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      “Vaccine Diplomacy”: Historical Perspectives and Future Directions

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          Abstract

          Vaccine diplomacy is the branch of global health diplomacy that relies on the use or delivery of vaccines, while vaccine science diplomacy is a unique hybrid of global health and science diplomacy. Both offer innovative opportunities to promote United States (US) foreign policy and diplomatic relations between adversarial nations. Vaccine science diplomacy could also lead to the development and testing of some highly innovative neglected disease vaccines. Introduction: Origins and Definitions International cooperation for purposes of infectious and tropical disease control goes back to at least the 14th century, when early concepts of quarantine were introduced in Dubrovnik on the Adriatic Coast of Croatia [1], [2], and to the later date of 1851, when Europe held its first International Sanitary Conference for multilateral cooperation to prevent the spread of cholera and, subsequently, plague and yellow fever [3]. Such efforts led to a series of international sanitary treaties and conventions and ultimately to the formation of the Pan American Health Organization and the later establishment of the World Health Organization (WHO) [3], [4]. Some scholars trace our current framework for global health diplomacy to the writings of Dr. Peter G. Bourne in his role as special assistant for health issues to US President Jimmy Carter [5] and later (during the first years of the 21st century) to the launch of the Millennium Development Goals (MDGs) and the release of the “Report of the Commission for Macroeconomics and Health”, when global health was placed squarely in the international diplomacy arena [6]. Among the driving forces for these activities was an urgent need for diplomatic collaboration to combat pandemics caused by HIV/AIDS and seasonal and avian influenza, which came with the revelation that such diseases are threats to economic development and both national security and foreign policy interests [7]. There were also practical considerations concerning potential bioterrorist threats and situations that required international diplomacy, such as when Indonesia balked at sharing its time-sensitive avian influenza data or when Nigeria and Pakistan halted polio and other immunization initiatives because of religious tensions [7]–[11]. In 2007, foreign ministers from seven countries—Brazil, France, Indonesia, Norway, Senegal, South Africa, and Thailand—issued the landmark “Oslo Ministerial Declaration” that formally linked global health to foreign policy [12]. At that time, Kickbusch et al. defined global health diplomacy in terms of processes by which governments and civil societies both “position health in foreign policy negotiations” and create new types of “global health governance” [13], [14]. More recently, Kickbusch and Lokeny defined it as a “system of organization and communications and negotiation processes that shape global policy environment in the sphere of health and its determinants” [15]. A key element of modern global health diplomacy is that “no longer do diplomats just talk to other diplomats”, but instead a variety of experts in different areas and disciplines are now brought in to solve timely global health issues [13]. Katz et al. [9] have since categorized different aspects of global health diplomacy to include the following: (1) core diplomacy, referring to “classical Westphalian negotiations” between nations leading to bilateral and multilateral treaties, such as the recent WHO Framework Convention on Tobacco Control and International Health Regulations (IHR) 2005; (2) multistakeholder diplomacy, i.e., negotiations between or among nations and international agencies such as WHO, the GAVI Alliance, United States Agency for International Development (USAID), and nongovernmental organizations (NGOs); and (3) informal diplomacy, which includes peer-to-peer scientific partnerships, private funders such as the Bill & Melinda Gates Foundation, and even some government employees from USAID or the US military working more or less independently in the field due to unique circumstances [9]. Michaud and Kates have identified similar forms of global health diplomacy [16]. Kickbusch and Lokeny have also noted recently that the WHO director-general made frequent mention of health diplomacy in her remarks at the January 2013 executive session [15]. Among the factors responsible for this emphasis are globalization associated with the renewed emphasis on “soft power”, security policy, trade agreements, and policies concerning the environment and international development, as well as the inclusion of health issues as part of the United Nations and summits held by various government organizations and agencies, such as the Group of Eight (G8) and Group of Twenty (G20) nations, the European Union (EU), the Organization of the Islamic Conference (OIC), and the BRICS (Brazil, Russia, India, China, and South Africa) countries [15]. Still another factor is the increasing use of health attachés embedded in foreign delegations and agencies and increasing dialogue with low- and middle-income countries [15]. With regards to the G20 (and their BRICS-country components), I introduced the term “blue marble health” to refer to the unexpectedly high neglected disease burden among the poor living in emerging economies and even some G20 countries, circumstances such that these nations could drastically reduce global burdens of neglected diseases by taking greater responsibility for their own health concerns [17], [18]. Vaccine Diplomacy and Vaccine Science Diplomacy: Definitions Beginning in 2001, the broad framework of global health diplomacy outlined above helped to generate the concepts of vaccine diplomacy and vaccine science diplomacy [19]–[24]. Vaccine diplomacy refers to almost any aspect of global health diplomacy that relies on the use or delivery of vaccines and encompasses the important work of the GAVI Alliance, as well as elements of the WHO, the Gates Foundation, and other important international organizations. Central to vaccine diplomacy is its potential as a humanitarian intervention and its proven role in mediating cessation of hostilities and even cease-fires during vaccination campaigns [20]–[22], [25]. In this case, the lead actor may come from an international organization, such as WHO or the United Nations Children's Fund (UNICEF), or an associated nongovernmental organization. A subset of vaccine diplomacy is vaccine science diplomacy, which is a hybrid of elements of global health diplomacy and science diplomacy. I use the term “vaccine science diplomacy” narrowly to refer to the joint development of life-saving vaccines and related technologies, with the major actors typically scientists. Of particular interest, the scientists may be from two or more nations that often disagree ideologically or even from nations that are actively engaged in hostile actions. This definition is along the lines of what Katz et al. would call informal global health diplomacy based on peer-to-peer scientific interactions [9], together with elements of science diplomacy in which the representative nation projects power through its scientific prowess and reputation, as Abelson and others articulated for US science and applied technology during the Cold War [26]–[28] or more recently as can be seen in outreach to the Islamic world [29] and targeted initiatives for less developed countries [30]. Unlike many forms of global health diplomacy, this aspect of vaccine diplomacy is led by scientists. An underlying theme of both vaccine and vaccine science diplomacies is that vaccines are unique in comparison to other medical or public health interventions. By some estimates, vaccines are the single most powerful intervention ever developed by humankind in terms of the lives that they save. By one estimate, modern vaccines have saved more lives than those that were lost in the world wars during the 20th century [21]–[23]. The Historical Context Both vaccine diplomacy and vaccine science diplomacy might be best understood by reviewing their historical successes (Table 1). Indeed, an interesting but little-known feature is how diplomacy is intimately tied to the initial development and delivery of many vaccines. 10.1371/journal.pntd.0002808.t001 Table 1 Historical milestones in vaccine diplomacy. Years Specific Vaccine(s) Actions Reference 1800–1805 Smallpox Edward Jenner promotes vaccine use in Russia, Turkey, and Spain and with Native Americans in the Spanish colonies of Mexico, the Five Nations of Canada, and the United States. [31], [32] 1801 Smallpox The chaplain of Congress, Dr. Edward Gantt, vaccinates Native American diplomats visiting Washington, D.C. [32] 1803 Smallpox The Lewis and Clark Expedition provides vaccine intended for Native Americans, but it is unclear if successful vaccinations were performed. [32] 1803–1815 Smallpox During the Napoleonic Wars, Jenner calls for prisoner release and other diplomatic functions. In a letter to the National Institute of France, he writes that “the sciences are never at war.” [31] 1851 - The First International Sanitary Conference is held in Europe. [3] 1888 - In a speech on the inauguration of the Pasteur Institute, Louis Pasteur states, “Science knows no country, because knowledge belongs to humanity and is the torch which illuminates the world.” [31], [33] 1891–present - International network of Pasteur Institutes begins, initially in Saigon, for purposes of fundamental research and research on vaccines for rabies and other infectious diseases. [34] 1892–1897 Cholera and plague After first testing the vaccines on himself, Dr. Waldemar Haffkine travels to India to inoculate tens of thousands of people with his prototype cholera and plague vaccines. [35] 1902 - Formation of the International Sanitary Bureau (present-day Pan American Health Organization) [4] 1946–48 - Formation of the World Health Organization [3] 1956–1959 Polio Dr. Albert Sabin travels to the USSR and collaborates with Dr. Mikhail Chumakov, ultimately testing an oral vaccine on 10 million children and then on 100 million people under the age of 20. [36] 1962–1966 Smallpox The USSR provides 450 million doses of vaccine for an eradication campaign, while the US provides financial support. [37] 1968 - Formation of the Fogarty International Center of the NIH Mid-1970s Formation of PATH 1980s and 1990s Polio and other vaccines “Days of tranquility” for immunizations are held in more than a dozen war-torn countries. [25] 1987 - Indo-US Vaccine Action Program (VAP) is administered under the auspices of NIAID, NIH. [38] 1990–91 - Children's Vaccine Initiative (CVI) 1993 - Formation of the Sabin Vaccine Institute [58] - Formation of the Infectious Diseases Research Institute 1997 - Formation of the International Vaccine Institute 1997 - Formation of the Bill & Melinda Gates Foundation 2000 - GAVI Alliance is established, ultimately providing vaccines for North Korea. [39], [41] 2001 - “Vaccine diplomacy” enters the literature. [19] 2007 Formation of program in Sustainable Immunization Financing at Sabin Vaccine Institute [65] 2007 Influenza Under the auspices of the WHO, Brazil, India, Indonesia, Mexico, Thailand, and Vietnam receive US and Japanese grants for influenza vaccine manufacturing capacity and technology transfer. [52] 2008 Yellow Fever Outbreak of urban yellow fever—the neighboring countries of Paraguay mobilize to ensure access to yellow fever vaccine. [45] 2009 H1N1 Influenza A Intergovernmental Meeting (IGM) on Pandemic Influenza Preparedness Framework for the Sharing of Influenza Viruses and Access to Vaccines and Other Benefits [43] 2010 Cholera Call for international cholera vaccine stockpile as a humanitarian and diplomatic resource [44] 2011 - Decade of Vaccines Collaboration [46] 2012 - The Global Vaccine Action Plan (GVAP)—endorsed by the 194 Member States of the World Health Assembly in May 2012 [47], [48] 2013 Leishmaniasis and other neglected tropical diseases Joint statement on vaccine diplomacy between US and Iran [54] 2013 - State Department forms new Office of Global Health Diplomacy. The first vaccine discovered in modern times was in 1798 by Britain's Edward Jenner, who found that cowpox administered as an inoculum could prevent smallpox [31]; the term vaccine is derived from vacca, the Latin term for “cow”. Because smallpox produced such devastating and massive killer epidemics (especially among indigenous populations in the New World), the first vaccine almost immediately attained international acclaim in the first years of the 19th century [31], [32]. For example, from 1800 to 1805, Jenner corresponded widely and internationally and advised countries as diverse as Russia, Spain, and Turkey and Native American tribes and nations in Canada and Mexico on how to prepare and administer the smallpox vaccine [31], [32]. Among the earliest examples of vaccine diplomacy, in 1801 Dr. Edward Gantt, the chaplain of the US Congress, vaccinated Native American diplomats who were visiting Washington, D.C., and in 1803 the Lewis and Clark Expedition was provided smallpox vaccine intended for Native Americans living on the western frontier, although it is unclear if successful vaccinations were actually performed [32]. From 1803 to 1815 during the Napoleonic wars between England and France, Jenner himself was called on for diplomatic functions, including prisoner releases [31]. Jenner was honored in France and wrote in a letter to the National Institute of France that “the sciences are never at war,” while Napoleon was supposed to have once stated, “Jenner—we can't refuse that man anything” [19], [31]. The next set of vaccines, including a new rabies vaccine, was developed almost one hundred years later by France's Louis Pasteur. In a speech at the inauguration of his institute in Paris in 1888, Pasteur stated that “science knows no country, because knowledge belongs to humanity and is the torch which illuminates the world” [31], [33]. Before the close of the century, scientists from the Pasteur Institute spread out to create a network of laboratories in Francophone countries in Indochina (beginning with the Saigon Pasteur Institute [1891]) and North Africa [34], especially for the preparation and administration of rabies vaccine. Around this time (from 1892–1897), Dr. Waldemar Haffkine, a Jewish scientist from Ukraine working in France and Switzerland, traveled to India in order to inoculate tens of thousands of people with his prototype cholera and plague vaccines, but he did so only after first testing the vaccines on himself [35]. Today, the Haffkine Institute in Mumbai is an important microbiology research institute. Vaccine science diplomacy entered its golden age during the Cold War between the US and the Union of Soviet Socialist Republics (USSR). Between 1956 and 1959, Dr. Albert Sabin from the US traveled to the USSR and collaborated with his Soviet virology counterparts, including Dr. Mikhail Chumakov, to develop a prototype oral polio vaccine and test it on 10 million Soviet children and ultimately 100 million people under the age of 20 [36]. The success of the collaboration depended on each scientist going to great lengths to convince their diplomatic liaisons to put aside ideologies for purposes of joint scientific cooperation [19]–[23], [36]. Today, the oral polio vaccine is leading to global eradication efforts. Similarly, between 1962 and 1966, the USSR pioneered a freeze-drying technique for smallpox vaccine and provided 450 million doses of vaccine to support global smallpox eradication campaigns in developing countries, while the US provided key financial support [37]. Such international collaborative efforts led to the global eradication of smallpox by the late 1970s, an effort led by Dr. D. A. Henderson [37]. Later, in the 1980s and following the visit of US Nobel Laureate Fred Robbins to India, the Indo-US Vaccine Action Program (VAP) was established to foster international collaboration in the areas of epidemiology, laboratory investigation, and vaccine clinical trials, quality control, and delivery [38]. VAP is maintained under the auspices of the National Institute of Allergy and Infectious Diseases of the US National Institutes of Health (NIH) [38]. In 1990–91, a Children's Vaccine Initiative was launched as an early attempt at global governance for developing pediatric vaccines for developing countries. Vaccine diplomacy also flourished in the later decades of the 20th century. According to WHO's Health as a Bridge to Peace—Humanitarian Cease-Fires Project (HCFP), vaccines and vaccinations were used to negotiate so-called “days of tranquility” in more than a dozen countries during the 1980s and 1990s, including Afghanistan, Angola, Chechnya, Democratic Republic of Congo, El Salvador, Guinea Bissau, Iraq, Lebanon, Philippines, Sierra Leone, Sri Lanka, and Sudan [25]. Modern Day Vaccine and Vaccine Science Diplomacy Beginning in 2000, vaccines became integrated as key tools in helping developing nations achieve their MDGs and targets. Following the launch of the GAVI Alliance, many developing countries for the first time gained access to vaccines for combating rotavirus and Haemophilus influenzae type b (Hib), and a new vaccine for pneumococcal vaccine was developed [39], [40]. Partly because of these interventions, child mortality was reduced by almost one-half [40]. Included among these activities was GAVI's important work in providing vaccines for North Korea and other fragile states [41]. Among the initiatives relevant to vaccine diplomacy in the 21st century are international efforts to ensure universal or equitable access for low- and middle-income countries to urgently needed vaccines for diseases of pandemic potential. It was noted that many developing countries were on the “outside looking in” when it came to having access to influenza vaccines, including the vaccine for the H1N1 pandemic influenza in 2009 and prototype H5N1 avian influenza vaccines [42], [43]. As a result, Indonesia went through a period in which it refused to share timely influenza surveillance data with the WHO [42]. It was noted that IHR 2005 did not adequately spell out provisions on providing equitable access for vaccines [43], and it was probably not intended for this purpose. In 2009, an Intergovernmental Meeting (IGM) was held on pandemic influenza preparedness as a means to establish a framework for sharing influenza and other vaccines with developing countries [43]. Issues of developing country access again arose when cholera emerged in sub-Saharan Africa and Haiti; there was no mechanism to rapidly mobilize cholera vaccine, and calls went out to stockpile cholera vaccine as a humanitarian and diplomatic resource [44]. Also, in 2008 when yellow fever vaccine supplies were depleted during the first urban yellow fever outbreak in the Americas in decades, countries neighboring Paraguay helped to ensure that the vaccine was made available in that country [45]. In 2012, following the earlier launch of the Decade of Vaccines Collaboration [46], the Global Vaccine Action Plan (GVAP) was endorsed by the 194 Member States of the World Health Assembly as “a framework to prevent millions of deaths by 2020 through more equitable access to existing vaccines for people in all communities” [47]. A World Health Assembly resolution was adopted that recognizes access to vaccines as a fundamental right to human health [48]. The diplomatic community was also called on to address critical issues of noncompliance for polio and other vaccines intended for vulnerable populations living in Islamic countries. In 2003, a boycott of polio vaccinations in three northern Nigerian states from fears that the vaccine was contaminated with antifertility drugs (in order to sterilize Muslim girls) necessitated diplomatic intervention from the Government of Malaysia and the OIC [49]. Similar interventions are now required in Pakistan, where the Taliban and other extremist groups have assassinated vaccinators and other aid workers [50]. Some assassinations may have been carried out in retaliation for the Central Intelligence Agency (CIA)'s alleged role in establishing a fake vaccination campaign in Abbottabad, Pakistan, as a ruse in order to confirm the identity of members of Osama bin Laden's family [51]. Such activities represent a significant setback to vaccine diplomacy. Of relevance to both vaccine and vaccine science diplomacy, in 2007 under the auspices of the WHO and the Global Pandemic Influenza Action Plan, six countries—Brazil, India, Indonesia, Mexico, Thailand, and Vietnam—received grants from the US and Japanese governments to establish in-country manufacturing capacity for influenza vaccines [52]. Future Directions and Moving towards a Framework While the historical and modern-day track records of vaccine and vaccine science diplomacy are impressive, they have not yet led to an overarching framework for its expanded role in foreign policy. Establishing such a framework might be especially useful for US foreign policy. In 2009, President Obama traveled to Cairo where he spoke out about engaging scientists in the Muslim world and extending a hand in science diplomacy [53]. Despite the establishment of a valuable US Science Envoy program, to date such activities have not led to substantive joint vaccine partnerships despite the observation that several Islamic countries in the Middle East and Asia, including Egypt, Indonesia, Iran, and Saudi Arabia, have some capacity for vaccine product development [23]. With an Iranian scientist from the Tehran University of Medical Sciences, Dr. Mohammed Rokni, I recently advocated launching such efforts between the US and Iran and provided as an example the opportunity for developing a vaccine for leishmaniasis, which has devastated areas of conflict in the Middle East and North Africa [54]. Similar opportunities exist in order to partner with nations such as Cuba, which has considerable technical expertise both in producing and delivering vaccine [55], and possibly even countries such as North Korea, which has some technical capabilities [56]. Our Sabin Vaccine Institute and Texas Children's Hospital Center for Vaccine Development (Sabin), a nonprofit product development partnership (PDP) that uses industry practices to develop and test neglected disease vaccines, could occupy a key niche in vaccine diplomacy. Sabin's vaccine portfolio targets neglected tropical diseases (NTDs) that specifically affect the poorest people living in low- and middle-income countries. Because NTDs have been shown to promote poverty through their adverse effects on worker productivity, the health of girls and women, and child development, the vaccines under development at Sabin are sometimes referred to as the “antipoverty vaccines” [57], [58]. Moreover, most of the diseases targeted by the Sabin portfolio of vaccines occur in countries of direct relevance to vaccine diplomacy (Table 2) [59]. For example, more than one-third of the world's cases of hookworm infection, ascariasis, and trichuriasis occur in nations of the OIC, i.e., the world's Muslim countries (Figure 1), while almost one-half of the cases of schistosomiasis occur among the OIC countries [59]. Furthermore, both cutaneous and visceral leishmaniasis have emerged as the most significant infections arising in settings of ongoing conflict, with the former affecting hundreds of thousands of people in Syria and Syrian refugees, while the latter was the leading killer in the war between northern and southern Sudan during the 1980s and 1990s [60]. Some of these diseases are also widespread in some Latin American countries where leaders have expressed varying degrees of anti-American sentiment. While Sabin is currently conducting joint vaccine development with public-sector vaccine manufacturers in Brazil and Mexico, it is ready to embark on joint vaccine development with countries such as Cuba, Indonesia, and Iran, i.e., nations with either strained or even overtly hostile foreign relations with the US in past and recent years. As a form of projecting soft power with both allies and potential adversaries, such activities are consistent with what former Secretary Hillary Clinton termed “civilian power” [24]. 10.1371/journal.pntd.0002808.g001 Figure 1 The OIC member nations. Figure adapted from Wikipedia: http://en.wikipedia.org/wiki/File:OIC_map.png. 10.1371/journal.pntd.0002808.t002 Table 2 Sabin PDP vaccines under development of potential relevance to US foreign policy interests. Disease Targeted (Approximate Number of People Affected) Affected Geographic Areas of Interest to US Foreign Policy Interests Stage of Development Human hookworm infection (400 million) OIC countries in Africa, the Middle East, and Asia Phase 1 India and China Schistosomiasis (250 million) OIC countries in Africa and the Middle East Completed current good manufacturing practice (cGMP) manufacture Ascariasis and Trichuriasis (>800 million) OIC countries in Africa, the Middle East, and Asia Preclinical India and China Leishmaniasis (10 million) Areas of conflict in the Middle East and North Africa, including OIC countries Preclinical Chagas disease (7–8 million) Venezuela, Ecuador, Bolivia Preclinical SARS (None currently) China Preclinical Beyond US foreign relations, there are opportunities for vaccines to promote cooperation between Asian nations. For instance, each of the largest Asian countries, i.e., China, India, Indonesia, Japan, and Vietnam, has capabilities to develop and produce new vaccines [56], [61]. China and India engaged in overt hostilities in 1964, while China's recent territorial claims in the East China Sea have sparked fresh tensions in the region [61]. Both Sabin and another PDP, the International Vaccine Institute (IVI) based in Seoul, Korea [62], could help mediate vaccine diplomacy between these nations. In addition, Brazil, which also has major vaccine capabilities, has initiated South-South partnerships with Lusophone Africa and could become an important actor in vaccine diplomacy [63]. Vaccine manufacturing organizations associated with many of the key OIC and Asian nations targeted for vaccine science diplomacy belong to the unique Developing Countries Vaccine Manufacturers Network (DCVMN) [64]. Both the GAVI Alliance and WHO could have key roles in coordinating these activities. These organizations also have a key role in a new Sustainable Immunization Financing program inaugurated with Gates Foundation support by Dr. Ciro De Quadros at the Sabin Vaccine Institute, which focuses on 12 African countries, five Asian countries, and one Central Asian country [65]. Today, the Division of International Relations of the NIH's Fogarty International Center maintains an important role in promoting international agreements between the US and governments throughout the world [66]. In the coming years, vaccine and vaccine science diplomacy activities could become incorporated into the new US State Department Office of Global Health Diplomacy [67], as well as into the WHO and its regional offices and within organizations such as the Bill & Melinda Gates Foundation and the Carlos Slim Health Institute. The power of vaccine and vaccine science diplomacy has been underexplored despite a noble track record that included promoting peace between the Cold War powers of the 1950s and 1960s, which also led to the development, testing, and delivery of two of the most important 20th century health interventions, i.e., the freeze-dried smallpox vaccine and oral polio vaccine, and the resulting global eradication of smallpox and near elimination of polio. The historical lessons from these accomplishments still have critical relevance to global health and blue marble health. Box 1. Potential Sites for Vaccine Diplomacy and US Foreign Policy Sabin Vaccine Institute and Texas Children's Hospital Center for Vaccine Development, Houston, Texas, United States of America International Vaccine Institute, Seoul, Korea IDRI (Infectious Disease Research Institute), Seattle, Washington, United States of America PATH Vaccine Development Global Program, Washington, D.C., United States of America Finlay Institute, Havana, Cuba Birmex, Mexico, D.F., Mexico FIOCRUZ Bio-Manguinhos, Rio de Janeiro, Brazil Instituto Butantan, Sao Paulo, Brazil Vacsera, Cairo, Egypt Razi Vaccine and Serum Institute and Institut Pasteur, Tehran, Iran Biopharma, Bandang, Indonesia

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          Lessons from the History of Quarantine, from Plague to Influenza A

          The risk for deadly infectious diseases with pandemic potential (e.g., severe acute respiratory syndrome [SARS]) is increasing worldwide, as is the risk for resurgence of long-standing infectious diseases (e.g., tuberculosis) and for acts of biological terrorism. To lessen the risk from these new and resurging threats to public health, authorities are again using quarantine as a strategy for limiting the spread of communicable diseases ( 1 ). The history of quarantine—not in its narrower sense, but in the larger sense of restraining the movement of persons or goods on land or sea because of a contagious disease—has not been given much attention by historians of public health. Yet, a historical perspective of quarantine can contribute to a better understanding of its applications and can help trace the long roots of stigma and prejudice from the time of the Black Death and early outbreaks of cholera to the 1918 influenza pandemic ( 2 ) and to the first influenza pandemic of the twenty-first century, the 2009 influenza A(H1N1)pdm09 outbreak ( 3 ). Quarantine (from the Italian “quaranta,” meaning 40) was adopted as an obligatory means of separating persons, animals, and goods that may have been exposed to a contagious disease. Since the fourteenth century, quarantine has been the cornerstone of a coordinated disease-control strategy, including isolation, sanitary cordons, bills of health issued to ships, fumigation, disinfection, and regulation of groups of persons who were believed to be responsible for spreading the infection ( 4 , 5 ). Plague Organized institutional responses to disease control began during the plague epidemic of 1347–1352 ( 6 ). The plague was initially spread by sailors, rats, and cargo arriving in Sicily from the eastern Mediterranean ( 6 , 7 ); it quickly spread throughout Italy, decimating the populations of powerful city-states like Florence, Venice, and Genoa ( 8 ). The pestilence then moved from ports in Italy to ports in France and Spain ( 9 ). From northeastern Italy, the plague crossed the Alps and affected populations in Austria and central Europe. Toward the end of the fourteenth century, the epidemic had abated but not disappeared; outbreaks of pneumonic and septicemic plague occurred in different cities during the next 350 years ( 8 ). Medicine was impotent against plague ( 8 ); the only way to escape infection was to avoid contact with infected persons and contaminated objects. Thus, some city-states prevented strangers from entering their cities, particularly, merchants ( 10 ) and minority groups, such as Jews and persons with leprosy. A sanitary cordon—not to be broken on pain of death—was imposed by armed guards along transit routes and at access points to cities. Implementation of these measures required rapid, firm action by authorities, including prompt mobilization of repressive police forces. A rigid separation between healthy and infected persons was initially accomplished through the use of makeshift camps ( 10 ). Quarantine was first introduced in 1377 in Dubrovnik on Croatia’s Dalmatian Coast ( 11 ), and the first permanent plague hospital (lazaretto) was opened by the Republic of Venice in 1423 on the small island of Santa Maria di Nazareth. The lazaretto was commonly referred to as Nazarethum or Lazarethum because of the resemblance of the word lazaretto to the biblical name Lazarus ( 12 ). In 1467, Genoa adopted the Venetian system, and in 1476 in Marseille, France, a hospital for persons with leprosy was converted into a lazaretto. Lazarettos were located far enough away from centers of habitation to restrict the spread of disease but close enough to transport the sick. Where possible, lazarettos were located so that a natural barrier, such as the sea or a river, separated them from the city; when natural barriers were not available, separation was achieved by encircling the lazaretto with a moat or ditch. In ports, lazarettos consisted of buildings used to isolate ship passengers and crew who had or were suspected of having plague. Merchandise from ships was unloaded to designated buildings. Procedures for so-called “purgation” of the various products were prescribed minutely; wool, yarn, cloth, leather, wigs, and blankets were considered the products most likely to transmit disease. Treatment of the goods consisted of continuous ventilation; wax and sponge were immersed in running water for 48 hours. It is not known why 40 days was chosen as the length of isolation time needed to avoid contamination, but it may have derived from Hippocrates theories regarding acute illnesses. Another theory is that the number of days was connected to the Pythagorean theory of numbers. The number 4 had particular significance. Forty days was the period of the biblical travail of Jesus in the desert. Forty days were believed to represent the time necessary for dissipating the pestilential miasma from bodies and goods through the system of isolation, fumigation, and disinfection. In the centuries that followed, the system of isolation was improved ( 13 – 15 ). In connection with the Levantine trade, the next step taken to reduce the spread of disease was to establish bills of health that detailed the sanitary status of a ship’s port of origin ( 14 ). After notification of a fresh outbreak of plague along the eastern Mediterranean Sea, port cities to the west were closed to ships arriving from plague-infected areas ( 15 ). The first city to perfect a system of maritime cordons was Venice, which because of its particular geographic configuration and its prominence as a commercial center, was dangerously exposed ( 12 , 15 , 16 ). The arrival of boats suspected of carrying plague was signaled with a flag that would be seen by lookouts on the church tower of San Marco. The captain was taken in a lifeboat to the health magistrate’s office and was kept in an enclosure where he spoke through a window; thus, conversation took place at a safe distance. This precaution was based on a mistaken hypothesis (i.e., that “pestilential air” transmitted all communicable diseases), but the precaution did prevent direct person-to-person transmission through inhalation of contaminated aerosolized droplets. The captain had to show proof of the health of the sailors and passengers and provide information on the origin of merchandise on board. If there was suspicion of disease on the ship, the captain was ordered to proceed to the quarantine station, where passengers and crew were isolated and the vessel was thoroughly fumigated and retained for 40 days ( 13 , 17 ). This system, which was used by Italian cities, was later adopted by other European countries. The first English quarantine regulations, drawn up in 1663, provided for the confinement (in the Thames estuary) of ships with suspected plague-infected passengers or crew. In 1683 in Marseille, new laws required that all persons suspected of having plague be quarantined and disinfected. In ports in North America, quarantine was introduced during the same decade that attempts were being made to control yellow fever, which first appeared in New York and Boston in 1688 and 1691, respectively ( 18 ). In some colonies, the fear of smallpox outbreaks, which coincided with the arrival of ships, induced health authorities to order mandatory home isolation of persons with smallpox ( 19 ), even though another controversial strategy, inoculation, was being used to protect against the disease. In the United States, quarantine legislation, which until 1796 was the responsibility of states, was implemented in port cities threatened by yellow fever from the West Indies ( 18 ). In 1720, quarantine measures were prescribed during an epidemic of plague that broke out in Marseille and ravaged the Mediterranean seaboard of France and caused great apprehension in England. In England, the Quarantine Act of 1710 was renewed in 1721 and 1733 and again in 1743 during the disastrous epidemic at Messina, Sicily ( 19 ). A system of active surveillance was established in the major Levantine cities. The network, formed by consuls of various countries, connected the great Mediterranean ports of western Europe ( 15 ). Cholera By the eighteenth century, the appearance of yellow fever in Mediterranean ports of France, Spain, and Italy forced governments to introduce rules involving the use of quarantine ( 18 ). But in the nineteenth century, another, even more frightening scourge, cholera, was approaching ( 20 ). Cholera emerged during a period of increasing globalization caused by technological changes in transportation, a drastic decrease in travel time by steamships and railways, and a rise in trade. Cholera, the “Asiatic disease,” reached Europe in 1830 and the United States in 1832, terrifying the populations ( 21 – 24 ). Despite progress regarding the cause and transmission of cholera, there was no effective medical response ( 25 ). During the first wave of cholera outbreaks, the strategies adopted by health officials were essentially those that had been used against plague. New lazarettos were planned at western ports, and an extensive structure was established near Bordeaux, France ( 26 ). At European ports, ships were barred entry if they had “unclean licenses” (i.e., ships arriving from regions where cholera was present) ( 27 ). In cities, authorities adopted social interventions and the traditional health tools. For example, travelers who had contact with infected persons or who came from a place where cholera was present were quarantined, and sick persons were forced into lazarettos. In general, local authorities tried to keep marginalized members of the population away from the cities ( 27 ). In 1836 in Naples, health officials hindered the free movement of prostitutes and beggars, who were considered carriers of contagion and, thus, a danger to the healthy urban population ( 27 , 28 ). This response involved powers of intervention unknown during normal times, and the actions generated widespread fear and resentment. In some countries, the suspension of personal liberty provided the opportunity—using special laws—to stop political opposition. However, the cultural and social context differed from that in previous centuries. For example, the increasing use of quarantine and isolation conflicted with the affirmation of citizens’ rights and growing sentiments of personal freedom fostered by the French Revolution of 1789. In England, liberal reformers contested both quarantine and compulsory vaccination against smallpox. Social and political tensions created an explosive mixture, culminating in popular rebellions and uprisings, a phenomenon that affected numerous European countries ( 29 ). In the Italian states, in which revolutionary groups had taken the cause of unification and republicanism ( 27 ), cholera epidemics provided a justification (i.e., the enforcement of sanitary measures) for increasing police power. By the middle of the nineteenth century, an increasing number of scientists and health administrators began to allege the impotence of sanitary cordons and maritime quarantine against cholera. These old measures depended on the idea that contagion was spread through the interpersonal transmission of germs or by contaminated clothing and objects ( 30 ). This theory justified the severity of measures used against cholera; after all, it had worked well against the plague. The length of quarantine (40 days) exceeded the incubation period for the plague bacillus, providing sufficient time for the death of the infected fleas needed to transmit the disease and of the biological agent, Yersinia pestis. However, quarantine was almost irrelevant as a primary method for preventing yellow fever or cholera. A rigid maritime cordon could only be effective in protecting small islands. During the terrifying cholera epidemic of 1835–1836, the island of Sardinia was the only Italian region to escape cholera, thanks to surveillance by armed men who had orders to prevent, by force, any ship that attempted to disembark persons or cargo on the coast ( 27 ). Anticontagionists, who disbelieved the communicability of cholera, contested quarantine and alleged that the practice was a relic of the past, useless, and damaging to commerce. They complained that the free movement of travelers was hindered by sanitary cordons and by controls at border crossings, which included fumigation and disinfection of clothes (Figures 1,2,3). In addition, quarantine inspired a false sense of security, which was dangerous to public health because it diverted persons from taking the correct precautions. International cooperation and coordination was stymied by the lack of agreement regarding the use of quarantine. The discussion among scientists, health administrators, diplomatic bureaucracies, and governments dragged on for decades, as demonstrated in the debates in the International Sanitary Conferences ( 31 ), particularly after the opening, in 1869, of the Suez Canal, which was perceived as a gate for the diseases of the Orient ( 32 ). Despite pervasive doubts regarding the effectiveness of quarantine, local authorities were reluctant to abandon the protection of the traditional strategies that provided an antidote to population panic, which, during a serious epidemic, could produce chaos and disrupt public order ( 33 ). Figure 1 Disinfecting clothing. France–Italy border during the cholera epidemic of 1865–1866. (Photograph in the author's possession). Figure 2 Quarantine. The female dormitory. France–Italy border during the cholera epidemic of 1865–1866. (Photograph in the author's possession). Figure 3 The control of travelers from cholera-affected countries, who were arriving by land at the France–Italy border during the cholera epidemic of 1865–1866. (Photograph in the author's possession). A turning point in the history of quarantine came after the pathogenic agents of the most feared epidemic diseases were identified between the nineteenth and twentieth centuries. International prophylaxis against cholera, plague, and yellow fever began to be considered separately. In light of the newer knowledge, a restructuring of the international regulations was approved in 1903 by the 11th Sanitary Conference, at which the famed convention of 184 articles was signed ( 31 ). Influenza In 1911, the eleventh edition of Encyclopedia Britannica emphasized that “the old sanitary preventive system of detention of ships and men” was “a thing of the past” ( 34 ). At the time, the battle against infectious diseases seemed about to be won, and the old health practices would only be remembered as an archaic scientific fallacy. No one expected that within a few years, nations would again be forced to implement emergency measures in response to a tremendous health challenge, the 1918 influenza pandemic, which struck the world in 3 waves during 1918–1919 (Technical Appendix). At the time, the etiology of the disease was unknown. Most scientists thought that the pathogenic agent was a bacterium, Haemophilus influenzae, identified in 1892 by German bacteriologist Richard Pfeiffer ( 35 ). During 1918–1919, in a world divided by war, the multilateral health surveillance systems, which had been laboriously built during the previous decades in Europe and the United States, were not helpful in controlling the influenza pandemic. The ancestor of the World Health Organization, the Office International d’Hygiène Publique, located in Paris ( 31 ), could not play any role during the outbreak. At the beginning of the pandemic, the medical officers of the army isolated soldiers with signs or symptoms, but the disease, which was extremely contagious, quickly spread, infecting persons in nearly every country. Various responses to the pandemic were tried. Health authorities in major cities of the Western world implemented a range of disease-containment strategies, including the closure of schools, churches, and theaters and the suspension of public gatherings. In Paris, a sporting event, in which 10,000 youths were to participate, was postponed ( 36 ). Yale University canceled all on-campus public meetings, and some churches in Italy suspended confessions and funeral ceremonies. Physicians encouraged the use of measures like respiratory hygiene and social distancing. However, the measures were implemented too late and in an uncoordinated manner, especially in war-torn areas where interventions (e.g., travel restrictions, border controls) were impractical, during a time when the movement of troops was facilitating the spread of the virus. In Italy, which along with Portugal had the highest mortality rate in Europe, schools were closed after the first case of the unusually severe hemorrhagic pneumonia; however, the decision to close schools was not simultaneously accepted by health and scholastic authorities ( 37 ). Decisions made by health authorities often seemed focused more on reassuring the public about efforts being made to stop transmission of the virus rather than on actually stopping transmission of the virus ( 35 ). Measures adopted in many countries disproportionately affected ethnic and marginalized groups. In colonial possessions (e.g., New Caledonia), restrictions on travel affected the local populations ( 3 ). The role that the media would play in influencing public opinion in the future began to take shape. Newspapers took conflicting positions on health measures and contributed to the spread of panic. The largest and most influential newspaper in Italy, Corriere della Sera, was forced by civil authorities to stop reporting the number of deaths (150–180 deaths/day) in Milan because the reports caused great anxiety among the citizenry. In war-torn nations, censorship caused a lack of communication and transparency regarding the decision-making process, leading to confusion and misunderstanding of disease-control measures and devices, such as face masks (ironically named “muzzles” in Italian) ( 35 ). During the second influenza pandemic of the twentieth century, the “Asian flu” pandemic of 1957–1958, some countries implemented measures to control spread of the disease. The illness was generally milder than that caused by the 1918 influenza, and the global situation differed. Understanding of influenza had advanced greatly: the pathogenic agent had been identified in 1933, vaccines for seasonal epidemics were available, and antimicrobial drugs were available to treat complications. In addition, the World Health Organization had implemented a global influenza surveillance network that provided early warning when novel influenza (H2N2) virus, began spreading in China in February 1957 and worldwide later that year. Vaccines had been developed in Western countries but were not yet available when the pandemic began to spread simultaneously with the opening of schools in several countries. Control measures (e.g., closure of asylums and nurseries, bans on public gatherings) varied from country to country but, at best, merely postponed the onset of disease for a few weeks ( 38 ). This scenario was repeated during the influenza A(H3N2) pandemic of 1968–1969, the third and mildest influenza pandemic of the twentieth century. The virus was first detected in Hong Kong in early 1968 and was introduced into the United States in September 1968 by US Marines returning from Vietnam. In the winter of 1968–69, the virus spread around the world; the effect was limited and there were no specific containment measures. A new chapter in the history of quarantine opened in the early twenty-first century as traditional intervention measures were resurrected in response to the global crisis precipitated by the emergence of SARS, an especially challenging threat to public health worldwide. SARS, which originated in Guangdong Province, China, in 2003, spread along air-travel routes and quickly became a global threat because of its rapid transmission and high mortality rate and because protective immunity in the general population, effective antiviral drugs, and vaccines were lacking. However, compared with influenza, SARS had lower infectivity and a longer incubation period, providing time for instituting a series of containment measures that worked well ( 39 ). The strategies varied among the countries hardest hit by SARS (People’s Republic of China and Hong Kong Special Administrative Region; Singapore; and Canada). In Canada, public health authorities asked persons who might have been exposed to SARS to voluntarily quarantine themselves. In China, police cordoned off buildings, organized checkpoints on roads, and even installed Web cameras in private homes. There was stronger control of persons in the lower social strata (village-level governments were empowered to isolate workers from SARS-affected areas). Public health officials in some areas resorted to repressive police measures, using laws with extremely severe punishments (including the death penalty), against those who violated quarantine. As had occurred in the past, the strategies adopted in some countries during this public health emergency contributed to the discrimination and stigmatization of persons and communities and raised protests and complaints against limitations and travel restrictions. Conclusions More than half a millennium since quarantine became the core of a multicomponent strategy for controlling communicable disease outbreaks, traditional public health tools are being adapted to the nature of individual diseases and to the degree of risk for transmission and are being effectively used to contain outbreaks, such as the 2003 SARS outbreak and the 2009 influenza A(H1N1)pdm09 pandemic. The history of quarantine—how it began, how it was used in the past, and how it is used in the modern era—is a fascinating topic in history of sanitation. Over the centuries, from the time of the Black Death to the first pandemics of the twenty-first century, public health control measures have been an essential way to reduce contact between persons sick with a disease and persons susceptible to the disease. In the absence of pharmaceutical interventions, such measures helped contain infection, delay the spread of disease, avert terror and death, and maintain the infrastructure of society. Quarantine and other public health practices are effective and valuable ways to control communicable disease outbreaks and public anxiety, but these strategies have always been much debated, perceived as intrusive, and accompanied in every age and under all political regimes by an undercurrent of suspicion, distrust, and riots. These strategic measures have raised (and continue to raise) a variety of political, economic, social, and ethical issues ( 39 , 40 ). In the face of a dramatic health crisis, individual rights have often been trampled in the name of public good. The use of segregation or isolation to separate persons suspected of being infected has frequently violated the liberty of outwardly healthy persons, most often from lower classes, and ethnic and marginalized minority groups have been stigmatized and have faced discrimination. This feature, almost inherent in quarantine, traces a line of continuity from the time of plague to the 2009 influenza A(H1N1)pdm09 pandemic. The historical perspective helps with understanding the extent to which panic, connected with social stigma and prejudice, frustrated public health efforts to control the spread of disease. During outbreaks of plague and cholera, the fear of discrimination and mandatory quarantine and isolation led the weakest social groups and minorities to escape affected areas and, thus, contribute to spreading the disease farther and faster, as occurred regularly in towns affected by deadly disease outbreaks. But in the globalized world, fear, alarm, and panic, augmented by global media, can spread farther and faster and, thus, play a larger role than in the past. Furthermore, in this setting, entire populations or segments of populations, not just persons or minority groups, are at risk of being stigmatized. In the face of new challenges posed in the twenty-first century by the increasing risk for the emergence and rapid spread of infectious diseases, quarantine and other public health tools remain central to public health preparedness. But these measures, by their nature, require vigilant attention to avoid causing prejudice and intolerance. Public trust must be gained through regular, transparent, and comprehensive communications that balance the risks and benefits of public health interventions. Successful responses to public health emergencies must heed the valuable lessons of the past ( 39 , 40 ). Technical Appendix List of publications chronicling the influenza pandemic of 1918–1919.
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            Negotiating Equitable Access to Influenza Vaccines: Global Health Diplomacy and the Controversies Surrounding Avian Influenza H5N1 and Pandemic Influenza H1N1

            As part of the PLoS Medicine series on Global Health Diplomacy, David Fidler provides a case study of the difficult negotiations to increase equitable access to vaccines for highly pathogenic avian influenza A (H5N1) and pandemic 2009 influenza A (H1N1).
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              Oslo Ministerial Declaration--global health: a pressing foreign policy issue of our time.

              (2007)
              Under their initiative on Global Health and Foreign Policy, launched in September, 2006, in New York, the Ministers of Foreign Affairs of Brazil, France, Indonesia, Norway, Senegal, South Africa, and Thailand issued the following statement in Oslo on March 20, 2007-In today's era of globalisation and interdependence there is an urgent need to broaden the scope of foreign policy. Together, we face a number of pressing challenges that require concerted responses and collaborative efforts. We must encourage new ideas, seek and develop new partnerships and mechanisms, and create new paradigms of cooperation. We believe that health is one of the most important, yet still broadly neglected, long-term foreign policy issues of our time. Life and health are our most precious assets. There is a growing awareness that investment in health is fundamental to economic growth and development. It is generally acknowledged that threats to health may compromise a country's stability and security. We believe that health as a foreign policy issue needs a stronger strategic focus on the international agenda. We have therefore agreed to make impact on health a point of departure and a defining lens that each of our countries will use to examine key elements of foreign policy and development strategies, and to engage in a dialogue on how to deal with policy options from this perspective. As Ministers of Foreign Affairs, we will work to: increase awareness of our common vulnerability in the face of health threats by bringing health issues more strongly into the arenas of foreign policy discussions and decisions, in order to strengthen our commitment to concerted action at the global level; build bilateral, regional and multilateral cooperation for global health security by strengthening the case for collaboration and brokering broad agreement, accountability, and action; reinforce health as a key element in strategies for development and for fighting poverty, in order to reach the Millennium Development Goals; ensure that a higher priority is given to health in dealing with trade issues and in conforming to the Doha principles, affirming the right of each country to make full use of TRIPS flexibilities in order to ensure universal access to medicines; strengthen the place of health measures in conflict and crisis management and in reconstruction efforts. For this purpose, we have prepared a first set of actionable steps for raising the priority of health in foreign policy in an Agenda for Action. We pledge to pursue these issues in our respective regional settings and in relevant international bodies. We invite Ministers of Foreign Affairs from all regions to join us in further exploring ways and means to achieve our objectives.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS Negl Trop Dis
                PLoS Negl Trop Dis
                plos
                plosntds
                PLoS Neglected Tropical Diseases
                Public Library of Science (San Francisco, USA )
                1935-2727
                1935-2735
                June 2014
                26 June 2014
                : 8
                : 6
                Affiliations
                [1 ]Sabin Vaccine Institute and Texas Children's Hospital Center for Vaccine Development, Departments of Pediatrics and Molecular Virology and Microbiology, National School of Tropical Medicine at Baylor College of Medicine, Houston, Texas, United States of America
                [2 ]Departments of Medical Humanities and Biology, Baylor University, Waco, Texas, United States of America
                [3 ]James A. Baker III Institute for Public Policy, Rice University, Houston, Texas, United States of America
                Lindsley F. Kimball Research Institute, New York Blood Center, United States of America
                Author notes

                The author has read the journal's policy and has the following conflicts: The author is principal investigator and patent holder on vaccines in development or clinical trials for hookworm, Chagas disease, leishmaniasis, schistosomiasis, SARS, ascariasis, and trichuriasis. This does not alter our adherence to all PLOS policies on sharing data and materials.

                Article
                PNTD-D-13-02021
                10.1371/journal.pntd.0002808
                4072536
                24968231
                39f1cdac-3c5e-4443-9dd6-d5160d976701

                Hotez. 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.

                Page count
                Pages: 7
                Funding
                The author has indicated that no funding was received for this work.
                Categories
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                Biology and Life Sciences
                Veterinary Science
                Veterinary Diseases
                Zoonoses
                Leishmaniasis
                Medicine and Health Sciences
                Infectious Diseases
                Viral Diseases
                Influenza
                Infectious Disease Control
                Parasitic Diseases
                Protozoan Infections
                Chagas Disease
                Tropical Diseases
                Neglected Tropical Diseases

                Infectious disease & Microbiology

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