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Home , Cervarix, Gardasil, Hepatitis B vaccine, Influenza vaccine, MMR vaccine, Pandemrix

Do trigger neurological ? , Guillain- Barre syndrome and from epidemiological perspective ESCMID eLibrary Dr Julia Stowe, Immunisation and Countermeasures, ECCMID Sunday14© byApril 2019 16:00author-18:00, Hall B Cause or Coincidence?

• No medical intervention is 100% safe so it is a balance of risk and benefit • Rare reactions are not picked up in trials • Vaccines are given to very large numbers so more opportunity to see rare reactions • More likely to see coincidental events after vaccines • May seem plausible on individual case basis due to temporal association • As disappears reactions may become more of a ESCMIDrisk to an individual than disease eLibrary 2 © by author cases and coverage England and Wales 1940-2006

200 Immunisation 180 introduced 80 160 140 120 40 Coverage 100 80 60 0

Notifications (thousands) Notifications 40 20 ESCMID0 eLibrary 1940 1950 1960 1970 1980 1990 2000 Year © by author Neurological conditions in temporal relationship to vaccines Biological Plausible

• Acute Flaccid Paralysis and oral vaccine - risk 4 in 1,000,000

• Bells Palsy & vaccine (nasal)- risk OR 84.0 • Bells Palsy & (parenteral) - no effect

• & MMR- (Urabe strain) – risk 1 in 12,000 doses

• Febrile convulsions & MMR- risk 1 in 1200 doses

Unsubstantiated & Unexpected

• Neurological complications & whooping cough vaccine- no effect

• & MMR- no effect

• Gait disturbance and MMR vaccine- no effect

• and developmental delay - no effect

• Guillain-Barre Syndrome • ESCMIDNarcolepsy eLibrary • Multiple Sclerosis 4 © by author Epidemiological Statistical Methods

• Compare disease in vaccinated and unvaccinated- Odds ratio • Need to know if person truly vaccinated • Need to match on DOB- short age range in baby vaccines Case- coverage method • Vaccine coverage data • Matched on risk group, age • Reference date is first symptoms in case • Similar to a case control study with 1000’s of controls per individual.

• Incidence of disease in vaccinated compared to unvaccinated • Need to have great number of confounder variables • Small unvaccinated population not representative • Unvaccinated truly not vaccinated ESCMID eLibrary• Case only methods- Self-controlled case series • Only use vaccinated cases 5 © by author Self-Controlled Cases-Series (SCCS) method • For each individual each day and event in the study period will fall inside or outside the risk period.

• Pre specified risk period after

• Unbiased ascertainment of cases in a given age group and study period and their vaccination details.

vaccination Event Jan 01 Dec 01

risk period

Compare risk of events in risk period to background RelativeESCMID incidence = Events inside risk periodeLibrary / days inside risk period . Events outside risk period / days outside risk period

Farrington CP. Control without separate controls: evaluation of vaccine safety using case- 6 only methods.© Vaccine. 2004by May 7;22(15 author-16):2064-70 Which design to use?

The design will depend on the precise question, data sources available, likely important confounding variables May be a trade off between the ideal and the practical Data sources….. Immunisation registries Linkage Disease registers Hospital Episode databases Individual Hospital data General Practice databases Health Maintenance data bases Prospective cohorts (e.g. whole birth cohorts followed up) TheESCMID best designs may vary – buteLibrary key to causality is consistency from well designed studies. © by author Neurological disease and vaccines • Common features: • Serious conditions • Rare • Aetiology and pathophysiology poorly understood • believed that immune stimulation plays a role in the conditions pathogenesis • Because of vaccines effect on the immune ESCMIDsystem it makes it biologicallyeLibrary plausible 8 © by author Multiple sclerosis & B vaccine

• Mass vaccine campaign in in 1994 • Few cases of MS reported within a few weeks of the vaccine in France • Hypothesis is that the vaccine could cause an acute autoimmune reaction in susceptible persons soon after administration • Response was not robust- no background rates in relevant population • Lead to mistrust of the vaccine • 1998 school based vaccine programme in France suspended as a precaution • ESCMIDMany studies since have demonstrated eLibrary no association © by author vaccination and the putative risk of central demyelinating diseases -A systematic review and meta- analysis. MouchetJ, Salvo F, Raschi E, PoluzziE, Antonazzo IC, De Ponti F, BégaudB. Vaccine.2018 Mar 14;36(12):1548-1555. doi: 10.1016/j.vaccine.2018.02.036. Epub2018 Feb 15.

ESCMID eLibrary • No evidence of association 10 © by author Guillain-Barré syndrome and vaccines

• Commonest cause of acute neuromuscular paralysis in the developed world • Causes muscle weakness and sometimes paralysis • Can lead to respiratory failure – 10% fatality rate • Strongest evidence as vaccine reaction:1976 US vaccine programme- this programme was subsequently suspended • Since remained as potential adverse event after vaccine • More recently linked to vaccines given in adolescence – when often diagnosed - Influenza vaccines -ESCMIDVaccines given in adolescence eLibrary -HPV vaccine 11 © by author Guillain-Barré syndrome Meta-analysis of risk of GBS and flu vaccines

Decreased risk Increased risk Decreased risk Increased risk

Conclusion: the receipt of any influenza vaccine carried a small relative increased risk of 1.41 (1.20- 1.66)

Two other meta-analysis found similar marginal statistical significance for seasonal vaccines- Dodd et al. RI=2.1 (1.1-3.4); SalmonESCMID et al. IRR=2.3 (1.4-4.0) eLibrary Pandemic vaccine: differences between countries- lower in US and Europe -Adjuvanted / unadjuvanted difference (England/US) 12 © by author GBS and flu-like illness General Practice Research Database (GPRD) 1990-2005 RESULTS from 775 GBS episodes

Interval between influenza-like illness and GBS

ESCMID eLibrary © by Stoweauthor et al, Am. J. Epidemiol. 2008, 169: 382 - 388 ESCMID eLibrary 14 © byFrom: Stoweauthor et al, Am. J. Epidemiol. 2008, 169: 382 - 388 Guillain-Barré syndrome and Influenza vaccines: Conclusions: • Small overall risk seen in the meta analysis • Slightly larger overall risk seen in pandemic season • Geographic differences seen • Mechanism may be multi factored: different vaccines used- adjuvanted/unadjuvanted other circulating Susceptibility to develop GBS • These small risks do not outweigh the risk getting GBS ESCMIDafter flu itself eLibrary • More work to be done! 15 © by author Is there a risk of GBS after HPV vaccine?

• HPV vaccine given at age when autoimmune disorders diagnosed • A French study reported a signal for GBS among a group of other conditions • GBS cases identified in hospital discharge database for England (HES) • Primary care practitioners (GPs) contacted for the vaccination history • GP asked to confirm GBS diagnosis- provide an onset date and send supporting documentation • Diagnosis certainty levels were assigned – confirmed, probable or not • GBS index date derived from the earliest date from GP questionnaire / ESCMIDsupporting documentation / admission eLibrary date (HES) 16 © by author No increased risk of Guillain-Barré syndrome after human vaccine Andrews N, Stowe J, Miller E. No increased risk of Guillain-Barré syndrome after human papilloma virus vaccine: A self- controlled case-series study in England. Vaccine. 2017 Mar 23;35(13):1729-1732.

Analysis (total episodes) Risk period Episodes in the RI (95% CI) (days) risk period

Primary (101) 0-91 9 1.04 (0.47-2.28)

Alternative risk windows (101) 92-183 5 0.78 (0.27-2.21)

184-365 10 1.41 (0.61-3.22)

0-183 14 0.83 (0.41-1.69)

0-365 24 1.10 (0.57-2.14)

Just confirmed cases (79) 0-91 9 1.26 (0.55-2.92)

The quadrivalent vaccine ® (15) 0-91 4 1.61 (0.39-6.54)

The ESCMIDbivalent vaccine 0- 91 eLibrary5 0.84 (0.30-2.34) ® (86) 17 © by author Narcolepsy and pandemic influenza vaccine, : High Coverage: 75% of those Partinen et al under 19 years received the Plos One Pandemrix vaccine March 2012 Ecological study

ESCMID eLibrary © by author WHO Global Advisory Committee on Vaccine Safety - April 2011 “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 where a pandemic vaccine similar to pandemrix was used. This complicates interpretation of the findings in Finland and . It seems likely that some as yet unidentified ESCMIDadditional factor was operating eLibrary in Sweden and Finland.” © by author Narcolepsy and pandemic influenza vaccine

Google searches for “narcolepsy” or “narkolepsi” from UK and Sweden *Relative scaling is based on the average traffic

25

August 2010 - 20 fold st 20 increase when 1 cases reported UK Sweden

15 Dec 2011- small peak coincided 10 with BBC documentary 5 ESCMID eLibrary 0 00-yy00-yy00-yy00-yy00-yy00-yy00-yy00-yy00-yy00-yy00-yy00-yy00-yy00-yy00-yy00-yy00-yy00-yy00-yy00-yy00-yy00-yy00-yy00-yy00-yy00-yy © by author Narcolepsy and pandemic influenza vaccine The epidemiological challenge- getting the data right!

Disease misclassification • Using wrong onset of symptoms date • Perhaps more rapid reporting and diagnosis if vaccinated? • Vaccinated cases more likely to be diagnosed as narcolepsy if vaccination status and possible association known at time of diagnosis Exposure misclassification • Vaccination status incorrect • If vaccine date recalled to be before event onset

Selection bias • Issue if those patients/centres agreeing to be included in a study are different to those who do not (e.g. vaccinated cases more likely to agree or centres with vaccinated cases referred to them agree) UncontrolledESCMID confounding eLibrary • Time period and age usually controlled for, but could there be others such as those in a risk group for vaccination / prior pandemic influenza. © by author Narcolepsy childhood study: Results – case coverage Miller et al BMJ 2013

75 cases by onset of symptoms date and vaccination status

ESCMID eLibrary © by author Narcolepsy Childhood study in England: Results Miller et al BMJ 2013 Significantly increased risk of narcolepsy in children who received Pandemrix OR = 14.4 (4.3-48.5) Attributable risk of 1.9 per 100,000 doses

Narcolepsy Adult study in England : Results Stowe et al. Sleep 2016 Significantly increased risk of narcolepsy in adults who received Pandemrix OR = 9.06 (1.90-43.17) AttributableESCMID risk of 0.59 cases pereLibrary 100,000 doses. 23 © by author Multiple studies have shown associations for Pandemrix –review by Sarkenen (Sleep Med Rev. 2018)

Increased risk Decreased risk

• Even with practical challenges consistent association is strong • Increased risk seen in all countries where Pandemrix used in large amounts • ESCMIDAssociation only seen with Pandemrix eLibrarynot other AS03 adjuvanted or other pandemic or seasonal vaccine © by author Do vaccines trigger neurological diseases?

• No medical intervention is 100% safe so it’s a balance of risk and benefit

• Some evidence that flu vaccine may trigger GBS in some individuals - Need to look at risk flu in that season/ effectiveness of vaccine • Risk of GBS after flu illness is far greater • Strong association between narcolepsy and Pandemrix • No evidence of risk of MS and • Vaccine remains the safest way to protect against disease • Need to have clear robust methods in place in order to demonstrate thisESCMID eLibrary © by author Acknowledgments

Professor Liz Miller Professor Nick Andrews

The global community of hard working vaccine safety epidemiologists! ESCMID eLibrary 26 © by author