The Cervical Cancer Vaccine

By now you've already heard the news about Gardasil, Merck's new cervical cancer vaccine targeting the human papillomavirus (HPV):

NEW YORK (Reuters) Oct 06 - An experimental vaccine completely prevented early-stage cervical cancer and precancerous cervical lesions caused by human papillomavirus type 16 and 18, Merck & Co. said on Thursday.

"This trial confirms that a vaccine can give young women a high level of protection from developing precancerous lesions and early cervical cancers," Laura Koutsky, a professor of epidemiology at the University of Washington who led the study, told Reuters.

The favorable findings were seen in a phase III trial sponsored by the U.S. drugmaker, which included more than 12,000 women from 13 countries, aged 16 to 26, who were not infected with either of the virus types when the trial began.

HPV 16 and 18 are responsible for an estimated 70% of cervical cancer cases, and are the targets of Merck's Gardasil vaccine. Such cancers kill about 300,000 women worldwide each year, including almost 4,000 in the United States, Merck said.

...

Half the women in the trial received three doses of Gardasil over a 6-month period, while the other women received placebo. The women were then followed for an average of 17 months.

Merck said Gardasil was 100% effective in preventing precancerous lesions and early-stage cancers associated with HPV 16 and 18 among women who remained free of infection until they received their final dose of the vaccine. The vaccine thereby easily met its primary trial goal.

By contrast there were 21 cases of lesions and early-stage cancers associated with the two virus types among those taking placebos, Merck said.

Although the vaccine was completely protective against the two virus types, Koutsky said she hopes the vaccine will eventually be improved to protect against up to another half dozen types of the virus that cause cervical cancer.

"In that case, you could be blocking viruses that cause 87% of cervical cancer cases, instead of 70%," she said.

We have already discussed HPV, so let's try to address some of the questions you might have about the vaccine.

Q: Why do we need to vaccinate the population at large?

It's estimated that 75% of the population gets exposed to this very common virus at some point during their lives. Overall:

1% (1.4 million) have genital warts.

4% (5 million) have subclinical disease (evidence of HPV manifestations that are not visible to the naked eye, but could be detected with colposcopic magnification. These subclinical manifestations are most important on the cervix, but may be found anywhere on the lower genital tract. Many of these individuals will have an abnormal Pap smear.)

10% (14 million) are HPV positive (on colposcopy there is no evidence of disease.)

60% (81 million) have been exposed to HPV (A reliable HPV antibody test is likely to be positive, but a direct test for the virus would be negative, indicating that there had been an infection in the past, but the patient developed an immune response and suppressed the virus.)

So, 75% of the population is exposed to HPV. Once infected, most people's immune system, and/or treatment keep the infection in check. The majority of people with the disease do not progress to cervical cancer. Unfortunately, it is not possible to predict how any one individual will react to being infected with HPV.

Q: Why are the vaccine trials focused on preferentially vaccinating young women?

First, why females? By design--because of the cervix--women (young women, as well as pregnant women, regardless of age) are more susceptible. [On the cervix there's an area of transition--from vaginal- to uterine-type tissue. This area is called the transformation zone (TZ); it's an area of high activity. Not only are TZ cells more vulnerable to HPV infection, but, once infected, they're more likely to undergo HPV-induced cancerous transformation. Approximately 90% of cervical cancers occur in this small anatomic region. There is no TZ equivalent on the penis.]

Click [WARNING! graphic pics] here to see cervical manifestations of HPV in the TZ.

Second, why young females?

Because our aim is to prevent infection in the first place.

In the United States, the average age of menarche [first period] is about 12 years of age. Girls typically initiate intercourse in their mid to late teens. By the age of 20 many would have been exposed to HPV.

Currently, the way we deal with HPV is to intervene *after* the infection has occurred. However, the ideal approach is to prevent infection in the first place. This could be achieved by the use of a prophylactic HPV vaccine.

Click here to see a very nice illustration of this concept (Slide 12).

Q: Why are HPV 16 and 18 the target of Merck's vaccine?

Because [o]ne of the most important determinants of whether an HPV infection will progress to precancer or cancer is the HPV type.

Recall that HPV can infect many different sites--the larynx, skin, mouth, esophagus, and the anogenital tract. Over 100 HPV types have been detected; ~20 different types of HPV can infect the anogenital tract. Persistent infection with an oncogenic [cancer-causing] HPV type is the most important risk factor for cervical cancer.

Infection with high-risk HPV types, most commonly types 16 and 18, cause low-grade cervical cell abnormalities as well as high-grade cervical cell abnormalities that are precursors to invasive cervical cancer. They're also associated with other malignancies including vulvar and anal cancer. [Other high-risk HPV types are 31, 33, and 45.] Infections with low-risk types most commonly types 6 and 11 cause benign or low-grade cervical cell changes and condylomata acuminata otherwise known as genital warts.

Fast Fact: You have a 60% risk of getting the infection in a single sexual contact with someone who has genital warts.

So, if you're trying to combat cervical cancer, you need to come up with a vaccine that works against HPV types 16, and 18. If your focus is genital warts you need to develop a vaccine that targets HPV types 6 and 11. [Of course, the ideal solution is to come up with a vaccine that works against all four HPV types--16, 18, 6, and 11. Researchers are working on just such a quadrivalent HPV vaccine.]

To read a detailed account of the HPV vaccine trials, go here. Of note, the safety of the vaccine:

When looking at serious adverse effects, we find the numbers in this study are very similar to the numbers in the last study. Notice that for serious adverse effects related to vaccine, the numbers are again zero in both placebo and the vaccine arms, and that during the study 22 patients in the vaccine group and 19 patients in the placebo arm had some sort of adverse reaction.

Q: Are the researchers working on the HPV vaccine aware of potential barriers to its acceptance?

Yes they are:

There are many specific issues that a health care provider may need to deal with when educating patients and their families about HPV vaccination. Foremost are family or parental issues regarding HPV vaccination. The ideal age group for HPV vaccination may well be young teenagers who do not normally have to deal with issues related to sexually transmitted diseases or cancer prevention. Many parents may or may not decide that the vaccine is a good thing for their daughter or feel that their daughter is specifically at risk for the diseases the vaccines prevent. They also may think that it's an issue that can be put off since the child is not sexually active, not understanding the fact that it is best to give the vaccine before initiation of sexual activity.

...

There are also specific individual issues that may have to be addressed. There are a lot of health beliefs and lifestyle issues that may be pulled into the debate about whether HPV vaccine is right for specific patients. Specifically, a patient may have issues about perceived susceptibility to the disease process itself, the severity and nature of HPV infection, and the benefits of immunization. We already know from studies that many patients do not know about HPV and are unaware of the serious sequelae that can occur from HPV infection. In fact, less than one-third of men and women in the general population are aware of HPV and its sequelae.

There may also be cultural issues that have to be dealt with. Some folks may feel that the HPV infection, being an STD, is a deterrent to sexual activity. They may also see the HPV vaccine as condoning or encouraging teenage sexual activity. There also may be distrust of the vaccine itself, or any sort of medical activity or device, and there are specific groups out there who feel like all vaccines are bad.

Bottom line: The HPV vaccine is an extremely significant development because it offers tremendous possibility in helping reduce the incidence of abnormal Pap smears, cervical cancer, and genital warts in the United States as well as worldwide.