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Clinical Updates

HPV Vaccines in the Prevention of Genital Warts

Dany Nassar, Selim Aractingi

Wednesday, April 14, 2010

Human papillomavirus (HPV) is a double-stranded DNA virus that tends to affect the malpighian epithelia of the skin and mucosa. The HPV genome encodes early proteins that enable viral replication (E1 to E7) and late structural capsid proteins (L1 and L2). More than 100 serotypes have now been identified based on the L1 DNA sequence. Serotypes that infect the anogenital mucosa are divided into low-risk serotypes, which cause benign anogenital warts (mainly serotypes 6 and 11), and high-risk serotypes, which can cause cervical uterine cancer and anogenital cancers (mainly serotypes 16 and 18).

Genital HPV infection is the most prevalent sexually transmitted disease in humans in all studies performed in the Americas, Australia and Europe. HPV can either remain as an asymptomatic infection or manifest as external or internal genital warts. In a subgroup of patients, there might also be a risk of developing carcinoma.

Anogenital Warts

In the United States, 1% of sexually active people have genital warts, of these 90% are induced by HPV serotypes 6 and 11. However, not all infected people go on to develop genital warts. Although as many as 30% of warts regress spontaneously, recurrence is common, in approximately 30%, whether clearance occurs spontaneously or following treatment.

HPV Infection and Cervical Cancer

The majority of HPV infections are cleared by the immune system despite which is the causal virus. There are two ways for carcinogenesis to develop after HPV infection. In a small group of patients, the infection with high-risk serotypes persists for a long period of time and causes epithelial dysplasia and then carcinoma. Carcinogenesis is therefore caused by the integration of oncogenic HPV DNA into the cell genome and the inhibition by the E6 and E7 viral proteins of the p53 and retinoblastoma protein (Rb) tumor suppressors. Progression is associated with histological transformation known as dysplasia. If not treated, this is the stage of intra-epithelial neoplasia that leads to invasive cancer. Another pathway is secondary to prolonged infection with low-grade HPV6, 11 serotypes in immunosuppressed patients, such as those infected with HIV or organ transplant recipients. In these patients, there is a risk of developing a low-grade verrucous carcinoma, previously known as giant condyloma (Buschke Lowenstein tumour). These lesions might recur locally and, on a long-term basis, could show anaplastic transformation into high-grade invasive squamous cell carcinoma.

Vaccines

Two commercially launched vaccines are now available for the primary prevention of genital HPV infections. Both are based on the virus-like particle (VLP) technique. Recombinant L1 protein is the target antigen in both vaccines. Capsid proteins assemble into a virus-like structure that does not contain viral genome and thus is not infective (Figure 1). This structure is highly immunogenic and induces the production of neutralizing antibodies. Vaccination is efficient only as a preventive method; the antibodies induced by vaccination, as described above, are secreted in the cervical and vaginal mucus and prevent the later attachment of invasive HPV virus to the mucosa.

Figure 1. Reproduced from Schiller JT, Davies P. Nat Rev Microbiol 2004;2:343-347. 

Gardasil® (Merck) is a quadrivalent vaccine that contains four types of VLP particles for serotypes 6, 11, 16 and 18 in an aluminium-containing adjuvant. Cervarix® (GlaxoSmithKline) is a bivalent vaccine that contains VLP particles for serotypes 16 and 18 formulated in an original ASO4 adjuvant that the company has developed and showed to be highly potent. Vaccination protocols require intramuscular injection of 0.5 ml at 0, 2, and 6 months for the quadrivalent vaccine and 0, 1, and 6 months for the bivalent strain.

Very large randomized double-blind placebo-controlled clinical trials tested the efficacy of the vaccines for the primary prevention of cervical intraepithelial neoplasia (CIN) of moderate and high-grade (2 and 3) adenocarcinoma in situ caused by HPV 16 or 18, or external genital warts in young women aged between 16 and 24 years. Both vaccines were shown to reduce tumoral events by more than 90% compared with placebo in females who were naive for the viruses. Vaccination did not prevent pre-cancerous lesions in women already infected with HPV 16 or 18 at the time of vaccination. Those participants infected with one or more vaccine HPV types before vaccination were protected against disease caused by the other vaccine HPV types.

Data from phase III studies conducted with the quadrivalent vaccine showed a significantly decreased incidence of anogenital warts in the vaccine group compared with the placebo group. In the type-specific per-protocol analysis of the Females United to Unilaterally Reduce Endo/Ectocervical Disease (FUTURE) I study, which included the patients with negative polymerase chain reaction (PCR) for vaccine-type HPV before and 1 month after the vaccination period, HPV vaccine was 100% effective (95% confidence interval [CI] = 94 to 100; 0/2261 cases in the vaccine group vs. 60/2279 cases in the placebo group) in preventing anogenital intraepithelial lesions or warts related to vaccine-type HPV. Intent-to-treat analysis included all patients who received at least one dose of the vaccine, including those with wart or PCR-positive infection with a vaccine-type HPV strain. In this "unfavorable" group, the efficacy of vaccine-type HPV remained at 73% (95% CI = 58 to 83; 71 cases in the vaccine group vs. 155 cases in the placebo group). It was shown that there was no clear evidence that vaccination altered the course of vaccine-related HPV infection present before administration of the first dose.

In a combined analysis of one phase II and two phase III studies, the efficacy of quadrivalent HPV vaccine against HPV 6-, 11-, 16-, or 18-related external genital warts was 98.9% (CI = 93.7% to 100.0%) in a per protocol analysis. Efficacy against HPV 16- or 18-related vulvar intraepithelial neoplasia grade 2 or 3 was 100% (CI = 55.5-100.0).

Adverse Events

Mild adverse effects of vaccination included pain, erythema and swelling at the injection site, mild fever, headache, fatigue, nausea, and myalgia. Post-licensing monitoring reported less than 0.1% adverse events, and of these 94% were considered not serious. The remaining 6% that were deemed to be serious adverse events included bronchospasm, thromboembolism, Guillain-Barré syndrome and death.

Recommendations

Recommendations vary between countries. Vaccination is usually recommended for girls aged between 11 and 12 years before contracting the virus. Catch-up vaccination for young women aged 13 and 18 (or even 26) years is also achievable, as well as for those who are negative for HPV infection. I would recommend that HPV vaccines should be introduced as part of a co-ordinated strategy to prevent cervical cancer and HPV-related diseases that include education, cervical-cancer screening, and prevention of other sexually transmitted infections.

Conclusion

The efficacy of HPV vaccination in preventing the development of uterine cervical cancer is the first successful model of cancer immunoprevention. These vaccines, especially the quadrivalent, not only prevent primary HPV infection, but also stop the development of genital warts. Wide population vaccination could modify the epidemiology of HPV infections, thus changing the prevalence of the different serotypes. However, patients should always be reminded that vaccination does not change the importance of practicing safe sexual behaviour to prevent other potentially severe sexually transmitted infections. Vaccinated women should also continue with regular Pap screening, as current vaccines do not target all high-risk HPV types and the duration of immunoprotection is unknown.

References

  1. Urman CO, Gottlieb AB. New viral vaccines for dermatologic disease. J Am Acad Dermatol 2008;58:361-370.
  2. Schiller JT, Davies P. Delivering on the promise: HPV vaccines and cervical cancer. Nat Rev Microbiol 2004;2:343-347.
  3. Kahn JA. HPV vaccination for the prevention of cervical intraepithelial neoplasia. N Engl J Med 2009;361:271-278.
  4. Garland SM, Hernandez-Avila M, Wheeler CM, et al. Quadrivalent vaccine against human papillomavirus to prevent anogenital diseases. N Engl J Med 2007;356:1928-1943.
  5. Markowitz LE, Dunne EF, Saraiya M, et al. Quadrivalent Human Papillomavirus Vaccine: Recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep 2007;56(RR-2):1-24.
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