HPV vaccine update: Will there be more options for women and men?
HPV vaccine update: Will there be more options for women and men?
FDA committee gives nod to Cervarix use in females, Gardasil in males
Get set for possible changes in human papillomavirus (HPV) vaccine use. A Food and Drug Administration (FDA) review committee has voted that clinical data support the efficacy and safety of GlaxoSmithKline's Cervarix vaccine candidate for the prevention of cervical precancers and cervical cancer related to HPV types 16 and 18 in girls and young women. The committee also agreed that efficacy, immunogenicity, and safety data support the use of Merck's Gardasil vaccine in boys and young men for the prevention of genital warts caused by HPV types 6 and 11.
The decisions were reached at a Sept. 9, 2009, committee meeting. While the FDA is not bound by the committee's guidance, it does take its advice into consideration when reviewing vaccines. The committee's recommendation will be considered by the FDA in its decisions regarding GlaxoSmithKline's request for approval of its HPV vaccine for use in females, as well as Merck's supplemental application for use of Gardasil in boys and young men.
Both vaccines are scheduled to be examined at the Oct. 21-22, 2009, meeting of the Advisory Committee on Immunization Practices (ACIP) at the Centers for Disease Control and Prevention. The committee develops written recommendations for the routine administration of vaccines to children and adults. If the FDA has taken final action on either vaccine, the ACIP will vote on recommendations for such use.
If the FDA approves Cervarix, there will be two HPV vaccines on the market for use in girls and young women. How will recommendations be stated for the two vaccines? Will the vaccines be able to be use interchangeably in the vaccination series for protection against HPV 16/18?1 Gardasil is approved for use in girls and young women ages 9-26 years for prevention of cervical, vulvar, and vaginal cancers caused by HPV types 16 and 18; genital warts caused by HPV types 6 and 11; and precancerous or dysplastic lesions caused by HPV types 6, 11, 16, and 18.
Those two questions will be subjects of discussion at the October 2009 ACIP meeting, says Laurie Markowitz, MD, CDC medical epidemiologist. The Gardasil and Cervarix vaccines have similarities and differences, she notes. While both vaccines cover the two cervical cancer types of HPV (16 and 18), Gardasil also includes protection against two types of HPV that cause genital warts (6 and 11).
"For the first time, we have these two vaccines and they cover slightly different things," notes Markowitz. "That will be the challenge for communication about these two vaccines."
Data presented at the September 2009 FDA meeting showed Cervarix has been demonstrated to be effective in preventing genital dysplasias (CIN2+ and CIN1) associated with HPV 16 and/or 18 in women ages 15-25 who are naïve for the relevant vaccine HPV types. The vaccine is not effective in preventing genital dysplasias (CIN2+ and CIN1) related to vaccine HPV types for which the subject has been exposed, data indicate. Cervarix might have an impact on reducing genital dysplasias (CIN2+) related to HPV-31, but analyses involving multiple HPV types (vaccine and nonvaccine) are complicated.2
In clinical trials, the most common side effects after vaccination with Cervarix include pain, redness and swelling, fatigue, headache, joint and muscle aches, gastrointestinal symptoms, and fever. Serious adverse events generally were comparable between the groups receiving Cervarix and the control groups, data indicate.2
An observer-blind study compared Cervarix and Gardasil by assessing immunogenicity and safety through one month after completion of the three-dose vaccination course. A total of 1,106 women were stratified by age (18-26, 27-35, 36-45) and randomized to receive Cervarix or Gardasil. The study looked at two key measures of immune response, neutralizing antibodies and memory B cells, two factors that might determine how well such vaccines will protect women from HPV infection and subsequent cervical cancer.3
In the total vaccinated cohort (all women who received at least one vaccine dose, regardless of their serological and DNA status prior to vaccination), Cervarix induced higher serum-neutralizing antibody titers in all age strata (p < 0.0001). Positivity rates for anti-HPV-16 and -18 neutralizing antibodies in cervicovaginal secretions and circulating HPV-16 and -18 specific memory B-cell frequencies also were higher after vaccination with Cervarix compared with Gardasil. Both vaccines generally were well tolerated, and the incidence of unsolicited adverse events was comparable between vaccinated groups.3
The comparison study did not measure which vaccine was more effective at preventing actual cases of cervical cancer or precancerous lesions. Such a trial would require a longer and larger trial, which is not in plans set forth by GlaxoSmithKline.4
Men to get shot?
At the FDA committee meeting, Merck presented data in support of its supplemental application for Gardasil, which would indicate use of the vaccine in boys and men ages 9-26 for the prevention of genital warts (condyloma acuminata) caused by HPV types 6 and 11.
Data presented came from a Phase III randomized, placebo controlled study of 4,065 males ages 16-26. The point estimate for efficacy against genital warts in the per protocol population was 89.4% with 95% confidence interval (65.5%-97.9%). Analysis of safety outcomes after Gardasil compared to alum control was unremarkable, with similar rates of overall adverse events (69% vs. 64%) and serious adverse events (0.4% vs. 0.6%).5
Merck conducted bridging studies to compare antibody responses to HPV in male subjects from the pivotal trial to males 9-15 years of age. Antibody responses to each of the four virus-like particle types in the adolescent population were noninferior to those of older subjects. The company conducted the bridging studies to demonstrate protection, because the incidence of HPV-related genital lesions is very low before the onset of sexual relations, making a placebo-controlled efficacy trial in boys younger than age 16 years of age impractical.5
Research presented at the FDA committee meeting indicated Gardasil's safety profile observed in boys and men ages 9-26 is consistent with the safety profile observed in clinical studies in girls and women of similar ages.5
A joint review of more than 12,000 adverse events reported after administration of the quadrivalent HPV vaccine in women indicates Gardasil use in women continues to be safe and effective.6
Vasovagal syncope is among the most frequently reported adverse event following vaccination with Gardasil. With the increased use of adolescent vaccines, vaccine providers should diligently implement the ACIP recommendations for a routine 15-minute waiting period following vaccination, researchers note.6
References
- Markowitz LE. Update on HPV Vaccines. Presented at the National Immunization Conference. Dallas; April 2009.
- Miller N. Cervarix. FDA briefing document. Presented at the FDA Vaccines & Related Biological Products Advisory Committee Meeting. Sept. 9, 2009. Accessed at www.fda.gov/downloads/AdvisoryCommittees.
- Einstein MH, Baron M, Levin MJ, et al. Comparison of the immunogenicity and safety of Cervarix and Gardasil human papillomavirus (HPV) cervical cancer vaccines in healthy women aged 18-45 years. Hum Vaccin 2009; 5. Epub ahead of print.
- Loftus P. Glaxo study: Cervarix immune response tops Merck's Gardasil. The Wall Street Journal May 11, 2009. Accessed at online.wsj.com/article/SB124178398935000581.html.
- Robert JN. VRBPAC Briefing Document for the Vaccines and Related Biological Products Advisory Committee (VRBPAC). Presented at the FDA Vaccines & Related Biological Products Advisory Committee Meeting. Sept. 9, 2009. Accessed at www.fda.gov/downloads/AdvisoryCommittees.
- Slade BA, Leidel L, Vellozzi C, et al. Postlicensure safety surveillance for quadrivalent human papillomavirus recombinant vaccine. JAMA 2009; 302:750-757.
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