Contents

9 Human papillomavirus (HPV)

9.4 Vaccines

9.4.1 Available vaccines

Two HPV vaccines are approved for use (registered) and are available for distribution (marketed) in New Zealand: HPV9 (Gardasil 9, Seqirus/MSD) and HPV4 (Gardasil, Seqirus/MSD).

Both vaccines are registered for use in females aged 9–45 years and in males aged 9–26 years. HPV9 is registered as a two- or three-dose schedule in individuals aged 14 years and under, and as a three-dose schedule in older individuals. HPV4 is registered as a three-dose schedule for all age groups, but may be used as a two-dose schedule for those aged 9–14 years.

Both vaccines contain HPV virus-like particles (VLPs), which are composed of the L1 protein (a component of the virus outer layer) aggregated into clumps that mimic the outer structure of the HPV virion. The VLPs do not contain viral DNA and are incapable of causing infection. The L1 proteins are produced by genetically engineered yeast cells.

Funded HPV vaccines

Each 0.5 mL dose of HPV9 vaccine (Gardasil 9, Seqirus/MSD) contains:
  • 30 µg of HPV6 L1 VLP, 40 µg of HPV11 L1 VLP, 60 µg of HPV16 L1 VLP, 40 µg of HPV18 L1 VLP, 20 µg of HPV31 L1 VLP, 20 µg of HPV33 L1 VLP, 20 µg of HP45 L1 VLP, 20 µg of HPV52 L1 VLP, and 20 µg of HPV58 L1 VLP
  • 500 µg of aluminium hydroxyphosphate sulphate.
Each 0.5 mL dose of HPV4 vaccine (Gardasil, Seqirus/MSD) contains:
  • 40 µg of HPV16 L1 VLP, 20 µg of HPV18 L1 VLP, 20 µg of HPV6 L1 VLP and 40 µg of HPV11 L1 VLP
  • 225 µg of aluminium hydroxyphosphate sulphate.
The vaccines do not contain any preservative or antibiotics.

9.4.2 Efficacy and effectivenessTop

The efficacy (protection against HPV-related disease) of HPV vaccines can only be studied in older age groups due to the sexual naivety of the younger age group that is the main target for vaccination. Immunological bridging is therefore used to infer efficacy in the younger age group, that is, by comparing the antibody responses (immunogenicity) between the younger and older age groups. Because the antibody responses are non-inferior to those seen in older age groups, efficacy is inferred for the younger age group.

Immunogenicity

Although there is no known correlate of protection (that is, the antibody level required for protection against HPV-related disease), HPV vaccines generate good antibody responses in most recipients.

HPV4

Immunisation with three doses of HPV4 vaccine produces antibody responses against HPV16, HPV18, HPV6 and HPV11 in more than 99 percent of vaccine recipients. The height of the antibody titres following three doses of HPV vaccine is greater than that following natural infection.

Differences in seroconversion rates and antibody titres were seen in immunocompromised individuals. The immune response to HPV4 among immunocompromised children appears adequate, 33, 34 although antibody titres were lower than those in healthy children of the same age groups.33 Seroconversion among HIV-infected individuals has been demonstrated to be robust and higher among those with lower HIV loads or on antiretroviral therapy.35, 36, 37 While some immunosuppression regimes can attenuate the immune response to HPV4, patients with autoimmune diseases generally appear to respond well to the vaccine.38 In contrast, adult solid organ transplant recipients produce suboptimal responses to HPV4.39

The immunogenicity of three doses of HPV4 vaccine has been established to be robust and long-lasting.40, 41, 42 Anamnestic responses have been demonstrated out to 8.5 years.

Two doses of HPV4 are more immunogenic in recipients aged between 9–15 years than older age groups and comparable to three doses in older recipients.43 In young females, two doses have been found to be non-inferior to three doses, particularly when the interval between doses is at least six months.44

HPV9

The immunogenicity of HPV9 was initially assessed in women aged 16–26 years.45 Antibody responses generated by the HPV9 vaccine to HPV types 6, 11, 16 and 18 were non-inferior to those generated by the HPV4 vaccine. HPV9 has also demonstrated non-inferiority to HPV4 in girls and boys aged 9–15 years.46

Antibody responses to all nine vaccine HPV types in girls and boys aged 9–15 years and men aged 16–26 years were non-inferior to women aged 16–26 years.47, 48

Men who have sex with men appear to produce lower antibody titres than heterosexual men (although seroconversion rates to all nine vaccine types were greater than 99 percent in both groups).47 This lower antibody response is possibly due to greater exposure to the virus, highlighting the importance of vaccination at a young age.

The immunogenicity of two doses of HPV9 in girls and boys aged 9–14 years was compared with three doses in women aged 16–26 years,49 the age group in which efficacy was demonstrated. Antibody responses in girls and boys after two HPV9 doses were non-inferior to the antibody responses in women who received three doses.

Efficacy

HPV-related cancers

No studies have yet been undertaken to look for protection against invasive cervical cancer because these would require extremely long periods of follow-up and because study participants who develop precancerous lesions (CIN2/3 or adenocarcinoma in situ) require treatment to prevent progression to invasive cancer. However, protection against CIN2/3 or adenocarcinoma in situ is widely accepted as a surrogate for protection against invasive cancer. Bivalent and quadrivalent HPV vaccines have been shown to be highly effective in preventing these HPV16- and 18-related precancerous lesions in females.2, 50 In the pivotal efficacy trial in women aged 15–26 years,51 HPV4 vaccine efficacy for the prevention of precancerous lesions related to HPV16 or HPV18 was 98 percent (95% CI: 26–58) in the per-protocol susceptible population.

Studies in males, including men who have sex with men, have shown that HPV4 vaccine is efficacious against anal HPV infection and associated precancerous lesions.52, 53, 54

HPV9 efficacy was studied in women aged 16–26 years and compared with HPV4.45 HPV9 prevented cervical, vulvar and vaginal disease and persistent infection related to HPV types 31, 33, 45, 52 and 58 (the five additional serotypes in HPV9). The antibody response and incidence of disease related to HPV types 6, 11, 16 and 18 was similar in the two vaccine groups.

Effectiveness

A 2016 systematic review of literature55 summarised the global experiences with HPV4 from the literature published from 1 January 2007 to 29 February 2016. It assessed the global effect of HPV4 vaccine on HPV infection, genital warts and cervical abnormalities based on 57 publications across nine countries. The greatest impact was seen in countries with high vaccine uptake and among girls vaccinated prior to HPV exposure. Maximal reductions of around 90 percent were reported for vaccine-type HPV infections (6, 11, 16, 18) and genital wart cases.

Duration of protection

As vaccination programmes have only been in place for a maximum of ten years, the duration of protection is not yet known. Follow-up studies 8–10 years after HPV vaccination have shown no waning of protection.2 Long-term studies are ongoing to determine the duration of efficacy for all HPV vaccines.

Herd immunity

Australia has seen a reduction in the prevalence of vaccine-type HPV infections (6, 11, 16, 18) in unvaccinated young men after the introduction of the vaccine to young women, supporting the role of herd immunity.56, 57, 58 There was also a significant decrease in the prevalence of vaccine-type HPV infections in unvaccinated women (aged 25 years or younger).59

In a study of data from a sexual health clinic in Melbourne,58 the researchers noted the near disappearance of genital warts in women and heterosexual men aged under 21 years. In addition, the data indicated that the basic reproductive rate (see section 1.1.1) had fallen below one. This reduction in cases occurred without any corresponding reduction in women aged over 30 years, men who have sex with men and non-residents. Similar trends were noted in the data from the Australian genital warts national surveillance network.

Previous exposure to HPV

While efficacy is unclear, there are no safety concerns in offering vaccination to women who have had HPV-related disease and would like to use the vaccine to reduce the risk of further disease.

A retrospective analysis of the HPV4 vaccine’s pivotal efficacy trial data (Future I and Future II) studied a group of women who were vaccinated before they had their first treatment for HPV-related disease.60 This showed a reduction in subsequent HPV-related disease in vaccinated women aged 15–26 years who had received treatment for cervical, vulvar or vaginal disease during the trial. The study showed a 46.2 percent reduction (95% CI: 22.5–63.2) after cervical surgery of any HPV-related disease and 35.2 percent reduction (95% CI: 18.8–51.8) after diagnosis of genital warts or vaginal or vulvar disease.

In contrast, a systematic review61 explored efficacy against CIN3+ precancers in women with evidence of prior vaccine-type HPV exposure in three randomised controlled trials and two post-trial cohort studies and showed no evidence that HPV vaccines were effective in preventing vaccine-type HPV-associated precancer in pre-exposed women. Despite these findings, it was concluded that longer-term benefits in preventing re-infection could not be excluded.

International recommendations

The World Health Organization recommends a two- or three-dose HPV4 schedule for individuals aged under 15 years and a three-dose schedule for older individuals.62

HPV9 was registered for use as a two- or three-dose schedule for individuals aged under 15 years and a three-dose schedule for older individuals by the European Medicines Agency63 in June 2015 and by the New Zealand Medicines and Medical Devices Safety Authority (Medsafe) in July 2016.

9.4.3 Transport, storage and handlingTop

Transport according to the National Standards for Vaccine Storage and Transportation for Immunisation Providers 2016.64 Store in the dark at +2oC to +8oC. Do not freeze.

9.4.4 Dosage and administrationTop

The dose of HPV vaccine is 0.5 mL, administered by intramuscular injection in the deltoid area (see section 2.3).

Co-administration with other vaccines

HPV vaccine may be co-administered with any live or inactivated vaccine indicated at the same visit.2

Interchangeability

All HPV vaccines may be used interchangeably for completion of a course.65