Smallpox was declared eradicated in 1980, with known seed stock retained in two high security Biosafety Level 4 laboratories in the United States and Russia (1). In the decades since eradication, the risk of smallpox has been thought to be from clandestine stockpiles of virus outside of the official repositories. Experts agree the likelihood of theft from these laboratories is low, and that synthetic creation of smallpox is a theoretical possibility (2). Until 2017 it was believed that synthetic smallpox was technically too complex a task to be a serious threat. However, in 2017, Canadian scientists synthesised a closely related orthopoxvirus, horsepox, using mail order DNA and $100,000 (3). The experiment was not detected by any defence, intelligence or security surveillance systems, and was not known until the scientists themselves informed the WHO (3). In 2018, terrorist groups declared an intent for biological attacks against Western societies (4). There is capability for such an attack, with the recent open access publication of methods to manufacture an orthopoxvirus (5). The genome of the smallpox virus, variola, is publicly available, and the world’s population is largely susceptible to smallpox due to the cessation of smallpox vaccination programs nearly 40 years ago and waning vaccine immunity in vaccinated older adults (6).
The Pacific is a unique and highly diverse geographic region and includes large islands such Papua New Guinea and Fiji, and small island nations such as Kiribati, with many islands and informal maritime transport networks. The region is affected by many disasters such as cyclones, tsunamis, volcano eruptions, earthquakes, rising sea levels and political conflict, which create systems vulnerability to infectious diseases epidglobal emics (7). The Pacific Island states bear a disproportionate burden of the global crisis of human resources in health because of weak health systems, insufficient production of trained health personnel and significant outward migration. Limited diagnostic and therapeutic capacity and the lack of funding for simple diagnostics and for therapeutic monitoring also impact on epidemic response.
System problems such as coordination across countries, jurisdictions, agencies and disciplines, including those outside of the health system, may hinder emergency response to epidemics. A key aspect of strengthening health security during a bioterrorism incident is improving collaboration of responses between health, emergency management, defence, law enforcement and other sectors. The Pacific region is a critical part of the world in view of its geo-political strategic significance and unique vulnerabilities, which make control of infectious diseases a greater challenge in this region than elsewhere (8). A smallpox epidemic in the Pacific could spread globally and could be challenging to contain due to dispersed island geography, informal maritime travel and shortage of human resources. In this context, a smallpox simulation exercise was held in August 2018, with a focus on bringing together international stakeholders from a wide range of sectors including health, defence, law enforcement, emergency management and relevant non-government organisations.
To review preparedness for a bioterrorism attack in the Asia-Pacific region and globally.
- To review potential gaps in preparedness for smallpox release
- To identify modifiable factors which could prevent a severe smallpox epidemic.
Design and facilitation
An exercise was conducted by The National Health and Medical Research Council (NHMRC) Centre for Research Excellence, Integrated Systems for Epidemic Response, with contextual input from the Ministry of Health and Medical Services Fiji. The simulation was designed by Professor Raina MacIntyre from the Kirby Institute, who is the head of the Centre for Research Excellence in Integrated Systems for Epidemic Response (ISER), Associate Professor David Heslop, Chief Investigator of ISER from UNSW Medicine’s School of Public Health and Community Medicine, and Dr Devina Nand of the Fiji Ministry of Health and Medical Services. Mathematical modelling of smallpox transmission (9) was used to simulate the epidemic under different conditions and to test the effect of interventions. An interactive format was used to explore decision making during the scenario. This paper has been prepared based on discussions during the exercise, and expert input from participants.
Stakeholders from government and non-government organisations from Australia, New Zealand, several Pacific Island countries (PNG, Tonga, Vanuatu, Fiji, FSM, Samoa, Guam), the United States of America (USA) as well as industry and non-government organisations based in the United Kingdom, Singapore, Denmark and Switzerland were present.
Exercise date and location
Exercise Mataika was held on August 16 2018 in Sydney, Australia.
An outbreak simulation tabletop exercise was developed by the ISER team at UNSW. The exercise alternated between clinical, public health, emergency and societal responses, with participants discussing cross-sectoral capability in responding collaboratively across the region and the world. Key weak points that are influential in determining the final size and impact of the epidemic were identified (based on mathematical modelling of transmission in Fiji and globally).
Participants analysed the scenario from start to finish and identified and discussed key interventions that could prevent the worst possible outcome. This included identifying which determinants of epidemic size are potentially within our control, and which are not, thus providing a framework for interventions to prevent and mitigate an epidemic of smallpox. Based on the scenario and discussions about response, recommendations were made to guide improved and more rapid and effective responses.
A first case of haemorrhagic smallpox occurs in a private hospital in Fiji, but the diagnosis is missed, as clinicians are not familiar with the disease. It is not until multiple cases are reported to the Ministry of Health and Medical Services that smallpox is considered as a diagnosis. The index case in the scenario was based on the index case in the Yugoslavian outbreak of 1972 (10). The patient had haemorrhagic smallpox, making the rash less obvious than the classic form. The index case in Fiji is misdiagnosed as having an adverse reaction to an antibiotic, which is what occurred in Yugoslavia, a country that had not seen a case of smallpox for over 30 years at the time (10). While autopsy results are awaited, more cases start appearing. A team of four epidemiologists from WHO responds to assist with the outbreak investigation while the diagnosis is still unknown. They, together with local public health officials, consider chickenpox, dengue, monkeypox and smallpox as a differential diagnosis. Samples are sent to Australia for testing. Days after the first case presented, case numbers have risen to at least 200. Initial case fatality estimates are about 40%. The health system is overwhelmed, with multiple hospitals treating cases and media reports causing public panic.
Test results confirm variola virus on a Friday afternoon, 13 days after the index case presented, and the WHO promptly declares a Public Health Emergency of International Concern. Hundreds of cases have occurred by this time and case interviews determine that all were at Nadi International Airport, either as travellers or visitors, on August 1st, making this the likely day of infection. Smallpox has an average incubation period of 12 days, with a range of 7-17 days. The index patient presented 12 days after landing at Nadi airport, supporting the airport as the likely site of infection. Law enforcement agencies and military are called in to investigate.
The WHO vaccine stockpile is comprised of 2.7 million doses of first-generation vaccine held in Geneva and 31 million doses (about 2/3rd second generation vaccine) pledged by various member states (11). Vaccine is deployed by WHO on day 27 post-release, the Monday after the diagnosis, reaching Fiji on day 28. However, the public health teams tasked with the initial response are unvaccinated, so they must first be vaccinated and protected before deploying to vaccinate others. Vaccine take occurs after 7 days, so a decision is made to deploy 7 days after vaccination, although there is evidence for protection earlier than this (12). After travel and logistics are arranged, vaccination begins on day 40 in Fiji.
In this scenario, ring vaccination is used. Ring vaccination requires tracing and vaccinating all contacts of smallpox cases, with contacts prioritised by the closeness and degree of contact. Ring vaccination was used to eradicate smallpox and is the most efficient vaccination strategy to control the epidemic if vaccine supply is limited (13).
Forensic investigation by local agencies and Interpol identifies a bioterrorism attack to have taken place at Nadi International Airport in Fiji on August 1st, with many people infected simultaneously and some travelling onward to other countries on day zero. The airport is closed on day 25 post-release, for decontamination and forensic investigation. Many people in Fiji are desperate to leave, but tourists and locals alike are trapped, although boat travel increases and locals move to outer islands and other Pacific Island nations through informal, undocumented travel.
The phylogenetic analysis shows a likely engineered strain. Clinically, it is responsive to available antiviral drugs and vaccine appears to be highly protective. The clinical response comprises case finding, isolation and supportive therapy. There are no supplies of the antivirals cidofivir, brincidofivir or TPOXX in Fiji at this time, and there is limited human clinical evidence of the use of these drugs.
Other pressing issues include protection of health workers and other first responders, crisis communication and management of the worried well. Fiji has 24 public hospitals, 3 private hospitals and 1 military hospital, with a combined total of 1753 hospital beds. By day 25 there are already >2000 smallpox cases, exceeding the total available beds. Other urgent medical care, such as myocardial infarction and trauma, is compromised. Of the 2800 nurses in Fiji, 500 are infected and 320 are dead by day 30. There are 873 doctors in Fiji, of whom 185 are infected and 79 are dead. The health system is in crisis, and there are few other clinicians to draw upon. The Fiji Nursing Association calls a strike, demanding vaccination and personal protective equipment (PPE), which are in short supply. Conflict between private and public hospitals occurs, with rumours that vaccine and PPE will be prioritised for workers in public hospitals.
Based on modelled smallpox transmission using a published model (6), adapted for Fiji and the world, we follow the epidemic as it spreads across the globe in a matter of weeks. The attack at the airport results in cases arising in several other countries from people travelling out of Fiji on day zero. Smallpox has a R0 that may be as high as 4-5 (6), and is therefore potentially more infectious than influenza (R0 ~2)(14) or Ebola (R0 ~2) (14-17). It is spread by the respiratory route and rapidly propagates in a largely non-immune population (6). In the period prior to eradication, smallpox epidemics occurred often due to importations of smallpox by a single infected person, but in a deliberate attack there are likely to be hundreds or more infections on day zero, which makes it much more difficult to control the epidemic, especially as infected people disperse around a highly interconnected world.
Cases that were infected in the initial attack at Nadi International airport have occurred in multiple different countries, and second-generation cases are appearing overseas. Law enforcement investigations identify the method of attack and uncover possible planning for a second or multiple other attacks on the Dark Web. Identification of perpetrators is difficult, but there appears to be a large network of global colluders, which are using cryptocurrency for financial transactions to support their activities.
As the epidemic spreads globally, Australia, New Zealand and other international carriers cease all flights to and from Fiji. Meanwhile, locals and stranded tourists desperately try to escape Fiji. Illegal boat travel escalates between islands in Fiji and within the Pacific, including boats of infected people approaching New Zealand and Australia. The boats are not allowed to land, creating ethical dilemmas and a media frenzy. Cruise ships companies immediately divert and avoid Fiji, and other ports refuse entry to cruise ships which have passed through Fiji. Food and supplies are running short on stranded cruise ships. Regional governments begin to pressure Fiji to assist with evacuation of their nationals.
Multiple conflicting requests and demands are made of Fiji and its government. On the ground responses from key allies of Fiji are not forthcoming immediately, although advice is provided on conference calls and essential supplies are provided by air drop. Countries are also focused on managing their own domestic cases of smallpox by now. There is resistance to military or health deployment into Fiji from other countries, due to a minimal risk appetite and a protectionist mentality exacerbated by upcoming elections in some countries. WHO GOARN puts out an alert calling for volunteers to respond. Compared to past outbreaks, there far fewer offers from trained epidemiologists and 10/39 offers are from people with contraindications to second generation vaccines, leaving 29 potential immediate responders. Another group of 50 offers from semi-skilled or inexperienced people are assessed for suitability for deployment. US CDC offers 10 people, but the remainder of their public health teams are working on their own domestic response.
In Fiji there were >1000 first generation cases infected at the airport and >5,000 second generation cases, with case numbers rising rapidly. The Fiji MOH is conducting contact tracing but has over 100,000 contacts to trace and only 50 trained public health staff and 20 NGO volunteers, none of whom are yet vaccinated. Non-government aid agencies are unable to come to Fiji because of travel bans. With a shortage of hospital beds for patients, the issue of who will trace contacts and where they will be quarantined is discussed in Fiji and other affected countries. Community mobilization is recognized as critical.
As 32,000 doses of vaccine arrive in Fiji, a larger scale attack occurs in a much larger, more populous country in Asia. With resources focussed on Fiji, this catches the world off guard and stretches the limited global stockpile of vaccine. Globally, critical delays occur in coordination of the response, including the need to vaccinate first responders before they can deploy. Staff need to be trained in vaccination procedures, care of the vaccination site and assessing vaccine take. Vaccinating the vaccinators and procuring supplies of bifurcated needles cause some delays. As the epidemic escalates, hospital beds reach capacity and other industries are affected by severe absenteeism. Lack of resources, including human resources, is a major problem. Modelling shows that the epidemic is most sensitive to case isolation, contact tracing and vaccination, and speed of response (9). Speed of response for isolation, contact tracing and vaccination is most critical in the early stages of the epidemic.
Shortages of human resources and physical space to isolate cases are a problem, and health workers are dying of smallpox. Community engagement and mobilisation are recognised as essential but are not well coordinated, and crisis communication is poor. In a worst-case scenario, at the peak of the epidemic, worldwide, only 50% of smallpox cases are isolated (mostly through use of community volunteers and use of makeshift buildings as isolation facilities) and only 50% of contacts are tracked and vaccinated, causing a catastrophic blow-out in the epidemic. Under these conditions, modelling shows it will take more than a billion doses and 10 years to stop the epidemic (9). The WHO stockpile comprises less than 10% of doses held by WHO, with the remainder of doses being pledged from donor countries (11). Stockpiles of certain countries remain unknown, but WHO estimates there may be up to 900 million doses in the world. The world’s population is 7 billion. There is up to a 12-18 month lag time in vaccine production, and it is estimated that 300 million doses could be produced in this time by the very few producers of smallpox vaccines globally. In the scenario, countries are reluctant to provide pledged doses, as they are facing domestic epidemics of smallpox. Fiji must manage with 32,000 doses and must decide the best use of these doses. Discussions about diluting the available vaccine are held. The U.S. sends 1000 doses of the antiviral drug TPOXX from their stockpile to Fiji early in the epidemic but retains the rest for domestic smallpox cases.
Critical infrastructure, travel and trade are affected, and countries scramble to get access to limited antiviral drugs, vaccine and personal protective equipment supplies. Foreign aid is reduced as countries divert resources to managing their own crises. Managing communications becomes challenging. Rioting besets major cities and both military and police responses are required. Mass gathering bans are implemented in Fiji and other countries. A black market has emerged in illegal boat travel, with irregular movements between outlying islands increasing and limited capacity to patrol all parts of the maritime border. Border disputes occur between countries. By day 40 post-release, the epidemic has spread to 26 countries. Around 50% of staff at key services in affected countries are absent during the peak of the epidemic. Reasons for absence include fear, family obligations and illness. Basic services supporting the economy and critical infrastructure including power are now impacted and economic activity is severely impacted. Supply chains are disrupted globally, causing shortages of essential medicines, supplies and food.
PPE is in short supply and vaccine is prioritised for health workers. Health workers, police and military are dying of smallpox, leaving systems weakened and unable to cope with the response. There is not enough vaccine, antiviral or personal protective equipment for health workers, police and military, who require protection as critical first responders. Police use riot gear as improvised PPE, but supplies are minimal. Health workers use home-made PPE. Other at-risk groups such as mortuary workers, waste services, cleaners and service personnel are also affected. Management of dead bodies and disposal of medical waste is a major problem, with transport companies refusing to transport medical waste.
In the final phase of the epidemic, which becomes a pandemic, the workforce is decimated, leaving critical infrastructure, transport, power, communications and food supplies compromised. Government assets are generally dispersed, depleted, and not readily available, resulting in severe conflicts regarding prioritization of limited supplies to health, police and border protection. Dissent is quashed using various means and penalties for insubordination are increased in uniformed services. Key modern systems become unreliable, including wireless and data communications, economy and banking (cash supply), replacement parts and manufactured items, processed food, and medications.
Globally, due to lack of human resources and physical space for patient isolation and the larger attack in a highly populated developing country, only 50% of case are isolated and 50% of contacts traced and vaccinated. Recovered people are mobilized to help with contact tracing and case finding, but food supplies are short and resilience is low. Vaccine production by the few manufacturers is occurring but cannot meet demand. Available supplies go to wealthier countries and not to the areas of greatest need where transmission is most intense. A major donor’s funding is helping novel vaccine development and scaled up production. Trials of reduced dose schedules have commenced and accelerated vaccine development has been approved, with mixed academic and public reaction. Ethicists are alarmed about the possible harms of rapidly implementing human experimentation and caution that the risks may outweigh the benefits. Misinformation and poor crisis communication exacerbate the situation. Differentiation between accurate and inaccurate information is now impossible. Reported information about case numbers, fatalities and affected regions vary drastically. Many governments attempt to control information and establish authoritative information sources, but frequently contradict themselves. Trust in government and authority structures has disappeared, and legitimate attempts at communication by authorities are viewed with suspicion and fuel conspiracy theories
Rural areas, including Pacific islands, are more resilient due to retained skills in subsistence living, including basic primary healthcare, but large urban cities are badly affected. Mass displacement and migration of human beings occurs within countries and across national borders. This situation may meet the definition of a Global Catastrophic Biological Risk (GCBR) event (18). The final impact of the pandemic is more severe than a single nuclear strike, and societies are left decimated. Societal recovery worldwide starts from a lower baseline than in the pre-epidemic era.
Key factors that are influential in determining the final size and impact of the epidemic were identified (empirically and based on mathematical modelling of transmission in Fiji and globally). Input was provided from multinational experts in health, defence, law enforcement and emergency management. Based on the scenario and discussed response, recommendations were made to guide improved, more rapid and effective response. The purpose of exercising a severe scenario was to analyse the conditions that gave rise to the situation and how these can be modified and mitigated. Participants analysed the scenario from start to finish and identified and discussed decision making and key interventions that could prevent the worst possible outcome. Polling software was used to record individual decision making, results were provided in real time to the group, and participants reviewed responses and reached consensus. To conclude the exercise, participants identified determinants of epidemic size. These were then divided into those which are potentially modifiable, and those which are not, thus providing a framework for feasible interventions to prevent and mitigate an epidemic of smallpox (Figure 1). The general principles would apply to prevention and mitigation of any contagious serious infectious disease. Key recommendations around each of the modifiable factors shown in Figure 1 are summarised below.
Recommendations on modifiable determinants of a smallpox attack
The recommendations arising from discussion at the workshop are summarised below in Boxes 2-11.
Exercise Mataika enabled cross-sectoral expert input into considering many aspects of a smallpox release and subsequent pandemic. We provide a framework for identifying and focusing on factors potentially within our control along the entire spectrum from pre-attack to recovery, from intelligence, legislation and law enforcement to public health measures and social mobilisation. We recommend that critical weak points be mitigated with prior careful planning, maximising prevention of planned attacks through intelligence gathering, and optimising a timely response and the recovery phase, whilst recognising substantial physical, infrastructure and human resources surge requirements in a pandemic. The exercise also highlighted the importance of international cooperation and the tensions which may arise between this need and domestic responses within each country, especially regarding the WHO pledged vaccine stockpile. Preparedness for a potentially catastrophic epidemic requires an inclusive and collaborative approach with all first response sectors and across nations, rather than a health-centric, localised approach to planning. Traditional planning focuses predominantly on medical counter-measures after an attack has occurred.
The impact of an epidemic and subsequent pandemic of smallpox would be substantial if arising in a low-income country with weak health systems and may have a very long duration. Practical aspects, like communication, the need to use community volunteers, requirements for case isolation, protection of first line responders, vaccination strategies, international cooperation and having surge capacity in both personnel and physical facilities should be central to planning. Planning for such an event is often based on assumed probability of the event alone. However, risk analysis is required which considers impact of such an attack and other factors such as human to human transmission potential (50), intent and capability. We know that there is declared intent for bioterrorism attacks against Western societies (4). There is also capability for such an attack, given the recent publication of synthetic biology methods to manufacture a virus very similar to smallpox. The genome of the smallpox virus, variola, is publicly available. We do not know if those with intent have the capacity to generate variola virus in vitro, but the possibility is higher now than any time in the past. As synthetic biology and genetic engineering technology continues to advance and become cheaper and more accessible, the risk will continue to increase. The principles of identifying influential and modifiable factors along the entire timeline of an event (from planning of an attack to recovery) and focusing on these factors for preparedness can be applied to any serious emerging infectious disease threat.
Acknowledgments and disclosures
The workshop was sponsored by the NHMRC Centre for Research Excellence Integrated Systems for Epidemic Response (ISER). Additional sponsorship was provided by Emergent BioSolutions and Bavarian Nordic, who had no input into the design of the exercise nor the assumptions sets going into the mathematical modelling.
We acknowledge the input of all participants, of the ISER team (logistics and modelling), and of the Fiji Ministry of Health and Medical Services.
1. World Health Organization (WHO). WHO Advisory committee on variola virus research: report of the nineteenth meeting, 1-2 November 2017, Geneva, Switzerland: World Health Organization; 2018 [cited 2018 October 23]. Available from: http://apps.who.int/iris/bitstream/handle/10665/272441/WHO-WHE-IHM-2018.2-eng.pdf?sequence=1&isAllowed=y.
2. Koblentz GD. The de novo synthesis of horsepox virus: implications for biosecurity and recommendations for preventing the reemergence of smallpox. Health security. 2017;15(6):620-8. DOI: https://doi.org/10.1089/hs.2017.0061
3. Kupferschmidt K. How Canadian researchers reconstituted an extinct poxvirus for $100,000 using mail-order DNA. Science, July. 2017;6. DOI: https://doi.org/10.1126/science.aan7069
4. Coats DR. Statement for the Record, Worldwide Threat Assessment of the US Intelligence Community: Office of the Director of National Intelligence; 2018 [cited 2018 October 23]. Available from: https://www.dni.gov/files/documents/Newsroom/Testimonies/2018-ATA---Unclassified-SSCI.pdf.
5. Noyce RS, Lederman S, Evans DH. Construction of an infectious horsepox virus vaccine from chemically synthesized DNA fragments. PloS one. 2018;13(1):e0188453. DOI: https://doi.org/10.1371/journal.pone.0188453
6. MacIntyre CR, Costantino V, Chen X, Segelov E, Chughtai AA, Kelleher A, et al. Influence of Population Immunosuppression and Past Vaccination on Smallpox Reemergence. Emerging infectious diseases. 2018;24(4):646. DOI: https://doi.org/10.3201/eid2404.171233
7. McIver L, Kim R, Woodward A, Hales S, Spickett J, Katscherian D, et al. Health impacts of climate change in Pacific island countries: a regional assessment of vulnerabilities and adaptation priorities. Environmental health perspectives. 2015;124(11):1707-14. DOI: https://doi.org/10.1289/ehp.1509756
8. Coker RJ, Hunter BM, Rudge JW, Liverani M, Hanvoravongchai P. Emerging infectious diseases in southeast Asia: regional challenges to control. The Lancet. 2011;377(9765):599-609. DOI: https://doi.org/10.1016/S0140-6736(10)62004-1
9. MacIntyre CR, Costantino V, Mohanty B, Nand D, Kunasekaran M, Heslop DJ. Epidemic size, duration and vaccine stockpiling following a large-scale attack with smallpox. Global Biosecurity. 2019; 1(1). DOI: http://doi.org/10.31646/gbio.13
10. Ilic M, Ilic I. The last major outbreak of smallpox (Yugoslavia, 1972): The importance of historical reminders. Travel medicine and infectious disease. 2017;17:69-70. DOI: https://doi.org/10.1016/j.tmaid.2017.05.010
11. Yen C, Hyde TB, Costa AJ, Fernandez K, Tam JS, Hugonnet S, et al. The development of global vaccine stockpiles. The Lancet Infectious Diseases. 2015;15(3):340-7. DOI: https://doi.org/10.1016/S1473-3099(14)70999-5
12. Kennedy R, Lane, JM, Henderson, DA, Poland, GA. Smallpox and vaccinia. In: Plotkin SA, Orentein WA, Offit PA editors. Vaccines, 6th ed. Amsterdam: Elsevier Inc. 2012; 718-745.
13. Porco TC, Holbrook KA, Fernyak SE, Portnoy DL, Reiter R, Aragón TJ. Logistics of community smallpox control through contact tracing and ring vaccination: a stochastic network model. BMC public health. 2004;4(1):34. DOI: https://doi.org/10.1186/1471-2458-4-34
14. Biggerstaff M, Cauchemez S, Reed C, Gambhir M, Finelli L. Estimates of the reproduction number for seasonal, pandemic, and zoonotic influenza: a systematic review of the literature. BMC infectious diseases. 2014;14(1):480. DOI: https://doi.org/10.1186/1471-2334-14-480
15. Gomes MF, y Piontti AP, Rossi L, Chao D, Longini I, Halloran ME, et al. Assessing the international spreading risk associated with the 2014 West African Ebola outbreak. PLoS currents. 2014;6. DOI: https://doi.org/10.1371/currents.outbreaks.cd818f63d40e24aef769dda7df9e0da5
16. Fisman D, Khoo E, Tuite A. Early epidemic dynamics of the West African 2014 Ebola outbreak: estimates derived with a simple two-parameter model. PLoS currents. 2014;6. DOI: https://doi.org/10.1371/currents.outbreaks.89c0d3783f36958d96ebbae97348d571
17. Althaus CL. Estimating the reproduction number of Ebola virus (EBOV) during the 2014 outbreak in West Africa. PLoS currents. 2014;6. DOI: https://doi.org/10.1371/currents.outbreaks.91afb5e0f279e7f29e7056095255b288
18. Schoch-Spana M, Cicero A, Adalja A, Gronvall G, Kirk Sell T, Meyer D, et al. Global catastrophic biological risks: toward a working definition. Health security. 2017;15(4):323-8. DOI: https://doi.org/10.1089/hs.2017.0038
19. Gryphon. S. Risk and benefit analysis of Gain of function research Final Report-April 2016. 2016 [updated 2016 April; cited 2018 August 27 ]. Available from: http://www.gryphonscientific.com/wp-content/uploads/2016/04/Risk-and-Benefit-Analysis-of-Gain-of-Function-Research-Final-Report.pdf.
20. House T, Hall I, Danon L, Keeling MJ. Contingency planning for a deliberate release of smallpox in Great Britain-the role of geographical scale and contact structure. BMC infectious diseases. 2010;10(1):25. DOI: https://doi.org/10.1186/1471-2334-10-25
21. The United Nations Office at Geneva (UNOG). Investigations of Alleged Biological Weapons Use: Overlap with Public Health Assistance under Article VII of the Biological and Toxin Weapons Convention: United States of America. 2018 [cited 2018 November 1]. Available from: https://www.unog.ch/80256EDD006B8954/(httpAssets)/30A686E930E89D75C12582E8003DD111/$file/MX4+WP+2+-+UNSGM-Art+VII+working+paper+FINAL.pdf ].
22. Butler D. Anthrax case not closed, says Nature: Declan Butler. Report. 2008 [updated 2008 August 20; cited 2018 August 27]. Available from: http://declanbutler.info/blog/?p=136.
23. Murray BE, Anderson KE, Arnold K, Bartlett JG, Carpenter CC, Falkow S, et al. Destroying the life and career of a valued physician-scientist who tried to protect us from plague: was it really necessary? Clinical infectious diseases. 2005;40(11):1644-8. DOI: https://doi.org/10.1086/431348
24. Gonzalez T. Individual Rights Versus Collective Security: Assessing The Constitutionality Of The USA Patriot Act. 2003 [updated 2003 January 10; cited 2018 October 10]. Available from: https://repository.law.miami.edu/cgi/viewcontent.cgi?article=1102&context=umiclr.
25. Amanna IJ, Slifka MK, Crotty S. Immunity and immunological memory following smallpox vaccination. Immunological reviews. 2006;211(1):320-37. DOI: https://doi.org/10.1111/j.0105-2896.2006.00392.x
26. MacIntyre CR, Engells TE, Scotch M, Heslop DJ, Gumel AB, Poste G, et al. Converging and emerging threats to health security. Environment Systems and Decisions. 2017:1-10.
27. Smith CL, Hughes SM, Karwowski MP, Chevalier MS, Hall E, Joyner SN, et al. Addressing needs of contacts of Ebola patients during an investigation of an Ebola cluster in the United States-Dallas, Texas, 2014. MMWR Morbidity and mortality weekly report. 2015;64(5):121-3.
28. Fasina FO, Shittu A, Lazarus D, Tomori O, Simonsen L, Viboud C, et al. Transmission dynamics and control of Ebola virus disease outbreak in Nigeria, July to September 2014. Eurosurveillance. 2014;19(40):20920. DOI: https://doi.org/10.2807/1560-7917.ES2014.19.40.20920
29. Kim S, Yang T, Jeong Y, Park J, Lee K, Kim K. Middle East respiratory syndrome coronavirus outbreak in the Republic of Korea, 2015. Osong Public Health Res Perspect. 2016;6(4):269-78.
30. MacIntyre CR, Zhang Y, Chughtai AA, Seale H, Zhang D, Chu Y, et al. Cluster randomised controlled trial to examine medical mask use as source control for people with respiratory illness. BMJ open. 2016;6(12):e012330. DOI: https://doi.org/10.1136/bmjopen-2016-012330
31. Eichner M. Case isolation and contact tracing can prevent the spread of smallpox. American journal of epidemiology. 2003;158(2):118-28. DOI: https://doi.org/10.1093/aje/kwg104
32. Igonoh A. Through the Valley of the Shadow of Death.Dr. Ada Igonoh survived Ebola – This is her Story: BellaNaija.com. 2014 [updated 15 September 2014; cited 2018 August 26]. Available from: https://www.bellanaija.com/2014/09/must-read-through-the-valley-of-the-shadow-of-death-dr-ada-igonoh-survived-ebola-this-is-her-story/.
33. Nevin RL, Anderson JN. The timeliness of the US military response to the 2014 Ebola disaster: a critical review. Medicine, Conflict and Survival. 2016;32(1):40-69. DOI: https://doi.org/10.1080/13623699.2016.1212491
34. Kim SH, Yeo SG, Jang HC, Park WB, Lee CS, Lee KD, et al. Clinical responses to smallpox vaccine in vaccinia-naive and previously vaccinated populations: undiluted and diluted Lancy-Vaxina vaccine in a single-blind, randomized, prospective trial. The Journal of infectious diseases. 2005;192(6):1066-70. DOI: https://doi.org/10.1086/432765
35. Couch RB, Winokur P, Edwards KM, Black S, Atmar RL, Stapleton JT, et al. Reducing the dose of smallpox vaccine reduces vaccine-associated morbidity without reducing vaccination success rates or immune responses. The Journal of infectious diseases. 2007;195(6):826-32. DOI: https://doi.org/10.1086/511828
36. Prem K, Cook AR, Jit M. Projecting social contact matrices in 152 countries using contact surveys and demographic data. PLoS computational biology. 2017;13(9):e1005697. DOI: https://doi.org/10.1371/journal.pcbi.1005697
37. Grigg C, Waziri NE, Olayinka AT, Vertefeuille JF. Use of group quarantine in Ebola control—Nigeria, 2014. MMWR Morbidity and mortality weekly report. 2015;64(5):124.
38. McLeod MA, Baker M, Wilson N, Kelly H, Kiedrzynski T, Kool JL. Protective effect of maritime quarantine in South Pacific jurisdictions, 1918–19 influenza pandemic. Emerging infectious diseases. 2008;14(3):468. DOI: https://doi.org/10.3201/eid1403.070927
39. Boyd M, Baker MG, Mansoor OD, Kvizhinadze G, Wilson N. Protecting an island nation from extreme pandemic threats: Proof-of-concept around border closure as an intervention. PloS one. 2017;12(6):e0178732. DOI: https://doi.org/10.1371/journal.pone.0178732
40. Boyd M, Mansoor OD, Baker MG, Wilson N. Economic evaluation of border closure for a generic severe pandemic threat using New Zealand Treasury methods. Australian and New Zealand journal of public health. 2018;42(5):444-6. DOI: https://doi.org/10.1111/1753-6405.12818
41. Nishiura H. Determination of the appropriate quarantine period following smallpox exposure: an objective approach using the incubation period distribution. International journal of hygiene and environmental health. 2009;212(1):97-104. DOI: https://doi.org/10.1016/j.ijheh.2007.10.003
42. Ministry of Health. Responding to Public Health Threats of International Concern at New Zealand Air and Sea Ports: Guidelines for public health units, border agencies and health service providers. Wellington: Ministry of Health. 2016 [cited 2018 Sept 27]. Available from: https://www.health.govt.nz/system/files/documents/publications/responding-public-health-threats-international-concern-nz-air-sea-ports-aug16.pdf.
43. Priest PC, Duncan AR, Jennings LC, Baker MG. Thermal image scanning for influenza border screening: results of an airport screening study. PloS one. 2011;6(1):e14490. DOI: https://doi.org/10.1371/journal.pone.0014490
44. Priest PC, Jennings LC, Duncan AR, Brunton CR, Baker MG. Effectiveness of border screening for detecting influenza in arriving airline travelers. American journal of public health. 2013;103(8):1412-8. DOI: https://doi.org/10.2105/AJPH.2012.300761
45. MacIntyre C, Chughtai, AA, Seale H, Richards, GA, Davidson, PM. Respiratory protection for healthcare workers treating ebola virus disease (evd): are facemasks sufficient to meet occupational health and safety obligations? International Journal of Nursing Studies. 2014;51(11):1421-6. DOI: https://doi.org/10.1016/j.ijnurstu.2014.09.002
46. Wade N. New smallpox case seems lab-caused. Science. 1978;201(4359):893-. DOI: https://doi.org/10.1126/science.684414
47. Thomas G. Air sampling of smallpox virus. Epidemiology & Infection. 1974;73(1):1-8. DOI: https://doi.org/10.1017/S0950268800001060
48. Meiklejohn G, Kempe C, Downie A, Berge T, Vincent LS, Rao A. Air sampling to recover variola virus in the environment of a smallpox hospital. Bulletin of the World Health Organization. 1961;25(1):63.
49. Tak S, Jareb A, Choi S, Sikes M, Choi YH, Boo H-w. Enhancing 'Whole-of-Government'Response to Biological Events in Korea: Able Response 2014. Osong public health and research perspectives. 2018;9(1):32. DOI: https://doi.org/10.24171/j.phrp.2018.9.1.06
50. MacIntyre CR, Seccull A, Lane JM, Plant A. Development of a risk-priority score for category A bioterrorism agents as an aid for public health policy. Military medicine. 2006;171(7):589-94. DOI: https://doi.org/10.7205/MILMED.171.7.589