UICC HPV and CERVICAL CANCER CURRICULUM
01 Chapter 5. Application of HPV vaccines Director of Microbiological Research Director of Clinical Microbiology and Infectious Diseases The Royal Women's Hospital Melbourne, Australia
02 Selection of the right age group for vaccination Genital HPV infections are common sexually transmitted infections - Readily transmissible: within few months of start of sexual activity - Cumulative lifetime risk of infection = 50-80% - Cumulative lifetime exposure to HPV 16 and/or HPV 18 20% 1 Natural history of HPV - Most HPV infections are transient: the majority of young women clear HPV infection within 1-2 years 2 HPV type prevalence - HPV prevalence among different populations of women range from 2-44%, with worldwide overall prevalence of 10.4% - Age dependent - Different profiles in different countries 3 1 Baseman J et al. Clin Virol 2005;32:16-24. 2 Sankaranarayanan R et al. Vaccine 2008; 26: Suppl 12:M43-52. 3 de Sanjosé S et al. Lancet Inf Dis 2007;7:7 453-459.
03 Selection of the right age group for vaccination Antibody responses in known age groups Antibody responses have been used as a surrogate to bridge efficacy against cervical and/or vaginal disease in: 1-3 - Young women - Pre-adolescence - Mature women Basis for registration 4 1 Munoz N et al. Lancet 2009;373:1949-57. 2 Block SL et al. Pediatrics 2006;118(5):2135-45. 3 Pedersen C et al. J Adolesc Health 2007;40(6):564-71. 4 Skinner SR et al. Med J Aust 2008;188(4):238-242.
04 Selection of the right age group for vaccination Efficacy against HPV vaccine-related disease correlates with the presence of serum antibodies 1-4 Recipients show rapid development of high titre (many fold greater than natural infection) Currently no identified correlate of protection Immune responses are age-dependent 5,6 1 Harper et al Lancet 2006:1247-55. 2 Villa LL et al Brit J of Cancer 2006;95(11):1459-66. 3 Villa LL et al. Vaccine 2006;24:4931-39. 4 Harper D et al. Gynec Oncol 2008;109(1):158. 5 Block SL et al. Pediatrics 2006;118(5):2135-45. 6 Pedersen C et al. J Adolesc Health 2007;40(6):564-71
05 Selection of the right age group for vaccination Dependent on age of sexual debut (culture-dependent): age of sexual debut is decreasing over time in some countries, but this trend is less pronounced and less widespread than sometimes supposed 1 Prophylactic HPV vaccines are licensed for the ages of 9 to 12 years in many countries 1 Wellings K et al. Lancet 2006; 368:1706-28
06 Selection of the right age group for vaccination Needs to be practical for vaccine delivery - School-based programmes - Adolescent health programme focus - Practitioner-based programme Collaborate with already existing childhood extended immunisation programmes (EPI) - Maximise implementation using already established vaccination infrastructure
07 HPV vaccination in boys? Clinical trials in boys - Immunogenicity has been shown with both vaccines 13,14 - Preliminary results are available showing protection from infection and external genital warts for the quadrivalent vaccine 15 Cost-effectiveness? Would allow destigmatisation of females Herd immunity: effect on females with lower uptake of vaccine 13 Reisinger KS et al. Pediatr Infect Dis J. 2007 Mar;26(3):201-9. 14 Petäjä T et al. J Adolesc Health. 2009 Jan;44(1):33-40. 15 Palefsky J. Eurogin February 2010.
08 Does prophylactic vaccination replace cervical screening? Efficacy following three doses of vaccine for those naïve to vaccine-related HPVs is nearly 100% 16-18 About 30% of cancers are caused by non-vaccine related- HPVs - Immunity largely type-specific Some cross-protection to HPV types phylogenetically related to HPV 16 and HPV 18 16 Garland SM et al. NEJM 2007;356:1928-1943. 17 FUTURE II SG. NEJM 2007;356:1915-1927. 18 Paavonen J et al. Lancet 2007;369:2161-2170.
09 Does prophylactic vaccination replace cervical screening? Some form of screening is still required Challenges with an implemented vaccine programme: 19 - Screening sensitivity and positive predictive value for high-grade lesions will be reduced with vaccination - Reduced future cancer burden through primary prevention, cervical screening programmes will be much less cost-effective - Vaccinees may be unclear as to the need for Pap test 19 Cuzick et al. Vaccine 26S; 2008: K29-41.
10 Vaccinating sexually active women: is prior HPV DNA testing mandatory? From a public health point of view, this is not recommended - A negative test does not tell you whether a woman has previously been infected - A positive test could be a newly acquired infection or a persistent infection - More likely negative if transient infection
11 Vaccinating sexually active women: measure antibodies before vaccinating? HPV antibodies - A poor marker of past or present infection, ~ 60% of those HPV DNA-positive have a measurable serological response 20 - Serological responses are slow (take up to 12-18 months post-infection) - No reliable diagnostic assays exist - Assays need to be standardised 21 20 Carter JJ et al J Infect Dis 2000, 181,1911-1919. 21 Pagliusi SR, Garland SM. Molecular Markers 2007;9(32):1-14.
12 Opportunities for HPV vaccination in low-resource countries GAVI-subsidized childhood vaccination programmes for 72 countries (late 2008/early 2009) Need for similar GAVI endorsement of HPV vaccines Reduced pricing of HPV vaccines for poorer countries - Accelerated Development and Introduction Plans (ADIPs) - Mechanisms such as the Advanced Market Commitment (AMC)
13 Are three injections mandatory for efficient protection? Very limited data on prevention of infection or disease with two-dose schedule - High compliance of study participants to three-dose schedule Given the nature of the vaccine, likely that three doses will be required as with HBV Studies to evaluate modifications to current vaccine schemes are ongoing
14 Vaccine effectiveness: need for ongoing surveillance HPV genotyping - Prevalence: normal cytology, cervical dysplasia/cancer - Vaccine-related type prevalence change? - Protection against phylogenetically related non-vaccine types? - Replacement of vaccine HPV types? - HPV serosurveillance Genital wart surveillance (females and males)
15 Putting all the pieces together: HPV vaccination programme in Australia Australia was the first country to implement a national vaccine programme funded by the government Vaccination in both girls and boys Included a catch-up programme in women Cervical screening programme already in progress
16 The Australian National HPV Vaccination Programme (1) November 2006 - Commonwealth Minister for Health announced funding for HPV vaccine (Gardasil ) April 1 st 2007 - Added to National Immunisation Programme on an ongoing basis for 12-13 year-old girls via schools July 2007 December 2009 - Two-year catch-up programme for 12-26 year-old females
17 The Australian National HPV Vaccination Programme (2) Three components: Ongoing school-based programme 1. Girls aged 12-13 years (first year of high school) Two-year catch-up programme to 2009 2. Girls/adolescent females aged 12-18 years - School-based +/- community-based mop up 3. Young women aged 18-26 years - General practitioners and other community-based services
18 The Australian National HPV Vaccination Programme (3) Vaccination coverage (by the end of May 2009) - 5 million doses of the vaccine distributed (~80%) first year s cohort - ~60% coverage of the eligible population in the catch-up group of young females - Rural areas: 70% of target age groups received first dose
19 Community-based programme: 18-26 year-olds Difficult demographic to ensure completion of 3-dose vaccine schedule Implementation strategy: - Motivate and empower young women to protect themselves - Support GP clinics to run pro-active vaccination campaign - High-profile advertising and public relations campaign
20 National HPV Vaccination Register National HPV Vaccination Register launched by the Australian Government (VCCR) - Collect information on vaccination programme - Evaluate impact of vaccination on cervical abnormality and cancer rates by matching with Pap test registers Document doses of HPV vaccine and dates administered - Assess age-specific coverage achieved - Contact if booster doses required - Link to Pap Screen registers - Evaluate the impact of the vaccine on cervical cancer Providers must report vaccination in 12-18 year age group - Victorian councils using Immunisation Provider System (ImPS) to collect data
21 Lessons learned, future directions and challenges Opportunities to link the National HPV vaccine Register with: - Cervical cytology screening registers - HPV genotype prevalence surveillance pre- and postvaccine implementation - Ultimately cancer registers for ongoing surveillance Communication, feedback, goodwill, etc. Vaccine effectiveness Evaluation of cervical screening practices
22 Lessons learned, future directions and challenges Approaches for implementation of HPV vaccination programmes are different between countries Australia, UK, Canada: successful public-sector HPV vaccination programmes primarily based on school-based provision, and largely covered by public sector funds for all age-eligible female adolescents 1-3 Resulted in relatively high rates of HPV vaccination coverage: e.g. Australia coverage up to 80% 2,3 1 Shefer et al. Vaccine 2008;26(Suppl 10):K68-75 2 Brotherton JM et al. Commun Dis Intell 2008;32:457-61 3 Garland SM et al. Vaccine 2008;26(Suppl 12):M80-8
23 Challenges and future directions Largely vaccinated cohort of Australian women Review and re-engineer National Cervical Screening Programme (NCSP) introduced in 1991 NSCP currently recommends cervical cytology screening for all women who have ever had sex - Start at 18-20 years or 1-2 years after start of sexual intercourse, which ever is later - Repeat Pap smear every 2 years - Screening ends at age 70 if 2 normal Pap smears within last 5 years
24 Thank you This presentation is available at www.uicc.org/cervicalcancercurriculum