Vaccine against four common HPV strains may offer some protection against additional strains

Kelly Safreed-Harmon
Published: 27 March 2009

A vaccine designed to protect against four high-risk strains of human papilloma virus (HPV) appears to also provide women with some protection against related strains. Two studies published in the April 1st edition of The Journal of Infectious Diseases reached this conclusion after analysing levels of cross-protection among participants in the original vaccine efficacy trials. Even though the vaccine, Gardasil, only had a modest impact on non-vaccine strains, the findings are still important because they indicate that Gardasil may be able to prevent more cases of cervical cancer than originally estimated.

HPV is the most common sexually transmitted infectiom worldwide, and cervical cancer, which is nearly always caused by HPV, affects approximately 500,000 women annually. It is the most common cancer among women in developing countries.

Gardasil, which was approved in the United States and the European Union in 2006, is almost 100% effective against HPV types 6, 11, 16, and 18 in women not previously infected with those strains. HPV types 6 and 11 are the two strains most commonly associated with genital warts. HPV types 16 and 18 cause approximately 70% of cervical cancers.

HIV-positive women are at elevated risk for cervical cancer, and antiretroviral therapy does not appear to greatly reduce the risk. HPV also causes anal cancer, another health concern in HIV-positive populations. Clinical trials are underway to determine the impact of Gardasil in HIV-positive populations and in males.

The two recent studies assessed how well Gardasil protected women aged 16 to 26 against ten HPV strains that collectively cause up to 20% of all cervical cancers. The HPV types under investigation were 31, 33, 35, 39, 45, 51, 52, 56, 58, and 59.

One study, published by Brown et al., conducted analyses on women who did not have any of the Gardasil strains or the other ten strains on their first day of study participation. The other study, published by Wheeler et al., included women who had pre-existing HPV infection or HPV-related disease. Given the high overall prevalence of HPV, this study population was much more representative of sexually active women.

Both studies used the same dataset, which was created by combining data from FUTURE I and FUTURE II, the Phase III randomised placebo-controlled trials that demonstrated Gardasil’s efficacy. Participants in both studies were followed for an average of 3.6 years after they had received the first dose in a three-dose vaccine regimen.

Brown and colleagues examined infection endpoints for 2068 study participants. Infection was defined as having the same HPV type identified in two or more cervicovaginal/anogenital swabs at least six months apart or as having cervical/genital disease associated with an HPV type identified by a cervicovaginal/anogenital swab taken at the first visit before or after biopsy.

The researchers found that the vaccine study arm had 40.3% lower incidence of HPV-31/45 infection than the placebo arm (95% confidence interval [CI], 13.9-59%). The vaccination arm also had 25.0% lower incidence of HPV-31/33/45/52/58 (95% CI, 5-40%). After types 16 and 18, types 31 and 45 are the two types most commonly associated with cervical cancer, and 31, 33, 45, 52, and 58 are the five types most commonly associated with cervical cancer.

Analyses of incidence of cervical disease also showed the vaccine to be efficacious against non-vaccine types. In a group of 9296 study participants, the vaccine arm had a 23.4% reduction in cervical intraepithelial neoplasia of any grade/adenocarcinoma in situ (CIN1-3/AIS) associated with the ten HPV types of interest (95% CI, 7.8-36.4%), as well as a 32.5% reduction in CIN2-3/AIS (95% CI, 6-51.9%). Rates of reduction for HPV-31/45-related CIN1-3/AIS and HPV-31/33/45/52/58-related CIN1-3/AIS were 43.6% and 29.2%, respectively (95% CI, 12.9-64.1%, and 95% CI, 8.3-45.5%, respectively).

Cervical intraepithelial neoplasia is an abnormal growth in the lining of the cervix. The numbers one through three indicate the level of abnormal growth, with CIN1 being the least severe. CIN3, which encompasses adenocarcinoma, may progress to cervical cancer.

Wheeler and colleagues, in their study of women with pre-existing HPV infection or disease, also found evidence of vaccine cross-protection. Their intent-to-treat analysis used the same definitions of infection and disease used in the other study. In a group of 3459 study participants, approximately half belonging to the vaccine arm and half to the placebo arm, Gardasil was shown to reduce HPV-31/45 infection by 31.6% (95% CI, 15.4-44.7%). There was a 17.7% reduction in HPV-31/33/45/52/58 infection (95% CI, 5.1-28.7%).

When disease incidence was analysed in an 8582-member vaccine arm and an 8598-member placebo arm, further evidence of cross-protection was found. The vaccine arm had a 22.2% reduction in incidence of HPV-31/45-related CIN1-3/AIS (95% CI, 4.1-40.8%). The vaccine arm also had an 18.8% reduction in incidence of HPV-31/33/45/52/58-related CIN1-3/AIS (95% CI, 7.4-28.9%).

However, these reductions were largely due to reductions in CIN1, which is the least severe type. The vaccine had 24.6% efficacy against HPV-31/45-related CIN1 (95% CI, 4.1-40.8%) and 23.5% efficacy against HPV-31/33/45/52/58-related CIN1 (95% CI, 10.8-34.4%). There were no statistically significant reductions in incidence of CIN2-3/AIS.

An accompanying editorial commentary notes that Gardasil may be less effective in developing countries, where HPV-16 is not as widespread. Still, the author says, “In areas where screening has not been implemented, an affordable vaccine could be the only viable intervention for the prevention of cervical cancer. … In this context, cross-protection, even if limited, may help prevent more cancers.”

Women undergo HPV screening at high rates in developed countries, but the screening technologies are generally not available in many developing countries. Before there were effective treatments for HIV, cervical cancer was only one of many illnesses that commonly struck HIV-positive women. As antiretroviral therapy becomes more widely available in developing countries, mortality rates from other HIV-related illnesses are dropping. But without widespread HPV screening or vaccination, cervical cancer remains a major threat to HIV-positive women in developing countries.

Citing findings from another study, the editorial commentary also calls attention to the possibility that “cross-protective efficacy might not only be lower but also be of shorter duration than efficacy against vaccine types.” This suggests a need for close follow-up regarding long-term nonvaccine HPV incidence.

The same issue of The Journal of Infectious Diseases carries a study on the occurrence of genital warts in the placebo arms of FUTURE I and FUTURE II. The authors describe the prevalence of the four vaccine HPV types and ten non-vaccine HPV types in biopsy-confirmed genital warts.

DNA testing indicated the presence of HPV-6 and HPV-11, the two types most commonly associated with genital warts, in 350 (4.0%) of 8708 placebo recipients and 55 (0.6%) of 8720 placebo recipients, respectively. Among 8791 placebo recipients who underwent serologic testing, 724 (8.2%) and 181 (2.1%) had antibodies for HPV-6 and HPV-11, respectively.

Three hundred and fifty-one (4%) of 8800 placebo recipients developed genital warts during the study period. Among these women, 520 lesions were tested for the 14 HPV types. Four hundred and forty-seven (86%) of 520 lesions contained HPV-6, HPV-11, or both. The incidence rate for developing HPV-6- or HPV-11-related genital warts was 0.87 cases per 100 person-years-at-risk.

Not surprisingly, infection with HPV-6 or HPV-11 at baseline was associated with increased risk of developing genital warts. Forty-four (12.6%) of 350 women who were DNA-positive for HPV-6 at baseline developed genital warts, as did 3 (5.4%) of 55 women who were DNA-positive for HPV-11 at baseline. Other risk factors included having a higher number of sexual partners and acquiring a new sexual partner in the twelve months preceding the onset of genital warts.

The researchers also looked at how long it took for HPV-6- or HPV-11-related genital warts to develop. Among women who were DNA-negative for HPV-6 in all swab samples obtained from day one through month seven, the median time to detection of genital warts was 25.7 months. For women who were DNA-negative for HPV-11, the median time to detection was 23.8 months.

Median time to genital warts detection was also assessed in women who were DNA-positive for HPV-6 and HPV-11 one or more times from day one through month seven. The median time to detection for HPV-6 was 6 months, and the median time for HPV-11 was 4.9 months.


Brown DR et al. The impact of quadrivalent human papillomavirus (HPV; types 6, 11, 16, and 18) L1 virus-like particle vaccine on infection and disease due to oncogenic nonvaccine HPV types in generally HPV-naive women aged 16–26 years. The Journal of Infectious Diseases 199: 926–935, 2009.

Garland SM et al. Natural history of genital warts: analysis of the placebo arm of 2 randomized Phase III trials of a quadrivalent human papillomavirus (types 6, 11, 16, and 18) vaccine. The Journal of Infectious Diseases 199: 805–814, 2009.

Herrero R Human papillomavirus (HPV) vaccines: limited cross-protection against additional HPV types. The Journal of Infectious Diseases 199: 919 –922, 2009.

Wheeler CM et al. The impact of quadrivalent human papillomavirus (HPV; types 6, 11, 16, and 18) L1 virus-like particle vaccine on infection and disease due to oncogenic nonvaccine HPV types in sexually active women aged 16–26 years. The Journal of Infectious Diseases 199: 936–944, 2009.

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