Review on epidemiology and pathology of yellow fever virus

I
LIST OF ABBREVIATIONS
AST Aspartate Transaminase
ELISA Enzyme linked Immunosorbent assay
EPHI Ethiopian Public Health Institute
IGM Immune globulin M
NHP Nonhuman Primate
PHEM Public Health Emergency Management
RNA Ribonucleic Acid
YF Yellow Fever
YFV Yellow Fever Virus

II
III
IV
1. INTRODUCTION
Human health is highly associated to animal health and production systems. The link is close
in developing countries where animals are used in human for different purpose like that of
being sources of food such as meat, eggs and milk, transportation, draught power, fuel and
cloths (WHO, 2010).

The interaction is becoming largely increased in the 21st century which contributes for
transmission of infectious zoonotic diseases from animal to humans (Mbugiet al., 2012).
Zoonotic diseases are any infectious disease that can be transmitted from animals, both wild
and domestic, to humans naturally (Coleman, 2002).

A comprehensive review by Cleave land et al.(2001) identified 1,415 species of infectious

organisms known to be pathogenic to humans, including 217 viruses and prions, 538 bacteria
and rickettsia, 307 fungi, 66 protozoa and 287 helminthes. Out of these, 868 (61%) were
classified as zoonotic and 175 pathogenic species were considered to be associated with
emerging diseases. Out of the 175 emerging pathogens, 132 (75%) are zoonotic (Woolhouse
et al., 2005).

In developing countries every year 2.4 billion human infections with origins in animals
(zoonotic) occur, causing widespread illness and 2.2 million human deaths. These diseases are
often endemic and include anthrax, tuberculosis, leptospirosis, yellow fever, rift valley fever,
rabies and others that are under diagnosed, underreported and which may highly affect those
who live nearest to animals.

Even where zoonotic diseases do not cause death, they invariably deepen poverty and destroy
livelihoods (World Bank, 2012). Many countries face significant health issues associated with
a high incidence of neglected but endemic zoonosis whose control has been limited by a lack
of integrated control measures, accounting for both animal and human population (Pfeiffer,
2013).

The world health organization/food and agriculture organization of the united nations/ world
organization for animal health joint consultation on emerging zoonotic diseases held in
Geneva, defined an emerging zoonosis as ‘a zoonosis that is newly recognized or newly
1
evolved, or that has occurred previously but shows an increase in incidence or expansion in
geographical, host or vector range’ (WHO et al., 2004).

Many factors lead to the emergence of zoonotic diseases and these are associated with
pathogens and their reservoir hosts are constantly changing and the rate of change is
increasing. The drivers of change include the modernization of farming practices, particularly
in the developing world, habitat destruction, human encroachment and climate change
(Woolhous et al., 2005; Jones et al., 2008).

Climate and habitat changes have a significant effect on vector distribution, introducing
formerly geographically restricted pathogens into naive populations of potentially susceptible
animals and humans. The geographical ranges of zoonotic pathogens such as yellow fever
virus, dengue virus, west Nile virus and other virus are expanding, with the movement of
vectors into newly established habitats (McKeever et al., 2013).

Yellow fever (YF) is one of the re-emerging zoonotic viral hemorrhagic diseases (Monath,
2001). It is perpetuated in a transmission cycle involving mosquitos and non-human primate
hosts. Because the new world primate hosts are especially susceptible to yellow fever
virus(YFV) infection, acute clusters of mortality in these populations can signal YFV activity
and alert authorities to increased risk of human infection, thereby serving as an early warning
system for public health protection (Faria et al., 2018).

Therefore, the objectives of this review paper are:

 To highlight transmission cycles of yellow fever virus.

 To discuss the epidemiology and pathology of yellow fever.

2
2. LITERATURE REVIEW
2.1. Etiology
Yellow fever is a non-contagious infectious disease caused by an arbovirus (arthropod-borne
virus) belonging to the Flaviviridae family, which closely related to Dengue virus. Yellow
fever is caused by the yellow fever virus, an arthropod-borne virus from the genus Flavivirus.
YFV is the prototype member of the genus Flavivirus (family Flaviviridae), with a single-
strand positive-sense RNA virus (Landini et al., 2013). Until now, one YFV serotype and
seven genotypes have been described in Africa and South America. In Africa, five genotypes
are described, named West Africa I, West Africa II, East Africa, East/Central Africa, and
Angola (Douam and Ploss,2018).Each of the five genotypes in Africa circulates in a distinct
geographical region, whilst the two in South America do not have a distinct geographical
distribution (Barrett and Higgs,2007).
2.2. Transmission Cycles of Yellow Fever Virus
The natural transmission cycle of YF involves NHP and diurnally active mosquitoes that breed
in tree holes in the forest canopy (Monath, 2001). The primary transmission cycle involves
monkeys and daytime biting mosquitoes (Aedes species in Africa, Haemagogus species in
South America). The natural epidemiology of YF on both continents is a cycling of the virus
between forest mosquitoes and wild primates (James, 2011).

In sylvatic cycle non-human primates are the main hosts and amplifiers of the virus. The virus
is kept in the wild by transmission between monkeys and wild mosquitoes. At times, in ideal
conditions for transmission, a larger number of monkeys become ill and die, accentuating the
epizootic factor of the disease. In this cycle, humans act as accidental hosts when entering
forest areas for working for different purpose and inhabited by mosquito (sylvatic)
vectors(Cupertino et al.,2018).

Intermediate savannah cycle- occurs in isolated rural communities on the rainforest periphery
where infected mosquito species feed simultaneously on both primate and human hosts. In
Africa, preferentially feeds on primates while Aedes simpsonii feeds indiscriminately on
nonhuman primates and human (CDC, 2019).

3
Urban cycleis maintained invasive domesticated mosquitoes (Aedes aegypti) that facilitate
YFV transmission from human-to-human in areas of high human and vector population
density. Urban YFV outbreaks are associated with Ae. Aegypti transmission, although the
Asian tiger mosquito, Aedes albopictus, is also competent for YFV transmission (Amraou et
al., 2016) because both species are invasive, are able to breed in water containers and have
drought-resistant eggs. Like other arboviruses, which are transmitted by mosquitoes, yellow
fever virusis taken up by a female mosquito which ingests the blood of an infected human or
non-human primate. Viruses reach the stomach of the mosquito, and if the virus concentration
is high enough, the virions can infect epithelial cells and replicate there. From there, they reach
the haemocoel(the blood system of mosquitoes) and from there the salivary glands. When the
mosquito next sucks blood, it injects its saliva into the wound, and the virus reaches the
bloodstream of the bitten person or animals (Gardner et al., 2011).

Figure 1: Transmission cycle of yellow fever virus (Source: CDC, 2019)

2.3. Epidemiology of Yellow Fever
The yellow fever virus is maintained by different cycles in tropical and subtropical regions of
sub-Saharan Africa and South America via transmission among different mosquitoes and NHP
(Hanley et al.,2013) and (Klitting et al.,2018).Historically, devastating urban YF epidemics

4
have occurred in Europe, Africa, and South, Central and North America (Monath,2006). In the
absence of a sylvatic cycle, improved sanitation and mosquito abatement programs eliminated
epidemic urban YF from North American and European cities, with the last outbreak occurring
in New Orleans in 1905 (Tomlinson and Hodgson et al., 2005). However, it is estimated that
YF continues to affect over 200,000 persons annually in tropical regions of Africa, South
America, and Central America, with at least 30,000 fatalities (Monath, 2001).

Forty-four countries in Africa and South and Central America (Burnett et al.,2010) are within
the modern YF endemic zone, with almost 900 million people at risk of infection. This total
includes an estimated 508 million people in 32 African countries, and the remainder in 12
South and Central American countries (Briand et al.,2009).

Most YF cases occur in sub-Saharan Africa, including periodic, unpredictable outbreaks of

urban YF. An alarming resurgence of virus circulation and expansion of the endemic zones
have been detected in Africa (Onyango et al., 2004)and South America (Bryan et al., 2007)in
recent years. The incidence of endemic disease is not well established, but approximately 1
percent of individuals with severe hepatitis in endemic areas of Africa may be caused by
yellow fever (Monath, 2012).An estimate from serologic and epidemiologic data indicated that
there were 130,000 cases with viscerotropic disease and 78,000 deaths in Africa in 2013
(Garske et al., 2014).

It is useful to analyze what elements are necessary for a YF outbreak to occur in non-human
population and human population. Outbreaks of yellow fever have highlighted a number of
issues, predominantly related to lack of vaccination campaigns in East and Central Africa
(Kraemer and Hill, 2018). One expressed fear is that outbreak will facilitate world-wide
distribution of the virus due to the establishment of direct air travel routes from east Africa
into areas with susceptible mosquito populations (Wasserman et al., 2016).Another host risk
factor of yellow fever is migration of susceptible individuals to forested regions where the
disease is transmitted and increasing urbanization of the disease (Filippis et al.,2001).

Urbanization or densely population and working nearby side of forest area where yellow fever
endemic is one of environmental related risk for yellow fever occurrence in populations.

5
Yellow fever outbreak has been favored by changes in environmental factors which include
temperature, humidity, high rainfall and other eco-social factors (Possas et al., 2018).
Yellow fever virus’s surface macromolecules are its main virulence factors and contribute to
the entry, signaling and cell-cell interactions of the virus. The flavivirus E protein has many
functions, but its role in binding, fusion and cell entry is most important. The genome of the
YFV has two distinct non-coding regions these regions are a control mechanism for the virus's
replication and level of virulence (CDC,2004).
2.4. Clin
2.4.1. Clinical sign in non-human primates
Yellow fever is medically important and reemerging arthropod-borne virus originated in
NHPs, which typically show no clinical signs of infection but become viraemic and help
maintain the virus in nature (Jones et al., 2008). Non-human primates does not show clinical
spectrum of yellow fever because they are reservoir of virus (Month, 2000).
2.4.2. Clinical sign in human
Yellow fever symptoms are more common in human than in non-human primates and it is
characterized by subclinical infection, abortive, nonspecific febrile illness without jaundice,
jaundice, renal failure and heamorrgic. Yellow fever affects all ages, but disease severity and
lethality is highest in older and the onset of illness appears abruptly three to six days after the
bite of mosquitoes(Johansson et al.,2010) and this classical illness is characterized by three
stages: infection,remission,and intoxication. Period of infection  consists of viremia, which
lasts for three to four days. The patient is febrile and complains of generalized headache,
lumbosacral pain, pain in the lower extremities, anorexia, nausea, vomiting and restlessness
are common (Barnett,2007).

Period of remission-A period of remission lasting up to 48 hours may follow the period of
infection, characterized by the abatement of fever and symptoms. Period of intoxication
(severe yellow fever)-The period of intoxication begins on the third to sixth day after the onset
of infection with return of fever, prostration, nausea, vomiting, epigastric pain, jaundice,
oliguria, and hemorrhagic. The viremia disappears at this stage and antibodies appear in the
blood, although ongoing viremia has also been reported (Kallas et al.,2019). This phase is
characterized by variable dysfunction of multiple organs including the liver, kidneys, and
cardiovascular system. Multiorgan failure in yellow fever is associated with high levels of
6
proinflammatory cytokines similar to that seen in bacterial sepsis and systemic immune
response syndrome (CDC, 2000).Besides the liver complications, YFV is very similar to other
viral infections, beginning with very minor flu-like symptoms that can progress to a severe and
toxic stage(WHO,2014).

The outcome is determined during the second week after onset, at which point the patient
either dies or rapidly recovers. Approximately 20 to 50 percent of patients who enter the
period of intoxication succumb to the disease. Poor prognostic signs include anuria, shock,
hypothermia, agitation, delirium, intractable hiccups, seizures, hypoglycemia, hyperkalemia,
metabolic acidosis, Cheyne-Stokes respirations, stupor, and coma. A study in a tertiary
hospital setting in Brazil identified the following predictive factors for progression to severe
yellow fever: older age, male sex, elevated leukocyte and neutrophil counts, elevated alanine
aminotransferase, aspartate transaminase (AST), bilirubin, creatinine, prolonged prothrombin
time, and higher YFV RNA plasma viral load. In a multivariate regression model, older age,
elevated neutrophil count, increased AST, and higher viral load were independently associated
with death (Johansson et al., 2010).

2.5. Pathogenesis of Yellow Fever

Yellow fever virus enters through the bite of a mosquito where it can remain dormant for 6 to
8 days causing massive viremia or quick infection of host cells (CDC, 2011).Then virus enters
its hosts via receptor-mediated endocytosis and then, utilizing its messenger RNA-like
structure, begins protein synthesis in the host’s endoplasmic reticulum so that it can begin viral
replication in the cytoplasm. After that the viruses replicate in the lymph nodes and infect
dendritic cells of the hosts. From there they reach the liver and infect hepatocytes via Kupffer
cells leads to eosinophilia degradation of these cells and to the release of cytokines and as
result apoptotic masses knowns councilman bodies appear in the cytoplasm of hepatocytes.
YFV, due to its injection via mosquito, is believed to first encounter the immune system via
dendritic cells. Thus the cascade of nonspecific immune responses begins. NK cell and
interferon are the most prominent immune responses in controlling YFV replication in cells
(Douam and Ploss, 2018).

7
2.5.1. Gross pathology of yellow fever
Gross examination detected animals with a body weight within normal limits for the species
and mucosa with intense yellowish color (ocular, oral, anal, and vaginal/preputial). An internal
examination showed that the main organs affected were the liver, which was a normal size and
had an evident reticular pattern with the color varying from pale yellow to intense yellowish;
the kidneys uniformly yellowish, in both the cortical and medullar regions, and without any
change in size; and in some of these animals, the color of the omentum varied from yellow to
intense orange. The animals have hemorrhagic fluid and coagulated blood in the abdominal
cavity.

8
Figure3: Alouatta caraya species (monkey) which dead by yellow fever (a) place where the
animal was found, (b) Kidney midsagittal section, showing yellowish coloration (c) Liver with
yellowish coloration and reticular pattern evidenced (d) Mesentery with yellowish coloration
and intense hemorrhage (Source:Moreno et al., 2009).

2.5.2. Microscopic lesions

Microscopic examination indicate the following for all animals: zonal bridging (largely
midzonal and centrilobular) or massive liver necrosis with councilman bodies, varying degrees
of macrovacuolar and micro vacuolar steatosis, and pleocellular (mainly lymphohistiocytic)
inflammatory infiltrates, accompanied by hemorrhage, hemosiderosis, splenic lymphoid
depletion and follicular necrosis/lymphocytolysis(Leal et al.,2016).

Figure 2: Microscopic findings of (Alouatta caraya species) liver which was died by yellow
fever A) Midzonal and centrilobular bridging B) Massive hepatocellular necrosis with severe
centrilobular and midzonal hemorrhage.C) Massive macrovacuolar steatosis. D)
Immunoglobulin confined to remaining periportal hepatocytes (source; Monath, 2001).
2.6. Diagnosis

9
2.6.1. In animals
Virus isolation is accomplished by inoculation of mosquito or mammalian cell cultures,
intracerebral inoculation of suckling mice, or intrathoracic inoculation of mosquitoes. Rapid
diagnostic tests include polymerase chain reaction to detect viral genome in the blood or tissue
and enzyme-linked immunosorbent assay (ELISA) for determination of IgM antibody (Bea et
al., 2005).

The tools are increasingly available in national and regional laboratories in the endemic areas.
A reverse-transcription loop-mediated isothermal amplification (RT-LAMP) yellow fever
diagnostic test, which does not require thermocycling equipment and can be read visually, has
shown promise as a sensitive and rapid test for use in field conditions (Nunes et al.,
2015).Serologic diagnosis is best accomplished using an ELISA for immunoglobulin IgM.

The presence of IgM antibodies in a single sample provides a presumptive diagnosis of yellow
fever in nonhuman primates (Gibney et al., 2012).

2.6.2. In human

Yellow Fever infection should be considered as a differential diagnosis in all cases of febrile
syndrome in individuals with contact to endemic regions (CDC,2016). The diagnosis is made
from a detailed clinical evaluation, with specific and non-specific laboratory tests. The specific
tests define the diagnosis of the disease, while the non-specific tests act as a prognosis of the
disease. Specific methods include hemogram (leukopenia with neutropenia and lymphocytosis
with thrombocytopenia and anemia); erythrocyte sedimentation rate (very low, possibly zero);
Aminotransferases (extremely high); bilirubin (elevated); nitrogenous compounds elevation of
urea and creatinine (Faria et al.,2018).

2.7. Differential Diagnosis

Like influenza in humans, NHPs infected with influenza virus exhibit fever, malaise, nasal
discharge and nonproductive cough; virus replication can be detected in the nasal passages and
respiratory tract (Bodewe et al.,2010). It is not associated with severe hepatic involvement or
jaundice. Malaria is characterized by fever and anemia; clinical manifestations include

10
jaundice due to hemolysis. The diagnosis of malaria is established by visualization of parasites
on peripheral of specimen (Coatney et al., 2003).

Leptospirosis is a bacterial infection characterized by leukocytopenia. The septicemic phase of

leptospirosis is associated with damage to vascular lining cells, which combined with the
release of bacterial toxins and inflammatory responses to the bacteria (Szonyi et al.,2010).

Hemorrhagic fever: yellow fever may be distinguished from other viral hemorrhagic fevers
(Marburg virus, Ebola virus) in that these other viral hemorrhagic fevers are not usually
associated with jaundice (Wilder-Smith et al., 2019). Rift valley fever: unlike the majority of
other animals, infection of NHPs with Rift valley fever virus does not seem to produce a
uniformly fatal infection and the NHPs became viremic and developed a fever, and
leukocytosis was evident, followed by leukopenia, but no signs of disease resulted, except for
a decrease in activity during the peak of fever (Findlay, 2000).
2.8. Treatment
Yellow fever has no antiviral drug treatment. Supportive care is given in which patient become
comfortable and reduces anybody damage caused by the disease. The typical supportive care
includes giving plenty of water to make up for fluids lost during vomiting. Oxygen is also
provided to make up for the gas exchange lost by the damaged lungs. Medications may be
administered to regulate the blood pressure and the heart rate. Patients with severe yellow
fever may need blood and kidney dialysis. Some patients need transfusions of blood liquids to
replace proteins that improve blood clotting and healing of damage from hemorrhaging. All
stakeholders should cooperate on zoonotic important of yellow fever virus spread between
animals, humans and the environment and monitor and prevent major outbreaks (Eskild,2016).
2.9. Control and Prevention
2.9.1. Vaccination
Vaccination is the main strategy in which yellow fever is effectively prevented in areas where
the disease is epidemic which provide high levels of protection, with seroconversion rates of
95%. The 17D live attenuated vaccine strain is used and a single vaccination dose will be
enough to provide long-term immunity (Weiten,2016).

11
Several vaccination strategies are used to protect against outbreaks: routine infant
immunization; mass vaccination campaigns designed to increase coverage in countries at risk;
and vaccination of travelers going to yellow fever endemic areas. A mass vaccination
campaign is the most effective public health strategy to control YF outbreaks. When outbreaks
begin it is important to have widespread vaccination. In more developed areas the need for
vaccination only exists for those traveling in YF "hot spots". The YF vaccine is 99% effective
within the first 30 days and provides life-long immunity (WHO, 2014).
2.9.2. Mosquito control
Vector control is another way in which the disease is controlled. The risk of yellow fever
transmission in urban areas can be reduced by eliminating potential mosquito breeding sites and
water storage containers and other places where standing water collects. In addition to this
reduction of mosquito population by using insecticides and larvicides in areas with high
mosquito density is a way in which yellow fever vector can be controlled.

The first method used at combating YF was pest control, which is still very effective where
vaccination is not cost effective. The use of pesticides in areas where shallow water accumulates
can often halt a potential epidemic. It should be noted mosquito control is only feasible for the
urban cycle of transmission and not for the Jungle or Savannah cycle (WHO,2014).
2.10. Status of Yellow Fever in Ethiopia
Ethiopia is one of YF transmission at risk countries in Africa (Monath, 2006).Different
research and outbreak investigation reports showed that YFV had been circulating In Ethiopia
(Williams, 1968). From 1960 to 1962, there was a large outbreak of YF in different parts of
Ethiopia mainly around Gamo Gofa, Jinka, Kaffa and Wollega areas which approximately
affected about 100,000 persons and killed 30,000 (case fatality rate: 0.3). Similarly, in 1966,
YF reappeared in Arba-Minch, east of Lake Abaya, in an area unaffected by the outbreak of
1960 and affected 2200 persons with 450 deaths (Andral,1968).

South Omo Zonal Health Department reported deaths with unknown causes from South Ari
district to Public Health Emergency Management (PHEM) of the Southern Nations
Nationalities and Peoples Region (SNNPR) in November 2012. The main clinical
manifestations were fever, headache, nausea and bloody vomiting.

12
The regional PHEM conducted field investigations in January and February 2013 but the cause
of the outbreak could not be determined and the regional PHEM notified Ethiopian Public
Health Institute (EPHI) in late of March 2013 for conducting further investigation and
characterizing the outbreak. After the request, team from EPHI and World Health
Organization (WHO) Country Office deployed to the affected area in the end of March 2013
to identify the causative agent, and a single confirmed case of YF was considered as an
outbreak in Ethiopia (EHNRI,2012).

However, the recent status of yellow fever in Ethiopia is indicated as that, the outbreak of
yellow fever was reported eight month before in Gurage Zone of Southern Nations
Nationalities and Peoples Regional State, and it has been continued since 29 th March 2020,
according to Ethiopian Ministry of Health. The outbreak started with an index case on
March 3, 2020, and the last case was reported on 29 th March in the same year (EPHI, 2020).

13
3. CONCLUSION AND RECOMMENDATIONS

Yellow Fever is vector borne zoonotic viral disease which is an acute and often fatal infectious
disease that is responsible for continuous outbreak of viral heamorrgic fever in both human
and non-human primates.

Yellow fever is caused by yellow fever virus that transmitted in tropical and subtropical areas,
mainly through the bite of infected Aedes spp. mosquitoes in Africa and by Haemagogus spp.
mosquitoes in South America. Yellow fever has three transmission cycles namely jungle,
intermediate and urban. The jungle cycle is less important from public health significance
perspective. Yellow fever is an important public health problem in endemic area causing
considerable mortality and fatality.

Yellow fever outbreak is favored by changes in environment like high temperature, humidity,
high rainfall, and other eco-social factors. Recent epidemics in Africa particularly in Ethiopia
emphasizes the threat from this re-emerging pathogen remains high despite availability of
long-standing a protective vaccine.

Based on the above conclusion and the following recommendations are forwarded:

 Identifying which transmission cycle is predominant in Ethiopia need to be given due

attention by public health institutions and other stakeholders.
 Yellow fever assessment is imperative to expand knowledge of the complex
transmission cycle and its public health significance.
 Prevention and control approaches used in particular area should mainly target on the
dominant transmission cycle in the area
 Since there is effective vaccine, vaccinating high risk groups should be given due
attention
 In areas where the disease is endemic, all human population should be vaccinated
against the disease.

14
4. REFERENCES

Almeida, M.A., Santos, E., Cardoso, J.C., Fonseca, D.F., Noll, C.A. and Silveira, V.R. (2012):
Yellow fever outbreak affecting Alouatta populations in Southern Brazil (Rio Grande
do Sul). Am. J. Primatol., 74:68-76

Amraou, F., Vazeille, M. and Failloux, A.B. (2016): French Aedes albopictus are able to
transmit yellow fever virus. Euro.Surveill.,21:209-229.

Andral, L. (1968): Etudes sur la fievre jaune en Ethiopie. Bull. Wld. Hlth. Org., 38:855–861.

Bea, H.G, Drosten, C. and Emmerich,P. (2005): (Analysis of two imported cases of yellow
fever infection from Ivory Coast and The Gambia to Germany and Belgium. J. Clin.
Virol., 33: 274-279

Barnett, E.D. (2007): Yellow fever: epidemiology and prevention. Clin Infect Dis.,44(6):850-
857

Barrett, A. D. T. and Higgs, S. (2007). Yellow fever: A disease that has yet to be conquered.
Annual Rev. Entomol., 52(1): 209-229

Bodewe, R., Rimmelzwaan, G.F. and Osterhaus,A.D. (2010):Animal models for the
preclinical valuation of candidate influenza vaccines.Expert. Rev. Vacc.,9:59–72.

Briand, S., Beresniak, A. and Nguyen, T. (2009): Assessment of yellow fever epidemic risk:
an original multi-criteria modeling approach. PLoS. Negl. Trop. Dis., 3:e483.

Bryan, J.E., Holmes, E.C. and Barrett, A.D. (2007): Out of Africa: a molecular perspective on
the introduction of yellow fever virus into the Americas. PLoS Pathog.,3(5):e75

CDC, Centers for Disease Control and Prevention (2000): Centers for Disease Control and
Prevention (CDC). Fatal yellow fever in a traveler returning from Venezuela, 1999.
MMWR Morb Mortal Wkly Rep, 49:303.

15
CDC, Centers for Disease Control and Prevention (2011): Yellow Fever. Centers for Disease
Control and Prevention. Centers for Disease Control and Prevention.

CDC, Centers for Disease Control and Prevention (2016):Centers for Disease Control and
Prevent. Infectious Disease Related to Travel. Yellow fever: related-to-travel/yellow-
fever.

CDC, Centers for Disease Control and Prevention (2019):Centers for Disease Control and
Prevention. National Center for Emerging and Zoonotic Infectious Diseases
(NCEZID), Division of Vector-Borne Diseases (DVBD).

Cleaveland, S., Laurenson, M.K. andTaylor,L.H (2001): Diseases of humans and their
domestic mammals: pathogen characteristics, host range and the risk of emergence.
Philos Trans R Soc Lond B. Biol. Sci., 356:991–999.

Coatney,G.R., Collins,W.E., Warren,M. and Contacos, P.G. (2003):The primate malarias.

Version 1.0 (originally published in 1971). Atlanta: Centers for Disease Control and
Prevention.

Coleman, P.(2002): Zoonotic diseases and their impact on the poor. In: Perry, B. D.,
Randolph, T. F., McDermott, J. J., Sones, K. R. and Thornton, P. K. (2002) “Investing
in animal health research to alleviate poverty” International Livestock Research
Institute (ILRI) Nairobi.

Costa, Z.G., Elkhoury, A.N. and Romano, A.P. (2011):Historical development and evolution
of epidemiological surveillance and control of yellow fever in Brazil. Rev. Pan‒Amaz
Saude.,2(1):11‒16.

Cupertino, M.C., Bayão, T., Gomes, A.P., Mayers, N. and Siqueira-Batista, R. (2018):
Epidemiological aspects of mosquitoes of the genus Haemagogus and Sabethes
involved in sylvatic yellow fever transmission in Brazil. Trends Entomol.,14: 1-9.

Douam, F. and Ploss, A. (2018):Yellow Fever Virus: Knowledge Gaps Impeding the Fight
Against an Old Foe. Trends Microbio.,20:1–16.

16
EHNRI, Ethiopian Health and Nutrition Research Institute (2012):Ethiopian Health and
Nutrition Research Institute. Public Health Emergency Management Guideline. Addis
Ababa: Ethiopian Public Health Institute, Pp. 43–44.

. Eskild,P. (2016):Taking forward a 'One Health' approach for turning the tide against the
Middle East respiratory syndrome coronavirus and other zoonotic pathogens with
epidemic potential. Int. J. Infect. Dis., 47:5-9.

Faria, N.R., Kraemer, M.U., Hill, S.C., De Jesus, J.G. and Aguiar, R.S. (2018): Genomic and
epidemiological monitoring of yellow fever virus transmission potential.
Science,361(6405): 894-899.

Filippis, A.M., Schatzmayr, H.G., Nicolai, C., et al. (2001): Jungle yellow fever: Rio de
Janeiro. Emerg. Infect. Dis.,7:484–485.

Findlay, G.M. (2000): The infectivity of Rift Valley fever for monkeys. Trans. R. Soc. Trop.
Med. Hyg.,26:161–168.

Gardner, C.L. and Ryman, K.D. (2011):Yellow fever: A re-emerging threat. Clin. Lab. Med.,
30:237–260.

Garske, T., Van Kerkhove, M.D. and Yactayo, S. (2014): Yellow Fever in Africa: estimating
the burden of disease and impact of mass vaccination from outbreak and serological
data. PLoS Med., 11: 1115–1120

Gibney, K.B., Edupuganti, S., Panella, A.J., Kosoy, O.I., Delorey, M.J., Lanciotti, R.S.,
Mulligan, M.J., Fischer, M. and Staples, J.E (2012): Detection of Anti-Yellow Fever
Virus Immunoglobulin M Antibodies at 3–4 Years Following Yellow Fever
Vaccination. Am. J. Trop. Med. Hyg., 87(6): 1112–1115

Hanley, K.A., Monath, T.P., Weaver, S.C., Rossi, S.L., Richman, R.L. and Vasilakis, N.
(2013): Fever versus fever: the role of host and vector susceptibility and interspecific
competition in shaping the current and future distributions of the sylvatic cycles of
dengue virus and yellow fever virus. Infect. Genet. Evol., 19:292-311.

17
Johansson, M.A., Arana-Vizcarrondo, N., Bigger staff, B.J. and Staples, J.E. (2010):
Incubation periods of Yellow fever virus. Am. J. Trop. Med. Hyg.,83:183.

Jones, K.E., Patel, N.G., Levy,M.A., Storeygard, A., Balk, D. and Gittleman, J.L. (2008):
Global trends in emerging infectious diseases. Nature, 451:990–999.

Kallas, E.G., D'Elia Zanella, L.G. and Moreira, C.H. (2019): Predictrs of mortality in patients
with yellow fever: an observational cohort study. Lancet Infect. Dis.,19:750-760
Klitting, R., Gould, E., Paupy, C,and, de Lamballerie X.( 2018):What Does the Future Hold
for Yellow Fever Virus.9:291-300.

Kraemer, M.U. and Hill S.C (2018): Genomic and epidemiological monitoring of yellow fever
virus transmission potential. Science. 361 (6405): 894–899.

Landini M.P. (2013).West Nile virus in Europe: emergence, epidemiology, diagnosis,

treatment, and prevention. Clin. Microbio. infect.,19, 699–704.

Leal,S.G., Romano,A.P., Monteiro,R.V., Melo,C.B., Vasconcelos, P.F. andCastro,M.B.

(2016):Frequency of histopathological changes in Howler monkeys naturally infected with
yellow fever virus. Rev. Soc. Bras. Med. Trop.,49:.29–33

Mbugi, E., Katale, B., Kendall, S., Good, L., Kibiki, G., Keyyu, J., Godfrey-FaussettHelden,
P. and Matee, M. (2012): Tuberculosis cross species transmission in Tanzania to wars
a One-Health concept. J. Vet. Res., 79(2): 1-6.

McKeever,D., Mutua, F.,Young ,J., McDermott and Pfeiffer, D.U. (2013). Zoonosis
emergence linked to agricultural intensification and environmental change. Proc. natl
Acad. Sci. USA., 110: 8399–8404.

Monath, T.P. (2000): Yellow fever a medically neglected disease. Report. seminar, 9: 165-
170.

Monath, T.P. (2006): Yellow fever as an endemic/epidemic disease and priorities for
vaccination. Bull Soc. Pathol. Exotic, 99(5): 341-347

18
Monath, T.P. (2012). Review of the risks and benefits of yellow fever vaccination including
some new analyses. Expert. Rev. Vacc., 11: 427-431

Monath,T.P. (2001): Yellow fever: an update. Lancet Infec. Dis.,1:11-20.

Moreno, E. S., Spinola, R. and Tengan, C. H. (2009): Yellow fever epizootics in non-human
primates, São Paulo State, Brazil, 2008-2009. Revista do Instituto de Medicina
Tropical de São Paulo., 55(1):45–50.

Nunes, M.R., Vianez, J.L. and Nunes, KN. (2015): Analysis of a Reverse Transcription Loop
mediated Isothermal Amplification (RT-LAMP) for yellow fever diagnostic. J. Virol
Methods, 226:45-49.

Onyango, C.O., Ofula, V.O and Sang, R.C. (2004): Yellow fever outbreak, Imatong, southern
Sudan. Emer. Infec. Dis., 10(6): 1063–1068.

Pfeiffer, D.U. (2013): Zoonosis emergence linked to agricultural intensification and

environmental change. Proc. natl Acad. Sci. USA., 110: 8399–8404.

Possas, C., Lourenço-de-Oliveira, R. and Tauil, P.L. (2018): Yellow fever outbreak in Brazil:
the puzzle of rapid viral spread and challenges for immunization. Memórias Do Instituto
Oswaldo Cruz., 1:45-51

Robertson, S.E., Hull, B.P., Tomori, O., Bele, O and LeDuc, K.E. (2015): Yellow fever: a
decade of Re-emergence. J.A.M., 276(14): 1158–1162

Szonyi, B., Agudelo-Florez, P., Ramírez, M., Moreno, N and Ko, A.I. (2010): An outbreak of
severe leptospirosis in capuchin (Cebus) monkeys. Vet. J., 188: 237-239

Tomlinson, H and Hodgson, R.S. (2005): Centennial year of yellow fever eradication in New
Orleans and the United States, 1905-2005. La. State .Med. Soc., 157(2): 216–217.

Weiten, R.W. (2016): A Single 17D Yellow Fever Vaccination Provides Lifelong Immunity:
Characterization of Yellow Fever Specific Neutralizing Antibody and T-Cell
Responses after 147: Vac. Plos One.11:1-18.

19
WHO, World Health Organization (2010): managing zoonotic public health risk at the human-
animal ecosystem interface. Strong intersectional partnerships in health, food safety.

WHO. World Health Organization, FAO and OIE (2004): World Health Organization (WHO),
(FAO) and World Organisation for Animal Health (OIE). Report of the
WHO/FAO/OIE joint consultation on emerging zoonotic diseases,

WHO, World Health Organization. (2014): Yellow Fever. WHO. WHO Media.

Wilder-Smith, A., Ooi, E.E., Horstick, O and Wills, B. (2019): Dengue. Lancet, 93: 350-354.

Williams, M.C. (1968): study of yellow fever in Ethiopian. (1968): Bull Wild Health
Organization, 38: 843–854.

Woolhouse, M.E., Haydon, D.T. and Antia, R. (2005): Emerging pathogens: the epidemiology
and evolution of species jumps. Trends Ecol. Evol., 20: 238–244

World Bank (2012): People, Pathogens and Our Planet. Vol. 2, The Economics of One Health.

Mayhob AS, Khaliq M, Kuhn RJ, Cushman M: Design, Synthesis, and Biological Evaluation
of Thiazoles Targeting Flavivirus Envelope Protein. J Med Chem 2011, 54: 1704-
1714

20