Intended for healthcare professionals

CCBYNC Open access

Rapid response to:


Risk of narcolepsy in children and young people receiving AS03 adjuvanted pandemic A/H1N1 2009 influenza vaccine: retrospective analysis

BMJ 2013; 346 doi: (Published 26 February 2013) Cite this as: BMJ 2013;346:f794

Rapid Response:

Re: Risk of narcolepsy in children and young people receiving AS03 adjuvanted pandemic A/H1N1 2009 influenza vaccine: retrospective analysis

We read with interest the findings of Miller and colleagues on the association of narcolepsy with the AS03-adjuvanted pandemic A(H1N1)pdm09 vaccine in England and, in particular, their call for investigations of other A(H1N1)pdm09 vaccines to ascertain their risk to cause narcolepsy.1 Risk estimates above ten are unusual, and in pharmacoepidemiology lead to the suspicion of unknown confounding factors. The UK data, confirming previous reports,2,3 considerably lessens the likelihood of confounding. However, the mechanisms by which the AS03-adjuvanted pandemic vaccine’s components may have contributed to an increased risk for narcolepsy are unclear and may be difficult to dissect, as the still uncertain pathogenesis of Guillain Barre syndrome (GBS) following influenza vaccination illustrates.

Previous observations suggest that similar vaccines may have subtle differences that manifest themselves in different ways or in different seasonal formulations – e.g., oculorespiratory syndrome has been associated prominently with one split seasonal vaccine product but not with others4, and perhaps appropriate in the context of narcolepsy cases occurring in 2009-10, the incidence of GBS associated with seasonal influenza vaccines has fluctuated though never to as high an incidence as was seen in 1976, in association with the A/New Jersey/76 (Hsw1n1) pandemic vaccine.5 In addition, as noted by Miller, one observation suggested that the pandemic infection itself may have triggered an increase in narcolepsy cases.6,7 Thus, the pandemic virus, or its antigens, cannot be excluded as having contributed to the origin of narcolepsy in pandemic vaccine-associated cases in 2009-10.

Novartis Vaccines and Diagnostics distributed approximately 107 million doses of two pandemic vaccines containing the emulsion adjuvant, MF59® (unpublished data, Novartis Vaccines and Diagnostics). In response to Miller et al, we briefly summarise the available data on the occurrence of narcolepsy cases in conjunction with the distribution of these vaccines. The MF59®-adjuvanted vaccines, containing egg or cell culture derived viral subunit antigens, were distributed in more than 17 countries, though the actual number of doses administered and their deployment by age are unknown to us. The association between narcolepsy and MF59-adjuvanted pandemic vaccine was investigated through active case finding only in the Netherlands, where an estimated 72% of individuals 5-64 years of age with risk factors were vaccinated with that vaccine.8 No MF59-adjuvanted vaccine associated-cases of narcolepsy were identified during the primary study period through active case finding at nine referral sleep centres.8

Passively-acquired data come from Argentina, where only an MF59-adjuvanted vaccine was used in the national pandemic response and high coverage was achieved in high risk persons 5-64 years-old, but no cases were reported to the Administración Nacional de Medicamentos, Alimentos y Tecnología Médica.9 A search of the Novartis Pharmacovigilance database disclosed one spontaneously reported case from Switzerland meeting a level 2 Brighton Collaboration and European Narcolepsy Network case definition of narcolepsy, and another with insufficient confirmatory information classified as > level 3 (Novartis data on file).10-12 Other events of special interest that included certain autoimmune and neurological diseases were not spontaneously reported at unusual frequency in connection with the adjuvanted pandemic vaccines or MF59-adjuvanted subunit seasonal vaccine, which was first licensed in 1997.13,14,

The absence of a narcolepsy signal in connection with pandemic vaccine adjuvanted with MF59 may reflect differences in adjuvant compositions (Table 1) and mechanisms of action. 15,16 Notably, MF59 is comprised of a single emulsified oil, squalene, and does not contain alpha-tocopherol. While MF59 is a local activator only of the mouse transcriptome in muscle at the injection site, it does not upregulate genes controlling innate immunity distally, in draining lymph nodes.15 In contrast, AS03, which contains squalene co-emulsified with the ‘immunomodulator’ alpha-tocopherol, activates innate immune responses in the draining lymph nodes of immunized mice, independently of antigen.16 Its more generalized immune potentiation is mediated directly by alpha-tocopherol which further amplifies the adjuvant activity of AS03, making it more potent than a squalene only adjuvant.16 But, as alluded to above, other factors may be operative. The association of narcolepsy, which is believed to be an autoimmune disorder, with the AS03-adjuvanted vaccine may not be due strictly to the vaccine adjuvant. Reporting rates for autoimmune disorders (not including narcolepsy) within EudraVigilance were no greater for adjuvanted pandemic vaccines (including both MF59 and AS03-adjuvanted vaccines) than for nonadjuvanted pandemic vaccines.17

In summary, the available but limited observations have not signalled an increased risk of narcolepsy associated with MF59-adjuvanted pandemic vaccines. The aetiology of cases in 2009-10 appears complex and contributory roles of the pandemic virus or vaccine antigens should not be excluded, while attributing the elevated risk associated with AS03-adjuvanted vaccine solely to the adjuvant may be premature.

Table 1. Composition of MF59 and AS03: oil-in-water emulsion adjuvants that are components of licensed adjuvanted vaccines (mg/dose)
MF59 AS03
Squalene 9.75 10.68
Tween 80 (sorbitan oleate) 1.17 4.85
Span 85 1.17 nil
DL alpha-tocopherol nil 11.86
Buffer citrate, pH 6.5 phosphate, pH 6.8
Mean diameter 160 nM 160 nM

1. Miller E, Andrews N, Stellitano L, Stowe J, Winstone AM, Shneerson J, et al. Risk of narcolepsy in children and young people receiving AS03 adjuvanted pandemic A/H1N1 2009 influenza vaccine: retrospective analysis. BMJ 2013;346:f794
2. Nohynek H, Jokinen J, Partinen M, Vaarala O, Kirjavainen T, Sundman J, et al. AS03 adjuvanted AH1N1 vaccine associated with an abrupt increase in the incidence of childhood narcolepsy in Finland. PLoS One. 2012;7(3):e33536. doi: 10.1371/journal.pone.0033536. Epub 2012 Mar 28.
3. Partinen M, Saarenpää-Heikkilä O, Ilveskoski I, Hublin C, Linna M, Olsén P, et al. Increased incidence and clinical picture of childhood narcolepsy following the 2009 H1N1 pandemic vaccination campaign in Finland. PLoS One. 2012;7(3):e33723. doi: 10.1371/journal.pone.0033723. Epub 2012 Mar 28.
4. National Advisory Committee on Immunization. Supplementary statement for the 2001–2002 season: influenza vaccination of persons who experienced oculorespiratory syndrome following previous influenza vaccination. Can Commun Dis Rep 2001;27:1-7
5. Sejvar JJ, Pfeifer D, Schonberger LB. Guillain-barré syndrome following influenza vaccination: causal or coincidental? Curr Infect Dis Rep. 2011;13:387-98.
6. Yuan Y, Strohl KP, Mignot E. Narcolepsy onset is seasonal and increased following the 2009 H1N1 pandemic in China. Ann Neurol 2011;70:410-7
7. Han F, Lin L, Li J, Dong XS, Mignot E. Decreased incidence of childhood narcolepsy 2 years after the 2009 H1N1 winter flu pandemic. Ann Neurol 2012: doi:10.1022/ana.23799
8. European Centre for Disease Control. ECDC TECHNICAL REPORT Narcolepsy in association with pandemic influenza vaccination - a multi-country European epidemiological investigation. 2012.
9. Biscayart C, Argentina´s integral prevention of influenza: a successful experience of an emerging country. Influenza vaccines for the world. Valencia, Spain, 2012
10. Tsai TF, Crucitti A, Nacci P, Nicolay U, Della Cioppa G, Ferguson J, et al. Explorations of clinical trials and pharmacovigilance databases of MF59®-adjuvanted influenza vaccines for associated cases of narcolepsy. Scand J Infect Dis 2011;43:702-6
11. Crucitti A, Tsai TF. Explorations of clinical trials and pharmacovigilance databases of MF59®-adjuvanted influenza vaccines for associated cases of narcolepsy: a six-month update. Scand J Infect Dis 2011;43:993.
12. Haba-Rubio J, Rossetti AO, Tafti M, Heinzer R. Narcolepsy with cataplexy associated with H1N1 vaccination. Rev Neurol (Paris). 2011;167:563-6.
13. Banzhoff A, Haertel S, Praus M. Passive surveillance of adverse events of an MF59-adjuvanted H1N1v vaccine during the pandemic mass vaccinations. Hum Vaccin. 2011; 7:539-48.
14. Schultze V, D'Agosto V, Wack A, Novicki D, Zorn J, Hennig R. Safety of MF59 adjuvant. Vaccine. 2008;26:3209-22.
15. O'Hagan DT, Ott GS, De Gregorio E, Seubert A. The mechanism of action of MF59 - an innately attractive adjuvant formulation. Vaccine. 2012;30:4341-8.
16. Morel S, Didierlaurent A, Bourguignon P, Delhaye S, Baras B, Jacob V, et al. Adjuvant System AS03 containing α-tocopherol modulates innate immune response and leads to improved adaptive immunity. Vaccine 2011;29:2461-73
17. Isai A, Durand J, Le Meur S, Hidalgo-Simon A, Kurz X. Autoimmune disorders after immunisation with Influenza A/H1N1 vaccines with and without adjuvant: EudraVigilance data and literature review. Vaccine 2012;30:7123-9

Competing interests: All authors are full time employees of Novartis Vaccines and Diagnostics, a manufacturer of adjuvanted pandemic influenza vaccines.

29 March 2013
Theodore Tsai
Giuseppe Del Giudice, Antonio Crucitti, John Weil, Vas Narasimhan
Novartis Vaccines and Diagnostics
350 Massachusetts Ave Cambridge, MA 02139 USA