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Technologies to Address Global Catastrophic Biological Risks – Tara Kirk Sell

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Technologies to Address Global Catastrophic Biological Risks – Tara Kirk Sell

  1. 1. Technologies to Address Global Catastrophic Biological Risks Tara Kirk Sell, PhD Assistant Professor, Johns Hopkins Center for Health Security Special thanks to Crystal Watson, DrPH, MPH Lead Project PI
  2. 2. Global Catastrophic Biological Risks (GCBRs) ►Global Catastrophic Risks are a class of risks – naturally or technologically driven – that have potential to inflict serious damage to human wellbeing on a global scale ►GCBRs might include: ►Naturally occurring severe pandemics ►Deliberately created and released pathogens ►Laboratory engineered and escaped pathogens
  3. 3. Why We Chose This Focus • Few past analyses have focused on technologies to prevent or respond to pandemics • None have addressed GCBRs • Technology development for infectious disease pandemics primarily focuses on vaccine development • Other technologies are often neglected
  4. 4. Opportunities for Intervention in Severe Pandemics
  5. 5. Categories of Applicable Technologies
  6. 6. Project Approach • Structured exploration of extant and emerging technologies with the potential to radically alter the trajectory of severe infectious disease events with catastrophic potential • Goals: • ID areas of need for tech solutions to address pandemic and GCBRs; • ID technologies that have significant potential to reduce GCBRs; and • Provide context for those technologies • Uses: results should be used to guide further detailed analyses
  7. 7. Technology Properties • Properties that transformative technologies in GCBR reduction would likely possess: • Approaches that are distributed rather than centralized • Ability to increase the capacity to make response decisions earlier • Rugged or easy to use in a variety of settings • Ability to reduce time lags in development/delivery of treatment/countermeasures
  8. 8. Technology Identification Process • Technology Scan and Review of the Literature • Structured review using key words • Review of both grey and peer-reviewed literature • Resulted in identified themes and individuals for interview • Semi-Structured Interviews with Experts • Using snowball sampling (asking for recommendations), we identified experts • Asked a series of questions about technologies and their applicability to pandemics and GCB events • After each interview, the team met and identified technologies for further review
  9. 9. Technology Evaluation Process • Series of standardized questions • Questions were modeled on the Heilmeier Catechism: Process used by George Heilmeier for the Defense Advanced Research Projects Agency (DARPA) • Our Questions: • What is the technology? • What problem does it solve? • How do we do it now? • What does success look like?
  10. 10. Results 10
  11. 11. Categories of Applicable Technologies
  12. 12. Disease Detection, Surveillance, and Situational Awareness Technologies
  13. 13. • What is the technology? • Rapid, accurate, affordable, and fieldable nucleotide sequencing for detection of pathogens in human and environmental samples – nanopore sequencing • What problem does it solve? • Sequencing can be used to detect novel or unexpected pathogens, whereas other molecular diagnostics like PCR only test for known pathogens • How do we do it now? • Prior to nanopore, sequencing was centralized and laboratory-based • What does success look like? • Ubiquitous sequencing will allow for the near real-time characterization of pathogen biology, including determinations of virulence, transmissibility, sensitivity or resistance to medicines or vaccines. Ubiquitous Genomic Sequencing and Sensing
  14. 14. • What is the technology? • Drone networks sampling air, water and soil and processing biological samples onboard • What problem does it solve? • Help detect an aerosolized attack or potentially catastrophic change in aquatics ecosystems • How do we do it now? • Environmental surveillance is conducted on a small scale, and is not networked • What does success look like? • A network of land, sea, and air-based drones autonomously conducting environmental surveillance 14 Drone Networks for Environmental Detection
  15. 15. 15 Remote Sensing for Environmental Pathogens • What is the technology? • Satellite imagery that measures intensity and color bands of reflected light from plants to determine health • What problem does it solve? • Early detection of a plant pathogen that might devastate the world’s crops • How do we do it now? • Individual farmers monitor their land and report problems to the national plant diagnostic network or US Department of Agriculture • What does success look like? • The technology exists, but its widespread use for monitoring does not. A national organization charged with monitoring and acting on identified threats could improve agricultural biosecurity
  16. 16. Infectious Disease Diagnostics
  17. 17. 17 Microfluidic Devices • What is the technology? • Small lab-on-chip or paper diagnostics with very rapid results. • What problem does it solve? • Paper diagnostics can be used in the field to diagnose, enable treatment, and help with isolation and quarantine • How do we do it now? • Most diagnostics are processed in centralized laboratories requiring days of processing time • What does success look like? • Low cost point of care confirmatory testing would decrease time to diagnosis, isolation, and treatment. It could enable social distancing and help slow disease spread
  18. 18. 18 Hand-Held Mass Spectrometry • What is the technology? • Portable handheld mass spectrometers for identification of pathogen-specific proteins • What problem does it solve? • Reduction in the time to specific identification of a pathogen • How do we do it now? • Culture is still the gold standard, but it takes time and cannot be done in the field • What does success look like? • Diagnostic for a wide range of pathogens in the field, with very high sensitivity and specificity
  19. 19. 19 Cell-Free Diagnostics • What is the technology? • Cell-free diagnostics take bioengineered cellular machinery from lysed cells, freeze dries these components, and uses them for diagnosis • What problem does it solve? • It provides cheap, accurate, and portable diagnostics • How do we do it now? • Diagnostics like polymerase chain reaction (PCR) require laboratories and expensive equipment • What does success look like? • Cell-free diagnostics could be rapidly manufactured and distributed widely
  20. 20. Distributed Medical Countermeasure Manufacturing
  21. 21. 21 Synthetic Biology for MCM Manufacturing • What is the technology? • Genetically engineered strains of chassis bacterial organisms, such as yeast can be programmed to manufacture drugs and vaccines • What problem does it solve? • Discovery, availability, and accessibility of drugs and vaccines in a pandemic or GCB event • How do we do it now? • Centralized manufacturing by pharmaceutical companies • What does success look like? • Synthetically modified bacteria could be distributed around the world for production in bioreactors. Even breweries could be harnessed in worst case scenarios
  22. 22. 22 3D Printing of Chemicals and Biologics • What is the technology? • 3D printing (additive manufacturing) of drugs and vaccines • What problem does it solve? • Even when a drug or vaccine is developed in time to respond to a pandemic, getting access to them will be difficult in many parts of the world. 3D printers could be used in doctors’ offices, pharmacies, and even at home • How do we do it now? • Most MCM manufacturing occurs at centralized sites and on dedicated platforms • What does success look like? • 3D printing could allow for greater and earlier access to medical countermeasures developed in response to or identified in a GCB event
  23. 23. Medical Countermeasure Distribution, Dispensing, and Administration
  24. 24. 24 Microarray (Microneedle) Patch Vaccines • What is the technology? • Microarray patches can be used in place of needle and syringe for vaccination • What problem does it solve? • With needle and syringe, you need healthcare providers to administer vaccines. MAPs eliminate that need • How do we do it now? • Vaccines can be given only by healthcare providers • What does success look like? • Elimination of needle and syringe, and move toward self- administration for vaccines in a pandemic or GCBR
  25. 25. 25 Self-Spreading Vaccines • What is the technology? • Self-spreading, also known as transmissible or self-replicating vaccines, are genetically engineered to move through populations like viruses, but to confer protection instead of causing disease • What problem does it solve? • Many people will not get access to vaccines in time to make a difference in a GCBR • How do we do it now? • Traditional vaccination models • What does success look like? • Transmissible vaccines could help protect populations of wild animals that might harbor zoonotic diseases. They could also be used to protect human populations quickly in a severe pandemic
  26. 26. 26 Ingestible Bacteria for Vaccination • What is the technology? • Ingested capsules of bacteria are released in the gut, encounter macrophages and are phagocytosed. Within the macrophage, the bacteria begin to express antigens that stimulate the immune system. • What problem does it solve? • Because antigen is made within the body’s own cells and not passively introduced, the vaccine is as or more effective than traditional vaccines. • It also simplifies production, storage, administration • How do we do it now? • Vaccine and syringe, and less-effective oral vaccines • What does success look like? • Rapid manufacturing of capsules to be delivered around the world for easy administration
  27. 27. 27 Drone Delivery to Remote Locations • What is the technology? • Unmanned aerial delivery of medical countermeasures and supplies to remote locations • What problem does it solve? • Drones can reach locations that cannot be accessed by traditional supply chains. They can also reduce spread of disease by enabling delivery without personal contact • How do we do it now? • Medical supply chains use ground-based transportation, which may not be functional during a pandemic • What does success look like? • Drone networks available to deliver MCMs and supplies around the world
  28. 28. 28 Synthetic Vaccinology: Self- Amplifying mRNA Vaccines • What is the technology? • SAM vaccines use the genome of a modified RNA virus to introduce an antigen of interest and replicate in the body • What problem does it solve? • Safer and easier to deliver than other nucleic acid vaccines • Reduces dose needed, and induces a broader immune response than other vaccines • How do we do it now? • Viral vectors hampered by immune response and have risk of reversion to wild type • Large amounts of antigen and sometimes multiple doses and difficulty manufacturing • What does success look like? • Fast, dose-sparing technology could mean a vaccine that is available rapidly and can protect many more people
  29. 29. Medical Care and Surge Capacity
  30. 30. 30 Robotics and Telehealth • What is the technology? • A suite of technologies that allow care to be provided without the physical presence of a healthcare provider. • What problem does it solve? • They can augment medical surge capacity – i.e. too many patients, not enough HCWs • How do we do it now? • Routine medical model • What does success look like? • Mass care provided to large populations without hospitalization or contact with the traditional healthcare system
  31. 31. 31 Portable, Easy to Use Ventilator • What is the technology? • Respiratory support that’s usable by non-expert care providers • What problem does it solve? • Allows for care of the severely ill during pandemics of respiratory disease • How do we do it now? • Critically ill patients are admitted to ICU’s, where they are intubated and managed by highly expert care teams • What does success look like? • Respiratory support is able to be provided outside of ICU’s – potentially in alternate care sites
  32. 32. Conclusions ► Technologies – while not a panacea – will be a critical part of the response to severe pandemics and GCBR’s ► Horizon scanning is a useful exercise to identify new technologies and use cases ► Scalable technology solutions will be needed if we’re going to protect the health of 8 billion + individuals ► Fortunately, with a few exceptions, most of the technologies that we think could make a difference either already exist, or are linear projections of the state of the art
  33. 33. Call to Action ► Innovative thinking, a willingness to bend the rules, and a certain amount of risk taking will be required if humanity faces a major pandemic ► Routine and ongoing technology horizon scanning is needed to identify risks and benefits ► Dedicated thought and resources are needed to integrate technologies into practice in preparation for the next pandemic ► The next step is to do further analysis on use cases and viability of the highlighted technologies
  34. 34. THANK YOU! Contact Information Tara Kirk Sell tksell@jhu.edu

Editor's Notes

  • GCRS are a class of risks – could be naturally or technologically driven – that have potential to derail humanity in a serious way.
    Global Catastrophic Biological Risk (GCBR) is a special category of risk involving biological agents which could lead to sudden, extraordinary, widespread disaster beyond the collective capability of national and international organizations and the private sector to control. If unchecked, GCBRs could lead to great suffering, loss of life, and sustained damage to national governments, international relationships, economies, societal stability, and/or global security.

    GCBRs might include:
    Naturally occurring severe pandemics
    Deliberately created and released pathogens
    Laboratory engineered and escaped pathogens
  • We chose to focus on severe pandemics and GCBRs because up until this point, there has been relatively little focus on severe pandemics or biological events that could be truly catastrophic. We think there is value in focusing some small amount of our collective effort on addressing these risks that are high consequence, even though they may be low probability

    Pandemic preparedness efforts have focused primarily on vaccine development, and other technologies have been relatively neglected. Furthermore, public health is notoriously slow in adopting new technologies.
  • Broadly, in order to alter the course of a potential pandemic event, technologies must either help avoid the emergence and geographic spread of a biological pathogen and/or reduce disease severity and societal consequences. There are several inflection points during an unfolding biological event at which effective interventions can be implemented to interrupt event progression. Here are examples of those potential points of intervention:
  • Because GCBRs are a new topic of interest and inquiry, one wouldn’t expect there to be an established body of literature surrounding this problem. However, in order to identify potentially relevant technology solutions for GCBRs, the project team conducted a modified horizon scan to understand the technology space, and highlight areas of technology development and upcoming changes that could benefit GCBR reduction. While not a fully systematized horizon scan, because of the very broad nature of GCB event prevention and response, the project team scanned the horizon through a technology and literature review and interviews with experts in the field to inform judgments regarding the state of the science.
  • In looking for a way to evaluate these technologies, we found the Heilmeier Catechism a useful guide. This is the process used by DARPA, which was developed by George Heilmeier. Those questions were,
    What are you trying to do? Articulate your objectives using absolutely no jargon.
    How is it done today, and what are the limits of current practice?
    What is new in your approach and why do you think it will be successful?
    Who cares? If you are successful, what difference will it make?
    What are the risks?
    How much will it cost?
    How long will it take?
    What are the mid-term and final “exams” to check for success?

    The study team perceived value in this approach, but for the sake of brevity and because our aim was to produce a more descriptive report, as opposed to a comprehensive technology assessment, we modified the above questions to the following:
    What is the technology?
    What problem does it solve?
    How do we do it now?
    What does success look like?
    These questions provided a common framework with which to describe and evaluate the potential impact of the selected technologies and technology classes that may be called upon to detect or counter a GCB event.
  • The ability to rapidly, accurately, and affordably determine the nucleotide sequence of a gene(s) or gene fragment in a clinical or environmental sample is one of the most important advances in the history of the biological sciences, and is a prerequisite to an enhanced ability to detect and describe microbial life.
    Recent advances have raised the possibility of ubiquitous sequencing, whereby the locus of sequencing would move from the laboratory to any interested individual or organization. To do achieve this end, mobile, easy to use sequencing technologies will be needed

    Nanopore sequencing describes a process in which strands of DNA are threaded through an electrified pore. The physical passage of nucleotides (i.e. the constituent molecules of DNA – adenine, thymine, guanine, and cytosine) through the pore is what generates the sequence data, as each has a distinct shape and causes a correspondingly distinct change in electrical resistance that can be captured and analyzed.

    From an epidemiological perspective, the rapid availability and analysis of sequence data has become a hallmark of the modern infectious disease outbreak response. From SARS onwards, it has become routine and expected that a group of microbiologists with access to samples of the causative pathogen would sequence it and make those data available on a publically maintained repository called GenBank.

    One significant benefit of using sequencing technologies as a surveillance and diagnostic tool is that it’s unbiased. Other molecular diagnostics such as PCR are used to test for the presence of a known pathogen, or, in the case of multiplexed assays, multiple pathogens. If properly implemented, sequencing can be used to identify any pathogen for which sequence data are available. This is true for both nanopore sequencing, and other next-generation sequencing modalities.

    The response to infectious disease emergencies would look very different in a world in which sequencing capacity is ubiquitous. Presumably, the identification, characterization and analysis of emerging, engineered, or novel pathogens would be expedited, and subsequent public health surveillance efforts and drug and vaccine research would benefit as a result.

    In terms of applications relevant to preparedness for and response to GCBRs, ubiquitous sequencing appear to hold significant promise. Three fields in particular, public health surveillance, clinical diagnostics, and medical countermeasure (MCM) research and development stand to benefit significantly from the continued improvement and diffusion of sequencing technologies.
    As a surveillance tool, ubiquitous sequencing will allow for the near real-time characterization of pathogen biology, including determinations of virulence, transmissibility, sensitivity or resistance to medicines or vaccines. In the future, these tools may be able to provide evidence of genetic enhancement or modification.

    Further refinement of nanopore sequencing technologies will be result in it being taken up by a much broader range of users in multiple fields. As a result of this transition from research tool to real-time sensor, one can imagine the collection of data from nontraditional sources. Recent proposals have included sequencing the contents of airline lavatories, hospital laundries, municipal sewage systems, and HVAC systems for the presence of high impact pathogens.
  • What is the technology?: Drones are unmanned, remotely-piloted vehicles. They are perhaps best known for their military applications, including aerial reconnaissance or weapons systems. However, drone technology also extends to land and submarine vehicles for civilian and commercial applications. Each drone is paired with a remote controller, which can range from semi-autonomous to human-piloted.
    Aerial drones, now commonly available for consumer use, have been developed for myriad of applications, including sampling and aerial imaging,
    Submarine drones have long been used by scientists, explorers, and the military. The older generation of submarine drones were connected to a marine vessel by a tether. Newer drones are capable of operating independently, and have improved capacity and operating time. These drones have been used to identify mines, survey the ocean floor, and explore shipwrecks. They can also collect water samples and analyze them onboard.
  • The current system for monitoring crop health is based on stakeholder engagement. Individual farmers monitor their land, and report pest and pathogen problems to National Plant Diagnostic Network (NPDN) or the US Department of Agriculture (USDA). Universities and cooperative extension offices may also identify and report problems. A 2007 Institute of Medicine report on global surveillance notes that for certain plant pathogens or plant systems, effective surveillance systems have been implemented. However, these systems are not flexible enough to accommodate new or unusual pathogens, and may therefore overlook emerging threats.

    The technology to implement ongoing, widespread, systematic collection conduct of agricultural surveillance already exists in the form of high-resolution satellites and digital image processing methods. What is missing according to a 2007 Institute of Medicine report is a central organization charged with monitoring and protecting agricultural security, similar to CDC’s charge for human health. Although USDA and NPDN both have responsibilities in this area, their mission is more closely aligned to the short-term business interests of the agricultural industry than to long-term safety and security. This entity, proposed as a National Center for Plant Biosecurity, could integrate surveillance through remote sensing of crop health with response operations to contain the outbreak. The realization of this vision would significantly reduce the risk of a devastating disruption to agricultural security.


  • Microfluidic devices “lab on a chip” devices that  have the potential to replace or augment traditional laboratory testing equipment. Plastic microfluidic devices are credit-card sized objects with embedded channels throughout. The channels are lined with cells, reagents, antibodies, or other diagnostic components. Diagnostic samples taken from a suspected case flow through the channels, usually propelled by a pump. The fluids interact with the reagents in the channels, yielding some reaction or test result. Several processing steps can be combined on a single chip, which increases efficiency and decreases required user training.
    Another version of microfluidic devices is made of paper rather than plastic. The paper versions work just like a pregnancy test, with samples drawn through the paper fibers through capillary action. The device contains one or more reagents; when the sample encounters the reagent, it changes color to indicate the test result. Paper microfluidic devices are disposable, easy to administer and interpret, and could potentially cost just a few cents each. However, they are often limited to less complex reactions than the plastic versions.
    Microfluidic devices would be most successful if they were mass-produced and distributed at very low cost. Rapid, point of care confirmatory testing would increase testing capacity and decrease time to diagnosis and isolation. The very low cost of paper-based tests would make repeat testing feasible, so that individuals could test themselves daily. If caught early enough through regular testing, people could self-isolate and reduce their number of contacts potentially to zero. Those who test negative on a given day could continue to participate in the community, which would reduce societal disruption and fear. 
  • In very basic terms, a mass spectrometer precisely determines the mass of chemical and biological material in a specimen and conducts complex analysis based on the mass of these particles in order to determine the composition of the sample. Mass spectrometry has been used for decades in the analysis of chemical samples; however, it has evolved rapidly in recent years to include analysis of biological specimens. In fact, the US FDA approved the first mass spectrometer diagnostic test in 2013 for bacterial and fungal infections. Advances in mass spectrometry have enabled devices to detect proteins and peptides that serve as biomarkers for specific pathogens without requiring culture of the specimen.
    Traditional mass spectrometers ionize and vaporize sample particles and then accelerate a beam of these particles through a magnetic field. The spectrometer determines the mass of the particles based on the time required for them to reach the detector or their deflection from the center of the beam. Newer approaches utilize carbon nanopores through an electrically resistant membrane rather than ion beams. When these nanopores are temporarily blocked (fully or partially) by particles (eg, molecules, proteins) in solution, it results in disruptions to the electrical current that can be analyzed to determine the mass of the objects in the specimen.
  • Cell-free diagnostics harnesses the power of engineered genetic circuits and brings it out of the lab and into the field using freeze dried cell-free extracts.

    By lysing cells and collecting only the transcription/translation machinery, researchers create cell-free extracts capable of making proteins. These, combined with genetic circuits - which consist of the necessary genetic regulatory network that controls expression of specific genes – allow the production of a measurable precise product. Similar to PCR amplification of DNA for measurement

    By lysing cells and collecting only the transcription/translation machinery, researchers create cell-free extracts capable of making proteins. These, combined with genetic circuits - which consist of the necessary genetic regulatory network that controls expression of specific genes – allow the production of a measurable precise product

    Currently, it is estimated to take about one week’s time from sequence acquisition to manufacturing of cell-free paper- based diagnostic sensors. The cost of which can be reduced to as little as 2¢ to 4¢ per sensor. Detection time has been recorded in as early as 25min when high concentration of RNA is present and 40 min when just 3nM is present. Importantly, these freeze-dried cell-free paper- based reactions maintained their activity for over one year stored at room temperature, while fresh from frozen reactions normally require storage at -80° Celsius.

  • Genetically engineered strains of chassis bacterial organisms, such as yeast and salmonella, can increasingly be programmed to manufacture drugs and vaccines. Bacterial biosynthetic pathways have natural built-in modularity which can be harnessed for industrial production of both small molecules and proteins. This technology is still in its early phases, but is developing at a rapid pace. One of the first successful test cases for pharmaceutical production using synthetic biology is for the drug artemisinin – an antimalarial compound usually obtained in limited supply from plant sources – which can now be produced on large scale in yeast (Saccharomyces cervisiae). Production of artemisinin both proved the viability of synthetic biology for drug production, and advanced the science of programming bacteria for this purpose. Even drug discovery may benefit greatly from this approach, with the ability to rapidly produce and test new compounds. In particular, discovery of novel antibiotics may be made much easier through synthetic biology approaches.

    In addition to chemicals, biological organisms can be engineered to secrete therapeutic proteins like human growth hormone and interferon-alpha2b, antigens to be used in vaccines, or monoclonal antibodies for treatment of infectious diseases. Recent research shows it is possible to combine genetic engineering of chassis organisms and hardware to rapidly produce therapeutically relevant levels of biologic drugs using portable bioreactors within short periods of time. As one participant noted, experimental platforms have been tested in locations like ambulances.

    With continued advancement in synthetic biology approaches to chemical and protein synthesis for medical countermeasures, there is a strong possibility that legacy models of centralized drug production will be severely disrupted in the near future. In the context of a pandemic or GCB event, the vision of success is that rapidly edited chassis organisms like yeast, that express MCMs like monoclonal antibodies, could be rapidly disseminated to scientists around the world, who in turn could begin to use both small/portable bioreactors and larger reactors to produce the desired product locally.
    In a worse-case scenario, bioreactors used for production of other types of products like beer could be commandeered to produce drugs and vaccines, thus distributing production capacity to many more places around the world and making products available to those who need it in time to make a difference. While there would be challenges in ensuring reliability of products produced in this way, in a truly severe event, this may be one of the only options to slow the progression and prevent catastrophic impacts on the human population.
  • 3D printing is a type of additive manufacturing, building an object in successive layers by fusing or depositing materials. Importantly, this technology is increasingly available at a size and price scale that allows broad distribution of 3D printing capabilities to users at an individual level. Using digital instructions, a 3D printer can produce an object out of existing materials or reagents in almost any shape. This technology could be applied to devices and parts, biological components, and pharmaceuticals, among other uses.
    3D printing was originally used for rapid prototyping. However, use of 3D printing in reducing the impact of a GCB event would most likely hinge on the potential for 3D printing capabilities to be established locally, in businesses and homes. For example, continued gains in accessibility and affordability have already enabled a consumer market for basic 3D printers.
    The range of uses and the potential for 3D printing is expanding as the field explores differing applications and develops additional new processes. Importantly, although 3D printing is a broad term, many different applications currently require different types of manufacturing choices – from hardware, to software, to the materials being used in the manufacturing process.
    3D printing of pharmaceuticals could improve distributed countermeasure manufacturing as well as personalized drug dosing, unique dosage forms, and more complex drug release profiles.i Although much of the current excitement around this technology is based on it’s ability to facilitate personalized medicine, this is only a minor application in the context of a GCBR. A subcategory of 3D printing, 3D bio printing, utilizes 3D printing techniques to create living tissues and other biological materials that could be used in the exploration of medical countermeasures. Work is also underway to explore the potential to use of this technology to print vaccines.  
  • Self-spreading, also known as transmissible or self-replicating vaccines, are genetically engineered to move through populations like viruses, but to confer protection instead of causing disease. The vision is that a small number of the target population could be vaccinated; the vaccine strain would then circulate in the population much like a pathogenic virus. These vaccines have the potential to dramatically increase vaccine coverage in human or animal populations without
    requiring each individual to be inoculated directly.

    There are two main types of self-spreading vaccines. Recombinant vector vaccines combine the elements of a pathogenic virus that induce immunity with a transmissible viral vector. Cytomegalovirus is one candidate vector for recombinant vaccines because it is highly species specific, generally nonpathogenic, and moderately transmissible. Live viral vaccines are attenuated live virus, much like the oral polio vaccine or the LAIV.

    Although there are substantial technical challenges in genetically engineering virus, these hurdles can likely be overcome in coming years. Self-disseminating vaccines have already been used to protect wild rabbits from myxomatosis, and to control Sin Nombre virus in rodent populations. Additional work is targeting Ebola virus in apes and bats, Lassa virus in rats, and bovine tuberculosis in badgers.

    Despite these successes, several challenges remain. There is a significant risk of the virus evolving to wild-type virulence, as seen with the oral poliovirus and LAIV products, neither of which is meant to be transmissible. This is both a medical risk and a public perception risk; the possibility of vaccine-induced disease is likely unpalatable to the broader public. However, modeling work suggests that making weakly transmissible self-disseminating vaccines would limit some of the concerns about evolution to wild-type virulence, while still providing good coverage.

    For animal use, successful use of self-spreading vaccines would prevent spillover of pandemics of pandemic potential into the human population. For example, inoculation bats and nonhuman primates against Ebola could potentially limit or eliminate human outbreaks. Sufficient coverage could potentially even eradicate animal diseases, permanently buying down the risk to humans.


    targeted release early in an outbreak could act as a backfire to prevent spread outside a localized area. If successful, this strategy would prevent an outbreak from becoming a pandemic. If introduced later after the outbreak has become too widespread to control, self-spreading vaccines could help to protect susceptible individuals and limit the number of new cases
  • Prokarium has developed an oral vaccine platform (Vaxonella) that genetically engineers an attenuated strain of the Salmonella enterica bacterium into an in vivo bioreactor to create recombinant vaccines. These bacteria are placed inside capsules that once swallowed dissolve in the small intestine and release the bacteria. Through natural processes these bacteria traverse the intestinal mucosa through microfold cells, which will carry them to aggregated lymphoid follicles known as Payers Patches. Within these lymphoid follicles, antigen presenting cells (APC), such as dendritic cells and macrophages, naturally respond and phagocytose the invading bacterium. Consequently, in the presence of macrophage and dendritic cell specific promoters, the engineered bacterium begins to express antigens that trigger the APCs to stimulate all arms of the immune system. The bacterium itself is then quickly destroyed by the body’s immune cells.
    Typhella, a vaccine for typhoid fever, has already been made using this platform and has proven safe in five phase I and three phase II clinical trials. The ease with which the Salmonella enterica strain can be genetically manipulated lends itself to the ability to produce a wide range of vaccine antigens.

    Success of this vaccine platform heavily relies on improvements in timely identification of disease specific antigens as well as having the necessary supportive regulatory environment in place. It is currently estimated that in a pandemic situation where the disease is known, the very earliest you can have vaccine would be two months, plus two weeks for manufacturing time. However, if the disease is unknown it becomes more difficult to create a vaccine because the disease specific antigens are not known. Discovery of these disease specific antigens could add several months to the estimated timeline.
  • A significant advantage of using drones during infectious disease outbreaks, particularly those with global catastrophic potential, is that they remove humans from the affected environment and reduce or eliminate the potential for exposure to deadly pathogens. Because drones can be operated remotely or autonomously, humans are not required to ever enter potentially contaminated areas (eg, after a bioterror attack) or contact a potentially exposed individual or bodily fluids (eg, when providing medical supplies or transporting laboratory specimens). By reducing the risk to responders and the broader public, drones could have significant potential to reduce disease transmission without cutting off affected populations from clinical care, laboratory diagnostics, or other services, particularly in areas in which it is not possible for humans to operate safely.

    Current efforts to transport clinical specimens, countermeasures, and other medical supplies largely rely on human-operated, ground-based vehicles such as trucks. While these are effective in areas with well-established and maintained roadways and infrastructure to provide the necessary fuel, these are not always available in lower-income areas that are at the greatest risk from infectious diseases and natural disasters.
  • SAM vaccines use the genome of a modified virus with positive sense RNA. Positive sense RNA is recognizable to our human translational machinery. Normally, once a positive sense RNA virus enters a human cell, it is translated by the cell into various structural proteins and a viral replicase (which creates copies of the viral genome). The SAM vaccine platform works by synthesizing a positive sense RNA strand from a complementary DNA template; however, the sequence that would normally code for the viral structural proteins is instead replaced with a sequence that codes for an antigen of interest.

    Consequently, once inside a cell, the SAM is immediately translated and creates 2 proteins: the antigen of interest and the viral replicase. The viral replicase is then able to drive intracellular amplification by synthesizing a negative sense copy of the originally injected RNA, which will then result in production of additional positive sense viral RNA. The use of a positive, singlestrand RNA viral backbone for vaccine ensures self-amplification in a human host, while the removal of viral structural proteins eliminates the production of viral particles, effectively preventing a potentially harmful infectious cycle.

    The safety, efficacy, and ease of manufacturing of mRNA vaccines make them potentially attractive alternatives to other vaccination methods. Using mRNA, which replicates in the cytoplasm and not in the nucleus, avoids the technical barrier of nuclear delivery (getting through the nuclear membrane). It also avoids the risk of insertional mutagenesis or integration into the host genome, which could potentially lead to cancer and other problems, a common concern associated with DNA-based vaccines.

    The ability of SAM to self replicate results in a stronger, broader, and more effective humoral and cellular immune response than some other vaccines. Additionally, these vaccines can be produced through in vitro transcription reactions, which avoids the need for cell-based manufacturing and allows for rapid and highly scalable vaccine production. During the 2013 H7N9 outbreak in China, a prototype SAM(H7) vaccine was synthesized in only 8 days, whereas other vaccines, using cell-based production, took between 6 and 12 weeks.

    Current vaccine delivery technologies lack flexibility and require costly manufacturing processes. Recombinant viral vector technologies have the advantage of efficient delivery of the nucleic acid payload, but their utility is often hampered by anti-vector immunity, production limitations due to traditional egg-based culture methods, and safety concerns of reverting back to wild-type. Although a potentially safer alternative, subunit vaccines are less efficient and do not induce a cellular immune response, and thus they often require inclusion of adjuvants to make them more potent. Certain antigen protein folding patterns are difficult to create with current technology. Additionally, current protein purification methods are difficult, thus driving up manufacturing cost.

    Synthetic RNA vaccine technology has the potential to substantially shorten the time frame between pathogen sequence acquisition in the field to vaccine manufacturing. The speed provided by this platform could result in potential vaccine candidates just days after the discovery of a new virus, thus allowing responders to act much earlier in an unfolding epidemic.

    In addition to the speed, the self-amplifying nature of the vaccine means that protective immunity may arise from a much smaller vaccine dose. In the context of a GCBR, the dose-saving potential of SAM vaccines would allow the initial batch of vaccine to reach a much wider population, potentially saving many more lives.

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