Do vaccines trigger neurological diseases? Multiple sclerosis, Guillain- Barre syndrome and Narcolepsy from epidemiological perspective ESCMID eLibrary Dr Julia Stowe, Immunisation and Countermeasures, Public Health England 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 disease disappears reactions may become more of a ESCMIDrisk to an individual than disease eLibrary 2 © by author Whooping cough cases and vaccine 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 polio vaccine - risk 4 in 1,000,000 • Bells Palsy & influenza vaccine (nasal)- risk OR 84.0 • Bells Palsy & influenza vaccine (parenteral) - no effect • Aseptic meningitis & MMR- (Urabe mumps strain) – risk 1 in 12,000 doses • Febrile convulsions & MMR- risk 1 in 1200 doses Unsubstantiated & Unexpected • Neurological complications & whooping cough vaccine- no effect • Autism & MMR- no effect • Gait disturbance and MMR vaccine- no effect • Thiomersal 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 vaccination • 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 & Hepatitis B vaccine • Mass vaccine campaign in France 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 Hepatitis B 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 swine influenza vaccine programme- this programme was subsequently suspended • Since remained as potential adverse event after vaccine • More recently linked to vaccines given in adolescence – when autoimmune disease 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 infections 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 papilloma virus 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 Gardasil ® (15) 0-91 4 1.61 (0.39-6.54) The ESCMIDbivalent vaccine 0- 91 eLibrary5 0.84 (0.30-2.34) Cervarix ® (86) 17 © by author Narcolepsy and pandemic influenza vaccine, Pandemrix Finland: 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 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 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