The onset of narcolepsy, an irreversible sleep disorder, has been associated with 2009 influenza pandemic (pH1N1) infections in China, and with ASO3-adjuvanted pH1N1 vaccinations using Pandemrix in Europe. Intriguingly, however, the increased incidence was only observed following vaccination with Pandemrix but not Arepanrix in Canada. In this study, the mutational burden of actual vaccine lots of Pandemrix (n = 6) and Arepanrix (n = 5) sourced from Canada, and Northern Europe were characterized by mass spectrometry. The four most abundant influenza proteins across both vaccines were nucleoprotein NP, hemagglutinin HA, matrix protein M1, with the exception that Pandemrix harbored a significantly increased proportion of neuraminidase NA (7.5%) as compared to Arepanrix (2.6%). Most significantly, 17 motifs in HA, NP, and M1 harbored mutations, which significantly differed in Pandemrix versus Arepanrix. Among these, a 6-fold higher deamidation of HA146 (p.Asn146Asp) in Arepanrix was found relative to Pandemrix, while NP257 (p.Thr257Ala) and NP424 (p.Thr424Ile) were increased in Pandemrix. DQ0602 binding and tetramer analysis with mutated epitopes were conducted in Pandemrix-vaccinated cases versus controls but were unremarkable. Pandemrix harbored lower mutational burden than Arepanrix, indicating higher similarity to wild-type 2009 pH1N1, which could explain differences in narcolepsy susceptibility amongst the vaccines.

The onset of narcolepsy, an irreversible sleep disorder, has been associated with 2009 influenza pandemic (pH1N1) infections in China, and with ASO3-adjuvanted pH1N1 vaccinations using Pandemrix in Europe. Intriguingly, however, the increased incidence was only observed following vaccination with Pandemrix but not Arepanrix in Canada. In this study, the mutational burden of actual vaccine lots of Pandemrix (n=6) and Arepanrix (n=5) sourced from Canada, and Northern Europe were characterized by mass spectrometry. The four most abundant influenza proteins across both vaccines were nucleoprotein NP, hemagglutinin HA, matrix protein M1, with the exception that Pandemrix harbored a significantly increased proportion of neuraminidase NA (7.5%) as compared to Arepanrix (2.6%). Most significantly, 17 motifs in HA, NP, and M1 harbored mutations, which significantly differed in Pandemrix versus Arepanrix. Among these, a 6-fold higher deamidation of HA146 (N to D) in Arepanrix was found relative to Pandemrix, while NP257 (T to A) and NP424 (T to I) were increased in Pandemrix. DQ0602 binding and tetramer analysis with mutated epitopes were conducted in Pandemrix-vaccinated cases versus controls but were unremarkable. Pandemrix harbored lower mutational burden than Arepanrix, indicating higher similarity to wild-type 2009 pH1N1, which could explain differences in narcolepsy susceptibility amongst the vaccines.

Background: Neurofibrillary tangles (NFTs) are hallmarks of Alzheimer's disease (AD) and formed by aggregation of the microtube‐associated protein tau that undergoes many modifications, including acetylation on lysine (K) in tau. A piece of tau consisting of six amino acid residues, paired helical filament (PHF)6 (VQIVYK), plays a predominant role in tau aggregation. Merging evidence supports adaptive immune system plays an important role. However, the pieces of antigens, the types and functions of T cells, and HLA types associated with AD remain largely unknown. Methods: We analyzed HLA associations in ∼176,000 individuals with PD or AD versus controls across ancestry groups. We also compared postmortem brain density of NFTs and amyloid plaques in brain, tau and Aβ42 levels in cerebrospinal fluid (CSF) of ∼8,000 individuals (controls and AD), and examined association of HLA in ∼2,500 patient with pathologically demonstrated Lewy Body Dementia. This was followed by HLA binding, tetramer T cell studies and TCR activation by tau PHF6 in Jurkat cell. Results: We found that HLA‐DRB1*04:04 has protective effect in AD. We detected clonally expanded T cells recognizing tau, especially modified PHF6 with acetylation at lysine 311 (PHF6 aK311) when presented by DRB1*04:04, and the phenotypes of these T cells are distinct in AD patients versus cognitively healthy controls. Further, we identified different TCR clones from both AD patients and healthy controls only activated by tau PHF6 aK311 presented by DRB1*04:04. Conclusion: An HLA‐DRB1*04‐mediated adaptive immune response against tau PHF6 aK311 decreases AD risk, offering the possibility of new therapeutic avenues.

Guo Luo; Hypocretin mRNA loss in Pandemrix vaccinated mice, Sleep, , zsae029, https://doi.org/10.1093/sleep/zsae029