Dataset Information

No serological evidence of influenza A H1N1pdm09 virus infection as a contributing factor in childhood narcolepsy after Pandemrix vaccination campaign in Finland.

ABSTRACT:

Background

Narcolepsy cataplexy syndrome, characterised by excessive daytime sleepiness and cataplexy, is strongly associated with a genetic marker, human leukocyte antigen (HLA) DQB1*06:02. A sudden increase in the incidence of childhood narcolepsy was observed after vaccination with AS03-adjuvanted Pandemrix influenza vaccine in Finland at the beginning of 2010. Here, we analysed whether the coinciding influenza A H1N1pdm pandemic contributed, together with the Pandemrix vaccination, to the increased incidence of childhood narcolepsy in 2010. The analysis was based on the presence or absence of antibody response against non-structural protein 1 (NS1) from H1N1pdm09 virus, which was not a component of Pandemrix vaccine.

Methods

Non-structural (NS) 1 proteins from recombinant influenza A/Udorn/72 (H3N2) and influenza A/Finland/554/09 (H1N1pdm09) viruses were purified and used in Western blot analysis to determine specific antibody responses in human sera. The sera were obtained from 45 patients who fell ill with narcolepsy after vaccination with AS03-adjuvanted Pandemrix at the end of 2009, and from controls.

Findings

Based on quantitative Western blot analysis, only two of the 45 (4.4%) Pandemrix-vaccinated narcoleptic patients showed specific antibody response against the NS1 protein from the H1N1pdm09 virus, indicating past infection with the H1N1pdm09 virus. Instead, paired serum samples from patients, who suffered from a laboratory confirmed H1N1pdm09 infection, showed high levels or diagnostic rises (96%) in H1N1pdm virus NS1-specific antibodies and very high cross-reactivity to H3N2 subtype influenza A virus NS1 protein.

Conclusion

Based on our findings, it is unlikely that H1N1pdm09 virus infection contributed to a sudden increase in the incidence of childhood narcolepsy observed in Finland in 2010 after AS03-adjuvanted Pandemrix vaccination.

SUBMITTER: Melen K

PROVIDER: S-EPMC3738560 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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Publications

No serological evidence of influenza A H1N1pdm09 virus infection as a contributing factor in childhood narcolepsy after Pandemrix vaccination campaign in Finland.

Melén Krister K Partinen Markku M Tynell Janne J Sillanpää Maarit M Himanen Sari-Leena SL Saarenpää-Heikkilä Outi O Hublin Christer C Olsen Päivi P Ilonen Jorma J Nohynek Hanna H Syrjänen Ritva R Kilpi Terhi T Vuorela Arja A Kirjavainen Turkka T Vaarala Outi O Julkunen Ilkka I

PloS one 20130808 8

<h4>Background</h4>Narcolepsy cataplexy syndrome, characterised by excessive daytime sleepiness and cataplexy, is strongly associated with a genetic marker, human leukocyte antigen (HLA) DQB1*06:02. A sudden increase in the incidence of childhood narcolepsy was observed after vaccination with AS03-adjuvanted Pandemrix influenza vaccine in Finland at the beginning of 2010. Here, we analysed whether the coinciding influenza A H1N1pdm pandemic contributed, together with the Pandemrix vaccination, t ...[more]

PMID: 23950869

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Project description:The incidence of narcolepsy type 1 (NT1) increased in Sweden following the 2009-2010 mass-vaccination with the influenza Pandemrix-vaccine. NT1 has been associated with Human leukocyte antigen (HLA) DQB1*06:02 but full high-resolution HLA-typing of all loci in vaccine-induced NT1 remains to be done. Therefore, here we performed HLA typing by sequencing HLA-DRB3, DRB4, DRB5, DRB1, DQA1, DQB1, DPA1 and DPB1 in 31 vaccine-associated NT1 patients and 66 of their first-degree relatives (FDR), and compared these data to 636 Swedish general population controls (GP). Previously reported disease-related alleles in the HLA-DRB5*01:01:01-DRB1*15:01:01-DQA1*01:02:01-DQB1*06:02:01 extended haplotype were increased in NT1 patients (34/62 haplotypes, 54.8%) compared to GP (194/1272 haplotypes, 15.3%, p = 6.17E-16). Indeed, this extended haplotype was found in 30/31 patients (96.8%) and 178/636 GP (28.0%). In total, 15 alleles, four extended haplotypes, and six genotypes were found to be increased or decreased in frequency among NT1 patients compared to GP. Among subjects with the HLA-DRB5*01:01:01-DRB1*15:01:01-DQA1*01:02-DQB1*06:02 haplotype, a second DRB4*01:03:01-DRB1*04:01:01-DQA1*03:02//*03:03:01-DQB1*03:01:01 haplotype (p = 2.02E-2), but not homozygosity for DRB1*15:01:01-DQB1*06:02:01 (p = 7.49E-1) conferred association to NT1. Alleles with increased frequency in DQA1*01:02:01 (p = 1.07E-2) and DQA1*03:02//*03:03:01 (p = 3.26E-2), as well as with decreased frequency in DRB3*01:01:02 (p = 8.09E-3), DRB1*03:01:01 (p = 1.40E-2), and DQB1*02:01:01 (p = 1.40E-2) were found among patients compared to their FDR. High-resolution HLA sequencing in Pandemrix-associated NT1 confirmed the strong association with the DQB1*06:02:01-containing haplotype but also revealed an increased association to the not previously reported extended HLA-DRB4*01:03:01-DRB1*04:01:01-DQA1*03:02//*03:03:01-DQB1*03:01:01 haplotype. High-resolution HLA typing should prove useful in dissecting the immunological mechanisms of vaccination-associated NT1.

Project description:BackgroundA recent publication suggested molecular mimicry of a nucleoprotein (NP) sequence from A/Puerto Rico/8/1934 (PR8) strain, the backbone used in the construction of the reassortant strain X-179A that was used in Pandemrix® vaccine, and reported on anti-hypocretin (HCRT) receptor 2 (anti-HCRTR2) autoantibodies in narcolepsy, mostly in post Pandemrix® narcolepsy cases (17 of 20 sera). In this study, we re-examined this hypothesis through mass spectrometry (MS) characterization of Pandemrix®, and two other pandemic H1N1 (pH1N1)-2009 vaccines, Arepanrix® and Focetria®, and analyzed anti-HCRTR2 autoantibodies in narcolepsy patients and controls using three independent strategies.MethodsMS characterization of Pandemrix® (2 batches), Arepanrix® (4 batches) and Focetria® (1 batch) was conducted with mapping of NP 116I or 116M spectrogram. Two sets of narcolepsy cases and controls were used: 40 post Pandemrix® narcolepsy (PP-N) cases and 18 age-matched post Pandemrix® controls (PP-C), and 48 recent (≤6 months) early onset narcolepsy (EO-N) cases and 70 age-matched other controls (O-C). Anti-HCRTR2 autoantibodies were detected using three strategies: (1) Human embryonic kidney (HEK) 293T cells with transient expression of HCRTR2 were stained with human sera and then analyzed by flow cytometer; (2) In vitro translation of [35S]-radiolabelled HCRTR2 was incubated with human sera and immune complexes of autoantibody and [35S]-radiolabelled HCRTR2 were quantified using a radioligand-binding assay; (3) Optical density (OD) at 450 nm (OD450) of human serum immunoglobulin G (IgG) binding to HCRTR2 stably expressed in Chinese hamster ovary (CHO)-K1 cell line was measured using an in-cell enzyme-linked immunosorbent assay (ELISA).ResultsNP 116M mutations were predominantly present in all batches of Pandemrix®, Arepanrix® and Focetria®. The wild-type NP109-123 (ILYDKEEIRRIWRQA), a mimic to HCRTR234-45 (YDDEEFLRYLWR), was not found to bind to DQ0602. Three or four subjects were found positive for anti-HCRTR2 autoantibodies using two strategies or the third one, respectively. None of the post Pandemrix® narcolepsy cases (0 of 40 sera) was found positive with all three strategies.ConclusionAnti-HCRTR2 autoantibody is not a significant biological feature of narcolepsy or of post Pandemrix® autoimmune responses.

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Dataset Information

No serological evidence of influenza A H1N1pdm09 virus infection as a contributing factor in childhood narcolepsy after Pandemrix vaccination campaign in Finland.

Background

Methods

Findings

Conclusion

Publications

No serological evidence of influenza A H1N1pdm09 virus infection as a contributing factor in childhood narcolepsy after Pandemrix vaccination campaign in Finland.

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