Yellow Fever Part Finally!

Virus Isolation

Although the Yellow Fever vector was discovered in the early 1900’s, the virus itself was not isolated until almost 1930 as a result of the formation of the second West African Yellow Fever Commission. The commission was formed in 1925. The expedition, lead by Major Henry Beeuwkes, was charged with furthering research into Leptospira (a bacterium considered a potential causative agent), studying the epidemiology of the disease, and determining whether African Yellow Fever was similar to South American Yellow Fever.

In the summer of 1927, blood was taken from a mildly ill African and injected into a monkey, imported from India, which then became the first laboratory host to become infected. Unfortunately, the scientist who made the discovery, a professor from London by the name of Adrian Stokes, died from Yellow Fever not long after. He was, in the grand tradition of science history, quickly replaced by selfish incompetence in the form of a scientist by the name of Hideyo Noguchi. Noguchi had previously attempted to prove a species Leptospira to the be the causative agent and he rekindled his efforts in Africa, though Stokes had already attempted and failed to verify the Leptospira theory.

Not only did Noguchi have a hard time letting go of his theories, he was also a careless and secretive and nobody liked him. He also died of Yellow Fever in 1928, followed by another scientist, William Young, who autopsied Noguchi. As was the case for Reed’s team during the mosquito experiments, this Yellow Fever investigation once again proved itself to be a dangerous puzzle.

Vaccine Development

The development of the Yellow Fever vaccine is long and complex, with many adjustments being made along the way. While this post will not cover every aspect of the process, it is likely to be a bit longer and drier than previous posts. Do your best, dear readers (all 5 of you) to bear with me for the moment. I’ll be starting my second topic this weekend, but I still wanted to finish up with Yellow Fever.

Several years prior to the formation of the West African Yellow Fever Commission, the Rockefeller Foundation’s International Health Commission sent a team to Ecuador to attempt mosquito control. Included in that team was Hideyo Noguchi who, though not completely unimpressive as a person, was evidently not prepared for his theories to be incorrect. Despite the fact that bacteria-based vaccines had been abandoned (since no one had previously been able to filter out a bacterial pathogen) Noguchi claimed he’d been able to find a similar, but not identical, bacteria to the cause of Weil’s disease in the livers of Yellow Fever patients.

While it’s possible he did find bacteria in these patients, it could easily have been a co-infection or even something different from Yellow Fever entirely. After all, many illnesses do share symptoms. In any case, he created a new bacteria-based vaccine for Yellow Fever and began to distribute it widely throughout several countries plagued by the disease. Unfortunately, though likely unsurprisingly to the reader, despite Noguchi’s claims of more than 7,000 successful vaccine administrations, no other scientists were able to replicate his results. In 1926 the vaccine was discontinued.

Following the initial isolation of the virus in a laboratory animal, some attempts were made at creating a vaccine. However, these relied on virus preserved in liver tissue and it became clear pretty quickly that a live virus would be required as well as a more economically feasible laboratory host. Max Theiler, who earlier demonstrated the flaws in Noguchi’s research, knew that mice had been used to grow other viruses and was able to successfully repeat the process using the Yellow Fever virus. He joined the International Health Division of the Rockefeller Institute’s Yellow Fever lab and began work on a vaccine that was needed, initially, to protect researchers.

In 1931 the first viral vaccine was put to trial. Dr. Bruce Wilson, the first to be given the new vaccine, was hospitalized and monitored closely. There were only very minor side effects. While this vaccine created by the Rockefeller Institute was considered the safest of currently available vaccines (others had simultaneously developed a different version) the fact that it required human serum made it expensive and not ideal for large-scale use. Luckily, Hugh Smith, who worked with Theiler, had noticed earlier that a mutated version of the virus appeared to be safer than other versions and could be administered more broadly. It was called 17D and it was put to the test in 1937. By 1939 over a million people had been vaccinated.

Unfortunately, and after a reasonably short time, severe complications began to appear. Over 100 cases of encephalitis (brain swelling, not good) occurred in Brazil and while that was addressed fairly quickly, cases of jaundice were also appearing. During World War II over 7 million vaccines were given and over 25,000 cases of jaundice resulted. The cause was later found to be from people who had donated human serum to be used in the vaccine. While most of the donors were healthy, a few had a history of jaundice that was not discovered until after the vaccine-related cases began appearing in large enough numbers to warrant a strict investigation.

In the 1960’s another complication arose that involved contamination with avian leukosis virus, which is related to the development of cancer cells in mammals. However, filtration and inoculation of the vaccines with antibodies against avian leukosis virus took care of those issues and by the 1980’s there were no more contaminants in the vaccine.

The majority of the information in this post comes from http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2892770/

Present Day

Yellow Fever is far from being a thing of the past. In fact, cases have been increasing over the past 20 years or so, with over 90% of those cases occurring in Africa. This increase is likely a result of increased urbanization and movement of populations in endemic areas, as well as deforestation. The endemic regions include the tropics in both Africa and South America, which includes a population of over 900 million in over 45 different countries. While a vaccine is available to travelers, the disease should not be completely dismissed by people in the United States. The more the number of cases increases, the more likely we are to the see the virus spread to other regions. After all, it’s not as if we’re lacking the vector and it only takes one mosquito to bite one unvaccinated person before we’ve got a problem.

Yellow Fever: Part 3

Severe Historical Outbreaks

Yellow Fever plagued the eastern and southern regions of the United States from the late 1700’s to the early 1900’s. Severe outbreaks occurred in several major cities, including Boston, New York, New Orleans, Baltimore, and Philadelphia. The death rate from the virus is estimated at somewhere between 5 and 10% and– during a time when nobody understood how it was spread or, consequently, what to do about it—that could mean hundreds or even thousands of people dying. This, in combination with increased funeral and medical costs plus mass fleeing of survivors in a number of situations had serious socioeconomic consequences for some of these cities. Since there is so much to choose from, I’ve decided to focus on one major historical outbreak in the United States and the impacts of Yellow Fever on the Panama Canal project.

Memphis 

One of the major factors in my choosing to specialize in disease vectors when I began looking for entomology programs was a book called “The American Plague” by Molly Caldwell Crosby, which tells the story of Yellow Fever in that Memphis. I was also invited to graduate school in Tennessee after completing an internship, so it seems only appropriate to focus on an outbreak in Tennessee.

In 1878 the Yellow Fever virus hit the city of Memphis with an especially devastating epidemic. The disease was poorly understood, but attempts at risk management were made in the form of quarantining boats coming from New Orleans. This is exactly what happened when a nearby town experienced an outbreak, but an infected steamboat worker disobeyed the quarantine and traveled to Memphis. He eventually died from the disease and the first Memphis resident, as far as we know, died of Yellow Fever on August 13^th. What started as a city of 47,000 people rapidly shrank to fewer than 15,000. At least 25,000 people fled and 17,000 of those remaining contracted Yellow Fever. Over 5,000 people died and countless more were left permanently damaged by the disease.

The city was in shambles by the end. Wagons travelled through the streets calling out for survivors to bring out the dead. Entire families were destroyed. Those who were unfortunate enough to be alone when the severe symptoms hit (though their friends and family members almost certainly don’t regret being spared these horrors) were running through the city, delirious, or writhing yellow with jaundice and in serious pain on blood-stained sheets, vomiting black onto the walls around them. Many survivors fled, but some remained behind to help care for the sick. Those who stayed faced a city, once flourishing and full of promise, suddenly bankrupt and all but deserted. Although many who had fled later returned and the city was able to rebuild, the Yellow Fever outbreak of 1878 left a lasting impression.

Panama (Part 1)

In the early 1900’s the Hay-Bunau-Varilla treaty allowed for the start of an intense, politically charged and, for the majority of workers, personally dangerous and devastating project. This was the construction of the Panama Canal. In addition to the direct challenges of labor, the risk of contracting Yellow Fever was high and ever-present. Between 1904 and 1906, over 85% of the workers became ill with either Yellow Fever or Malaria.

The French attempted to construct a canal, but abandoned the project just a decade before the United States began. Over 20,000 workers died from Yellow Fever or Malaria during the French attempt and many who survived disease were left unable to continue working. However, President Roosevelt, in all his mad, glorified, stubborn ambition, would not be deterred. Racist, imperialistic attitudes of American superiority led to carelessness and a belief in a sort of invisibility that only left them terribly unprepared, both emotionally and practically, to deal with an epidemic. In 1905 it became abundantly clear that Americans were by no means safe from disease and almost three quarters of US workers fled in fear…

Yellow Fever: Part 2

The Disease

Yellow Fever is a hemorrhagic fever, meaning it has the potential to cause severe bleeding from mucus membranes (eyes, nose, mouth, stomach lining). While the majority of people who contract the Yellow Fever virus will never show symptoms and will not get sick, for those that do, the outcome could put the worst horror movies (or the best, depending on your preference) to shame. Zombies have nothing on the victims of toxic Yellow Fever and, though it’s true that most people never get sick, enough people do that without prevention methods like good mosquito control tactics, personal protection, and vaccinations the situation can become very devastating very quickly.

There are two symptomatic stages of Yellow Fever: an acute stage and a toxic stage. The acute stage is certainly unpleasant– resulting in fevers, headaches, nausea, and sometimes vomiting, red eyes, general muscle pain, and dizziness. These symptoms will show up somewhere between 3 and 6 days after a bite from an infected mosquito and they will disappear just as quickly. If you’re lucky, that will be the end of it and you can confidently brag to all your friends about how you survived Yellow Fever. Hell, exaggerate the pain a little and maybe get some free drinks out of it.

If you’re not lucky, however, you’ll enter the toxic phase and all of your symptoms will return just a day or two after you started feeling better. In addition, you may develop jaundice—your skin and eyes will begin to turn yellow. Your nausea and vomiting may be replaced with severe abdominal pain and vomiting of blood or black material that, while it may resemble coffee grounds, is really dead blood cells. The bleeding won’t stop there, either. You may bleed from your eyes, your nose, your mouth. Your heart rate will slow. Your immune system may betray you with a cytokine storm. Your organs will start failing. You’ll stop peeing. Your brain will malfunction. Dizziness can become delirium or seizures. Or you may just lapse into a coma. Eventually, if enough of these symptoms take over your body for long enough, you will die. (But, hey, if you don’t die you’ve got a much better story than that other fool who only went through the acute symptoms… in fact, that fool should be buying YOU a drink.)

Again, while the fact that most people will never show symptoms should provide some comfort, the toxic form of the disease is horrific and something that nobody (well… most people) deserves to go through. For this reason, if you’re going to be in an area where Yellow Fever is present it is very important to take preventative measures like getting vaccinated and wearing mosquito repellent. If you do contract the virus, avoid mosquitoes at all cost until it’s out of your system (easier said than done, I know, but there is no treatment for this disease and you don’t want to be the reason someone else got sick).

Yellow Fever: Part 1

The Virus
Yellow Fever is a member of the family Flaviviridae, genus Flavivirus, which cause several different hemorrhagic and encephalitide diseases (aka “bleed-to-death-internally” and “insane-brain-swelling” diseases; aka “no thank you” and “why is this happening”). These viruses are spread by insects—mosquitoes, in this case—as almost everything in this blog will be. For those who are interested in the molecular and structural side of things, Yellow Fever is a positive-sense, single-stranded, RNA virus. What that means for people like me is that, if I’m ever collecting mosquitoes in the field to be screened for the Yellow Fever virus, I’ll have to get them identified, sorted, and stored in a -80ºC freezer as quickly as possible or risk the degradation of the virus and essential destruction of my samples. These viruses are very fragile, which makes their ability to devastate entire cities full of people all the more frustrating, terrifying, and absolutely fascinating.

The Mosquito
Yellow Fever is transmitted to humans mainly by the female Aedes aegypti or, conveniently, the “Yellow Fever” mosquito. 

Originating in Africa and likely transported via ship to the New World during colonization, this mosquito found the warmth and humidity of the southeastern United States to be an ideal breeding ground (though it has since been outcompeted in many areas by Aedes albopictus). As is the case with most mosquitoes in the genus Aedes, these mosquitoes that prefer to lay eggs in shallow pools of standing water. They are desiccant-tolerant, meaning they prefer to dry out and become re-submerged following a rain before they hatch. Basically, they can survive a drought and, being well hidden in their tiny pools and often protected from sprays, can be very difficult to control. This small, dark insect sporting white stripes on her legs and a white lyre-shaped marking on her back has no idea she has been responsible for the deaths of millions of people throughout history.

The Cycle
The Yellow Fever virus is maintained in three transmission cycles: Jungle or Sylvan Yellow Fever is transmitted mainly between mosquitoes and monkeys, but it may also infect researchers and others who venture far enough into the jungles. The mosquito Haemagogus leucocelaenus has been discovered as a potential vector in these cases. Intermediate or Savannah Yellow Fever may be easily transmitted between mosquitoes and either humans or non-human primates and Urban Yellow Fever is almost exclusively transmitted between humans and mosquitoes. This ease of transmission between humans and mosquitoes makes Yellow Fever all the more terrifying. In many cases, as with West Nile virus (another Flavivirus) for example, the mosquito would need to take  blood meal from a reservoir host, such as bird or small mammal before biting a human in order to transmit the virus. Take out the reservoir and the risk of transmission to humans greatly increases. In the case of Yellow Fever, there is the added fact that the female mosquito can pass the virus to her offspring. This means one infected person bitten by one mosquito can quickly become a few hundred more infected mosquitoes and countless more infected persons in a very short period of time.