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TWO DOSES (or maybe even 1) OF HPV VACCINE
  "women receiving two or even one dose of an HPV vaccine in a trial in Costa Rica had equivalent persistent HPV 16/18 infection rates as those receiving the full three-dose regimen"

U.S. Department of Health and Human Services
National Cancer Institute (NCI)
September 9, 2011


Two doses of the human papillomavirus (HPV) vaccine Cervarix were as effective as the current standard three-dose regimen after four years of follow-up, according to researchers from the National Cancer Institute (NCI), part of the National Institutes of Health, and their colleagues. The results of the study, based on data from a community-based clinical trial of Cervarix in Costa Rica, appeared online Sept.9, 2011, in the Journal of the National Cancer Institute.

Worldwide, approximately 500,000 new cases of cervical cancer are diagnosed every year, and about 250,000 women die from the disease. An overwhelming majority of these new cases and deaths occur in low-resource countries. Virtually all cases of cervical cancer are caused by persistent infection with HPV. Cervarix is one of two vaccines approved by the U.S. Food and Drug Administration to protect against persistent infection with two carcinogenic HPV types, 16 and 18, which together account for 70 percent of all cervical cancer cases. The vaccine is intended to be administered in three doses given over the course of six months. To date, investigators have observed up to eight years of protection from persistent HPV infection with the vaccine. Studies are ongoing to determine the maximum length of protection.

The cost of the vaccine as well as the logistical difficulties of administering three doses to an adolescent population in resource-poor countries is greater than administering two doses. Even in wealthier countries such as the United States, few adolescent females complete the entire course of three vaccinations. According the Centers for Disease Control and Prevention, although approximately 49 percent of American girls ages 13 to 17 received one dose of the vaccine in 2010, only 32 percent received all three doses. In the United States, the predominately used HPV vaccine is Gardasil, which has a different formulation than Cervarix. Gardasil also protects against up to 90 percent of genital warts because it targets HPV strains 6 and 11 as well as 16 and 18.

The NCI-sponsored Costa Rica Vaccine Trial was designed to assess the efficacy of Cervarix in a community-based setting. Women ages 18 to 25 years were randomly assigned to receive the HPV vaccine or a Hepatitis A vaccine as the control treatment. Although the investigators intended to administer all three doses of the assigned vaccine to all 7,466 women in the study, about 20 percent of the participants received only one or two doses of the HPV or control vaccine. A third of women did not complete the vaccine series because they became pregnant or were found to have possible cervical abnormalities, reasons that would not likely bias the findings.

The investigators found that, after four years of follow up, two doses of the vaccine conferred the same strong protection against persistent infection with HPV 16 and 18 as did the full three-dose regimen. From just a single dose, they also observed a high level of protection, but they are cautious about the long-term efficacy of a single dose because other vaccines of this type usually require a booster dose. Additional studies are needed to evaluate the efficacy of a single dose, as well as the duration of protection for both one and two doses.

"Our study provides evidence that an HPV vaccine program using two doses will work. It may be that vaccinating more women, with fewer doses for each, will reduce cervical cancer incidence more than a standard three-dose program that vaccinates fewer women," said Aimee R. Kreimer, Ph.D., lead author and investigator in NCI's Division of Cancer Epidemiology and Genetics. "The main question will be whether the duration of protection from fewer doses is adequate."

Kreimer emphasized that findings from this study of the Cervarix vaccine in women in Costa Rica may not be relevant for all populations, such as those in which HIV infection, malnutrition, or endemic diseases may influence the immune response. In addition, it is not known whether the same results would be obtained with the other FDA-approved HPV vaccine, Gardasil, because the vaccine formulations are different.

"Further studies are needed to confirm our findings in other populations as well as to quantify the duration of protection for fewer than three doses," said Kreimer. "If other studies confirm that fewer than three doses provide adequate protection against persistent cervical HPV 16 and 18 infection, we may be one step closer to prevention of cervical cancer, especially for women in resource-poor settings, where the need is greatest."

It is important to note that regulatory agencies have approved the HPV vaccine based on prevention of cervical precancers, not persistent infections. From studying the natural history of HPV and cervical cancer, experts know that persistent infections are first steps toward precancer. Furthermore, vaccine recommendations take into consideration many factors and studies. In the United States, the CDC's Advisory Committee on Immunization Practices determines federal recommendations regarding vaccination.

This study was carried out by an international team of experts from the NCI, the Costa Rica HPV Vaccine Trial, and colleagues at DDL Diagnostic Laboratory in the Netherlands.

NCI leads the National Cancer Program and the NIH effort to dramatically reduce the burden of cancer and improve the lives of cancer patients and their families, through research into prevention and cancer biology, the development of new interventions, and the training and mentoring of new researchers. For more information about cancer, please visit the NCI Web site at or call NCI's Cancer Information Service at 1-800-4-CANCER (1-800-422-6237).

About the National Institutes of Health (NIH): NIH, the nation's medical research agency, includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. NIH is the primary federal agency conducting and supporting basic, clinical, and translational medical research, and is investigating the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit .


Three HPV Vax Doses May Be Overkill

By John Gever, Senior Editor, MedPage Today

Published: September 08, 2011

Action Points

· Explain that women receiving two or even one dose of an HPV vaccine in a trial in Costa Rica had equivalent persistent HPV 16/18 infection rates as those receiving the full three-dose regimen.

· Note that while women receiving fewer doses were followed, the study was not randomized to address the question, but the investigators pointed out that achieving the full three-dose regimen encounters both logistic and cost barriers.

Two doses of a bivalent vaccine against human papillomavirus (HPV) appeared just as effective in preventing persistent infections as the recommended three doses in young women, according to a study in Costa Rica.

In fact, the study -- led by researchers at the U.S. National Cancer Institute -- found that a single dose was effective as well, although the number of participants in that arm was relatively small.

The findings were important because, in low-income regions, providing the full three-dose regimen of HPV vaccines to all eligible women and teens may not be economically feasible, explained Aimee R. Kreimer, PhD, of the NCI's epidemiology division in Rockville, Md., and colleagues.

"The cost and logistical difficulties of the standard three-dose vaccine regimen compromises implementation of this life-saving measure in resource-poor settings," the researchers wrote online in the Journal of the National Cancer Institute.

"Our clinical efficacy data provide suggestive evidence that an HPV vaccine program that could vaccinate 50% more women with a two-dose regimen could potentially reduce cervical cancer incidence more than a standard three-dose program that uses the same number of total doses but in fewer women."

The study was designed as a randomized trial involving nearly 7,500 women, who were to receive either three doses of the bivalent Cervarix vaccine active against HPV serotypes 16 and 18 or a hepatitis A vaccine that served as a control.

Participants were women 18 to 25 years old in general good health, HPV-negative at baseline according to liquid cytology and molecular testing, had no history of hepatitis A infection or vaccination, and were willing to use contraception during the vaccination period.

But some participants missed scheduled doses -- 929 ended up receiving only two doses and 551 had just one dose.

About half of both groups had received active HPV vaccine and half had the control product. Outcomes were tracked in these women as they were in those receiving the full three-dose regimen.

The primary outcome measure was infection with HPV 16 or 18 that lasted as least 10 months. Participants were followed for a median of 4.2 years.

HPV vaccine efficacy rates by this measure were as follows:

· Three doses: 80.9% (95% CI 71.1% to 87.7%)

· Two doses: 84.1% (95% CI 50.2% to 96.3%)

· One dose: 100% (95% CI 66.5% to 100%)

The most common reason for missing doses was pregnancy, followed by missed appointments and medical conditions.

Kreimer and colleagues expressed surprise at the apparent efficacy of a single vaccine dose. "Other subunit vaccines typically require boosting following the prime dose to confer long-term protection," they wrote.

But, they added, "perhaps many of our sexually active participants had been previously exposed to HPV16 or HPV18."

The researchers also cautioned that the efficacy rate calculated for the single dose was based on a relatively small sample (only 10 participants receiving one dose of the control vaccine developed persistent HPV infections) and follow-up lasted only about four years.

Other limitations of the study included that it was not randomized for fewer than three vaccine doses, that the persistent infection endpoint might or might not translate to protection against the development of cervical intraepithelial neoplasia, and that the study was not performed in younger girls.

Experience in other HPV vaccine trials has suggested that the products give protection with less than the full recommended series, Kreimer and colleagues noted.

Still, they suggested it would be premature to recommend less than three doses of the bivalent product for all recipients.

The full regimen "may confer greater cross-protection against heterologous HPV types," they wrote, and the study results may not apply to other populations or to other vaccine products.

"Finally, the duration of protection for fewer than three doses must be quantified," Kreimer and colleagues wrote. They indicated that an ongoing trial in India, sponsored by the WHO, may help settle some of these issues.

In an accompanying editorial, Cosette Marie Wheeler, PhD, of the University of New Mexico, agreed that the study had enough limitations that the results should be interpreted cautiously -- even for "resource-poor" locations where stretching the available vaccine stocks is tempting.

"If, over the long term, clinically meaningful and durable cross-protection is achieved with a three-dose but not with a two-dose regimen of the bivalent HPV vaccine, the trade-offs will need to be considered in the context of cost-effectiveness and resource availability," Wheeler wrote.

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