The Committee was presented with an update of research on the association of adjuvanted p2009HN1NI influenza vaccines and narcolepsy. During the influenza pandemic of 2009, oil-in-water emulsion adjuvants (AS03 and MF59) were used in vaccines to maintain immunogenicity when antigen availability was limited and dose sparing was required. As was noted previously by GACVS in the meeting report of December 2015,4 there is consistent evidence in Europe of an increased risk of narcolepsy following use of Pandemrix, despite the varying datasets and methods used. New research was presented from a multicountry study sponsored by the United States Centers for Disease Control and Prevention.5

The aims of the study were to assess the association of narcolepsy with other adjuvanted vaccines: Arepanrix, an AS03 adjuvanted vaccine used in Canada only, and Focetria, an MF59 adjuvanted vaccine. A small amount of additional data on Pandemrix from the Netherlands was also collected. Adjuvants have been used to produce effective vaccines for the control of many infections, and might be used in future pandemics; hence any evidence to inform their safety profiles is useful. The Committee noted the extensive work required to establish data collection from multiple settings (Canada, Argentina, Taiwan, Netherlands, Spain and Switzerland) to conduct case–control studies as well as to examine time trends in rates of narcolepsy in those and additional settings (Denmark, Sweden and the United Kingdom).

The population-based narcolepsy rates before and after the pandemic were calculated using diagnosed cases from healthcare databases. Provisional analyses suggested little in the way of signals except in Sweden, one of the 2 signalling countries (the other being Finland) where Pandemrix was the only vaccine used and where coverage was high. The recruitment of controls for the case–control studies varied from population-based to hospital-based, depending on the setting, with matching on age, sex and time to cases carried out. Preliminary evidence from the case–control studies was reassuring for Focetria and Arepanrix. For Pandemrix, data were too sparse in this study to draw further conclusions. GACVS is aware that additional data for Pandemrix could be available from several European countries including extended follow-up of published studies that could improve understanding of the association between narcolepsy and Pandemrix. To date, the data presented provide reassurance that, with the exception of the ASO3 adjuvanted Pandemrix in several European countries where adolescents and young adults were frequently vaccinated, no other substantial association between the use of p2009H1N1 pandemic virus vaccines and narcolepsy has been identified.

⁴ See N°. 3, 2016, pp. 21–32.

5 The Systematic Observational Method for Narcolepsy and Influenza Immunization Assessment (SOMNIA): a Study to Assess the Risk of Narcolepsy Following Adjuvanted 2009 H1N1 Influenza Vaccines. [In preparation.]

Full report of GACVS meeting of 30 November-1 December 2016, published in the WHO Weekly Epidemiological Record of 13 January 2017

GACVS last reviewed the potential association between 2009 H1N1 influenza vaccine and narcolepsy at the June 2013 meeting.⁹ On that occasion it was noted that for the vaccine Pandemrix® there was evidence from several studies of a possible risk in adults which was lower than that seen in children, and that this needed further research to confirm the strength of the observed association and the magnitude of the risk. In addition the need for further research to identify the underlying pathophysiological mechanism was highlighted.

Since the last review a Canadian study has been published assessing the risk of narcolepsy following the use of another monovalent AS03 adjuvanted vaccine Arepanrix®.¹⁰ This vaccine was produced in a separate facility from Pandemrix® with different processes for inactivation and purification. The cohort study, which had a much lower background incidence of narcolepsy than reported in the studies in Europe and which only had the power to assess all ages combined, found a much smaller relative and attributable risk with this vaccine. Further data on the Pandemrix®-narcolepsy risk in adults from a study in England submitted for publication were also reviewed. This study also found an association in adults which was of smaller magnitude than that seen in children.

Following recent publications critiquing the published narcolepsy studies and highlighting possible biases^{11, 12} GACVS examined how the studies had dealt with this. The main issue was whether media attention led to ascertainment bias. Most studies did address this potential bias by restricting key analyses to periods prior to media attention. Suggestions in the critiques that there was evidence of longer delays from onset of diagnosis in unvaccinated individuals when compared to vaccinated individuals were found to be based on misinterpretation of these delays. Overall the studies to date have produced consistent results for the risk following Pandemrix® despite various sources of data and study designs.

Several hypotheses have been proposed to explain the pathophysiological mechanism of narcolepsy following adjuvanted 2009 H1N1 vaccination. A differential content of viral nucleoproteins has been observed between Pandemrix and Arepanrix^{13, 14} that occurred in the production process. The high immunogenicity of the adjuvanted vaccine has also been proposed as a co-factor for producing immune-mediated damage to hypocretin or hypocretin receptors in the hypothalamus. Narcolepsy has been known since 2000 to be due to low levels of this neuropeptide in the cerebrospinal fluid. The autoimmune nature of narcolepsy has not yet been directly demonstrated but is suggested by a close association with HLA type DQB1*0602. Cross-reactivity of T-cells and antibodies to vaccine antigens and hypocretin receptors has been documented but is also found among healthy controls. GACVS therefore concluded that at this stage, the evidence for a clear cross-reactive pathogenic mechanism remains limited.

GACVS discussed the fact that the association of childhood narcolepsy with Pandemrix could not have been predicted and therefore could not have been put on the list of possible adverse effects of special interest used in influenza vaccine pharmacovigilance post licensure. In addition, there is a possibility that without the high immunization coverage achieved in Finland and Sweden and the vigilance of individual neurologists, the signal could have been missed. The committee also noted that despite the very low incidence of narcolepsy, signal detection was facilitated in this instance by the greatly elevated risk in a relatively short post-vaccination window period.

Large databases for signal strengthening such as PRISM (Post-licensure Rapid Immunization Safety Monitoring system) and the Vaccine Safety DataLink in the USA are seen as important tools to be encouraged in other settings. However, care needs to be taken in pooling data from different databases with different variables and whose potential biases and confounders may operate to obscure a signal. Separate analyses should also be carried out. The existence of new EMA guidelines on good pharmacovigilance practices for all vaccines in general published in December 2013 were also highlighted at the meeting.¹⁵

⁹ See No. 29, 2013, pp. 309–312.

¹⁰ Montplaisir J, Petit D, Quinn MJ, et al. Risk of narcolepsy associated with inactivated adjuvanted (AS03) A/H1N1 (2009) pandemic influenza vaccine in Quebec. PLoS One. 2014 Sep 29;9(9):e108489.

¹¹ Verstraeten T1, Cohet C2, Dos Santos G3, et al. Pandemrix™ and narcolepsy: A critical appraisal of the observational studies. Hum Vaccin Immunother. 2015 Sep 17:1–7.

¹² Sturkenboom MC. The narcolepsy-pandemic influenza story: can the truth ever be unravelled? Vaccine. 2015 Jun 8;33 Suppl 2:B6-B13.

¹³ Varaala O, Vuorela A, Partinen M, et al. Antigenic differences between AS03 adjuvanted influenza A (H1N1) pandemic vaccines: implications for pandemrix-associated narcolepsy risk. PLoS One. 2014 Dec 15;9(12):e114361

¹⁴ Ahmed SS, Volkmuth W, Duca J, et al. Antibodies to influenza nucleoprotein cross-react with human hypocretin receptor 2. Sci Transl Med. 2015 Jul 1;7(294):294ra105.

¹⁵ See http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/document_listing/document_listing_000345.jsp&mid=WC0b01ac058058f32c

Full report of GACVS meeting of 2-3 December 2015, published in the WHO Weekly Epidemiological Record of 22 January 2016

The Committee has previously reviewed data from studies on the use of the pandemic influenza vaccine (monovalent A(H1N1)pdm09 vaccine) in Finland, Sweden, Ireland, the UK and France which all demonstrated an increased risk of narcolepsy following Pandemrix® vaccination in children and adolescents. The studies in Sweden and France also found evidence of an increased risk in adults. The Committee reviewed newly available data from Finland about the safety of Pandemrix® vaccine in adults. The retrospective cohort study linked vaccination data of the whole adult population to incident cases of narcolepsy identified through the national care register during the follow-up period from 1 January 2009 to 31 December 2011. The comparison of incidence rates indicated a 3–5-fold (after sensitivity analysis 2–4-fold) risk of narcolepsy among vaccinated compared to unvaccinated adults. The increased risk was seen 8 months post vaccination; thereafter, no increased risk was observed. The reports from Sweden, France and Finland concur that young adults have an increased risk of narcolepsy after Pandemrix® vaccination. GACVS acknowledges this finding suggesting a possible risk of narcolepsy among adults, although it remains lower than that seen among children. Further follow-up research is required to confirm the strength of the observed association and size of the risk. Because of the continued threat of emergence of new pandemics and the expected need for new pandemic vaccines, the Committee reiterated the urgency of continued research to identify the underlying biological mechanisms of this association.

Full report of GACVS meeting of 12-13 June 2013, published in the WHO Weekly Epidemiological Record on 19 July 2013

GACVS reviewed 2 safety updates on influenza A(H1N1)pdm09 vaccines, which included associations with narcolepsy and with GBS. The association between use of the adjuvanted pandemic vaccine Pandemrix® (GlaxoSmithKline) and abrupt juvenile narcolepsy has thus far been confirmed in 4 countries (Finland, Ireland, Norway and Sweden) with high uptake of vaccine among children and adolescents. In all these countries the absolute risk was low but the relative risk was significantly raised, ranging from 6.6 (95% confidence interval [CI]: 3.1–14.5) in Sweden to 13.0 per 100 000 (95% CI: 4.8– 34.7) in Ireland. An association in adults has so far been observed only in France. Additional studies are also being finalized in the United Kingdom (UK) and Canada. Although this vaccine is no longer being used and all lots of Pandemrix® (2009 H1N1) have now expired, GACVS considered that research should continue to better characterize the possible underlying biological mechanisms of this association. Most cases of narcolepsy, with or without exposure to Pandemrix®, occur in subjects who carry the HLA DQB1*0602 allele. The importance of understanding the triggers and causes of this association will be crucial, especially since new vaccines will be required to protect against future pandemics.

The association between GBS and influenza vaccine first emerged following swine influenza vaccination in the USA in 1976 (attributable risk: around 1 case of GBS per 100 000 vaccinations). GBS is a relatively rare (1–2 cases per 100 000 persons annually) acute peripheral immune-mediated neuropathy. In up to two-thirds of cases, GBS is preceded by an infectious illness, particularly a gastrointestinal or respiratory infection. The most frequently identified pathogen associated with subsequent GBS is Campylobacter jejuni (estimated at 1 GBS case per 3000 infectious episodes).

After 1976, several studies demonstrated no increased or a slightly increased risk of GBS after use of human seasonal influenza vaccines but vigilance remains high and GBS was carefully monitored during the influenza A(H1N1)pdm09 pandemic vaccination campaign.

GACVS has reviewed published and unpublished active surveillance studies that monitored GBS cases during influenza A(H1N1)pdm09 pandemic vaccination. The data are from single countries such as Canada, France, Germany, Sweden, the UK and the USA as well as a multinational European Union study and a global study. Some but not all of these studies have shown a relative incidence of GBS of 2.28 to 3.76 following both unadjuvanted and adjuvanted influenza A(H1N1)pdm09 pandemic vaccines. Overall, the data available are compatible with a small increased risk of GBS after influenza A(H1N1)pdm09 vaccination that is substantially lower than that observed following the 1976 swine influenza vaccination campaign in the USA.

Full report of GACVS meeting of 5-6 December 2012, published in the WHO Weekly Epidemiological Record on 8 February 2013

Safety of influenza A(H1N1)pdm09 vaccines

Overall, the safety information for the pandemic influenza vaccines continues to be reassuring. Other than the association of narcolepsy/cataplexy with an adjuvanted pandemic influenza vaccine in people aged 4–19 years, seen mainly in Finland and Sweden,¹ there were no new proven safety signals from passive surveillance systems.

Population-based epidemiological studies on the association of narcolepsy with the adjuvanted pandemic vaccine (Pandemrix) have been completed in Sweden² and Finland. Adhering to the precautionary principle, the European Medical Agency’s Committee for Medicinal Products for Human Use concluded “that the benefits of Pandemrix continue to outweigh its risks but that it may only be used in people <20 years of age if the recommended annual seasonal trivalent influenza is not available and if immunization against A(H1N1) is still needed, for instance in people at risk of the complications from infection”. Pandemrix marketing authorization has now expired and this vaccine is no longer in use. Epidemiological studies in other countries in Europe and Canada are under way. Immunological and animal model studies to help elucidate the biological mechanism of the observed association are also in progress.

Although preliminary analyses of active surveillance studies for Guillain-Barré syndrome in the United States, which evaluated both adjuvanted and non-adjuvanted pandemic influenza vaccines, indicated an increased risk, this finding has not been replicated elsewhere to date. Available data do not provide conclusive evidence for this increased risk. Were the risk to be confirmed, it would be much lower than that observed following the 1976 swine influenza vaccination campaign in the United States and would be similar to that observed with use of seasonal influenza vaccines.

GACVS reviewed results from additional epidemiological studies on a possible association between influenza A(H1N1)pdm09 vaccines and certain autoimmune and other clinical syndromes. No major safety concerns appeared, although it was noted that the sample size or methodology of these studies might not have been optimal for establishing causal relations. The Committee acknowledged the need for further analysis in this area.

The safety of pandemic vaccines when administered to pregnant women was reassuring. Data from an observational cohort study in Canada and from a birth and infant health registry in the United States did not point to any safety concerns related to pandemic vaccines among women during gestation or their offspring. Several studies on the safety of pandemic vaccines among pregnant women are still being completed in other regions.

¹Statement on narcolepsy and Pandemrix. Geneva, World health Organization, 2011 (see below, related resources).

²Bardage C et al. Neurological and autoimmune disorders after vaccination against pandemic influenza A (H1N1) with a monovalent adjuvanted vaccine: population based cohort study in Stockholm, Sweden. BMJ, 2011, 343:d5956.

Full report of GACVS meeting of 7-8 December 2011, published in the WHO Weekly Epidemiological Record on 10 February 2012

Safety of pandemic influenza A(H1N1) 2009 vaccines

GACVS reviewed data on the safety of pandemic influenza A (H1N1) 2009 vaccines. Overall, safety information for the pandemic influenza vaccines continues to be reassuring. Since the Committee’s earlier report in June 2010,⁵ data from passive surveillance from different countries has not generated any new safety concerns other than reports of narcolepsy from Finland and Sweden in August. These reports are being investigated by independent groups in Europe. Preliminary analyses of active surveillance studies for Guillain–Barré syndrome, which have evaluated both adjuvanted and unadjuvanted vaccines, suggest that there may be a small risk associated with vaccination (1–2 cases per million doses of vaccine administered). Even if this finding is confirmed, the data suggest that the risk would be much lower than that observed following the 1976 swine influenza vaccination campaign in United States; it would be similar to the risk that has been associated in some, but not all, studies with the use of seasonal influenza vaccine (an excess risk of the order of 1–2 cases/million doses). Final analyses of active surveillance studies are expected to be completed by late 2011.

⁵See No. 30, 2010, pp. 285–291.

Full report of GACVS meeting of 8-9 December 2010, published in the WHO Weekly Epidemiological Record on 28 January 2011

Safety of pandemic A (H1N1) influenza vaccines

Since its emergence in March 2009, pandemic influenza A (H1N1) 2009 virus has caused significant morbidity and mortality globally. For example, in the United States the pandemic A (H1N1) 2009 virus is estimated to have caused 61 million cases of illness, 274 000 hospitalizations, and 12 470 deaths between April 2009 and April 2010.3 In response to the pandemic, over 30 pandemic A (H1N1) 2009 vaccines were licensed worldwide: these included live attenuated vaccines; inactivated unadjuvanted vaccines (split, subunit virion or whole virion); and inactivated adjuvanted vaccines (split or subunit virion). Between September 2009 and June 2010, >350 million doses of vaccine were administered, targeting various populations.

As of 6 June 2010, more than 214 countries had reported laboratory-confirmed cases of pandemic A (H1N1) 2009 influenza, including at least 18 156 deaths. Younger age groups have been disproportionately affected by the pandemic virus and have had higher mortality from the disease than from seasonal influenza. Pregnant women have been disproportionately represented in admissions to intensive care units. Although older age groups have had lower rates of infection than with seasonal influenza, their hospitalization rates and mortality rates have been high.

Most of the safety information about pandemic influenza vaccines has been derived from passive surveillance, but there has been some active surveillance for specific conditions or circumstances for which it was thought, a priori, that there might be an increased risk (such as Guillain–Barré syndrome) or when the vaccine has been used for specific groups of patients (for example, in pregnant women or people who are immunocompromised).

Since the initiation of vaccination campaigns, WHO has coordinated an unprecedented and continuing exchange of safety information among regulatory and public health authorities from many countries. Follow-up of vaccinated populations continues, and additional data on safety are expected later in 2010. In order to establish reliably the risk–benefit balance of the vaccines, these findings should be considered along with additional observations on the impact of the pandemic disease itself. An interim assessment of the potential risks (or signals) of adverse reactions evaluated in different countries and geographical areas for several different products is given below.

In the United States, where an estimated 65 million people were vaccinated with inactivated unadjuvanted vaccines and 17 million individuals were vaccinated with live attenuated vaccine, no signals of unexpected side-effects were detected through passive surveillance. The occurrence of Guillain–Barré syndrome in people who had been vaccinated was evaluated through several different active surveillance systems, one of which yielded a weak signal; further analyses are under way. Preliminary analysis suggests that if an increase in the risk of Guillain–Barré in those vaccinated is confirmed, the risk may be approximately 1 case/1 000 000 doses, which is similar to the risk reported during some years with seasonal trivalent, inactivated, unadjuvanted vaccine. In addition, there were weak signals of thrombocytopenia and Bell’s palsy; these are also being investigated.

In Japan, approximately 18 million individuals were vaccinated with 21 million doses of inactivated unadjuvanted vaccine. Safety was monitored primarily through passive surveillance. Cases of interstitial lung disease, thrombocytopenia, idiopathic thrombocytopenic purpura and allergic purpura following immunization were evaluated, but were not considered to represent new safety issues.

As of April 2010, China reported that 97 million people, representing 7% of the population, had been vaccinated with locally produced, inactivated, unadjuvanted vaccines. Safety has been monitored through passive surveillance. The rate of adverse events following immunization was about 8.6/100 000 doses administered. The reported rate for serious reactions was around 1/100 000 doses administered; the majority of these reactions were Schönlein–Henoch purpura, anaphylactic shock, laryngeal oedema and febrile convulsions. The number of cases of Guillain–Barré reported was not higher than expected. Although deaths following vaccination were reported, these were found to result from underlying conditions.

In Canada, an estimated 12.5 million people were vaccinated with inactivated vaccine adjuvanted with AS03. Passive surveillance detected a signal for allergic events; this is being investigated.

In the European Economic Area, at least 38.5 million people were vaccinated with 1 of 3 authorized vaccines marketed in the area. These vaccines included: inactivated unadjuvanted whole virion vaccine; inactivated subunit vaccine adjuvanted with MF59; and inactivated split-virus vaccine adjuvanted with AS03. Additional vaccines were authorized nationally, and when these are included >46 million people are estimated to have been vaccinated. The safety of vaccines has been monitored at the European level using passive surveillance; adverse events following immunization have been reported to EudraVigilance (which covers products authorized by the European Union). After thorough evaluation of spontaneous reports, no new safety issues have been identified.

GACVS reached the following conclusions:

Reporting mechanisms for adverse events following immunization with pandemic A (H1N1) 2009 influenza vaccines have been enhanced in many countries. Continuing to monitor vaccine safety (maintaining pharmacovigilance) is critical; monitoring should include regular information-sharing with WHO by national regulatory and health authorities. Most of the safety information has been derived from passive surveillance. Data from active surveillance will be assessed as they become available.

Most of the adverse events that have been reported after immunization have not been serious. To date, no unexpected safety concerns have been identified.

Active surveillance for Guillain–Barré syndrome is under way in a number of countries, and analyses are pending in many of these. So far, the risk of Guillain–Barré syndrome, if any, appears to be no greater than has been reported previously for some seasonal, trivalent, inactivated influenza vaccines.

Active surveillance of pregnancy outcomes also continues. So far, available data on the safety of the vaccines are reassuring.

It is critical to strengthen adverse event reporting following immunization, which relies on existing infrastructure for ongoing pharmacovigilance. Prospectively agreed-upon case definitions for adverse events (e.g. for anaphylaxis, Guillain–Barré syndrome, convulsions) are also important because they facilitate global comparisons of safety profiles of vaccines used in different countries.

³Updated CDC estimates of 2009 H1N1 influenza cases, hospitalizations and deaths in the United States, April 2009 – April 10, 2010. United States Centers for Disease Control and Prevention. (http://www.cdc.gov/h1n1flu/pdf/CDC_2009_H1N1_Est_PDF_May_4_10_fulltext.pdf). Information E-mail Print

Full report of GACVS meeting of 16-17 June 2010, published in the WHO Weekly Epidemiological Record on 23 July 2010

Safety of pandemic A (H1N1) influenza vaccines

Since its emergence in March 2009, influenza A (H1N1) 2009 virus has caused significant morbidity and mortality. For example, the United States Centers for Disease Control and Prevention (CDC) estimates that in the USA there have been about 100 000 hospitalizations and nearly 4000 deaths caused by pandemic (H1N1) 2009 virus during the period April to 17 October 2009. In response to the pandemic, >30 pandemic (H1N1) 2009 vaccines have been developed and licensed. Since September 2009, >50 countries have implemented immunization programmes targeting various populations. These populations include health-care workers, children, pregnant women, and individuals with certain underlying medical conditions, including chronic lung disease, diabetes, and heart disease, as well as those whose immune systems are compromised.^3,4

From 21 September to 2 December 2009, tens of millions of doses of the pandemic (H1N1) 2009 vaccine were administered, thereby providing the basis for this first safety review by the GACVS. The review is mainly based on passive surveillance data.⁵ Under the coordination of WHO, there is an unprecedented, ongoing exchange of safety information among regulatory and public health authorities from many countries around the world.

Pandemic influenza vaccines include live attenuated vaccines, inactivated unadjuvanted vaccines (split, sub-unit virion, or whole virion) and inactivated adjuvanted vaccines (split or sub-unit virion). At the time of the GACVS review, it was estimated that nearly 150 million vaccine doses had been distributed in many countries around the world. Approximately 30% of those 150 million doses are adjuvanted vaccines. No unexpected safety concerns have been identified for any of the pandemic (H1N1) 2009 vaccines. Product labelling for each vaccine contains a summary of expected side-effects.⁶

In the ongoing immunization campaigns, deaths in temporal association with vaccination have been reported in many countries. Given the large number of people who have been vaccinated, it is expected that deaths that were unrelated to vaccination would occur in temporal association with vaccination.⁷ Investigation of deaths that have been reported after immunization have identified that the cause of death has been unrelated to vaccination in all but a few instances. There have been a few individual reports of deaths associated with anaphylactic reactions to vaccination.

Immediate hypersensitivity reactions have been reported after the use of all types of pandemic (H1N1) 2009 vaccines. These events include urticaria, angioedema and anaphylaxis, with reactions ranging from mild to serious. The overall reporting rates for anaphylaxis range from 0.1 to 1.0 per 100 000 doses distributed. Anaphylaxis is a known, potentially life-threatening adverse effect of all vaccines and is a very rare event. Nonetheless, immunization providers must be prepared to recognize and appropriately treat such reactions.⁸

Although some cases of Guillain–Barré syndrome have been reported after receipt of pandemic (H1N1) 2009 vaccines, the evidence to date is reassuring, with no increase in reporting rates above what is expected, based on background rates. Active surveillance for GBS has been instituted in several countries and should provide additional information by the first quarter of 2010.

Concerns have been raised about the use of adjuvanted pandemic vaccines in patients with immune disorders, such as immunodeficiency, autoimmune disorders and solid organ transplants. To date, post-marketing surveillance has not found evidence for causality of any safety issues in such patients. Viral infections, such as influenza, can lead to severe complications in immunocompromised patients. Thus, the benefit of pandemic (H1N1) 2009 vaccines, adjuvanted or unadjuvanted, far outweighs the potential risks in these patients.

Programmatic errors have also been reported, including erroneously administering other drugs instead of vaccine, or errors in mixing adjuvant and antigen components as required for some of the vaccines. Immunization programmes should take appropriate measures to prevent such errors. In summary, GACVS concluded that:

Ten weeks into the worldwide immunization campaign against pandemic (H1N1) 2009, the GACVS reviewed the safety of pandemic (H1N1) 2009 vaccines currently in use. To date, the safety data are reassuring.

Most of the adverse events that have been reported after immunization have not been serious. To date, no unexpected safety concerns have been identified.

Reporting mechanisms have been enhanced. Ongoing vaccine safety monitoring (pharmacovigilance) is critical, including regular information-sharing with WHO by national regulatory and health authorities. Most of the safety information to date is from passive surveillance. Data from active surveillance will be assessed as they become available.³

³See No. 30, 2009, pp. 301–308.

⁴ See No. 49, 2009, pp. 505–516.

⁵Passive surveillance refers to a system designed to collect adverse events that follow vaccination. This type of surveillance typically relies on health professionals noting and reporting to the appropriate authority adverse events that occur in individuals after vaccination. This system relies on spontaneous reporting by health-care staff. By contrast, active surveillance is a mechanism through which specific health conditions are monitored through a systematic and continuous review of medical records.

⁶The Committee noted the recent warning from the European Medicines Agency (EMEA), after review of data from an ongoing clinical trial submitted by the manufacturer, that a higher proportion of young children may experience fever after their second dose of an adjuvanted pandemic influenza vaccine, Pandemrix, than after their first dose. The EMEA recommended that prescribers and parents should monitor the temperature of the vaccinated child and, if necessary, take measures to lower the fever. Additional information is available at: http://www.emea.europa.eu/pdfs/general/direct/pr/78440409en.pdf (accessed January 2010).

⁷Black S et al. Importance of background rates of disease in assessment of vaccine safety during mass immunisation with pandemic H1N1 influenza vaccines. Lancet, 2009 (doi:10.1016/S0140-6736(09)61877–8).

⁸The Public Health Agency of Canada identified a higher-than-normal rate of anaphylaxis (4.1/100 000 doses distributed) linked to one particular lot of the adjuvanted pandemic (H1N1) 2009 vaccine. Pending further investigation of adverse event reports linked to the lot, unused vaccines from this lot were withdrawn from use on 24 November 2009.

Full report of GACVS meeting of 3-4 December 2009, published in the WHO Weekly Epidemiological Record on 29 January 2010

Statement on narcolepsy and Pandemrix

27 JULY 2011 - In August 2010, the Swedish authorities reported an unexpected increase of cases of juvenile narcolepsy following immunization with Pandemrix. The Finnish authorities subsequently suspended the use of the vaccine as a similar signal was seen in that country. Since then, GACVS has closely monitored investigations ongoing in countries where the vaccine was used. In April 2011, GACVS indicated that an increased risk of narcolepsy had not been observed in association with the use of any vaccines in the past and that it did not appear that narcolepsy following vaccination against pandemic influenza was a general worldwide phenomenon.

On 21 July 2011, the European Medicine Agency's Committee for Medicinal Products for Human Use (CHMP) published its conclusion following a review of findings on Pandemrix and narcolepsy from Finland and Sweden. EMA, on a precautionary basis, recommends restricting use of Pandemrix in persons under 20 years of age but indicates that overall the benefit-risk of the vaccine remains positive.

GACVS concurs with the recommendation, which states that in persons under 20 years of age Pandemrix may only be used if the recommended seasonal trivalent influenza vaccine is not available and if immunisation against H1N1 is still needed (e.g., in persons at risk of the complications of infection).

GACVS acknowledges also that the benefit-risk balance of Pandemrix remains positive where H1N1 influenza is prevalent. Currently data are limited on the association between juvenile narcolepsy and Pandemrix; additional epidemiological studies are underway.

GACVS will continue to monitor the situation closely and updates will be provided as further information becomes available.

Related link

Press release from European Medicines Agency

Statement on narcolepsy and vaccination

21 April 2011

Since August 2010, following widespread use of vaccines against influenza (H1N1) 2009, cases of narcolepsy, especially in children and adolescents, have been reported. Narcolepsy is a rare sleep disorder that causes a person to fall asleep suddenly and unexpectedly. The rates reported from Sweden, Finland and Iceland have been notably higher than those from other countries. Swedish and Finnish authorities have presented preliminary statements on their investigations in the first quarter of 2011.

On 1 February 2011, the National Institute for Health and Welfare of Finland issued a preliminary statement following an investigation into the cases of narcolepsy in Finland¹. A systematic retrospective registry-based review was conducted of all new narcolepsy cases diagnosed during 2006-2010. Cases from 2009-2010, who were born in 1990 or later, were reviewed using newly developed Brighton collaboration criteria for the disease. During 2009-2010 they found that the risk of narcolepsy among people aged 4-19 years old who had received pandemic influenza vaccine was nine times higher than that among those who had not been vaccinated. This corresponds to a risk of about 1 case of narcolepsy per 12,000 vaccinated in this age group. No increased risk has been seen in younger or older age groups.

The Swedish Medical Products Agency issued a preliminary report on 28 March 2011 following an investigation on pandemic influenza vaccination using data drawn from regional vaccination registries of four Swedish counties². Covering a population of 5.3 million, the risk of narcolepsy was compared in vaccinated and unvaccinated individuals from October 2009 to December 2010. The Agency reported that the relative risk of narcolepsy was four times higher in vaccinated children and adolescents (born from 1990) compared to unvaccinated individuals. The relative risk estimate translates into an absolute risk of about 3 cases of narcolepsy in 100,000 vaccinated adolescents/children. The incidence rates for narcolepsy in adults irrespective of vaccination status were similar to historical national registry- based rates during the years before the pandemic period (i.e. about 1/100,000).

The only pandemic influenza vaccine used in Finland and Sweden was Pandemrix, an adjuvanted influenza A (H1N1) 2009 monovalent vaccine manufactured by GlaxoSmithKline.

Narcolepsy is a condition that has a strong genetic linkage, being almost uniquely seen in persons who have the (HLA) DQB1*0602 genotype. Of the cases of narcolepsy tested so far in Finland (n=29), diagnosed during 2009-2010, all have that genotype. The National Institute for Health and Welfare of Finland considers it probable that the Pandemrix vaccine was a contributing factor to this observed increase, and has called for further investigation of other co-factors that may be associated with the increased risk. They consider it most likely that the vaccine increased the risk of narcolepsy in a joint effect in those genetically disposed with some other, still unknown, genetic and/or environmental factors. The final report from the Finnish National Narcolepsy Task Force is expected by 31 August 2011.

The Swedish Medical Products Agency recognizes that further work is needed with respect to the findings in their preliminary report - particularly with regards to the verification of the diagnoses of the cases ascertained from the county health care databases. Also, in the report there is no assessment as to whether publicity about the purported association influenced rates in vaccinated compared to unvaccinated persons. Further investigations include a review by the European Medicines Agency (EMA) on the benefit-risk balance of Pandemrix, which is expected by July 2011. At their meeting in April 2011, the EMA Committee for Medicinal Products for Human Use (CHMP) agreed an interim recommendation for prescribers to take into account preliminary results from epidemiological studies on Pandemrix and narcolepsy, and to perform an individual benefit-risk assessment when considering the use of Pandemrix in children and adolescents3. Results from an epidemiological study of narcolepsy and pandemic vaccines in nine EU States by the VAESCO project are expected by June 2011⁴.

WHO's Global Advisory Committee on Vaccine Safety (GACVS) reviewed the available data from Finland on 4 February 2011 and the new data from Sweden on 18 April 2011. GACVS agrees that further investigation is warranted concerning narcolepsy and vaccination against influenza (H1N1) 2009 with Pandemrix and other pandemic H1N1 vaccines. An increased risk of narcolepsy has not been observed in association with the use of any vaccines whether against influenza or other diseases in the past. Even at this stage, it does not appear that narcolepsy following vaccination against pandemic influenza is a general worldwide phenomenon, as no excess of narcolepsy has been reported from several other European states where Pandemrix was used, or from Canada where a pandemic vaccine similar to pandemrix was used. This complicates interpretation of the findings in Finland and Sweden. It seems likely that some as yet unidentified additional factor was operating in Sweden and Finland. The findings from the VAESCO project and further investigations in Finland and Sweden, may help clarify the determinants of any increased risk of narcolepsy, which currently appears to be restricted to the months following vaccination and by age group and country.

GACVS will continue to monitor the situation closely and updates will be provided as further information becomes available and is assessed.

1. Statement from the National Institute for Health and Welfare of Finland of 1 February 2011

2. Statement from the Swedish Medical Products Agency of 28 March 2011

3. Recommended interim measures for Pandemrix from the European Medicines Agency 15 April 2011

4. ECDC – VAESCO investigation into narcolepsy 2 February 2011