HPV-VACCINE.

FORSKERENS BLIK PÅ

HISTORIEN !

Kåre Mølbak

Statens Serum Institut

1. HPV VACCINE PR FØDSELSKOHORTE, 30. JUNI 2017

Uptake of first HPV-vaccine by year of birth, females, 1993-2005

FORSKERENS PERSPEKTIV

Hvilken forsker ?

- Epidemiologen ?

- Biologen/immunologen ?

- Sociologen ?

- Antropologen ?

- Kommunikationsforskeren ?

- Psykologen ?

- Økonomen ?

Alle kan give relevante bidrag til forskning og til at genoprette tillid.

EPIDEMIOLOGENS BLIK

Velundersøgte vacciner, god effekt på HPV-relateret sygdom, meget sikre

- 100 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

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.

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.

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

HVORFOR GIK DET SÅ GALT ?

STORIES VERSUS NUMBERS

Actress Mira Wanting dies of

cervical cancer, 34 years of age, in

2012

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 .

11

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

HVORDAN KOMMUNIKERES EFFEKTIVT ?

HPV can infect your daughter and seriously harm her health. You can protect her by getting her vaccinated.

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

EXTRA SLIDES

LIDT OM HPV EPIDEMIOLOGI

Danmark:

• 380 tilfælde af livmoderhalskræft

• 120 dødsfald

• 15.000 celleforandringer

• > 5.000 keglesnit

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 1993-1995)

2009: Vaccination starter (12 til 15 år gratis vaccination)

Harald zur Hausen,

Nobelpris 2008

TIDSLINJE 2

2012-13: Omfattende catch-up program til kvinder årgang 1985-1992 (op

til 27 år)

2014: To dosis program for de 12-13 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 11

1. 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

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

- 100 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

Baldur-Erikson et al,

Cancer Causes Control 2014

CIN

2 +

Totale befolkning

Screenede

© Copyright 2016 American Sexually Transmitted Diseases Association. Published by Lippincott Williams & Wilkins, Inc.

2

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):238-242, April 2016.DOI: 10.1097/OLQ.0000000000000418

FIGURE 1 . Half-yearly IRs of GWs per 100,000 person-years in Denmark between 2006 and 2013, stratified by sex and age.

CARE-SEEKING BEFORE FIRST VACCINE

Case-control study

Cases: 361 females with severe adverse reactions reported to DMA

Controls: 163.910 matched on municipality, age, year of first HPV vaccine

- Females

- Vaccinated

- No reports of adverse reactions

AGE DISTRIBUTION (CASES)

The bimodal distributions reflects the

catch-up programme

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): e0162520. doi:10.1371/journal.pone.0162520

http://journals.plos.org/plosone/article?id=info:doi/10.1371/journal.pone.0162520

THE REPORTING OF SUSPECTED

ADVERSE EVENTS AND THE RESULTING

CONCERNS ABOUT VACCINE SAFETY

”THE DANISH SIGNAL”

From 2013: Danish Medicines Agency received an increasing number of

reports of suspected adverse events (AE)

- 2320 adverse events 2009-2016, 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

IN RELATION TO THE YEAR OF THE ONSET

0

20

40

60

80

100

120

140

160

2009 2010 2011 2012 2013 2014 2015

Reported adverse events per 100,000 vaccines soldSource: Danish Medicines Agency

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

From Brinth L et al, Dan Med J

2015

53 patients seen at one centre

Considerable overlap in

symptoms between POTS and

Chronic Fatigue

Syndrome/Myalgic

Encephalomyelitis (CFS/ME)