Increased risk of narcolepsy in children and adults after pandemic H1N1 vaccination in France

Abstract

An increased incidence of narcolepsy in children was detected in Scandinavian countries where pandemic H1N1 influenza ASO3-adjuvanted vaccine was used. A campaign of vaccination against pandemic H1N1 influenza was implemented in France using both ASO3-adjuvanted and non-adjuvanted vaccines. As part of a study considering all-type narcolepsy, we investigated the association between H1N1 vaccination and narcolepsy with cataplexy in children and adults compared with matched controls; and compared the phenotype of narcolepsy with cataplexy according to exposure to the H1N1 vaccination. Patients with narcolepsy-cataplexy were included from 14 expert centres in France. Date of diagnosis constituted the index date. Validation of cases was performed by independent experts using the Brighton collaboration criteria. Up to four controls were individually matched to cases according to age, gender and geographic location. A structured telephone interview was performed to collect information on medical history, past infections and vaccinations. Eighty-five cases with narcolepsy-cataplexy were included; 23 being further excluded regarding eligibility criteria. Of the 62 eligible cases, 59 (64% males, 57.6% children) could be matched with 135 control subjects. H1N1 vaccination was associated with narcolepsy-cataplexy with an odds ratio of 6.5 (2.1-19.9) in subjects aged<18 years, and 4.7 (1.6-13.9) in those aged 18 and over. Sensitivity analyses considering date of referral for diagnosis or the date of onset of symptoms as the index date gave similar results, as did analyses focusing only on exposure to ASO3-adjuvanted vaccine. Slight differences were found when comparing cases with narcolepsy-cataplexy exposed to H1N1 vaccination (n=32; mostly AS03-adjuvanted vaccine, n=28) to non-exposed cases (n=30), including shorter delay of diagnosis and a higher number of sleep onset rapid eye movement periods for exposed cases. No difference was found regarding history of infections. In this sub-analysis, H1N1 vaccination was strongly associated with an increased risk of narcolepsy-cataplexy in both children and adults in France. Even if, as in every observational study, the possibility that some biases participated in the association cannot be completely ruled out, the associations appeared robust to sensitivity analyses, and a specific analysis focusing on ASO3-adjuvanted vaccine found similar increase.

CD8 T cell-mediated killing of orexinergic neurons induces a narcolepsy-like phenotype in mice

“…Moreover, autoantibodies recognizing different antigenic targets expressed in the central nervous system (CNS) have been identified in the serum and cerebrospinal fluid (CSF) of narcoleptic patients (9-11). Finally, a dramatic increase in the incidence of T1N has been observed in Northern Europe during the 2009-2010 vaccination campaigns against pandemic H1N1 influenza virus using the Pandemrix vaccine (12)(13)(14). The immune mechanisms involved remain unknown, although molecular mimicry is strongly suspected (9,15).…”

Intravenous Immunoglobulin Therapy in Pediatric Narcolepsy: A Nonrandomized, Open-Label, Controlled, Longitudinal Observational Study

“…In support of the autoimmune hypothesis underlying narcolepsy, autoantibodies against Tribbles homolog 2 (TRIB2), a protein synthesized in hypocretin neurons, are evident in a proportion of patients with narcolepsy, a finding that has been replicated in three separate studies. [10][11][12] In addition, the surge of cases of narcolepsy following pandemic H1N1 infection and mass vaccination with Pandemrix (GlaxoSmithKline, Brentford, Middlesex, UK) lends further support to an autoimmune etiology, [13][14][15][16] likely due to serum antibodies to H1N1 nucleoprotein in patients with vaccine-associated narcolepsy cross-reacting with the hypocretin receptor 2 (an effect observed following Pandremix, but not Focetria [Novartis, Novartis International AG, Basel, Switzerland] vaccination). 17 However, in the absence of formal identification and detailed understanding of the mechanisms linking autoimmunity with the destruction of hypocretin neurons, no disease-modifying therapies for narcolepsy have yet been developed.…”

Laser vaccine adjuvants

“…[13][14][15] After the release of vaccines for H1N1 in 2009, the AS03-adjuvanted influenza vaccine Pandemrix® (GlaxoSmithKline) was linked to hundreds of cases of narcolepsy in the EU. [16][17][18][19] In the US, where Immunologic adjuvants are essential for current vaccines to maximize their efficacy. Unfortunately, few have been found to be sufficiently effective and safe for regulatory authorities to permit their use in vaccines for humans and none have been approved for use with intradermal vaccines.…”

“…[63][64][65][66] In 1978, the copper vapor laser was clinically introduced in Russia. Unlike the continuous laser light emitted by helium-neon lasers, copper vapor (CV) lasers release very short duration pulses (10-25 ns) at very high repetition rates (5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20). CV laser light is emitted at 2 wavelengths-about 510 and 580 nm-representing the yellow-green part of the visible light spectrum.…”