Vibrio cholerae , a bacterium comma-shaped contaminating water and food, can kill quickly. The acids in the stomach can erase billions of bacteria, but if a person swallows too little 1000 with food, some may survive the swim to the small intestine. There, the invaders will release enzymes to penetrate a thick layer of mucus that lines the epithelium. Once through, the bacteria will bind to epithelial cells and begin to divide, establish microcolonies that secrete toxins. Then the hour of death starts ticking.
Angered by the main cholera toxin, intestinal fluid gush, and a person will develop cramps, vomiting and, most notoriously, diarrhea that is fast becoming an impressive volume of "-water rice" plates: a aqueous liquid filled flakes mucosal and epithelial cells. In severe cases, people lose a liter of rice water stools per hour and without rehydration to replace the water lost from the body and electrolytes, may die in half a day.
The first question I ask is, "Do I want my children to participate ...?
In 1976, at the request of a panel of the US government, Myron "Mike" Levine 's University of Maryland School of Medicine in Baltimore began intentionally give humans V. cholerae . It is still today.
Myron "Mike" Levine
Paul Fetters
There are forty Levine was one of a small group of researchers doing studies supposedly human-intentionally challenge infect people with V. cholerae and other pathogens to test drugs and vaccines. But in recent decades, this practice, which has a long and checkered, "has become much more mainstream," says Levine. Stringent security procedures and new ways to reduce pathogens to reduce their risks lead investigators in the industry, universities and the government to take a new look at humans provocation tests, which provide a powerful tool for studying diseases and potential therapies. There is even a commercial enterprise, in hVIVO London, which specializes in human challenges. Today, people are deliberately infected with malaria, the flu, shigella, dengue fever, norovirus, tuberculosis, rhinovirus, Escherichia coli typhoid, giardia and campylobacter
the risks are obvious :. Otherwise healthy individuals may suffer damage and, if the disease is contagious, potentially sicken others. But if done well, the benefits are convincing a growing number of researchers say. The standard pharmaceutical development path for products that target pathogens slowly moves from the study of the security, administration, and biological responses in hundreds of people in a cost effective test with thousands of participants at high risk of being infected naturally. human challenge studies, which include a few dozen volunteers, accelerate the process of deciding to scrap or continue a promising, saving time and money. And tests that intentionally infect people can quickly and effectively flag potential side effects, lawyers say. "You can certainly make a $ 100 million study for each candidate vaccine seems safe and immunogenic," said Mark Mulligan, a molecular virologist who heads the vaccination center at Emory University in Atlanta and made human challenges with norovirus and tuberculosis.
Insights human challenges go well beyond drug and vaccine development. Christine Moe, another researcher from Emory University, has shown that the more easily transmitted norovirus via vomit diarrhea, and that "Ferrari viruses," famous for the speed at which it runs through vacationers on cruise ships, is impervious to alcohol based disinfectants and power wash oysters wear it. It notes that "sometimes human challenge studies are the only way to answer critical questions."
Checkered past
human challenges back to the 18th century and the first vaccine, when the English physician Edward Jenner tried to persuade the world that the infection of a person harmless cowpox could prevent the disease from its dreaded cousin smallpox. Jenner scratched the "material" taken from a cowpox sore on the hand of a dairymaid in the skin of 8 years old James Phipps, the son of his occasional gardener, then tried repeatedly to infect with smallpox. "Poor Phipps' as Jenner later called the boy never came down with smallpox. Jenner reported that some 6,000 people were vaccinated, then "well most of them" were challenged by smallpox. Two centuries later, the Jenner vaccine pioneer eradicated the virus in the human population.
Vaccine pioneer Edward Jenner used cowpox fluid in the arm of James Phipps in 1796, then challenged with smallpox.
University of Michigan Health System, gift UMHS.23 Pfizer Inc.
intentionally infecting a single human leave a child with a disfiguring disease and even mortal would never pass muster today ethic. But as recently as the early 20th century, the intentional infection has been considered before -garde: Austrian psychiatrist Julius Wagner-Jauregg won the 1927 Nobel Prize in physiology or medicine for injecting the blood of people with malaria in patients with neurosyphilis, which the putative cured of madness and paralysis. As reporter Lawrence Altman documented in his book Who goes first? , many researchers have themselves questioned by pathogens to prove the value of their own experimental drugs or theories. Some died.
In the 1940s, the University of Chicago in Illinois and the US military have collaborated on provocation experiments that tested drugs against malaria in 400 Illinois prisoners. Nazi doctors, who horrified the world with their own medical experiments, including malaria tests that have killed hundreds of people, quoted American studies in their defense when they were tried in Nuremberg, Germany, in 1947. this led to the Nuremberg Code, which specifies what are now the standard search principles of informed consent, voluntary participation, and freedom to leave a review.
However, US experiments on prisoners continued, leading to 1973 presentation investigative journalist Jessica Mitford in The Atlantic Monthly, "experiences behind bars." Levine, who has just started his career, then the hard man with shigella and typhoid to the Maryland House of Correction in Jessup experiences, he insists were conducted ethically. "Studies in Jessup were two decades ahead of their time in terms of methods of informed consent," he said. But in 1976, the US National Commission for the Protection of Human Subjects of Biomedical and comportementale- the first attempt bioethics policy homeland issued a report that actually experiences of human provocation in prisons stopped.
outside prisons, however, research has continued. in 1974, the National Institute of allergy and infectious diseases (NIAID) in Bethesda, Maryland USA, has awarded the University of Maryland has half a million dollars to create a new vaccine testing center, led by Levine, who recruit volunteers and college religious groups. the center started with the challenges of the flu, which were conducted in the renovated rooms at the University of Maryland Hospital which had bunk beds for 22 people and an isolated air system. The researchers had little trouble recruiting volunteers, who received the same charges as jurors ($ 20 per day), the researchers considered only coercive but no. The volunteers had to pass a written test to prove they understand the risks.
Two years later, at the request of the Group of NIAID Cholera, Levine's group adds challenges V. cholerae to test cholera vaccines. "A very big questions was, 'Someone willing to participate?" Remembers Levine. "It is one thing to make the flu that most people live every two years or more, and it is another thing to take this exotic tropical infection and implement that."
Maryland required hospital fly a yellow flag to warn of quarantine cholera. Again, find volunteers presented some obstacles. "These are the same young people who were going down the hairy parts of the rivers on rafts," says Levine.
in a 1970 University of Maryland study of cholera, this man needed 26 liters of electrolytes intravenously to replace lost fluids. with the permission of Myron M. Levine 
cholera studies led to the scuttling of a leading vaccine candidate, a more detailed understanding of effective immune responses, and, ultimately, convincing evidence that a vaccine against cholera different work. in June, the US Food and Drug Administration (FDA) will consider the approval of a vaccine against cholera for travelers based largely on the work of Levine. This is the most influential human challenge model has never played in the approval process of the FDA.
Modern volunteers
During the next decade, the Levine Group expanded with the challenges Salmonella typhi E. coli , and rotavirus. The only other important operation of human challenge was the common cold Unit established by the Medical Research Council in Salisbury, UK Then in 1985, a team led by Ripley Ballou began human challenges with malaria at Walter Institute Reed Army research (WRAIR) in silver Spring, Maryland. This pioneering program advances that have reduced the risk of human malaria problem and increased benefits, paving the way for successful tests today in several places.
Ballou, who now heads the R & D vaccine in the US to GlaxoSmithKline (GSK) and its high mosquito team in an insectarium, then have fed on human blood infected with the malaria parasite Plasmodium falciparum . He and five other colleagues from the army took each a candidate vaccine against malaria and let five infected mosquitoes, their group had determined was the number needed to transmit the parasite breakfast reliably on their arms then. "I am a full-fledged case of malaria and has never been sick in my life," says Ballou, although he was treated quickly. "It made a huge impression on me and I'm determined to find a way to stop this disease."
In the first WRAIR vaccine trial, all participants were "my friends in the laboratory or in the hallway," says Ballou, and they went home after being infected. Now WRAIR recruits special political-civilian governing the participation of persons serving in the army, which for a maximum of 10 days stay in a hotel together, where they receive regular checkups. Technology has also made safer experience when Ballou infected him Reaction test polymerase chain reaction can detect minute quantities of parasite DNA and identify infection two days earlier than the traditional microscope, and if volunteers receive immediate treatment, they rarely suffer symptoms [
Ripley Ballou led challenge malaria trials for testing vaccines at Walter Reed Army Institute of research from 1985 volunteers including Ballou willingly exposed their arms to malarial mosquitoes. Walter Reed Institute of Research Army 
impressive dividends challenge studies against the Army gave malaria. "We trashed a bunch of vaccines," said Ballou. They also contributed to the development of GSK RTS, S, the only vaccine against malaria, which has so far demonstrated its efficacy, albeit modest, in an essay on the large-scale field.
the resurgence
launched more recently trials face greater regulatory oversight as Levine and Ballou fact. Since the mid 190, the FDA found that the organisms used in the challenge studies are experimental drugs, and the agency has required researchers to submit new drug applications prior to testing. institutional review intensified, too .
human challenge studies with influenza provide an overview of the new landscape. in the 1980s and 190s, for example, Frederick Hayden of the University of Virginia School of Medicine in Charlottesville has conducted studies of provocation with the flu who have contributed to accelerate the development of Tamiflu and Relenza, drugs have become the mainstays of treatment. But the field work to a halt in 00 after a volunteer in one of the studies Hayden knew what the FDA calls an "adverse event". A 21-year-old man a heart defect testing drug against influenza developed after being questioned by the virus. "I still do not know what caused this incident," said Hayden. "There were a lot of sleepless nights." Mal Pas long occurred, but the incident has led to a thorough review of cardiac events in other influenza challenge studies.
So it was worrying when Matthew Memoli NIAID proposed new human challenge studies with the flu in 2011, which ultimately designed to test new treatments and vaccines . Some of his colleagues were so suspicious that the Department of ethics in the National Institutes of Health (NIH), the parent company of NIAID, was invited to conduct a formal review of the protocol. "We went through a lot 'steps, "said Memoli. Ethicists were particularly concerned about the proposed "high levels of payment" -up to $ 4000 but deemed this was not an "undue influence" because nobody was obliged to accept the offer.
the volunteers were "meticulously" projected, Memoli said. They had to be under 45 and undergo a battery of tests, including electrocardiograms Memoli and colleagues have also worked with the FDA to grow a strain of virus that has encountered good agency manufacturing practices, and they accurately calculated the minimum dose required to cause disease in most volunteers.
in ongoing studies, researchers spray the influenza virus in the nose of the volunteers through a fog, created by an atomizer that produces only particles larger than 10 microns. These relatively fat particles can cause infections of the upper respiratory tract, but do not reach the lungs, where the influenza virus can cause potentially fatal pneumonia. To avoid infecting others, participants remain in isolation rooms in the hospital for 9 days. "I challenged nearly 0 people and had no serious complications," said Memoli. "The worst thing that happened was a guy slipped in a shower."
Memoli notes that deliberately infecting people is a strange action for a doctor. "We deliberately make people sick," said Memoli . "It is a different idea of what you are going behind to medical school. But over the next few years I think we will get information that will be extremely useful. "In a study published online in MBIO April 19, Memoli and colleagues reported that their challenge studies indicated that a response largely ignored the antibodies against the flu vaccines could be better predictor of the effectiveness of the antibodies analyzed regularly today.
thereFive years, the small community studying dengue began to discuss the provocation tests, which made people nervous, Durbin said Anna Johns Hopkins Bloomberg School of public Health in Baltimore infection mosquitoes can trigger high fever, severe joint pain, skin rashes and intense;. in rare cases, it can lead to bleeding and death. no drugs specifically target the dengue virus. "We hear, 'you can not treat dengue so you can not make a model of human challenge," said Durbin. human challenges with dengue date back a century, but the last intentional voluntary infections occurred in WRAIR in 01, and some of the participants developed dengue fever.
In 2011, WRAIR and NIH sponsored a workshop to discuss "reintroduction" model of human challenge for dengue. Several participants, including Durbin, argued that the tests could be carried out safely and would accelerate the development of a necessary evil for this disease vaccine.
With the blessing of the FDA in June 2013 Durbin began challenging volunteers who received vaccine against dengue is by NIAID. Instead of using the dengue virus from wild type Durbin Hopkins and his team infected with a naturally low virus isolate that was more attenuated in the laboratory. "I do not think you need to make people sick" to see if they develop an infection, said Durbin.
As she and her group reported online March 16 in Science Translational Medicine , none of the 21 people who received the vaccine infected after challenge, but every 20 checks the virus in their blood, and 16 developed a rash. Based in part on these results, the Butantan Institute in Sao Paulo, Brazil, this year launched a vaccine efficacy trial that plans to enroll 17,000 people.
Regulation of human challenge studies differ from one place to another. In the UK, for example, officers are questioning are not considered drugs, and experiences with them so do not require regulatory approval. A group at the University of Oxford led by pediatrician Andrew Pollard led a study of experimental vaccines against typhoid and paratyphoid challenge. Although both diseases are contagious, researchers allow volunteers to go home instead of staying in isolation. "They are potentially agencies that are in a relief flush toilet," says Levine, who works with the Oxford Group. "This is something that is not likely to be made in the United States."
The UK is "much more permissive," Pollard agrees, but says the tests pass by ethical depth reviews and the risk of transmission is "close to zero" if people have good hygiene.
the human challenge model has limitations, Levine points out, noting that his group refused to participate in an experiment carried out . Besides that put Neisseria gonorrhoeae in a penile catheter to study the transmission of gonorrhea "the first question I ask is:" Do I want my children, siblings, or spouse participate? "Said Levine. "If the answer is 'no', we do not do." And he fears that even if the address of the researchers of today risk more carefully than ever, someone might go too far and cancel the field gains made. "This should not be a Wild West show," he said. "Some newcomers may not be fully aware of the burden of the pioneers lived. It took a long time to obtain the support of everyone imaginable. "
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