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The threat of yellow fever

The high number of yellow fever cases and deaths this summer is bringing back the fear of an urban epidemic in Brazil

James Gathany / CDC Mosquitos of the genera Haemagogus and Sabethes (photo)…James Gathany / CDC

In the 21st century, continuing globalization of people and products, deforestation and erosion of the borders between rural and urban areas, as well as the presence of large unvaccinated population groups seem to have created a favorable environment for the reappearance of yellow fever epidemics. Until recently, this disease, for which there has been an effective vaccine since the 1930s, was seen as being under control or restricted to endemic regions of the two continents where it occurs, the sub-Saharan part of Africa, one of the poorest areas in the world, and certain corners in South America, generally the channels of the Amazonas and Orinoco Rivers, or the Central-West region of Brazil. The recent outbreak of epidemics on both sides of the Atlantic brought yellow fever back into the international debate on public health.

In Africa, which accounts for 90% of the estimated 200,000 annual global cases of this disease, the most recent epidemic occurred last year in Angola, in the Democratic Republic of the Congo (formerly Zaire) and, to a lesser degree, in Uganda. There were more than 7,300 suspected or confirmed cases and some 400 deaths in these three countries. More than a dozen Chinese immigrants working in Africa were exposed to the virus and showed symptoms of yellow fever upon returning to Asia, a continent with no history of this disease, and with billions of people who were never immunized. Now the focus of concern is Brazil, the world’s largest producer of the vaccine. Between December 2016 and February 2017, there were 326 confirmed cases and 109 deaths caused by yellow fever in three states–92 in Minas Gerais, 14 in Espírito Santo and three in São Paulo. Another 916 cases and 105 deaths are being investigated to determine whether they were also caused by the disease.

Léo Ramos Chaves … which reproduce in holes in trees, transmit the disease in forested areas of BrazilLéo Ramos Chaves

Minas Gerais, where vaccination against yellow fever has been recommended for more than a decade, accounts for more than 80% of the cases and deaths. “The current outbreak shows similar characteristics to previous outbreaks, except for the large number of cases,” observes Carlos Eduardo Calzavara, vice-director of research at the René Rachou Research Center (Fiocruz Minas). In 2003, there were 58 cases and 21 deaths in the state, and in 2001, there were 32 confirmed cases and 16 deaths. “It is possible that the low vaccination rate in certain regions of the state has had a large influence on its occurrence, but this requires experimental confirmation.” Data from the Minas Gerais State Health Office indicate that on average, just one of every two residents in the state had been vaccinated before the outbreak of the current epidemic. The difficult access to rural areas, and the population’s lack of interest in receiving the immunizations are likely the principal causes for the low coverage. To prevent epidemics, the World Health Organization (WHO) recommends that at least 90% of the population in at-risk areas be vaccinated.

The arrival of the yellow fever virus in areas of Espírito Santo State, where it caused deaths in people and in Atlantic Forest monkeys, was noteworthy. Before the current epidemic, this state was not considered to be an at-risk region. It was outside the area of recommended vaccination, and a high percentage of its population had no immunological defense against this disease. As a result of the appearance of unexpected cases in Espírito Santo, almost the entire state was temporarily included in the zone of recommended vaccination. The same thing occurred in southern Bahia and in northern Rio de Janeiro, although there are no records of local transmission in these two states (see map).

Specialists say that the current yellow fever epidemic is the largest Brazil has seen in the past 70 years, although the official records of the Ministry of Health only date back to 1980 (see graph). “Yellow fever was forgotten. Since the vaccine is quite good, there is almost no research on this disease,” comments infectious disease specialist Benedito Antonio Lopes da Fonseca, of the Ribeirão Preto School of Medicine of the University of São Paulo (FMRP-USP). “We can’t play around with this. Yellow fever can kill up to half of the patients that present with serious symptoms.”

The majority of unvaccinated people who come into contact with the virus may be asymptomatic, or present with headache, fever, muscle pain, nausea, vomiting and fatigue for a period of three days. If it isn’t fatal, the patient becomes immune to the virus and is protected from future infections. For still unknown reasons, around 15% of the people infected by the yellow fever virus develop a severe form of the disease, which, after a week, can cause serious hemorrhaging and lead to death.

CDC / Erskine Palmer Around 15% of the people infected by the yellow fever virus develop a severe form of the diseaseCDC / Erskine Palmer

The circulation of the yellow fever virus that caused the epidemics in Brazil and in the African countries presents different dynamics. Here, the disease only occurs in wild environments, where the virus is kept alive in monkeys, its natural hosts, which are then bitten by Haemagogus and Sabethes mosquitos. In turn, these insects transfer the virus to new monkeys, maintaining a cycle of transmission. Sooner or later, they bite humans who go into the forest. These mosquitos do not live in urban areas. They only reproduce inside holes in trees, where they lay their eggs, which open when rain falls on them.

In Africa, in addition to circulating in forests, yellow fever is also disseminated in urban areas and in border regions between cities and the field through a third form of transmission that is specific to the continent, called rural or intermediary transmission. In cities, only the Aedes aegypti mosquito, the same one that transmits dengue fever, Zika and chikungunya, causes yellow fever if it carries the virus and bites people. In rural environments, Aedes simpsoni mosquitos, which live around human settlements as well as on the edges of forests, also spread yellow fever.

There have been no cases of urban yellow fever in Brazil since 1942. “Based on what we have seen in other epidemics of this disease, breakouts caused by transmission of yellow fever by Aedes aegypti occur when less than 30% of the settlements in a region are infested with the mosquito,” explains virologist Pedro Vasconcelos, director of the Evandro Chagas Institute (IEC), in Pará, one of the authorities on this disease. “I do not think that such high levels exist in Brazil. In the Angola epidemic, average infestation rates were above 50%.”

It is true that parks and wooded areas around cities or located inside city centers may harbor populations of wild mosquitos capable of transmitting yellow fever to humans if they are infected. A recent study conducted by entomologist Mauro Marrelli, of the USP School of Public Health, found more than 90 species of mosquitos in Cantareira State Park in the northern zone of the city of São Paulo, including specimens of the genera Haemagogus and Sabethes. There are also monkeys living in this large wooded area, such as the brown howler, which could theoretically serve as reservoirs for this virus. “We still need to conduct new studies to see whether or not the mosquitos are carrying the yellow fever virus,” says Marrelli.

Cantareira State Park is also the setting for another study, which was started in October 2016 by entomologist Rosa Maria Tubaki, of the Endemic Diseases Control Authority (Sucen), at the São Paulo State Department of Health. She is investigating whether wild yellow fever mosquitos prefer to reproduce in holes in certain trees, and which tree species are preferred by brown howler monkeys. “We hope to provide data that enable us to identify whether the metropolitan region can be an at-risk area for yellow fever outbreaks in humans and in monkeys,” explains Tubaki.

WHO/E. Soteras Jalil The 2016 epidemic in Angola and in the Congo…WHO/E. Soteras Jalil

One of the areas in debate between virologists and epidemiologists is whether yellow fever could once again become an urban disease in Brazil. For this to occur, it would have to go back to being transmitted by Aedes aegypti, which is adapted to Brazilian cities. “If our mosquito is as efficient as the African Aedes aegypti in transmitting yellow fever, we are sitting on top of a time bomb,” comments epidemiologist Eduardo Massad, of the USP School of Medicine. Infectious disease specialist Benedito Antonio Lopes da Fonseca, of FMRP-USP, considers a case or two of sporadic urban yellow fever to be likely in Brazil, but does not believe the objective conditions are present for the outbreak of an epidemic of this disease in the major cities. “If the situation becomes very critical, the entire country may become an area of recommended vaccination,” Fonseca believes. In recent decades, the share of the country in which immunization is recommended has only grown. Almost all of Rio Grande do Sul State is currently an area in which vaccination is permanently recommended.

Vaccine restrictions
Fonseca also questions whether Aedes mosquitos in Brazil are good transmitters of yellow fever. According to a study published in January 2016 in the journal Vector-Borne and Zoonotic Diseases, of which this infectious disease specialist is a co-author, dengue fever infections tend to predominate over yellow fever in cells of Aedes albopictus, a “cousin” of Aedes aegypti, when grown in vitro. If this hypothesis is true, Aedes mosquitos that carry dengue fever virus would be unlikely to be infected by yellow fever.

Vaccination is a major advantage in the fight against yellow fever, compared to other tropical diseases, both old and new, such as dengue fever, malaria, Zika and chikungunya, for which there is no vaccine. Theoretically, it would be easy to contain yellow fever epidemics if the vaccine, which is made with a weakened form of the live virus, could be given to 100% of the population of a region or country. However, there are two reasons why this is not feasible. The first is of a medical nature. The vaccine is not recommended for everyone due to the reactions that it can cause in specific groups, such as pregnant or nursing women, patients with weak immune systems, people over the age of 60, babies less than 6 months old, and those allergic to eggs and to gelatin. “A calculation must be made to determine the ideal percentage of a population that should be vaccinated,” explains Massad. Estimates indicate that for each one million individuals vaccinated, one may have a serious adverse reaction and die.

WHO/E. Soteras Jalil …was controlled using doses that contained 20% of the usual amount of vaccineWHO/E. Soteras Jalil

The second point preventing the generalized use of the vaccine is that it is a scarce product worldwide. There are only six manufacturers that produce it, four of which are certified by the WHO, which maintains an emergency inventory of 6 million doses of the vaccine. The outbreak of the epidemic in Angola and in the Congo caused an international movement that led to the rushed vaccination last year of 30 million people. The lack of vaccine made it necessary to use smaller doses, containing just 0.1 milliliter, a fifth of the normal amount. It is not known for how long such a low dose provides immunity to the disease, but this measure did put an end to the African epidemic.

The Institute of Technology in Immunobiologicals (Bio-Manguinhos), at Fiocruz, in Rio Janeiro, is the principal global producer of the yellow fever vaccine. The epidemic of this disease in Brazil led the Institute to triple its vaccine production in the two first months of 2017. “Previously, we would manufacture from 2 to 3 million doses of vaccine per month,” says chemical engineer Antônio de Padua Risolia Barbosa, vice-director of production at Bio-Manguinhos. “We are now producing between 7 and 9 million doses.” There are other research fronts at the Fiocruz units, such as developing a new vaccine that can be given to everyone, without restrictions. “We tested a DNA vaccine on mice two years ago that was 100% successful in creating immunity,” comments molecular biologist Rafael Dhalia, of Fiocruz in Pernambuco, one of the inventors of the vaccine. “We are looking for partners willing to pay for the clinical tests in humans, which are expensive and take years,” he stated.

1. Distribution of breeding sites in tree hollows for mosquito vectors of yellow fever (Diptera: Culicidae) in the territorial area of brown howlers (Alouatta clamitans) in Cantareira State Park, São Paulo (nº 15/13924-1); Grant Mechanism Regular Research Grant; Principal Investigator Rosa Maria Tubaki (Sucen); Investment R$62,009.70.
2. Biodiversity of mosquitos (Diptera: Culicidae) in Cantareira State Park and in the Capivari – Monos environmental protection area in the state of São Paulo (nº 14/50444-5); Grant Mechanism Regular Research Grant; Biota Program; Principal Investigator Mauro Marrelli (USP); Investment R$280,635.45.

Scientific article
MUCCI, L. F et al. Haemagogus leucocelaenus and other mosquitoes potentially associated with sylvatic yellow fever in Cantareira State Park in the São Paulo metropolitan area, Brazil. Journal of the American Mosquito Control Association. V. 32, No. 4. December 2016.