College of American Pathologists
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  New FDA approvals of HPV vaccines


CAP Today




January 2010
PAP/NGC Programs Review

Rodolfo Laucirica, MD
Rosemary Tambouret, MD
Mary R. Schwartz, MD

The Food and Drug Administration recently approved a new use for the Gardasil HPV vaccine and approved a new vaccine, Cervarix, for the prevention of human papillomavirus-related cervical cancer and preneoplastic disease.

Worldwide, HPV infection is the most common viral infection of the anogenital region, with a cumulative lifetime risk for infection approaching 70 percent.1 Of the roughly 100 types of HPV, 35 to 40 are known to infect the epithelium of the anogenital tract. Within this group, subtypes 16 and 18 are associated with 70 percent of cervical cancers and types 6 and 11 are responsible for 75 to 90 percent of genital warts.2,3 It is hoped that vaccines that target the high-risk subtypes 16 and 18 will reduce the incidence of HPV-induced anogenital dysplasias and cancers.

Gardasil (Merck and Co.) is a quadrivalent recombinant vaccine developed against HPV types 6, 11, 16, and 18. It is composed of L1 capsid proteins from these HPV subtypes. These L1 proteins can spontaneously self-assemble into viruslike particles (VLPs) that resemble complete HPV virions. Since these VLPs do not contain viral DNA, they can trigger an antibody response without exposing the recipient to infection or to cancer.4 Gardasil was approved by the FDA in 2006 for the prevention of: 1) cervical cancer caused by HPV types 16 and 18; 2) precancerous genital lesions caused by HPV types 16 and 18; and 3) genital warts caused by HPV types 6 and 11. Adolescent girls and young women, 9 to 26 years of age, are vaccinated. Gardasil was approved by the FDA in 2008 for prevention of vaginal and vulvar cancer caused by HPV 16 and 18, again by vaccination of girls and young women, ages 9 to 26. In October 2009, the FDA approved the use of Gardasil to prevent genital warts caused by HPV 6 and 11 in boys and young men, ages 9 to 26. 5,6

Gardasil’s effectiveness for preventing genital warts was studied in a randomized trial of 4,055 males, 16 to 26 years of age. The results showed that Gardasil was nearly 90 percent effective in preventing genital warts caused by HPV types 6 and 11 in those not infected by HPV at the initiation of the study. This trial included studies of safety and immunogenicity. Other safety and immunogenicity studies in 10- to 15-year-old boys (n=508) and in 9- to 15-year-old boys (n=839) documented a similar immune response to the vaccine and safety.7 From a cost-benefit standpoint, vaccination of boys remains controversial.8

Gardasil is administered in three injections over a six-month period, the second at two months and the third four months later. Of the 12,424 side effects reported to the Vaccine Adverse Event Reporting System, a national surveillance program cosponsored by the FDA and Centers for Disease Control and Prevention, from June 1, 2006 (date of FDA approval) through Dec. 31, 2008, 6.2 percent were serious and the remainder not serious.7 Side effects in decreasing order of frequency include syncope, local site reactions (pain, swelling, itching, bruising, redness), dizziness, nausea, headaches, hypersensitivity reactions, urticaria, venous thromboembolism, autoimmune disorders, Guillain-Barré syndrome, ana-phylaxis, and death.9 Syncope/fainting and thromboembolism have been disproportionately reported. Thirty-two deaths after the vaccine have been reported to this program, though it is unclear if any were directly caused by the vaccine.9 The Judicial Watch has reported 47 deaths since 2006.

On the same day the FDA approved Gardasil for preventing genital warts in boys and young men, it also approved Cervarix (GlaxoSmith-Kline) for preventing cervical cancer.10 Cervarix is a bivalent vaccine against HPV subtypes 16 and 18. Like Gardasil, the vaccine is derived from non-infective L1 viral capsid proteins from HPV 16 and 18 using DNA recombinant technology.

Phase two trials involving 1,113 women in North America and Brazil demonstrated 100 percent protection of the Cervarix vaccine against HVP 16 and 18.11 A large phase three randomized double-blind controlled study, PApilloma TRIal against Cancer In young Adults (PATRICIA), enrolled 18,644 women ages 15 through 25 to assess the efficacy of the Cervarix vaccine. The final event-driven analysis was published last year.12 For women not infected with oncogenic HPV at baseline, the efficacy of Cervarix was 92.1 percent against CIN2+ associated with HPV 16/18 and 87 percent against CIN3+. Studies in girls ages 10 through 14 years showed an immune response similar to the older females.13 Studies have shown that Cervarix provides protection for about 6.4 years after administration of the vaccine. This is longer than the duration of efficacy of Gardasil, which is now five years.14 Additional research is underway to determine if this protective window can be extended.

Cervarix is administered in three doses over a six-month span, with the second at one month and the third at six months. In the United Kingdom, where Cervarix has been used for several years, the most common observed side effects have been reactions at the injection site, headache, muscle tenderness or weakness, and fatigue. The next most common group of side effects includes GI symptoms, urticaria, joint pain, and fever. Uncommon side effects include upper respiratory infections, dizziness, and, rarely, anaphylaxis. A Glaxo-sponsored pooled analysis of 11 clinical trials found no clinically relevant differences in serious side effects between Cervarix and pooled control groups.15 Only rare deaths have been reported after Cervarix, and none have been proved to be directly due to the vaccine.

While Gardasil and Cervarix may play a role in preventing cervical cancer, it is important to recognize they do not target all high-risk HPV subtypes, the duration of efficacy is unknown, they are not therapeutic against HPV infections and HPV-related lesions, and no vaccine is 100 percent effective.16 Therefore, it is critical that routine cervicovaginal Pap test screening not be discontinued.


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4.  Markowitz LE, Dunne EF, Saraiya M, et al. Quadrivalent human papillomavirus vaccine: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Rep. 2007;56:1-24.
5.  Hull SC, Caplan AL. The case for vaccinating boys against human papillomavirus. Public Health Genomics. 2009;12:362-367.
6.  FDA approves new indication for Gardasil to prevent genital warts in men and boys. 2009.
7.  Block SL, Brown DR, Chatterjee A, et al. Clinical trial and post-licensure safety profile of a prophylactic human papillomavirus (types 6, 11, 16 and 18) L1 virus-like particle vaccine. Pediatr Inf Dis J. Nov. 30, 2009 [Epub ahead of print].
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10.  FDA approves new vaccine for the pre-vention of cervical cancer. 2009.
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14.  Harper DM. Currently approved prophylactic HPV vaccines. Expert Rev Vaccines. 2009;8:1663-1679.
15.  Descamps D, Hardt K, Spiessens B, et al. Safety of human papillomavirus (HPV)-16/18 AS04-adjuvanted vaccine for cervical cancer prevention: a pooled analysis of 11 clinical trials. Hum Vaccin. 2009;5:332-340.
16.  Kollar LM, Kahn JA. Education about human papillomavirus and human papillomavirus vaccines in adolescents. Curr Opin Obstet Gynecol. 2008;20:479-483.