Antibodies against influenza A/H1N1pdm2009 and B/Victoria strains but not A/H3N2 are increased in recent onset type 1 narcolepsy versus matched controls

<jats:title>Abstract</jats:title> <jats:sec> <jats:title>Study Objectives</jats:title> <jats:p>Onsets of Narcolepsy type-1 (NT1) increased following A/H1N1 vaccination with Pandemrix® in Europe and with A/H1N1pdm2009 infections in China and other countries. To test if other strains could trigger narcolepsy, we measured strain-specific antibodies in patients with recent onset NT1 compared to controls.</jats:p> </jats:sec> <jats:sec> <jats:title>Methods</jats:title> <jats:p>Antibodies against hemagglutinin (HA) and neuraminidase (NA) were tested in 62 patients with very recent onset (onset and blood collection following a single flu season, mean ± SEM: 0.44 ± 0.06 years since onset) and 100 controls matched by age, sex, season and year of collection (2000-2025). Results were next extended to 181 recent onset patients (mean± SEM: 1.00 ± 0.05 years) versus 260 controls, matched by sex, season and year, but having a slightly higher mean age. HA inhibition (HAI) and NA inhibition (NAI) assays were conducted using flu strains known to circulate during the corresponding flu seasons. HAI results are shown as % positive (titers ≥ 40) and NAI results as geometric mean titers. Odds ratio (OR) and β coefficient were used to compare antibody titers in NT1 versus controls. The contribution of each assay to prediction was finally quantified in the larger sample set using Shapley decomposition.</jats:p> </jats:sec> <jats:sec> <jats:title>Results</jats:title> <jats:p> NT1 patients had increased anti-HA and anti-NA antibodies against A/H1N1pdm2009 (anti-HA OR= 3.86, anti-NA β= 0.35) and B/Victoria (anti-HA OR=1.90, anti-NA β=0.22), but not A/H1N1pre2009, A/H3N2, or B/Yamagata, independent of HLA-DQB1*06:02 status, age, sex, and flu season. Correlations between anti-HA and anti-NA antibodies titers were weak to moderate but significant (r <jats:sup>2</jats:sup> =-0.10 to 0.34). Multivariable model outperformed age-only baseline (McFadden R <jats:sup>2</jats:sup> = 0.19 vs. 0.03; AUC = 0.79 vs. 0.64; likelihood-ratio test χ <jats:sup>2</jats:sup> = 51, p&lt;10 <jats:sup>-9</jats:sup> ), with anti-HA against A/H1N1pdm2009 (β = 0.78, p &lt; 10 <jats:sup>-6</jats:sup> ) and anti-NA against B/Victoria (β = 0.69, p &lt; 10 <jats:sup>-5</jats:sup> ) emerging as the strongest independent predictors. </jats:p> </jats:sec> <jats:sec> <jats:title>Conclusions</jats:title> <jats:p>A/H1N1pdm2009 and B/Victoria, but not other strains can trigger the autoimmune process leading to orexin cell loss in narcolepsy.</jats:p> </jats:sec>