Human papillomavirus (HPV)

What

There are several types of human papillomavirus (HPV) that infect cutaneous and mucosal epithelial tissues. Most people clear HPV infections, but the virus persists in some cases.

Who

9vHPV (9-valent HPV) vaccine is recommended for:

• adolescents aged 9–18 years
• people with significant immunocompromising conditions (except for asplenia or hyposplenia)
• men who have sex with men

How

The recommended schedule for adolescents aged 9–14 years is 2 doses, with a 6–12-month interval between doses.

The recommended schedule for people aged ≥15 years is 3 doses, with an interval of 2 months between dose 1 and dose 2, and 4 months between dose 2 and dose 3.

The recommended schedule for people with significant immunocompromising conditions, regardless of age, is 3 doses, with an interval of 2 months between dose 1 and dose 2, and 4 months between dose 2 and dose 3.

Why

Up to 90% of the general population will be infected with at least 1 genital type of HPV at some time in their lives. People with persistent HPV infection are at risk of developing HPV-associated cancers; the most common is cervical cancer.

Human papillomavirus vaccines available in Australia

The Therapeutic Goods Administration website provides product information for each vaccine.

See also Vaccine information and Variations from product information for more details.

Dose and route

The dose of all HPV vaccines is 0.5 mL given by intramuscular injection.

2- and 3-dose schedules

People who start the HPV vaccination course at 9–14 years of age (that is, before their 15th birthday) are recommended to receive a 2-dose schedule at the following times:

• 0 (the day the 1st dose is given)
• 6–12 months

People who receive their 1st HPV vaccine dose at ≥15 years of age (that is, on or after their 15th birthday) are recommended to receive 3 doses at the following times:

• 0 (the day the 1st dose is given)
• 2 months
• 6 months

See Table. Recommended doses and intervals between doses for human papillomavirus (HPV) vaccines, by age group at the start of the course.

If the person has received doses with shorter intervals, see Table. Catch-up schedule for people ≥10 years of age (for vaccines recommended on a population level). The person may need extra doses.

Extra doses of 9vHPV vaccine

People who have completed the recommended number of doses of 2vHPV (2-valent HPV) or 4vHPV (4-valent HPV) vaccine are not routinely recommended to receive 9vHPV vaccine, because the extra benefit is thought to be marginal.

However, if the person wants protection against the additional HPV types, there appears to be no safety concerns associated with giving 9vHPV after a completed 2vHPV or 4vHPV course. ¹³ The rate of injection site reactions may increase.

Co-administration with other vaccines

HPV vaccines can be given at the same time as the following vaccines, using separate syringes and injection sites:^14-20

• dTpa (reduced antigen content diphtheria-tetanus-acellular pertussis vaccine)
• dTpa-IPV (reduced antigen content diphtheria-tetanus-acellular pertussis, inactivated poliovirus vaccine)
• hepB (monovalent hepatitis B vaccine)
• MenACWY (quadrivalent meningococcal conjugate vaccine)

There are no clinical data about co-administering HPV vaccines with varicella vaccine. Theoretically, there are no concerns about safety or efficacy if the person receives the vaccines at the same time at different injection sites.

Interchangeability of HPV vaccines

9vHPV vaccine can be used to complete an HPV vaccination schedule that was started with either the 4vHPV or the 2vHPV vaccine, as long as the appropriate minimum intervals and dose numbers are used.

HPV vaccination is generally safe and well tolerated. The safety profile and the spectrum of adverse events after vaccination in males are similar to those in females.^26,27

For all HPV vaccines, injection site reactions are the most commonly reported adverse event.^21,28,29

In most clinical trials, systemic adverse events were comparable between HPV vaccine recipients and control vaccine recipients, and included:^29,30

• headache
• fever
• nausea
• dizziness
• fatigue

Meta-analyses on both the 2vHPV and 9vHPV vaccines show no increase in the number of serious adverse events in vaccine recipients compared with control recipients.^21,31 Rates of anaphylaxis are low and consistent with rates for other vaccines.^28,32,33

Adverse events following 9vHPV compared with 4vHPV

A safety review of 7 phase III clinical trials evaluated reactions to 9vHPV vaccine and compared them with 4vHPV vaccine or placebo in males and females aged 9–26 years who received 3 doses. Serious adverse reactions were reported in <0.1% of the more than 15,000 participants.²¹ This review concluded that overall safety profiles of the 4vHPV and 9vHPV vaccines given in 3-dose schedules were similar, but found that injection site reactions were slightly more common with 9vHPV vaccine (72.5% after dose 1 of 9vHPV vaccine vs 61.0% after dose 1 of 4vHPV vaccine).

Syncope in adolescents

Post-marketing passive surveillance of HPV vaccine use has identified syncope (fainting) as a common adverse event immediately after HPV vaccination in adolescents.^28,34,36

Syncope is a benign and manageable risk of adolescent vaccination. It is likely to be a reaction to the process of vaccination, rather than to the vaccine itself. Immunisation providers should ensure that procedures are in place to minimise the risk of syncope-related falls around the time of vaccination.

See also Adverse events following immunisation.

Guillain–Barré syndrome

A 2015 French study in more than 2 million girls suggested a possible very small risk (approximately 1 in 100,000 girls vaccinated) of Guillain–Barré syndrome (GBS). However, a relationship between HPV vaccination and GBS has not been observed in any other well-conducted studies.³⁷ Ongoing research is monitoring whether there is any increased risk of GBS after HPV vaccination.

Other adverse events

Reports of various other adverse events after HPV vaccination include:

• new-onset autoimmune disease
• primary ovarian insufficiency
• complex regional pain syndrome
• postural orthostatic tachycardia

Despite these reports, there is no consistent evidence for an increased risk of these events after vaccination, or a causal relationship between these events and vaccination.^28,31

The World Health Organization’s Global Advisory Committee on Vaccine Safety,³⁸ the European Medicines Agency,³⁹ the Australian Therapeutic Goods Administration and various other key global expert vaccine groups have reviewed the evidence for a causal association between HPV vaccine and a number of these reported adverse events. These extensive reviews have not found any safety issue that would change positive recommendations for the use of the vaccine. The reviews have concluded that HPV vaccines are extremely safe.³⁷

HPV infection is often subclinical, but can cause a range of lesions depending on the infecting HPV genotype.

Low-risk HPV types

Low-risk HPV types may cause lesions such as:

• cutaneous warts
• genital warts
• respiratory papillomatosis

Anogenital warts may present as painless lumps, or with local tenderness, itching or bleeding.

Recurrent respiratory papillomatosis is potentially fatal. It is characterised by multiple warty growths on the mucosal surface of the respiratory tract.⁴⁷

Most people clear genital HPV infections (that is, the infection is no longer detectable by HPV DNA testing) within 12–24 months. However, in some cases, the virus is thought to remain as a latent infection even though DNA is no longer detectable.

In about 3–10% of infections, the virus persists. People with persistent HPV infection are at risk of developing HPV-associated cancers.^48-50

High-risk HPV types

High-risk HPV types may cause dysplasias and cancers of the:

• cervix
• vulva
• vagina
• penis
• anus
• oral cavity
• oropharynx

Dysplasias may be:

• low grade — the viral cytopathic effect of HPV infection
• high grade — precursors to cancer

Cervical cancer

The causal link between persistent cervical HPV infection and cervical cancer is well established.⁵¹

Cellular changes in the cervix as a result of HPV infection are referred to as cervical intraepithelial neoplasia. Most of these changes regress, but some will progress to cervical cancer.

Malignant transformation in the cervix usually occurs 10–20 years after infection with high-risk HPV types, but has been reported within 2 years.⁵²

Other cancers

The strength of association between HPV infection and cancers other than cervical cancer varies by site and HPV type.⁵¹

The clinical features of HPV-associated cancers and their precursor lesions depend on the anatomical site. Clinical features also vary within the oropharynx and anogenital sites other than the cervix. The progression of HPV-associated precursor lesions to cancers is less well understood in non-cervical sites than in the cervix.

2 HPV vaccines are available for use in Australia:

• 2vHPV (Cervarix), which contains virus-like particles of HPV types 16 and 18
• 9vHPV (Gardasil 9), which contains virus-like particles of HPV types 6, 11, 16, 18, 31, 33, 45, 52 and 58

Virus-like particles are not infectious, and do not replicate or cause cellular abnormalities.^105,106

From 2007 to 2017, Australia’s National Immunisation Program used 4vHPV. This was replaced with 9vHPV from 2018.

Vaccine efficacy in females 16–26 years of age

Efficacy of the 2vHPV, 4vHPV and 9vHPV vaccines has been assessed in females in several international clinical trials.

2vHPV and 4vHPV vaccines

In women aged approximately 16–26 years who are naive to HPV types 16 and 18 before vaccination, the 2vHPV and 4vHPV vaccines (in a 3-dose schedule) are both about 90–100% effective at preventing type-specific persistent infection and related cervical disease.

The 4vHPV vaccine is 100% effective (95% CI: 94–100%) against vaginal and external anogenital lesions associated with HPV types 6, 11, 16 and 18 in women.^107-112

These include:

• genital warts
• vulval dysplasia
• vaginal dysplasia
• perineal dysplasia
• perianal dysplasia

The 2vHPV vaccine also provides considerable cross-protection against cervical infection with HPV types 31, 33 and 45.¹¹³

9vHPV vaccine

The 9vHPV vaccine has established efficacy (97.4%; 95% CI: 85.0–99.9%) against the following neoplasias and cancers that are associated with HPV types 31, 33, 45, 52 and 58:¹¹⁴

• cervical
• vulval
• vaginal

A clinical trial of 9vHPV vaccine in women aged 16–26 years established non-inferiority of the 9vHPV vaccine against the 4vHPV types (6, 11, 16 and 18). Incidence of disease endpoints was similarly low in women vaccinated with either 9vHPV or 4vHPV vaccine.¹¹⁴

Vaccine efficacy in males 16–26 years of age

1 clinical trial has shown the efficacy of 4vHPV vaccine in males aged 16–26 years.¹¹⁵

Vaccination was 84–100% protective against persistent anogenital infection and external genital lesions due to vaccine HPV types among HPV-naive participants.

Among HPV-naive participants in the trial, vaccine efficacy in men who have sex with men was:

• 95% against intra-anal HPV infection
• 75% against high-grade anal intraepithelial neoplasia

Efficacy of 2vHPV and 9vHPV vaccines in males has not been assessed to date. However, these vaccines have demonstrated safety and immunogenicity in adolescent and adult males.^27,27,116

Vaccine efficacy in people already infected with HPV

In women who are vaccinated regardless of their baseline HPV status (that is, women who may have pre-existing HPV infection), vaccine efficacy is lower than in HPV-naive women. This suggests reduced vaccine effectiveness among females who are already sexually active. This is because the HPV vaccines are prophylactic vaccines — they prevent primary HPV infection.

Vaccination does not:

• treat an existing HPV infection
• prevent disease that may be caused by an existing vaccine HPV-type infection^30,117-119

HPV vaccine protection is believed to be predominantly antibody mediated. Even low levels of antibodies can stop HPV entering the basal epithelial cells. HPV can only access the basal cell at sites of microtrauma, where there is a breach in the epithelium, and circulating HPV antibodies from sera are present at these sites.⁴¹

Because antibodies prevent viral entry, vaccination may still benefit sexually active men and women by protecting them against:

• new infections with other vaccine-preventable HPV types
• reinfection with vaccine-preventable types they have previously been exposed to — for example, from an infected partner
• auto-inoculation of existing persistent HPV infection to other sites

Immunogenicity in females and males <16 years of age

Pre-market trials did not assess the efficacy of HPV vaccines in females or males <16 years of age because these studies need genital samples. The trials used immunobridging studies to ensure that antibody responses in the target age of young adolescents were equivalent to those known to be protective in older women.

Young adolescents had higher antibody titres than older women.¹ Later studies confirmed that a widely spaced 2-dose HPV vaccine schedule for those aged 9–14 years at the time of the 1st dose also produced non-inferior antibody titres.¹²⁰

For the 2vHPV, 4vHPV and 9vHPV vaccines, antibody responses in pre-adolescent and adolescent females and males (>9 years of age) after 2 vaccine doses were equivalent to those in adult women, in whom clinical efficacy has been demonstrated.^1,2,121

Duration of immunity

It is currently unknown if immunity due to HPV vaccine is lifelong. However, current data support a persistent, stable antibody level after an initial plateau. Long-term population-based follow-up studies to assess this are underway. In clinical trials in women,^114,122-124 vaccine efficacy is up to:

• 6 years for 9vHPV vaccine
• 10 years for 4vHPV vaccine
• 10 years for 2vHPV vaccine

Not applicable.

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