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© Oxford University Press 2006.
NEWS |
U.S. Girls To Receive HPV Vaccine but Picture Unclear on Potential Worldwide Use, Acceptance
With an air that medical history was being made, a government committee unanimously recommended that U.S. girls ages 11 and 12 receive a vaccine that prevents infection by the most common strains of the human papilloma virus (HPV), which accounts for 70% of cervical cancer.
The vote approves the first cancer vaccine ever added to the Centers for Disease Control and Prevention's recommendations, and it represents a significant advance in prevention care, said Jon S. Abramson, M.D., chair of the agency's Advisory Committee on Immunization Practices (ACIP).
"This really is the first vaccine developed specifically to prevent cancer, and the world has been watching to see what we would do," said Abramson, chair of the department of pediatrics at Wake Forest University School of Medicine.
Several other countries have already approved the vaccine, including Mexico and Australia. But these decisions don't resolve questions about whether the vaccine will be widely available to the developing world, where the most women die from the disease. Questions of cost, acceptance, and prioritization among many health problems still loom large. But the high cost—$360 for the three vaccine series—may be the biggest problem.
"It's a very important day as a breakthrough for women's health—for prevention—and an exciting expansion of the childhood immunization schedule," Anne Schuchat, M.D., director of the CDC's National Center for Immunization and Respiratory Diseases, said at a press conference.
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Although the ACIP recommendations need the formal agreement of the CDC and Health and Human Services heads, Abramson said he sees no further hurdle to U.S. vaccine use, and he expects that most federal and private insurance companies will pay for the vaccine when it becomes clinically available. (The vaccine was already being shipped to physicians' offices within days of ACIP approval.)
HPV is the most common sexually transmitted infection in the United States. The CDC estimates that more than 20 million men and women are currently infected in this country. There are 6.2 million new infections each year. By age 50, at least 80% of women have acquired the infection, according to the agency. And although most of these infections clear up on their own, more than 9,700 new cases of cervical cancer are diagnosed in the United States each year, resulting in about 3,700 deaths, according to the American Cancer Society.
The Merck-manufactured vaccine, Gardasil, is designed to be used before the onset of sexual activity. A three-shot series provides protection against four prominent HPV types: 16 and 18, which are associated with cervical cancer, and 6 and 11, which are responsible for approximately 90% of genital warts.
States will decide whether the HPV vaccine should be mandated in school-age children, and the federal Vaccines for Children Program will provide the vaccine free for disadvantaged children. In addition to the primary recommendation, the committee also suggested vaccinations for females age 9–26. Because Merck researchers believe that eradication of HPV is possible only if boys are vaccinated as well, Gardasil is also being tested in boys. But studies of its effectiveness in boys have not been submitted to the FDA, which licensed Gardasil for use in females on June 8.
GlaxoSmithKline expects to submit its own HPV vaccine, Cervarix, to the FDA by the end of 2006. This vaccine, also delivered in three sequential shots, provides protection against types 16 and 18. It is being tested solely in females, including women aged up to 55 years.
Other countries have already approved the vaccine and are moving forward. Australia, which already bills itself as having the world's lowest cervical cancer rate, approved Gardasil's license in June for use in both females age 9–26 and males age 9–15. Although parents will have to pay out of pocket for the vaccine until it is listed on the country's Pharmaceutical Benefits Scheme (through a process similar to the ACIP), widespread use is expected when the vaccine becomes available later this year. Cervarix is also expected to be in the Australian market this year, and both vaccines will be considered for European use soon.
"In 1940, cervical cancer was the leading cause of cancer death in women in the United States, and now, four generations later, we can make the disease almost completely preventable," said Kevin Ault, M.D., an Emory University School of Medicine researcher who has tested both vaccines. "What was a major threat in my grandmother's time will not be one for my two young daughters, and that is the best part of the story to me."
Helping Those Who Need It Most
Now that U.S. girls and young women are among the first HPV vaccine customers worldwide, the question for international public health is when will women most at risk of developing cervical cancer benefit from the advance?
About 80% of cervical cancer incidence (approximately 470,000 new cases a year) and deaths (about 233,000) occur in developing countries because of a lack of preventive screening, but distribution efforts for both Gardasil and Cervarix appear to be much farther ahead in the countries with the lowest incidence of cervical cancer, including the United States, Europe, and Australia.
Although both vaccines have been tested in several other developing countries, such as the Philippines and Malaysia, only Mexico has granted a license for an HPV vaccine (Gardasil). Experts say that the hurdles to potential use of the vaccines are much higher in other Latin and South American, Asian, and African countries, given issues such as access, social acceptability, cost, and competition with other public-health needs.
"I wouldn't want to underestimate the challenges ahead," said Mark Feinberg, M.D., Ph.D., Merck's vice president of policy, public health, and medical affairs.
Access to the vaccines for preteen and adolescent girls is one of the top issues, according to PATH, an international nonprofit group that in June received a $27.8 million grant from the Bill and Melinda Gates Foundation to facilitate delivery of HPV vaccines to the developing world.
"Young people don't have a lot of contact with the health care system," said Vivien Tsu, Ph.D., a senior program advisor at PATH. "The vaccine infrastructure that has been established is aimed primarily at babies, so delivering three new shots for older children represents a new paradigm."
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Feinberg agrees. "The issue is a new one that the global public-health community hasn't confronted yet," he said. "There are no established approaches to getting vaccines to adolescents."
A related headache is the question of how long the vaccine's immunity lasts. So far, Merck has shown that antibody levels induced by Gardasil remain high up to 3.5 years after vaccination, and Cervarix is specifically designed to boost the immune response even higher, but no one yet knows if booster shots will be needed. That requirement would constitute another strain on the infrastructure.
PATH will conduct program research in India, Peru, Uganda, and Vietnam to determine whether young women have access to health care and to judge how the population views the risk of an HPV infection, Tsu said.
For example, PATH will look at whether the lag between infection and development of cancer reduces the chances that girls will see the need to take the vaccine. "Saying we can reduce the cancer rate in 30 years may have a bigger impact on people at the public-policy level than on young people who feel invincible and may not want to have shots in their arm," Tsu said. "This is a huge barrier to overcome."
Another issue, highlighted in an editorial in the June 24 issue of The Lancet, is the notion that protection against HPV will encourage girls to engage in sexual activity.
Realizing the vaccine's potential will "depend on addressing worldwide issues of social and cultural resistance, which are already threatening to slow Gardasil's rollout in the U.S.," according to the unsigned editorial. Giving recipients full information about the vaccine's purpose "will also necessitate teaching them about sex. In some people's eyes, this would undermine abstinence education and thereby encourage inappropriately young sexual activity."
But Abramson said that those objections, when voiced in the United States, evaporated in the face of studies that demonstrated no increase in sexual activity in girls who had received the vaccine and that the same may occur in other countries. Tsu says that although PATH will explore this question, "we don't need to jump to the conclusion that they will dominate the discussion everywhere.
"Some countries have already dealt with these issues because of AIDS," Tsu said. In other countries, "it may be enough to tell girls that it will prevent development of cancer in their 40s."
The Question of Cost and Priority
Because the Gardasil series is believed to set a record for the priciest vaccine, some experts wonder how the developing world can afford the vaccine, even at a deep discount.
Both Merck and GlaxoSmithKline say that they are committed to providing their HPV vaccines to low-income countries at an appropriate price, but they stress that an international effort is needed both to help fund the vaccine and to distribute it.
GlaxoSmithKline will work through its "Global Vaccine Availability Model," said Philippe Monteyne, M.D., Ph.D., their head of global vaccine development. The vaccines are first distributed in higher income countries, while the company reaps a return on its investment, and then they are transitioned into poorer countries with the help of "partners" such as UNICEF, the World Health Organization, and the Global Alliance for Vaccines and Immunization.
"We are the number one supplier of vaccines to UNICEF," Monetyne said. "We have a good track record."
The primary market for Cervarix and Gardasil in developing countries will likely be the middle-class population that can afford to pay reasonably high prices for vaccines, said John Schiller, Ph.D., of the laboratory of cellular oncology at the National Cancer Institute. This middle-class market is relatively large in many developing countries, and the strategy "introduces the vaccine into a country, protects at least some women, and builds up demand," said Schiller, who helped develop the vaccine, which was then licensed by NCI to GlaxoSmithKline and Merck.
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Monetyne acknowledges that the company will probably develop a complex tier-pricing system that takes into account differences in wealth between, and even within, countries. The poorest people will probably receive the vaccines through the help of international agencies and donor countries.
But the companies would need to charge at most "a dollar or two" to make the vaccines affordable enough for widespread use in the developing world, Abramson said.
Second- and third-generation HPV vaccines that are easier to distribute and to take—such as cheap oral vaccines now in early development, with support from the NCI, that use live bacterial vectors—may ultimately be the answer for developing countries, Schiller said.
"These current HPV vaccines are very difficult to manufacture, and so we look at them as part of a process to ultimately get a vaccine that everyone in the world can use," he said. "In my opinion, the long-term solution to disadvantaged populations' access to inexpensive vaccines is regional production in middle-tier countries."
Even if HPV vaccines were more affordable, some experts are concerned that cervical cancer prevention will not rise high enough on the list of health concerns in some regions, especially given that these vaccines do not prevent all types of HPV infection. If other long-needed vaccines and therapies become available in the coming decade, HPV vaccines could be pushed even farther down on the priority list.
"We are developing vaccines against the big killers, including malaria, HIV, and tuberculosis," Monteyne said. "And this means the budget will need to be there and that big-income countries will have to help out."
"In an ideal world, all these interventions would be available, but for the foreseeable future, different countries will have to make prioritization decisions," Feinberg said. "I don't know that this will be easy for them."
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  K. Outterson and A. S. Kesselheim Market-Based Licensing For HPV Vaccines In Developing Countries Health Aff., January 1, 2008; 27(1): 130 - 139. [Abstract] [Full Text] [PDF]
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