Risk of narcolepsy in children and young people receiving AS03 adjuvanted pandemic A/H1N1 2009 influenza vaccine: retrospective analysis. BMJ 346:f794

Immunisation, Hepatitis and Blood Safety Department, Health Protection Agency, Colindale, London NW9 5EQ, UK.
BMJ (online) (Impact Factor: 17.45). 02/2013; 346(feb26 2):f794. DOI: 10.1136/bmj.f794
Source: PubMed


To evaluate the risk of narcolepsy in children and adolescents in England targeted for vaccination with ASO3 adjuvanted pandemic A/H1N1 2009 vaccine (Pandemrix) from October 2009.
Retrospective analysis. Clinical information and results of sleep tests were extracted from hospital notes between August 2011 and February 2012 and reviewed by an expert panel to confirm the diagnosis. Vaccination and clinical histories were obtained from general practitioners.
Sleep centres and paediatric neurology centres in England.
Children and young people aged 4-18 with onset of narcolepsy from January 2008.
The odds of vaccination in those with narcolepsy compared with the age matched English population after adjustment for clinical conditions that were indications for vaccination. The incidence of narcolepsy within six months of vaccination compared with the incidence outside this period measured with the self controlled cases series method.
Case notes for 245 children and young people were reviewed; 75 had narcolepsy (56 with cataplexy) and onset after 1 January 2008. Eleven had been vaccinated before onset; seven within six months. In those with a diagnosis by July 2011 the odds ratio was 14.4 (95% confidence interval 4.3 to 48.5) for vaccination at any time before onset and 16.2 (3.1 to 84.5) for vaccination within six months before onset. The relative incidence from the self controlled cases series analysis in those with a diagnosis by July 2011 with onset from October 2008 to December 2010 was 9.9 (2.1 to 47.9). The attributable risk was estimated as between 1 in 57 500 and 1 in 52 000 doses.
The increased risk of narcolepsy after vaccination with ASO3 adjuvanted pandemic A/H1N1 2009 vaccine indicates a causal association, consistent with findings from Finland. Because of variable delay in diagnosis, however, the risk might be overestimated by more rapid referral of vaccinated children.

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    • "The SCCS methodology is now routinely used to evaluate vaccine safety. For instance, following H1N1 vaccination, it has recently been used to evaluate the risks of Guillain–Barré syndrome [14], narcolepsy [15], epileptic seizures [16], convulsions [17], and multiple sclerosis [18]. Its efficiency compared to the cohort design has been established, which is a desirable feature when studying rare events such as intussusception [19]. "
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    ABSTRACT: The increased risk of intussusception after vaccination with the rhesus-human reassortant rotavirus vaccine Rotashield led to its withdrawal in 2005. We assess the risk of intussusception following the pentavalent rotavirus vaccine (RV5) on the basis of worldwide reports to the manufacturer up to May 2014, using a self-controlled case series. The method had to be modified to account for the under-reporting, a specific feature of pharmacovigilance spontaneous reports. The risk of intussusception occurring in either of the 0- to 2-day, 3- to 7-day or 8- to 14-day risk periods, was compared to the risk in the 15- to 30-day period. A total of 502 cases occurring 0-30 days after a vaccine dose were studied, including 188 cases after the first dose, 190 cases after the second dose, and 124 cases after the third dose. The incidence risk ratio relative to the control period was highest for the 3- to 7-day period and equal to 3.45 (95% CI 1.84-6.55), 1.63 (0.86-3.13) and 1.73 (0.86-3.51) after the first, second and third dose, respectively. Rotavirus vaccination with RV5 increases the risk of intussusception 3-7 days following vaccination, mainly after the first dose and marginally after the second and third doses. The risk is small and restricted to a short time window. It does not outweigh the benefit of the vaccination, but parents of vaccinated infants should be informed in order to react appropriately to the first symptoms. With appropriate assumptions about the reporting rate, spontaneous reports of adverse events after vaccination can be studied to evaluate vaccine safety. Copyright © 2015. Published by Elsevier Ltd.
    Vaccine 01/2015; 33(8). DOI:10.1016/j.vaccine.2015.01.005 · 3.62 Impact Factor
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    • "Animal narcolepsy models and optogenetic device studies have shown that hypocretin maintains wakefulness, increases arousal, and suppresses REM and non-REM sleep [8] [9]. The observed association of narcolepsy with streptococcal [10] and H1N1 [11] infections and with H1N1 vaccination [12] [13] [14] [15] further supports the concept that narcolepsy is an immune-mediated disease. "
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    ABSTRACT: Despite published treatment recommendations and the availability of approved and off-label pharmacologic therapies for narcolepsy, clinical management of this incurable, chronic neurologic disorder remains challenging. While treatment is generally symptomatically driven, decisions regarding which drug(s) to use need to take into account a variety of factors that may affect adherence, efficacy, and tolerability. Type 1 narcolepsy (predominantly excessive daytime sleepiness with cataplexy) or type 2 narcolepsy (excessive daytime sleepiness without cataplexy) may drive treatment decisions, with consideration given either to a single drug that targets multiple symptoms or multiple drugs that each treat a specific symptom. Other drug-related characteristics that affect drug choice are dosing regimens, tolerability, and potential drug-drug interactions. Additionally, the patient should be an active participant in treatment decisions, and the main symptomatic complaints, treatment goals, psychosocial setting, and use of lifestyle substances (i.e., alcohol, nicotine, caffeine, cannabis) need to be discussed with respect to treatment decisions. Although there is a lack of narcolepsy-specific instruments for monitoring therapeutic effects, clinically relevant subjective and objective measures of daytime sleepiness (e.g., Epworth Sleepiness Scale, Maintenance of Wakefulness Test) can be used to provide guidance on whether treatment goals are being met. These considerations are discussed with the objective of providing clinically relevant recommendations for making treatment decisions that can enhance effective management of patients with narcolepsy.
    Sleep Medicine 10/2014; 16(1). DOI:10.1016/j.sleep.2014.10.002 · 3.15 Impact Factor
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    • "AS03, which also contains alpha-tocopherol as a constituent, is used in the US stockpile as a vaccine to pandemic influenza. Although it is regarded as a safe adjuvant, it is noted that AS03 has been reported to be associated (albeit rarely) with narcolepsy as a side effect in humans [93] "
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    ABSTRACT: Immunotherapeutic vaccines to drugs of abuse, including nicotine, cocaine, heroin, oxycodone, methamphetamine, and others are being developed. The theoretical basis of such vaccines is to induce antibodies that sequester the drug in the blood in the form of antibody-bound drug that cannot cross the blood brain barrier, thereby preventing psychoactive effects. Because the drugs are haptens a successful vaccine relies on development of appropriate hapten-protein carrier conjugates. However, because induction of high and prolonged levels of antibodies is required for an effective vaccine, and because injection of T-independent haptenic drugs of abuse does not induce memory recall responses, the role of adjuvants during immunization plays a critical role. As reviewed herein, preclinical studies often use strong adjuvants such as complete and incomplete Freund's adjuvant and others that cannot be, or in the case of many newer adjuvants, have never been, employed in humans. Balanced against this, the only adjuvant that has been included in candidate vaccines in human clinical trials to nicotine and cocaine has been aluminum hydroxide gel. While aluminum salts have been widely utilized worldwide in numerous licensed vaccines, the experience with human responses to aluminum salt-adjuvanted vaccines to haptenic drugs of abuse has suggested that the immune responses are too weak to allow development of a successful vaccine. What is needed is an adjuvant or combination of adjuvants that are safe, potent, widely available, easily manufactured, and cost-effective. Based on our review of the field we recommend the following adjuvant combinations either for research or for product development for human use: aluminum salt with adsorbed monophosphoryl lipid A (MPLA); liposomes containing MPLA [L(MPLA)]; L(MPLA) adsorbed to aluminum salt; oil-in-water emulsion; or oil-in-water emulsion containing MPLA.
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