Prevention of HPV-Related Diseases Following 4-Valent Vaccination in Australia
The Australian program
Following the positive data from phase 3 clinical trials of efficacy, immunogenicity and safety for the quadrivalent (4vHPV) HPV vaccine, from 2007 the Commonwealth Government of Australia funded the National HPV Vaccination Program, targeting girls aged 12–13 years in the first year of high school (as an ongoing 3-dose regimen). It was free for all, with no reimbursement step and delivered by school nurses qualified to administer vaccines. The first two years of the program included a catch-up component for 14-18 year olds (at school) and 18-26 year olds or those missing doses at school (through general practitioners).
In 2013, the National Immunisation Program took on a gender-neutral approach, with an ongoing school-based HPV program for boys targeting 12-13 year old boys (ongoing and as a 3-dose regimen), with a smaller catch-up for 14-15 year-olds to December 2014.
In line with WHO recommendations, in 2018, the program changed to 2-doses (6 months apart), and switched to 9-valent [9vHPV] HPV vaccine girls and boys, with a catch-up to 19 years of age (Figure 1).
Vaccine surveillance and coverage
A stand-alone register called the National HPV Vaccination Program Register (the Register), was established to record details of vaccine administration (including doses, dates, etc) as the existing childhood vaccination registry did not have the capacity to include the adolescent program. Reporting to the Register was obligatory (opt-out) for doses administered in schools, whereas for doses administered in the community in the catch-up program, it was voluntary.
Data from the Register has shown high national coverage for girls turning 15 years of age in 2017 (80% for 3 doses, 86% 2 doses and 89% 1 dose) and for boys, a comparable coverage (76% for 3 doses, 82% for 2 and 85% for 1 dose), with some variations by state and territory. Catch-up programs showed greater variation and included an unexpectedly high take-up rate for those 20 to 26 years of age in 2008 (Register data, 2018); two-dose coverage within the three-dose regimen for females aged 14-26 years varied between 24-81%, 39-81% and 43-80% for 2007, 2008 and 2009 respectively. There is under-reporting due to the voluntary nature of catch-up data registration.
From late 2018, HPV vaccine data has been reported to the Australian Immunisation Register (AIR); a newly created whole of life register with the ability to record details of all vaccinations administered by registered vaccination providers to people of all ages.
Vaccine surveillance and coverage
Having defined HPV genotype prevalence nationally in women (18-60 years) attending health services for cervical screening in 2005 to 2008, we have been able to subsequently measure a 92% reduction in vaccine-targeted types in samples collected from similar groups of women, post vaccination (Figure 2). Moreover, underpinned by the high vaccine coverage, particularly of the catch-up cohorts, we have shown herd protection in unvaccinated females and males as a consequence of the female-only program.1
With the renewed screening program in Australia in December 2017 moving from cervical cytology to nucleic acid detection for HPV, it is evident we now have a built-in surveillance system for women. In recent publications from Victoria2 and New South Wales3, dramatic changes in detection of vaccine-targeted types were noted (flat low prevalence of ~2%, which was stable across all ages in contrast to the peak among younger women seen pre-vaccination) (Figure 3).
Reduction in infection is an early indicator of vaccine impact ultimately of disease. Thus as cervical cancer is a rare outcome of a very common viral infection, reduction in HPV infection by vaccination, results in a smaller pool of virus to infect others (interruption of the transmission pathway) and ultimately reduction in disease (Figure 4).
Vaccine impact on disease
Genital warts, being common and of a short incubation period, were the first indicator of the remarkable impact of 4vHPV vaccine on HPV-related diseases. The reduction was dramatic (92%) and rapid, noted not only in those vaccinated, but also in those of vaccine-eligible age and as a reflection of herd protection. An additional bonus in the reduction of HPV 6/ 11 in young women of childbearing age has seen a large reduction in the rare, but serious juvenile onset recurrent respiratory papillomatosis in the offspring of those vaccinated (Figure 5).4
High-grade cervical disease, one of a longer incubation period (years), has also been significantly reduced in Australia in women under 34 years of age and readily documented by having high-quality and comprehensive vaccination and cervical screening registers.
A recent publication on cervical cancer and abnormality outcomes in an era of cervical screening in HPV vaccination in Australia to end of 2012 (Australian Institute of Health and Welfare [AIHW]) showed that women vaccinated against HPV had a 41% lower incidence of high-grade cervical abnormalities than those that were unvaccinated.5 Moreover, herd protection was evident for high-grade squamous intraepithelial lesions (HSIL) in unvaccinated, but vaccine-eligible age cohorts. It is noteworthy that vaccinated women for age strata were more likely to participate in cervical screening than those unvaccinated. Moreover, in observational national data at 7 years post-vaccination, one dose had comparable vaccine effectiveness as two or three doses in preventing high–grade disease in a high-coverage setting (Figure 6).6
Cervical cancer takes decades to occur following persistent HPV infection. On review of females born between 1 January 1981 and 1 January 2000, AIHW concluded that insufficient time had passed since the introduction of HPV vaccination to show a clear effect of HPV vaccination on cervical cancer. Overall, incidence rates were 1.6 (95% CI: 1.3–1.9) per 100,000 females for HPV-vaccinated women compared with 2.2 (95% CI: 1.9–2.6) for unvaccinated females. This slight difference could indicate the start of a trend, but further follow-up is required.5
Conclusion Australia is a country that has embraced HPV vaccination and cervical screening, and has had the infrastructure to measure outcomes and utilise linkages of different data sets. The above findings are those endorsed in the recent global meta-analysis and systematic review, that shows the outcomes of high coverage of the appropriate target populations include reduction in vaccine-targeted HPV and their related diseases.7 With the focus on cervical cancer elimination as a public health problem, modelling predicts Australia to be one of the first countries to achieve this, provided we can maintain high and sustained coverage in both programs and with continued comprehensive surveillance.
DISCLOSURE SMG has received institutional grants from the Commonwealth Department of Health for HPV genoprevalence surveillance post-vaccination. SMG has been sponsored by a MSD's Investigator-Initiated Study grant to evaluate HPV in a young women's study. SMG has received speaking fees from MSD for work performed in her personal time, and is a member of Merck Global Advisory Board. SMG is an advisor to WHO on HPV and is a member of the HPV Advisory committee to SAGE. SMG and GM had been related with SpeeDx for commercial and other purposes. DAM has received institutional grants and financial support for meetings from MSD and Seqirus.
References
1. Machalek DA, Garland SM, Brotherton JML, et al. Very low prevalence of vaccine human papillomavirus types among 18-to 35-year old Australian women 9 years following implementation of vaccination. J Infect Dis 2018; 217: 1590–1600. Available from: https://pubmed.ncbi.nlm.nih.gov/29425358/
2. Brotherton JM, Hawkes D, Sultana F, et al. Age-specific HPV prevalence among 116,052 women in Australia’s renewed cervical screening program: a new tool for monitoring vaccine impact. Vaccine 2019; 37: 412–416. Available from: https://pubmed.ncbi.nlm.nih.gov/30551987/
3. Machalek D, Roberts J, Garland SM, et al. Routine cervical screening by primary HPV testing: Early observations from the renewed National Cervical Screening program, Medical Journal of Australia 2019; 211(3):113. Available from: https://pubmed.ncbi.nlm.nih.gov/31168828/
4. Novakovic D, Cheng ATL, Zurynski Y, et al. A prospective study of the incidence of juvenile onset recurrent respiratory papillomatosis after implementation of a National HPV Vaccination Program, J. Infect. Dis. 2018; 217(2):208–212. Available from: https://pubmed.ncbi.nlm.nih.gov/29136168/
5. Australian Institute of Health and Welfare (AIHW) 2019. Analysis of cervical cancer and abnormality outcomes in an era of cervical screening and HPV vaccination in Australia. Cancer series no. 126. Cat. no. CAN 129. Available from: https://www.aihw.gov.au/reports/cancer-screening/analysis-of-cervical-cancer-and-abnormality/contents/table-of-contents
6. Brotherton JM, Budd A, Rompotis C, et al. Is one dose of human papillomavirus vaccine as effective as three? A national cohort analysis. Papillomavirus Research. Volume 8, December 2019, 100177. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6658930/
7. Drolet M, Benard E, Boily MC,, et al. Population-level impact and herd effects following human papillomavirus vaccination programmes: a systematic review and meta-analysis, Lancet Infect. Dis. 2015;15(5):565e80. Available from: https://doi.org/10.1016/S1473-3099%2814%2971073-4
8. Garland SM*, Brotherton JM*, Condon JR. et al. Human papillomavirus prevalence among indigenous and non-indigenous Australian women prior to a national HPV vaccination program. BMC Med 2011;9:104 (*co-first authors). Available from: https://doi.org/10.1186/1741-7015-9-104
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Interview with Elmar Joura
L Baandrup, P Valentiner-Branth, SK Kjaer. HPV Vaccination Crisis and Recovery: the Danish Case
B Huber, RBS Roden, R Kirnbauer. L2-Based Human Papillomavirus Vaccines: Current Status And Potential
M Drolet, M Brisson. Population-level Impact and Herd Effects of HPV Vaccination Programs in High-Income Countries: Real-life Data
M Kane, M Stanley. Pre-school HPV Immunization?
PM Kotulka, A Luxembourg, A Shaw. Challenges in HPV Vaccine Development and Supply
R Cameron, K Cuschieri, K Roy. Prevention of HPV Infection and Associated Disease Following Bivalent HPV Vaccination in Scotland
QY Yan, MJ González-Méndez, YL Qiao. Current Status of HPV Vaccine in China
L Xu, SM Garland, M Arbyn. Efficacy of HPV Vaccination To Prevent Vulvar and Vaginal Precancer
