first_imgThe 2009 H1N1 influenza pandemic left a troubling legacy in Europe: More than 1300 people who received a vaccine to prevent the flu developed narcolepsy, an incurable, debilitating condition that causes overpowering daytime sleepiness, sometimes accompanied by a sudden muscle weakness in response to strong emotions such as laughter or anger. The manufacturer, GlaxoSmithKline (GSK), has acknowledged the link, and some patients and their families have already been awarded cpmpensation. But how the vaccine might have triggered the condition has been unclear.In a paper in Science Translational Medicine (STM) this week, researchers offer a possible explanation. They show that the vaccine, called Pandemrix, triggers antibodies that can also bind to a receptor in brain cells that help regulate sleepiness. The work strongly suggests that Pandemrix, which was given to more than 30 million Europeans, triggered an autoimmune re action that led to narcolepsy in some people who are genetically at risk.“They put together quite a convincing picture and provide a plausible explanation for what has happened,” says Pasi Penttinen, who heads the influenza program at the European Centre for Disease Prevention and Control in Stockholm. “It’s really the kind of work we’ve been waiting for for 5 years.” But the results still need to be confirmed in a larger study, the authors and other narcolepsy researchers say. A 2013 paper in STM by another group, documenting a different type of vaccine-triggered autoimmune re action, was retracted after the results proved irreproducible (Science, 1 August 2014, p. 498). Narcolepsy, a mysterious malady that affects roughly one in 3000 people in Europe, most often appears in childhood or adolescence. Patients lose certain brain cells in the hypothalamus, leading to a deficiency of hypocretin, a molecule that helps regulate the sleep-wake cycle. Researchers suspect an autoimmune reaction is to blame because many people who develop narcolepsy—and just about everyone with the vaccine-associated form—have a specific variant in a gene in the HLA family, which helps the body distinguish its own proteins from those made by microbial invaders.When they heard about the rise in narcolepsy in 2010, neuroscientist Lawrence Steinman of Stanford University in Palo Alto, California, and rheumatologist Sohail Ahmed, who at the time was global head of clinical sciences at Novartis’s vaccines and diagnostics division in Siena, Italy, began scouring databases for proteins expressed in the brain that might resemble those in the vaccine.Their search turned up a suspect: a piece of a receptor for hypocretin resembles part of the H1N1 influenza nucleoprotein—which binds to the virus genome and plays a key role in its replication. “That was really an ‘Aha’ moment,” says Ahmed, who is now at GSK, which bought part of Novartis’s vaccine division. The flu vaccine is designed to trigger antibodies to influenza’s surface proteins, but if it elicits antibodies to the nucleoprotein as well, those might well latch on to the hypocretin receptor, and eventually lead to death of the cells, the researchers thought.Some of the same researchers already had circumstantial evidence that the nucleoprotein might be an important player. In December, Outi Vaarala of the University of Helsinki and her colleagues had reported that Pandemrix contained a much higher level of nucleoprotein than a GSK vaccine called Arepanrix, which was associated with a much smaller risk for narcolepsy. The group also found that children with narcolepsy had an altered immune response to the nucleoprotein in Pandemrix.In the new work, the researchers added serum from Finnish narcolepsy patients who had received Pandemrix to cells that were engineered to display human hypo cretin receptor 2 on their surface. Antibodies from the patients bound to these cells in 17 of 20 samples. Serum from Italians who had been vaccinated with a different pandemic vaccine from Novartis, called Focetria, did not have such antibodies. The researchers also showed that Focetria, which has not been linked to narcolepsy, had a much lower concentration of nucleoprotein than Pandemrix did.If a vaccine can trigger narcolepsy, can the flu virus itself—either H1N1 or other influenza strains? Cases of narcolepsy increased after the 2009 pandemic in China, where Pandemrix wasn’t used, and researchers discovered that serum from some H1N1 influenza patients does bind to the hypo cretin receptor. But the jury is still out, says virologist Ilkka Julkunen of the University of Turku in Finland, a co-author on the paper.In the meantime, the new insights might eventually lead to ways to help narcolepsy patients. Researchers could explore whether somehow unblocking the receptor might allow the hypocretin system to recover, says Noni MacDonald, a pediatric vaccine researcher at Dalhousie University in Halifax, Canada. The study also suggests ways to make influenza vaccines even safer, for instance by keeping the nucleoprotein levels low or removing the specific region of the protein that mimics the receptor. “We should do everything to understand the disease mechanism,” Julkunen says, “so that this kind of situation would never be repeated.” Country * Afghanistan Aland Islands Albania Algeria Andorra Angola Anguilla Antarctica Antigua and Barbuda Argentina Armenia Aruba Australia Austria Azerbaijan Bahamas Bahrain Bangladesh Barbados Belarus Belgium Belize Benin Bermuda Bhutan Bolivia, Plurinational State of Bonaire, Sint Eustatius and Saba Bosnia and Herzegovina Botswana Bouvet Island Brazil British Indian Ocean Territory Brunei Darussalam Bulgaria Burkina Faso Burundi Cambodia Cameroon Canada Cape Verde Cayman Islands Central African Republic Chad Chile China Christmas Island Cocos (Keeling) Islands Colombia Comoros Congo Congo, the Democratic Republic of the Cook Islands Costa Rica Cote d’Ivoire Croatia Cuba Curaçao Cyprus Czech Republic Denmark Djibouti Dominica Dominican Republic Ecuador Egypt El Salvador Equatorial Guinea Eritrea Estonia Ethiopia Falkland Islands (Malvinas) Faroe Islands Fiji Finland France French Guiana French Polynesia French Southern Territories Gabon Gambia Georgia Germany Ghana Gibraltar Greece Greenland Grenada Guadeloupe Guatemala Guernsey Guinea Guinea-Bissau Guyana Haiti Heard Island and McDonald Islands Holy See (Vatican City State) Honduras Hungary Iceland India Indonesia Iran, Islamic Republic of Iraq Ireland Isle of Man Israel Italy Jamaica Japan Jersey Jordan Kazakhstan Kenya Kiribati Korea, Democratic People’s Republic of Korea, Republic of Kuwait Kyrgyzstan Lao People’s Democratic Republic Latvia Lebanon Lesotho Liberia Libyan Arab Jamahiriya Liechtenstein Lithuania Luxembourg Macao Macedonia, the former Yugoslav Republic of Madagascar Malawi Malaysia Maldives Mali Malta Martinique Mauritania Mauritius Mayotte Mexico Moldova, Republic of Monaco Mongolia Montenegro Montserrat Morocco Mozambique Myanmar Namibia Nauru Nepal Netherlands New Caledonia New Zealand Nicaragua Niger Nigeria Niue Norfolk Island Norway Oman Pakistan Palestine Panama Papua New Guinea Paraguay Peru Philippines Pitcairn Poland Portugal Qatar Reunion Romania Russian Federation Rwanda Saint Barthélemy Saint Helena, Ascension and Tristan da Cunha Saint Kitts and Nevis Saint Lucia Saint Martin (French part) Saint Pierre and Miquelon Saint Vincent and the Grenadines Samoa San Marino Sao Tome and Principe Saudi Arabia Senegal Serbia Seychelles Sierra Leone Singapore Sint Maarten (Dutch part) Slovakia Slovenia Solomon Islands Somalia South Africa South Georgia and the South Sandwich Islands South Sudan Spain Sri Lanka Sudan Suriname Svalbard and Jan Mayen Swaziland Sweden Switzerland Syrian Arab Republic Taiwan Tajikistan Tanzania, United Republic of Thailand Timor-Leste Togo Tokelau Tonga Trinidad and Tobago Tunisia Turkey Turkmenistan Turks and Caicos Islands Tuvalu Uganda Ukraine United Arab Emirates United Kingdom United States Uruguay Uzbekistan Vanuatu Venezuela, Bolivarian Republic of Vietnam Virgin Islands, British Wallis and Futuna Western Sahara Yemen Zambia Zimbabwe Click to view the privacy policy. 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