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Key narcolepsy–influenza vaccine findings retracted Stanford researchers unable to replicate findings linking immune response to sleep disorder By Emily Underwood
S
ince swine flu swept the globe in 2009, scientists have scrambled to determine why a small percentage of children in Europe who received the flu vaccine Pandemrix developed narcolepsy, an incurable brain disorder that causes irresistible sleepiness. This week, a promising explanation was dealt a setback when prominent sleep scientist Emmanuel Mignot of Stanford University in Palo Alto, California, and colleagues retracted their influential study reporting a potential link between the H1N1 virus used to make the vaccine and narcolepsy. Some researchers were taken aback. “This was one of the most important pieces of work on narcolepsy that has come out,” says neuroimmunologist Lawrence Steinman, a close friend and colleague of Mignot’s, who is also at Stanford. The retraction, announced in Science Translational Medicine (STM), “really caught me by surprise,” he says. Others say that journal editors should have detected problems
498
with the study’s methodology. The work provided the first substantiation of an autoimmune mechanism for narcolepsy, which could explain the Pandemrix side effect, researchers say. The vaccine, used only in Europe, seems to have triggered the disease in roughly one out of 15,000 children who received it. The affected children carried a gene variant for a particular human leukocyte antigen (HLA) type—a molecule that presents foreign proteins to immune cells—considered necessary for developing narcolepsy. In the 18 December 2013 issue of STM, Mignot and colleagues reported that T cells from people with narcolepsy, but not from healthy controls, are primed to attack by hypocretin, a hormone that regulates wakefulness. They also showed molecular similarities between fragments of the H1N1 virus and the hypocretin molecule and suggested that these fragments might fool the immune system into attacking hypocretin-producing cells. Up to 95% of the neurons that produce hypocretin are missing in people with nar-
sciencemag.org SCIENCE
1 AUGUST 2014 • VOL 345 ISSUE 6196
Published by AAAS
Downloaded from http://science.sciencemag.org/ on March 5, 2018
IMMUNOLOGY
colepsy, and many researchers believe that they’re destroyed by a highly targeted autoimmune reaction, says Thomas Scammell, a neurologist at Harvard Medical School in Boston. The Mignot paper was the first “seemingly nice, objective piece of evidence” to support that hypothesis. The retraction states that Mignot and his colleagues were unable to replicate the results of the ELISpot assay, a widely used method for measuring how immune system cells such as T cells respond to fragments of foreign proteins, called antigens. Mignot told Science that while attempting to develop a diagnostic test for narcolepsy based on the assay, “my lab could not make the ELISpot test work.” T cell assays in general are notoriously difficult to reproduce, says immunologist Outi Vaarala of the National Institute for Health and Welfare (THL) in Helsinki, who spent several weeks earlier this summer in Mignot’s lab hoping to follow up on their finding. She’s tried to replicate it herself in several ways, with no success. Vaarala and others note several red flags about the research: For example, Mignot’s group studied cells from a small number of people with narcolepsy and controls and focused on only one aspect of T cell response to hypocretin. Katrina Kelner, editor of STM, says that “the paper was reviewed according to our usual rigorous standards of in-depth peer review, and in fact reported replication of the finding in three independent groups of patients.” Like Mignot and many other researchers, Vaarala still believes that some part of the influenza virus used to make Pandemrix likely mimics a native protein in the brain and triggered an autoimmune reaction that led to the destruction of hypocretin neurons in susceptible children. She is now looking for differences between Pandemrix and other flu vaccines and says she has already identified another promising protein candidate. The retraction “does not undermine the fundamental hypothesis” that narcolepsy is caused by an autoimmune reaction “all that dramatically,” Scammell says. He and others may consider different causes of narcolepsy, however. “Maybe there’s a very selective virus that’s very fond of targeting and then killing” hypocretin neurons, he says. Had Mignot’s results held, they could have led to the first proven example of a vaccine triggering an autoimmune response by mimicking the body’s own proteins, says vaccinologist Hanna Nohynek, who is working with Vaarala at THL. The retraction “sets us back to kind of a zero point.” ■
PHOTO: ASSOCIATED PRESS
Narcolepsy-vaccine link remains mysterious.
Key narcolepsy−influenza vaccine findings retracted Emily Underwood
Science 345 (6196), 498. DOI: 10.1126/science.345.6196.498
http://science.sciencemag.org/content/345/6196/498
PERMISSIONS
http://www.sciencemag.org/help/reprints-and-permissions
Use of this article is subject to the Terms of Service Science (print ISSN 0036-8075; online ISSN 1095-9203) is published by the American Association for the Advancement of Science, 1200 New York Avenue NW, Washington, DC 20005. 2017 © The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. The title Science is a registered trademark of AAAS.
Downloaded from http://science.sciencemag.org/ on March 5, 2018
ARTICLE TOOLS
Key narcolepsy–influenza vaccine findings retracted Stanford researchers unable to replicate findings linking immune response to sleep disorder By Emily Underwood
S
ince swine flu swept the globe in 2009, scientists have scrambled to determine why a small percentage of children in Europe who received the flu vaccine Pandemrix developed narcolepsy, an incurable brain disorder that causes irresistible sleepiness. This week, a promising explanation was dealt a setback when prominent sleep scientist Emmanuel Mignot of Stanford University in Palo Alto, California, and colleagues retracted their influential study reporting a potential link between the H1N1 virus used to make the vaccine and narcolepsy. Some researchers were taken aback. “This was one of the most important pieces of work on narcolepsy that has come out,” says neuroimmunologist Lawrence Steinman, a close friend and colleague of Mignot’s, who is also at Stanford. The retraction, announced in Science Translational Medicine (STM), “really caught me by surprise,” he says. Others say that journal editors should have detected problems
498
with the study’s methodology. The work provided the first substantiation of an autoimmune mechanism for narcolepsy, which could explain the Pandemrix side effect, researchers say. The vaccine, used only in Europe, seems to have triggered the disease in roughly one out of 15,000 children who received it. The affected children carried a gene variant for a particular human leukocyte antigen (HLA) type—a molecule that presents foreign proteins to immune cells—considered necessary for developing narcolepsy. In the 18 December 2013 issue of STM, Mignot and colleagues reported that T cells from people with narcolepsy, but not from healthy controls, are primed to attack by hypocretin, a hormone that regulates wakefulness. They also showed molecular similarities between fragments of the H1N1 virus and the hypocretin molecule and suggested that these fragments might fool the immune system into attacking hypocretin-producing cells. Up to 95% of the neurons that produce hypocretin are missing in people with nar-
sciencemag.org SCIENCE
1 AUGUST 2014 • VOL 345 ISSUE 6196
Published by AAAS
Downloaded from http://science.sciencemag.org/ on March 5, 2018
IMMUNOLOGY
colepsy, and many researchers believe that they’re destroyed by a highly targeted autoimmune reaction, says Thomas Scammell, a neurologist at Harvard Medical School in Boston. The Mignot paper was the first “seemingly nice, objective piece of evidence” to support that hypothesis. The retraction states that Mignot and his colleagues were unable to replicate the results of the ELISpot assay, a widely used method for measuring how immune system cells such as T cells respond to fragments of foreign proteins, called antigens. Mignot told Science that while attempting to develop a diagnostic test for narcolepsy based on the assay, “my lab could not make the ELISpot test work.” T cell assays in general are notoriously difficult to reproduce, says immunologist Outi Vaarala of the National Institute for Health and Welfare (THL) in Helsinki, who spent several weeks earlier this summer in Mignot’s lab hoping to follow up on their finding. She’s tried to replicate it herself in several ways, with no success. Vaarala and others note several red flags about the research: For example, Mignot’s group studied cells from a small number of people with narcolepsy and controls and focused on only one aspect of T cell response to hypocretin. Katrina Kelner, editor of STM, says that “the paper was reviewed according to our usual rigorous standards of in-depth peer review, and in fact reported replication of the finding in three independent groups of patients.” Like Mignot and many other researchers, Vaarala still believes that some part of the influenza virus used to make Pandemrix likely mimics a native protein in the brain and triggered an autoimmune reaction that led to the destruction of hypocretin neurons in susceptible children. She is now looking for differences between Pandemrix and other flu vaccines and says she has already identified another promising protein candidate. The retraction “does not undermine the fundamental hypothesis” that narcolepsy is caused by an autoimmune reaction “all that dramatically,” Scammell says. He and others may consider different causes of narcolepsy, however. “Maybe there’s a very selective virus that’s very fond of targeting and then killing” hypocretin neurons, he says. Had Mignot’s results held, they could have led to the first proven example of a vaccine triggering an autoimmune response by mimicking the body’s own proteins, says vaccinologist Hanna Nohynek, who is working with Vaarala at THL. The retraction “sets us back to kind of a zero point.” ■
PHOTO: ASSOCIATED PRESS
Narcolepsy-vaccine link remains mysterious.
Key narcolepsy−influenza vaccine findings retracted Emily Underwood
Science 345 (6196), 498. DOI: 10.1126/science.345.6196.498
http://science.sciencemag.org/content/345/6196/498
PERMISSIONS
http://www.sciencemag.org/help/reprints-and-permissions
Use of this article is subject to the Terms of Service Science (print ISSN 0036-8075; online ISSN 1095-9203) is published by the American Association for the Advancement of Science, 1200 New York Avenue NW, Washington, DC 20005. 2017 © The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. The title Science is a registered trademark of AAAS.
Downloaded from http://science.sciencemag.org/ on March 5, 2018
ARTICLE TOOLS
