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It was developed through an expert consultation involving both the Delphi method and multi-criteria decision analysis. Table 2.

Demystifying Medicine 2017: HIV: Frontiers and Vaccine Development

Beyond the included pathogens, diseases that are currently endemic in some areas, but could spread without proper control to others, represent another category of threat. Tuberculosis, malaria, and dengue are examples, as well as HIV. Pandemic influenza also merits special attention; indeed, the WHO has developed a separate Pandemic Influenza Preparedness Framework Meanwhile, the very drugs that helped produce miraculous declines in infectious disease mortality over the second half of the twentieth century are now beginning to lose their effectiveness.

While rapid transmission of resistant pathogens is unlikely to occur in the same way it may with pandemic threats, the proliferation of superbugs is making the world an increasingly risky place. AMR threats also differ from epidemic threats in a number of other respects: Most of the top AMR threats are bacterial, and many are typically contracted as nosocomial infections; pathogens of epidemic potential tend to be viral and often emerge from zoonotic reservoirs to cause outbreaks in human populations. The list was selected through a multi-criteria decision analysis incorporating both quantifiable evidence and the input of 70 experts with different backgrounds and from a variety of geographies.

Beyond the pathogens on this list, mounting resistance against the drugs used to treat TB, HIV, and malaria is especially concerning. Resistant TB, for instance, is already responsible for , deaths globally per year out of , total AMR-related deaths, which is likely an underestimate 43 , Finally, the global health community must also acknowledge the real threat posed by the possibility of a human-caused infectious disease outbreak, whether from the accidental release of infectious agents from a research facility or from an intentional biological attack.

Over the past half-century, several alarming but thankfully contained events of this sort have occurred. In , the Japanese doomsday cult Aum Shinrikyo sprayed anthrax spores from the top of a cooling tower in Tokyo in a failed attempt to start an epidemic 46 [In , the same group used a chemical weapon similar to sarin in an attack on the Tokyo subway system that caused 13 deaths and many injuries 47 ]. In , an attacker with unknown motives caused terror and chaos in the United States by mailing letters laced with anthrax to the offices of two senators and multiple members of the news media, resulting in five deaths And in , an accident involving live anthrax bacteria at the U.

Centers for Disease Control and Prevention potentially exposed dozens of workers to the pathogen As long as stores of dangerous pathogens, such as anthrax and smallpox, are maintained for research purposes , the potential for a damaging accident or intentional attack will remain. Advancements in gene editing and the end of a U.

As early as , researchers demonstrated the feasibility of chemically synthesizing highly infectious agents such as poliovirus More recently, another team of researchers synthesized horsepox, a relative of smallpox not known to harm humans The success of this latter experiment suggests that with rudimentary scientific knowledge and a relatively small amount of money, a group with nefarious intent could synthesize smallpox without significant difficulty and in a short amount of time Infectious disease threats—and the fear and panic that may accompany them—map to various economic and social risks.

With respect to outbreaks and epidemics whether naturally occurring or human-initiated , there are obvious costs to the health system in terms of medical treatment and outbreak control. A sizable outbreak can overwhelm the health system, limiting the capacity to deal with other routine health issues and thereby compounding the stress on the system. Beyond shocks to the health sector, epidemics force those who are ill and their caretakers to miss work or be less effective at their jobs, disrupting productivity.

When critical human resources like engineers, scientists, and physicians are affected, productivity impacts can be magnified. Fear of infection can result in social distancing or the closing of schools, enterprises, commercial establishments, transportation, and public services—all of which disrupt economic and other socially valuable activity. Concern over the spread of even a relatively contained outbreak can lead to decreased trade. For example, a ban imposed by the European Union on the export of British beef lasted for 10 years following the identification of a mad cow disease outbreak in the United Kingdom, despite relatively low hypothesized transmission to humans 53 , Travel and tourism to regions affected by outbreaks are also likely to decline, as has happened in Brazil and several southeast Asian countries when dengue incidence spiked 55 — In the case of some long-running epidemics, such as HIV and malaria, foreign direct investment can be deterred as well 59 , The economic risks of epidemics are not trivial.

The large projected economic impact of an influenza pandemic stems primarily from the anticipated high mortality and morbidity. However, even when the health impact of an outbreak is relatively limited, its economic consequences can quickly become magnified. Liberia, for example, saw GDP growth decline 8 percentage points from to during the recent Ebola outbreak in West Africa, even as the country's overall death rate fell over the same period 4 , As with outbreaks and epidemics, the economic risks of AMR begin with increased costs to the health system.

Resistant infections demand the use of more expensive second- and third-line treatments and are sometimes associated with prolonged hospital stays 65 — As incidence of resistant infections grows, the cumulative magnitude of these costs will grow as well.

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Perhaps the biggest fear with AMR is that it will progress to the point where a significant number of infections are entirely untreatable. Absent that calamity, we can nonetheless envision a world in which contracting infectious diseases will carry an increased risk of mortality or severe morbidity. As broad-spectrum antibiotics lose their effectiveness, certain procedures including some common surgeries that rely on prophylactic antibiotic use may be deemed too risky to administer, resulting in additional morbidity.

Some level of decreased productivity is almost certain to be a consequence of AMR's health impact, as excess morbidity and mortality will remove people from the labor force or otherwise diminish their capacity to work. In some economies, reductions in livestock output due to the spread of disease in animal populations could have major repercussions.

In a high-impact scenario, AMR may also lead to notable reductions in international trade. Projections of AMR's potential economic impact vary significantly, as the magnitude of AMR's eventual health burden is difficult to predict for a variety of reasons. The upper bounds of existing estimates are alarming. While the likelihood of these extreme scenarios is debatable, it is certain that AMR poses a sizeable economic risk. Infectious disease threats pose additional social risks beyond those that are strictly economic.

Outbreaks and epidemics have the potential to induce geopolitical instability. Fear of an outbreak could lead people to flee their homes [as occurred following an outbreak of plague in Surat, India in 15 ], potentially causing an international migration crisis. Epidemics could also increase the vulnerability of a weak government—especially one with an accompanying weak health system—leading to state fragility.

There are a number of complicating factors when it comes to managing the risk of infectious disease. Several ongoing demographic trends point toward an increased potential for transmission of pathogens. While the populations of many developed countries are stabilizing or even declining in size, rapid population growth continues in regions where infectious disease outbreaks are likely to originate and where many countries have weak health systems that may struggle to cope with epidemics.

The population of Sub-Saharan Africa, for instance, is increasing at a rate of 2. Urbanization means more humans living in close quarters with each other, amplifying the transmissibility of contagious disease. In areas experiencing rapid urbanization, housing shortages can lead to the growth of slums, which forces more people to live in conditions with substandard sanitation and poor access to clean water, compounding the problem.

Global Immunization and Gavi: Five Priorities for the Next Five Years

Finally, with the share of older adults increasing in every country 4 , global population aging could further exacerbate the potential for widespread transmission of infectious disease, as immunosenescence leaves the elderly more vulnerable to infection Climate change may also play a role in driving pathogen transmission, as the habitats of various common disease-carrying vectors—such as the Aedes aegypti mosquito, which can spread dengue, chikungunya, Zika, and yellow fever, among other pathogens—expand Human interactions with animal populations have always carried a risk of producing pathogen spillovers 72 , and the changing nature of these interactions—as factory farming increases to meet food demand and humans continue encroaching on natural habitats, for example—could promote additional zoonoses.

Civil conflict often results in new disease outbreaks or the exacerbation of ongoing ones, especially when populations are displaced, public health infrastructure is affected, or the provision of basic care and immunizations is interrupted 73 — The phenomenon of globalization compounds the risks posed by the aforementioned challenges.

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  • Many diseases with epidemic potential can be transmitted rapidly, both within and across countries. The proliferation and ease of international air travel and trade increase the difficulty and importance of containing outbreaks in their early phases. Globalization also has implications for AMR: The movement of people makes populations with low rates of circulating resistance vulnerable to transmission of resistant strains from other areas of the globe. Perhaps the chief challenge for managing AMR is that the use of antimicrobials constitutes the most powerful driver of resistance.

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    Each dose of antimicrobials consumed places evolutionary pressure on target and bystander pathogen populations to develop and proliferate mechanisms of resistance. The baked-in nature of the problem is compounded by the fact that there is currently tremendous need for increased access to antimicrobials in low- and middle-income countries LMICs , where many continue to die every year from infectious diseases that are easily treated in the developed world As the international community strives to close this access gap, national and global AMR response plans should be carefully designed to avoid exacerbating the unmet need for antimicrobials in LMICs and its consequences for human health.

    Several factors complicate the management of the risk for biological accidents and attacks. With respect to accidents, there is a complicated tradeoff between enabling socially valuable research on dangerous pathogens in order to better understand their spread or contribute to the development of countermeasures, for example and imposing necessary safeguards to limit any potential danger.

    Removing the barriers to research on deadly pathogens including through the manipulation of their genetic makeup may allow us to be better prepared for naturally occurring outbreaks and attacks, but some specialists worry about the possibility of human error leading to catastrophe Experts cite the relative ease and low cost of producing certain biological agents as a concern when it comes to intentional biological attack, which could come at the hands of a terrorist organization 79 , In addition, some biological agents that may be used in an attack such as anthrax have lengthy incubation periods, which could make it difficult for national governments to locate and apprehend attackers or otherwise organize a response There are numerous economic and political challenges to implementing the measures needed to prepare for and respond to infectious disease threats.

    First, the likelihood of any single infectious agent sparking an epidemic including via an accident or attack is relatively low, even if the aggregate risk is high. The diffuse nature of these threats can make it difficult to both prioritize available responses and summon the necessary political will to invest in prevention and preparedness. Similarly, the magnitude of AMR's consequences is not immediately obvious to many policymakers nor to the general public. Currently, AMR is a slow-burning problem that directly affects the lives of a relatively small portion of the global population.

    If left unchecked, however, that problem could grow exponentially. Another political challenge involves the lack of a reliable mechanisms for incentivizing international collaboration in the development of new biomedical countermeasures. In these concerns prompted Indonesia to refuse sharing influenza samples needed for vaccine development with the WHO The Nagoya Protocol, which came into effect in 92 countries in , was intended to help address this problem by creating an enforceable system to ensure the sharing of benefits resulting from research based on genetic resources shared between countries.

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    • However, some feel that the requirements imposed by the Nagoya Protocol are too cumbersome and that potential jail sentences for scientists who are found to be in violation of its provisions could suppress important research The global community must continue working to find the right balance between ensuring that manufacturers intent on developing critical products for global health can access needed resources expeditiously and promoting an equitable distribution of benefits resulting from those products.

      There are established financing issues for global public goods, such as vaccines, to fight epidemics. While the social value of these vaccines and similar products may be very high, the expected private value to the companies most likely to manufacture them is often quite low Social investment has also suffered, at times, when no immediate crisis spurs public and political interest. For example, U. This cycle of panic and neglect makes it difficult for the global health community to make long-term commitments to necessary epidemic preparedness programs. There are also scientific and economic barriers specific to the development of effective responses to AMR. Scientifically, bacteria have developed numerous mechanisms for evading antibiotics, and finding new points of attack is becoming increasingly challenging. Economically, there is a misalignment of interests between the public which has an interest in limiting the use of novel antimicrobials as much as possible to protect their effectiveness, while ensuring their availability at low cost to those who most need them and pharmaceutical companies which have an interest in producing products that will be used widely and yield substantial profits.

      These barriers have conspired to produce no truly novel class of antibiotics in over three decades Beyond the demographic, social, and economic challenges we have enumerated, the world faces a number of organizational challenges to its ability to manage infectious disease threats.

      The global system for monitoring, preventing, and responding to infectious diseases is massively complex. Key elements of this system include local and national governments, supranational governmental organizations e. The good news is that a number of organizations and entities are in place to help protect the world from calamity. The bad news is that deficiencies exist within this complex system, especially when it comes to coordinating activities among all the players.

      The Ebola crisis in West Africa highlighted significant gaps between the WHO's intended functions and its real-world effectiveness as a protector of global health security, as well as more general gaps within the global health system 87 — Multiple post-mortem reports on the crisis explicitly called for the establishment of a new Center for Health Emergency Preparedness and Response within the WHO to ensure that the organization would better manage epidemic risks moving forward 87 — 89 , The WHO answered these calls by instituting a new Health Emergencies Programme in to streamline its activities related to health emergencies and create better internal alignment.

      While the establishment of this Programme represents a step in the right direction, and while the WHO appears to be faring relatively better with the ongoing Ebola outbreak in the Democratic Republic of Congo in difficult circumstances, a vacuum still remains when it comes to the critical role of coordination. While the GPMB is intended to take on some portion of the coordinating role that is dearly needed, the Board has an initial term of only 5 years without expectation of continuation, and members will only meet twice per year.

      This lack of a sustainable organizational plan and lack of dedicated resources especially human resources calls into question whether creation of the GPMB represents sufficient change. National governments have also taken it upon themselves to address the shortcomings revealed by the Ebola crisis. The Global Health Security Agenda GHSA , which was started by the United States and launched in , is now a partnership of over 64 countries, international organizations, and non-governmental stakeholders. The GHSA has similar aims to the International Health Regulations IHR , with a focus on helping participating countries build core capacities for outbreak detection, preparedness, and response.

      The GHSA is a welcome addition to the global health landscape. It also adds another layer of complexity to the global health system, as its responsibilities overlap with those assigned to the WHO under the IHR.