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Efficacy and Safety of the Quadrivalent HPV Vaccine

Two randomized controlled trials provide an additional year of follow-up.

Anogenital infection with human papillomavirus (HPV) causes both genital warts and cervical cancer in women; HPV types 16 and 18 are responsible for approximately 70% of cervical cancers worldwide. A three-dose quadrivalent vaccine (HPV types 6, 11, 16, and 18) was licensed in the U.S. in June 2006, based partly on interim results from two manufacturer-sponsored, prospective, placebo-controlled trials. Now, investigators report longer-term results from those trials.

The first trial involved 5455 women aged 16 to 24 in 16 countries. Analyses performed approximately 2.5 years after the vaccine series was completed showed the vaccine to be 100% efficacious in preventing anogenital intraepithelial lesions or warts (0 vs. 60 cases), as well as cervical intraepithelial neoplasia grades 1–3 or adenocarcinoma in situ (0 vs. 65 cases), caused by vaccine-type HPV. In an intention-to-treat analysis, the vaccine’s efficacy in reducing the incidence of cervical lesions caused by all HPV types was 20% (344 vs. 421 cases). Vaccine recipients had a slightly higher incidence of local (87% vs. 77%) and mild febrile reactions (13% vs. 10%) than did placebo recipients.

In a similarly designed trial involving 12,167 women aged 15 to 26 years, investigators assessed the vaccine’s ability to reduce the incidence of HPV-16/18–related high-grade cervical neoplasia in participants who were still HPV-16/18–negative 1 month after receiving the third vaccine dose. The primary composite endpoint encompassed cervical intraepithelial neoplasia grade 2 or 3, adenocarcinoma in situ, and invasive carcinoma of the cervix. Approximately 2.5 years after the third injection, the vaccine showed 98% efficacy in preventing the primary endpoint (1 vs. 42 cases). Intention-to-treat analysis showed a vaccine efficacy of 44% in preventing high-grade HPV-16/18–associated cervical neoplasia (83 vs. 148 cases) and 17% in preventing all high-grade cervical neoplasias (219 vs. 266 cases). The vaccine did not appear to alter disease course in women with existing HPV-16/18 infection. Vaccine recipients again had a slightly higher incidence of local reactions than did placebo recipients; no adverse effects were noted for pregnancies occurring in temporal proximity to immunization.

Comment: Interim results from these two trials provided some of the primary evidence supporting vaccine licensure. Given the relatively short follow-up period even in the present studies, we do not know the duration of protection or the overall benefit afforded by the vaccine in preventing neoplastic disease from subsequent infection. Additionally, as editorialists note, given the vaccine’s high cost and lack of efficacy in women with previous HPV-16/18 infection, optimal use will be either among 11- and 12-year-old girls (a group not enrolled in the studies) or through targeted immunization of populations likely to be HPV-16/18–naive.

— Richard T. Ellison III, MD

Published in Journal Watch Infectious Diseases May 9, 2007

Citation(s):

Garland SM et al. Quadrivalent vaccine against human papillomavirus to prevent anogenital diseases. N Engl J Med 2007 May 10; 356:1928-43.

• Original article (Subscription may be required)
• Medline abstract (Free)

The FUTURE II Study Group. Quadrivalent vaccine against human papillomavirus to prevent high-grade cervical lesions. N Engl J Med 2007 May 10; 356:1915-27.

• Original article (Subscription may be required)
• Medline abstract (Free)

Sawaya GF and Smith-McCune K. HPV vaccination — More answers, more questions. N Engl J Med 2007 May 10; 356:1991-3.

• Original article (Subscription may be required)
• Medline abstract (Free)