Published: 8 December 2016

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Gardasil 9 – The Next Generation Human Papillomavirus (HPV) Vaccine

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Prescriber Update 37(4): 52-53
December 2016

Gardasil 9, the next generation human papillomavirus (HPV) vaccine, provides protection against the four HPV subtypes found in Gardasil (HPV 6, 11, 16 and 18) and an additional five subtypes (HPV 31, 33, 45, 52 and 58).

HPV infection

HPV is the most common sexually transmitted infection worldwide. The lifetime risk for HPV infection is greater than 50%. Most HPV infections are asymptomatic and 90% of HPV infections are cleared within 24 months¹.

Infection with one of the numerous low-risk HPV types may result in genital warts. Infection with high-risk types can cause cancer, particularly in the 10% of infections that are not cleared. The risk of cancer is increased with smoking and infection with multiple cancer-causing HPV subtypes¹.

The different cancer types where at least some cases can be associated with HPV infection and the incidence rate in New Zealand are shown in Table 1.

Table 1: New Zealand cancer registrations in 2013²

Cancer	Incidence per 100,000 per year	Number of registrations 2013
Cervical cancer	6.3 (Mortality rate 1.4)	158
Vulvar cancer	1.5	56
Vaginal	0.7	23
Penile	0.6	19
Anal	1.0 in men, 1.2 in women	32 in men, 38 in women
Oropharyngeal	0.4 in men, 0.1 in women	11 in men, 5 in women
Tonsil	1.6 in men, 0.3 in women	48 in men, 9 in women

Infection with HPV can be avoided by vaccinating with the HPV vaccine and/or using condoms. Although there is a screening programme for cervical cancer, there are no screening programmes for other cancers caused by HPV infection. The screening programme is not 100% effective, and women still die from cervical cancer (Table 1).

The prevalence of different subtypes of HPV varies between regions. For Australia and New Zealand, 86.5% of HPV-induced cervical cancer is caused by the HPV subtypes included in the Gardasil 9 vaccine¹.

Efficacy of Gardasil 9

Gardasil 9 was approved for use in New Zealand based on clinical studies which included more than 15,000 subjects who received at least one dose of Gardasil 9^{3,4,5,6,7,8,9}. Medsafe’s assessment of these studies has been published (www.medsafe.govt.nz/publications/OIAContents.asp).

In the pivotal study, Gardasil 9 was compared with Gardasil using a three-dose regimen in females aged 16 to 26 years³. Gardasil was used as the comparator since it would have been unethical to use a placebo. The study was conducted at multiple sites, including sites in New Zealand. Gardasil 9, like Gardasil, is only effective if given prior to first sexual contact/exposure to HPV. Therefore, the results of this study were analysed according to whether there was evidence that the clinical trial subjects were HPV-uninfected. The incidence of high-grade cervical, vulvar and vaginal disease in the HPV-uninfected group was 2.4 per 1,000 person-years in the Gardasil 9 group and 4.2 per 1,000 person-years in the Gardasil group³.

The efficacy results from the pivotal study were extrapolated (immunologically bridged) to younger girls and boys^4,5. Gardasil may also be administered at the same time as meningococcal and Tdap vaccines^6,8.

The immunogenicity of Gardasil 9 in females who had already been vaccinated with Gardasil was also assessed⁷. In this study, saline was used as the placebo comparator. The frequency of injection site reactions was 9.1 in every 10 subjects given Gardasil 9 and 4.4 in every 10 subjects given the placebo. The frequencies of systemic adverse events were 3.1 in every 10 of the Gardasil 9 subjects and 2.6 in every 10 of the placebo group⁷.

The immunological response to a two-dose schedule of Gardasil 9 has also been investigated in a non-inferiority trial. Two timing intervals were assessed at 6 months and 12 months. Non-inferiority was demonstrated for both time points. Antibody titres were higher when the two doses were separated by a period of 12 months rather than 6 months¹⁰.

The long-term efficacy of Gardasil 9 is still to be determined. Of interest, studies on Gardasil have now reported data for up to nine years since vaccination with no decrease in efficacy¹¹.

Safety of Gardasil 9

An integrated safety analysis of all the clinical studies has been published¹². The most common adverse events were injection site reactions, headache and pyrexia. Twenty of the 15,875 subjects given Gardasil 9 discontinued the vaccination course because of an adverse event. Recent safety concerns with Gardasil have focused on postural orthostatic tachycardia syndrome (POTS) and complex regional pain syndrome (CRPS). Two subjects were diagnosed with POTS, one did not have recurrent episodes, and in the other subject, the events occurred more than three years after vaccination. The two cases of CRPS were attributed to a previous injury.

Other concerns have been raised regarding the use of Gardasil. It has been suggested that vaccination with HPV vaccine may promote promiscuity. Several studies have been conducted, and to date, none has reported any change in sexual behaviour after vaccination^13,14.

Overall, Gardasil 9 has improved efficacy, and the safety profile is consistent with that for Gardasil. There was an increase in the number of injection site reactions compared to Gardasil, but this is expected as the vaccine contains an increased number of antigens.

Please continue to report all suspected adverse reactions to CARM (https://nzphvc.otago.ac.nz/).

References

1. Zhai L, Tumban E. 2016. Gardasil-9: A global survey of projected efficacy. Antiviral Research. 130: 101-109.
2. Ministry of Health. 2013. New cancer registrations 2013. 02 December 2015. URL: www.health.govt.nz/publication/new-cancer-registrations-2013 (accessed 17 October 2016).
3. Joura E, Giuliano A, Iversen O, et al. 2015. A 9-valent HPV vaccine against infection and intraepithelial neoplasia in women. The New England Journal of Medicine. 372(8): 711-723.
4. Van Damme P, Olsson SE, Block S, et al. Immunogenicity and safety of a 9-valent HPV vaccine. Pediatrics. 136(1): e28-39.
5. Van Damme P, Meijer C, Kieninger D, et al. 2016. A phase III clinical study to compare the immunogenicity and safety of the 9-valent and quadrivalent HPV vaccines in men. 34(35): 4205-4212.
6. Schilling A, Parra M, Gutierrez M, et al. 2015. Coadministration of a 9-valent human papillomavirus vaccine with meningococcal and Tdap vaccines. 136(3): e563-572.
7. Garland S, Cheung T, McNeill S, et al. 2015. Safety and immunogenicity of a 9-valent HPV vaccine in females 12-26 years of age who previously received the quadrivalent HPV vaccine. Vaccine. 33(48): 6855-6864.
8. Kosalaraksa P, Mehlsen J, Vesikari T, et al. 2015. An open-label, randomized study of a 9-valent human papillomavirus vaccine given concomitantly with diphtheria, tetanus, pertussis and poliomyelitis vaccines to healthy adolescents 11-15 years of age. The Pediatric Infectious Disease Journal. 34(6): 627-634.
9. Vesikari T, Brodszki N, Van Damme P, et al. 2015. A randomized, double-blind, phase III study of the immunogenicity and safety of a 9-valent human papillomavirus L1 virus-like particle vaccine (V503) versus Gardasil in 9–15-year old girls. The Pediatric Infectious Disease Journal. 34(9): 992-998.
10. Merck Sharp & Dohme. 2016. Gardasil 9 New Zealand Data Sheet. 27 June 2016. URL: www.medsafe.govt.nz/profs/Datasheet/g/gardasil9inj.pdf (accessed 17 October 2016)
11. Nygard M, Saah A, Munk C, et al. 2015. Evaluation of the long-term anti-Human Papillomavirus 6 (HPV6), 11, 16, and 18 immune responses generated by the quadrivalent HPV vaccine. Clinical and Vaccine Immunology. 22(8): 943-948.
12. Moreira E, Block S, Ferris D, et al. 2016. Safety profile of the 9-Valent HPV vaccine: a combined analysis of 7 phase III clinical trials. Pediatrics. 138(2).
13. Handler NS, Handler MZ, Majewski S, et al. 2015. Human papillomavirus vaccine trials and tribulations: Vaccine efficacy. Journal of the American Academy of Dermatology. 73(5): 759-767.
14. Forster AS, Marlow LA, Stephenson J, et al. 2012. Human papillomavirus vaccination and sexual behaviour: cross-sectional and longitudinal surveys conducted in England. Vaccine. 30(33): 4939-4944.