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Updates on Recommendations for Use of Human Papillomavirus Vaccines
Abstract & Commentary
By Mary-Louise Scully, MD Dr. Scully is Director, Travel and Tropical Medicine Center, Sansum Clinic, Santa Barbara, CA.
Dr. Scully reports no financial relationships relevant to this field of study.
Synopsis: A new bivalent HPV vaccine is now licensed for use in females aged 10-25 years, and the quadrivalent HPV vaccine is now licensed for use in males aged 9-26 years in the United States.
Sources: CDC. 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). MMWR 2010;59:626-629.
CDC. FDA licensure of quadrivalent human papillomavirus vaccine (HPV4, Gardasil) for use in males and guidance from the Advisory Committee on Immunization Practices (ACIP). MMWR. 2010;59: 630-632.
In October 2009, the Food and Drug administration (FDA) licensed the bivalent human papillomavirus vaccine (HPV2; Cervarix, GlaxoSmithKline) for use in females aged 10 through 25 years. This vaccine joins the quadrivalent HPV4 vaccine (Gardasil, Merck & Co) that was licensed in 2006 for use in females aged 9 through 26 years. Both HPV2 and HPV4 are composed of virus-like particles (VLPs) prepared from recombinant L1 capsid protein of HPV. Neither vaccine is a live vaccine. HPV2 and HPV4 include protection against HPV 16 and HPV 18, the two oncogenic HPV types that together account for 70% of cervical cancers. In addition, HPV4 protection includes HPV 6 and HPV 11, the two nononcogenic types that account for 90% of genital warts and most cases of recurrent respiratory papillomatosis.
The approval of HPV2 came after review of efficacy data in two randomized, double-blind, controlled clinical trials in females aged 15 through 25 years. One study was a phase IIb study, and the other was a phase III trial.1 The phase III trial included 18,644 females who were followed for a mean of 34.9 months. According to the protocol analysis, the efficacy against HPV 16 or 18 related cervical intraepithelial neoplasia grade 2 or 3 or adenocarcinoma in situ (CIN2+) was 92%.2 In both studies, greater than 99% of participants developed an HPV 16 and 18 antibody response 1 month after completing the 3-dose series.
ACIP recommends routine vaccination of females aged 11 or 12 years with 3 doses of either HPV2 or HPV4, but vaccination may be initiated as early as age 9, ideally before potential exposure to HPV through sexual contact. The antibody response after co-administration with Tdap (tetanus toxoid, diphtheria, and acellular pertussis) and meningococcal conjugate vaccine (MCV4) was noninferior for all vaccine antigens. Therefore, these vaccines can be administered at the same time, such as during a routine adolescent visit.
The 3-dose schedule for HPV2 and HPV4 vaccines are the same, namely 0, 1-2 months, and 6 months. The minimum interval between the first and second dose is 4 weeks. If the series is interrupted for any reason, the series does not need to be restarted. For example, if the series is interrupted after the first dose, the second dose should be administered as soon as possible, and the second and third doses should be separated by an interval of at least 12 weeks with a minimum interval of 24 weeks between first and third doses. Vaccine doses received after a shorter-than-recommended dosing interval should be repeated.
The FDA also licensed the HPV4 vaccine for use in males aged 9 through 26 years for prevention of genital warts (condyloma acuminata) caused by HPV types 6 and 11. A phase III efficacy study enrolled 4,065 males aged 16 through 26 years from North and South America, Europe, Australia, and Asia with a median duration of follow-up of 2.3 years. The efficacy for prevention of genital warts related to HPV types 6, 11, 16, or 18 in the per protocol population (i.e., patients who received all 3 vaccine doses, were seronegative at day 1, and DNA negative day 1 through 7 to the respective HPV type) was 89.4%. The efficacy in the intent to treat population (males who received at least one vaccine dose regardless of baseline DNA or serology) was 67.2%.3 Seroconversion rates were high for all four HPV types (HPV 6, 11,16, 18) after vaccination with HPV4, but antibody titers were significantly higher in males aged 9 through 15 years compared with males aged 16 through 26 years.
The approval of HPV4 vaccination for use in males is important in the ongoing effort to reduce the overall health burden of conditions associated with HPV. At this point, the ACIP is not recommending routine use of HPV4 in males, likely in part because mathematical modeling suggests that male HPV vaccination in addition to female-only vaccination is cost effective only when vaccine coverage of females is less than 80 %.4 However, data do show HPV4 has a high efficacy for prevention of intraepithelial neoplasias in men who have sex with men (MSM).5 Therefore, this may be an appropriate group in whom to first focus the use of HPV4 vaccine in males.
The vaccine schedules, administration, and potential adverse effects of HPV2 and HPV4 in males and females are similar, which is helpful for health care providers with the increasing complexity of childhood and adolescent vaccine schedules. The post-marketing addition of a warning of possible syncope associated with HPV4 vaccination led to the recommendation of a 15-minute period of observation after vaccine administration. Local injection site reactions were noted in 83.9% of females and 61.5% of males during HPV4 studies, but more than 94% of both groups judged their injection-site adverse reactions to be only mild to moderate in intensity.3
The HPV2 and HPV4 vaccines can be co-administered with any live or inactivated vaccine since neither is a live vaccine and both can be administered to immunocompromised patients. They are both category B for use in pregnancy since animal studies showed no evidence of impaired fertility or harm to the fetus. There are very limited data on use of HPV vaccine in lactating women. Since the vaccine consists of viral capsid proteins it is unlikely to have an adverse effect on the infant and therefore is not contraindicated in breastfeeding women.6 HPV4 is produced in baker's yeast (Saccharomyces cerevisiae) and is therefore contraindicated in persons with an immediate hypersensitivity to yeast. The pre-filled syringes of HPV2 have a latex rubber stopper and therefore should not be used in patients with an anaphylactic latex allergy. These patients can receive HPV2 from single-dose vials, which do not contain any latex.