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Patients with a history of vaccination with the pandemic influenza vaccine Pandemrix and narcolepsy were found to have antibodies to hypocretin receptor 2, possibly explaining this association after the 2009 (H1N1) pandemic.
The development of narcolepsy is associated with HLA-DQB1*0602 haplotype, loss of hypothalamic cells, and decrease production of hypocretin, a neuropeptide also known as orexin.
After the 2009 H1N1 influenza pandemic, there were increased reports of narcolepsy associated with the Pandemrix vaccine in Europe. Studies of this association found a 12.7-fold increased risk of narcolepsy within 8 months of Pandemrix vaccination. However, Focetria, the other H1N1 vaccine used in Europe in the 2009 pandemic, does not currently have a reported increased risk. Likewise, studies in China indicate an increased risk of narcolepsy after infection with the 2009 pandemic H1N1 influenza virus.
“We hypothesized that differences between the ‘adjuvanted’ A(H1N1)pdm09 vaccines Pandemrix and Focetria explain the association of narcolepsy with Pandemrix vaccinated subjects,” Dr. Syed Ahmed of Novartis Vaccines, Siena, Italy, and colleagues reported (Sci. Transl. Med. 2015;7:294ra105).
The researchers conducted a retrospective analysis of sera from narcoleptic individuals vaccinated with Pandemrix and a history of H1N1 infection as well as children from Finland without a history of narcolepsy and a history of Focetria vaccination. The samples were randomized and the investigators were blinded.
By aligning protein sequences of influenza strains, the researchers were able to identify an influenza nucleoprotein peptide similar to the hypocretin receptor. ELISA assays detected antibodies to hypocretin receptor 2 in a significantly higher percentage of sera samples from patients with a history of Pandemrix vaccination, HLA-DQB1*0602 haplotype, and narcolepsy (17 of 20), compared with patients with a history of Focetria vaccination (0 of 6; P < .001) or H1N1 infection (5 of 20; P < .001).
Furthermore, mass spectrometry indicated Focetria contained 72.7% less nucleoprotein than did Pandemrix. ELISA assays detected fewer nucleoprotein antibodies in individuals vaccinated with Focetria than in those infected with H1N1. Dr. Ahmed and his colleagues concluded that a possible mechanism for influenza and vaccine associated narcolepsy involves nucleoprotein antigen development after vaccination or infection and cross reaction with the hypocretin receptor 2. Furthermore, the difference in nucleoprotein content of the two vaccine types may further explain the association of Pandemrix vaccination with narcolepsy.
“The implications of the new work are important but specific. First of all, the findings show that in rare cases, vaccines can accidentally trigger autoimmunelike brain disease. The anti-H1N1 vaccine Pandemrix appears to make the case, stimulating in some individuals the production of hypocretin receptor cross-binding antibodies as a result of its high content of influenza [nucleoprotein].”
“Last, the work elegantly provides insight into vaccine-related narcolepsy but does not directly disclose whether similar mechanisms (autoimmune, parainfectious, etc.) contribute to sporadic narcolepsy. To settle this question definitively will require additional data from immune therapies, neuropathology, and much-needed narcolepsy animal models.”
Dr. Hartmut Wekerle is affiliated with the Max-Planck Institute of Neurobiology, Martinsried, Germany. These comments are taken from an editorial accompanying Dr. Ahmed and his colleagues’ report (Sci. Transl. Med. 2015;7:294fs27).
“The implications of the new work are important but specific. First of all, the findings show that in rare cases, vaccines can accidentally trigger autoimmunelike brain disease. The anti-H1N1 vaccine Pandemrix appears to make the case, stimulating in some individuals the production of hypocretin receptor cross-binding antibodies as a result of its high content of influenza [nucleoprotein].”
“Last, the work elegantly provides insight into vaccine-related narcolepsy but does not directly disclose whether similar mechanisms (autoimmune, parainfectious, etc.) contribute to sporadic narcolepsy. To settle this question definitively will require additional data from immune therapies, neuropathology, and much-needed narcolepsy animal models.”
Dr. Hartmut Wekerle is affiliated with the Max-Planck Institute of Neurobiology, Martinsried, Germany. These comments are taken from an editorial accompanying Dr. Ahmed and his colleagues’ report (Sci. Transl. Med. 2015;7:294fs27).
“The implications of the new work are important but specific. First of all, the findings show that in rare cases, vaccines can accidentally trigger autoimmunelike brain disease. The anti-H1N1 vaccine Pandemrix appears to make the case, stimulating in some individuals the production of hypocretin receptor cross-binding antibodies as a result of its high content of influenza [nucleoprotein].”
“Last, the work elegantly provides insight into vaccine-related narcolepsy but does not directly disclose whether similar mechanisms (autoimmune, parainfectious, etc.) contribute to sporadic narcolepsy. To settle this question definitively will require additional data from immune therapies, neuropathology, and much-needed narcolepsy animal models.”
Dr. Hartmut Wekerle is affiliated with the Max-Planck Institute of Neurobiology, Martinsried, Germany. These comments are taken from an editorial accompanying Dr. Ahmed and his colleagues’ report (Sci. Transl. Med. 2015;7:294fs27).
Patients with a history of vaccination with the pandemic influenza vaccine Pandemrix and narcolepsy were found to have antibodies to hypocretin receptor 2, possibly explaining this association after the 2009 (H1N1) pandemic.
The development of narcolepsy is associated with HLA-DQB1*0602 haplotype, loss of hypothalamic cells, and decrease production of hypocretin, a neuropeptide also known as orexin.
After the 2009 H1N1 influenza pandemic, there were increased reports of narcolepsy associated with the Pandemrix vaccine in Europe. Studies of this association found a 12.7-fold increased risk of narcolepsy within 8 months of Pandemrix vaccination. However, Focetria, the other H1N1 vaccine used in Europe in the 2009 pandemic, does not currently have a reported increased risk. Likewise, studies in China indicate an increased risk of narcolepsy after infection with the 2009 pandemic H1N1 influenza virus.
“We hypothesized that differences between the ‘adjuvanted’ A(H1N1)pdm09 vaccines Pandemrix and Focetria explain the association of narcolepsy with Pandemrix vaccinated subjects,” Dr. Syed Ahmed of Novartis Vaccines, Siena, Italy, and colleagues reported (Sci. Transl. Med. 2015;7:294ra105).
The researchers conducted a retrospective analysis of sera from narcoleptic individuals vaccinated with Pandemrix and a history of H1N1 infection as well as children from Finland without a history of narcolepsy and a history of Focetria vaccination. The samples were randomized and the investigators were blinded.
By aligning protein sequences of influenza strains, the researchers were able to identify an influenza nucleoprotein peptide similar to the hypocretin receptor. ELISA assays detected antibodies to hypocretin receptor 2 in a significantly higher percentage of sera samples from patients with a history of Pandemrix vaccination, HLA-DQB1*0602 haplotype, and narcolepsy (17 of 20), compared with patients with a history of Focetria vaccination (0 of 6; P < .001) or H1N1 infection (5 of 20; P < .001).
Furthermore, mass spectrometry indicated Focetria contained 72.7% less nucleoprotein than did Pandemrix. ELISA assays detected fewer nucleoprotein antibodies in individuals vaccinated with Focetria than in those infected with H1N1. Dr. Ahmed and his colleagues concluded that a possible mechanism for influenza and vaccine associated narcolepsy involves nucleoprotein antigen development after vaccination or infection and cross reaction with the hypocretin receptor 2. Furthermore, the difference in nucleoprotein content of the two vaccine types may further explain the association of Pandemrix vaccination with narcolepsy.
Patients with a history of vaccination with the pandemic influenza vaccine Pandemrix and narcolepsy were found to have antibodies to hypocretin receptor 2, possibly explaining this association after the 2009 (H1N1) pandemic.
The development of narcolepsy is associated with HLA-DQB1*0602 haplotype, loss of hypothalamic cells, and decrease production of hypocretin, a neuropeptide also known as orexin.
After the 2009 H1N1 influenza pandemic, there were increased reports of narcolepsy associated with the Pandemrix vaccine in Europe. Studies of this association found a 12.7-fold increased risk of narcolepsy within 8 months of Pandemrix vaccination. However, Focetria, the other H1N1 vaccine used in Europe in the 2009 pandemic, does not currently have a reported increased risk. Likewise, studies in China indicate an increased risk of narcolepsy after infection with the 2009 pandemic H1N1 influenza virus.
“We hypothesized that differences between the ‘adjuvanted’ A(H1N1)pdm09 vaccines Pandemrix and Focetria explain the association of narcolepsy with Pandemrix vaccinated subjects,” Dr. Syed Ahmed of Novartis Vaccines, Siena, Italy, and colleagues reported (Sci. Transl. Med. 2015;7:294ra105).
The researchers conducted a retrospective analysis of sera from narcoleptic individuals vaccinated with Pandemrix and a history of H1N1 infection as well as children from Finland without a history of narcolepsy and a history of Focetria vaccination. The samples were randomized and the investigators were blinded.
By aligning protein sequences of influenza strains, the researchers were able to identify an influenza nucleoprotein peptide similar to the hypocretin receptor. ELISA assays detected antibodies to hypocretin receptor 2 in a significantly higher percentage of sera samples from patients with a history of Pandemrix vaccination, HLA-DQB1*0602 haplotype, and narcolepsy (17 of 20), compared with patients with a history of Focetria vaccination (0 of 6; P < .001) or H1N1 infection (5 of 20; P < .001).
Furthermore, mass spectrometry indicated Focetria contained 72.7% less nucleoprotein than did Pandemrix. ELISA assays detected fewer nucleoprotein antibodies in individuals vaccinated with Focetria than in those infected with H1N1. Dr. Ahmed and his colleagues concluded that a possible mechanism for influenza and vaccine associated narcolepsy involves nucleoprotein antigen development after vaccination or infection and cross reaction with the hypocretin receptor 2. Furthermore, the difference in nucleoprotein content of the two vaccine types may further explain the association of Pandemrix vaccination with narcolepsy.
FROM SCIENCE TRANSLATIONAL MEDICINE
Key clinical point:Nucleoprotein antibodies possibly explain influenza vaccine associated narcolepsy.
Major finding: Patients with a history of Pandemrix vaccination, HLA-DQB1*0602 haplotype, and narcolepsy had detectable antibodies to hypocretin receptor 2.
Data source: Retrospective analysis of sera from the 2009 H1N1 pandemic.
Disclosures: The authors note no funding sources for the study, but an award from the National Center for Research Resources helped provide the mass spectrometer used during the study. Multiple authors disclosed employment and stock holdings in Novartis and Atreca. There were also authors who reported receiving honoraria and holding patents.