HPV Vaccines

2017 WHO Position Paper

What is the most frequent types of HPV worldwide?

HPV types 16 and 18 were the most frequent types worldwide, with HPV-16 the most common type in all regions.

HPV-16 and HPV-18 together are responsible globally for 71% of cases of cervical cancer.

More specifically, 60.6% of cases are attributed to HPV-16 and 10.2% to HPV-18.

HPV-31 accounts for 3.7%

HPV-33 for 3.8%

HPV-45 for 5.9%

HPV-52 for 2.8%

HPV-58 for 2.3%

HPV types 16, 18, 45, 31, 33, 52, and 58 account for approximately 90% of the squamous cell carcinomas which are positive for HPV DNA

Which are the most common high-risk HPV types after HPV-16?

HPV-18 and other high-risk types, such as types 31, 39, 51, 52, 56, 58, and 59, had similar prevalence and were among the most common high-risk HPV types after HPV-16.

True or False - Women infected with one HPV type may be co-infected or subsequently infected with other types.

True

Which countries have the highest prevalence of HPV in females?

Countries in sub-Saharan Africa (24%), such as Botswana and South Africa, as well as some areas in Latin America and the Caribbean (16%), Eastern Europe (14%) and south-eastern Asia (14%) have the highest prevalence of HPV in females.

What is the peak age specific prevalence of HPV?

Age-specific HPV prevalence peaked at younger ages (<25 years) with a prevalence of 24%, with lower prevalence at middle-ages.

In Central and South America an increase in prevalence at older ages (≥45 years) was documented, suggesting a potential resurgence of infection in older women.

In some low-income countries in Asia and Africa, HPV prevalence is very similar in women in all age groups.

What is the peak age specific prevalence of HPV in males in comparison to females?

Prevalence peaked at slightly older ages in males than in women and remained constant or decreased slightly with increasing age.

Which countries have the highest prevalence of HPV in males?

HPV prevalence in males is high in all regions but varied from:

• 1% to 84% among low-risk men

• 2% to 93% among high-risk men (sexually transmitted infection [STI] clinic attendees, HIV-positive men, and male partners of women with HPV infection or abnormal cytology)

• HIV-positive men who have sex with men showed the highest prevalence.

• Anal HPV infections are very common in men who have sex with men, and almost universal among those who are HIV infected.

• HPV was most prevalent in African men and least prevalent in men from the Asia-Pacific region.

What factors have the most risk of HPV infection in males?

Age was not associated with risk of positivity for HPV types 6, 11, 16, 18, or any tested HPV types. Having at least 3 lifetime female sexual partners had the greatest effect on HPV prevalence.

Other factors include having a male sexual partner, and sexual practices such as unprotected anal sex.

What is the most common high-risk HPV types in males?

The most common high-risk HPV types were HPV-16 and HPV-52.

HPV-6 was the most common low-risk HPV type in the general population.

What is the underlying cause of cervical cancer?

Persistent HPV infection which may eventually lead to invasive cervical cancer.

While infection with a high-risk HPV type is the underlying cause of cervical cancer, most women infected with high-risk HPV do not develop cancer. Infection persists in only a small percentage of women and only a small percentage of chronic infections progress to pre-cancer, of which even fewer will progress to invasive cancer.

Which HPV types are commonly associated with head and neck cancer?

HPV types 16 and 18 are associated with 85% of HPV-related head and neck cancers and 87% of anal cancers – the second and third most frequent HPV-related cancers with, respectively, 38 000 and 35 000 estimated cases per year.

Which family does the HPVs belong to?

Human papillomaviruses belong to the family Papillomaviridae.

Is HPV a DNA or RNA virus? Describe features of the pathogen.

The virions are non-enveloped and contain a double-stranded DNA genome. The genetic material is enclosed by an icosahedral capsid composed of major and minor structural proteins, L1 and L2 respectively.

These viruses are highly tissue-specific and infect both cutaneous and mucosal epithelium. Based on the genomic sequence of L1, the gene encoding the principal capsid protein, over 200 HPV types have been identified and characterized.

Papillomavirus isolates are traditionally described as ‘types’. HPV types may be classified in many ways, including the locations on the body that each virus tends to infect (cutaneous or mucosal types) and by their potential to induce cancer, i.e. high-risk vs low-risk types.

The International Agency for Research on Cancer currently defines 12 high-risk HPV types which are associated with cancers in humans (types 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59) and additional types for which there is limited evidence of carcinogenicity (types 68 and 73).

Describe the pathogenic of HPV infection.

HPV viruses are spread through contact with infected genital skin, mucous membranes, or bodily fluids, and can be transmitted through sexual intercourse including oral sex.

Most (70–90%) of HPV infections are asymptomatic and resolve spontaneously within 1–2 years. If not detected and treated appropriately, persistent infection with high-risk types may progress to invasive carcinoma at the site of infection, mainly of the genital tract.

Persistent HPV infection is a necessary cause of cervical cancer. Persistent HPV infection is defined by the presence of type-specific HPV DNA on repeated clinical biological samples over a period of time, usually 6 months, although this time period is not universally accepted. About 5–10% of all infected women develop persistent infection. Persistent infections, within months or years, may progress towards premalignant glandular or squamous intra-epithelial lesions, classified histopathologically as cervical intra-epithelial neoplasia (CIN), and to cancer. CIN is further classified as: CIN 1: mild dysplasia; CIN 2: moderate to marked dysplasia; and CIN 3: severe dysplasia to carcinoma in situ. Most CIN lesions regress spontaneously, though over a number of years, lesions on the cervix can slowly become cancerous

What is the interval between HPV infection and progression to cancer?

The interval between the acquisition of HPV infection and progression to invasive carcinoma is usually 20 years or longer.

The basis for this progression is not well understood but the predisposing conditions and risk factors include the following: HPV type; immune status (susceptibility is greater in persons who are immunocompromised, HIV-infected, or receiving immunosuppressive therapy); co-infection with other STIs (herpes simplex, chlamydia and gonococcal infections); parity and young age at first pregnancy; tobacco smoking. HIV-infected women have a higher prevalence of persistent HPV infection, often with multiple HPV types, and are at increased risk of progression to highgrade CIN and cervical cancer compared to women without HIV infection.26

What are the risk factors for progression of HPV infection to cancer?

The basis for this progression is not well understood but the predisposing conditions and risk factors include the following:

• HPV type

• Immune status (susceptibility is greater in persons who are immunocompromised HIV-infected, or receiving immunosuppressive therapy)

• Co-infection with other STIs (herpes simplex, chlamydia and gonococcal infections)

• Parity and young age at first pregnancy

• Tobacco smoking.

What is the pathogenicity of infection from low-risk HPV types?

HPV infection with low-risk types causes anogenital warts in females and males (condylomata acuminata or venereal warts).

Over 90% of these are associated with types 6 and 11.

The reported median time between infection with HPV types 6 or 11 and the development of anogenital warts is 11–12 months in men and 5–6 months in young women.

HPV-6 and HPV-11 can also cause a rare condition known as recurrent respiratory papillomatosis (RRP), in which warts form on the larynx or other parts of the respiratory tract with the risk of airway obstruction.

RRP occurs in 2 forms: juvenile onset RRP which is caused by vertical transmission of HPV from mother to a susceptible child perinatally and usually presents in childhood, and adult onset RRP which is probably transmitted horizontally through sexual activity with onset in young adulthood, typically in the third decade of life.28 RRP causes significant morbidity and may require multiple surgical interventions to maintain a patent airway. It can be fatal and lesions may undergo malignant change.

What is the body’s immune response following HPV infection?

The median time from HPV infection to seroconversion is approximately 8–12 months, although immunological response varies by individual and HPV type.

HPV infections are restricted to the epithelial layer of the mucosa and do not induce a vigorous immune response.

The best-characterized and most type-specific HPV antibodies are those directed against the L1 protein of the virus. After natural infection, 70–80% of women seroconvert; their antibody responses are typically slow to develop and of low titre and avidity. However, in men there is little response to HPV infection, few men seroconvert, and even after seroconversion, the antibodies produced are not protective.

The available data on whether natural infection with HPV induces protection against reinfection are equivocal. There appears to be a reduced risk of reinfection with the same HPV type but infection does not seem to provide group-specific or general immune protection from reinfection with other HPV types. In most cases, those who develop lesions mount an effective cell-mediated immune (CMI) response and the lesions regress. Failure to develop an effective CMI response to clear the infection results in persistent infection and, in the case of the high-risk HPVs, an increased probability of progression to CIN 2/3.