**8. Compounding factors for emergence and resurgence of YF**

YF has been subjected to partial control for decades, but there are signs that case numbers are now increasing globally, with the risk of local epidemic outbreaks [33]. The agent of YF, yellow fever virus, can cause devastating epidemics of potentially fatal, hemorrhagic dis‐ ease. We rely on mass vaccination campaigns to prevent and control these outbreaks. How‐ ever, the risk of major YF epidemics, especially in densely populated, poor urban settings, both in Africa and South America, has greatly increased due to: (1) reinvasion of urban set‐ tings by the mosquito vector of YF, *Ae. aegypti*; (2) rapid urbanization, particularly in parts of Africa, with populations shifting from rural to predominantly urban; and (3) waning immu‐ nization coverage. Consequently, YF is considered an emerging, or reemerging disease of considerable importance [22].


**8.2. Climate change**

transmission period.

**8.3. Globalization**

**8.4. International travel and trade**

disease mainly of port cities [35].

**8.5. Rural-urban migration**

average global temperatures will have risen by 1.0-3.5o

would increase the speed of epidemic spread [39].

Climate change affects the spread of vector borne diseases both directly and indirectly. Global warming and increased rainfall contribute to the abundance and distribution of vectors like mosquitoes. Current evidence suggests that inter-annual and inter-decadal climate variability have a direct influence on the epidemiology of vector-borne diseases [36]. It is estimated that

Yellow Fever Encephalitis: An Emerging and Resurging Global Public Health Threat in a Changing Environment

of many vector-borne diseases [36]. If the water temperature rises, the larvae take a shorter time to mature [38] and consequently there is a greater capacity to produce more offspring during the

The extrinsic incubation period of dengue and yellow fever viruses is also dependent on temperature. Within a wide range of temperature, the warmer the ambient temperature, the shorter the incubation period from the time the mosquito imbibes the infective blood until the mosquito is able to transmit by bite. The implication is that with warmer temperatures not only would there be a wider distribution of *Ae. aegypti* and faster mosquito metamor‐ phosis, but also the viruses of dengue and yellow fever would have a shorter extrinsic incu‐ bation period and thus would cycle more rapidly within the mosquito. A more rapid cycle

Kelley Lee (2000) [40] has defined globalization as 'the process of closer interaction of human ac‐ tivity across a range of spheres, including the economic, social, political and cultural, experi‐ enced along three dimensions: spatial, temporal and cognitive'. The recent emergence and resurgence of vector-borne diseases are the result of human activities-transportation of goods and people-and will continue with increasing globalization of trade [41]. The increasing phe‐

Every year, about 9 million people from Asia, Europe, and North America travel to countries where yellow fever is endemic; the number of travellers who actually visit areas within these countries where transmission of the virus occurs might exceed 3 million in the coming years [42]. In Africa yellow fever was mainly a problem of the sub-Saharan countries of West Africa, but reached as far east as central Sudan and Kenya [43-46]. A large number of outbreaks were report‐ ed in eastern Mexico and other Central American countries. At this time, YF was an epidemic

West Africa is witnessing significant migratory flows owing to rural exodus, movements of religious groups such as the Mourides in Senegal, cross-border movements of seasonal workers and nomadic pastoral communities, trade routes stretching from the Sahel to the coast of the Gulf of Guinea, the phenomenon of new urban dwellers returning regularly to their rural communities of origin, and migration by populations fleeing armed conflicts.

nomenon of globalization has been observed to alter the YF disease pattern.

C by 2100 [37], increasing the likelihood

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**Table 2.** The history of Yellow fever outbreaks in the subtropical regions of Africa

#### **8.1. Unchecked and unplanned urbanization**

It is one of the key determinant in terms emergence and resurgence of many vector-borne diseas‐ es particularly YF. With an annual growth rate of nearly 4%, Africa's cities are the fastest expand‐ ing in the world. Not only are more and more people living in the cities but the number of cities is also increasing. Whereas today 62.1% of Africa's population lives in rural areas, it is predicted that by 2020 this proportion will be reversed, i.e. that 63% of the continent's population will be urban dwellers. Between now and 2015, it is estimated that the number of cities with more than 1 million inhabitants will increase from 43 to 70 in Africa [34]. On the edge of modern cities, shanty towns with no access to basic sanitation (running water and waste disposal) are also developing rapidly. Domestic water containers and all manner of refuse littering the streets (aluminium and tin cans, old tyres, etc.) favor the multiplication of breeding sites for mosquito larvae [35].

## **8.2. Climate change**

**Year Countries Number of**

**Epidemics between 1986 and 1994**

214 Encephalitis

**cases**

 Zaire NA **1994** Gabon 28 Zaire NA **1994** Ghana 79 **1927-1928** Zaire NA **1994** Kenya 7 Sudan, Uganda, Kenya NA **1994** Nigeria 1227 Sudan, Uganda, Kenya NA **1995** Gabon 16 Zaire NA **1995** Liberia 360 Sudan NA **1995** Senegal 79 **1960-1962** Ethiopia 100,000 **1995** Kenya 3 Senegal 20,000 **1995** Sierra Leone 1 Ethiopia, Sudan 10,000 **1996** Benin 120 Nigeria NA **1996** Ghana 27 Angola NA **1996** Senegal 128 Zaire NA **1997** Benin 18 Gambia 8400 **1997** Ivory Coast 11 Upper Volta NA **1997** Ghana 6 Angola NA **1997** Nigeria 7 **1992-1993** Kenya NA **1997** Liberia 1

Nigeria Approximately

**Table 2.** The history of Yellow fever outbreaks in the subtropical regions of Africa

**8.1. Unchecked and unplanned urbanization**

120,000

It is one of the key determinant in terms emergence and resurgence of many vector-borne diseas‐ es particularly YF. With an annual growth rate of nearly 4%, Africa's cities are the fastest expand‐ ing in the world. Not only are more and more people living in the cities but the number of cities is also increasing. Whereas today 62.1% of Africa's population lives in rural areas, it is predicted that by 2020 this proportion will be reversed, i.e. that 63% of the continent's population will be urban dwellers. Between now and 2015, it is estimated that the number of cities with more than 1 million inhabitants will increase from 43 to 70 in Africa [34]. On the edge of modern cities, shanty towns with no access to basic sanitation (running water and waste disposal) are also developing rapidly. Domestic water containers and all manner of refuse littering the streets (aluminium and

tin cans, old tyres, etc.) favor the multiplication of breeding sites for mosquito larvae [35].

 Cameroon 20,000 **2000** Nigeria 2 Kenya NA **2000** Liberia 102 Ghana 39 **2000** Guinea 512 Kenya 27 **2001** Ivory Coast 203 Nigeria 152 **2001** Guinea 18 Cameroon 10 **2005** Sudan 491

**Year Countries Number of**

**1998** Burkina Faso 2

**cases**

Climate change affects the spread of vector borne diseases both directly and indirectly. Global warming and increased rainfall contribute to the abundance and distribution of vectors like mosquitoes. Current evidence suggests that inter-annual and inter-decadal climate variability have a direct influence on the epidemiology of vector-borne diseases [36]. It is estimated that average global temperatures will have risen by 1.0-3.5o C by 2100 [37], increasing the likelihood of many vector-borne diseases [36]. If the water temperature rises, the larvae take a shorter time to mature [38] and consequently there is a greater capacity to produce more offspring during the transmission period.

The extrinsic incubation period of dengue and yellow fever viruses is also dependent on temperature. Within a wide range of temperature, the warmer the ambient temperature, the shorter the incubation period from the time the mosquito imbibes the infective blood until the mosquito is able to transmit by bite. The implication is that with warmer temperatures not only would there be a wider distribution of *Ae. aegypti* and faster mosquito metamor‐ phosis, but also the viruses of dengue and yellow fever would have a shorter extrinsic incu‐ bation period and thus would cycle more rapidly within the mosquito. A more rapid cycle would increase the speed of epidemic spread [39].

#### **8.3. Globalization**

Kelley Lee (2000) [40] has defined globalization as 'the process of closer interaction of human ac‐ tivity across a range of spheres, including the economic, social, political and cultural, experi‐ enced along three dimensions: spatial, temporal and cognitive'. The recent emergence and resurgence of vector-borne diseases are the result of human activities-transportation of goods and people-and will continue with increasing globalization of trade [41]. The increasing phe‐ nomenon of globalization has been observed to alter the YF disease pattern.

#### **8.4. International travel and trade**

Every year, about 9 million people from Asia, Europe, and North America travel to countries where yellow fever is endemic; the number of travellers who actually visit areas within these countries where transmission of the virus occurs might exceed 3 million in the coming years [42]. In Africa yellow fever was mainly a problem of the sub-Saharan countries of West Africa, but reached as far east as central Sudan and Kenya [43-46]. A large number of outbreaks were report‐ ed in eastern Mexico and other Central American countries. At this time, YF was an epidemic disease mainly of port cities [35].

#### **8.5. Rural-urban migration**

West Africa is witnessing significant migratory flows owing to rural exodus, movements of religious groups such as the Mourides in Senegal, cross-border movements of seasonal workers and nomadic pastoral communities, trade routes stretching from the Sahel to the coast of the Gulf of Guinea, the phenomenon of new urban dwellers returning regularly to their rural communities of origin, and migration by populations fleeing armed conflicts. These human movements increase the risk of contamination of non-immune persons travel‐ ling in areas where contaminated vectors persist and, conversely, favour the introduction of the disease into previously YF free zones [47].

**10. Yellow fever virus**

**11. Epidemiology**

**11.1. Transmission**

Ever since the causative agent of YF disease YFV, was first isolated in 1927 from a Ghanaian patient named Asibi [50], the Asibi YFV strain is still widely used by the scientists of today. YFV is the prototype member of the family Flaviviridae(from the Latin flavus, meaning yel‐ low), and genus Flavivirus, which get their name from the Latin word for yellow (flavus). The genome is a single-stranded, positive-sense RNA, 10,500 - 11,000 nucleotides in length. The genus Flavivirus contains approximately 70 viruses, and the major flavivirus diseases are yellow fever (YF), dengue, West Nile, Japanese encephalitis, and tick-borne encephalitis [51]. Unlike other mosquito-borne flaviviruses, YFV has a tropism for the liver and causes a viscerotropic disease whereas many other mosquito-borne flaviviruses have a tropism for the brain, or in the case of the DEN viruses they target cells of reticuloendothelial origin [52].

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It was one of the earliest viruses to be identified and linked to human disease. Although substantial variation exists among strains, they can be grouped into monophyletic geo‐ graphical variants, called topotypes. African isolates are usually grouped into two topo‐ types, associated with East and West Africa [53,54], although some studies have argued for up to five [55]. Two more have been identified from South America, although one has not been recovered since 1974, suggesting that it may be extinct in the wild. There is no evidence for a difference in virulence between the topotypes [56]. YF activity often occurs in areas af‐ ter increases in temperature and rainfall that will favor increased biodiversity, including in‐ creased numbers of animals and arthropods while reduced rainfall limits mosquito vector density [49]. It has been known for over 50 years that increased temperatures are associated with enhanced transmission of YF virus [56] due to shortened extrinsic incubation period

The virus is maintained in endemic areas of Africa and South America by enzootic transmis‐ sion between mosquitoes and monkeys, and obviously the epidemiology of the disease re‐

The enzootic transmission cycle involves tree-hole-breeding mosquitoes such as *Aemagogus janthinomys*(South America) and *Ae. africanus*(Africa), and nonhuman primates. Infection of mosquitoes begins after ingestion of blood containing a threshold concentration of virus (~3.5 log 10 ml¯1), resulting in infection of the midgut epithelium. The virus is released from the midgut into the hemolymph and spreads to other tissues, notably the reproductive tract and salivary glands. A period of 7-10 days is required between ingestion of virus and virus secretion in saliva (the extrinsic incubation period), after which the female mosquito is capa‐

and increased biting by mosquitoes of vertebrate hosts [49].

flects the geographical distribution of the mosquito vectors [57].

ble of transmitting virus to a susceptible host.

#### **8.6. Genetic and behavioral variation**

YF outbreaks are common in Africa despite the current knowledge of the disease transmis‐ sion and the availability of a vaccine. In Africa, YF cases are not uniformly distributed throughout the endemic area; rather, more cases are reported in West Africa compared to East and Central Africa. Genetic differences between genotypes of YF in Africa probably contribute to the observed distribution of YF outbreaks. Genetic and behavioral variation in mosquito vectors may also play a major role in the distribution of YF outbreaks. The other factors also contribute to the epidemiology of YF, including host genetic background, cli‐ mate, vaccination coverage, vertebrate hosts and movement of vertebrate hosts [48].

#### **9. Yellow fever vectors**

Yellow fever virus is transmitted principally by insects (mosquitoes), but ticks (*Amblyomma variegatum*) may play a secondary and minor role in Africa. It was not until 1901 that yellow fever transmission to humans was associated with the blood-feeding by the *Ae. aegypti* mos‐ quito (Figure 2), which was a major breakthrough in understanding this dreadful disease. Dispatched to Cuba by the United States government to investigate the cause of YF, Walter Reed and colleagues confirmed that the primary mode of YF transmission to humans was the *Ae. aegypti* mosquito (Figure 2) and the in ground-breaking virologic studies demonstrat‐ ed that the disease was caused by an agent that could be filtered from the blood of infected individuals [49]. The reservoirof yellow fever virus is the susceptible vector mosquito spe‐ cies that remains infected throughout its life and can transmit the virus transovarially. Yel‐ low fever can persist as a zoonosis in the tropical areas of Africa and America, with nonhuman primates responsible for maintaining the infection. Man and monkey play the role of amplifiers of the amount of virus available for the infection of mosquitos [50].

**Figure 2.** *Aedes aegypti*, the primary disease vector for yellow fever (Photo by Muhammad Mahdi Kharim, published under the GNU free documentation licences)
