HPV Vaccine: 2 Doses as Good as 3 Doses in Young Women

Troy Brown

April 30, 2013

Young women who received 2 doses of human papillomavirus (HPV) vaccine had immune responses to HPV-16 and HPV-18 that were noninferior to those of young women who received 3 doses of the vaccine, according to a new study that included 830 girls and young women in Canada.

Simon R.M. Dobson, MD, from the Department of Pediatrics at University of British Columbia and the Vaccine Evaluation Center in Vancouver, British Columbia, Canada, and colleagues present their findings in an article in the May 1 issue of JAMA. Dr. Dobson discussed the study at a JAMA media briefing on April 30.

Cervical cancer is the second most commonly diagnosed cancer in women worldwide, and HPV genotypes 16 and 18 account for approximately 70% of cervical cancer cases, the authors note in the journal.

"One of the barriers for this particular vaccine is its high cost," Dr. Dobson said in the media briefing. The required 3 doses are another barrier. "There are many girls who start a vaccine program but then don't complete it. The advantage of a reduced dosing schedule would be that you might be able to get better compliance," Dr. Dobson added.

The randomized, phase 3, postlicensure, multicenter, age-stratified, noninferiority immunogenicity study was conducted from August 2007 through February 2011. Follow-up blood samples were obtained from 675 participants (81%).

Girls aged 9 to 13 years were randomly assigned 1:1 to receive 3 quadrivalent HPV vaccine doses at 0, 2, and 6 months (n = 261) or 2 doses at 0 and 6 months (n = 259). Young women aged 16 to 26 years were given 3 doses at 0, 2, and 6 months (n = 310). The researchers measured antibody levels at 0, 7, 18, 24, and 36 months.

The primary outcome was noninferiority (95% confidence interval [CI], lower bound 0.5) of geometric mean titer (GMT) ratios for HPV-16 and HPV-18 for the girls who received 2 doses compared with that seen in the young women who received 3 doses 1 month after the last dose. The secondary outcomes were noninferiority of GMT ratios of the girls who received 2 vs 3 doses and durability of noninferiority to 36 months.

GMT ratios for girls (2 doses) to women (3 doses) were noninferior for all 4 genotypes. GMT ratios were 2.07 (95% CI, 1.62 - 2.65) for HPV-16 and 1.76 (95% CI, 1.41 - 2.19) for HPV-18. At 1 month after vaccination, girls (3 doses) had GMT responses for HPV-16 of 7736 milli-Merck units per milliliter (mMU/mL; 95% CI, 6651-8999 mMU/mL) and for HPV-18 of 1730 mMU/mL (95% CI, 1512 - 1980 mMU/mL).

The GMT ratios for girls (2 doses) to girls (3 doses) were noninferior at 0.95 (95% CI, 0.73 - 1.23) for HPV-16 and 0.68 (95% CI, 0.54 - 0.85) for HPV-18. For girls (2 doses) to women (3 doses), the GMT ratios remained inferior for all genotypes to 36 months. In the girls, antibody responses were noninferior after 2 vs 3 doses for all 4 vaccine genotypes at month 7. Antibody responses were not noninferior for HPV-18 by month 24 or HPV-6 by month 36.

It is not known how long protection will last with the 3-dose regimen or the 2-dose regimen, Dr. Dobson explained. "Nor is it known if 2 doses will work as well as 3 doses in terms of preventing cervical cancer precursors," Dr. Dobson said.

A 10-year study is planned that will look at HPV infection and HPV persistent infection as the outcomes, Dr. Dobson added.

In an accompanying editorial, Jessica A. Kahn, MD, MPH, from the Division of Adolescent Medicine and David I. Bernstein, MD, MA, from the Division of Infectious Diseases in the Department of Pediatrics at Cincinnati Children's Hospital Medical Center and the University of Cincinnati College of Medicine in Ohio, comment, "If future studies establish that a 2-dose series leads to a durable immune response and effectively prevents HPV-related cancers in both women and men, the benefits would be substantial for reducing the global burden of cervical cancer and other HPV-related diseases."

The Ministries of Health in the provinces of British Columbia, Nova Scotia, and Quebec funded this project. Provincial Health Services Authority conducted the HPV DNA assays. Merck Laboratories Inc conducted the antibody assays at no cost to the study. Dr. Dobson received grant support from the Michael Smith Health Foundation, served on the advisory board and consulted for GlaxoSmithKline, and received funding for travel and accommodations from Merck. Several other researchers reported a variety of relationships with pharmaceutical companies that manufacture vaccines, including receipt of grant funding, consulting fees, and lecture fees. A complete list can be found with the journal article. The funding for the grant program was provided to the Society for Adolescent Health and Medicine by Merck. Dr. Kahn served as the chair of a grant review committee for a grant program administered by the Society for Adolescent Health and Medicine, which is funding projects designed to improve adolescent vaccination rates, and as cochair of 2 clinical trials of the quadrivalent HPV vaccine in HIV-infected women and men funded by the National Institutes of Health. Merck provided vaccine and immunogenicity testing for these studies. Dr. Bernstein received lecture fees and royalties from GlaxoSmithKline for sales of a rotavirus vaccine.

JAMA. 2013;309:1793-1802.


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