Yellow fever, a much-feared mosquito-borne virus, has sickened thousands of people and killed hundreds in Angola over the past six months.



A cluster of cases first appeared in Angola's capital, Luanda, in December, and as of June 1, the virus had led to the death of 325 people in 16 of the country's 18 provinces.



Though cases in Angola have been declining in recent weeks, people infected there have already taken the virus to China, Kenya, Mauritania, and the Democratic Republic of the Congo (where at least 21 people have died), a pattern that has the World Health Organization worried. (The agency previously called the outbreak "a potential threat for the entire world.") Three other countries — Ethiopia, Republic of Congo, and the island nation São Tomé and Príncipe — have reported suspected yellow fever cases.

A leading researcher of mosquito-borne diseases, Duane Gubler at Duke-NUS Medical School, is gravely concerned about the outbreak too. "We're sitting on a time bomb waiting for it to blow," he said, "and we're really not doing anything about it."



As scientists try to get a grip on the outbreak in Angola, one fact is already clear: Many other countries are at risk because they're not adequately prepared. Yellow fever is part of an uptick in mosquito-borne diseases all over the world that are suddenly threatening global heath in new and scary ways.

We've had a yellow fever vaccine since 1936, but the global stockpile is running low

Unlike Zika, a virus that until recently was little understood and hardly bothered humans, yellow fever has plagued humanity for centuries.



The virus is carried by infected mosquitoes, most commonly the Aedes aegypti, the same type that carries Zika and dengue. But yellow fever is a much deadlier disease. Symptoms in most people are mild and flu-like: muscle pain, fever, headache, nausea, vomiting, and fatigue. But 15 percent of patients go on to experience a much more severe second phase of illness: high fever, yellowing of the skin and eyes, internal bleeding, and organ failure. Of those, up to half die within two weeks.



The first epidemic was reported in 1648, according to JAMA. In 1793, a yellow fever outbreak wiped out 10 percent of the population of Philadelphia (then the capital of the United States), "causing 17,000 people, including President Washington and other members of the federal government, to flee to the countryside," according to one history of the disease. In 1878, an epidemic "destroyed" Memphis, Tennessee, killing 5,000.



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There's no cure for yellow fever, but a vaccine was developed in 1936, and it's highly effective. Within three or four weeks after receiving the shot, nearly all people are protected from the virus. But in order for the vaccine to really prevent outbreaks, many people need to be immunized.



That's not happening in many parts of Africa, including Angola, where the virus is endemic. Starting in 2006, the World Health Organization, with support from Gavi (an international organization focused on improving vaccine access), ramped up efforts to make sure at-risk communities get vaccinated. But many countries on the continent still have vaccine coverage rates that are much too low to make the vaccine effective.



Take Nigeria. According to Gavi, yellow fever immunization coverage stood at just 49 percent in 2014. There, an outbreak that started in 1986 eventually infected 116,000 people and killed 24,000.



To stop the outbreak, more people in and around Angola will need to be immunized. But there have been challenges with this strategy: Vaccine stockpiles were, until recently, running gravely low. "We have a vaccine," said Seth Berkley, head of Gavi, "but we don't have adequate supplies."

Since the Angolan outbreak sparked late last year, the WHO has given more than 8 million doses to people in the country of more than 21 million. Still, the WHO reported, "The outbreak in Angola remains of high concern due to persistent local transmission in Luanda."



"We don't use [the vaccine] for prevention — we use it for emergency response," said Gubler.



Berkley noted that when the outbreak started to spread in Angola, the systems in place to scale vaccine production couldn't meet the rapid uptick in demand and stockpiles were running low in the spring. By the end of May, the World Health Organization reported that stockpiles were being replenished.



But the outbreak caught the global health community off guard. Globally, there are only six manufacturers of yellow fever vaccine. The supply is usually low because there have been few outbreaks in recent years, and the disease hasn't been as much of a priority for global health groups relative to other diseases.

Researchers fear spread beyond Angola

The countries most at immediate risk are Angola and the Democratic Republic of the Congo — mainly because vaccination efforts haven't been able to stamp out the persistent disease transmission.

For now, global spread has slowed. (That's one reason the WHO decided the outbreak is "serious and of great concern" but not yet an official global health emergency.) But if this situation continues, there's a risk for other highly urbanized areas in sub-Saharan Africa and South America, where a combination of a warm climate, weak health systems, a ready mosquito vector, and densely packed populations with unvaccinated people is particularly worrisome, according to Gubler. (Much of South America is already currently battling outbreaks of dengue and Zika, again both related to yellow fever and carried by the same mosquito.)



There's also some worry that the virus could spread to countries in Asia, including China, where immunization rates are practically nonexistent. Already, unvaccinated guest workers from China returned from Angola with the virus. And infectious disease experts there foresee a potential public health emergency.



"With growing migration and an increasing density of Aedes aegypti [mosquitoes] in Asia, there is an increased risk of yellow fever outbreaks in Asia," researchers from Shanghai Public Health Clinical Center wrote in a recent paper. "If no action is taken, it may spread in Southern China."



The probability of large outbreaks in the US is low, Gubler said, for the same reasons public health officials believe Zika wouldn't spread very far here: Many people live in air-conditioned homes that aren't hospitable to mosquitoes. We also have much stronger health systems to prepare and respond to outbreaks.



But in a PLOS post, tropical medicine experts Peter Hotez and Kristy Murray from Baylor College of Medicine asked the question, "Could Yellow Fever Return to the United States?" Their answer was a resounding yes.



Berkley agreed that if the outbreak isn't contained and spreads in the regions most at risk, it will inevitably reach the US. "If you want to protect the US from yellow fever," he said, "you have to have those countries that have yellow fever now vaccinated."

Why yellow fever started to spread in Angola is still a mystery

It's not clear why, after decades of only sporadic outbreaks in Africa, yellow fever suddenly got nasty in Angola. But the outbreak is a reminder of what can happen when our short-term planning for epidemics collides with the rapid globalization of tropical diseases.



Yellow fever is related to the Zika, dengue, and chikungunya viruses, all spread by Aedes aegypti and all seen outbreaks in new regions of the world lately.



African cities have also grown extensively, said Gubler, and the Aedes aegypti mosquito lives very comfortably in urban areas, feeding off the densely packed humans.



Heidi Brown, a professor of epidemiology at the University of Arizona, explained there are at least three factors that help viruses like these spread: the number of mosquitoes out there, the number that are biting humans infected with the virus, and the number that are surviving long enough to infect other humans.



"The survival of the mosquito is driven a lot by temperature," she added — it also needs moisture to thrive. "So people go to the idea of global warming — that climate change and changes in precipitation patterns and temperature are helping mosquitoes survive in different areas." In other words, warming is helping expand the range of places that are habitable to mosquitoes.



There are other factors that may be driving the trend, too: People are traveling more than ever, bringing diseases to new locales. And with more people living in crowded cities, it's easy for viruses to jump from person to person and for mosquitoes to find large concentrations of humans to feast on.



It also doesn't help that the mosquito control programs that started after the Second World War have also been victims of their own success.



"Health authorities couldn't see any sense in continuing to spend a lot of money to control diseases that weren't occurring, so the programs were disbanded," explained Gubler. "At the same time, many countries disbanded their public health infrastructure to deal with vector-borne diseases." That's why some countries may be woefully unprepared if yellow fever comes surging in.



Researchers will need to study Angola's yellow fever outbreak to better understand precisely why the disease is back and whether the virus has mutated to spread more effectively among humans. For now, though, Gubler wants to see fast mobilization to prevent the Angola outbreak from getting worse. He thinks vector control and a scaling up of vaccine production so more people in at-risk communities can be immunized will help.



"We live in a crisis-oriented society," he said. "We're always chasing the fire instead of preventing it. With dengue, Zika, chikungunya, you can get away with that. But yellow fever has a high fatality rate, and it could create chaos in the world."