HPV vaccine shows good efficacy, but how valuable will it be in 'real world' settings?

Vaccine to protect against warts and cell changes caused by HPV-6/11/16/18

A total of 5,455 women aged between 16 and 24 were randomised in the FUTURE I study to receive either three doses of the quadrivalent vaccine over six months or a placebo. Both arms of the study were then intensively monitored at regular intervals over four years for the emergence of external anogenital HPV-related disease. At baseline, individuals were screened for the presence of HPV infection. The median duration of follow-up was three years.

The investigators performed three sets of analyses:

• An analysis of the effectiveness of the vaccine under optimum conditions – this involved individuals who received all three doses of the vaccine and were negative for HPV-6/11/116/18 at baseline.
• An analysis of the vaccine’s effectiveness under variable dose intervals – this involved all the uninfected women at baseline, but also included women who violated the protocol of the study, for example by not receiving all the vaccine doses as specified.
• An analysis of the population effect amongst all vaccinated individuals – this intent-to-treat analysis included women even if they were infected with HPV-6/11/16/18 at baseline, had HPV-associated disease, or violated the study protocol.

The vaccine was 100% effective at preventing HPV-associated anogenital disease in the per-protocol analysis. None of the women who met the criteria for inclusion in this analysis developed anogenital warts or pre-cancerous or cancerous cell changes, compared to 60 women in the placebo arm.

The investigators also found that the vaccine was 95% effective at preventing HPV-associated external anogential and vaginal lesions and 98% effective against cervical disease in women, uninfected with HPV at baseline, but who violated the terms of the study protocol.

To see how the vaccine would perform in the ‘real world’ the investigators conducted two sets of intent-to-treat analysis. The first looked at how effective the vaccine was at preventing anogenital disease caused by HPV-6/11/16/18 in women infected with one or more of these strains at baseline. Their analysis revealed a 73% efficacy (28 versus 102 cases) against anogenital and external vaginal lesions and 55% against cervical lesions (71 versus 55 cases).

A second intent-to-treat analysis was then performed. Once again, this included women infected with HPV-6/11/16/18 at baseline, but this time it explored the efficacy of the vaccine at preventing disease caused by any strain of HPV. This showed a vaccine efficacy of 34% (104 cases versus 157) in the reduction of external anogenital warts or lesions and an efficacy of 20% in the reduction of cervical lesions (344 versus 421 cases).

Vaccine recipients were more likely than those in the placebo arm (87% versus 77%) to experience injection site reactions, but similar proportions of women from both arms of the study (13% versus 10%) reported fever after vaccination.

“These results of the FUTURE I study show that a prophylactic quadrivalent HPV vaccine is highly effective in preventing clinical disease”, comment the investigators.

A vaccine against the types of human papilloma virus (HPV) that cause most anogenital disease and cancerous and pre-cancerous cell changes is highly effective at preventing the development of anogenital warts and progression to pre-cancerous and cancerous cell changes in women who were not infected with these types of HPV before receiving the vaccine, investigators have shown.

However the research, published in May 10^th edition of the New England Journal of Medicine, found that the vaccine may have much lower levels of efficacy in a ‘real world’ setting, when it would be administered to individuals already infected with the types of HPV it is intended to protect against. This finding may serve as a timely caution for individuals in both the United Kingdom and United States who are unaware of their HPV infection status yet are paying for private HPV vaccination.

The investigators also stressed that their studies did not include men or women with HIV, so they were unable to comment on the efficacy of the vaccine in these groups.

Anogenital infection with HPV can cause warts, pre-cancerous cell changes and invasive cancers. The types of HPV most commonly associated with anogenital warts and pre-cancerous cell changes are HPV-6/11/16/18, and HPV types 16/18 are the most common cause of high-grade pre-cancerous and cancerous cell changes in the cervix.

Both anal and cervical cancers caused by HPV infection are seen more often in HIV-positive individuals than in the general population. Although potent antiretroviral therapy can help the body mount a more effective response to HPV and pre-cancerous cell changes, it does not have any direct effect against HPV.

Investigators from the pharmaceutical company Merck wished to see how safe and effective their quadrivalent vaccine against these types of HPV was at preventing both anogenital disease and high-grade pre-cancerous and cancerous cell changes in women.

They therefore designed two randomised, double-blind, placebo controlled trials. The first, FUTURE 1 (Females United to Unilaterally Reduce Endo/Ectocervical Disease), was intended to see if the vaccine prevented external anal or vaginal warts, and cervical cell changes and disease. The second, the FUTURE II study, was designed to determine the efficacy of the vaccine at preventing pre-cancerous cell changes in the cervix (cervical intraepithelial neoplasia – CIN-2 and CIN-3) caused by HPV-16/18.

The studies recruited women in both resource-rich and resource-limited countries between 2002 and 2003 and the investigators published three-year follow-up data.

Protection against high-grade pre-cancerous cervical cell changes

The FUTURE II study involved over 12,000 women and was designed to test the safety and efficacy of the quadrivalent vaccine against the development of CIN-2 and CIN-3 caused by HPV-16/18. The women enrolled in the study were aged between 15 – 26 years and were randomly assigned to either receive three doses of the vaccine over six months or a placebo. The study is designed to last four years. Three years of follow-up were reported by the investigators.

In their first analysis, the investigators found that the vaccine was 98% effective at preventing CIN-2 or CIN-3 in women uninfected with HPV-16/18 at baseline. Only one case of CIN developed in a woman provided with the vaccine in this analysis and she was positive for HPV-52 at baseline.

In the second analysis, which once again included women uninfected with HPV-16/18 at baseline but who did not strictly follow the study protocol, an efficacy of 95% was found.

Intent-to-treat analysis, involving women infected with HPV-16/18 at baseline, found that the vaccine had 44% efficacy at preventing high grade CIN caused by HPV-16/18. However, efficacy was only 17% against high-grade CIN caused by any other type of HPV.

The investigators note that the study did not look at the effectiveness of the vaccine in men, and excluded HIV-positive women.

An accompanying editorial is generally enthusiastic about the findings of the studies, the authors writing, “investigators in these trials have hit their mark soundly.” But they are more circumspect about the usefulness of the vaccine for women who are already sexually active, stressing that the vaccine has very modest efficacy in women already infected with HPV.