Implications of One Dose of HPV Vaccine. Kate Cuschieri Scottish HPV Reference Laboratory SHINe Meeting 26 th April 2016

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1 Implications of One Dose of HPV Vaccine Kate Cuschieri Scottish HPV Reference Laboratory SHINe Meeting 26 th April 2016

2 Scottish HPV immunisation programme and associated surveillance HPV immunisation initiated in September 2008 schools based programme year olds girls = routine/ target cohort Three year Catch up ran for girls 18 years Bivalent vaccine until September 2012, changed to quadrivalent Three dose schedule changed to two dose in 2014 Partner programme of longitudinal surveillance to determine impact

3 Vaccine uptake is high in Scotland Topics/Child Health/publications/data tables.asp?id=1300#1300

4 Scottish HPV immunisation surveillance (initiated 2008) Facilitated through Unique person identifier CHI number Existing national databases for cervical screening, colposcopy, immunisation and cancer; linkage between them possible through CHI. Funding for a specific programme through National Services Division National pathology networks, reference laboratory facility 1, Scottish HPV Investigators Network 2, National HPV Sample Archive. 3 Age at cervical screening initiation =20 years, so women immunised as part of catch up have been entering the programme since 2011/

5 Scottish HPV immunisation surveillance (2008) Programme includes Baseline assessments (pre immunised population) 1,2,3 Monitoring impact of immunisation on disease outcomes over time (histological 4, cytological 5, colposcopic 6 ) Monitoring impact of immunisation on HPV infection In women attending for first smear (yearly) residual LBC 7 In women diagnosed with CIN2/3 residual biopsy Assessment of < 3 doses of vaccine 1: O'Leary MC, Sinka K, Robertson C, Cuschieri K, Lyman R, Lacey M, Potts A, Cubie HA, Donaghy M. HPV type specific prevalence using a urine assay in unvaccinated male and female 11 to 18 year olds in Scotland. Br J Cancer Mar 29;104(7): :Cuschieri K, Brewster DH, Williams AR, Millan D, Murray G, Nicoll S, Imrie J, Hardie A, Graham C, Cubie HA. Distribution of HPV types associated with cervical cancers in Scotland and implications for the impact of HPV vaccines. Br J Cancer.2010 Mar 2;102(5): : Kavanagh K, Sinka K, Cuschieri K, Love J, Potts A, Pollock KG, Cubie H, Donaghy M, Robertson C. Estimation of HPV prevalence in young women in Scotland; monitoring of future vaccine impact. BMC Infect Dis Nov 5;13:519. 4: Pollock KG, Kavanagh K, Potts A, Love J, Cuschieri K, Cubie H, Robertson C, Cruickshank M, Palmer TJ, Nicoll S, Donaghy M. Reduction of low and high grade cervical abnormalities associated with high uptake of the HPV bivalent vaccine in Scotland. Br J Cancer Oct 28;111(9): : Palmer, T. J., Robertson, C., Cuschieri, K., Nicoll, S. & Pollock, K. G. J. Effect of HR HPV immunisation on the performance of cervical cytology, presented at EUROGIN 2015 OC12, p206 6: Cruickshank M et al Implications of HPV immunisation on colposcopy services and practice IPV 2015 Fri 18/09/15 and Sun 20/09/15 7: Kavanagh K, Pollock KG, Potts A, Love J, Cuschieri K, Cubie H, Robertson C, Donaghy M. Introduction and sustained high coverage of the HPV bivalent vaccine leads to a reduction in prevalence of HPV 16/18 and closely related HPV types. Br J Cancer May 27;110(11):

6 Percentage of women positive for any HPV Significant reduction of HPV 16,18,31,33 and 45 Unvaccinated (0 dose) Vaccinated (3 doses) Significant reduction of HPV 16,18,31,33 and Kavanagh et al BJC 2014 HPV type

7 Delivery of less than 3 doses of HPV vaccine Clear cost implications and benefits Underpinned by evidence on non inferiority of antibody levels associated with delivery of 3 doses vs 2 doses delivered as a primeboost The protection offered by 2 doses in non randomised clinical trials has been shown to be comparable to that offered by 3 doses against incident and persistent infections of vaccine targeted HPV types Demonstrated for both bivalent, quadrivalent vaccine (and nonavalent) Basu P, Bhatla N, Ngoma T, Sankaranarayanan R, Less than 3 doses of the HPV vaccine review of efficacy against virological and disease end points. Hum Vaccin Immunother Mar 2:1 9.

8 Global implementation Increasing move towards 2 doses (UK, Australia, France, Switzerland, Quebec, Columbia) WHO recommends 2 doses for 15 year old girls and 3 doses for those >=15 and those who are HIV pos. Doses to be minimum 6 months apart. Less data/guidance on alternative dosing schedules for men

9 Will one dose do? Post hoc analysis of Costa Rica Vaccine trial In women who were HPV 16/18 negative at the time of first vaccination,hpv 16/18 vaccine efficacy was uniformly high against incident HPV 16/18 infections that persisted for at least 6 months for recipients of one two and three doses of vaccination at 4 years 1 dose: 100% (79 100) 2 dose: 81%, (53 94) Antibody responses with 1 dose were nearly 4 times lower than those associated with 2 or 3 doses over the period although same pattern of peak, decline and plateau observed Quadrivalent vaccine against human papillomavirus to prevent high grade cervical lesions. N Engl J Med 2007; 356:

10 Will one dose do? Kreimer et al Combined analysis of Costa Rica Vaccine Trial and PATRICIA both efficacy studies of the bivalent vaccine.

11 Post hoc analysis in modified total vaccinated cohort HPV naïve at time of enrollment Primary study endpoint efficacy againt incident HPV 16/18 infection at 4 years 22,327 women with 3 doses 1185 women with 2 doses 543 with 1 dose Efficacy against incident HPV 31,33 and 45 also assessed

12 Vaccine efficacy (VE) against incident vaccine type Infection and cross protective types No doses VE 16/18 VE 31/33/ ( ) 36.6 ( ) ( ) 37.7 ( ) ( ) 59.7 ( )

13 Can we see similar impact in Scotland Assess data from women attending for their first smear given that a proportion will have been genotyped for HPV as a consequence of yearly surveillance stratify by vaccine dose Few with < 3 doses. Bolster with additional samples from the Scottish HPV Archive associated with < 3 vaccine doses

14 Methods Analysis was based on women who had received vaccine as part of a catchup programme that ran for girls up to age 17 years and 364 days (women born in ) To boost the number of samples from women who received < 3 doses, all additional stored samples (n=234) associated with < 3 doses collected from women both in were also tested. Final analysis 300 samples from women who had received 2 doses, generally administered at 0 and 1 month(s) 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.

15 Methods To estimate vaccine effectiveness, the adjusted odds ratio (OR) of prevalent infection with both HPV 16/18 and HPV 31/33/45 (in aggregate) for 1, 2, and 3 doses of vaccination was estimated by comparing to the unvaccinated group The odds of HPV infection was adjusted for deprivation (SIMD), birth cohort (to account for any potential temporal changes in HPV prevalence) and age at receipt of first dose for those vaccinated, as those who were vaccinated at older ages and therefore outside the schools based programme were more likely to have received < 3 doses. VE for women who received 3 doses over the same time frame is presented for context and comparison.

16 Variable Number % Variable distribution (%) in unvaccinated Variable distribution (%) in 1 dose vaccinated Variable distribution (%) in 2 dose vaccinated Variable distribution (%) in 3 dose vaccinated Birth cohort SIMD Age at vaccine for those vaccinated Over Demographics stratified by vaccine status

17 No. Doses of No. of samples No. pos 16/18 % (95% CI s) No. pos 31/33/45 % (95% CI s) (27.9, 30.8) (11.9, 14.1) (18.1, 30.5) (10.2, 20.7) (16.8, 26.0) (5.4, 11.6) (9.7, 12.5) (5.2, 7.4) Table 2: Prevalence (unadjusted) of vaccine and cross reactive HPV types according to number of vaccine doses Prevalence (unadjusted) of vaccine and cross reactive HPV types according to number of vaccine doses

18 Unadjusted P value Adjusted P value No. of VE VE: Doses [%, (95 CI s)] [%, (95 CI s)] HPV 16/ (-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) HPV 31/33/45 Table 2: Prevalence (unadjusted) of vaccine and cross reactive HPV types according to number of vaccine doses (-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)

19 Summary of Scottish data Impact of one dose of the bivalent vaccine was observed on prevalenct infection with HPV 16/18 One dose of vaccine was not associated with an impact on the prevalence of cross protective types(hpv 31/33/45) VE was assessed on women who were immunised as part of catch up so likely and underestimate of VE in women who receieve one dose during the routine programme aged 12~13 First data on impact of 1 dose of bivalent vaccine in a population based setting (BJC in press) Consistent with data from Australia that indicate 1 dose of quadrivalent vaccine offers protection from HR cytology [Hazard Ratio 0.44, 95% CI )]* * Brotherton et al Papillomavirus Research 1 (2015) 59 73

20 Implications Likely that prospective RCTs to assess 1 dose of vaccine will ensue discussed at EUROGIN 2016 meeting? More data will emerge from population based programme settings including from routinely vaccinated women An option and opportunity for low and middle income countries and beyond? More data on the effectiveness on the impact of <3 doses of vaccine in males required.

21 Thanks to HPV Surveillance Team at HPS All members of SHPVRL and HPV Research Group All Scottish Pathology Laboratories SHINe