Safety News about Influenza Vaccine from June ACIP Meeting1
Christopher J. Harrison, MD, FAAP, FPIDS | Director, Infectious Diseases Research Laboratory | Director, Vaccine and Treatment Evaluation Unit | Professor of Pediatrics
We recently heard from ACIP that live attenuated influenza vaccine (LAIV) is again an optional 2018-19 seasonal vaccine, albeit not preferred, but did we miss a few safety tidbits, including data on narcolepsy?
VAERS (Vaccine Adverse Event Reporting System) A CDC review of VAERS found 94-96 percent of adverse effects were not serious, and categories were consistent with previous years. No new safety signals were found in this rapid detection system that can detect rare adverse events, but cannot assign causality.
VSD (Vaccine Safety Datalink) – This more detailed review of 5.3 million administered doses in a rapid cycle analysis (RCA) contains data on more than 10 million persons each year. There were no new RCA signals compared to prior years. This analysis did focus on anaphylaxis due to its severity as a known, but rare adverse effect. Of the 10 anaphylaxis episodes, nine had symptoms before vaccination and five were noted to have possible/probable environmental causes. One probable episode started 12 hours post-vaccine without any other definable cause, i.e., final rate = 1/5 million vaccine doses.
Guillain-Barre Syndrome (GBS) – An elephant in the room each year is GBS post-influenza vaccination. A review of Medicare data in near real time surveillance during weeks 7-11 of influenza season, plus a post-season secondary review of the entire season, compared GBS episodes to five-year historical controls. Of note, post- vaccine GBS has a primary risk window of days 8-21 post-dosing. There was no evidence of any increase in GBS compared to controls.
Narcolepsy Risk Following Influenza Vaccine. Most remember the initial concern about the apparent increase in narcolepsy in 2010-2011 in Sweden among pediatric recipients of adjuvanted H1N1 pandemic-influenza vaccine.2 This concern comes in focus as adjuvanted influenza vaccines are in U.S. trials for FDA approval.
Narcolepsy and influenza relationship:
Narcolepsy (excessive daytime sleepiness leading to problems with school and work) occurs at 25-50/100,000 people (incidence 0.7/100,000 person-years). Type I narcolepsy is associated with HLA DQB1 *0602 allele (a narcolepsy susceptibility gene) and diminished numbers of hypocretin secreting neurons in the brain. Hypocretin secreting neurons are necessary for wakefulness.3
Only a minority of DQB1 *0602 carriers develop narcolepsy. The allele occurs in relatively high rates in Scandinavian populations, e.g., 31 percent in Finland, compared to other countries, e.g., 15 percent in the U.S., 5 percent in Canada.
The H1N1 pandemic virus nucleoprotein (NP) has similarities to the hypocretin receptor, HCRT-R2; a specific epitope in the receptor seems key.4
Antibodies induced by some versions of NP from H1N1 pandemic strain appear to cross-react with the HCRT-R2 epitope. These antibodies may damage hypocretin secreting neurons.
One particular adjuvanted vaccine used in Europe had high concentrations of NP compared to other vaccines and appeared associated with narcolepsy in children. That vaccine is no longer available.4
China had an increase in narcolepsy during the 2009-2010 pandemic, but did not have a vaccine initiative. So, it appears that H1N1 pandemic virus itself can trigger narcolepsy without influenza vaccinations.4
SOMNIA report1: The report included international data from before, during and after the 2009 pandemic and the global vaccine initiatives. Sweden had increased narcolepsy in 5-19-year-olds, but only in 2009-10. Interestingly, new narcolepsy diagnoses decreased in Sweden for 2011. There may be some evidence of increased risk in adults. There is no evidence of increased rates of narcolepsy since 2010.
Steps to Type 1 Narcolepsy
The take-away about influenza vaccine safety is that it remains safe in all its current formulations. It now appears there is a known cause of the narcolepsy increase – H1N1 pandemic virus NP whether in the vaccine or not - mostly in people at increased genetic risk of narcolepsy. A single, no-longer-available, adjuvanted vaccine was linked to increased narcolepsy, mostly in Europe. However, the culprit was not the adjuvant, but a version of NP protein in the vaccine.
For the coming season, we can stay confident that we are recommending and administering a vaccine that is as safe as possible. Now if we could only get that universal highly effective influenzae vaccine soon.
Meeting of the Advisory Committee on Immunization Practices (ACIP) of the Centers for Disease Control and Prevention. June 20-21, 2018 Atlanta, Ga., 30329.
AS03 Adjuvanted AH1N1 Vaccine Associated with an Abrupt Increase in the Incidence of Childhood Narcolepsy in Finland. Nohynek H, et al. PLoS One. 2012;7(3):e33536. doi: 10.1371/journal.pone.0033536. Epub 2012 Mar 28.
Prevalence of Narcolepsy in King Count, Washington, USA. Longstreth Jr. WT, Ton TGN, Koepsell T, et al. Sleep Med. 2009 April ; 10(4): 422–426. doi:10.1016/j.sleep.2008.05.009.
Antibodies to Influenza Nucleoprotein Cross-react with Human Hypocretin Receptor 2. Ahmed SS, Volkmuth W, Duca J, et al. Sci Transl Med 2015;7:294ra105. 10.1126/scitranslmed.aab2354.