How will HPV vaccines affect cervical cancer?

Abstract

Cancer of the uterine cervix is the second largest cause of cancer deaths in women, and its toll is greatest in populations that lack screening programmes to detect precursor lesions. Persistent infection with 'high risk' genotypes of human papillomavirus (HPV) is necessary, although not sufficient, to cause cervical carcinoma. Therefore, HPV vaccination provides an opportunity to profoundly affect cervical cancer incidence worldwide. A recently licensed HPV subunit vaccine protects women from a high proportion of precursor lesions of cervical carcinoma and most genital warts. Here we examine the ramifications and remaining questions that surround preventive HPV vaccines.

Figure 1. The cumulative frequency of HPV genotypes present in cervical cancer and the potential impact of interventions

The subset of human papillomavirus (HPV) genotypes that are associated with most cervical cancers and deemed ‘high-risk’ genotypes are shown. Yellow bars and percentages next to each bar indicate the percentage of cervical cancer cases attributed to each HPV genotype, and red bars indicate the cumulative percentage of cases. A type-restricted vaccine comprising HPV16 and HPV18 L1 virus-like particles (VLPs) (16 and 18) would provide protection against ~70% of cervical cancers. It is estimated that Pap screening and intervention has reduced the incidence of cervical cancer by ~80%. Similarly, the HPV16 and HPV18 L1 VLP vaccine formulated in ASO4 might protect against ~80% of cancers owing to cross-protection against the most closely related types to HPV16 and HPV18 (REF. 40). Munoz et al. predict that a type-specific octavalent HPV VLP vaccine (8VLP) would provide ~90% protection, although type-specificity is unlikely to be absolute so protection might be better. L2 vaccines induce broadly cross-neutralizing antibodies and are protective in animal models, but have not been tested in patients for the prevention of HPV infection. As HPV is associated with 99.7% of cervical cancers, several groups are examining the potential of L2-based vaccines for broad protection against oncogenic HPV genotypes (L2?). Image modified with permission from REF. © (2004) Wiley.

Figure 2. Cervical carcinogenesis by HPV

a The cervical squamocolumnar junction. The basal cells rest on the basement membrane, which is supported by the dermis. Normal squamous epithelium differentiates as shown. The transformation zone is the most common site for the development of cervical cancer. Prophylactic vaccines induce L1- or L2-specific antibodies that neutralize the virus. b After the human papillomavirus (HPV) infection of basal keratinocytes, the early HPV genes E1, E2, E5, E6 and E7 are expressed (red nuclei) and the viral DNA replicates. Low-grade squamous intraepithelial lesions (LSILs) support productive viral replication. In the upper layers of epithelium the viral genome is replicated further, and E4 (green cytoplasm), L1 and L2 (orange nuclei) are expressed. L1 and L2 encapsidate the viral genomes to form progeny virions in the nucleus. The shed virus then re-initiates infection. c A significant fraction of high-risk HPV infections progress to high-grade squamous intraepithelial lesions (HSILs), which show a lesser degree of differentiation. HSILs are effectively treated by loop electrosurgical excision (LEEP). Pap screening and HPV tests can be used to detect SILs (BOX 2). d The progression of untreated lesions to microinvasive and frankly invasive cancer is associated with the integration of the HPV genome into the host chromosomes, loss of E2 and upregulation of viral oncogene expression and genomic instability. These cancers are treated with surgery, chemotherapy or radiotherapy with limited success. Therapeutic vaccines and immune stimulants such as imiquimod can potentially induce an infiltration of T cells specific for the early viral antigens and clearance. Patients with immune suppression due to HIV infection or organ transplantation suffer more frequent and severe HPV-related disease.

Figure 3. Protection by human papillomavirus L1 virus-like particle (HPV L1 VLP) vaccination is type restricted

a A plot of data described in Mao et al. for women vaccinated with HPV16 L1 VLPs (vaccine) or placebo. Bars show the infection rate per 100 person-years for women in each group with cervical intraepithelial neoplasia 1 or worse (CIN1+), or CIN2 or worse (CIN2+), or CIN3. These lesions are presented as either HPV16 DNA positive, or DNA positive for any genotype other than HPV16. b A plot of data described in Harper et al. showing that vaccination with HPV16 and HPV18 L1 VLPs in ASO4 provided complete protection over 4 years against HPV16 or HPV18-related CIN1 or greater. Bars show the percentage of total women in each group with atypical squamous cells of unknown significance (ASCUS) or worse (≥ASCUS), a low-grade squamous intraepithelial lesion or worse (≥LSIL), CIN1 or worse (CIN1+), or CIN2 or worse (CIN2+). These lesions are presented as either HPV16 or HPV18 DNA positive, or DNA positive for any type other than HPV16 or HPV18. However, significant protection against CIN related to any other type (en masse) was not observed. Note that the study found 94% (95% CI 63.9–99.9) protection against HPV45 infection, and 54% (95% CI 11.5–77.7) HPV31 infection, showing that the type restriction of protection is not absolute.