| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
© Oxford University Press 2006.
NEWS |
Coming Soon: Cervical Cancer Vaccines, and an Array of Public Health Issues
One vaccine to prevent cervical cancer could be available in just months and another may come next year as regulatory agencies begin their reviews of the two candidates. Both vaccines use virus-like particles (VLPs) to block infection with human papillomavirus (HPV) types 16 and 18, which cause most cervical cancers (see box, p. 432).
The vaccine furthest along is Gardasil, a product of Merck & Co., Whitehouse Station, N.J., which expects a decision on its licensure application to the U.S. Food and Drug Administration by June 8. U.K.-based GlaxoSmithKline (GSK) is submitting its vaccine, Cervarix, to the European regulatory agency in the first half of this year and to the FDA at the end of this year. Both drugs have proven effective in clinical trials.
But it's not only regulatory agencies that are scrutinizing the vaccines. Their imminent availability has spotlighted some major public health issues surrounding them, and many groups—governmental, professional, advocacy, and philanthropic—are now considering how the vaccines should be used.
"There are a number of really interesting, outstanding implementation questions surrounding the vaccines," said John Schiller, Ph.D., in the Laboratory of Cellular Oncology at the National Cancer Institute, who briefed the National Cancer Advisory Board on these issues at its December meeting. On the table are vaccination age and sexual behavior, public acceptability, the impact of vaccines on screening, and how the vaccines will get to women in developing countries, Schiller said.
|
To this list, Lauri Markowitz, M.D., at the Centers for Disease Control and Prevention, adds current pediatric practice and how HPV vaccination would best fit in. Markowitz advises the HPV vaccine working group that is developing recommendation options for the Advisory Committee on Immunization Practices (ACIP), whose guidelines are widely followed in the United States. ACIP discussed the vaccines at its February meeting and expects to vote on final recommendations at the end of June.
The most immediate question before ACIP and other groups is who should get the vaccines. Scientifically, there is little debate: Young people have the highest immune response to the vaccines. In one GSK trial, for example, vaccinated 10- to 14-year-olds produced antibody levels twice as high as those of 15- to 25-year-olds. And there is evidence that HPV infection peaks soon after sexual activity begins, another reason to vaccinate early.
The working group has proposed that 11- and 12-year-old girls be routinely vaccinated. The rationale for routine, rather than targeted, vaccination rests partly on the widespread prevalence of the virus, which makes it difficult to define a high-risk group, Markowitz said. The group also considered "the health care provider visit and other vaccines that are already recommended at this age," she said.
One unknown, however, is how long immunity lasts. Will a girl vaccinated at age 10 or 11 still have immunity when she becomes sexually active?
Merck has 3.5 years of follow-up data showing that antibody levels plateau but remain high for at least that amount of time, said Eliav Barr, M.D., who leads Merck's HPV program. And GSK, whose vaccine includes a proprietary adjuvant designed to boost response, found that the vaccine increased antibody levels more than with the conventional alum adjuvant and that levels remained higher for a comparable period, said Gary Dubin, M.D., head of the company's HPV program.
| The Vaccines and the Trials Both vaccines use virus-like particles based on the L1 protein of human papillomavirus (HPV) types 16 and 18, which cause 70% of cervical cancers. Gardasil, Merck & Co.: Also protects against HPV types 6 and 11, which cause benign genital warts; uses conventional alum adjuvant.
Cervarix. GlaxoSmithKline: Uses proprietary adjuvant AS04.
|
But vaccination age also raises cultural issues. The Abstinence Clearinghouse, for example, is concerned that vaccinating young girls could send the message that society endorses sexually promiscuity (see News, Vol. 97, No. 14, p. 1030, "Targeting Teens and Adolescents for HPV Vaccine Could Draw Fire").
However, one large profamily group, the Family Research Council, has voiced cautious support for the vaccine. Its statement to ACIP urged abstinence as the only full protection but also recognized "strong reasons why even someone practicing abstinence and fidelity may benefit from HPV vaccines," such as marriage to someone already infected. Both Barr and Dubin said that, outside the United States, they encountered no resistance to the idea of vaccinating young girls in clinical trials in either developed or developing countries. "It was just the opposite, the trials enrolled very quickly," said Dubin.
Whom Else To Vaccinate?
ACIP and others must also decide whether to recommend vaccination for older women who may already be infected. Doug Lowy, M.D., head of NCI's Laboratory of Cellular Oncology, told ACIP that the current vaccines are not likely to eradicate established HPV infections, since the viral genome is maintained in basal cells and which aren't susceptible to VLP-induced immune responses.
Stopping spread of the infection from one cell to another is "theoretically possible," he said, so a vaccine might help block progression. However, once lesions become dysplastic, they stop producing the L1 protein. That means neither vaccine would be expected to treat established precancerous lesions.
The ACIP working group noted only that vaccinating women aged 13–26 years was an option under discussion, as were vaccinations for a "more limited age range."
One potentially contentious question is whether to vaccinate men and boys. Male vaccination might prevent HPV-related cancers in men, such as anal cancer, and might prevent transmission of the virus to women. Merck has shown that its vaccine induces antibodies in men, but there are no data yet on whether it prevents infection and transmission.
"There's much more bang for the buck in vaccinating women," Schiller said, citing modeling studies that suggest it's more effective to vaccinate 80% of women than to vaccinate 40% of men and 40% of women.
Merck's FDA application requests licensure for boys as well as girls ages 9–15. However, the ACIP working group said it would not have a recommendation on this issue in June. Markowitz said that the CDC is looking "further at issues of target ages for vaccination and male vaccination."
Screening Impact
A long-term issue surrounding the vaccines is their impact on cervical cancer screening programs. Few if any changes are expected immediately because the vaccines—at least for the time being—prevent infection with only two of the approximately 15 oncogenic HPV types. Moreover, women who are sexually active now are still at risk and should continue to be screened.
But screening guidelines may well change for women who received the vaccine before becoming sexually active. Ultimately, prevention programs may combine vaccination for younger women and screening for older women, said NCI's Mark Schiffman, M.D., writing in the New England Journal of Medicine in November.
According to modeling studies by Sue Goldie, M.D., of the Harvard School of Public Health in Boston, and colleagues, the most cost-effective strategy would be to combine vaccination at age 12 with conventional screening every 3 years, beginning at age 25. Most current guidelines call for annual screens beginning at age 21 or sooner.
Although screening versus vaccination is an issue in the developed world, the bigger question worldwide is how the vaccine will reach poor women in countries where there is less screening and where cervical cancer rates are high (see Stat Bite, p. 434). Obstacles in these countries are partly logistical—the current vaccines must be kept cold and require three doses over a 6-month period—and partly related to the cost of the vaccines, which could be about $100 a dose.
Both Merck and GSK say they will use tiered pricing, charging less in some countries than in others, and both are working with the Gates Foundation and the World Health Organization on the issue. The International Union Against Cancer (UICC) is also mounting a program to "address the issue of introducing vaccines particularly in low-resource settings," said executive director Isabel Mortara.
Second-Generation Vaccines
Still, the best hope for developing countries may lie in efforts to develop second-generation vaccines that pose fewer difficulties.
One candidate vaccine now in development is based on the L2 protein. Developed by Richard Roden, Ph.D., first at NCI and now at the Johns Hopkins School of Medicine, Baltimore, the monovalent vaccine may offer cross-protection against multiple HPV types, unlike the current L1-based VLP vaccines. The wider coverage could be advantageous both for countries without organized screening and for countries with large screening programs, since 30% of cervical cancers are caused by HPV types other than 16 and 18.
Roden is working with Shantha Biotechnics in Hyderabad, India, to develop a product that could be tested in humans. Clinical trials could begin as early as 2008, according to Srinivasa Rao, M.D., Shantha's U.S. representative.
Another second-generation approach is to use a live bacterial vector to generate and deliver L1 VLPs. If successful, this product could be taken orally, would not require cold storage, and would be inexpensive to manufacture. Researchers, led by Denise Nardelli-Haefliger, Ph.D., at the Centre Hospitalier Universitaire Vaudois in Lausanne, Switzerland, have shown that attenuated vaccine strains of salmonella expressing the VLPs induce high levels of neutralizing antibodies in mice. A trial of this vaccine is planned by Indian Immunologicals Ltd., in Hyderabad, and will begin in early 2007.
Both researchers and companies are working with Lowy and Schiller at NCI, who hope new approaches will have a bigger impact on cervical cancer rates worldwide than is likely with the current vaccines.
"None of us is going to be satisfied if the only women getting the vaccine are the same women already covered by screening programs," said Schiller.
CiteULike 
Connotea 
Del.icio.us What's this?
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||