FDA Licensure of Bivalent Human Papillomavirus Vaccine (HPV2, Cervarix) for Use in Females and Updated HPV Vaccination Recommendations from the Advisory Committee on Immunization Practices (ACIP)

FDA Licensure of Bivalent Human Papillomavirus Vaccine (HPV2, Cervarix) for Use in Females and Updated HPV Vaccination Recommendations from the Advisory Committee on Immunization Practices (ACIP)
Weekly
May 28, 2010 / 59(20);626-629


On October 16, 2009, the Food and Drug Administration (FDA) licensed bivalent human papillomavirus vaccine (HPV2; Cervarix, GlaxoSmithKline) for use in females aged 10 through 25 years. Cervarix is the second human papillomavirus (HPV) vaccine licensed for use in females in the United States. Quadrivalent HPV vaccine (HPV4; Gardasil, Merck & Co, Inc.) was licensed in 2006 for use in females aged 9 through 26 years, and the Advisory Committee on Immunization Practices (ACIP) recommended routine HPV4 vaccination of females aged 11 or 12 years, and catch-up vaccination for females aged 13 through 26 years (1). This report provides updated recommendations for routine and catch-up vaccination of females with either HPV2 or HPV4.

Both HPV2 and HPV4 are composed of virus-like particles (VLPs) prepared from recombinant L1 capsid protein of HPV; the two vaccines are not live vaccines (Table 1). HPV2 is directed against two oncogenic types (HPV 16 and 18). HPV4 is directed against two oncogenic types (HPV 16 and 18) and two nononcogenic types (HPV 6 and 11). Both vaccines have high efficacy against HPV 16 and 18-related cervical precancer lesions. HPV4 also has high efficacy against HPV 6 and HPV 11-related genital warts and HPV 16 and 18-related vaginal and vulvar precancer lesions (Table 2) (2--5).

HPV 16 and 18 cause about 70% of cervical cancers; each of the other oncogenic HPV types accounts for a small percentage of all cervical cancers. Other HPV-associated cancers in females include a subset of vulvar, vaginal, anal, and oropharyngeal and oral cavity cancers, caused primarily by HPV 16. HPV 6 and 11 cause approximately 90% of genital warts and most cases of recurrent respiratory papillomatosis.

In anticipation of FDA licensure of HPV2, ACIP reviewed data on the immunogenicity, efficacy, and safety of HPV2, as well as information on HPV4. At its October 21, 2009, meeting, ACIP approved updated recommendations for use of HPV vaccines in females.

HPV2 Clinical Trial Data

HPV2 efficacy was evaluated in two randomized, double-blind, controlled clinical trials in females aged 15 through 25 years, including a phase IIb study (6,7) and a phase III study (4). The phase III trial included 18,644 females, followed for a mean of 34.9 months. Efficacy against HPV 16 or 18-related cervical intraepithelial neoplasia grade 2 or 3 or adenocarcinoma in situ (CIN2+) was 92.9% in the according to protocol analysis (Table 2) (4). Among women who were HPV 16 or 18 DNA positive at study enrollment, the vaccine had no efficacy against CIN2+ due to that type. A subset of participants in the phase IIb study has been followed for up to 6.4 years (mean: 5.9 years) after dose one with high efficacy against HPV 16 or 18-related CIN2+ demonstrated throughout the follow-up period (7).

Protection against cervical lesions due to nonvaccine HPV types was evaluated. In an analysis limited to lesions without HPV 16 or 18 coinfection, efficacy against CIN2+ due to any of 12 nonvaccine oncogenic types (HPV 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66, and 68) was 37.4% (96.1% confidence interval [CI] = 7.4--58.2). In a post hoc analysis, efficacy against HPV 31-related CIN2+ in the according to protocol population was 89.4% (99.7% CI = 29.0--99.7) (5).

In all studies, ≥99% of participants developed an HPV 16 and 18 antibody response 1 month after completing the 3-dose series. Bridging immunogenicity studies were conducted among 1,193 females aged 10 through 14 years; geometric mean titers (GMTs) 1 month after the third dose were noninferior to those in females aged 15 through 25 years (5). The antibody responses for all vaccine antigens were noninferior after concomitant administration of HPV2 with tetanus toxoid, diphtheria toxoid, and acellular pertussis vaccine and/or with meningococcal conjugate vaccine in females aged 11 through 18 years compared with those after administration at separate visits. Rates of solicited and unsolicited symptoms and events were similar in all study groups (8).

HPV2 vaccinees were evaluated for injection-site and systemic symptoms, medically significant conditions, new onset autoimmune disorders, new onset chronic diseases, deaths, serious adverse events, and pregnancy outcomes. Safety was evaluated by pooling data from 11 clinical trials of bivalent vaccine in females aged 10 through 25 years (9), and by a meta-analysis of safety databases of bivalent vaccine as well as other vaccines with the same adjuvant (10). The pooled safety analysis included 23,713 females aged 10 through 25 years; approximately 12,000 females received at least 1 dose of HPV2. In an analysis of local and general adverse events, a larger proportion of persons reported at least one injection-site symptom in the HPV2 group compared with controls (5). In the HPV2 group, 92% reported injection-site pain, 48% redness, and 44% swelling compared with 64%--87%, 24%--28%, and 17%--21% in the control groups. Fatigue, headache, and myalgia were the most common general symptoms. No differences were observed in unsolicited symptoms within 30 days of vaccination between the vaccine group and control groups.

Serious adverse events and deaths were evaluated in a pooled safety analysis that included 29,953 females aged 10 through 72 years (16,142 received HPV2). Proportions of persons reporting a serious adverse event were similar in vaccine and control groups (5.3% and 5.9%, respectively), as were the types of serious adverse events reported (5). In the pooled safety analysis, including 12,533 women who received HPV2 and over 10,730 in the control groups, incidence of potential new autoimmune disorders did not differ (0.8% in both groups).

Clinical protocols excluded women who were pregnant, and participants were instructed to avoid pregnancy until 2 months after the last vaccination. However, 3,696 pregnancies occurred in the vaccine group and 3,580 in the pooled control groups. Overall, no differences were observed in rates of any specific pregnancy outcomes between groups (5). Among 761 pregnancies around the time of vaccination (defined as last menstrual period 30 days before to 45 days after vaccination), 13.6% of pregnancies ended in spontaneous abortion in the vaccine group compared with 9.6% in the control group. HPV2 has been classified as Category B on the basis of animal studies that revealed no evidence of impaired fertility or harm to the fetus. No data are available on use of HPV2 in lactating women.

Vaccine Recommendations for HPV2 and HPV4

open here to see the full-text (large):
FDA Licensure of Bivalent Human Papillomavirus Vaccine (HPV2, Cervarix) for Use in Females and Updated HPV Vaccination Recommendations from the Advisory Committee on Immunization Practices (ACIP)