Narcolepsy and adjuvanted pandemic influenza A (H1N1) 2009 vaccines – Multi-country assessment

Abstract

Other than elevated narcolepsy IRs in the period after vaccination campaigns in Sweden, we did not find an association between AS03- or MF59-adjuvanted pH1N1 vaccines and narcolepsy in children or adults in the sites studied, although power to evaluate the AS03-adjuvanted Pandemrix brand vaccine was limited in our study.

0016 Autoimmunity To Hypocretin And Molecular Mimicry To Flu In Type 1 Narcolepsy

“…The NP [17][18][19][20][21][22][23][24][25][26][27][28][29][30][31] sequence is representative of seasonal H1N1 before the 2009 pandemic flu (descendant of 1918H1N1, which disappeared around 1957 and reappeared in 1976) and seasonal H2N2 "Asian flu" strains that circulated from 1956 to 1958. Whether or not involved in mimicry, our data also suggest that flu epitopes derived from multiple flu strains (pH1N1, PR8-like, H3N2) may be needed to favor immune response toward T1N autoimmunity (10,32,33,35,55). In this context, Pandemrix vaccination coincidental with pH1N1 pandemic or other strains may also have been a perfect storm in some countries.…”

“…2). Pandemrix has been linked with T1N onset in northern Europe (34); however, the latter correlation varies across countries, suggesting interactions with other factors (33). Of particular interest was the fact that one peptide, pHA 273-287 , is specific of 2009H1N1, while another peptide NP 17-31, was derived from the vaccine backbone sequence strain PR8, an old seasonal H1N1 strain originally derived from 1918H1N1.…”

“…Onset has also been associated with Streptococcus pyogenes infections (9,30) and influenza A (10), suggesting the trigger may be a winter infection, followed by a delay in peaking at 5 mo once sufficient HCRT cell loss has occurred (>80%) and symptoms appear. Most strikingly, prevalence of T1N increased several-fold in mainland China and Taiwan, with a similar delay following the 2009-2010 "Swine Flu" H1N1 influenza pandemic (pH1N1) (10,(31)(32)(33), although this association is less clear in other countries (11). Similarly, cases of T1N have been triggered by the pH1N1 vaccine Pandemrix in Europe with relative risk increasing 5-to 14-fold in children and adolescents and 2-to Significance This work shows that the amidated terminal ends of the secreted hypocretin (HCRT) peptides (HCRT NH2 ) are autoantigens in type 1 narcolepsy, an autoimmune disorder targeting HCRT neurons.…”

“…Genes associated with narcolepsy mark the particular HLA heterodimer (DQ0602) involved in presentation of these antigens and modulate expression of the specific T cell receptor segments (TRAJ24 and TRBV4-2) involved in T cell receptor recognition of these antigens, suggesting causality. 7-fold in adults after vaccination (33,34). Because Pandemrix is an AS03 adjuvanted vaccine containing the artificially produced reassortant strain X-179A, a mix of PR8, an old H1N1 strain derived from pre-2009 seasonal H1N1, and A/California/07/ 2009 containing key H1N1 2009 surface proteins (hemagglutinin, HA and neuraminidase, NA) (35), flu proteins are likely critically involved in triggering T1N.…”

Oil-in-water emulsion adjuvants for pediatric influenza vaccines: a systematic review and meta-analysis

“…Antibodies to nucleoproteins of inactivated influenza virus in Pandemrix TM , which cross-react with human hypocretin receptor 2, may trigger the immune-mediated pathogenesis of narcolepsy 56 . The other two AS03-or MF59-adjuvanted H1N1 vaccines, Arepanrix TM and Focetria TM , contain a much lower amount of viral nucleoproteins than that in Pandemrix 56,57 , and were not associated with a detectable increase in risk of narcolepsy [48][49][50][56][57][58][59] . However, it remains unknown whether removal of viral nucleoprotein from adjuvanted influenza vaccines, through a better purification process during manufacturing, would eliminate the risk of narcolepsy.…”