HUMAN PAPILLOMAVIRUS VACCINES AND CERVICAL CANCER Virology The Human Papillomavirus (HPV) is a relatively small virus, belonging to the family Papillomaviridae, containing circular double-stranded DNA within a spherical shell (capsid). The viral capsid is composed of two proteins, the major L1 and the minor L2 protein. More than 170 HPV types have been identified based on the genetic sequence of the outer capsid protein L1. HPV can infect cutaneous epithelium (skin) and mucosal epithelium (e.g. cervical and other anogenital mucosae). Mucosal HPV types infect mucosal epithelium and can be designated as high-risk or low-risk genotypes according to their propensity for cancer development. Low-risk mucosal HPV genotypes, such as HPV6 and 11, cause genital warts and recurrent respiratory papillomatosis (RRP), whereas high-risk HPV genotypes, such as HPV16 and 18, cause squamous intraepithelial lesions that can progress to invasive squamous cell carcinoma. Rosette-like surface structures are pentamers each consisting of five molecules of L1. One molecule of L2 fits into the centre of each pentamer. Figure 1: Human Papillomavirus (Source: Illustration: adapted from Florence Gendre) Epidemiology Cervical cancer is the most prevalent HPV-related cancer, but HPV can also cause other anogenital cancers (vulvar, vaginal, penile and anal cancer), and head and neck cancers. Cervical cancer is the most common HPV associated cancer with 530 000 new cases per year. The global burden of cancer attributable to HPV other than cervical cancer (113 000 cases) is substantially lower than that of cervical cancer. HPV-related cancer in women is around 570000 new cases per year. HPV-related cancer in man is around 66 000 new cases per year. A persistent infection with high-risk HPV types is a prerequisite for the development of cervical cancer. Annually, there are an estimated 530 000 newly diagnosed cervical cancer cases, with 266 000 deaths globally, of which 85% occur in resource-constrained countries. 1 HPV vaccines
High-risk HPV types, such as HPV16 and 18 account for about 70% of all cervical cancer cases globally. A further 10-15% of cervical cancer cases can be attributed to HPV types 31, 33, 45, 52 and 58. Pathogenesis and Clinical Manifestations HPV is easily transmitted by skin-to-skin contact during sexual activity with an infected person. Up to 80% of women will acquire an HPV infection in their lifetime and 50% of these infections will be with a high-risk HPV type. HPV infection is often acquired within 5 years after sexual debut and peaks in the age group of 18-25 years. Most infections are asymptomatic and are cleared within 2 years. Only a fraction of women (persistent) infected with high-risk HPV types will develop cervical cancer. Figure 2: Progression to cervical cancer (figure courtesy of Dr B. Benninghoff) CIN: Cervical Intraepithelial neoplasia A persistent infection with a high risk or oncogenic HPV type is the necessary cause of cervical cancer. Factors that could be adding to the risk of developing a persistent HPV infection and cervical cancer include: smoking; high parity; long-term use of oral contraceptives; co-infections; immune-suppression. HIV-infected women have a higher prevalence of persistent HPV infection, often with multiple HPV types. They are at an increased risk of progression to high-grade CIN and cervical cancer as compared to women without HIV infection. Progression from infection to pre-cancerous lesions and cancer is usually a slow process, but can be rapid in women with immune-suppression. 2 HPV vaccines
Vaccines Current HPV vaccines are produced using recombinant technology, by inserting the L1 gene into a host (e.g. yeast or baculovirus), which then produces L1 proteins in abundance. These L1 proteins self-assemble into empty shells or virus like particles (VLPs). VLPs are similar in shape and size to the HPV virion, but do not contain viral DNA, and are therefore noninfectious and non-oncogenic. 5x 72 x Monomer Capsomer Capsid Figure 3: Schematic of development of Virus-Like Particles Three vaccines are currently on the market. The bivalent vaccine (Cervarix ) contains VLP antigens for HPV types 16/18. The quadrivalent vaccine (Gardasil ) contains VLP antigens for HPV types 16/18, as well as non-oncogenic HPV types 6/11 which cause genital warts. Crossprotection has been shown for the bivalent vaccine against HPV types 31/33/45; while the quadrivalent vaccine showed cross-protection against HPV31. The nine-valent HPV vaccine (Gardasil 9) contains VLP antigens for HPV types 6/11/16/18/31/33/45/52/58. More details on the respective HPV vaccines are summarised in Table 1. Table 1: Characteristics of three licensed HPV vaccines Characteristic Bivalent HPV vaccine Quadrivalent HPV vaccine Nine-valent HPV vaccine First licensed 2007 2006 2014 Protection Virus-like particle types (VLP) Protects against cervical neoplasia caused by HPV 16 & 18 Does not protect against genital warts Protects against cervical neoplasia caused by HPV 16 & 18 Protects against genital warts caused by HPV 6 & 11 Protects against cervical neoplasia caused by HPV 16, 18, 31, 33, 45, 52, 58 Protects against genital warts caused by HPV 6 & 11 16, 18 6, 11, 16, 18 6, 11, 16, 18, 31, 33, 45, 52, 58 L1 protein dose 20/20 µg 20/40/40/20 µg 30/40/60/40 µg 20/20/20/20/20 µg System for VLP L1 expression Adjuvant Trichoplusia ni Hi-5 insect cell line infected with L1 recombinant baculovirus ASO4 (500 µg aluminium hydroxide, 50 µg 3-O- deacylated-4 - monophosphoryl lipid A) Saccharomyces cerevisiae (yeast) expressing L1 AAHS (225 µg amorphous aluminium hydroxyphosphate sulfate) Saccharomyces cerevisiae (yeast) expressing L1 500 µg AAHS Administration Intramuscular Intramuscular Intramuscular 3 HPV vaccines
Vaccination schedule* Storage First licensed in 3-dose schedule: 0, 1, 6 months Currently recommended in a 2- dose schedule < 15 years of age +2 C to +8 C Freeze-sensitive First licensed in 3-dose schedule: 0, 2, 6 months Currently recommended in a 2- dose schedule < 15 years of age +2 C to +8 C Freeze-sensitive First licensed in 3-dose schedule: 0, 2, 6 months Currently recommended in a 2- dose schedule < 15 years of age +2 C to +8 C Freeze-sensitive * First licensed in a three-dose schedule. Now recommended in a two-dose schedule. More details are available in the text. The HPV vaccines were initially licensed in a three-dose schedule, to be administered intramuscularly at 0, 1 and 6 months (bivalent vaccine) and 0, 2 and 6 months (quadrivalent and nine-valent vaccines) respectively. The recommended target group is 9 to 14 year-old girls prior to becoming sexually active. Based on immunological non-inferiority data of a two-dose schedule compared to a three-dose schedule in young adult women in whom efficacy has been proven, a two-dose schedule has been approved for girls younger than 15 years of age. The three-dose schedule remains valid for girls older than 15 years of age or for high-risk groups such as immune-compromised individuals. All vaccines show high efficacy against the HPV types included in the respective vaccine. The quadrivalent and nine-valent vaccines also protect against genital warts. A high seroconversion rate is observed after vaccination. Antibody levels after vaccination are several times higher than those produced after natural infection. Antibody levels are higher in 9-15 year old girls as compared to 16-23 year old women, in whom efficacy has been observed. HPV vaccines have been found to be safe and well tolerated. Local reactions like pain, swelling and redness can occur, but are usually of short duration. Systemic adverse reactions could include fever, nausea, dizziness, fatigue, headache and myalgia. The vaccines can be safely administered with other paediatric and adolescent vaccines. The HPV vaccines can be administered to immune-compromised and HIV-infected individuals. The HPV vaccines are not recommended during pregnancy. Special features of HPV vaccination HPV vaccination programmes should focus on reaching girls prior to their sexual debut, with the aim of high coverage. The HPV vaccine is the first vaccine to face unique public health considerations and challenges involving an older target age group (9-14 year-olds instead of infants and young children), delivery platforms (the majority being school-based instead of primary health care facilities), involvement of multiple authorities at country level (Ministry of Health and Ministry of Education), socio-behavioural issues (gender issues as girls are being targeted, parental consent, and the stigma of HPV being a sexually transmitted infection) and health benefits (long delay of benefits as cervical cancer takes many decades to develop, hence it takes time to demonstrate control and impact). In view of the recommended age group, 9 to 14 years of age, the HPV vaccine could be delivered through school-based vaccination programmes. However, special attention needs to be given to reach out-of-school girls. Given the challenges in dealing with adolescents 4 HPV vaccines
who rarely attend primary health care facilities, the introduction of the HPV vaccine could be an entry point to deliver multiple interventions along with the HPV vaccine, to strengthen overall adolescent immunisation programmes and health services. Several health-related interventions could potentially be integrated with HPV vaccination programmes. Potential interventions alongside with HPV vaccination can be summarized in 4 categories: screening; information/skills building; commodity delivery; and delivery of other vaccines. Vaccination of males is not advocated for by WHO as a priority group especially in resourceconstrained settings. However, vaccinating males could provide benefits against HPV-related penile, anal, head and neck cancers in men. High vaccine coverage ( 80%) amongst girls prior to sexual debut should confer herd immunity to boys. In addition, expansion of the female vaccination cohort up to 18 year olds will be more cost-effective as compared to gender-neutral vaccination strategies. Mathematical modelling indicate that vaccinating the sex with the highest prevalence will reduce the population prevalence most effectively. The vaccines will impact on cancers caused by the HPV types contained in vaccine, with some cross protection against HPV types not contained in the vaccines. As no vaccine covers all HPV types, and to prevent disease in those who are not vaccinated, there is still a need for a screening programme. WHO recommendation WHO reiterates the importance of targeting HPV vaccination for girls aged 9-14 years, prior to initiation of sexual activity. A 2-dose schedule with an interval of at least 6 months between doses is recommended for girls under the age of 15 years (even for girls aged 15 or above at the time of the second dose). The recommended maximum interval should be no greater than 12-15 months. If for any reason the interval between the first and second doses is shorter than 5 months, then a third dose should be given at least 6 months after the first dose. The 3-dose schedule (0, 1-2, 6 months) remains recommended for girls above 15 years of age and for immune-compromised individuals, including those known to be HIV-infected. Further reading Einstein MH, Baron M, Levin MJ, Chatterjee A, Fox B, Scholar S et al. Comparative immunogenicity and safety of human papillomavirus (HPV)-16/18 vaccine and HPV- 6/11/16/18 vaccine: follow-up from months 12-24 in a phase III randomised study of healthy women aged 18-45 years. Human Vaccines 2011; 7 (12): 1343-58. Forman D, de Martel C, Lacey CJ, Soerjomataram I, Lortet-Tieulent J, Bruni L et al. Global burden of human papillomavirus and related diseases. Vaccine 2012;30 Suppl 5:F12-23. N. Broutet, N. Lehnertz, G. Mehl, A.V. Camacho, P. BLoem, V. Chandra-Mouli, J. Ferguson, B. Dick. Effective health interventions for adolescents that could be integrated with human papillomavirus vaccination programmes. Journal of adolescent health 2013; 53: 6-13. 5 HPV vaccines
J. Vandelaer & M. Olaniran. Using a school-based approach to deliver immunization Global update. Vaccine 2015; 33: 719 725. Markowitz LE, Tsu V, Deeks SL, Cubie H, Wang SA, Vicari AS, Brotherton JML. Human papillomavirus vaccine introduction the first five years. Vaccine 2012; 30S:F139- F148. World Health Organization. Human Papillomavirus Vaccines. WHO position paper. Weekly Epidemiological Record 2017; 92, 241-268. Last updated: March 2018 6 HPV vaccines