HPV VACCINES

Human papillomavirus vaccines

Both vaccines contain viral-like particles (VLPs) which are composed of the L1 protein (component of the virus outer layer). The vaccines do not contain viral DNA and cannot cause infection. HPV4 contains VLPs for HPV types 6, 11, 16 and 18, and HPV9 contains VLPs for 6, 11, 16, 18, 31, 33, 45, 52 and 58.

HPV9 has similar high efficacy against genotypes 6, 11,16 and 18 and it is 97% efficacious against the five additional genotypes included in the formulation.

Schedules and dosing

The number of doses depends on age. The vaccine is more effective at a younger age. Those aged 9-14 inclusively require two doses and those older, or in a high risk group (see later), require three doses.

The routine NZ HPV immunisation schedule from 2017 consists of two doses of HPV9 given at 0, and 6-12 months by injection (a minimum of 6 months between the first and second dose). A missed dose does not require the schedule to be restarted.(174,175)

Persons over the age of 14 years should receive a three-dose schedule.(176,177) There is flexibility in the three-dose schedule, provided the minimum interval between the first and last dose is four months.

Vaccine effectiveness

A 2016 systematic review of literature published from 1 January 2007 to 29 February 2016 summarised the global experiences with HPV4. The global effect of HPV4 vaccine on HPV infection, genital warts and cervical abnormalities based on 57 publications across nine countries were reviewed. The greatest impact was seen in countries with high vaccine uptake and among girls vaccinated prior to HPV exposure. Reductions of up to 90% were reported for vaccine-type HPV infections (HPV 6/11/16/18) and genital warts.(178)

HPV4 vaccine is highly efficacious. In the pivotal efficacy trials HPV4 demonstrated high levels of efficacy against persistent disease and other endpoints in both males and females.(179-182)

Since HPV vaccine has been both widely recommended and introduced in many countries it is no longer ethical to conduct placebo-controlled trials with these vaccines.

HPV9 efficacy is non-inferior to HPV4 and extends protection against five additional genotypes. It was assessed alongside the HPV4 comparator in 14,215 women aged 16 to 26 years in a double-blind, phase 2b-3 trial. Participants received either three doses of HPV4 or three-doses of HPV9 at 0, 2 and 6 months. In the per-protocol efficacy population, the incidence rate of high-grade disease related to HPV-31, 33, 45, 52, and 58 (the five additional HPV9 genotypes) was 0.1 per 1000 person-years in the HPV9 group and 1.6 per 1000 person-years in the HPV4 group (1 case vs. 30 cases). HPV9 efficacy was 96.7% (80.9 to 99.8).(183)

There is a range of variables that affect the effectiveness of a vaccine programme and therefore the reported effectiveness in different countries varies. However the positive association between vaccine coverage and effectiveness is clear and consistent.

Vaccine effectiveness, and its impact on disease become evident over time as they can only be measured after a vaccination programme has been implemented. Cancer endpoints cannot be measured for years after the vaccine has been introduced whereas

changes in genital warts epidemiology are evident almost immediately.

Among the cohorts eligible for vaccination and where coverage is highest HPV vaccination programmes are associated with significant reductions in the prevalence of vaccine-type HPV. In countries with high HPV vaccine coverage, such as Australia and Denmark, there has been a profound reduction in the number of genital wart cases. Data from Australia suggest elimination is possible. However countries with more moderate coverage, such as New Zealand, have also observed significant reductions.

The impact of HPV immunisation programmes on the incidence of cervical dysplasia is now evident across multiple countries. Early evidence of declines in cervical dysplasia is associated with the vaccine eligible cohorts. Younger women have the strongest evidence of protection after partial doses.(178)

Herd immunity has been observed and is evident for persistent infection, incidence of genital warts and cervical dysplasia.

In pivotal efficacy trials among males that included 4,065 boys and men aged 16-26 years, HPV4 also demonstrated high efficacy against all endpoints, as well as effectiveness in reducing the risk for subsequent HPV related disease.(184) Endpoints measured were external genital lesions and persistent infection. Among MSM enrolled in the study there was 94.9% (95% CI 80.4–99.4) per-protocol efficacy against anal infection and associated anal intraepithelial neoplasia (AIN).

Duration of protection

The vaccines are highly immunogenic.(185) HPV vaccines induce robust immunological memory and mathematical modelling suggests that protection from vaccination is likely to be sustained long-term.(186,187) To date, stable protective efficacy from the HPV vaccines has been demonstrated to 10 years and long-term follow-up studies support this.(188-190) We turn to postlicensure effectiveness studies to monitor the ongoing performance of vaccines.

Effectiveness against genital warts

Evidence shows that high HPV4 vaccination coverage has been associated with dramatic reductions in the diagnosis of genital warts. Australia has published 11 studies on the impact of HPV vaccination on genital warts.(191-195) Reductions in inequities are also evidence with reductions similar in Indigenous females, and the relative reduction across different levels of disadvantage similar.(196) Australian data also suggest elimination is possible. There have been no cases of genital warts diagnosed in women under 21 years reported as being vaccinated.(197)

Other countries to have reported significant declines in genital warts include Denmark and Sweden.(197-199)

New Zealand introduced HPV4 (Gardasil) in 2008. Data from Auckland in 2010 and again in 2013 shows a steady decline, 63% and 83% respectively, in the rate of genital warts.(200) Nationally the rates of reported new cases of genital warts have declined from 4,299 in 2008 to 1,659 in 2015, a 61% reduction.(201)

Human papillomavirus immunisation in special groups

Immunosuppressed patients

Immunosuppressive conditions are associated with a higher risk for HPV-associated disease.

Immunogenicity of HPV vaccine in adult solid organ transplant patients is suboptimal when the vaccine is administered early after transplant, and depends upon the type of transplant and immunosuppression.(202) However, limited data suggest seroconversion among adolescent kidney and liver transplant patients indicating good immune response.(203)

HPV vaccine has been demonstrated to be immunogenic in HIV-infected men (204) and women.(205)

Females aged 9–26 years on immunosuppressive therapy for inflammatory bowel disease developed antibody responses similar to healthy females.(206)

When vaccinating immunosuppressed patients a three-dose schedule should be used regardless of age.

Frequently Asked Questions

Can the vaccine be given to people who are already sexually active or already have HPV infection?

• Yes. HPV vaccine can be offered to people who have HPV and would like to use the vaccine to reduce the risk of further acquisition of new HPV or further disease.
• The decision to vaccinate older age groups or those already sexually active should be based on the individuals’ assessment of potential benefit and future risk.
• Vaccine protects against the HPV genotypes which a person has not previously encountered.

Limited data in women shows that vaccination may help to prevent recurrence or reactivation of HPV infection. The therapeutic benefit of vaccine in the context of existing external warts or other HPV disease is anecdotal only.(207,208)

Can people be tested for infection before getting vaccinated?

There is no test to determine the HPV status of a person. Blood serology is not reliable and ‘swabs’ cannot be used for this purpose. Current HPV DNA testing is only used to detect particular high-risk types in order to guide clinical management in cervical screening, so cannot be used as a screening test for ”all HPV” types.

Does natural infection induce protective immunity?

Not always. Current evidence suggests that overall naturally acquired immunity is unlikely to be effective because of the ability of the virus to evade the immune system, but this does not appear to be the case with vaccine derived immunity.

Naturally acquired immunity to reinfection: Seroresponse to natural infection varies depending on the anatomical site infected and the individual themselves. There is some evidence that there is a reduced risk of reinfection with the same HPV type, but not against other types (no cross-protection).

Naturally acquired immunity to persistent infection: Once an infection has become established, resolution is largely dependent on innate and cell-mediated immunity. Reactivation of previously latent infection has commonly been observed in women who become immunosuppressed.

Naturally acquired immunity to tumorigenesis: As natural immunity is very slow to develop, CIN can develop during the period of persistent infection.(209-213)

Will cervical screening still be needed?

Yes. Irrespective of whether a woman has been vaccinated, routine cervical screening will need to continue for the foreseeable future. This is because of possible prior infection with HPV types causing CIN, or new infection with other HPV types not covered by vaccination.

What if the vaccine is given to a pregnant woman?

These vaccines are not specifically recommended for use in pregnancy at this time. However, enquiry about possible pregnancy is not required before vaccination. Completion of the vaccine course should be deferred if a woman is found to be pregnant. However, there are no safety concerns with the use of non-live vaccines in pregnant women and a number are routinely recommended in this group. Also, there is no evidence from the clinical trials that administration of HPV vaccine adversely affects fertility, pregnancy, or infant outcomes. Many pregnancies occurred in the trial participants.(75,214) The key message is “don’t do it, but if you do don’t worry about it!”

Women may safely breastfeed if they receive the vaccine during that period.

Could less common genotypes replace types 16 and 18?

In theory widespread vaccination may allow less common genotypes to replace the vaccine types, but expert opinion believes this to be unlikely.(94) Programmes will be monitoring changes in genotyping to ensure prevention continues to be effective. The phenomenon can occur where different strains or types of an agent compete with each other, such as with pneumococcal vaccination. This is not the case with human papillomavirus. A person can be co-infected with several types at one time.

Can people be tested to check immunity after vaccination?

There is no clinically useful test for immunity after vaccination. The minimum level of antibody required to provide protection is currently unknown and not likely to be important.

Does the quadrivalent vaccine provide any cross-protection against non-vaccine types?

Yes. The quadrivalent vaccine provided statistically significant levels of protection against type 31 and serum neutralising antibody to types 33 and 52.(215)

Can the HPV vaccine be given with other vaccines?

Yes, HPV vaccine can be co-administered with other non-live and live vaccines. Separate injection sites should be used.

Are the HPV vaccines interchangeable?

Yes. Either vaccine may be used to complete the recommended schedule.

Is the vaccine safe in patients who are on biologic agents?

Yes, as it is not a live vaccine.

How safe is the vaccine?

Very safe. HPV vaccine has an excellent safety profile and is well tolerated in all age groups. In the pivotal trials, the majority of adverse events were reported as mild or moderate, with injection site reactions the most common.(216)

No safety signals have been raised since the vaccine was licensed. A summary of the published post-licensure safety data on HPV4 from both active and passive surveillance studies to 2015 included data from more than one million preadolescents, adolescents and adults. The review concluded syncope to be associated with the administration of the vaccine, and possibly skin infections; more detailed analysis of the “infections” suggested some were likely injection site reactions. Serious events were carefully examined with no increase in incidence over background rates.(207)

A further review has summarised the postlicensure safety studies from many countries to 2016. Some individual studies include over one million participants. With the exception of syncope, which is an injection not a vaccine reaction, no safety signals have been identified.(208)