Eye on ID

Yellow fever: Still a menace for humans and other primates

Yellow fever virus and its mosquito vector, Aedes aegypti, arrived in Barbados in 1647 from forests in Africa — where it still is endemic — via the slave trade and quickly spread to other Caribbean islands. Twenty-five major outbreaks subsequently occurred in the United States. Probably the most famous of these outbreaks happened in Philadelphia, which at that time was the U.S. capital. The first outbreak occurred there in 1793 and left 5,000 people dead out of a population of 50,000. Other significant outbreaks in the U.S. occurred over a nearly 100-year period: Savannah, Georgia, in 1820; New Orleans in 1853; Norfolk, Virginia, in 1855; Texas and Louisiana in 1867; and the Lower Mississippi Valley in 1878. That is ancient U.S. history, so why worry now?

Recent large outbreaks

Currently, yellow fever is endemic only in parts of South America and Africa. Outbreaks are still occurring in some of these areas, despite the availability of a very effective vaccine that provides lifelong immunity.

Thomas M. Yuill
Donald Kaye

An outbreak in Angola began with the report of a single case in December 2015, followed by 26 confirmed cases in Viana, a suburb of the capital Luanda, in January 2016. The outbreak rapidly spread throughout the province and beyond as viremic individuals traveled around the country. The disease spilled over into neighboring Democratic Republic of the Congo (DRC), posing a threat to the 12 million people living in and around its capital, Kinshasa. WHO and 55 other international organizations stepped in to assist with massive vaccination campaigns in both countries. Official mention was made of control of the mosquito vector, A. aegypti, but with no indication of the measures used nor how effective they were in halting or slowing the outbreak. As the outbreak progressed, there was not enough vaccine available to cover the millions of people at risk, so fractionated doses (one-fifth the usual volume) were administered. The outbreak caused 965 confirmed cases of yellow fever across the two countries, with thousands more cases suspected. The last case detected in Angola was on June 23, 2016, and DRC’s last case was on July 12 of that year. More than 30 million people were vaccinated in the two countries in emergency vaccination campaigns. This unprecedented response exhausted the global stockpile of yellow fever vaccines on several occasions.

The current outbreak in Brazil is epidemiologically different. Yellow fever virus is endemic in the Amazon basin, including Brazil. Every year, there are a few sporadic, isolated human cases when the virus spills over from the sylvan (forest or jungle) transmission cycle to humans. That cycle involves forest mosquitoes in the genera Haemagogus and Sabethes, which feed preferentially on nonhuman primates. Some of the monkeys develop clinical yellow fever and die. In November 2016, the Center for Epidemiological Surveillance of the state of São Paulo’s Secretariat of Health issued a health alert following a series of deaths of monkeys that contracted the disease in regional municipalities, indicating a risk for human infection as well. This concern was well-founded. Instead of isolated human cases and monkey deaths in several states, human cases began to increase. The Brazilian Ministry of Health reported an ongoing outbreak of yellow fever starting in December 2016. In Minas Gerais state in January 2017, there were 48 suspected human cases and 14 deaths, most of which were in three municipalities. Those numbers increased within 2 weeks to 110 cases and 30 deaths, and the governor of the state declared a health emergency. Health officials initiated vaccination campaigns; a significant proportion of the population in the affected towns had not been vaccinated previously. There were A. aegypti present, posing a real danger of an urban outbreak, which occurred in Paraguay in 2008. Additional cases were reported from several other states. As of Jan. 26, 2017, 550 human cases were reported nationally (many suspected but not laboratory confirmed), with 502 cases in Minas Gerais state, 33 in Espírito Santo state, seven in Bahia state, three each in the Federal District and São Paulo state and one in Goiás state. By Feb. 2, 2017, the number of reported cases increased to 901, with 65 confirmed deaths. Most cases occurred in the southeastern Minas Gerais state, where 56 people died.

The outbreak has continued to the present time. Brazil had 1,157 confirmed cases and 342 deaths from July 1, 2017, to April 17 of this year. The states most affected during the outbreak have been São Paulo with 2,558 reported cases, Minas Gerais with 1,444, Rio de Janeiro with 453, and Espírito Santo with 119. Of great concern is that the yellow fever virus is circulating in metropolitan regions of the country, where most of the population lives, totaling 35.6 million residents — including those living in areas that have never been recommended for vaccination. The good news so far is that all these human cases have resulted from spillover of the sylvan transmission cycle, and not from urban transmission via A. aegypti, which could result in much larger outbreaks. The recent occurrence of dengue, chikungunya and Zika viruses in these areas indicates that there are abundant populations of A. aegypti that could transmit yellow fever virus in addition to transmitting these other endemic viruses.

Effect on nonhuman primates

The expansion of yellow fever in Brazil, besides being a public health problem, also has raised concerns about potential conservation problems for susceptible nonhuman primate species. By late February 2017, reports of dead monkeys had come from the Federal District and 14 states. Of the New World primates, howler (Alouatta species) and spider (Ateles species) monkeys are the most susceptible species, and infection with yellow fever virus is almost always fatal. At greatest risk for adverse population effects is the muriqui monkey, Brazil’s largest primate and one of the planet’s 25 most endangered primate species. There are two species of muriqui monkey in Brazil — the northern muriqui (Brachyteles hypoxanthus), which has been on the International Union for Conservation of Nature’s critically endangered list for more than 25 years, and the southern muriqui (Brachyteles arachnoides), which has been placed on that list more recently. In Brazil’s Atlantic rainforest region in Espírito Santo state, deaths have been mostly in brown (Alouatta guariba) and masked titis (Callicebus personatus), which are the nonhuman primates most affected in this outbreak. However, the buffy-headed marmoset (Callithrix flaviceps), a rare species of marmoset endemic to the rainforests of southeastern Brazil, was also infected.

Unfortunately, there is no feasible way to prevent these primates from becoming infected with yellow fever virus in the forest.

Potential for spread of yellow fever

Although the recent yellow fever outbreaks in Angola and the DRC as well as the current outbreak in Brazil have been located far from the U.S., there is reason for concern here and elsewhere. The virus is endemic in sub-Saharan Africa and in South America but has been spread by viremic individuals via international air transport to other countries where the virus has been absent. The first of these instances that sounded alarm bells occurred in April 2016, when 11 unvaccinated Chinese workers in Angola became infected and returned to China while ill. These are the first documented cases of yellow fever in Asia. Fortunately, there were no vector mosquitoes active during the season of their return. At that time, it was estimated that there were 259,000 Chinese workers in Angola, and reports indicated that only some of them had been vaccinated against yellow fever, despite vaccination being required by International Health Regulations. The Brazilian outbreak also has been a source of infection of international travelers, mostly from Europe, where there was no possibility of ongoing mosquito transmission.

Howler monkeys are among the New World primates at greatest risk for yellow fever virus infection.

Source: Adobe Stock

A recently published study of the risk of international dissemination of yellow fever virus to countries currently free of the virus is sobering. The authors reported that in 2016, 45.2 million international air travelers spent time in yellow fever-endemic areas of the world. Of 11.7 million travelers with destinations in 472 cities where yellow fever was not endemic but were suitable for virus transmission, 7.7 million (65.7%) were not required to provide proof of vaccination upon arrival even though they came from countries where yellow fever is endemic. Brazil, China, India, Mexico, Peru and the U.S. had the highest volumes of travelers arriving from yellow fever-endemic areas and the largest populations living in cities suitable for yellow fever transmission. Researchers pointed out that all of Central America, many areas in Mexico and South and Southeast Asia are at risk for yellow fever virus introduction and ongoing transmission because they have abundant populations of A. aegypti, and most of the population is unvaccinated. Getting ahead of an outbreak in any of these regions could be difficult, as it was in Angola and has been in Brazil. Currently, global yellow fever vaccine supplies are diminished, and an epidemic in a densely populated city could have substantial health and economic consequences before the disease is brought under control.

Concerns for the US

Should those residing in the U.S. be concerned? Locally acquired dengue and Zika viruses have both been reported in south Florida in recent years, transmitted by A. aegypti. Almost 2.8 million people flew to the U.S. from endemic yellow fever areas in 2016. Miami is at risk for a yellow fever outbreak because the city does not check travelers arriving from endemic areas. In early 2017, the CDC warned American citizens to take extra precautions if traveling to affected areas in Brazil. Those warnings are relevant for travel to any yellow fever virus-endemic area.

Vaccine availability

Steps are being taken internationally to reduce the risk for yellow fever outbreaks. A broad coalition of partners, including WHO, recently developed a new strategy called Eliminate Yellow Fever Epidemics (EYE) to strengthen global action and integrate lessons learned from the outbreaks in Angola and the DRC. Key components of the EYE strategy include measures to ensure that people are vaccinated before an outbreak strikes, to increase the number of global vaccine stockpiles for outbreak response, and support for greater preparedness in the most at-risk countries. However, vaccine availability is likely to be a limiting factor in the prevention and control of outbreaks. Current supplies may not be adequate to halt a swiftly moving outbreak. Even in preventive vaccination campaigns, vaccine availability may be a limiting factor. As a matter of public health policy, Brazil plans to vaccinate all 77.5 million of its citizens within the next year. WHO-preapproved vaccines are produced by only four companies. There are two additional companies that produce vaccines that are not preapproved. In total, 50 to 100 million doses are produced annually. Rapid increases in vaccine production are not possible because the vaccine is produced in embryonated chicken eggs. A shift to production in a continuous line of cell cultures that would permit rapid scale-up has not been successful in the past but may be possible in the future.

Control of A. aegypti

Vaccination remains the main preventive measure because control of A. aegypti populations has been very difficult. However, there have been some promising developments on this front. Two of these are the release of genetically modified male mosquitoes that introduce genes in the population that result in larvae that do not develop; and the production and release of sterile male mosquitoes that mate with wild females resulting in infertile eggs. Both approaches have been successfully field tested but both require the establishment of “mosquito factories,” and the mosquitoes must be released in the field over long periods of time. One approach that avoids that kind of long-term commitment is to infect populations of A. aegypti with Wolbachia bacteria. These endosymbiont bacteria block the establishment of midgut infections by Zika and dengue viruses, and probably would do so for yellow fever virus as well. Using drones to air drop genetically altered males or Wolbachia-infected mosquitos has been shown to be feasible, making these approaches logistically more practical.

Future challenges

Many lessons have been learned from the recent yellow fever outbreaks, but many challenges remain. At the local level, can high percentages of the population remain vaccinated over the long term? Can active surveillance be maintained to detect yellow fever cases due to spillover from the sylvan cycle before an urban cycle is triggered? Will contingency plans be continuously updated and teams ready to respond quickly when cases are identified? Will laboratory support with the necessary trained personnel and reagents be continuously available? All these measures require training and financing. With a disease such as yellow fever, which may occur only sporadically, preparedness is not easy because an integrated detection-response system must compete with other immediate social demands for resources. As time passes, decision-makers come and go, and institutional memory fades. One hopes this is not the case in countries at risk for yellow fever outbreaks.

Disclosures: Kaye and Yuill report no relevant financial disclosures.

Yellow fever virus and its mosquito vector, Aedes aegypti, arrived in Barbados in 1647 from forests in Africa — where it still is endemic — via the slave trade and quickly spread to other Caribbean islands. Twenty-five major outbreaks subsequently occurred in the United States. Probably the most famous of these outbreaks happened in Philadelphia, which at that time was the U.S. capital. The first outbreak occurred there in 1793 and left 5,000 people dead out of a population of 50,000. Other significant outbreaks in the U.S. occurred over a nearly 100-year period: Savannah, Georgia, in 1820; New Orleans in 1853; Norfolk, Virginia, in 1855; Texas and Louisiana in 1867; and the Lower Mississippi Valley in 1878. That is ancient U.S. history, so why worry now?

Recent large outbreaks

Currently, yellow fever is endemic only in parts of South America and Africa. Outbreaks are still occurring in some of these areas, despite the availability of a very effective vaccine that provides lifelong immunity.

Thomas M. Yuill
Donald Kaye

An outbreak in Angola began with the report of a single case in December 2015, followed by 26 confirmed cases in Viana, a suburb of the capital Luanda, in January 2016. The outbreak rapidly spread throughout the province and beyond as viremic individuals traveled around the country. The disease spilled over into neighboring Democratic Republic of the Congo (DRC), posing a threat to the 12 million people living in and around its capital, Kinshasa. WHO and 55 other international organizations stepped in to assist with massive vaccination campaigns in both countries. Official mention was made of control of the mosquito vector, A. aegypti, but with no indication of the measures used nor how effective they were in halting or slowing the outbreak. As the outbreak progressed, there was not enough vaccine available to cover the millions of people at risk, so fractionated doses (one-fifth the usual volume) were administered. The outbreak caused 965 confirmed cases of yellow fever across the two countries, with thousands more cases suspected. The last case detected in Angola was on June 23, 2016, and DRC’s last case was on July 12 of that year. More than 30 million people were vaccinated in the two countries in emergency vaccination campaigns. This unprecedented response exhausted the global stockpile of yellow fever vaccines on several occasions.

The current outbreak in Brazil is epidemiologically different. Yellow fever virus is endemic in the Amazon basin, including Brazil. Every year, there are a few sporadic, isolated human cases when the virus spills over from the sylvan (forest or jungle) transmission cycle to humans. That cycle involves forest mosquitoes in the genera Haemagogus and Sabethes, which feed preferentially on nonhuman primates. Some of the monkeys develop clinical yellow fever and die. In November 2016, the Center for Epidemiological Surveillance of the state of São Paulo’s Secretariat of Health issued a health alert following a series of deaths of monkeys that contracted the disease in regional municipalities, indicating a risk for human infection as well. This concern was well-founded. Instead of isolated human cases and monkey deaths in several states, human cases began to increase. The Brazilian Ministry of Health reported an ongoing outbreak of yellow fever starting in December 2016. In Minas Gerais state in January 2017, there were 48 suspected human cases and 14 deaths, most of which were in three municipalities. Those numbers increased within 2 weeks to 110 cases and 30 deaths, and the governor of the state declared a health emergency. Health officials initiated vaccination campaigns; a significant proportion of the population in the affected towns had not been vaccinated previously. There were A. aegypti present, posing a real danger of an urban outbreak, which occurred in Paraguay in 2008. Additional cases were reported from several other states. As of Jan. 26, 2017, 550 human cases were reported nationally (many suspected but not laboratory confirmed), with 502 cases in Minas Gerais state, 33 in Espírito Santo state, seven in Bahia state, three each in the Federal District and São Paulo state and one in Goiás state. By Feb. 2, 2017, the number of reported cases increased to 901, with 65 confirmed deaths. Most cases occurred in the southeastern Minas Gerais state, where 56 people died.

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The outbreak has continued to the present time. Brazil had 1,157 confirmed cases and 342 deaths from July 1, 2017, to April 17 of this year. The states most affected during the outbreak have been São Paulo with 2,558 reported cases, Minas Gerais with 1,444, Rio de Janeiro with 453, and Espírito Santo with 119. Of great concern is that the yellow fever virus is circulating in metropolitan regions of the country, where most of the population lives, totaling 35.6 million residents — including those living in areas that have never been recommended for vaccination. The good news so far is that all these human cases have resulted from spillover of the sylvan transmission cycle, and not from urban transmission via A. aegypti, which could result in much larger outbreaks. The recent occurrence of dengue, chikungunya and Zika viruses in these areas indicates that there are abundant populations of A. aegypti that could transmit yellow fever virus in addition to transmitting these other endemic viruses.

Effect on nonhuman primates

The expansion of yellow fever in Brazil, besides being a public health problem, also has raised concerns about potential conservation problems for susceptible nonhuman primate species. By late February 2017, reports of dead monkeys had come from the Federal District and 14 states. Of the New World primates, howler (Alouatta species) and spider (Ateles species) monkeys are the most susceptible species, and infection with yellow fever virus is almost always fatal. At greatest risk for adverse population effects is the muriqui monkey, Brazil’s largest primate and one of the planet’s 25 most endangered primate species. There are two species of muriqui monkey in Brazil — the northern muriqui (Brachyteles hypoxanthus), which has been on the International Union for Conservation of Nature’s critically endangered list for more than 25 years, and the southern muriqui (Brachyteles arachnoides), which has been placed on that list more recently. In Brazil’s Atlantic rainforest region in Espírito Santo state, deaths have been mostly in brown (Alouatta guariba) and masked titis (Callicebus personatus), which are the nonhuman primates most affected in this outbreak. However, the buffy-headed marmoset (Callithrix flaviceps), a rare species of marmoset endemic to the rainforests of southeastern Brazil, was also infected.

Unfortunately, there is no feasible way to prevent these primates from becoming infected with yellow fever virus in the forest.

Potential for spread of yellow fever

Although the recent yellow fever outbreaks in Angola and the DRC as well as the current outbreak in Brazil have been located far from the U.S., there is reason for concern here and elsewhere. The virus is endemic in sub-Saharan Africa and in South America but has been spread by viremic individuals via international air transport to other countries where the virus has been absent. The first of these instances that sounded alarm bells occurred in April 2016, when 11 unvaccinated Chinese workers in Angola became infected and returned to China while ill. These are the first documented cases of yellow fever in Asia. Fortunately, there were no vector mosquitoes active during the season of their return. At that time, it was estimated that there were 259,000 Chinese workers in Angola, and reports indicated that only some of them had been vaccinated against yellow fever, despite vaccination being required by International Health Regulations. The Brazilian outbreak also has been a source of infection of international travelers, mostly from Europe, where there was no possibility of ongoing mosquito transmission.

PAGE BREAK
Howler monkeys are among the New World primates at greatest risk for yellow fever virus infection.

Source: Adobe Stock

A recently published study of the risk of international dissemination of yellow fever virus to countries currently free of the virus is sobering. The authors reported that in 2016, 45.2 million international air travelers spent time in yellow fever-endemic areas of the world. Of 11.7 million travelers with destinations in 472 cities where yellow fever was not endemic but were suitable for virus transmission, 7.7 million (65.7%) were not required to provide proof of vaccination upon arrival even though they came from countries where yellow fever is endemic. Brazil, China, India, Mexico, Peru and the U.S. had the highest volumes of travelers arriving from yellow fever-endemic areas and the largest populations living in cities suitable for yellow fever transmission. Researchers pointed out that all of Central America, many areas in Mexico and South and Southeast Asia are at risk for yellow fever virus introduction and ongoing transmission because they have abundant populations of A. aegypti, and most of the population is unvaccinated. Getting ahead of an outbreak in any of these regions could be difficult, as it was in Angola and has been in Brazil. Currently, global yellow fever vaccine supplies are diminished, and an epidemic in a densely populated city could have substantial health and economic consequences before the disease is brought under control.

Concerns for the US

Should those residing in the U.S. be concerned? Locally acquired dengue and Zika viruses have both been reported in south Florida in recent years, transmitted by A. aegypti. Almost 2.8 million people flew to the U.S. from endemic yellow fever areas in 2016. Miami is at risk for a yellow fever outbreak because the city does not check travelers arriving from endemic areas. In early 2017, the CDC warned American citizens to take extra precautions if traveling to affected areas in Brazil. Those warnings are relevant for travel to any yellow fever virus-endemic area.

Vaccine availability

Steps are being taken internationally to reduce the risk for yellow fever outbreaks. A broad coalition of partners, including WHO, recently developed a new strategy called Eliminate Yellow Fever Epidemics (EYE) to strengthen global action and integrate lessons learned from the outbreaks in Angola and the DRC. Key components of the EYE strategy include measures to ensure that people are vaccinated before an outbreak strikes, to increase the number of global vaccine stockpiles for outbreak response, and support for greater preparedness in the most at-risk countries. However, vaccine availability is likely to be a limiting factor in the prevention and control of outbreaks. Current supplies may not be adequate to halt a swiftly moving outbreak. Even in preventive vaccination campaigns, vaccine availability may be a limiting factor. As a matter of public health policy, Brazil plans to vaccinate all 77.5 million of its citizens within the next year. WHO-preapproved vaccines are produced by only four companies. There are two additional companies that produce vaccines that are not preapproved. In total, 50 to 100 million doses are produced annually. Rapid increases in vaccine production are not possible because the vaccine is produced in embryonated chicken eggs. A shift to production in a continuous line of cell cultures that would permit rapid scale-up has not been successful in the past but may be possible in the future.

PAGE BREAK

Control of A. aegypti

Vaccination remains the main preventive measure because control of A. aegypti populations has been very difficult. However, there have been some promising developments on this front. Two of these are the release of genetically modified male mosquitoes that introduce genes in the population that result in larvae that do not develop; and the production and release of sterile male mosquitoes that mate with wild females resulting in infertile eggs. Both approaches have been successfully field tested but both require the establishment of “mosquito factories,” and the mosquitoes must be released in the field over long periods of time. One approach that avoids that kind of long-term commitment is to infect populations of A. aegypti with Wolbachia bacteria. These endosymbiont bacteria block the establishment of midgut infections by Zika and dengue viruses, and probably would do so for yellow fever virus as well. Using drones to air drop genetically altered males or Wolbachia-infected mosquitos has been shown to be feasible, making these approaches logistically more practical.

Future challenges

Many lessons have been learned from the recent yellow fever outbreaks, but many challenges remain. At the local level, can high percentages of the population remain vaccinated over the long term? Can active surveillance be maintained to detect yellow fever cases due to spillover from the sylvan cycle before an urban cycle is triggered? Will contingency plans be continuously updated and teams ready to respond quickly when cases are identified? Will laboratory support with the necessary trained personnel and reagents be continuously available? All these measures require training and financing. With a disease such as yellow fever, which may occur only sporadically, preparedness is not easy because an integrated detection-response system must compete with other immediate social demands for resources. As time passes, decision-makers come and go, and institutional memory fades. One hopes this is not the case in countries at risk for yellow fever outbreaks.

Disclosures: Kaye and Yuill report no relevant financial disclosures.

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