Mass Spectrometric Characterization of Narcolepsy-Associated Pandemic 2009 Influenza Vaccines.

Aditya Ambati,Thomas Poiret,Ling Lin,Emmanuel Mignot,Christopher Adams,Hanna Maria Ollila,Guo Luo,Jacob Louis,Ryan D Leib,Elora Pradhan

doi:10.3390/vaccines8040630

Aditya Ambati, Thomas Poiret + Show 8 more

Open Access

https://doi.org/10.3390/vaccines8040630

Copy DOI

Journal: Vaccines	Publication Date: Oct 30, 2020
Citations: 6	License type: CC BY 4.0

Affiliation: Karolinska Institutet, Stanford University

Abstract

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.

Highlights

Type 1 Narcolepsy (T1N) is a disabling disorder characterized by excessive daytime sleepiness, irresistible daytime sleep attacks, and sudden episodes of loss of muscle tone following emotions such as laughter, a symptom known as cataplexy [1]
X-179Aare reassortant virus consisting of PR8 backbone and pH1N1reassortant surface proteins
As it was conceivable that the N146 sequence found in Pandemrix and wild type H1N1 but not Arepanrix was essential to explain narcolepsy susceptibility, we further examined binding of both N146 and D146 peptides on DQ0602 molecules, confirming in vitro prediction indicating that 146 binds with lower affinity to DQ0602, another factor that could contribute to different susceptibility

Summary

Introduction

Type 1 Narcolepsy (T1N) is a disabling disorder characterized by excessive daytime sleepiness, irresistible daytime sleep attacks, and sudden episodes of loss of muscle tone following emotions such as laughter, a symptom known as cataplexy [1]. Genetic and immunological studies have shown that the disorder is autoimmune, and likely mediated by T cell attacks targeting hypocretin producing neurons, a population of 20,000 neurons located in the posterior hypothalamus [2,3]. The rationale for an autoimmune basis for narcolepsy was based mainly on epidemiological and genetic evidence. Vaccines 2020, 8, 630 and 6p21.3, a region of the genome, including the human leukocyte antigen HLA locus, 97% of narcoleptic patients carry at least one copy of HLA DQB1*06:02 (DQ0602) across ethnicities, an HLA class II allele found in 25% of the general population [6,7,8]. Additional weak effects in HLA-A*11:01 [9] and an impact of DQB1*03:01 on the age of onset were observed [10]

Methods

Results

Discussion

Conclusion