Gardasil®9 became available in Australia from the 1st January, 2018. Compared to the quadrivalent vaccine, the nonavalent Gardasil®9 vaccine will protect against an additional five strains of human papillomavirus (HPV).
HPV is associated with a large burden of malignant and non-malignant disease primarily affecting the anogenital area and aerodigestive tract of men and women. There are more than 100 types of HPV, around 40 of which are responsible for infections of the genital tract. The majority of HPV infections are asymptomatic and resolve spontaneously within 12 to 24 months. However, an estimated 3% to 10% of HPV infections persist and may cause abnormalities that can progress to cancer. High-risk genital HPV types include types 16 and 18. These types can cause cancer of the cervix as well as some vaginal, vulval, penile, and anal cancers. Low-risk genital HPV types such as 6 and 11 can cause genital warts.
HPV vaccines are often referred to as “cervical cancer vaccines” and were originally only promoted for use in females. This reflects the significance of HPV infection in the development of cervical cancer. It is reported that virtually all cases of cervical cancer can be attributed to HPV infection. Just two HPV types, type 16 and 18, are responsible for 70% of cervical cancers. The remaining 30% of cases are due to 13 other high-risk HPV types.
The bivalent vaccine, Cervarix® boasts an impressive efficacy against HPV types 16 and 18. A long-term follow-up study demonstrated a 95.6% efficacy against incident infection and a 100% efficacy against persistent infection at both six months and twelve months. In addition, all participants in the active arm remained seropositive to HPV types 16 and 18 with respective antibody titers 7.7-fold and 4.0-fold higher than levels provoked by natural infection.
The quadrivalent vaccine, Gardasil® also offers protection against HPV types 6 and 11. While these types are classified as low-risk, they are responsible for around 95% of genital warts in males and females and can also cause respiratory papillomatosis. The efficacy of quadrivalent Gardasil® has been well studied since its release over ten years ago. This vaccine is highly effective in preventing persistent infection with HPV types 6, 11, 16, and 18; cervical, vulval, vaginal, and anal disease; and genital warts. A study of Australian women aged 18-24 years demonstrated a 76% reduction in infection with these four types after administration of one or more vaccine doses; efficacy increased to 86% when three doses were given. This translates to real-world benefits with a 92.6% reduction in the diagnosis of genital warts observed in Australian women under 21 years of age in the four years following the introduction of the quadrivalent HPV vaccine. Reductions in the incidence of HPV infections were noted in unvaccinated populations, possibly reflecting herd immunity.
The progression from HPV infection to invasive disease is usually very slow. Therefore, the absolute benefits of HPV vaccination programs may not be apparent for some time. However, emerging data demonstrate a significant reduction in the incidence of high-grade cervical lesions detected in vaccinated women. One study showed significant vaccine efficacy for the prevention of cervical intraepithelial neoplasia 2, 3, and adenocarcinoma in situ (CIN2+) attributed to HPV types 16 and 18. Compared to unvaccinated women, the proportion of CIN2+ attributed to HPV types 16 and 18 was 72% lower in women who had initiated vaccination 48 months or more before their diagnosis of CIN2+.
Although Gardasil® was originally only included on the National Immunisation Program (NIP) for females, it was extended to include males in 2013. HPV infection is common in males and can result in genital warts as well as anal, penile, and oropharyngeal cancer. A gender-neutral initiative like the Australian National HPV Vaccination Program delivers the greatest overall benefits in terms of reduced disease burden in both sexes and lower rates of transmission.
The newly registered Gardasil®9 provides the most comprehensive protection against HPV infection of all three vaccines. A large, double-blind, randomised study demonstrates that this nonavalent vaccine delivers similar protection against infection and disease due to HPV types 6, 11, 16, and 18 when compared with the quadrivalent vaccine. The efficacy of the nonavalent vaccine against the additional HPV types was also investigated. The incidence of persistent infection with these virus types was found to be 2.1 per 1000 person-years in the group receiving the nonavalent vaccine compared to 52.4 per 1000 person-years in the population receiving the quadrivalent vaccine. Studies suggest that the nonavalent vaccine has the potential to prevent approximately 90% of all cervical cancers and 80% of high-grade cervical dysplasia. This high efficacy matches or exceeds the efficacy of most cervical cancer screening programs. The relevance of the additional coverage provided by this new vaccine is summarised in Table 1.
Table 1. Estimated worldwide contribution of HPV types to HPV-related disease
|Estimated contribution of HPV types to disease|
|HPV-related condition||HPV types in quadrivalent vaccine||HPV types in 9-valent vaccine|
|High-grade cervical pre-cancers||50%||80%|
|Low-grade cervical lesions||25%||50%|
HPV vaccines do not treat HPV infection or HPV-associated disease such as cancer or genital warts. It is, therefore, preferable to administer these vaccines to adolescents before they become sexually active and potentially exposed to HPV. For this reason, HPV vaccines are provided under the NIP to school students between 10 and 15 years of age. Individual State and Territory Health Departments can provide further advice on the timing of vaccination initiatives.
A summary of the key differences between the three HPV vaccines is shown in Table 2.
Table 2. A comparison of TGA-registered HPV vaccines
|Gardasil® 9 (new)||Gardasil® (original)||Cervarix®|
|HPV types covered||6, 11, 16, 18, 31, 33, 45, 52, and 58||6, 11, 16, and 18||16 and 18|
|Indication||Prevention of HPV infection and related cancers and non-cancerous lesions in males and females||Prevention of HPV infection and related cervical cancer in females|
|Suggested dosing schedule||9-14 years of age: 2 doses*||3 doses||10-15 years of age: 2 doses|
|15-26 years of age: 3 doses||80%||15-45 years of age: 3 doses|
*Studies demonstrate that two doses (administered at 0 and 6 months) provide effective protection for children aged 9-14 years. If the second dose is administered sooner than 5 months after the first dose, the manufacturer recommends a 3-dose schedule in this age group.
The safety of Gardasil® has been extensively studied, with over 205 million doses distributed worldwide as of December 2015. This vaccine, like the other HPV vaccines, does not contain live virus and is, therefore, unable to initiate infection. The vaccine is composed of immunogenic virus-like particles that trigger an immune response without the concern of introducing oncogenic viral DNA. Studies comparing the safety of the quadrivalent and nonavalent vaccines found a higher incidence of local injection site reactions in trial participants receiving the nonavalent vaccine (90.7%) compared to the quadrivalent vaccine (84.9%). These reactions include pain, swelling, erythema, and pruritus. However, the majority of these reactions were documented to be mild to moderate in intensity. This study also found that the incidence of systemic adverse events was very similar for the two vaccines, 55.8% in the nonavalent group and 54.9% in the quadrivalent group. The most common systemic adverse events reported included headache, pyrexia, nausea, dizziness, and fatigue.
The safety of these vaccines continues to be monitored carefully to identify any potential side effects not initially recognised at the time of registration. The European Medicines Authority(EMA) recently conducted a review of HPV vaccines (including Cervarix®, Gardasil®, and Gardasil9®) due to individual case reports suggesting a possible association with chronic regional pain syndrome (CRPS) and postural orthostatic tachycardia syndrome (POTS). This in-depth review found no evidence of an increased incidence of CRPS and POTS in vaccinated girls compared to non-vaccinated girls. The EMA concludes that the evidence does not support a causal link between HPV vaccines and the development of these conditions.
The long-term efficacy of the nonavalent vaccine is yet to be established due to the limited duration of follow-up studies. However, no evidence of waning immunity has been observed in long-term cohorts vaccinated with the quadrivalent vaccine. This suggests that the new nonavalent vaccine may also provide durable protection.
It is anticipated that universal vaccination with a nonavalent HPV vaccine could virtually eradicate genital warts and recurrent respiratory papillomatosis and significantly reduce the incidence of HPV-related cancers. As with previous HPV vaccines, the nonavalent vaccine does not protect against all virus types that cause cervical cancer. It is, therefore, imperative that women continue to participate in cervical screening programs regardless of their vaccination status. The test performed under the National Cervical Cancer Screening Program changed on the 1st of December, 2017. The Pap test, used to detect changes in cervical cells, has been replaced with a test to detect the presence of HPV. Women are due for this new test two years after their last Pap test. The results of this test will determine how patients are managed. For women whose tests reveal no presence of oncogenic HPV, a repeat test in five years can be offered rather than the usual two years for a Pap test. Samples that test positive for oncogenic HPV will have reflex cytology testing to detect any cellular abnormalities. Further information on risk stratification and repeat screening recommendations are available from the Department of Health.
- Ali H, Donovan B, Wand H, Read TR, Regan DG, Grulich AE, et al. Genital warts in young Australians five years into national human papillomavirus vaccination programme: national surveillance data. BMJ. 2013; 346: f2032.
- De Vincenzo R, Conte C, Ricci C, Scambia G, Capelli G. Long-term efficacy and safety of human papillomavirus vaccination. Int J Womens Health. 2014; 6: 999-1010.
- European Medicines Agency. Assessment Report: Review under Article 20 of Regulation (EC) No 726/2004; Human papillomavirus (HPV) vaccines. London: EMA; 2015.
- Garland SM, Kjaer SK, Muñoz N, Block SL, Brown DR, DiNubile MJ, et al. Impact and effectiveness of the quadrivalent human papillomavirus vaccine: a systematic review of 10 years of real-world experience. Clin Infect Dis. 2016; 63(4): 519-27.
- Hariri S, Bennett NM, Niccolai LM, Schafer S, Park IU, Bloch KC, et al. Reduction in HPV 16/18-associated high grade cervical lesions following HPV vaccine introduction in the United States – 2008–2012. Vaccine 2015; 33(13): 1608-13.
- Joura EA, Giuliano AR, Iverson OE, Bouchard C, Mao C, Mehlsen J, et al. A 9-Valent HPV vaccine against infection and intraepithelial neoplasia in women. N Engl J Med. 2015; 372: 711-23.
- National Centre for Immunisation Research & Surveillance. Human papillomavirus (HPV) vaccines for Australians: information for immunisation providers. NCIRS: Westmead; 2016.
- Naud PS, Roteli-Martins CM, De Carvalho NS, Teixeira J, De Borba PC, Sanchez N, et al. Sustained efficacy, immunogenicity, and safety of the HPV-16/18 AS04-adjuvanted vaccine. Hum Vaccin Immunother. 2014; 10(8): 2147-62.