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

Study Objectives: Onsets of Narcolepsy type-1 (NT1) increased following A/H1N1 vaccination with PandemrixTM 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. Methods: 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 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. Results: NT1 patients had increased anti-HA and anti-NA antibodies against A/H1N1pdm2009 (anti-HA OR = 3.86, anti-NA coefficient = 0.35) and B/Victoria (anti-HA OR =1.90, anti-NA coefficient = 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 (r2=-0.10 to 0.34). Multivariable model outperformed age-only baseline (McFadden R2 = 0.19 vs. 0.03; AUC = 0.79 vs. 0.64; likelihood-ratio test X2 = 51, p<0.001), with anti-HA against A/H1N1pdm2009 (coefficient = 0.78, p < 0.001) and anti-NA against B/Victoria (coefficient = 0.69, p < 0.001) emerging as the strongest independent predictors. Conclusions: A/H1N1pdm2009 and B/Victoria, but not other strains can trigger the autoimmune process leading to orexin cell loss in narcolepsy.