* Science against yellow fever

The story of the fight against yellow fever is related to military needs, as evidenced by a publication of the United States of America's "Walter Reed" Army Medical Center  ("Biography of Major Walter Reed"), and documents collected for years by Philip Hench (available at the "Philip S. Hench Walter Reed Yellow Fever Collection", the Rector and Visitors of the University of Virginia, http://yellowfever.lib.virginia.edu/reed). And even though the vaccine that fights it already has over 70 years of use since its discovery, all who might ever need it, or their parents or guardians, must be correctly informed about the benefits and risks of this method of prevention, as warned by Sanofi Pasteur, one of the manufacturers.

This disease probably reached the New World from Africa, imported on board ships of the infamous slave trade. The first epidemic that has been reported occurred between 1647 and 1649 in Barbados, Cuba and Mexico. Griffin Hughes is credited with first using the term "yellow fever" in 1750.

The illness passed from the Caribbean and Central America to North America, where until 1900 one hundred epidemics had been declared. The one of 1793 killed 10% of the population of Philadelphia, at that time still the capital of the United States of America, forcing the evacuation of the government.

In 1802, almost 90% of Napoleon's expeditionary troops were killed by this disease. This would have later influenced the sale, by France, of the territory of Louisiana.

Perhaps the most famous setback that the French received was the paralyzing of the construction of the Panama Canal in the late nineteenth century.

By 1900, after the war between the U.S. and Spain, Dr. Walter Reed was sent by his commander George Sternberg to Cuba to study the yellow fever situation. Apparently, there was no place more infested than the city of La Havana.

At the beginning they followed a theory by Italian Giuseppe Sanarelli, that yellow fever would be the outcome of a bacterium, implying direct contact or through objects, but with help from Aristides Agramonte they found that this idea was not sustainable.

Then, apparently following tips from British researchers, Reed's team paid special attention to what a local physician, Carlos Finlay, was theorizing. Since 1881, he held that yellow fever was transmitted by a mosquito. In 1882 he concluded that it was the one now known as "Aedes aegypti", but his proofs were not conclusive. The suspicions of Finlay and other scientists before and after him, were based in part on the fact that yellow fever infected some members of a household but not others, despite the daily cohabitation. There was also a noticeable waiting period of several weeks between one infection and the next, longer than the incubation time, a phenomenon that Dr. Henry Rose Carter (performing observations in Mississippi) hinted that was due to some intermediate host, to the point of applying to this phenomenon the technical name of extrinsic incubation period. 

When Carter also came to Cuba, he commented his findings to Jesse Lazear, from the "Yellow Fever Commission" headed by Dr. Reed. Dr. Finlay provided eggs of "Aedes aegypti" to this commission and several of its members began to manipulate these mosquitoes. Some became sick, and still one of them, the same Jesse Lazear, unfortunately died.

Reed was moved by the death of his collaborator, but this terrible loss became hope, when analyzing the field notes he had left.

To remove any doubt about the method of transmission of yellow fever, Reed's team decided to conduct controlled experiments, but failed to find any animal susceptible to be infected with yellow fever. Then they saw no choice but to organize a dramatic experiment with human volunteers, Spanish and U.S. persons, to whom the risk were explained. Regarding this decision, we must understand that, anyway, the probability of contracting yellow fever in the streets of La Havana was also very high.

Two cottages were prepared in an isolated place and under strict quarantine, near the town of Quemados, 10 km from La Havana. In one of them a group of volunteers would be in constant contact with clothing, blankets and other items from people who had fallen ill. In the other cottage, half of its inhabitants would be exposed to infected mosquitoes, while the other half would be protected. The experiment ran between 30 November 1900 and 31 January 1901. The result was that those who had been exposed to mosquitoes got sick, and the rest did not. Finlay's theory was proven: the "Aedes aegypti" was responsible for the epidemics of yellow fever. (Happily, all volunteers in this experiment who got sick recovered, although many did not want to ever hear about Dr. Reed anymore.)

Armed with this knowledge, William Gorgas, then Chief of Health, Department of Cuba, sent inspection crews to verify all households in La Havana, making sure there were no standing water that could serve as nursery, and properly cover other household reservoirs. With this, a disease that had been a constant hell to the city for over 150 years, practically disappeared almost miraculously in 150 days. (The official press in Cuba defends another version, concentrating the accomplishments around Carlos Finlay and accusing the U.S. of plagiarism).

Some years later, U.S. specialists applied the same techniques to the Panama Canal zone, controlling yellow fever and malaria (which, as discovered in 1898, is transmitted by the "Anopheles" mosquito), and allowing the conclusion of one of the most important civil works in History.

YELLOW FEVER VACCINE

In 1901, another of Reed's collaborators, James Carroll, found that contaminated blood could cease to be if heat was applied, indicating that a microbe was present, but at the same time he could not remove it by special filtration processes, leading him to suppose that it should be very small: a virus.

Gorgas and Dr. Juan Guiteras were intrigued by the absence of deaths in Reed's experiments, and set out to see if there was any way to generate immunity to individuals through slight exposures to the illness. Their experiments produced some interesting results, but everything ended in tragedy when three volunteers, including nurse Clara Maass, got seriously ill and died. From there on, these dangerous experiments on humans were suspended.

In 1927, Carroll's assumption was confirmed by Adrian Stokes, Johannes Bauer, and Paul Hudson, of the Rockefeller Foundation, and by researchers of the Pasteur Institute, who were able to isolate the yellow fever virus. (Unfortunately Stokes also became a victim.)

It was discovered that certain species of monkeys are susceptible of getting sick from the virus, and under certain conditions also mice, greatly facilitating the works.

By 1937, starting by the virus obtained from a young patient from Ghana named Asibi, a team led by Max Theiler and Hugh Smith finally managed to produce a vaccine (called 17D), which in two variants is the one used to this day.

For his achievements in the fight against yellow fever, Dr. Max Theiler received The Nobel Prize in Physiology or Medicine 1951.

VACCINE EFFICACY AND SIDE EFFECTS

There are currently two versions of the yellow fever vaccine: the 17DD, made by Bio-Manguinhos/FIOCRUZ in Brazil, and 17D-204, produced, among others, by Sanofi Pasteur France (trade name Stamaril) and Sanofi Pasteur U.S.A. (YF-VAX).

Bio-Manguinhos/FIOCRUZ reports that immunity occurs after the tenth day, lasting for at least 10 years.

Sanofi Pasteur complements that 17D vaccines were evaluated in several non-controlled studies since the late 1930. In 24 studies conducted in different parts of the world between 1962 and 1997, comprising a total of 2529 adults and 991 infants and children, the efficacy was over 91% in all but two studies, in which a value of 81% was reached. Five of these studies were conducted in the United States of America until 1993, with 208 adults. In one, with 32 people, the efficacy was 81% and in the other four studies it ranged from 97% to 100%.

In 2001, the U. S. Sanofi Pasteur vaccine was compared in a clinical trial with a vaccine produced by Evans Vaccines, United Kingdom (Arilvax). In nine medical centers, a total of 715 people (over 18 years old) received the vaccine from Evans Vaccines and 725 the other from Sanofi Pasteur. Blood tests were performed on 283 and 291 people at the beginning of the experiment and after 30 days. In the first group 98,6% developed immunity, and 99,3% in the second group.

Bio-Manguinhos/FIOCRUZ reports that adverse reactions to yellow fever vaccine are generally mild. Between 2% and 5% of vaccinees may experience headaches, muscle aches, mild fever and other symptoms between the fifth and tenth day.

Sanofi Pasteur reports that there have been no 17D vaccine experiments using placebos ("fake" drugs but identical in appearance to the real ones, to rule out psychological effects). However, between 1953 and 1994 the 17D-204 was studied, although in non-controlled ways, in 3933 adults and 264 children over 4 months old. Local reactions such as redness and pain at the injection site as well as headaches and fever occurred in less than 5% of the patients, 5 to 7 days after vaccination. In a study with 115 infants from 4 to 24 months old the incidence of fever reached 21%.

The study from 2001 quoted above, conducted by Thomas Monath and colleagues ("American Journal of Tropical Medicine and Hygiene," Vol 66, No.5, 2002, pages 553-541), was of the "double blind" type, in order to minimize psychological effects, that is, neither the patient nor the physician knew which injection was applied to each individual, only the directors of the study. For the English vaccine and the U.S. vaccine respectively, 35% and 28% of people had no side effects, 29% and 30% felt weakness, 11% and 10% chills, 14 and 15% fever, 32 and 31% headache, 2 and 3% infections, 9 and 20% edema at the site of injection, 16 and 29% local inflammation, 24 and 39% local pain, 4 and 6% localized reaction, 19 and 18% malaise, and 2 and 2% various pains. Nausea, 3% and 3%; muscle pains, 24% and 25%; nervous system problems, 5 and 5%; pharyngitis, 2 and 1%; rhinitis, 3 and 2%; and rash, 3 and 3%. Urticaria (strongly-itchy cutaneous rash) was present in 0,1% and 0,3% of vaccinees, respectively.

In addition, some people have severe allergic reactions almost instantly. In 1999, John Kelso, Gina Mootrey and Theodore Tsai observed that their incidence is in 1 in 130 000 people. Sanofi Pasteur warns that measures shall be taken to always have available, for immediate use and instantly, an injection of adrenaline (also known as epinephrine) at a concentration of 1 : 1000, to succor anyone who might be affected ("Yellow Fever Vaccine YF-VAX ®." Product Information, Sanofi Pasteur Inc., Swiftwater, Pennsylvania, August 2007). 

Serious complications of unknown origin exist too. Between 1952 and 2004, there were 21 cases of serious neurological problems. In a study conducted in Kenya in 1993, it was estimated that the incidence is 5 cases per million people vaccinated. Also, between 1996 and 1998 there were 4 cases of severe multiple organ failure in the United States of America, the incidence being calculated at 1 in 400 000 people. There were reports in Australia and Brazil, although more sparsely. These reactions have not yet been explained.

If you had any problems, please inform the authorities. Due to its side effects, the yellow fever vaccine is only given to people in endemic areas. But without it, according to estimates from 2002 by Thomas Monath and Martin Cetron, the probability of dying is 1 in 17 000, per season.

A. L.

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Originally published in ABC Color, on 30 March 2008. Photo: "Camp Lazear", near Quemados, Cuba, where Walter Reed dramatically tested the theory of Carlos Finlay on yellow fever transmission, in 1900-1901. On the left, in foreground, the "infected mosquito building"; on the right, further back, the "infected clothing building". Credit: from the negative number 40731 of the U.S. Army Medical Museum, now the National Museum of Health and Medicine, via the S. Philip Hench Walter Reed Yellow Fever Collection, available at http://etext.virginia.edu/healthsci/reed, courtesy of the Historical Collections & Services, Claude Moore Health Sciences Library, University of Virginia. Reprinted with permission. Special thanks to Joan Echtenkamp Klein and Sonya Coleman for this kindness. The image was digitally processed to eliminate handwritten curator notes.

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