those earlier experiments raised such an alarm that publication of the research was halted in the U.S. while the NSABB federal advisory committee evaluated the risk of publication (both were eventually published). The proposed experiments fall into the category of DURC (dual research of concern), defined as such:
Dual use research of concern(DURC) is a subset of dual use research 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.
The declaration of intent by the scientists is presumably an attempt to increase transparency and invite deliberation at the front end of the process and avoid the panicked reaction that followed the announcements of the earlier H5N1 experiments in 2011. The authors also include materials outlining the biosafety precautions that would accompany the experiments. Early official reaction from the CDC and NIH declares that such experiments will receive extra scrutiny before U.S. government funding will be made available, according to recently issued federal guidelines for DURC issued earlier this year. The CDC has also issued specific biosafety guidelines for working with the H7N9 virus. The following kinds of gain-of-function experiments were announced in the letter:
•Immunogenicity. To develop more effective vaccines and determine whether genetic changes that confer altered virulence, host range or transmissibility also change antigenicity.
•Adaptation. To assist with risk assessment of the pandemic potential of field strains and evaluate the potential of A(H7N9) viruses to become better adapted to mammals, including determining the ability of these viruses to reassort with other circulating influenza strains.
•Drug resistance. To assess the potential for drug resistance to emerge in circulating viruses, evaluate the genetic stability of mutations conferring drug resistance, and evaluate the efficacy of combination therapy with antiviral therapeutics. Also, to determine whether A(H7N9) viruses could become resistant to available antiviral drugs, and to identify potential resistance mutations that should be monitored during antiviral treatment.
•Transmission. To assess the pandemic potential of circulating strains and perform transmission studies to identify mutations and gene combinations that confer enhanced transmissibility in mammalian models (such as ferrets and guinea pigs).
•Pathogenicity. To aid risk assessment and identify mechanisms, including reassortment and changes to the haemagglutinin cleavage site, that would enable circulating A(H7N9) viruses to become more pathogenic.
These proposed experiments – altering the critical variables of spread and virulence for the viruses, changing drug resistance and vaccine susceptibility – will likely produce viruses that are potentially more dangerous than those we currently know about. The stated goal of such work is to learn which mutations alter the risk profile of a virus – confer pandemic potential – and use that knowledge to design vaccines or discover antivirals that can respond to these viruses. Further, it is argued that ongoing surveillance efforts can be focused on identifying virus isolates that display such mutations and pose an elevated public health risk, although this point is contested by other scientists. It’s not clear whether the NSABB will be involved at this early stage – to date, it has not advised on the merits of funding specific experiments which can be characterized as DURC. The recent tightening of federal review of such research will be put to the test with these proposed experiments as the investigators seek U.S. funds. With respect to the publication of results, the influenza researchers anticipate the possible fallout:
To advance A(H7N9) virus research, findings should be shared in refereed publications. Investigators agree to adhere to guidelines for responsible communication of results and every effort will be made to put the results in context and reduce sensationalism.
The questions that were raised by the H5N1 influenza controversy - what criteria are to be used when evaluating the funding for DURC or what conditions need to attach to such funding – will now surface with this H7N9 research declaration – and their resolution might establish a template for future research proposals.
The research moratorium called by influenza researchers following published experiments that created novel and possibly pandemic-capable genetically engineered H5N1 influenza viruses has formally ended (see here and here for more background). This voluntary halt in research on highly pathogenic avian influenza (HPAI) H5N1 began in January 2012, and was described as “a pause to this important research to provide time to explain the public health benefits of this work, to describe the measures in place to minimize possible risks, and to enable organizations and governments around the world to review their policies (for example, on biosafety, biosecurity, oversight, and communication) regarding these experiments.” The new statement supports the resumption of such research in countries where the biosafety and biosecurity concerns have been addressed. “Scientists should not restart their work in countries where, as yet, no decision has been reached on the conditions for H5N1 virus transmission research.” The U.S. is one of those countries. In fact, the NIH has undertaken a review of its policies for conducting dual-use research, which would include these influenza virus experiments. The new statement also notes international disagreement regarding the level of physical containment for the research, whether BL-3 or BL-4 (Canada). The U.S.-based H5N1 experiments have been conducted in less secure BL-3 facilities. Currently HHS has been collecting comments on the possible designation of H5N1 (or specifically HPAI H5N1) as a select agent; the practical consequences would be that laboratories would need to register with the government and follow strict CDC regulations for the physical conditions in which experiments with these viruses could occur. There is professional disagreement regarding the advisability of a select agent classification. The NIH has promised to release finalized guidelines for funding such research in the near future, which will be the result of a more detailed look by NIH at its own funding policies. The controversial research in both H5N1 publications was supported with grants from NIH.
The recent meeting of the National Science Advisory Board on Biosecurity this month was a public event to consider the status of gain-of function experiments with highly pathogenic avian influenza H5N1 (HPAI). Such experiments were the basis of two controversial papers published earlier this year that elevated concerns over whether scientific research carried the danger of producing dangerous viruses that posed threats to human health. The meeting considered biosafety issues as well as the new NIH research funding framework. The development of a more stringent review process for NIH funding of such research is underway; public comments on the proposed policy are invited until January 10, 2013. Reports from the meeting indicate an emerging consensus from the participants that the current voluntary moratorium on HPAI research should be ended. Separately, the comment period to respond to the CDC’s question of whether HPAI viruses should now be included in the most stringent class of biological agents, Tier 1, has been extended to January 13, 2013.
A recent review paper by Dr. Anthony Fauci, director of the National Institute of Allergy and Infectious Diseases, and colleagues looks at 20 years of emerging infectious diseases (EID). The concept of EID was elevated into prominence with the publication of an Institute of Medicine report in 1991 that considered EID as threats to U.S. health. The 20 year period since encompasses the AIDS and SARS pandemics, although the AIDS crisis began in the 1980’s. Both are viral diseases, and the difficulty in designing effective treatment regimens underscores the fears associated with a possible emergence of pandemic influenza. The concept of EID as a critical focus of public health research and surveillance is well-established, and the SARS pandemic in 2003 illustrated not only the obvious scientific challenges, but how international cooperation (e.g., data-sharing) was essential to tracking outbreaks. Another recent paper in PLOS Medicine analyzes pandemic preparation with reference to lessons learned from SARS and other international public health crises, noting that although pandemics will appear in the developed countries because of global travel, etc., the likelihood of initial pathogen emergence in less-developed countries means that public health infrastructure remains a general gatekeeper to the world's overall health. The authors caution that disease-specific programs (e.g., AIDS-specific, vertical) can shift focus and resources from baseline public health maintenance in a manner that facilitates the development of pandemic outbreaks. In an effort to locate the “proximate driver implicated in each outbreak” the authors find that the most significant predicate is the “breakdown of public health measures includes inadequate sanitation and hygiene, e.g., the shortage of potable water, poor immunization coverage or the lack of infrastructure to purchase and deliver vaccine, and the deterioration of vector-borne and zoonotic disease control.” Thus, pandemic preparedness relies on a combination of high-tech and low-tech measures; determining the genome sequence of an emerging virus is routine today, but such a technical achievement does not supplant the need for investment in the low-tech infrastructure that helps to limit the spread of any emerging pathogen.
Earlier this year, the controversy over recent scientific experiments that produced potentially pandemic-level viruses (highly pathogenic avian influenza H5N1; HPAI) largely centered on the merits of publishing such research. The National Science Advisory Board for Biosecurity (NSABB) initially recommended against publication by scientific journals, but later relented and supported publication (one in full, one edited). The broader question of whether such experiments should be funded by the National Institutes of Health (NIH) at all – the HPAI H5N1 work in both laboratories received NIH support – was left unanswered. However, in March, the NIH published its policy for the oversight of life sciences dual research of concern (DURC) (research capable of benign and malicious uses, such as the recent HPAI H5N1 experiments). More recently, the NSABB has returned to the difficult questions regarding the funding of DURC. At last week's NSABB meeting, the NIH unveiled a potentially more exacting review process to determine whether or how the “gain-of-function” experiments that produced the HPAI H5N1 viruses should be funded. "Gain-of-function” refers to research that is undertaken to investigate the genetic structure of viruses, but, in the process, results in the production of an even more dangerous virus. Could such an outcome be avoided? To illustrate how NIH would assess that possibility, the proposed NIH framework asks that applicants declare that their work is unlikely to produce a “gain of function” virus, unless that could demonstrate that such a virus is likely to occur naturally. Can that be meaningfully answered? The
wild card in the attempt to set up a risk-managed funding program is how scientists can imagine the biological sources of risk
before actual research has identified or confirmed such details.
The proposed framework from NIH also links public funding with public disclosure: “As a general matter, HHS should only fund research that is reasonably anticipated at the proposal stage to generate information, products, and technologies that can be openly communicated.” This statement recalls the controversy earlier this year, where the risks from already completed research were to be managed by publication controls imposed after the fact. The NSABB will hold a public workshop on gain-of function experiments with HPAI H5N1 viruses on Dec.17-18, 2012 to discuss "the implications of such research for global public health, risks and concerns associated with this research; the risks of not pursing this type of research; fundamental principles regarding the conduct and oversight of such research; and conditions under which such research might be conducted." The lineage of these discussions post-9/11 goes back to the 2004 National Research Council report, Biotechnology Research in an Age of Terrorism (Fink Report), as well as the NSABB’s own 2007 framework, which amplified the Fink Report’s concerns and signaled the need for points of intervention at the funding or communication stages of the research trajectory. Thus, these questions are not new; they are just made more acute by recent events and HPAI H5N1 viruses have become the pathogens of concern. To illustrate that point, the Centers for Disease Control (CDC) has published an announcement in the Federal Register asking for comments on whether HPAI H5N1 influenza should be added to the CDC list of select agents (such classification would authorize closer monitoring of research projects). Further, HHS has carved out a class of select agents with the greatest risk of misuse (Tier 1) and asks whether the classification should obtain for this influenza strain, given its properties. Comments are due by December 17, 2012.
The FDA has approved a rapid, in-home test for Human Immunodeficiency Virus (HIV), the virus that causes AIDS. This is an approval of the premarket approval application (PMA) by the FDA's Center for Biologics Evaluation and Research, which oversees the review of devices that involve the use of a biologic reagent. This is the first in-home test for HIV infection that produces immediate results, and will be sold over the counter (OTC) by pharmacies. The single-use test, OraQuick, detects antibodies to viral strains HIV-1 and HIV-2, and allows an individual to take an oral swab (no blood required) and receive results at home in 20-40 minutes. The package insert instructs users that this test be a predicate to confirmation by a physician. This is the first at-home test for an infectious disease, and the need (and potential market) for such a test is supported by HIV statistics from the CDC, which suggest that at least 20% of those infected with HIV are unaware of their status. Several developments in the last several decades suggest that this test might be useful to some who suspect possible HIV infection – decreased stigma over HIV-positive status, coupled with the availability of more effective antiviral treatments. However, the cost of the test will be over $17.50 (current price to clinics), which will be pricey for many, and, furthermore, to note that antiviral regimens for HIV have improved over time does not mean that access to treatment is universal. The test is only approved for sale to those 17 and older, and pharmacies may screen for verified age in selling the product. There are other FDA-approved HIV home tests available, but they require sending a sample to a laboratory. While this test expands options for those at risk of HIV infection, it is a relatively straightforward application of long-existing technologies; the FDA resisted the approval of other HIV home test applications for years. The CDC estimates that approximately 50,000 people are newly infected with HIV each year in the United States. Although some of the stigma associated with HIV has decreased, there is still a visible effort to encourage testing for high-risk groups (or those engaged in high-risk behaviors); National HIV Testing Day was just observed on June 27 of this year.
At the annual World Health Assembly meeting, the World Health Organization (WHO) has once again delayed the planned destruction of the remaining smallpox stocks, currently held solely by the U.S. and Russia. A study commissioned by the WHO reported in March that the viral stocks are currently secured at the Centers for Disease Control and Prevention (CDC) (Atlanta) and the State Research Centre for Virology and Biotechnology (Koltsovo, Russian Federation). In addition, a reserve of smallpox vaccine is held in Switzerland. Smallpox is considered to be one of the most effective bioweapons that can be procured; more details here; the relevant factors are its contagiousness, the relatively low dose needed to infect, and a high mortality rate. This decision by WHO will be revisited in 3 years, intead of the usual 5-year review period. Arguments pro and con regarding maintaining smallpox stocks have raged for years; ironically, both sides invoke public health concerns - those wishing to destroy the stocks argue that it removes a known deadly pathogen from a terrorist portfolio; those who argue for its preservation believe that there may be smallpox stocks that remain undetected and that scientists will need virus stocks for research should an unforeseen outbreak occur. I think it is more likely that undetected stockpiles remain outside the protection of the WHO regulatory regime, and that public health officials could find that the official stocks are invaluable in an emergency. Moreover, there is always more research that can be done on the virus to unravel its pathogenicity and provide a more detailed road map for antiviral strategies.
