A recently-published study (New England Journal of Medicine, Nov. 21) describes a new vaccine that can prevent persistent infection from a virus HPV, the human papillomavirus known to be a causative factor in about one-half of all cases of cervical cancer. This is a major breakthrough, for the fight against cervical cancer and, more broadly, for the burgeoning field of pharmaceutical products that may be useful in preventing human cancer.
Cervical cancer is a major problem: worldwide, it is one of the top three cancer killers of women, along with breast and lung cancer, with almost 500,000 cases and over 250,000 deaths annually, according to recent World Health Organization statistics. In the United States, it is much less of a problem than it is in the less-developed countries. Here, around 14,000 cases and 4,100 deaths occur each year. While the large majority of these deaths could be prevented, theoretically, with optimal utilization of Pap smears, in fact not all women who should get this screening actually do, and even those screened do not always get adequate follow-up care.
Cervical cancer has long been known to be a sexually-transmitted disease, but only in the past thirty years has its specific causal relationship with HPV been established. While there are many different types of HPV, only about five have been implicated as causative agents of human cervical cancers, and just two of these strains HPV-16 and HPV-18 have been shown to cause 70% of cervical cancers.
While cervical cancer seemingly requires infection with HPV to occur, the large majority of women who contract this virus do not develop cancer. Indeed, one study showed that about 60% of female college seniors had HPV infecton. (Condoms reduce, but do not eliminate, the risk of sexual HPV transmission). But most infected women fight off the infection with their own immune systems and develop no untoward effects. Some, however, develop early signs of abnormal cells, detected with Pap tests as "cellular atypia." If untreated, this condition may progress to "cervical intra-epithelial neoplasia," or CIN, which is early-stage cancer it has not spread and is still completely curable surgically. Only if this is not addressed does it spread and, potentially, kill.
The New Vaccine
The strain most commonly implicated in cervical cancer, HPV-16, is associated with about half of all such cancers. The current study involved administration of a vaccine against this strain to 768 young women who were found to be free of HPV-16 infection at the beginning of the study. A comparison group of 765 women, aged sixteen to twenty-three, received inactive placebo injections; subjects in both groups received three injections over a period of six months. The study subjects were then followed over an average period of eighteen months (although the study will be continued until all have been followed for four years).
The vaccine was produced by growing DNA-free, virus-like particles in yeast cells at the Merck Research Laboratories in West Point, Pennsylvania; the study subjects were evaluated at sixteen medical centers around the U.S. The fact that the virus-like particles lack DNA makes them unable to replicate thus, they are non-infectious.
The study results showed that forty-one women who did not get the vaccine (i.e., women from the placebo group) developed persistent HPV-16 infection, and nine of those developed HPV-16-associated CIN. However, no woman who received the active vaccine developed persistent infection with HPV-16, and none developed CIN associated with that strain of the virus. That is the very good news. It should be noted that twenty-two women who received the vaccine developed CIN associated with a different strain of HPV and the same number did so in the placebo group. This illustrates the fact that other strains of HPV are responsible for some cases of cervical cancer.
So, what does the future hold? Merck and other companies, as well as the National Cancer Institute, are feverishly working on developing and testing HPV vaccines against several different combinations of strains in hopes of preventing an even larger proportion of cervical cancer cases and the atypical Pap tests that precede them. A successful program would not only prevent much disease and death, it would also save huge amounts of scarce public health funds now devoted to treating cancer and to following up abnormal Pap tests many of which are false positives. It must be noted, though, that neither this nor any future vaccines similar to it are likely to be effective after the virus has already taken hold; thus, to be effective, it will have to be administered prior to exposure to HPV that is, prior to sexual initiation. This approach, while appropriate from a public-health viewpoint, creates marketing conundrums from a political perspective, since parents may be reluctant to vaccinate teens or embarrassed about discussing the purpose of the vaccine.
A potential side benefit: Since other types of HPV cause ano-genital warts, which are ugly, unpleasant, and persistent but not lethal and occur in both sexes, an anti-HPV vaccine could be produced that protected against those types as well, in which case boys would also become candidates to get the vaccine again at a relatively young age. (A similar approach has proven effective with the hepatitis B vaccine. Hepatitis B infection is a major cause of liver cancer. The hepatitis B vaccine has been shown to reduce the rate of liver cancer in those areas where it had been prevalent.)
All of this may be merely wishful thinking, however, given the current climate involving vaccines and liability issues. Several vaccine-makers have left that market, due to liability concerns and the low profit margin on vaccines in general. Indeed, shortages of children's vaccines long known to be both safe and effective have recently occurred when large manufacturers withdrew from the field, fearing litigation. Fears encouraged by self-styled "consumer advocacy" groups and their converts in Congress may yet work to inhibit pharmaceutical innovation including the potential cancer prevention agent described in this piece.
What are the prospects of drug therapy to prevent cancer? I conclude with a comment made by Winston Churchill after the British defeated the Germans in North Africa in November 1942: "Now is not the end. It is not even the beginning of the end. But it is, perhaps, the end of the beginning."