Advertisement

Yellow fever cases in Asia: primed for an epidemic

Open AccessPublished:May 05, 2016DOI:https://doi.org/10.1016/j.ijid.2016.04.025

      Highlights

      • A large yellow fever epidemic is underway in Angola, from where infected travellers are arriving in China, representing the first ever reported cases in Asia.
      • There is an abundance of the urban yellow fever vector, Aedes aegypti, in the Asia-Pacific region, raising the possibility of local yellow fever transmission, particularly as the period of peak dengue activity approaches.
      • The current conditions of a large Chinese expatriate community in Angola, the high volume of air travel from Angola to Asia, a favourable ecology for yellow fever transmission, and a large unimmunized population together represent a global health threat.
      • Outbreak preparedness and planning needs to be prioritized, and must include enhanced surveillance, vaccination of travellers, stockpiling of additional emergency vaccine, and consideration of administering a reduced vaccine dose as an outbreak response to maximise vaccination coverage.

      Summary

      There is currently an emerging outbreak of yellow fever in Angola. Cases in infected travellers have been reported in a number of other African countries, as well as in China, representing the first ever documented cases of yellow fever in Asia. There is a large Chinese workforce in Angola, many of whom may be unvaccinated, increasing the risk of ongoing importation of yellow fever into Asia via busy commercial airline routes. Large parts of the region are hyperendemic for the related Flavivirus dengue and are widely infested by Aedes aegypti, the primary mosquito vector of urban yellow fever transmission. The combination of sustained introduction of viraemic travellers, an ecology conducive to local transmission, and an unimmunized population raises the possibility of a yellow fever epidemic in Asia. This represents a major global health threat, particularly in the context of a depleted emergency vaccine stockpile and untested surveillance systems in the region. In this review, the potential for a yellow fever outbreak in Asia is discussed with reference to the ecological and historical forces that have shaped global yellow fever epidemiology. The limitations of surveillance and vector control in the region are highlighted, and priorities for outbreak preparedness and response are suggested.

      Keywords

      1. A yellow fever outbreak emerges in Africa

      On January 22, 2016, the internet-based disease outbreak reporting system of the International Society for Infectious Diseases – ProMED – posted an alert of 23 cases of yellow fever (YF) amongst locals, as well as Congolese and Eritreans, in a heavily populated suburb of Luanda, the Angolan capital.

      ProMED. Yellow fever—Africa (02): Angola (Luanda) request for information: International Society for Infectious Diseases. ProMED-mail; 2016. Available at: http://www.promedmail.org/post/3958601 (accessed April 11, 2016).

      This was based on an official Angolan Ministry of Health announcement. Three days later, the number of suspected cases had grown to 99 (26 confirmed), including eight deaths. On January 29, ProMED reported additional cases in southern Huila Province nearly 1000 km from Luanda.

      ProMED. Yellow fever—Africa (05): Angola (Huila): International Society for Infectious Diseases. ProMED-mail; 2016. Available at: http://www.promedmail.org/post/3977685 (accessed April 11, 2016).

      Over the following weeks, a major urban YF epidemic unfolded in Angola, and by April 10, a total of 1751 suspected cases (582 laboratory-confirmed) with 242 deaths had been reported. The outbreak is widespread, involving 59 districts in 12 of the 18 provinces in the country, including the capital Luanda, which has recorded 406 confirmed cases. Three confirmed cases in neighbouring Democratic Republic of Congo have been connected with the Angolan outbreak,

      World Health Organization. Yellow fever—Democratic Republic of the Congo, 11 April 2016. Geneva: WHO; 2016. Available at: http://www.who.int/csr/don/11-april-2016-yellow-fever-drc/en/ (accessed April 20, 2016).

      and infected travellers have been reported in Kenya.

      World Health Organization. Yellow Fever—Kenya, 6 April 2016. Geneva: WHO; 2016. Available at: http://www.who.int/csr/don/6-april-2016-yellow-fever-kenya/en/ (accessed April 20, 2016).

      Of major concern, the first YF cases have been reported in Asia, occurring in infected travellers from Angola. By April 10, 10 laboratory-confirmed cases had been imported into China, including six in Fujian Province, an area where dengue transmission has occurred.
      • Lai S.
      • Huang Z.
      • Zhou H.
      • Anders K.L.
      • Perkins T.A.
      • Yin W.
      • et al.
      The changing epidemiology of dengue in China, 1990–2014: a descriptive analysis of 25 years of nationwide surveillance data.
      With a large expatriate Chinese community in Angola, it is likely that additional undetected cases may have been imported. If ongoing introduction of cases occurs in areas with a high density of the urban YF mosquito vector, Aedes aegypti, it is possible that local transmission could occur in China and potentially spread to Southeast Asia.
      Approximately two billion people live in Ae aegypti-infested countries in Asia. The prospect of a YF introduction into this unvaccinated population poses a major global health threat. In this review, the potential for a YF outbreak in Asia is discussed in the context of the ecological and historical forces that have shaped global YF epidemiology. The aim is to draw attention to this emerging epidemic and to provide impetus for the necessary public health response.
      PubMed was searched for papers written in English with the search terms “yellow fever” and “Aedes aegypti”, and all articles that focused on epidemiology, recent outbreaks, and control and prevention were selected. The World Health Organization (WHO) website and Google Scholar were also searched for epidemiological reports. The bibliographies of review articles and other selected articles were scanned for other relevant references.

      2. The ecology and clinical manifestations of yellow fever

      YF is a viral haemorrhagic fever transmitted by mosquitoes. The YF virus (YFV) is the prototype virus of the family Flaviviridae, a group that includes the epidemic arthropod-borne viruses causing dengue, Japanese encephalitis (JE), and Zika, amongst others. YF is enzootic in rainforests of Africa and South America, and is maintained in sylvatic transmission cycles between monkeys and arboreal mosquitoes. Sporadic human infection can occur after intrusion into this ‘jungle cycle’ through occupational or recreational exposure to infected mosquitoes, resulting in single cases or limited sylvatic outbreaks. In South America, this may spill over into nearby towns to enter an inter-human urban cycle. In the wet African savannah, where mosquito vectors reach high densities in the rainy season and overlap with areas of human activity, there is intense enzootic transmission with increased risk of human infection. Inter-human transmission that occurs as a result of these epizootics is usually self-limited, but can lead to the emergence of rural epidemics. This is known as the intermediate cycle, or ‘zone of emergence,’ because extension of an epizootic into dry savannah areas with larger human and domestic vector populations may establish an urban epidemic cycle that can lead to explosive outbreaks.
      Ae aegypti is the vector for urban YF epidemics in both Africa and South America, and is also the main vector for dengue and Zika virus transmission. It is exquisitely well-adapted for this purpose: Ae aegypti breeds in man-made containers of water, feeds predominantly on human blood and bites multiple individuals in a single blood meal, lives in close association with human dwellings, and efficiently transmits YFV in its saliva.
      The clinical manifestations of YF range from asymptomatic infection to multi-organ failure and death. Most infections are asymptomatic. Most symptomatic cases experience a self-limiting febrile illness associated with myalgia, back pain, and prostration. The fever, which lasts about 4 days, is accompanied by high levels of viraemia, increasing the risk for mosquito infection during a blood meal.
      • Monath T.P.
      Yellow fever: an update.
      Approximately 15–25% of infected individuals enter a ‘period of intoxication’ after a brief remission of fever. This is a multisystem disease dominated by hepato-renal failure, profound jaundice, and a bleeding diathesis. Death occurs in 20–50% of these cases.
      • Monath T.P.
      Yellow fever: an update.
      This is a much higher mortality than dengue, which causes death in 5% of patients, and as low as 1% in settings with experience in dengue management.
      World Health Organization
      Dengue: guidelines for diagnosis, treatment, prevention and control.
      Morbidity in survivors is substantial, with a prolonged convalescent phase characterized by weakness and fatigue.

      3. Epidemiology

      YFV almost certainly originated in Africa.
      • Carrington C.V.
      • Auguste A.J.
      Evolutionary and ecological factors underlying the tempo and distribution of yellow fever virus activity.
      Its initial spread to Central and South America, along with Ae aegypti, was a consequence of the trans-Atlantic slave trade.
      • Cathey J.T.
      • Marr J.S.
      Yellow fever, Asia and the East African slave trade.
      • Bryant J.E.
      • Holmes E.C.
      • Barrett A.D.
      Out of Africa: a molecular perspective on the introduction of yellow fever virus into the Americas.
      • Tabachnick W.J.
      Evolutionary genetics and arthropod-borne disease: the yellow fever mosquito.
      • Rogers D.J.
      • Wilson A.J.
      • Hay S.I.
      • Graham A.J.
      The global distribution of yellow fever and dengue.
      The appalling conditions on slave ships supported an intense and sustained introduction of YFV into the Americas: hundreds of thousands of West Africans were transported together with domesticated Ae aegypti mosquitoes, which presumably set up breeding and transmission cycles during the long voyages,
      • Reiter P.
      Yellow fever and dengue: a threat to Europe.
      delivering a critical mass of viraemic hosts and vectors into a receptive environment. This allowed for the establishment of enzootic YF in the forests surrounding slave ports and its rapid dissemination throughout the continent to become the most important epidemic disease in the region for three centuries.
      • Gubler D.J.
      The changing epidemiology of yellow fever and dengue, 1900 to 2003: full circle?.
      Yellow fever epidemics had significant impact as far north as Philadelphia in the 18th century. The conditions for YF introduction into the Americas are not dissimilar to the current scenario in Angola, where thousands of foreign workers are rapidly transported via air to Asian cities that have dense infestations of Ae aegypti vectors and unvaccinated populations.
      Epidemic YF in the Americas was successfully controlled in the mid 20th century through mass vaccination and vector reduction programmes.
      • Gubler D.J.
      The changing epidemiology of yellow fever and dengue, 1900 to 2003: full circle?.
      • Soper F.L.
      The elimination of urban yellow fever in the Americas through the eradication of Aedes aegypti.
      However, sporadic cases and small, limited outbreaks continue to occur, associated with forest exposure.
      • Gubler D.J.
      Resurgent vector-borne diseases as a global health problem.
      After a major resurgence in the region in the late 20th century,
      • Robertson S.E.
      • Hull B.P.
      • Tomori O.
      • Bele O.
      • LeDuc J.W.
      • Esteves K.
      Yellow fever: a decade of reemergence.
      there now appears to be a downward trend of reported cases.

      Pan American Health Organization. Technical Report: Recommendations for scientific evidence-based yellow fever risk assessment in the Americas. PAHO; 2013. Available at: http://www.paho.org/hq/index.php?option=com_docman&task=doc_download&Itemid=270&gid=30613&lang=en (accessed April 11, 2016).

      Between 1985 and 2012, there were an estimated 4066 reported cases and 2351 deaths from YF (58% case fatality rate) in the Americas. Failure to sustain vector control and vaccination programmes has led to the reinvasion of Ae aegypti across large swaths of the Americas, as evidenced by ongoing chikungunya and Zika outbreaks. If sufficient YF cases occur in cities to facilitate urban transmission, we may yet see YF epidemics again in the Americas.
      In Africa, YF continues to place an enormous burden on communities living in endemic areas. Between 1980 and 2012, 150 yellow fever outbreaks in 26 African countries were reported to the WHO, and over 90% of the estimated 200 000 annual global cases occur on the continent. However, field studies suggest that the actual number of cases may be 10 to 500 times higher.
      • Monath T.P.
      Yellow fever: Victor, Victoria? Conqueror, conquest? Epidemics and research in the last forty years and prospects for the future.
      • Nasidi A.
      • Monath T.P.
      • Vandenberg J.
      • Tomori O.
      • Calisher C.H.
      • Hurtgen X.
      • et al.
      Yellow fever vaccination and pregnancy: a four-year prospective study.
      This is supported by a recent modelling study, which showed that YF may infect up to 1.8 million individuals in Africa annually, resulting in 180 000 (95% confidence interval 51 000–380 000) cases and 78 000 (95% confidence interval 19 000–180 000) deaths;
      • Garske T.
      • Van Kerkhove M.D.
      • Yactayo S.
      • Ronveaux O.
      • Lewis R.F.
      • Staples J.E.
      • et al.
      Yellow fever in Africa: estimating the burden of disease and impact of mass vaccination from outbreak and serological data.
      this accounts for 0.8% of all-cause mortality in endemic regions, and up to 3% in West Africa where most cases occur.
      • Garske T.
      • Van Kerkhove M.D.
      • Yactayo S.
      • Ronveaux O.
      • Lewis R.F.
      • Staples J.E.
      • et al.
      Yellow fever in Africa: estimating the burden of disease and impact of mass vaccination from outbreak and serological data.
      Although complete eradication of YF is not possible due to the sylvatic reservoir, significant progress has been made with the introduction of YF vaccine into routine child immunization programmes.
      • Monath T.P.
      Yellow fever as an endemic/epidemic disease and priorities for vaccination.
      Mass vaccination has led to a 27% reduction in overall annual burden and a 57% reduction in cases in targeted countries.
      • Garske T.
      • Van Kerkhove M.D.
      • Yactayo S.
      • Ronveaux O.
      • Lewis R.F.
      • Staples J.E.
      • et al.
      Yellow fever in Africa: estimating the burden of disease and impact of mass vaccination from outbreak and serological data.
      However, according to WHO and United Nations Children's Emergency Fund (UNICEF) estimates, only 41% of the target population had received YF vaccination in 2014,

      World Health Organization. Global and regional immunization profile: African region. Geneva: WHO; 2015. Available at: http://www.who.int/immunization/monitoring_surveillance/data/gs_afrprofile.pdf?ua=1 (accessed April 12, 2016).

      well below the recommended 80% threshold for the prevention of an epidemic. In Angola, the YF vaccine coverage of 77% in 2014 (dropping to 70% in 2015), has clearly been inadequate to prevent the current outbreak.

      4. Re-emergence of yellow fever in the Americas and Africa: implications for Asia

      In dengue-endemic areas, the basic reproduction numbers (R0) of YF and dengue are closely connected, suggesting that the introduction of a single YF-infected individual has the potential to trigger an urban YF epidemic.
      • Massad E.
      • Coutinho F.A.
      • Burattini M.N.
      • Lopez L.F.
      The risk of yellow fever in a dengue-infested area.
      This has been a concern in South American countries where there has been a reinvasion by Ae aegypti in most large cities.
      • Gubler D.J.
      Resurgent vector-borne diseases as a global health problem.
      • Monath T.P.
      Facing up to re-emergence of urban yellow fever.
      • Barrett A.D.
      • Higgs S.
      Yellow fever: a disease that has yet to be conquered.
      Although the last urban YF outbreak in South America occurred in 1942 in Brazil, further cases of spill-over with documented urban transmission have been reported in Bolivia
      • Van der Stuyft P.
      • Gianella A.
      • Pirard M.
      • Cespedes J.
      • Lora J.
      • Peredo C.
      • et al.
      Urbanisation of yellow fever in Santa Cruz.
      and Paraguay.
      World Health Organization
      Outbreak news. Yellow fever, Paraguay.
      Both of these outbreaks were limited in space and time: in Paraguay, a rapid national response with mass vaccinations and surveillance terminated the outbreak.
      • Johansson M.A.
      • Arana-Vizcarrondo N.
      • Biggerstaff B.J.
      • Gallagher N.
      • Marano N.
      • Staples J.E.
      Assessing the risk of international spread of yellow fever virus: a mathematical analysis of an urban outbreak in Asuncion, 2008.
      A similar situation exists in Africa, where there are regular large epidemics involving partially immune populations living at the forest–urban interface. This occurs mainly in West Africa, but even Kenya has experienced a recent large sylvatic outbreak.
      • Sanders E.J.
      • Marfin A.A.
      • Tukei P.M.
      • Kuria G.
      • Ademba G.
      • Agata N.N.
      • et al.
      First recorded outbreak of yellow fever in Kenya, 1992–1993. I. Epidemiologic investigations.
      During urban epidemics in Africa, the incidence of infection is as high as 20%. Up to 40% of the affected population demonstrate serological evidence of recent YF infection, which may reflect partial immunity from prior vaccination or infection.
      • Tomori O.
      Yellow fever: the recurring plague.
      This incidence highlights the devastating potential of a YF introduction into a completely non-immune population.
      With increasing volumes of air travel, the international spread of emerging and vector-borne infections has become a substantial risk.
      • Johansson M.A.
      • Arana-Vizcarrondo N.
      • Biggerstaff B.J.
      • Gallagher N.
      • Marano N.
      • Staples J.E.
      Assessing the risk of international spread of yellow fever virus: a mathematical analysis of an urban outbreak in Asuncion, 2008.
      This risk is particularly acute in the Asia-Pacific region, where systems for YF surveillance and detection are largely untested, and YF vaccination is limited to travellers.
      • Gubler D.J.
      The changing epidemiology of yellow fever and dengue, 1900 to 2003: full circle?.
      • Gubler D.J.
      Resurgent vector-borne diseases as a global health problem.
      The volume of south-to-south travel – between Asia and South America, or between Asia and Africa – has been less well-documented. This has now become an important consideration, as underscored by the chikungunya and Zika experience. For YF, Africa, with over 90% of global YF cases, is the most likely source for YF importations into Asia. The 10 YF cases reported in China suggests that not all travellers were effectively vaccinated despite Chinese public health regulations. The current confluence of a significant urban YF outbreak in Angola together with a large expatriate Chinese workforce (estimated at 20 000) with suboptimal vaccination levels may provide the ideal ecological conditions for the introduction and urbanization of YFV in China and other Asian countries. These reports of imported cases from Angola in China therefore need to be taken extremely seriously.

      5. Barriers to yellow fever introduction into Asia

      Despite an abundance of people, monkeys, and Ae aegypti throughout tropical and subtropical latitudes, yellow fever virus has not previously been reported in Asia. In contrast, dengue virus has established an urban transmission cycle in large populations in the region, where it is now hyperendemic with major public health and economic impacts. The failure of YF to become established in the Asia-Pacific is unexpected, given the closely shared disease ecology with dengue. The actual epidemiological difference suggests that local factors in the Asia-Pacific have prevented YF from gaining a foothold in the region, and may provide some reassurance that there are sufficient barriers to prevent the establishment of YF in the Asia-Pacific.
      Urban outbreaks of YF are much less common in East Africa, and are associated with enzootic YFV genotypes transmitted by sylvatic mosquito vectors, rather than Ae aegypti.
      • Mutebi J.P.
      • Barrett A.D.
      The epidemiology of yellow fever in Africa.
      This suggests that the East African Ae aegypti mosquitoes are less favourable vectors for human disease and may therefore have limited adaptation to human environments, reducing the possibilities for survival during the long trade crossings by boat to Asia historically.
      • Powell J.R.
      • Tabachnick W.J.
      History of domestication and spread of Aedes aegypti—a review.
      Phylogenetic data suggest that Ae aegypti may eventually have reached Asia from the West, and not via the East African trade route, and Asia thus probably became infested with Ae aegypti later than the Americas.
      • Mutebi J.P.
      • Barrett A.D.
      The epidemiology of yellow fever in Africa.
      • Powell J.R.
      • Tabachnick W.J.
      History of domestication and spread of Aedes aegypti—a review.
      Additionally, there is some evidence of geographical variation in Ae aegypti susceptibility to YF,
      • Beaty B.
      • Aitken T.
      In vitro transmission of yellow fever virus by geographic strains of Aedes aegypti.
      raising the possibility that Asian strains may be less competent YF vectors.
      • Carrington C.V.
      • Auguste A.J.
      Evolutionary and ecological factors underlying the tempo and distribution of yellow fever virus activity.
      • Barrett A.D.
      • Higgs S.
      Yellow fever: a disease that has yet to be conquered.
      Notwithstanding the above limitations, there may have been importations of YF into Asia after its widespread infestation with Ae aegypti, potentially during the large African epidemics in Sudan,
      • Mahaffy A.
      • Hughes T.
      • Smithburn K.
      • Kirk R.
      The isolation of yellow fever virus in the Anglo-Egyptian Sudan.
      Ethiopia,
      • Serie C.
      • Andral L.
      • Poirier A.
      • Lindrec A.
      • Neri P.
      [Studies on yellow fever in Ethiopia. 6. Epidemiologic study].
      and Kenya.
      • Sanders E.J.
      • Marfin A.A.
      • Tukei P.M.
      • Kuria G.
      • Ademba G.
      • Agata N.N.
      • et al.
      First recorded outbreak of yellow fever in Kenya, 1992–1993. I. Epidemiologic investigations.
      But, these would have involved few cases from isolated rural and remote regions amongst populations unlikely to travel by commercial airlines, and thus had a low potential for sustained or transcontinental transmission.
      • Monath T.P.
      Yellow fever: an update.
      • Carrington C.V.
      • Auguste A.J.
      Evolutionary and ecological factors underlying the tempo and distribution of yellow fever virus activity.
      • Barrett A.D.
      • Higgs S.
      Yellow fever: a disease that has yet to be conquered.
      • Gubler D.J.
      The global emergence/resurgence of arboviral diseases as public health problems.
      Together with delayed historical introduction, this low risk of importation of viraemic YF individuals to Asia has been the dominant explanation for the absence of the disease in the region. However, it is less compelling in the contemporary context of a large outbreak in a major urban centre such as Luanda with direct flight connections to Aedes-infested cities in Asia.
      The delayed and limited introduction of YF into Asia may have left open an ecological niche for the establishment and dominance of dengue and other flaviviruses in the region through the native Aedes albopictus, and later the well-adapted Ae aegypti mosquito. This may have impacted on the ecology of YF in Asia in two key ways. First, dengue virus may out-compete YFV within Ae aegypti,
      • Gubler D.J.
      The global emergence/resurgence of arboviral diseases as public health problems.
      either preventing co-infection or reducing infectiousness by induction of a latently infected state.
      • Abrão E.
      • Fonseca B.
      Yellow fever virus interferes with dengue-2 replication and might prevent reurbanization of yellow fever. XVII National Meeting of Virology, Campos do Jordão, SP.

      Abrão E, Fonseca B. Viral interference among flaviviruses: the case of dengue-2 and yellow fever viruses. 26th Annual Meeting of The American Society for Virology; 2007, p. 273.

      Second, the high population seroprevalence of dengue and JE in Asia may provide cross-protective immunity and act as a barrier to the establishment of YF.
      • Monath T.P.
      Yellow fever: an update.
      In strong support of this hypothesis, experimental animals with previous heterologous flavivirus exposure experience lower levels of viraemia and less severe disease when challenged with YFV.
      • Theiler M.
      • Anderson C.R.
      The relative resistance of dengue-immune monkeys to yellow fever virus.
      • Xiao S.Y.
      • Guzman H.
      • da Rosa A.P.
      • Zhu H.B.
      • Tesh R.B.
      Alteration of clinical outcome and histopathology of yellow fever virus infection in a hamster model by previous infection with heterologous flaviviruses.
      Thus, although the presence of heterotypic flavivirus antibody does not lower the risk of infection, dengue-immune individuals who become infected with YF may be less likely to transmit YF to mosquitoes. Using a mathematical transmission model, Amaku and colleagues showed that YF prevalence is strongly affected by cross-immunity, and that this best accounted for the absence of YF in Asia compared with other competing hypotheses.
      • Amaku M.
      • Coutinho F.A.
      • Massad E.
      Why dengue and yellow fever coexist in some areas of the world and not in others?.
      This raises the possibility that areas that are endemic but not hyperendemic for dengue, such as southern China or Hong Kong and Singapore, may be vulnerable to YF outbreaks, as the level of dengue and JE immunity in the population may not be as complete as in other parts of Southeast Asia. However, these findings do not explain the presence of both dengue and urban YF in Africa, suggesting that additional factors may have a role in the failure of YF to become a dominant flavivirus in Asia.
      These other factors may relate to the YFV itself and its transmission dynamics. YF has lower peak viral loads compared to dengue,
      • Monath T.P.
      Facing up to re-emergence of urban yellow fever.
      limiting its transmission potential in dengue-endemic environments. And unlike dengue, YF has maintained is sylvatic character. Urban transmission is thus always initiated by spill-over from the jungle or savannah,
      • Barrett A.D.
      • Higgs S.
      Yellow fever: a disease that has yet to be conquered.
      and consequently may have a lower risk of occurring in urban centres in Asia. The higher mortality of YF may further limit its introduction and persistence in an urban cycle and allow dengue to dominate in Asia.
      A virological explanation for the lower frequency of YF outbreaks in East Africa, and its absence in Asia, may be the observed regional differences in YF viral genotypes,
      • Mutebi J.P.
      • Wang H.
      • Li L.
      • Bryant J.E.
      • Barrett A.D.
      Phylogenetic and evolutionary relationships among yellow fever virus isolates in Africa.
      which potentially influence virulence phenotypes in humans and non-human primates.
      • Tomori O.
      Yellow fever: the recurring plague.
      • Mutebi J.P.
      • Barrett A.D.
      The epidemiology of yellow fever in Africa.
      The genetic differences between geographic strains of Ae aegypti influence its competence as a YF vector,
      • Black W.C.
      • Bennett K.E.
      • Gorrochotegui-Escalante N.
      • Barillas-Mury C.V.
      • Fernandez-Salas I.
      • de Lourdes Munoz M.
      • et al.
      Flavivirus susceptibility in Aedes aegypti.
      and it has been suggested that this also contributes to a lower YF transmission risk in Asia.
      • Carrington C.V.
      • Auguste A.J.
      Evolutionary and ecological factors underlying the tempo and distribution of yellow fever virus activity.
      • Gubler D.J.
      The changing epidemiology of yellow fever and dengue, 1900 to 2003: full circle?.
      • Barrett A.D.
      • Higgs S.
      Yellow fever: a disease that has yet to be conquered.
      Finally, although it is possible that humans and non-human primates in Asia have a lower genetic susceptibility to YF, this has never been demonstrated.

      6. Factors conducive to yellow fever entry into Asia

      In the face of the above limitations, there is a modern precedent for large-scale introduction of other Aedes-borne viral infections into receptive populations. In 2004, a Kenyan outbreak of the alphavirus chikungunya (CHIKV) spread via the India Ocean basin to India and Southeast Asia, leading to an explosive epidemic involving millions of people from populations with historical CHIKV exposure.
      • Burt F.J.
      • Rolph M.S.
      • Rulli N.E.
      • Mahalingam S.
      • Heise M.T.
      Chikungunya: a re-emerging virus.
      The same epidemic strain, which is spread by Ae aegypti,
      • Arankalle V.A.
      • Shrivastava S.
      • Cherian S.
      • Gunjikar R.S.
      • Walimbe A.M.
      • Jadhav S.M.
      • et al.
      Genetic divergence of chikungunya viruses in India (1963–2006) with special reference to the 2005–2006 explosive epidemic.
      is causing an ongoing chikungunya epidemic in the Americas, and has already led to 39 000 infections this year. The WHO has recently declared a Public Health Emergency of International Concern in response to the Zika virus (ZIKV) outbreak in the same region. Like YFV, ZIKV is a flavivirus that originated in Africa and is mainly transmitted by Ae aegypti. It entered South America via the Pacific in 2014, and has rapidly spread to infect over a million people, with autochthonous cases reported from 26 countries
      • Petersen L.R.
      • Jamieson D.J.
      • Powers A.M.
      • Honein M.A.
      Zika virus.
      • Petersen E.
      • Wilson M.E.
      • Touch S.
      • McCloskey B.
      • Mwaba P.
      • Bates M.
      • et al.
      Rapid spread of Zika virus in the Americas—implications for public health preparedness for mass gatherings at the 2016 Brazil Olympic Games.
      by early April 2016. The Zika and chikungunya epidemics provide powerful counterpoints to the most important putative limitations for YF introduction into Asia, namely that a shared vector and prior population exposure do not necessarily constrain the entry of a new arbovirus into dengue-endemic regions.
      In the particular case of YF there are a number of other contemporary factors that, when taken together, represent the ideal conditions for an Asian epidemic. These are summarized in Table 1. First, and perhaps the most critical, is the volume of travellers entering the region on commercial airlines. This allows for the introduction of symptomatic individuals during the period of maximal viraemia, as well as those incubating the virus or asymptomatically infected, raising the potential for transmission to mosquito vectors. The Asia-Pacific region will represent the largest regional market for air transport in 2016,

      IATA press release: Airlines to welcome 3.6 billion passengers in 2016. IATA; 2012. Available at: http://www.iata.org/pressroom/pr/pages/2012-12-06-01.aspx (accessed April 15, 2016).

      accounting for a third of global passengers. Even a limited YF outbreak in China could therefore rapidly disseminate to the higher risk regions of India or Southeast Asia though air travel. Second, the ongoing importation of YF-infected individuals into China in April 2016 is nearing the peak period of dengue transmission, starting in July.
      • Lai S.
      • Huang Z.
      • Zhou H.
      • Anders K.L.
      • Perkins T.A.
      • Yin W.
      • et al.
      The changing epidemiology of dengue in China, 1990–2014: a descriptive analysis of 25 years of nationwide surveillance data.
      The very high vector densities during this time may overcome other barriers to YF urbanization, including the theoretical possibility that Asian strains of Ae aegypti are less competent than their African counterparts.
      • Miller B.R.
      • Monath T.P.
      • Tabachnick W.J.
      • Ezike V.I.
      Epidemic yellow fever caused by an incompetent mosquito vector.
      Third, there appears to be low effective vaccination coverage of Chinese workers in Angola. The risk of illness for an unimmunized person spending 2 weeks in an area of epidemic activity has been estimated at one in 267,
      • Monath T.P.
      • Cetron M.S.
      Prevention of yellow fever in persons traveling to the tropics.
      translating into a substantial number of potential cases amongst returning workers, with the consequence of sustained regional YF exposure. Finally, there is a strong possibility that widespread epidemic transmission could occur in Asia before it is recognized.
      • Gubler D.J.
      Resurgent vector-borne diseases as a global health problem.
      This is related to the difficulty in YF diagnosis due to serological cross-reactivity with prevalent flaviviruses such as dengue and JE, and a similar clinical presentation to other endemic diseases such leptospirosis, typhoid fever, rickettsiosis, malaria, and viral hepatitis.
      Table 1Factors supporting the introduction of yellow fever into Asia
      Risk factorComments
      Favourable local ecologyAbundance of the primary mosquito vector, high human population density, and forested areas with monkey hosts. This will support both an enzootic cycle and urban transmission.
      Large numbers of returning travellers from an active outbreak in AngolaThere are an estimated 20 000 Chinese workers in Angola, plus many from other Asian countries, including India. This could support sustained, high volume YF introduction into Asia.
      High volumes of passenger air travel between an active epidemic and China, and with other Asian countriesAir travel allows the introduction into China of viraemic cases or of people incubating YF, and facilitates subsequent dissemination within Asia.
      Possibly low vaccine coverage of Chinese workersUnimmunized travellers increase the risk of infection and subsequent importation.
      Importation of cases during Aedes aegypti breeding season, starting JulyThis will coincide with peak vector densities, increasing the risk for local transmission.
      YF cases imported into dengue-endemic areasSix cases have been reported from Fujian Province, where the local transmission of dengue occurs with high Aedes aegypti concentrations.
      Difficulty in recognition of imported casesOverlapping clinical presentation with other endemic infections and cross-reactivity of YF serology with other endemic flaviviruses may delay the recognition of an incipient epidemic.
      Inadequate vaccine stocksThe current vaccine supply would not support a full outbreak response in Asia.
      Poor surveillance structuresAsian laboratories are not geared for YF detection, airport screening is not sufficiently sensitive for passive surveillance (misses cases in the incubation period, fever masked by antipyretics), and there are limited numbers of travel medicine experts.
      • Kraemer M.U.
      • Sinka M.E.
      • Duda K.A.
      • Mylne A.Q.
      • Shearer F.M.
      • Barker C.M.
      • et al.
      The global distribution of the arbovirus vectors Aedes aegypti and Ae.
      YF, yellow fever.
      Using the successful introduction and threats of re-emergence of YF in South America as a historical model, there appear to be four main conditions that need to be fulfilled to support YF introduction into a new population: (1) sufficient migratory flow of viraemic individuals from YF-endemic/epidemic areas (i.e., intense and sustained introduction), (2) a high density of competent vectors in receptive ecological conditions, (3) a susceptible or partially susceptible human and monkey population, and (4) inadequate surveillance with delayed recognition leading to ineffective vaccination programmes. Current conditions in many parts of Asia therefore appear to be favourable for the introduction of YF and the establishment of a transmission cycle in the region
      • Rogers D.J.
      • Wilson A.J.
      • Hay S.I.
      • Graham A.J.
      The global distribution of yellow fever and dengue.
      (Figure 1). In this context, the occurrence of YF cases from the Angolan outbreak imported to China creates a situation primed for an Asian epidemic, and demands an adequate response.
      Figure thumbnail gr1
      Figure 1Map showing the distribution of Ae aegypti across Africa and the Asia-Pacific region
      • Jentes E.S.
      • Poumerol G.
      • Gershman M.D.
      • Hill D.R.
      • Lemarchand J.
      • Lewis R.F.
      • et al.
      The revised global yellow fever risk map and recommendations for vaccination, 2010: consensus of the Informal WHO Working Gr oup on Geographic Risk for Yellow Fever.
      (areas shaded pink). The red outline delineates yellow fever-endemic regions.

      HealthMap. Available at: http://www.healthmap.org/promed/ (accessed April 27, 2016).

      Yellow dots represent the location of yellow fever cases related to the Angolan outbreak (source: HealthMap).

      FLIRT. Available at: http://flirt.eha.io/ (accessed April 27, 2016).

      Commercial flight routes with direct connections between Luanda and Beijing and indirect connections from Luanda to South and Southeast Asia via Dubai (source: FLIRT)
      World Health Organization
      Risk assessment on yellow fever virus circulation in endemic countries: working document from an informal consultation of experts: a protocol risk assessment at the field level.
      are also represented.

      7. Responses to prevent yellow fever introduction into Asia

      Actions in Central and South America in the early 20th century demonstrated that urban YF epidemics can be successfully prevented and controlled. As with other arboviruses, the tenets underlying YF prevention are surveillance, vaccination, and vector control. This should be coupled with the development of systems that can support a rapid outbreak response. These include strengthening laboratory capacity, the ability to carry out epidemiological and entomological investigations, and emergency measures to interrupt transmission, such as mass vaccination, destruction of urban mosquito breeding sites, education about mosquito avoidance, use of ovitraps, and domiciliary residual spraying.
      • Bres P.L.
      A century of progress in combating yellow fever.
      • Tomori O.
      Yellow fever in Africa: public health impact and prospects for control in the 21st century.
      • Morrison A.C.
      • Zielinski-Gutierrez E.
      • Scott T.W.
      • Rosenberg R.
      Defining challenges and proposing solutions for control of the virus vector Aedes aegypti.
      World Health Organization
      International Health Regulations 2005.
      The extent and nature of Ae aegypti infestation in Asia prohibits the use of vector elimination as a feasible short-term intervention for outbreak prevention,
      World Health Organization
      International Health Regulations 2005.
      and so the urgent focus needs to be on coordinated programmes of surveillance and vaccination of travellers. Unfortunately, the high proportion of asymptomatic infections and the non-specific nature of the mild clinical disease limit the usefulness of passive surveillance to detect YF introduction into a new population. In the event of an outbreak in Asia, even active case finding will be challenging in the context of overlapping clinical presentation with other endemic infections and the limitations in diagnostic tests described above. To mitigate these limitations, governments could consider enforcing a 7-day quarantine for returning travellers from endemic countries without YF vaccination certificates. Most countries in the Asia-Pacific require proof of YF vaccination for travellers arriving from countries with a risk of YF transmission,
      • Martins R.M.
      • Maia Mde L.
      • Farias R.H.
      • Camacho L.A.
      • Freire M.S.
      • Galler R.
      • et al.
      17DD yellow fever vaccine: a double blind, randomized clinical trial of immunogenicity and safety on a dose-response study.
      and this clearly needs to be more strictly enforced after the importation of YF-infected travellers to China. In response to this, the WHO has recommended the reinforcement of vaccination requirements in China, and the Chinese government has deployed teams to Angola to provide vaccination to its citizens there. However, there is a delay of 10 days until the development of protective immunity after vaccination, and surveillance for imported cases in Asia should be ongoing. Unofficial disease reporting systems, such as ProMED, are becoming increasingly useful for the early detection and communication of new cases in emerging outbreaks, and have an important role in raising situational awareness.
      The most powerful tool in YF control is vaccination. Mass vaccination campaigns are extremely effective at reducing the YF burden in populations with low immunity, both in the prevention of enzootic spill-over and in the rapid control of urban epidemics.
      • Gubler D.J.
      The changing epidemiology of yellow fever and dengue, 1900 to 2003: full circle?.
      • Robertson S.E.
      • Hull B.P.
      • Tomori O.
      • Bele O.
      • LeDuc J.W.
      • Esteves K.
      Yellow fever: a decade of reemergence.
      • Garske T.
      • Van Kerkhove M.D.
      • Yactayo S.
      • Ronveaux O.
      • Lewis R.F.
      • Staples J.E.
      • et al.
      Yellow fever in Africa: estimating the burden of disease and impact of mass vaccination from outbreak and serological data.
      As of April 10, the Angolan government, together with international partners, had administered 5.9 million doses of YF vaccine in the Luanda province (accounting for 90% of the city's population); preparations for mass vaccination in Huambo and Benguela provinces are underway. However, the global emergency YF vaccine stockpile is depleted, and there is currently not enough vaccine to cover Angola's population. The production of new vaccine using the current method of embryonated chicken eggs is slow and limits capabilities to rapidly produce large vaccine quantities in response to an outbreak. It is therefore highly unlikely that sufficient YF doses would be available for an effective emergency YF outbreak response in Asia, further emphasizing the vulnerability of the situation. Much lower doses of YF vaccine are likely to be as effective as the currently used full-dose vaccine,
      • Monath T.P.
      • Woodall J.P.
      • Gubler D.J.
      • Yuill T.M.
      • Mackenzie J.S.
      • Martins R.M.
      • et al.
      Yellow fever vaccine supply: a possible solution.
      and it has been suggested that a fifth of the current dose should be administered to expand vaccine stockpiles in the context of the global threat posed by the current outbreak.
      • Lim P.L.
      Schistosoma haematobium in China, ex-Africa: new populations at risk?.
      This should be considered seriously and implemented as a matter of urgency.

      8. Conclusions

      There is no single factor that accounts for the absence of YF in Asia, and it is likely that a complex combination of virological, environmental, and social processes have shaped the current global epidemiology of YF restricting the disease to Africa and the Americas. The current scenario of a YF outbreak in Angola, where there is a large community of non-immune foreign nationals, coupled with high volumes of air travel to an environment conducive to transmission in Asia, is unprecedented in history. These conditions raise the alarming possibility of a YF epidemic, with a case fatality of up to 50%, in a region with a susceptible population of two billion people and where there is extremely limited infrastructure to respond effectively. The growing number of imported cases in China shows how critical it is to recognize this risk now in order to take adequate pre-emptive action so that a global catastrophe can be averted.
      Funding: None.
      Conflict of interest: None.

      References

      1. ProMED. Yellow fever—Africa (02): Angola (Luanda) request for information: International Society for Infectious Diseases. ProMED-mail; 2016. Available at: http://www.promedmail.org/post/3958601 (accessed April 11, 2016).

      2. ProMED. Yellow fever—Africa (05): Angola (Huila): International Society for Infectious Diseases. ProMED-mail; 2016. Available at: http://www.promedmail.org/post/3977685 (accessed April 11, 2016).

      3. World Health Organization. Yellow fever—Democratic Republic of the Congo, 11 April 2016. Geneva: WHO; 2016. Available at: http://www.who.int/csr/don/11-april-2016-yellow-fever-drc/en/ (accessed April 20, 2016).

      4. World Health Organization. Yellow Fever—Kenya, 6 April 2016. Geneva: WHO; 2016. Available at: http://www.who.int/csr/don/6-april-2016-yellow-fever-kenya/en/ (accessed April 20, 2016).

        • Lai S.
        • Huang Z.
        • Zhou H.
        • Anders K.L.
        • Perkins T.A.
        • Yin W.
        • et al.
        The changing epidemiology of dengue in China, 1990–2014: a descriptive analysis of 25 years of nationwide surveillance data.
        BMC Med. 2015; 13: 100https://doi.org/10.1186/s12916-015-0336-1
        • Monath T.P.
        Yellow fever: an update.
        Lancet Infect Dis. 2001; 1: 11-20https://doi.org/10.1016/s1473-3099(01)00016-0
        • World Health Organization
        Dengue: guidelines for diagnosis, treatment, prevention and control.
        World Health Organization, Geneva2009
        • Carrington C.V.
        • Auguste A.J.
        Evolutionary and ecological factors underlying the tempo and distribution of yellow fever virus activity.
        Infect Genet Evol. 2013; 13: 198-210https://doi.org/10.1016/j.meegid.2012.08.015
        • Cathey J.T.
        • Marr J.S.
        Yellow fever, Asia and the East African slave trade.
        Trans R Soc Trop Med Hyg. 2014; 108: 252-257https://doi.org/10.1093/trstmh/tru043
        • Bryant J.E.
        • Holmes E.C.
        • Barrett A.D.
        Out of Africa: a molecular perspective on the introduction of yellow fever virus into the Americas.
        PLoS Pathog. 2007; 3: e75https://doi.org/10.1371/journal.ppat.0030075
        • Tabachnick W.J.
        Evolutionary genetics and arthropod-borne disease: the yellow fever mosquito.
        American Entomologist. 1991; 37: 14-26
        • Rogers D.J.
        • Wilson A.J.
        • Hay S.I.
        • Graham A.J.
        The global distribution of yellow fever and dengue.
        Adv Parasitol. 2006; 62: 181-220https://doi.org/10.1016/s0065-308x(05)62006-4
        • Reiter P.
        Yellow fever and dengue: a threat to Europe.
        Euro Surveill. 2010; 15: 19509
        • Gubler D.J.
        The changing epidemiology of yellow fever and dengue, 1900 to 2003: full circle?.
        Comp Immunol Microbiol Infect Dis. 2004; 27: 319-330https://doi.org/10.1016/j.cimid.2004.03.013
        • Soper F.L.
        The elimination of urban yellow fever in the Americas through the eradication of Aedes aegypti.
        Am J Public Health Nations Health. 1963; 53: 7-16
        • Gubler D.J.
        Resurgent vector-borne diseases as a global health problem.
        Emerg Infect Dis. 1998; 4: 442-450https://doi.org/10.3201/eid0403.980326
        • Robertson S.E.
        • Hull B.P.
        • Tomori O.
        • Bele O.
        • LeDuc J.W.
        • Esteves K.
        Yellow fever: a decade of reemergence.
        JAMA. 1996; 276: 1157-1162
      5. Pan American Health Organization. Technical Report: Recommendations for scientific evidence-based yellow fever risk assessment in the Americas. PAHO; 2013. Available at: http://www.paho.org/hq/index.php?option=com_docman&task=doc_download&Itemid=270&gid=30613&lang=en (accessed April 11, 2016).

        • Monath T.P.
        Yellow fever: Victor, Victoria? Conqueror, conquest? Epidemics and research in the last forty years and prospects for the future.
        Am J Trop Med Hyg. 1991; 45: 1-43
        • Nasidi A.
        • Monath T.P.
        • Vandenberg J.
        • Tomori O.
        • Calisher C.H.
        • Hurtgen X.
        • et al.
        Yellow fever vaccination and pregnancy: a four-year prospective study.
        Trans R Soc Trop Med Hyg. 1993; 87: 337-339
        • Garske T.
        • Van Kerkhove M.D.
        • Yactayo S.
        • Ronveaux O.
        • Lewis R.F.
        • Staples J.E.
        • et al.
        Yellow fever in Africa: estimating the burden of disease and impact of mass vaccination from outbreak and serological data.
        PLoS Med. 2014; 11: e1001638https://doi.org/10.1371/journal.pmed.1001638
        • Monath T.P.
        Yellow fever as an endemic/epidemic disease and priorities for vaccination.
        Bull Soc Pathol Exot. 2006; 99: 341-347
      6. World Health Organization. Global and regional immunization profile: African region. Geneva: WHO; 2015. Available at: http://www.who.int/immunization/monitoring_surveillance/data/gs_afrprofile.pdf?ua=1 (accessed April 12, 2016).

        • Massad E.
        • Coutinho F.A.
        • Burattini M.N.
        • Lopez L.F.
        The risk of yellow fever in a dengue-infested area.
        Trans R Soc Trop Med Hyg. 2001; 95: 370-374
        • Monath T.P.
        Facing up to re-emergence of urban yellow fever.
        Lancet. 1999; 353: 1541https://doi.org/10.1016/s0140-6736(99)00155-5
        • Barrett A.D.
        • Higgs S.
        Yellow fever: a disease that has yet to be conquered.
        Ann Rev Entomol. 2007; 52: 209-229https://doi.org/10.1146/annurev.ento.52.110405.091454
        • Van der Stuyft P.
        • Gianella A.
        • Pirard M.
        • Cespedes J.
        • Lora J.
        • Peredo C.
        • et al.
        Urbanisation of yellow fever in Santa Cruz.
        Bolivia. Lancet. 1999; 353: 1558-1562
        • World Health Organization
        Outbreak news. Yellow fever, Paraguay.
        Wkly Epidemiol Rec. 2008; 83: 105
        • Johansson M.A.
        • Arana-Vizcarrondo N.
        • Biggerstaff B.J.
        • Gallagher N.
        • Marano N.
        • Staples J.E.
        Assessing the risk of international spread of yellow fever virus: a mathematical analysis of an urban outbreak in Asuncion, 2008.
        Am J Trop Med Hyg. 2012; 86: 349-358https://doi.org/10.4269/ajtmh.2012.11-0432
        • Sanders E.J.
        • Marfin A.A.
        • Tukei P.M.
        • Kuria G.
        • Ademba G.
        • Agata N.N.
        • et al.
        First recorded outbreak of yellow fever in Kenya, 1992–1993. I. Epidemiologic investigations.
        Am J Trop Med Hyg. 1998; 59: 644-649
        • Tomori O.
        Yellow fever: the recurring plague.
        Crit Rev Clin Lab Sci. 2004; 41: 391-427https://doi.org/10.1080/10408360490497474
        • Mutebi J.P.
        • Barrett A.D.
        The epidemiology of yellow fever in Africa.
        Microbes Infect. 2002; 4: 1459-1468
        • Powell J.R.
        • Tabachnick W.J.
        History of domestication and spread of Aedes aegypti—a review.
        Mem Inst Oswaldo Cruz. 2013; 108 Suppl 1: 11-17https://doi.org/10.1590/0074-0276130395
        • Beaty B.
        • Aitken T.
        In vitro transmission of yellow fever virus by geographic strains of Aedes aegypti.
        Mosquito News. 1979; 39: 232-238
        • Mahaffy A.
        • Hughes T.
        • Smithburn K.
        • Kirk R.
        The isolation of yellow fever virus in the Anglo-Egyptian Sudan.
        Ann Trop Med Parasit. 1941; 35: 141-148
        • Serie C.
        • Andral L.
        • Poirier A.
        • Lindrec A.
        • Neri P.
        [Studies on yellow fever in Ethiopia. 6. Epidemiologic study].
        Bull World Health Organ. 1968; 38: 879-884
        • Gubler D.J.
        The global emergence/resurgence of arboviral diseases as public health problems.
        Arch Med Res. 2002; 33: 330-342
        • Abrão E.
        • Fonseca B.
        Yellow fever virus interferes with dengue-2 replication and might prevent reurbanization of yellow fever. XVII National Meeting of Virology, Campos do Jordão, SP.
        Virus Rev Res. 2006; 2006: 130-131
      7. Abrão E, Fonseca B. Viral interference among flaviviruses: the case of dengue-2 and yellow fever viruses. 26th Annual Meeting of The American Society for Virology; 2007, p. 273.

        • Theiler M.
        • Anderson C.R.
        The relative resistance of dengue-immune monkeys to yellow fever virus.
        Am J Trop Med Hyg. 1975; 24: 115-117
        • Xiao S.Y.
        • Guzman H.
        • da Rosa A.P.
        • Zhu H.B.
        • Tesh R.B.
        Alteration of clinical outcome and histopathology of yellow fever virus infection in a hamster model by previous infection with heterologous flaviviruses.
        Am J Trop Med Hyg. 2003; 68: 695-703
        • Amaku M.
        • Coutinho F.A.
        • Massad E.
        Why dengue and yellow fever coexist in some areas of the world and not in others?.
        Bio Systems. 2011; 106: 111-120https://doi.org/10.1016/j.biosystems.2011.07.004
        • Mutebi J.P.
        • Wang H.
        • Li L.
        • Bryant J.E.
        • Barrett A.D.
        Phylogenetic and evolutionary relationships among yellow fever virus isolates in Africa.
        J Virol. 2001; 75: 6999-7008https://doi.org/10.1128/jvi.75.15.6999-7008.2001
        • Black W.C.
        • Bennett K.E.
        • Gorrochotegui-Escalante N.
        • Barillas-Mury C.V.
        • Fernandez-Salas I.
        • de Lourdes Munoz M.
        • et al.
        Flavivirus susceptibility in Aedes aegypti.
        Arch Med Res. 2002; 33: 379-388
        • Burt F.J.
        • Rolph M.S.
        • Rulli N.E.
        • Mahalingam S.
        • Heise M.T.
        Chikungunya: a re-emerging virus.
        Lancet. 2012; 379: 662-671https://doi.org/10.1016/s0140-6736(11)60281-x
        • Arankalle V.A.
        • Shrivastava S.
        • Cherian S.
        • Gunjikar R.S.
        • Walimbe A.M.
        • Jadhav S.M.
        • et al.
        Genetic divergence of chikungunya viruses in India (1963–2006) with special reference to the 2005–2006 explosive epidemic.
        J Gen Virol. 2007; 88: 1967-1976https://doi.org/10.1099/vir.0.82714-0
        • Petersen L.R.
        • Jamieson D.J.
        • Powers A.M.
        • Honein M.A.
        Zika virus.
        N Engl J Med. 2016; 374: 1552-1563https://doi.org/10.1056/NEJMra1602113
        • Petersen E.
        • Wilson M.E.
        • Touch S.
        • McCloskey B.
        • Mwaba P.
        • Bates M.
        • et al.
        Rapid spread of Zika virus in the Americas—implications for public health preparedness for mass gatherings at the 2016 Brazil Olympic Games.
        Int J Infect Dis. 2016; 44: 11-15https://doi.org/10.1016/j.ijid.2016.02.001
      8. IATA press release: Airlines to welcome 3.6 billion passengers in 2016. IATA; 2012. Available at: http://www.iata.org/pressroom/pr/pages/2012-12-06-01.aspx (accessed April 15, 2016).

        • Miller B.R.
        • Monath T.P.
        • Tabachnick W.J.
        • Ezike V.I.
        Epidemic yellow fever caused by an incompetent mosquito vector.
        Trop Med Parasitol. 1989; 40: 396-399
        • Monath T.P.
        • Cetron M.S.
        Prevention of yellow fever in persons traveling to the tropics.
        Clin Infect Dis. 2002; 34: 1369-1378https://doi.org/10.1086/340104
        • Kraemer M.U.
        • Sinka M.E.
        • Duda K.A.
        • Mylne A.Q.
        • Shearer F.M.
        • Barker C.M.
        • et al.
        The global distribution of the arbovirus vectors Aedes aegypti and Ae.
        albopictus. eLife. 2015; 4: e08347https://doi.org/10.7554/eLife.08347
        • Jentes E.S.
        • Poumerol G.
        • Gershman M.D.
        • Hill D.R.
        • Lemarchand J.
        • Lewis R.F.
        • et al.
        The revised global yellow fever risk map and recommendations for vaccination, 2010: consensus of the Informal WHO Working Gr oup on Geographic Risk for Yellow Fever.
        Lancet Infect Dis. 2011; 11: 622-632https://doi.org/10.1016/s1473-3099(11)70147-5
      9. HealthMap. Available at: http://www.healthmap.org/promed/ (accessed April 27, 2016).

      10. FLIRT. Available at: http://flirt.eha.io/ (accessed April 27, 2016).

        • World Health Organization
        Risk assessment on yellow fever virus circulation in endemic countries: working document from an informal consultation of experts: a protocol risk assessment at the field level.
        WHO, Geneva2014
        • Bres P.L.
        A century of progress in combating yellow fever.
        Bull World Health Organ. 1986; 64: 775-786
        • Tomori O.
        Yellow fever in Africa: public health impact and prospects for control in the 21st century.
        Biomedica. 2002; 22: 178-210
        • Morrison A.C.
        • Zielinski-Gutierrez E.
        • Scott T.W.
        • Rosenberg R.
        Defining challenges and proposing solutions for control of the virus vector Aedes aegypti.
        PLoS Med. 2008; 5: e68https://doi.org/10.1371/journal.pmed.0050068
        • World Health Organization
        International Health Regulations 2005.
        WHO, Geneva2008
        • Martins R.M.
        • Maia Mde L.
        • Farias R.H.
        • Camacho L.A.
        • Freire M.S.
        • Galler R.
        • et al.
        17DD yellow fever vaccine: a double blind, randomized clinical trial of immunogenicity and safety on a dose-response study.
        Hum Vaccin Immunother. 2013; 9: 879-888https://doi.org/10.4161/hv.22982
        • Monath T.P.
        • Woodall J.P.
        • Gubler D.J.
        • Yuill T.M.
        • Mackenzie J.S.
        • Martins R.M.
        • et al.
        Yellow fever vaccine supply: a possible solution.
        Lancet. 2016; 387: 1599-1600https://doi.org/10.1016/S0140-6736(16)30195-7
        • Lim P.L.
        Schistosoma haematobium in China, ex-Africa: new populations at risk?.
        J Travel Med. 2013; 20: 211-213https://doi.org/10.1111/jtm.12031

      Linked Article

      • Why is the yellow fever outbreak in Angola a ‘threat to the entire world’?
        International Journal of Infectious DiseasesVol. 48
        • Preview
          The short answer to the World Health Organization (WHO) declaration is because yellow fever has spread throughout the country, causing probably thousands of cases and hundreds of deaths, and the world has run out of vaccine. This is very bad because cases so far have been imported into the Democratic Republic of the Congo (DRC), Mauritania, Kenya, and even China, the first time in history that cases have been confirmed in Asia. In fact, more travelers infected with yellow fever have now been seen than in the last 50 years, each one with the potential to spread it on arrival, and still further to more countries worldwide via international airlines.
        • Full-Text
        • PDF
        Open Access