The effects of immunisation on infection and Disease

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1 The effects of immunisation on infection and Disease Jepser Bonde and Kate Cuschieri Presented at ECC Liverpool October 2016

2 Scotland's Cervical Screening Programme Scotland popn = 5.3 million (2011 census) National, organised call/recall cervical screening programme. All liquid based cytology delivered in 8 NHS Labs ( K tests p/a) Age range years until June 2016 then changed to year olds. 3 yearly screening up to age 50 then 5-yearly ~70% uptake Centralised IT systems which capture - cytology, call recall, histology, colposcopy, HPV and immunisation status HPV testing performed as a test of cure of treatment (not as triage) Business case for primary HPV testing submitted

3 % HR-HPV Positive HPV prevalence is high in Scotland HR-HPV Prevalence in Scottish Screening Population % HR- HPV in women aged attending for routine cervical screening HR-HPV HPV 16 HPV 18 ~280,000 infections in screen age women in Scotland Age CIN3 2,405 2,658 3,230 2,599 2,596 2,536 2,280 Cervical Cancer

4 Cancer of the Female Genital Organs Incidence by NHS Region of Residence, Scotland Numbers of registrations, with age-specific and age-standardised incidence rates (using ESP2013): period Numbers Under All Ages SCOTLAND ,658

5 The rising prevalence of HPV associated non-cervical disease? Wakeham & Kavanagh 2014

6 Scottish HPV immunisation programme and associated surveillance HPV immunisation initiated in September schools based programme year olds girls = routine/ target cohort & Three year Catch-up ran for girls 18 years Uptake ~ 90% for target population and around ~65% for catch up Bivalent vaccine until September 2012, changed to quadrivalent Three dose schedule- changed to two dose in 2014 Females immunised as part of the catch up programme have been entering the Scottish cervical screening programme since opportunities to monitor impact Partner programme of longitudinal surveillance to determine impact

7 Longitudinal assessments - as a consequence of vaccination, do we see impact on HPV infection in women attending for first smear? The types of HPV infection associated with CIN2+? Overall rates of CIN? Overall rates of cytological abnormalities? Herd Immunity? The performance of cytology? The performance of colposcopy? The performance of primary HPV testing? Uptake at first smear? And also an impact of Less than 3 doses of vaccine?

8 HPV infection in women attending for first smear? Positivity for HPV 16/18 was 11% ( %) in fully-vaccinated 20 year olds vs 29.4% ( ) in unvaccinated women Evidence of significant cross protection for HPV types 31,33 and 45 Annual prevalence of 16/18 decreased over time 28.8% of samples collected in 2009 were +ve vs 10.1% in 2013 Cameron et al 2016

9 Overall rates of CIN? With 3 doses risk of CIN of all grades is significantly lower: CIN 1 (RR 0.71, 95% CI 0.58 to 0.87, p=0.0008) CIN 2 (RR 0.5, 95% CI 0.4, 0.63, p<0.0001) and CIN 3 (RR 0.45, 95% CI 0.35 to 0.58, p< ) for women who received 3 doses of vaccine compared with unvaccinated women adjusting for deprivation and age women received vaccine Pollock et al BJC 2014

10 The types of HPV infection associated with CIN2+? Adjusted OR HPV 16 or 18 95% CI Vaccine status Unvaccinated (0.19, 2.25) (0.14, 1.13) (0.21, 0.56) Unknown 0.88 (0.57, 1.37) Year (0.49,0.93) Histology CIN2 1 CIN (1.67, 2.97) Reduced odds of CIN2+ harbouring an infection with HPV 16 or 18 associated with immunisation

11 Ranking of most common HPV types in CIN2 & 3 by immunisation status CIN 2 Ranking Unvaccinated Point Est (95% CI) 1 hpv (57.8, 67.6) 2 hpv (12.3, 19.7) 3 hpv (11.6, 18.8) 4 hpv (7.8, 14) 5 hpv (5.3, 10.7) Vaccinated 1 hpv16 41 (27.1, 56.6) 2= hpv 31,33, (7.2, 29.7) 3= hpv 52, 58 and (4.1, 23.6) 4= hpv 11, 51, (2.7, 20.3) 5= hpv 39,42,45, (1.4, 16.9) CIN 3 Ranking Unvaccinated 1 hpv (73.8, 82.1) 2 hpv (11.9, 19.1) 3 hpv (11.1, 18.2) 4 hpv (5.9, 11.4) 5 hpv (5.2, 10.5) Vaccinated 1 hpv (39.8, 69.3) 2 hpv (8.7, 31.9) 3 hpv (7.1, 19.1) 4 hpv (5.5, 26.1) 5= hpv 58, (4, 23.1)

12 Herd Immunity? Study Year No. Women No. Pos % Pos (95% Cl) , ( ) , ( ) ( ) ( ) ( ) HPV 16/18 HPV 31/33/45 OR (95% Cl) No. Pos %Pos (95% Cl) 1 (reference) ( ) 1.13 ( ( ) 16.0) 1.05 ( ( ) 15.8) 1.18 ( ( ) 16.0) 0.67 ( ( ) 14.5) OR (95% Cl) 1 (reference) 1.10 ( ) 0.99 ( ) 0.88 ( ) 0.71 ( ) Initial evidence of herd immunity for HPV 16 or 18 in unimmunised women Cameron et al 2015

13 One dose of Vaccine? Analysis samples from women who had received 2 doses, generally administered at 0 and 1 month(s) - via Scottish Programme 177 had received 1 dose only. This compared to 1853 that had 3 doses of vaccine over the same time frame for who we had HPV genotyping results associated with vaccine status.

14 Even one dose of vaccine may be efficacious for HPV 16/18 P value infection No. of Doses HPV 16/18 Unadjusted Vaccine efficacy [%, (95 CI s)] Adjusted Vaccine efficacy [%, (95 CI s)] P value HPV 31/33/ (-5.7,48.0) (16.8,68.9) < (15.3, 52.3) 54.8 (30.7, 70.8) < < (65.0, 74.7) 72.8 (63.8, 80.3) Cuschieri et al (-74.6, 25.9) (-85.1, 45.3) (12.1, 62.8) (7.6, 71.8) < < (45.1, 64.1) 55.2 (32.6, 70.2)

15 Impact of vaccination is being observed at the population level Pattern of infection and disease is changing particularly that relating to HPV 16/18 These changes are likely to be more profound as the routinely immunised girls enter the screening programme (from 2015) How do we best manage residual infection/associated disease in those both eligible and not eligible for vaccination?

16 SHPVRL All Scottish Cytopathology Labs HPV Research Group (R Bhatia) HPS HPV surveillance team (K Pollock) Scottish HPV Investigators Network Heather Cubie Tim Palmer Maggie Cruickshank Camille Busby-Earle

17 Using the cer vical screening program to monitor the effect of HPV vaccine Jesper Bonde, PhD, Dipl.Med.Sci. Senior Researcher, Laboratory manager Copenhagen University Hospital, Denmark

18 B a c k g ro u n d Since 2009, girls age 12 years, have been offered HPV vaccination free of charge through the Danish childhood immunization program Choice of vaccine through national tender was the Gardasil (protects against HPV16/18 and 6/11). 1st Jan 2016: Gardasil has been replaced with Cervarix (HPV16/18). Since 2015 a media shit-storm on alleged vaccine side effects has decreased vaccine uptake from 85% (2010) to 42% (october 2016)...

19 B a c k g ro u n d A national review conducted by the Statens Serum Institut under charter from the Ministry of Health has conclusively shown that the majority of all young women with nonconfirmed, alleged vaccine side effects were indeed already describing symptoms prior to vaccination similar to the reported vaccine side effect(s). Pre-Vaccination Care-Seeking in Females Reporting Severe Adverse Reactions to HPV Vaccine. A Registry Based Case-Control Study. Kåre Mølbak et al. PLoS One Sep 9;11, 2016.

20 H o w t o m o n i t o r t h e va c c i n e e f fe c t AIM To evaluate the genotype specific incidence of CIN2 (treatment cut-off) in women years at histology level using a historical reference group. Perspective I: To establish the foundation for an on-going vaccine monitoring. P e r s p e c t i v e II: Use of extended genotyping assays for primary screening (In Denmark 2018??) to enable monitoring of HPV changes in the screening population.

21 T h e VA C - C I N Pro j e c t Composition of overall vacine efficacy HPV only Co infection HPV plus other HPV No HPV Found (other HPV or no HPV detected) Type attribution in cervical lesions

22 VA C - C I N Materials Control group: Women born , up to 400 histology biopsies and conus specimens, CIN2, material from 2007 (pre-vaccination, between 23-29, participated in screening that year). Case group: Women born , up to 400 histology biopsies and conus specimens, CIN2, material from 2016 (between 23-29, participated in screening in 2016)

23 VA C - C I N Method 400 histology biopsies and conus specimens, CIN2, per group Case group Control group Linkage to National Vaccine register/ National prescription register HPV negative Linkage to screening history and result Split sample HPV DNA full genotyping CLART2/InnoLipa and BD Onclarity(?) HPV positive Linkage to screening history and result HPV only Co infection HPV plus other HPV No HPV Found (other HPV or no HPV detected)

24 VA C - C I N Perspectives With an established control group, we can repeat this exercise every year come December. In 2017, we will test who fullfill the criterions In 2018, we will test who fullfill the criterions Etc. As central screening unit, we control the screening as well as the resulting histologi material = easy, complete access. All histology is archieved indefinitely. Extracted DNA will be biobanked.

25 VA C - C I N Thank you for your attention M o l e c u l a r Pa t h o l o g y L a b o ra to r y Dept. Pathology Copenhagen University Hospital, Hvidovre Copenhagen Jesper.hansen.bonde@regionh.dk