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Protecting an island nation from extreme pandemic threats: Proof-of-concept around border closure as an intervention
research-article
Author(s):
Matt Boyd
1 ,
Michael G. Baker
2 ,
Osman D. Mansoor
3 ,
Giorgi Kvizhinadze
2 ,
Nick Wilson
2
,
*
Publication date (Electronic):
16 June 2017
Journal:
PLoS ONE
Publisher:
Public Library of Science
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There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.
Abstract
Background
Countries are well advised to prepare for future pandemic risks (e.g., pandemic influenza, novel emerging agents or synthetic bioweapons). These preparations do not typically include planning for complete border closure. Even though border closure may not be instituted in time, and can fail, there might still plausible chances of success for well organized island nations.
Objective
To estimate costs and benefits of complete border closure in response to new pandemic threats, at an initial proof-of-concept level. New Zealand was used as a case-study for an island country.
Methods
An Excel spreadsheet model was developed to estimate costs and benefits. Case-study specific epidemiological data was sourced from past influenza pandemics. Country-specific healthcare cost data, valuation of life, and lost tourism revenue were imputed (with lost trade also in scenario analyses).
Results
For a new pandemic equivalent to the 1918 influenza pandemic (albeit with half the mortality rate, “Scenario A”), it was estimated that successful border closure for 26 weeks provided a net societal benefit (e.g., of NZ$11.0 billion, USD$7.3 billion). Even in the face of a complete end to trade, a net benefit was estimated for scenarios where the mortality rate was high (e.g., at 10 times the mortality impact of “Scenario A”, or 2.75% of the country’s population dying) giving a net benefit of NZ$54 billion (USD$36 billion). But for some other pandemic scenarios where trade ceased, border closure resulted in a net negative societal value (e.g., for “Scenario A” times three for 26 weeks of border closure–but not for only 12 weeks of closure when it would still be beneficial).
Related collections
Most cited references12
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Public Health Interventions and SARS Spread, 2003
David M Bell (2004)
The 2003 outbreak of severe acute respiratory syndrome (SARS) is a modern example of containing a global epidemic through traditional or nonmedical public health interventions. The interventions included finding and isolating case-patients; quarantining contacts; measures to "increase social distance," such as canceling mass gatherings and closing schools; recommending that the public augment personal hygiene and wear masks; and limiting the spread of infection by domestic and international travelers, by issuing travel advisories and screening travelers at borders. Some measures were implemented pursuant to recommendations of the World Health Organization (WHO); others were implemented by governments on their own initiative. A novel technology, infrared scanning, was used extensively in some countries to try to identify persons with fever at international borders and in public places. After the outbreaks, WHO sought information to help assess the effectiveness of interventions in preventing the transmission of SARS in the community and internationally. Of particular interest was information on the effectiveness of thermal scanning of travelers. Methods Information was obtained by reviewing scientific literature and surveying members of an informal WHO working group about preventing community and international transmission of SARS. Members were surveyed with standardized questionnaires regarding measures taken in their countries and evaluation studies known to them. Preventing transmission in healthcare settings was not addressed but had a major impact on preventing the transmission of SARS into the community and internationally ( 1 , 2 ). Results Local and National Interventions Identifying Patients and Quarantining Contacts Ascertaining and isolating case-patients, combined with rapid identification and management of contacts, were highly effective in interrupting transmission in several countries ( 1 – 6 ). 2 For example, a study in Singapore demonstrated a correlation between rapidly isolating patients after onset of symptoms and a decreased number of secondary cases among their contacts ( 4 ) (Figure). Contacts in these countries were placed in various forms of quarantine or, less commonly, monitored for symptoms without confinement and isolated if and when symptoms emerged. The location of quarantine was usually at home but was sometimes at a designated residential facility (e.g., for travelers, persons who did not wish to remain at home for fear of exposing their families, homeless persons, and noncompliant persons). In some cases, quarantined persons were allowed to leave the quarantine site with the permission of local health authorities if they wore masks and did not use public transportation or visit crowded public places. In at least one area, these restrictions were applied to essential workers and termed "work quarantine." Figure Severe acute respiratory syndrome cases in Singapore, February 25–May 5, 2003. Number of primary cases (light gray) by time from symptom onset to isolation, number of secondary cases infected by such cases (dark gray), and mean number of secondary cases per primary case. Reprinted with permission from Lipsitch M, Cohen T, Cooper B, Robins JM, Ma S, James L, et al. Science 2003;300:1966–70. Copyright 2003 by the American Association for the Advancement of Science. http://www.sciencemag.org Several respondents emphasized that the modern concept of quarantine differs greatly from quarantine in past centuries. Quarantine is most acceptable and arguably most effective when protecting the health and rights of quarantined persons is emphasized. In previous centuries, sick and exposed persons were often locked up together and received limited medical care. Moreover, quarantine was sometimes applied in an arbitrary and discriminatory fashion, targeting lower socioeconomic classes and racial minorities. The modern concept emphasizes science-based interventions with attention to the medical, material, and mental health needs of quarantined persons and protecting fundamental human rights. Exposed persons who are not sick should be separated from symptomatic patients, monitored for the minimum time necessary (e.g., one maximum incubation period), and provided appropriate medical care at the first sign of illness during the monitoring period. Quarantine may be applied to individual persons, to small groups, or, in extreme cases, to entire neighborhoods or other geographic districts ("cordon sanitaire") ( 7 , 8 ). In the SARS epidemic, persons under quarantine were mostly confined at home and actively monitored for symptoms. In several countries, quarantine was legally mandated and monitored by neighborhood support groups, police and other workers, or video cameras in homes. In other areas, compliance was "requested," but court orders were issued for a small percentage of noncompliant persons. Reports indicate that SARS was diagnosed in 0.22% of quarantined contacts in China-Taiwan, 2.7% in China-Hong Kong Special Administrative Region (SAR), and 3.8%–6.3% in China-Beijing. These different rates were partly due to different criteria for placing persons in quarantine. Contacts at highest risk (aside from healthcare workers with certain unprotected patient care exposures) had been exposed to ill family members ( 6 , 9 – 11 ). Quarantine led to financial and psychosocial stresses, risk communication, compensation, and workforce staffing issues for persons, families, employers, and governments. Legal appeals and defiance of quarantine orders were rare ( 2 , 6 , 8 – 13 ). The optimal management of contacts, stratified according to risk of becoming ill, remains under discussion in several countries, e.g., whether confinement is always needed or close monitoring of health status without confinement would suffice. Reports from Canada indicate that the insidious onset of symptoms sometimes posed challenges for clinicians and public health officials. "Timely diagnosis and isolation of cases were sometimes hindered by delays in patient recognition of symptoms, obtaining medical evaluation, and/or physician recognition of the significance of symptoms, which occasionally waxed and waned early in illness" (A. McGeer and D. Low, Mount Sinai Hospital Toronto, pers. comm.). "In Toronto, some healthcare workers continued to work without recognizing that they were ill, perhaps confusing their symptoms with fatigue, despite daily screening and repeated messages not to come to work if ill. This resulted in transmission to patients and staff" (B. Henry, Toronto Public Health, pers. comm.). Measures To Decrease Time from Symptom Onset to Isolation of Patients Public campaigns to accelerate reporting and evaluating symptomatic patients appeared to decrease the interval between onset of symptoms and isolation of ill patients in several areas (3,4). Novel interventions included urging the entire population of affected areas to measure their temperature at least once daily, fever telephone hotlines ( 14 ), and fever evaluation clinics with appropriate infection control measures. Thermal scanning in public places was implemented in several areas where community transmission was suspected. Data on the effectiveness of this practice are not available, but in Beijing thermal screening was not an efficient way to detect cases among intercity travelers ( 5 ). Measures To Increase Social Distance Measures to increase social distance, e.g., canceling mass gatherings; closing schools, theaters, and public facilities; and requiring masks for all persons using public transport, working in restaurants, or entering hospitals, were implemented in areas where extensive unlinked community transmission of SARS coronavirus (SARS-CoV) was suspected. Many persons in these areas also chose to wear masks outside their homes. These measures were often applied simultaneously with other measures, including enhanced contact tracing, which makes their independent effectiveness difficult to assess. However the simultaneous introduction of a variety of measures was temporally associated with dramatic declines in new SARS cases. A case-control study in Beijing found that wearing a mask more frequently in public places may have been associated with increasing protection ( 15 ). Another case-control study in China-Hong Kong found that using a mask "frequently" in public places, washing one's hands >10 times per day, and "disinfecting living quarters thoroughly" appeared to be protective ( 16 ). The types of masks used were not specified. With the exception of the Amoy Gardens cluster in which SARS-CoV was apparently transmitted through accidentally produced aerosols of sewage ( 17 ), SARS transmission in the community from aerosols or in social settings appeared to be rare. Disinfection In some areas, disinfectants were applied inside the homes and vehicles of persons with SARS, ambulance tires, and pedestrian walking zones. Little information exists on the effectiveness of disinfectant use in reducing community or hospital transmission. In Hong Kong, disinfecting living quarters thoroughly (not otherwise defined and reported retrospectively by telephone) appeared to be protective ( 16 ). Measures for International Travel Travel Advisories Travel advisories (e.g., advice to postpone nonessential travel) were issued by WHO and various governments. Air travel to areas affected by the advisories decreased dramatically during the epidemic (M.A. Hinayon and D. Gamper, Airports Council International, communication to WHO), although the impact of advisories compared with other sources of information to travelers, such as news media reports of SARS cases, is difficult to assess. Measures for International Borders Passive and active methods were used to provide information and screen entering and exiting travelers. These methods included signs, videos, public address announcements, distributing health alert notices, administering questionnaires to assess symptoms and possible exposure, visual inspection to detect symptoms, and thermal scanning. Few data exist on the relative effectiveness of methods of providing information to travelers. Available data on the effectiveness of screening and other measures directed to travelers are sometimes difficult to interpret because they may not distinguish between entry and exit screening, specify how many entering travelers were from affected countries, distinguish the epidemic period from subsequent, or include the number of SARS cases detected. Health Alert Notices to Entering Travelers Combined data from Canada, China (mainland, Hong Kong SAR, and Taiwan), France, Singapore, Switzerland, Thailand, and the United States indicate that approximately 31 million travelers entering these countries received health alert notices. Of these, approximately 1.8 million were reported as arriving from affected areas; this estimate is likely low given the difficulties in tracking travelers and the fact that many airline passengers change planes en route. Inadequate data exist to evaluate the effect of distribution of most of these notices. China-mainland reported distributing 450,000 notices and detecting four SARS cases that may have been linked to the notices (M. Song, China Dept of Health and Quarantine Supervision and Management, communication to WHO). Thailand reported having printed 1 million notices and detecting 113 cases of illness directly linked to the notices (108 at airports, 1 at a seaport, and 4 at land crossings). Twenty-four cases were suspected or probable SARS: all of which were detected at airports (S. Warintrawat, Ministry of Public Health, Thailand, communication to WHO). Entry Screening Preliminary data from a worldwide survey indicate that among 72 patients with imported probable or confirmed SARS cases, 30 (42%) had onset of symptoms before or on the same day as entry into the country and symptoms developed in 42 patients (58%) after entry (J. Jones, United Kingdom Health Protection Agency, communication to WHO). A small percentage of persons completing entry health declaration questionnaires in affected areas during the SARS epidemic were diagnosed with SARS (Table 1). Table 1 Health declarations by entering travelers at international borders, March 1–July 15, 2003a Area No. completed
declarations (millions) No. reporting
symptoms No. reporting
contact with SARS No. with SARS
detected by declarations Canada 10 3,481 0 0 China-mainland 13.2 2,035 500 2 (both had
SARS contact) China-Hong Kong SARb 19.3 2,380 NA 2 (both had
symptoms) China-Taiwan 1.0 5,287 NA 0 Singapore 1.9 Very low 0 0 Total 45.4 13,000 500 4 aSARS, severe acute respiratory syndrome; SAR, special administrative region.
bIncludes border between China-Hong Kong SAR and China-mainland. Results combined from Canada, China (including the mainland and Hong Kong SAR), and Singapore indicate that no cases of SARS were detected by thermal scanning among >35 million international travelers scanned at entry during the SARS epidemic (Table 2; data for Hong Kong SAR include travelers arriving from China-mainland). Temperature screening of 13,839,500 travelers entering or leaving Beijing by air, train, or automobile identified 5,097 patients with fever, of whom 12 had probable SARS. These 12 included 10 of 952,200 domestic airline passengers and 2 of 5,246,100 train passengers. None of 275,600 international travelers who underwent temperature screening had SARS ( 5 ). Table 2 Thermal scanning of entering travelers at international borders, March 1–July 15, 2003a Area No. scanned (millions) No. febrile by scan (confirmed orally) No. SARS found by scanning Canada 0.6 248 (215) 0 China-Mainland 13.0 4,070 (351) 0 China-Hong Kong SARb 15.1 NA (451) 0 China-Taiwan 1.0 1,211 (0) 0 Singapore 6.0 5,200 (3,160) 0 Total 35.7 10,729 (4,177) 0 aSARS, severe acute respiratory syndrome; SAR, special administrative region.
bIncludes border between China-Hong Kong SAR and China-mainland. In China-Taiwan, incoming travelers from affected areas were quarantined; probable or suspected SARS was diagnosed in 21 (0.03%) of 80,813. None of these 21 was detected by thermal scanning when they entered Taiwan ( 9 ) (S.K. Lai, Taiwan Center for Disease Control, pers. comm.). Exit Screening After WHO recommended exit screening on March 27, 2003 ( 18 ), no additional cases from airline travel were documented from countries with screening. Combined data from China (Hong Kong SAR and Taiwan) indicate that among 1.8 million people who completed health questionnaires at exit, 1 probable case of SARS was detected. Combined data from Canada, China (Hong Kong SAR and Taiwan), and Singapore indicate that no cases of SARS were detected among >7 million people who underwent thermal scanning at exit (Table 3) (S. Courage, Health Canada, S.K. Lai, China-Taiwan Center for Disease Control; P.L. Ma, Hong Kong SAR China Dept of Health; and B.K.W. Koh, Singapore Ministry of Health, communications to WHO). In some areas, "stop lists" were used at borders to prevent persons on isolation or quarantine lists from exiting. Anecdotes suggest that exit screening may have helped dissuade ill persons from traveling by air but may have been more successful in dissuading local residents from traveling abroad than in dissuading ill travelers from attempting to return home. Table 3 Exit screening of travelers at international borders, March 1–July 15, 2003a Area No. health declarations No. thermally scanned No. SARS Canada 584,819 397,563 0 China-Hong Kong SARb 700,000 2.5 million 0 China-Taiwan 1.1 million 1.0 million 1— by health declaration Singapore NA 4 million 0 Total 2.4 million 7.9 million 1— by health declaration aSARS, severe acute respiratory syndrome; SAR, special administrative region.
bIncludes border between China-Hong Kong SAR and China-mainland. Transmission on Commercial Aircraft Five commercial international flights were associated with transmission of SARS from patients with symptomatic probable cases to passengers and crew ( 1 ). Notification of exposed passengers and studies of transmission risk were greatly hampered by difficulties in identifying and tracing passenger contacts ( 19 – 23 ). In the most comprehensive investigation, involving three flights with extensive passenger tracing and laboratory confirmation of index and secondary cases, a wide range of risk was noted (Table 4). For flight 2, in which the secondary attack rate was 18.3%, the risk of infection was increased for persons seated close to the index patient, but most passengers who became infected were seated farther away, even though their individual risk was lower ( 19 ). In another study, one person with SARS, who had difficulty breathing but was not coughing, infected two other passengers. One of these sat in the row in front of the index patient but the other passenger sat four rows, plus a passageway, behind and on the opposite side of the plane ( 20 ). On nine flights arriving in Singapore, the incidence of transmission from passengers with SARS who had respiratory symptoms was estimated at 1 in 156 persons ( 21 ). A fourth study found no transmission to passengers seated near a patient who took multiple flights ( 22 ). In comparison, an influenzalike illness developed within 3 days in 72% of passengers in a plane containing a person with symptomatic influenza and grounded for 3 hours without ventilation ( 24 ). The risk for transmission of tuberculosis during a long flight was also increased among, but not limited to, passengers seated close to a highly infectious index patient ( 25 ). Table 4 Rates of severe acute respiratory syndrome transmission on commercial aircrafta Flight Duration Index patient(s) No. infected/no. on plane (%) 1 90 min 1 presymptomatic 0/315 (0.0) 2 3 h 1 fever, cough 22/120 (18.3) 3 90 min 2 fever;
2 fever, cough 1/246 (0.4) aSource: ref 19 . Discussion SARS-CoV was contained in human populations in 2003 largely by aggressive use of traditional public health interventions (case finding and isolation, quarantine of close contacts, and enhanced infection control measures in settings where care was provided to persons with SARS, especially in healthcare facilities and homes). These measures also contained a smaller SARS outbreak in 2004 that originated from a laboratory-acquired infection ( 26 ). Measures to decrease the interval between onset of symptoms and isolation were effective in containing community transmission. The independent effectiveness of general community measures to increase social distance (in addition to contact tracing and quarantine) and improve hygiene and wearing masks in public places requires further evaluation. Limited information exists on the relative effectiveness of methods of providing information on SARS (or other illnesses) to travelers. For inbound travelers who may have been exposed to SARS, such information should include what to do if symptoms develop and the need to inform healthcare workers who provide care for them in advance to take appropriate precautions. Entry screening of travelers by using health declarations or thermal scanning at international borders had little documented impact in detecting SARS cases. Exit screening appeared only slightly more effective; however, the possible value of these interventions in deterring travel by ill persons and building public and business confidence was not assessed. Preventing passengers with SARS from boarding aircraft would likely have reduced transmission of infection, but the most cost-effective ways to accomplish this are uncertain. The difficulties in identifying and tracing passengers exposed on aircraft highlight the need for public health authorities to have a mechanism for rapid access to passenger contact information. In the case of SARS, the data on border screening indicate that if resources are limited, interventions at a country's international borders should not detract from efforts to identify and isolate infected persons within the country, monitor and quarantine their close contacts appropriately, and strengthen infection control in healthcare settings. In retrospect, although SARS-CoV was transmitted primarily through the respiratory droplet route, certain epidemiologic parameters facilitated its containment through public health interventions. Presymptomatic transmission was not observed. Infectivity in most patients was low at onset of illness and seemed to peak during week 2 of illness in association with maximal respiratory symptoms, when patients were often in the hospital. Virus transmission was primarily by respiratory droplets, with little natural airborne dissemination but some environmental spread. With some important exceptions (Hotel M and Amoy Gardens in Hong Kong), transmission occurred primarily in healthcare or household settings, with close person-to-person contact. Cases among children were uncommon, and children did not seem to be involved in transmission. Although the reproductive number for SARS (R0, the average number of new cases resulting from a single infection in a susceptible community) was approximately 2–4, contact tracing was facilitated by its relatively long serial interval (time between onset of symptoms in successive patients in a chain of transmission: mean 8–10 days) and incubation period (median 4–5 days). Most infections did not lead to further transmission, although a small number of "super-spreading" events occurred in which single unrecognized cases transmitted to many people, usually in hospitals or households, before appropriate infection control precautions were in place ( 1 ). Traditional public health interventions will likely be required again to combat an emerging or reemerging infection for which specific antimicrobial drug therapy and vaccines are nonexistent or in short supply. For infections that are relatively less transmissible (e. g., SARS or a strain of avian influenza not fully adapted to human-to-human transmission), early and bold use of such interventions may contain transmission. For more readily transmissible infections (e.g., an emerging pandemic strain of influenza), they would not completely halt transmission but might "buy time" during a narrow window of opportunity during which an effective vaccine could be produced and other preparations made. For countries lacking specific countermeasures, such as drugs and vaccines, nonmedical public health interventions may be the only measures available to combat epidemics ( 27 ). Decisions regarding implementation should be based on expert scientific advice from WHO and national authorities; the epidemiologic features of the disease and available resources should be taken into account. This article does not address political and economic factors that may lead to calls for adopting certain measures or the economic and social consequences that may ensue, but governments will also consider such factors in their decisions. The WHO SARS Scientific Research Advisory Committee has identified further research needs for SARS ( 28 ). Priorities include evaluating the effectiveness of public health interventions in terms of cases detected, cases prevented, costs, and alleviating public concerns; identifying ways to make quarantines and other restrictions more focused and less burdensome for persons and societies; assessment of how "leaky" restrictions can be before they become ineffective; and developing rapid diagnostic tests. Limitations of the information include that it was collected retrospectively, and in some studies, laboratory testing to confirm SARS-CoV infection was not performed. In the event of future outbreaks, these issues will need to be studied prospectively so that decisions can be based on the best scientific information.
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Entry screening to delay local transmission of 2009 pandemic influenza A (H1N1)
Benjamin Cowling, Lincoln LH Lau, Peng Wu … (2010)
Background After the WHO issued the global alert for 2009 pandemic influenza A (H1N1), many national health agencies began to screen travelers on entry in airports, ports and border crossings to try to delay local transmission. Methods We reviewed entry screening policies adopted by different nations and ascertained dates of official report of the first laboratory-confirmed imported H1N1 case and the first laboratory-confirmed untraceable or 'local' H1N1 case. Results Implementation of entry screening policies was associated with on average additional 7-12 day delays in local transmission compared to nations that did not implement entry screening, with lower bounds of 95% confidence intervals consistent with no additional delays and upper bounds extending to 20-30 day additional delays. Conclusions Entry screening may lead to short-term delays in local transmission of a novel strain of influenza virus. The resources required for implementation should be balanced against the expected benefits of entry screening.
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Risks and Benefits of Gain-of-Function Experiments with Pathogens of Pandemic Potential, Such as Influenza Virus: a Call for a Science-Based Discussion
Editorial Influenza virus is one of a handful of infectious disease agents that can cause devastating pandemics with high mortality and morbidity in human populations. The human species is vulnerable to zoonotic infection with new influenza viruses, with the last occurring as recently as 2009. Influenza kills thousands of people each year, and the world is continuously confronting new epidemics. Today the complexity and interconnectivity of our society create vulnerabilities, such that pandemics with even low mortality have the potential to cause widespread suffering and economic disruption. Epidemics can have catastrophic effects on the social order and result in the disruption of benefits that we associate with current society, such as law and order and reliable food distribution (for a vivid and dramatic representation of the effect of epidemics on society, readers are invited to see the movie Contagion, where an outbreak with a new fictional virus leads to the breakdown of the social order). Hence, epidemics pose existential threats to civil society even when morbidity and mortality occur in a fraction of those infected. Given the biological characteristics of the influenza virus that ensure the continuous generation of antigenic variability, this virus poses a continuous extant threat, with the likelihood of new pandemics being determined by variables that remain poorly understood. In this environment, the influenza virus research community is humanity’s best defense against influenza virus. Consequently, anything that impacts influenza virus research is of utmost importance to societal well-being. In recent years, some members of the scientific community have been involved in a vigorous debate over so-called “gain-of-function” (GOF) experiments involving pathogens with pandemic potential (PPP), such as influenza virus. Proponents and opponents of GOF work engaged in extensive discussion about the value, safety, ethics, and validity of this type of research. The debate was initially catalyzed by research experiments published in 2012, which reported that serial passage in ferrets rendered variants of the highly pathogenic avian influenza virus (HPAIV) H5N1 transmissible in a mammalian species (1, 2). These experiments were performed, in part, because there was debate in the field as to whether H5N1 could become transmissible in humans. The result was accompanied by publication of the specific mutations associated with this new function, which was essentially a “species jump” to mammalian transmission. Although influenza virus has historically demonstrated the capacity to move across species, in this particular experiment, the GOF was the acquisition of mammalian transmissibility for a virus that previously lacked it. The debate over this type of experimentation (i.e., that which changes the transmissibility of an influenza virus to include a mammalian species) resulted in a temporary moratorium on GOF experiments involving HPAIV, followed by continuation of the work with additional biosafety precautions and regulations (3, 4). There followed a period of relative quiescence as the new status quo established itself. However, several papers describing similar experiments with other influenza virus strains have subsequently been published (5 – 7), along with accompanying editorials that explain the decision for publication (8, 9). In recent months the controversy over GOF experiments has been rekindled by reports of the generation of new viruses that are similar to the 1918 strain (6) and further fueled by two laboratory accidents at the Centers for Disease Control that heightened concern about accidental escape of laboratory strains with pandemic potential. With this backdrop, GOF experiments have been severely criticized in the general media, and 18 individuals, including both authors of this editorial, signed a statement of concern involving influenza virus GOF experiments (http://www.cambridgeworkinggroup.org/). The essence of this statement from the Cambridge Working Group (CWG) was a call for curtailment of such experiments, during which time there could be a risk-benefit analysis of future work and the convening of a conference to discuss the many issues involved in this developing situation. The CWG statement has been criticized, but there appears to be some agreement on the need for an Asilomar-type conference to explore the many issues involved in GOF experiments (http://www.twiv.tv/2014/07/20/twiv-294/). Most recently, a group called Scientists for Science posted its own statement emphasizing the importance of research on potentially dangerous pathogens and also calling for a conference to discuss the issues (http://www.scientistsforscience.org/). We note that both statements share many points of agreement, which provides a promising base for constructive dialog. In the past, mBio has provided a forum for discussion and debate on the merits of this work. Here we take up the pen (or keyboard) to highlight some issues pertinent to the ongoing debate and promote further discussion, our major goal in signing the CWG statement. We note that the issues surrounding the GOF debate are enormously complex and involve deep questions of science, philosophy, and ethics. WHAT IS “GAIN OF FUNCTION”? Given that symbolic language is the basis for much of human communication, we begin with terminology and dissect the phrase “gain of function,” or GOF. When applied to influenza virus research, the term GOF has taken on the meaning of something dangerous, risky, and possibly nefarious. However, GOF means exactly what it says, that the entity in question has gained a new property. In the case of influenza virus, the concern regarding GOF has been associated with the acquisition of a new function, such as mammalian transmissibility, increased virulence for humans, or evasion of existing host immunity. For example, passage of H5N1 virus in ferrets allowed selection for variants with ferret-to-ferret transmissibility, and the GOF was the acquisition of mammalian transmission. However, the same type of experiment can be beneficial to humanity, since the principle of passage in a nonnative host can be used to generate attenuated vaccines. For example, some human-pathogenic viruses, such as poliovirus, were attenuated by passage in cells of another species, such as monkey cells. In those experiments, the GOF was replication in another species, and this property reduced the efficiency of replication in human cells, thus resulting in a new attenuated strain that could be used as a vaccine. Indeed, those attenuated viruses manifested a GOF, namely, attenuation. One of us recently published a GOF experiment with BK polyomavirus, in which mutation of a regulatory microRNA (miRNA) greatly enhanced replication (10). Hence, GOF is a powerful experimental tool that is routinely used in biomedical research, and the concern with influenza virus research is not gain of function per se but rather the selection of variants with increased mammalian transmissibility and virulence that could affect human populations if there were deliberate or accidental release. It is clear that GOF is a problematic phrase, and this term has acquired a particular meaning in the ongoing debate and particularly in the lay media. Unfortunately, the term GOF has come to only represent something that can be used to confer dangerous properties to a microbe. Despite these problems in terminology, we use the expression GOF in this essay with the understanding that we are referring to the narrow category of experiments that involve primarily changes to the virulence and transmissibility of PPP, such as influenza virus. Although influenza virus is the subject of the ongoing debate, it is important to note that these issues extend to other PPP, such as severe acute respiratory syndrome (SARS) coronavirus. THE VALUE OF INFLUENZA VIRUS GOF EXPERIMENTS Recent history has shown that GOF experiments in influenza virus research can provide unique insights into the potential threat posed by influenza virus strains and mechanisms of viral pathogenesis. Much of the debate involving the H5N1 experiments which demonstrated the “gain” of ferret transmissibility focused on the publication of the specific mutations that conferred this property. However, the major scientific finding was the observation that this virus had the biological capacity to be transmitted between mammals after alterations in a few amino acids. In fact, this finding is of great value to humanity, because it suggested that a human H5N1 pandemic might be able to occur if and when similar mutations occurred spontaneously, as is characteristic of influenza viruses, along with conditions favorable for bird-to-mammal transmission. In another set of GOF experiments, the HPAIV H7N1 was shown to be capable of mammalian transmission due to mutations that did not change receptor specificity (5). As a result of these experiments humanity has much more knowledge and stands warned of the potential perils these viruses pose. This information emerged from GOF experiments. In fact, it is difficult to imagine another mechanism for obtaining the information that has been gained from GOF-type experiments, particularly because it is only through experiments that can control the expression of given determinants that proof can be obtained. Since proof of the germ theory, modern scientific proof generally requires the use of approaches that attribute a given property to a given determinant. Hence, GOF-type experiments are of particular epistemological value because they directly imply causality. Apart from informing on the potential for virulence and transmissibility, GOF experiments are powerful tools for dissecting questions concerning viral pathogenesis. For example, H5N1 mutational analysis showed that the efficiency of viral replication in avian and mammalian cells is dependent on hemagglutinin polymorphisms that facilitate activation at lower pH (7, 8). This finding could be exploited to increase the yield of virus during preparation of vaccine stocks. Furthermore, the identification of sequence changes associated with GOF could in theory lead to the identification of new antiviral targets, thus providing a potential societal benefit. The power of GOF experiments is that they are a highly efficient, reliable, and effective tool that can identify certain phenotypes that often cannot be identified by using other scientific approaches. Hence, we feel that there is ample evidence that GOF experiments can provide important information and are useful tools for investigation of influenza virus-related questions. In fact, we believe that the crux of the debate surrounding GOF experiments is not their value but their potential risk. THE RISK-BENEFIT CONUNDRUM At the heart of the scientific debate over influenza virus GOF experiments are different perceptions of the risk-benefit ratio of such experiments. Proponents of continued GOF experiments emphasize the benefit and downplay or even deny the risk, while opponents do the converse. Since both risk and benefit involve quantitative assessments, in this case with limited information, the debate is fueled by the reality that weighing risks and benefits involves judgment calls. The risks fall into two general categories that are separate but related: namely, biosecurity and biosafety. Biosecurity risk is the likelihood that someone would use products or information gained from GOF experiments that led to a more pathogenic virus to carry out intentional damage in the form of bioterrorism. Biosafety risk is the likelihood of accidental escape that could trigger an outbreak and epidemic. When the National Science Advisory Board for Biosecurity (NSABB) considered the H5N1 GOF papers, the original discussions were focused on biosecurity, which was the charge of the NSABB, but as time passed, the concern evolved from biosecurity to biosafety. Biosecurity estimates are difficult, because they involve a calculation of the risk of deliberate nefarious action, and such information is simply not always available. In fact, these assessments are so difficult that we have called for the formation of a national board to handle questions related to dual-use research of concern (11). On the other hand, biosafety estimates can rely on historical data. Prior experience with lab accidents was used by Lipsitch and Bloom to suggest that there is a significant likelihood that a major lab accident could occur with GOF influenza virus strains (12). In fact, there is strong circumstantial evidence that the reintroduction of H1N1 into human circulation in 1977 after its disappearance in 1950 began with the accidental release of a laboratory strain (13). Calculations of risk must also consider that researchers have learned from mistakes in the past, that the biosafety precautions being taken today have improved over historical standards, and that new regulations were recently put in place for the laboratory of HPAIV (4), with the important caveat that the recent problems at the CDC show that even the most advanced laboratories are vulnerable to serious mishaps. While no one appears to have been harmed by the lapses at the CDC laboratories, there have been recent cases in which laboratory workers were infected with Yersinia pestis (14) and Brucella sp. (15), among others, highlighting the fact that laboratory accidents with virulent pathogens continue to occur despite knowledge of their potential danger and modern biosafety practices. Calculating the benefits of GOF research is also a somewhat challenging task, since the history of science shows that unexpected results can be more important than those that were originally anticipated when the experiment was designed. The importance of scientific findings is often not apparent at the time of discovery (16). Hence, the argument from GOF opponents that such experiments have little value due to their risk must be considered with caution, given historical precedents showing that the value of scientific information cannot always be judged with current understanding or knowledge. Given the problems in calculating the numerator and denominator of a risk-benefit assessment, we urge both sides to approach this complex problem with consideration of the opposite view and with humility. To argue that the risk is overwhelming relative to the perceived benefit is not a tenable position, given the precedent that GOF experiments have arguably already provided useful information and the fact that the actual benefit may not be appreciated at present. Similarly, to argue that the risk is minimal relative to the benefit defies hard evidence of human fallibility and a history of serious laboratory accidents. Perhaps an initial meeting point for GOF proponents and opponents would be to agree that risk-benefit calculations are difficult to perform with the data at hand. That said, we note that in other contexts, risk-benefit calculations are routinely done in everyday science and medicine, even with incomplete data. For example, institutional biosafety and human subjects review committees debate risk routinely and do make decisions despite having to make judgment calls. We assert that actually doing a risk-benefit analysis with available data can lead to discussions and experimental modifications that could minimize risk and enhance benefit. Even though proponents and opponents of influenza virus GOF research place very different values on the parameters of the calculations, both sides are actually already doing risk-benefit analyses and using them to support their respective positions. Despite the disagreements on the value of the numerator and the denominator, risk-benefit analyses are always a good idea. They stimulate discussion, and such discussion can lead to improved experimental design and safety, and generate and prioritize the acquisition of additional knowledge. Therefore, we argue that risk-benefit discussions should not be avoided because the parameters are difficult to quantify. UNANSWERED QUESTIONS Swirling around the GOF debate are a series of unanswered questions which are amenable to scientific study and which if answered could dramatically inform the debate. What is the case-fatality ratio of HPAIV in humans? The mortality associated with H5N1 virus is a key driver of the GOF risk-benefit debate. Although there seems to be no debate that the case-fatality ratio of individuals who come to medical attention with H5N1 is high, the ratio of asymptomatic to symptomatic infections has been the subject of debate in the literature (17, 18). This is a key parameter for which additional information could become available with additional studies. If the case-mortality ratio is indeed as high as 50%, then the risk is greater, while a much lower ratio would portend a significantly reduced risk. It is worthwhile for experts on serological studies and influenza epidemiology to come to agreement on the type of information needed and then carry out the studies to address this important issue. Such studies should be prioritized. Irrespective of where one stands in the case-fatality debate, it is worthwhile to note that even a case-fatality ratio as low as <0.1%, such as that associated with the 2009 pandemic, would cause immeasurable suffering to affected individuals and could create significant societal havoc. What is the relationship between transmissibility in one mammal to that in another? Much of the furor with the GOF H5N1 was experimental work showing that the virus could become transmissible in ferrets (19). However, we do not know the relationship between ferret transmissibility and human transmissibility. Opponents of GOF research worry that ferret transmissibility portends a high likelihood for human transmissibility, while proponents of GOF argue that such data do not exist and minimize any extrapolation from ferrets to humans. Clearly, information about this point would be valuable to estimating the risk associated with these experiments, and this should be a focus of future research. What is the relationship between transmissibility and virulence in HPAIV? Virulence and transmissibility are different properties of pathogenic microbes that can be related but are also distinguishable. BK virus is highly transmissible among humans but is associated with disease only in transplant recipients. In contrast, Mycobacterium tuberculosis spreads by aerosol during coughing associated with pulmonary disease. Hence, transmissibility from host to host appears to be associated with virulence for some microbes and not others. Are virulence and transmissibility separable for influenza viruses? Knowing the relationship between transmissibility and virulence is important for understanding the basic biology of this virus and could inform the risk-benefit debate. What is the relationship between laboratory-engineered and naturally selected influenza viruses with regard to pathogenicity? GOF opponents worry about laboratory-engineered viruses, while GOF proponents argue that nature is far more effective in selecting new dangerous variants than any laboratory experiment. However, this point and counterpoint misses important biological questions. Viruses recovered in the laboratory can be evolved in the absence of natural hosts and thus are not constrained by the environment of those hosts. Without host selection, such viruses may be more or less pathogenic, and there is no way of predicting their capacity for pathogenicity unless we understand the parameters that determine virulence. Consequently, efforts to understand the mechanism of virulence pertaining to naturally derived and laboratory-derived viruses could provide valuable insights, with the important caveat that virulence is an emergent property and as such may not be predictable (20). What are the possible public health benefits of the knowledge gained? This question can probably not be answered prospectively, but at least there should be a discussion of potential benefits in the context of existing public health capabilities. GOF experiments have been justified on the grounds that the information is helpful for surveillance and vaccine design. Opponents have argued, however, that vaccine design can be accomplished without changing transmission properties. In addition, it has been posited that current surveillance strategies are inadequate and cannot readily incorporate knowledge of the exact mutations that may lead to enhanced human virulence or transmission (21, 22). However, even if the information is not useful today, the availability of such information could drive new capabilities, such as the development of more robust surveillance methods. OTHER DANGERS Outside the debate on the usual GOF risk-benefit calculations, there are other dangers that need to be considered. First is the possibility that increased scrutiny of experimental science and regulation of influenza virus research will hobble the field. This is already occurring, as influenza virus investigators are forced to respond and adapt to increasing regulation of their field. One must also balance the possible effects on the careers of postdocs and graduate students in the field with increasing oversight due to the desire to protect against possible accidental releases. As the difficulty of carrying out experiments and meeting regulations increases, it may be hard to recruit the best and the brightest to this important field. Second is the danger posed by the absence of work that is simply not done to avoid controversy. Although the importance of work not done is impossible to document, experiments that are not being done could provide major insights simply because they provide more information to inform discussion and debate. Third is the possibility that additional laboratory mishaps will lead to even more draconian regulations that will curtail research more broadly. These dangers are interrelated but have in common a high likelihood that, singly or together, they could pose major disruptions to research on influenza virus and microbiology research in general. Given the importance of the influenza virus research community to preparedness against pandemics, anything interfering with this work is of societal concern, and these dangers need to be incorporated into any discussion of GOF risk-benefit analysis. AN ASILOMAR-LIKE MOMENT? When recombinant DNA technology first came into use, scientists and others convened at Asilomar to discuss the risks and benefits and to chart a path forward that would allow this important technology to be used safely (23, 24). The controversy over the HPAIV GOF experiments has led to calls for another Asilomar-like conference. The goal of such a conference would be to bring the parties interested in the issues related to GOF experiments together with the hope of finding common ground and finding a way to allow GOF research to go forward with minimal risk and maximal benefit. We think this is a good idea, and this was our primary intent in signing the CWG document. However, we caution that the times are very different now than in 1975, when the Asilomar meeting took place. Today, communication by e-mail and Twitter is instantaneous, and the information conveyed by these new media is different than the phone conversations and mail correspondence of that time. In fact, to date, much of the discussion between the interested camps on GOF research has been “Twitter-like,” with statements made via general media or e-mail messages to supporters. This type of communication reduces complex issues to terse, often definitive-sounding statements that can be polarizing. Thus, we think that there must be a broad-based, rational, face-to-face discussion. Hence, if such a conference is to be convened, we call on the organizers to assemble groups with wide representation of individuals with a direct stake in this research as well as thoughtful scientists with no skin in the game, to tackle such issues as risk-benefit, ethics, biosafety, biosecurity, etc. Ideally, just like treaty negotiations between countries, much of the work should be done by smaller groups that explore the various issues and identify areas where consensus is possible and those where both sides must agree to disagree. The conference would then function to inform on areas that hopefully have been agreed to, or explored and found to have no common ground, as well as involving all participants in more focused discussions. Interestingly, a similar call for discussion of the risks and benefits was recently raised with respect to the rapidly advancing use of gene drives, a research area ripe with risk-benefit uncertainties similar to those of the influenza virus GOF experiments (25, 26). THE WAY FORWARD Irrespective of where one stands on the GOF, it is important to reflect on the issues at stake. Perhaps most important is that there is a need to lower the level of rhetoric and focus on the scientific questions at hand. Proponents of GOF research are not reckless scientists but rather individuals who are driven to answer important scientific questions and hope to make a difference in the human struggle against this deadly virus. Opponents of GOF are not unsophisticated luddites determined to hinder influenza virus research but rather individuals who are primarily concerned about biosafety issues related to the work. A disheartening aspect of the GOF debate is that many participants seem to be focused on only one aspect of the controversy without considering the enormous complexity of the issues involved and the potential dangers associated with taking extreme views. Such dangers include catalyzing further polarization, proliferation of GOF research in laboratories that lack proper safety precautions, creating misinformation, and eliciting overreactions by elected officials and/or government agencies. Each of these dangers has the potential to hinder future research and leave society more vulnerable to influenza and other diseases. In writing this essay, we hoped to dissect the issues involved and provide a broader canvas for discussion. For the near horizon, a conference sponsored by neutral parties appears to be one mechanism for further communication about which both parties appear agreeable. We are optimistic that most people in the pro- and anti-GOF camps are believers that information, discussion, and reason can lead the way to the best solutions to the intricate problems posed by this research. Despite all the uncertainties about risks and benefits, there must be a risk-benefit calculation, with proponents providing their reasons for benefit and opponents their assessment of risk. Obviously, one way to help achieve a consensus is for benefits of the work to be clearly articulated and for the risks to be minimized. For example, it may be helpful to revisit the biocontainment regulations to ascertain whether existing protocols are adequate or should be modified, keeping in mind that it is impossible to decrease the risk of an accident to zero. However, we must also face the possibility that there will be no consensus in this matter. If an impasse develops, it will be important to channel the debate into different areas of discourse. For example, if pro- and anti-GOF research proponents reach an impasse, perhaps the debate could refocus on identifying the important questions in influenza virus research that both groups feel should be answered and in finding new creative experimental alternatives that satisfy both camps. Looking at the farther horizon, the influenza virus research community should consider making safer laboratory strains that would further mitigate the possibility of harm should lab accidents occur (27). Finally, we note that although this article and much of the debate are focused on HPAIV and PPP research, the issues considered here are relevant to the larger fields of microbiology and infectious diseases and that the outcome of these discussions will echo in other fields. It is possible that the GOF debate represents a historical moment for research in the microbiology community comparable to the advent of recombinant DNA technology in 1975 that led to the Asilomar conference. We note that the decisions made during and after Asilomar resulted in society’s reaping the benefits of the molecular biology revolution, including many new therapies made possible by recombinant DNA technology (11). Given the potential threats posed by PPP and the capacity of this debate to affect the course of microbiological research in the 21st century, we must get this right. We are confident that the scientific community can tackle this problem in a manner that will maximize our ability to continue to generate important knowledge that will protect the public in the future.
Author and article information
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David Hutton: Role: Editor
Journal
Journal ID (nlm-ta): PLoS One
Journal ID (iso-abbrev): PLoS ONE
Journal ID (publisher-id): plos
Journal ID (pmc): plosone
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PLoS ONE
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Volume: 12
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Electronic Location Identifier: e0178732
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Competing Interests: The first author (MB) is the sole employee (and owner) of Adapt Research Ltd. This does not alter our adherence to PLOS ONE policies on sharing data and materials.
* E-mail:
nick.wilson@
123456otago.ac.nz
Article
Publisher ID: PONE-D-16-44972DOI: 10.1371/journal.pone.0178732
PMC ID: 5473559
PubMed ID: 28622344
SO-VID: dd217c7a-7562-4d02-8b74-b4a717aae889
Copyright © © 2017 Boyd et al
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This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
History
Date
received
: 11
November
2016
Date
accepted
: 18
May
2017
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Pages: 12
Funding
The first author (MB) is the sole employee (and owner) of Adapt Research Ltd. Adapt
Research Ltd provided support in the form of salary for MB, but the study was otherwise
self-funded by the authors. The authors received no additional university or external
funding. Adapt Research Ltd had no additional role in the study design, data collection
and analysis, decision to publish, or preparation of the manuscript. The specific
roles of the authors are articulated in the 'author contributions' section.
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