Immunization Science

Development of an HPV-16 Vaccine

The article

A Controlled Trial of a Human Papillomavirus Type 16 Vaccine. Koutsky LA, Ault KA, Wheeler CM, Brown DR, Barr E, Alvarez FB, Chiacchierini LM, Jansen KU, for the Proof of Principle Study Investigators. The New England Journal of Medicine 2002;347(21):1645-1651.

Explanatory note: The primary reason to develop a vaccine for human papillomaviruses (HPVs) is to prevent cervical cancer in women.

Of the more than 100 different HPVs, more than 30 are sexually transmitted, often infecting the genital areas of both men and women. About 20 of these HPVs cause cervical and other anogenital cancers. For example, 18% of US women have been infected with HPV-16, the most common cause of cervical and other anogenital cancers.

When infected with cancer-causing types of HPV, most women have no symptoms and will recover uneventfully from the infection. However, some remain persistently infected with the virus and may go on to develop cancer.

Vaccines containing the L1 proteins of certain HPVs, such as HPV–16 (which causes approximately 50–60% of cervical cancers) and HPV–18 (which causes another 10–20% of these cancers) are being studied in clinical trials to determine whether such vaccines can prevent cervical cancer. This article reports the results of a “proof of principle” trial of a HPV-16 vaccine. The primary reason to develop a vaccine for human papillomaviruses (HPVs) is to prevent cervical cancer in women. Of the more than 100 different HPVs, more than 30 are sexually transmitted, often infecting the genital areas of both men and women. About 20 of these HPVs cause cervical and other anogenital cancers. For example, 18% of US women have been infected with HPV-16, the most common cause of cervical and other anogenital cancers. When infected with cancer-causing types of HPV, most women have no symptoms and will recover uneventfully from the infection. However, some remain persistently infected with the virus and may go on to develop cancer. Vaccines containing the L1 proteins of certain HPVs, such as HPV–16 (which causes approximately 50–60% of cervical cancers) and HPV–18 (which causes another 10–20% of these cancers) are being studied in clinical trials to determine whether such vaccines can prevent cervical cancer. This article reports the results of a “proof of principle” trial of a HPV-16 vaccine.

The question

Can the candidate HPV-16 vaccine prevent persistent HPV-16 infection in women?

The study

This study included 2,392 young women (between 16 and 25 years of age). One group (1,198) received three doses of placebo (an inert substance) and the other (1,194) received three doses of a HPV-16 L1 protein presented as “virus-like-particles”—that is it looks like a virus to the immune system but cannot replicate. The doses were given at day 0, month 2, and month 6.

The researchers collected genital samples to test for HPV-16 DNA at enrollment, one month after the third vaccination, and every six months thereafter. The women were followed for about three years after the first vaccination.

Women who were already infected with HPV-16 or who became infected before 7 months into the study—after the course of immunization was completed and enough time had elapsed for immunity to have been established—were excluded from the analysis.

The findings

The most common reason for exclusion from analysis was prior HPV-16 infection (233 vaccine and 277 placebo recipients).

Of the 1533 women who were analyzed, 74 developed evidence of HPV-16 infection at least once after the seventh month when analysis began.

Of the 74 women, 33 (6 who had received vaccine and 27 placebo recipients) had transient HPV-16 infection.

Of the 74 women, 41 in the placebo group developed persistent HPV-16 infection; 31 of these were persistent infections without cancerous changes of the cervix; and 9 had grade 1 or 2 changes (early precancerous changes) of their cervix. An additional woman was lost to follow-up.

Persistent HPV-16 infection did not occur in the vaccine group. Thus, the vaccine efficacy by this measure was 100%.

Early pathologic changes of the cervix not associated with HPV-16 were seen in 22 vaccine and 22 placebo recipients.

In the vaccine group, 99.7% of the women developed antibodies against HPV-16.

The most frequent adverse reaction—similar in both groups—was pain at the injection site. There were no vaccine related serious adverse events.

The relevance/bottom line

Many women were HPV-16 infected prior to entering the study.

This study provides “proof of principle” that this HPV-16 vaccine given prior to infection with HPV-16 protects against persistent HPV-16 infection. The vaccine had no effect on other causes of precancerous cervical changes.

NNii’s comments

Until the prevention of persistent HPV infection is established to be a good surrogate marker for the prevention of cervical cancer, the ultimate proof of vaccine effectiveness will need to come from studies that use precancerous changes of the cervix as study endpoints. This seems to be likely as more data are collected from this and other studies that are underway.

Multivalent vaccines that contain other major cancer causing types of HPVs are needed. A number of candidate vaccines are being evaluated.

To be maximally effective, HPVs vaccines will need to be administered prior to the time that young women become sexually active. Understanding parental concerns as well as the ethical considerations about vaccines that prevent complications of sexually transmitted diseases will be very important for vaccine acceptance.