HPV-VACCINE. FORSKERENS BLIK PÅ HISTORIEN! Kåre Mølbak Statens Serum Institut

Transkript

1 HPV-VACCINE. FORSKERENS BLIK PÅ HISTORIEN! Kåre Mølbak Statens Serum Institut

2 1. HPV VACCINE PR FØDSELSKOHORTE, 30. JUNI 2017 Uptake of first HPV-vaccine by year of birth, females,

3 FORSKERENS PERSPEKTIV Hvilken forsker? - Epidemiologen? - Biologen/immunologen? - Sociologen? - Antropologen? - Kommunikationsforskeren? - Psykologen? - Økonomen? Alle kan give relevante bidrag til forskning og til at genoprette tillid.

4 EPIDEMIOLOGENS BLIK Velundersøgte vacciner, god effekt på HPV-relateret sygdom, meget sikre millioner vaccinerede og givet ca 270 millioner vacciner på verdensplan - Gode registerbaserede studier styrker vor viden om vaccinen som en sikker vaccine Er der symptomer, som endnu ikke er fastslået som bivirkninger til HPV-vaccinen? Epidemiologen vil som minimum forvente, at disse ses hyppigere blandt eksponerede (dvs vaccinerede) end uvaccinerede (ikke-vaccinerede) - Denne dokumentation foreligger ikke for det danske HPV-vaccine syndrom Vi ved også: M edicinsk uafklarede symptomer er i forvejen hyppige blandt unge piger og kvinder I de relevante fødselsårgange er pigerne næsten alle vaccinerede Talrige historiske eksempler på sociale epidemier, hvor en årsagssammenhæng konstrueres socialt

5 HILLS CRITERIA (1965) 1. Strength: A small association does not mean that there is not a causal effect, though the larger the association, the more likely that it is causal. 2. Consistency: Consistent findings observed by different persons in different places with different samples strengthens the likelihood of an effect. 3. Specificity: Causation is likely if there is a very specific population at a specific site and disease with no other likely explanation. The more specific an association between a factor and an effect is, the bigger the probability of a causal relationship. 4. Temporality: The effect has to occur after the cause (and if there is an expected delay between the cause and expected effect, then the effect must occur after that delay). 5. Biological gradient: Greater exposure should generally lead to greater incidence of the effect. 6. Plausibility: A plausible mechanism between cause and effect is helpful. 7. Coherence: Coherence between epidemiological and laboratory findings increases the likelihood of an effect. However, Hill noted that "... lack of such [laboratory] evidence cannot nullify the epidemiological effect on associations". 8. Experiment: "Occasionally it is possible to appeal to experimental evidence". 9. Analogy: The effect of similar factors may be considered.

6 HILLS CRITERIA (1965) 1. Strength: A small association does not mean that there is not a causal effect, though the larger the association, the more likely that it is causal. 2. Consistency: Consistent findings observed by different persons in different places with different samples strengthens the likelihood of an effect. 3. Specificity: Causation is likely if there is a very specific population at a specific site and disease with no other likely explanation. The more specific an association between a factor and an effect is, the bigger the probability of a causal relationship. 4. Temporality: The effect has to occur after the cause (and if there is an expected delay between the cause and expected effect, then the effect must occur after that delay). 5. Biological gradient: Greater exposure should generally lead to greater incidence of the effect. 6. Plausibility: A plausible mechanism between cause and effect is helpful. 7. Coherence: Coherence between epidemiological and laboratory findings increases the likelihood of an effect. However, Hill noted that "... lack of such [laboratory] evidence cannot nullify the epidemiological effect on associations". 8. Experiment: "Occasionally it is possible to appeal to experimental evidence". [1] 9. Analogy: The effect of similar factors may be considered.

7 INGEN AF HILL S KRITERIER ER OPFYLDT Pigerne havde øget sygelighed før første vaccine: - Udelukker principielt ikke at der kan være bivirkninger - Men svækker den mulige hypotese, idet årsag skal komme før effekten (og med en plausibel latenstid) - Giver også en opfattelse af en særlig profil ift sundhedssøgende adfærd for disse kvinder

8 HVORFOR GIK DET SÅ GALT?

9 STORIES VERSUS NUMBERS Actress Mira Wanting dies of cervical cancer, 34 years of age, in 2012

10 Reporting of adverse events: Stimulated by the program The Vaccinated Girls broadcasted 26 March 2015, by TV2 Features interviews with families and vaccinated girls with medically unexplained symptoms.

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14 HVORFOR ER PIGERNE SYGE? Diagnoser er individuelle Bivirkninger - Utvivlsomt for enkelte, men sikkert få. Body Distress Syndrome? - Reaktion på skade/trauma, eksempelvis whiplash - Symptomer fra det autonome nervesystem, mave-tarmsystem, bevægeapparat Attribution den sociale/mentale konstruktion af en årsag - Sammenfald mellem symptomer og vaccination Iatrogenicitet - Artefakt af medicinsk specialisering og dårlig forskning Kan fastholdes ved en biologisk tilgang - Blame-X syndromet : En forhandling om at finde en forklaring Hellere bivirkninger end en vanskelig samtale Reducere angsten for det ukendte

15 HVORDAN KOMMUNIKERES EFFEKTIVT? HPV can infect your daughter and seriously harm her health. You can protect her by getting her vaccinated.

16 GRUND TIL OPTIMISME Skift i indhold af mediedækning - Godt hjulpet af diskursen om fake news Faldende antal rapporterede bivirkninger Vaccinationsdækningen er på vej op Spændende forskning på vej Forskere og myndigheder kommer ned fra tårnet for at møde de bekymrede mødre - Vigtigt at være modig og holde fast på kvalitet i forskning Tak til bl.a. Stine Jacobsen og Bolette Søborg, National Health Authority Camilla Hiul Suppli, Niels Dalum Hansen, Palle Valentiner-Branth, Tyra Krause, Morten Frisch og Anders Hviid, SSI Line Michan, Danish Medicines Agency No conflicts of interest to declare

17 EXTRA SLIDES

18 LIDT OM HPV EPIDEMIOLOGI Danmark: 380 tilfælde af livmoderhalskræft 120 dødsfald celleforandringer > keglesnit

19 UDVIKLING AF VACCINE MOD HPV 1976: Zur Hausen fremsætter hypotesen at humant papillomvirus spiller en rolle i udvikling af cervix-cancer 1983: HPV16 og HPV18 forbindes med cervixcancer - en nødvendig årsag Udvikling af vaccine starter - University of Queensland, Australien, patent 1991, på vaccine like particles (VLP) 2006: Første vaccine, Gardasil (Merck), godkendes 2007: Cervarix (GSK) godkendes 2007: Sundhedsstyrelsen laver en medicinsk teknologivurdering mhp inklusion i vaccinations programmet - Anbefaling om at oprette et vaccinationsregister 2008: Gardasil inkluderes i børnevaccinationsprogrammet (opstartsprogram til børn født i ) 2009: Vaccination starter (12 til 15 år gratis vaccination) Harald zur Hausen, Nobelpris 2008

20 TIDSLINJE : Omfattende catch-up program til kvinder årgang (op til 27 år) 2014: To dosis program for de årige piger indføres (EPI-NYT 28-32, 2014) 2014: Gardasil 9 godkendes - Højrisiko typer 16, 18, 31, 33, 45, 52 og 58 - Lavrisiko typer 6 og februar 2016: Danmark beslutter at skifte fra Gardasil til Cervarix pga udfald af et lovpligtigt udbud (se EPI-NYT 2/2016) Nu: Nyt udbud går efter Gardasil 9

21 FAKTA OM VACCINERNE Alle tre vacciner har høj effektivitet over for HPV-infektion - Blandt ikke inficerede Høj sygdomsbyrde af HPV relateret sygdom - Cervixcancer, men også anal, penis, vulva & vagina - Mundsvælget - Kondylomer Velundersøgte vacciner, god effekt, sikre millioner vaccinerede (ca 270 millioner personer) givet på verdensplan Langvarig beskyttelse - Også efter blot to doser Faldende priser - Vigtigt i globalt perspektiv vi har et ansvar

22 CIN2 + Totale befolkning Baldur-Erikson et al, Cancer Causes Control 2014 Screenede

23 Dramatic decline in the incidence of genital warts Significant Reduction in the Incidence of Genital Warts in Young Men 5 Years Into the Danish Human Papillomavirus Vaccination Program for Girls and Women. Bollerup, Signe; Baldur-Felskov, Birgitte; MD, PhD; Blomberg, Maria; MD, PhD; Baandrup, Louise; MD, PhD; Dehlendorff, Christian; Kjaer, Susanne; MD, MDSc Sexually Transmitted Diseases. 43(4): , April DOI: /OLQ FIGURE 1. Half-yearly IRs of GWs per 100,000 personyears in Denmark between 2006 and 2013, stratified by sex and age. Copyright 2016 American Sexually Transmitted Diseases Association. Published by Lippincott Williams & Wilkins, Inc. 2

24 CARE-SEEKING BEFORE FIRST VACCINE Case-control study Cases: 361 females with severe adverse reactions reported to DMA Controls: matched on municipality, age, year of first HPV vaccine - Females - Vaccinated - No reports of adverse reactions

25 AGE DISTRIBUTION (CASES) The bimodal distributions reflects the catch-up programme

26 Table 3. Final multivariable model showing health care-seeking in the two years prior to vaccination in 316 Danish females who reported suspected adverse events to HPV vaccination compared with 163,910 matched controls. Mølbak K, Hansen ND, Valentiner-Branth P (2016) Pre-Vaccination Care-Seeking in Females Reporting Severe Adverse Reactions to HPV Vaccine. A Registry Based Case-Control Study. PLoS ONE 11(9): e doi: /journal.pone

27 THE REPORTING OF SUSPECTED ADVERSE EVENTS AND THE RESULTING CONCERNS ABOUT VACCINE SAFETY

28 THE DANISH SIGNAL From 2013: Danish Medicines Agency received an increasing number of reports of suspected adverse events (AE) adverse events , of which 1023 were classified as severe Persistent or significant incapacity - Only 10% of the 488 reports received in 2015 had onset in 2015 Source: Danish Medicines Agency

29 IN RELATION TO THE YEAR OF THE ONSET 160 Reported adverse events per 100,000 vaccines sold Source: Danish Medicines Agency

30 THE CLINICAL PICTURE Medically unexplained physical symptoms - Symptoms from the nervous systems ( autonomic dysfunctions ) Including dizziness, syncope, weakness, headache, disordered sleep - Fatigue - Pain - Musculoskeletal symptoms Some recieved the diagnosis POTS postural orthostatic tachycardia syndrome - 60-degree head-up tilt table - Orthostatic intolerance and a sustained heart rate increment according to defined criteria Chronic fatigue syndrome Complex regional pain syndrome

31 From Brinth L et al, Dan Med J patients seen at one centre Considerable overlap in symptoms between POTS and Chronic Fatigue Syndrome/Myalgic Encephalomyelitis (CFS/ME)