The Pandora Report

By Greg Mercer

I attended ASM BioThreats 2017’s panel “Predicting Emergence by Understanding the Past: Methods that Move Us towards Predictive Biology,” where a panel of researchers presented their recent efforts to get ahead of the evolutionary curve and anticipate new developments in infectious disease.

Marco Vignuzzi, of the Pasteur Institute, described his efforts to monitor, predict, and target RNA virus evolution. RNA viruses mutate constantly; any response to them must into account incremental changes and variations. Vignuzzi described a large population of many low-frequency mutants as a quasi-species or “cloud.” One can sequence the average genetic profile of this cloud, known as the “consensus sequence.” This population exists across a fitness landscape, ranging from well-adapted to poorly-adapted. The natural evolutionary tendency of a fast-mutating RNA virus is to “climb” this landscape to the highest possible fitness—this is the most successful disease. But Vignuzzi suggests that a virus could be artificially altered to undergo exactly the wrong mutations, making it less fit and causing it to die off. Exactly how to do this remains a mystery, but it’s an exciting possibility.

Barbara Han, of the Cary Institute of Ecosystem Studies, presented her research on machine learning for forecasting zoonotic disease. Han takes a macro-ecological approach to disease, focusing on hosts. Factors like biodiversity and population density affect disease rates, so understanding zoonotic diseases means collecting a great deal of information about the animals that carry them. This information tends to be collected based on specific concerns about animal reservoirs; Han noted that since bats are a suspected reservoir for Ebola and other diseases, there’s been a massive surge in surveillance. It turns out, though, that they carry fewer zoonoses than we might expect. Right now, Han is studying bats to try to identify instances where viruses might spill back into bat reservoirs from human populations, making outbreaks harder to stop. She is also working with data about the health of rodent populations, with the hypothesis that lower biodiversity in a particular area will put humans at a higher risk for a spillover.

David O’Connor, from the University of Wisconsin-Madison, is looking at viruses that aren’t on the radar yet, though maybe they should be. O’Connor examines animal species to find traits that make spillover events likely. Specifically, he presented the theory that simian arteriviruses might be to blame for the mysterious simian hemorrhagic fever. There’s not enough information to know for sure without another outbreak, but O’Connor argues that there is enough information at our disposal to begin to make predictions “to the left of the surveillance curve,” and target surveillance at diseases that aren’t yet a top threat, but could emerge as one.

By Stephen Taylor

The ASM Biothreats Melioidosis Panel on Tuesday, February 7^th, shed light on a largely ignored infectious disease that runs rampant in developing Southeast Asian countries. The speakers, Dr. Direk Limmathurotsakul, the Head of Microbiology at Mahidol-Oxford Tropic Medicine Research Unit, and Dr. Frances Daily, of Diagnostic Microbiology Development Programme, brought a wealth of first-hand knowledge and experience diagnosing and treating this disease in Thailand and Cambodia.

Melioidosis is an infection caused by Burkholderia pseudomallei, a bacterium often found in soil and water.  It is known to cause fever, arthritis, and abscesses of vital organs.  Once inoculated with bacteria, carriers typically experience an incubation period between 1 and 21 days before melioidosis symptoms appear.  Humans acquire B. pseudomallei by inhaling contaminated dust, ingesting contaminated water, or coming into contact with contaminated soil.

In the United States, B. pseudomallei is classified by Health and Human Services and the U.S. Department of Agriculture as a Tier 1 Select Agent, meaning it poses a significant threat to human and animal health and safety and presents a great potential for deliberate misuse.  The Soviet Union and the United States are both believed to have studied B. pseudomallei as a potential biological warfare agent in the 1940s.

In his extensive work caring for patients in northeast Thailand, Dr. Limmathurotsakul documents numerous cases of melioidosis on an annual basis, many of them fatal.  Thailand’s Bureau of Epidemiology, however, only documents about 12 melioidosis deaths per year.  Dr. Limmathurotsakul chalks up the disparity to a poor public health surveillance apparatus and cultural barriers in reporting.  Public health laboratories in Thailand are poorly equipped for diagnostics. Furthermore, physicians in Thailand are not well trained to utilize laboratory diagnoses, nor are they well versed in the transmission and symptoms of melioidosis.  When local health professionals do detect outbreaks of the disease, they are hesitant to report them to the Bureau of Epidemiology for fear of being stigmatized as the only locale to have a significant melioidosis outbreak.

Dr. Daily has encountered similar problems working in Cambodia.  Due to climate change, the rainy season in Cambodia lasts longer every year and with it, the number of melioidosis outbreaks detected by her team also grows.  The Cambodian government, however, is unable to respond effectively to these outbreaks due to a lack of diagnostic capability, patient data, and funding.  Treatment for the infection, which averages a cost of 65 USD, is expensive compared to the Cambodian per capita income of just over 1,100 USD.  Many families struggle to pay for treatment, often going into debt or selling property to afford it.

What can be done to improve detection and treatment of melioidosis?  All of the panel members recommended improving the education and training of the public health and medical workforce.  Knowledge of melioidosis needs to be integrated into training for public health workers in laboratory diagnosis.  Protocols for diagnosis and treatment of melioidosis should be incorporated into medical school curricula.  The speakers also expressed hopes that Thailand and Cambodia would be able to build their capacity to detect and report infectious diseases. Combining his limited data on melioidosis with predictive modeling algorithms, Dr. Limmathurotsakul has estimated that there are 165,000 cases of melioidosis worldwide each year, 89,000 of which result in death.  He hopes the estimates will spur melioidosis researchers worldwide to compile confirmed-case data and paint a more accurate picture.  Then national and international policymakers will have better information to support clinicians and public health officials in their local efforts to fight the disease.

By HyunJung (Henry) Kim

Michael Merchlinsky, a subject matter expert from BARDA/CBRN, was the first speaker in this ASM Biothreats 2017 plenary session, overviewing history of the Animal Rule in the US. The Animal Rule is well-known as an innovative policy forming the foundation of U.S. biodefense policies. When no alternatives are available, the Animal Rule provides an investigational mechanism for figuring out “predictive” responses from new medical countermeasures (MCMs) relevant to calculating a dose in humans. Under the Animal Rule, licensure is a legal status awarded by FDA that assures the public that studies to demonstrate safety and efficacy have been performed. According to Merchlinsky’s presentation, it is worthy to note that the Animal Rule was born in the basis of national security purposes, increasingly apparent from Gulf War to 9/11. The primary purpose of the Animal Rule is to increase preparedness and provide means to confidently respond to a public health emergency. Based on the national security perspective at the state-level, Michael Merchlinsky reviews the pros and cons of the Animal Rule. He notes that the Animal Rule is the best course of action for assuring ‘safety’ and ‘efficacy’ where no other alternative is available. Moreover, MCMs under the Animal Rule can attain pre-EUA status during developmental path-MCMs saved in the Strategic National Stockpile (SNS). On the other hand, a critical limitation is that the Animal Rule is inherently longer, harder, and less predictive than traditional pathways.

Next, Dr. Mario Skiadopoulos and Christine Hall represented Emergent BioSolutions and spoke to the regulatory pathway for anthrax and botulism medical countermeasures. BioSolutions applies animal models based on the subject of rabbits as well as non-human primate (NHP) to develop vaccines against anthrax and botulism. It was very interesting to know that there are three types of experiments in animal modeling; Post-Exposure Prophylaxis (PEP), Pre-Exposure Prophylaxis (PrEP) and Passive Transfer. The PEP type demonstrates added value of vaccine over antibiotics alone, in post-exposure settings, whereas the PrEP type established correlation between pre-challenge TNA tilter and probability of survival. The Passive Transfer type demonstrates that neutralizing antibody alone is capable of protection. Compared with the speaker from government sector, speakers from the private sector point to more practical challenges that field researchers are facing under the Animal Rule. They argue that there is no regulatory precedent for licensing a vaccine under the Animal Rule. Technically speaking, it is not clear which time points or which kind of animal models can bridge animal-to-human data. For instance, we have never known which animal model is akin to human trials between rabbits and NHP, as well as which time point is appropriate to apply to humans among the 80%, 90% or 100% survival points from the result of animal models. Consequently, the Animal Rule is essential not only in MCMs development and the realm of national security, but also carries with it many challenges both in government and private sectors. Overall, the inclusion of both government and private sector viewpoints presented the full spectrum of the Animal Rule and its complexities regarding MCM development.

By Zach Goble

The theme of this ASM Biothreats 2017 symposia was perhaps one of the more noteworthy callings for collaboration among groups. With more than 17 years of experience as the director of Hazardous Materials Emergency Response at the Massachusetts Department of Fire, David Ladd emphasized the need for a unified response when encountering any number of hazards. His slogan during his dialog, “what happens on the left coast, then happens on the right coast”, stressed the importance of initiating and maintaining communication with organizations near and far. No one stays unaffected in the world of today and without the exchange of ideas, experiences, and procedures disasters can have an overwhelming effect.

Rich Ozanich, from Pacific Northwest National Laboratory and Christina Egan, from the NY Dept. of Health, both echoed that close collaboration is a key factor in response. While Rich laid out the Department of Homeland Security’s framework for “The Onion”, which is a set of procedures to guide first responders in the event of a biothreat incident. The emphasis here was that to be successful the training for such events needs to be coordinated at a local, state, and national level.  Christina detailed the many training programs tailored to biological threat response within Emergency Management Departments specific to various states such as Minnesota and Wisconsin. The message here was that while many great programs exist at the state level, there is not a unified national response to confront CBRN threats with the United States.

David Ladd concluded the panel by presenting a proposed model for National Bioterrorism Response that was submitted by the Interagency Board in January, 2017. In the absence of a nationally recognized system for protecting the nation against bioterrorism, the need for such a system is certainly justified. This document provides a model for bringing together various organizations and departments to create a network of local bioterrorism response teams ready to deploy when the need arises. Models such as these represent steps in the right direction to achieving a unified response in ensuring the public remains safe from biological threats.

By Zach Goble

The second day of the ASM Biothreats 2017 conference focused on a range of topics from synthetic biology to host immune response. Perhaps one of the most interesting was the session on international collaborations to defend against biological weapons. Immediately the conversation began with talk of recognizing foreign organizations for their help in aiding research endeavors or providing resources to further science. Stuart Perkins, from the Defense Science and Technology Laboratory (DSTL) in the United Kingdom, highlighted the importance of shared resources and capabilities when responding to emerging infectious diseases. One organization doesn’t hold all the information, and nor should they, because while one strives for consistency in research methods, it is helpful to have differences to cast a wider net against the many research topics out there.

Lloyd Hough, from the United States Department of Homeland Security, talked about how DSTL helped provided support to their department during the most recent Ebola epidemic. Prior to the Ebola outbreak, DSTL in the United Kingdom had conducted research on how Ebola virus thrived on various surfaces and this inspired new ways forward for the U.S. to aid the countries affected in 2015. When worldly public health events occur it is often unified efforts that bring about successful outcomes.

Andrii Pavlenko, from the State of Service in Ukraine, showed how support from the United States Defense Threat Reduction Agency (DTRA) helped provide equipment and laboratory upgrades to several Ukrainian facilities working with biological pathogens. Not only did these upgrades prevent unauthorized access to potentially dangerous pathogens, but also helped to prevent the spread of emerging infectious diseases. African Swine Flu (ASF), a virus with high mortality rates in pigs and prevalent in Eastern Europe region, was on the rise in Ukraine, but the equipped laboratories helped bolster biosecurity detection and thus prevented the spread of the disease.

The message was very clear that alone, organizations could not effectively deal with biological threats that have no borders and target unremittingly. Thankfully, the gears are already in motion towards international collaboration with the organizations in attendance, among others that exist around the world. The panel left the audience with a strong message in which trust of fellow organizations is needed for it is not always action that is needed, sometimes it is the non-action in letting your partner do the work, so you can tackle another issue. While replication is important, redundancy should be left at the wayside to make room for more knowledge as there is no shortage of scientific questions out there.

By Stephen B. Taylor

On February 7, 2017, Dr. Anthony Fauci, Director of National Institute of Allergy and Infectious Diseases, National Institutes of Health, gave the keynote speech at the ASM Biothreats 2017 conference. Dr. Fauci has spent over 35 years advocating infectious disease preparedness with United States policymakers. In his speech, Dr. Fauci discussed the substantial progress made in this arena since the 1980s when he first entered the field during the Reagan administration. At the time, there was a lack of appreciation in the U.S. about the potential of the newly emergent Human Immunodeficiency Virus (HIV).  Though Fauci tried to publish some disturbing initial findings about the nascent threat, the medical community rebuffed him for being an alarmist.  As the 1980s progressed, HIV/AIDS spread to epidemic proportions in the U.S.

During George H.W. Bush’s presidency, Dr. Fauci began making headway with national health and policy leaders to take seriously the threat of emerging infectious diseases. President Bush visited Dr. Fauci at NIH for a personal tutorial on HIV and took time to visit with HIV/AIDS patients. After President Bush received Dr. Fauci’s expert counsel and made a personal connection with the HIV/AIDS crisis, public health resources directed at the epidemic increased dramatically.

From the Clinton years onward, Dr. Fauci maintained his connection to lawmakers and executive leadership.  When infectious disease emergencies like West Nile Virus and antibiotic resistance came to a head during the Clinton years, politicians had a stronger relationship with the National Institutes of Health and funding came more quickly.

During George W. Bush’s term, the United States experienced the “double whammy” of 9/11 and Amerithrax.  This was a watershed moment for infectious diseases. For the first time since the early 20^th century, it became widely apparent that infectious disease outbreaks posed a major threat to U.S. public health and security.  As the U.S government turned its attention and resources toward developing countermeasures against a bioterror attack, Dr. Fauci urged Washington leaders not to lose sight of the threat posed by natural outbreaks. When the H5N1 bird flu hit in the latter half of Bush’s presidency, the Bush administration worked closely with experts in health security to affect a paradigm shift: instead of reacting to outbreaks as they happen, the U.S. should expend more resources on preparing for future ones.

During Barack Obama’s presidency, emerging and re-emerging infectious disease outbreaks came in rapid succession: the H1N1 flu pandemic in 2009, MERS in 2012, Ebola in 2014, and Zika in 2015.  In close conjunction with experts like Dr. Fauci however, policy-makers have learned important lessons about preparedness, surveillance, capacity building, and coordination in preparation for the next major outbreak. Indeed, even before Inauguration Day this year, the Trump transition team invited Dr. Fauci to the White House for a disaster-response exercise.  As the world grows more interconnected and its climate changes, the threat of emerging infectious diseases looms larger.  U.S. leaders should continue to heed the advice of subject matter experts like Dr. Fauci and work closely with health and defense institutions to prepare for the future.