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.
The Presidential Commission for the Study of Bioethical Issues (Bioethics Commission) has released a brief, titled Ethics and Ebola: Public Health Planning and Response, following its consideration of specific ethical questions that emerged while the U.S. government was responding to the Ebola virus outbreak in western Africa. Ebola virus cases in the U.S. began to appear last fall, the but Guinea, Sierra Leone and Liberia experienced significant outbreaks during 2014, and the World Health Organization reports an ongoing struggle in these countries. The commission advanced several recommendations to improve international responses, as well as the U.S. domestic response and capabilities:
Strengthening the capacity of the World Health Organization to respond to global health emergencies through the provision of increased funding and collaboration with other international, national, and non-governmental public health organizations.
Identifying and empowering a single U.S. health official accountable for all federal domestic and international public health emergency response activities.
Strengthening the deployment capabilities of the U.S. Public Health Service, including by streamlining command structure for deployment and providing appropriate resources to train and maintain skills needed for emergency response.
The Commission also highlighted the need to embed ethical considerations into disease management and responses in a coordinated ethics framework:
In addition, the Bioethics Commission recommend[s] that ethical principles be integrated into timely and agile public health decision making processes employed in response to rapidly unfolding epidemics. It call[s] for qualified public health ethics expertise to be readily available to identify ethical considerations relevant to public health emergencies and responses in light of real-time available evidence. Specifically, it recommends that a single U.S. health official should be accountable for ethics integration.
While recognizing that public health measures can compromise individual liberty in emergency situations, the Commission addressed the need for possible quarantine:
On the contentious issue of quarantine and other policies related to movement restrictions, the Bioethics Commission recommend[s] that governments and public health organizations employ the least restrictive means necessary—based on the best available scientific evidence—when implementing restrictive public health measures.
The Commission recognized that clinical trials during a public health emergency can pose ethical choices regarding trial design, and particularly regarding the use of placebos, but did not rule out their use:
Clinical research during a serious communicable disease epidemic creates a stark ethical dilemma: On one hand, using placebo controls appears to deny some patients the possibility—however small and uncertain—of a benefit from experimental interventions; on the other hand, research that does not yield conclusive results about an intervention’s safety or effectiveness could exacerbate the tragedy of the epidemic by providing misleading and potentially harmful information. Navigating this tension requires careful analysis of the range of possible trial designs coupled with a commitment to core principles of research ethics.
In upcoming work, the Bioethics Commission will further consider “the importance of democratic deliberation and public education in bioethics.” While the role of the Bioethics Commission is deliberative and advisory, it has a broad and singular mandate to consider how the government ethically responds to the emergence of new life science technologies and ethically reacts to medical or health crises that necessitate competent and agile federal involvement.
Several years of turbulence around the legitimacy and value of research that alters the genetics of highly dangerous pathogens in order to determine the relationship between DNA and function are the backdrop to a surprising announcement from the Obama administration regarding government funding of such research. Experiments that introduce genetic changes into the genomes of dangerous pathogens in order to study both transmissibility and pathogenicity may confer new or enhanced functions on a pathogen that make them more dangerous than in the native state. These are termed the “gain-of-function” (GOF) studies, a category of dual-use research of concern (DURC). Controversy ensued in 2011 over the publication of some of these experiments with highly pathogenic H5N1 influenza viruses. New federal policies regarding funding and oversight of DURC life science research were published, but those events presupposed the continuation of such research. Now the administration has issued a moratorium on federal funding of such research, asserting that more consideration is required as to the biosafety and biosecurity issues raised by this research:
Gain-of-function studies, or research that improves the ability of a pathogen to cause disease, help define the fundamental nature of human-pathogen interactions, thereby enabling assessment of the pandemic potential of emerging infectious agents, informing public health and preparedness efforts, and furthering medical countermeasure development. Gain-of-function studies may entail biosafety and biosecurity risks; therefore, the risks and benefits of gain-of-function research must be evaluated, both in the context of recent U.S. biosafety incidents and to keep pace with new technological developments, in order to determine which types of studies should go forward and under what conditions. In light of recent concerns regarding biosafety and biosecurity, effective immediately, the US.Government (USG) will pause new USG funding for gain-of-function research on influenza, MERS or SARS viruses, as defined below. This research funding pause will be effective until a robust and broad deliberative process is completed that results in the adoption of a new USG gain-of-function research policy.
The statement calls on the National Science Advisory Board for Biosecurity (NSABB) and the National Research Council to undertake more formal evaluative reviews of the pros and cons of these experiments. The NSABB held a public meeting last week to begin that work. This announcement did not occur in a vacuum: in the wake of the Ebola virus disease outbreaks and the recent reports of widespread biosafety lapses at high-profile federal laboratories, attention has focused on the status of research into pathogens that cause infectious diseases and into vaccines and drugs for prevention and treatment. The scientific community has been divided over the specific issue of GOF research; both sides have gone public with the formation of professional advocacy groups that support or oppose such research. The control of federal funding for research can be subject to executive branch discretion. An earlier high-profile example of an executive branch dictate is the Bush-era policy of refusing to fund the establishment of new embryonic stem cell lines. This announcement is directed to a pause in funding and the encouragement of what appears to have been missing for the past several years: official acknowledgement that the funding of such controversial research required a formal deliberative process that should precede, not follow, official decisions to allow the work. The statement also calls on those providing private funds for such research to implement a voluntary pause, pending the upcoming reviews.
The avian influenza A(H7N9) virus (official name) has emerged in China since February, and human cases of infection have increased steadily and spread to Taiwan. Of 112 cases reported, there are 22 deaths; China Daily updates; map of cases here. Just yesterday, the World Health Organization (WHO) issued this characterization: “This is an unusually dangerous virus for humans," said Keiji Fukuda, assistant director-general for health security of WHO. The true pathogenicity of the virus in humans is unclear; some reports state a mortality rate of 20% (deaths/cases); however, this is inexact because there may be mild disease that is not detected, and the actual lethality may be lower. The virus is avian in origin, a triple reassortant (mixture) of three avian viruses. Initial assessments are that humans are acquiring infection through contact with infected birds; the unanswered question is whether human-to-human transmission is occurring (a precursor to a true pandemic). H7N9 has been sequenced and genetic analysis reported by two groups, one from China and one an international collaboration, which noted: “These viruses possess several characteristic features of mammalian influenza viruses, which are likely to contribute to their ability to infect humans and raise concerns regarding their pandemic potential.” Since the outbreak originates from China, the level of transparency from this country is critical and so far, reports are positive. WHO has reported that it receives case notifications from Chinese public health officials, and that China has sent virus samples to all 5 international collaborating centers for influenza (which includes the U.S. Centers for Disease Control (CDC)).The virus genetic sequences (sequences of the coding regions of all eight viral genes) were deposited in the influenza sequence database maintained by the Global Initiative on Sharing All Influenza Data (GISAID). This is a global consortium that was started after the 2004-5 influenza A(H5N1) outbreaks, amid concerns that virus sequences were not being shared, due to concerns about asymmetry between virus sharing and access to antivirals and vaccines, particularly from developing countries (e.g., Indonesia withheld H5N1 viruses). Claims for patent rights surfaced in the H5N1 pandemic, including a patent application filed by the CDC (see here for my article on the set of patent rights relevant to influenza pandemics). Despite the fact that patent rights have been sought for H5N1 virus sequences and H1N1 virus sequences, the sensibility of GISAID is to encourage unrestricted access:
Influenza viruses have not been subject to intellectual property rights historically. This tradition has been important because the required changes in influenza viruses contained in human influenza virus vaccines to match those viruses circulating currently in the field must occur at a speed far in excess of the legal process associated with the attainment of commercial protection. In order to allow rapid development of products such as vaccines and other interventions on an equitable basis by all countries and other interested parties, the convention has been for human health professionals to share virus specimens and data openly without creating barriers of exclusivity such as the filing of patents.
Already, this public health crisis illustrates a strikingly different posture by China in contrast to its reaction to the emergence of SARS (Severe Acute Respiratory Syndrome) in 2003, most notably in transparency. During that period, China was not initially forthcoming with the details of the epidemic, and the absence of information impeded public health surveillance. When SARS appeared, the causative agent was not immediately known and it was finally identified as a novel coronavirus. In addition to the difficulties on obtaining actual epidemiological data during the crisis, the SARS crisis was also encumbered by the efforts of leading research groups to file patent applications on the SARS virus sequence. With respect to influenza viruses in general, progress in linking the sharing of virus genetic sequences to access to countermeasures (overcoming some of obstacles in the H5N1 pandemic) has occurred with the establishment in 2011 of the Pandemic Influenza Preparedness Framework Framework for the Sharing of Influenza Viruses and Access to Vaccines and Other Benefits (PIP) by WHO, which applies to influenza viruses with pandemic potential. PIP thus encourages the dissemination of virus samples and research results; it also provides for transparency in virus sequence tracing by contributing laboratories, and it embeds norms which discourage seeking intellectual property rights (but this is not legally binding). As PIP is recently enacted, it has yet to be tested in a declared pandemic, and it is not clear that the current H7N9 outbreaks will amplify into an official pandemic.
One other aspect of H7N9 is notable at present: the virus genetic sequence has two mutations linked to increased human-to-human transmission which were identified in the H5N1 research papers that were subject to debate in late 2011 as possible sources of dual-use information (the debate centered on whether the data should be published). For background, see here and here. The question: what does the observation of these mutations mean for the viability (and scientific merit) of the earlier dual-use experiments? Has their utility been increased as a result of what is being learned about H7N9?
