Cervical Cancer Vaccines
Introduction of vaccines that prevent cervical cancer and genital warts may foreshadow implementation and acceptability issues for a future AIDS vaccine
By Kristen Jill Kresge
Jessica Kahn is a pediatrician at Cincinnati Children's Hospital and a professor of medicine who studies sexually-transmitted diseases among adolescents. She is also a mother. And the decisions Kahn makes as a parent are strongly influenced by her day job. "I see herpes and genital warts all day long. And now that there can be vaccines to prevent these things, I know that I definitely want my daughter to get vaccinated."
Kahn would have liked to enroll her daughter in a clinical trial she was running at the hospital for a vaccine to protect against human papillomavirus (HPV) but she was too young to participate. Luckily her daughter and others her age may not have long to wait before protection is at hand against this common virus that is now widely accepted among scientists as a necessary, but not in itself sufficient, step in the development of cervical cancer. Two vaccine candidates that protect against HPV have proven highly effective in large clinical trials and should be approved and licensed later this year.
Cervical cancer is the second most common cancer in women and is the leading cause of cancer-related mortality among women in developing countries, accounting for more than 290,000 deaths annually worldwide. Even in the US, despite strict screening processes to detect the earliest stages of cervical cancer, more than 10,000 new cases are diagnosed each year, so without question there is a great need worldwide for a preventive vaccine. Yet some groups are preparing for a potential controversy over the administration of a vaccine for a sexually-transmitted infection (STI) that could impinge on how and when the licensed vaccine is used.
Such debate may even have influenced the way the companies approached developing their vaccines that guard against one of the most common STIs in the world; one candidate, developed by GlaxoSmithKline (GSK), is being touted as strictly for cancer prevention while the other, from Merck, protects against viral types that also cause genital warts, a lesser but unpleasant result of genital HPV infection.
Other issues surrounding the eventual introduction of these vaccines include the price and accessibility in developing countries where the disease burden is greatest. How these are tackled will have implications for when an effective AIDS vaccine is developed and this has many closely watching how the debut of this important vaccine plays out. "This is a sort of test case for HIV vaccines and there will be a lot of lessons on acceptability and delivery," says Kahn. "Similar moral issues may also be raised."
Behind the virus
HPV is a double-stranded DNA virus that most studies suggest infects at least 25% of sexually active adults—with one longitudinal study suggesting a cumulative prevalence close to 80% in a cohort of adolescent women in the US (Curr. Opin. Obstet. Gynecol. 17, 476, 2005; J. Infect. Dis. 191, 182, 2005). Variations in worldwide prevalence estimates are due to differences in the molecular sensitivity of DNA assays used to detect HPV infection around the world. More than 120 types of HPV infect humans and a third of these can cause genital infection (Vaccine10.1016/j.vaccine.2005.09.054). These are further classified as high- and low-risk based on their oncogenic properties, with 13 to 18 types that are associated with cancer and two that predominantly cause genital warts and low-grade cervical lesions.
HPV types 6 and 11 are the main culprits for genital warts, causing 90% of benign cell proliferation, which is much less serious but can also serve as an important marker for infection with high-risk HPV types. Two of the high-risk HPV types, 16 and 18, are responsible for 70% of the cervical cancer cases worldwide, according to Kahn, but the predominant HPV types can vary geographically and these two types are not as common in sub-Saharan Africa or Asia as they are in North America and Europe.
There is limited research on the epidemiology of HPV infection in developing countries, but a study that pooled data from 11 case-controlled studies in 2506 women with cervical cancer in Morocco, Mali, Colombia, Brazil, Paraguay, Peru, Thailand, the Philippines, and Spain reported that HPV type 16 was the most common type with an overall prevalence of 59%, reaching 70% in some countries (N. Engl. J. Med. 348, 6, 2003). The second most common HPV type was 18, with an overall prevalence of 15%, followed by types 45, 31, and 35. The authors suggest that an effective vaccine against these five HPV types could prevent about 90% of cervical cancers worldwide, but suggest that regional variation in predominant HPV types should be considered in the creation of vaccines specific to a geographic region. Philippe Monteyne, vice president of worldwide operations for GSK's cervical cancer vaccine program, acknowledges limited regional differences in HPV types but says the GSK vaccine "is really useful on a worldwide basis."
Although the natural course of cervical cancer isn't fully understood, screening protocols including Pap tests have been established to detect cervical cell abnormalities as early as possible. Many infections with HPV can be transient and cleared effectively by the immune system, but HPV becomes dangerous when persistent infection with an oncogenic type occurs. This can lead to high-grade pre-cancerous lesions known as cervical intraepithelial neoplasia (CIN), and eventually to non-invasive and then advanced cervical cancer. Persistent HPV infection is also strongly implicated in other malignancies, including anal and oral cancer in men and women.
Routine Pap smears are used to detect abnormalities in the cells of the cervix and HPV-DNA testing is also available to confirm infection and to identify the specific viral types. Catching cervical cancer in its earliest stages has substantially reduced the rate of mortality due to this disease in the US. "Most cervical cancer in this country is in women who don't get screened," says Kahn. Often these are women without medical insurance who are not receiving regular gynecological care.
But women in developing countries face the highest rates of cervical cancer, with India bearing almost a third of the world's mortalities from this detectable disease. "The vaccine is the solution for these countries where mandating good screening programs is difficult," says Monteyne.
There are also concerns that Pap smear results, or their interpretation, can be inaccurate, confirming a need for a vaccine even in countries with rigorous testing procedures. The value of the results from this qualitative test is highly dependent on analysis by a trained and conscientious professional. Laura Koutsky, an epidemiologist at the University of Washington, presented graphic images at the AIDS Vaccine 2005 meeting of women who had normal Pap smears but were found to have substantial cervical lesions when evaluated by a more invasive cervical colposcopy procedure.
Preventive HPV vaccines that are in development may help alleviate the reliance on screening methods in the future. Some HPV vaccine candidates might also be effective for therapy of moderate CIN (Curr. Opin. Obstet. Gynecol. 17, 476, 2005). A Phase I/II trial with one candidate, a modified vaccinia Ankara (MVA) virus vector carrying E2 HPV antigens, resulted in elimination of all cases of grades 1-3 CIN in 34 of 36 women, when delivered by direct inoculation into the uterus (Hum. Gene Ther. 15, 5, 2004).
This and other therapeutic candidates are mostly in the preliminary stages of development but both Merck's and GSK's preventive candidates could soon be on the market. Both consist of a recombinant form of the HPV L1 protein that encodes the nucleocapsid and can self assemble into a virus-like particle (VLP), a non-replicating shell that resembles an actual virus particle closely enough to fool the immune system into thinking it is encountering a natural HPV infection.
Initial data showed that these self-assembled VLPs from different HPV types are highly immunogenic, inducing both strong antibody and cellular immune responses. "Interestingly the vaccine induces even higher levels of antibody response than those induced in a naturally-occurring infection," says Mark Feinberg, a vice president in Merck's vaccine division. Studies have shown that the antibody response to the vaccine is up to 40 times greater with some HPV types.
Merck's vaccine candidate, known as Gardasil, is now in Phase III testing in over 25,000 men and women and an application was recently submitted to the US Food and Drug Administration (FDA) for approval and licensure. Gardasil is a quadrivalent VLP vaccine consisting of recombinant L1 proteins from types 6, 11, 16, and 18, administered with an aluminum adjuvant. The company recently presented data from one of their Phase III trials involving 12,167 women aged 16-26 in Brazil, Colombia, Denmark, Finland, Iceland, Mexico, Norway, Peru, Poland, Singapore, Sweden, the UK, and the US.
In women that received 3 doses of the vaccine there were no cases of high-grade CIN or non-invasive cervical cancer associated with the types included in the vaccine as compared to 21 cases of either in the placebo group over an average of 17 months follow up. "It's really hard to do better than that," says Feinberg. Follow-up data so far shows that the immune response generated by the quadrivalent vaccine lasts at least 2.5-3 years after completion of the 3-dose regimen, but researchers at Merck are still monitoring the persistence of protection afforded by the vaccine.
A secondary analysis found that in women who received at least one injection the vaccine reduced the risk of developing high-grade pre-cancer and non-invasive cancer associated with types 16 and 18 by 97%, a more real world example of the vaccine's efficacy since many people are unlikely to return for all 3 inoculations. Only one participant had pre-cancerous lesions or non-invasive cervical cancer in the group receiving Gardasil, while there were 36 in the placebo group.
Following closely behind Merck's candidate is the HPV vaccine in development at GSK in Rixensart, Belgium, in collaboration with MedImmune. Researchers at the company expect to file for licensure with the European Medicines Agency (EMEA) in the first half of this year and are also involved in ongoing discussions with the FDA. The vaccine, known as Cervarix, is also a VLP vaccine but includes L1 proteins from types 16 and 18 only. "We have a different strategy," explains Monteyne. "These are difficult decisions you have to make early on in the development of a vaccine and we wanted from the very beginning to focus on women and cervical cancer."
Another difference between the Merck and GSK candidates are the adjuvants. Cervarix relies on a proprietary adjuvant developed at GSK, called AS04, which is a bacterial molecule co-formulated with aluminum. Vaccine administered with AS04 resulted in significantly higher antibody titers than with a standard aluminum salt adjuvant. Monteyne also credits the AS04 adjuvant with extending the duration of the immune response, now shown at up to four years after vaccination.
GSK currently has 5 ongoing Phase III efficacy trials with Cervarix in 28,000 female volunteers. Last year they reported the results of one Phase II trial in more than 1100 women aged 15-25 in North America and Brazil who received 3 doses of the vaccine formulated with the AS04 adjuvant (Lancet 364, 1757, 2004). The vaccine was 100% effective at preventing persistent infection with the two strains of virus in the vaccine and 92% effective against transient viral infection. For women who received at least one injection the vaccine was 95% effective against persistent infection and 93% effective at preventing CIN, with only one woman in the vaccine group and 6 in the placebo group developing cervical lesions.
There may also be good news about the ability of the vaccines to prevent persistent infection with different HPV types because the L1 protein is one of the most highly conserved. At the annual HPV conference in Vancouver in May, GSK reported activity of its HPV vaccine against strains 31, 45, and 52, which can also cause cancer. Several previous studies have provided evidence for cross-immunity between genetically-related HPV types including 16, 31, 33, 35, 52, and 58. Monteyne calls this preliminary cross-protection data "extremely exciting". This phenomenon is not seen in natural infection and Monteyne is hopeful that it will mean the GSK vaccine can be given to women already infected with HPV types not in the vaccine and perhaps clear an established infection. Merck is also investigating potential cross-reactivity of Gardasil but is yet to report any data.
Implications for HIV
Since both HPV and HIV can be sexually-transmitted and enter the body through the same tissues, researchers have been studying the link between these two infections. The cervical lesions caused by persistent HPV infection can enhance women's risk of acquiring HIV because of increased bleeding and the recruitment of CD4+ T and dendritic cells to the cervical mucosa, believed to be a target site for establishment of HIV infection in women.
This may also be true with the anal manifestations of HPV infection. A study presented at last summer's International AIDS Society Conference in Brazil found that anal HPV infection was independently associated with HIV acquisition in a cohort of 1409 men who have sex with men (MSM; Abstract no. TuOa0403).
Several studies have also found that HIV-infected individuals are at greater risk for acquiring HPV and the two prove to be perilous partners. Co-infected individuals are more likely to develop severe lesions than those infected with HPV alone. It is estimated that HIV-infected women are three to five times more likely to develop cervical lesions due to HPV infection. HIV's ability to hinder the immune system may be at the root of this problem, either directly or indirectly, because it allows HPV to persist longer, making cancer development more likely. Even people on highly active antiretroviral therapy (HAART) for HIV infection are more likely to develop serious anal and cervical lesions and there has been no decline in the incidence of cervical or anal cancer since the initiation of HAART.
Good for the gander?
With results showing that anal HPV infection can increase the risk of acquiring HIV, many researchers eagerly await data on the efficacy of HPV vaccines in men. This information won't be coming from GSK. In keeping with their strategy of developing a cervical cancer vaccine the company has chosen not to test their vaccine in men and, with a name like Cervarix, there is little confusion about the vaccine's intended target.
Merck, however, is studying their more androgynously-named vaccine in both male and female adolescents, as well as in cohorts of MSM. "HPV does cause significant disease burden in males," says Feinberg, who sees clear benefits for giving Gardasil to men, including preventing anal and penile cancer and genital warts.
It is also likely that vaccinating both men and women will increase herd immunity and decrease overall the number of life-threatening infections in women. "Our major rationale is to increase the percentage of individuals in a population that are immune to an infection," Feinberg adds. Models show that 90% of the population would need to be vaccinated to eliminate strains 16 and 18.
Merck has yet to report results on the efficacy of Gardasil in male volunteers and their submission to the FDA will only be based on safety and immunogenicity data in women, but Feinberg says the vaccine looks quite good, especially in young men. This is consistent with results from female volunteers where researchers saw significantly higher immune response in younger individuals.
Ideally a preventive HPV vaccine would be administered prior to infection, which for such a common virus means vaccinating girls and boys before they become sexually active. This has researchers discussing whether parents will be willing to have their children vaccinated against an STI, perhaps even as early as age 9. Some conservative religious groups have vocally opposed the idea of vaccinating young adolescents (age 9-12) against HPV because they say it could promote sexual activity at an earlier age. As with HIV, these groups instead favor abstinence messages.
Vaccinating young adolescents also means that the vaccine would be administered by pediatricians or family practice physicians and not gynecologists who have more experience diagnosing and treating the manifestations of genital HPV infection. Some researchers like Kahn worry that this lack of familiarity could affect the physician's willingness to suggest HPV vaccination. "Cervical cancer is just not a disease of children and adolescents," she says. "It's a disease primarily of middle-aged women."
Kahn and colleagues have conducted several studies to gauge the willingness of pediatricians to recommend HPV vaccines to their patients and their parents or guardians, who will be required to provide consent. Significantly more of the pediatricians and family physicians she surveyed would recommend an HPV vaccine to girls than boys and to older versus younger patients (J. Pediatr. Adolesc. Gynecol. 18, 6, 2005). Kahn concludes that the vast majority of parents and healthcare providers want this vaccine, but she admits that there will be some pediatricians who just aren't comfortable giving a vaccine for an STI.
Another important factor for the acceptance of any new vaccine is education, and this is especially true for an HPV vaccine since public awareness of the disease and its possible implications is so low. A study that tested the knowledge of parents about HPV vaccines found that a single-page information sheet on the virus and its effects was able to sway 20% of parents who originally declined vaccination for their children.
Meanwhile both Merck and GSK are trying to steer clear of acceptance issues with the vaccine and stay focused on getting the vaccine approved. "There definitely will be some ethical debate, but our role is not to enter it," says Monteyne.
Rollout for developing countries
Acceptance of the vaccine will also be critical in some developing countries where discussion of sexual activity is particularly difficult with respect to young girls. India has one of the highest rates of cervical cancer and there is concern that societal restrictions may make it difficult to vaccinate only girls.
Another complication in some developing countries is getting adolescents into the clinics. Much of the progress with vaccination programs in developing countries has relied on infant immunizations and as Feinberg says, "There really isn't any infrastructure in developing countries for administering vaccine to adolescents."
So for HPV vaccines to be successful in these societies there will need to be public health campaigns and perhaps a new structure for vaccine delivery. These are significant challenges that some international organizations are now beginning to address. The Program for Appropriate Technology in Health (PATH), an advocacy group in Seattle, received a planning grant from the Bill & Melinda Gates Foundation to explore ways to make HPV vaccines available in developing countries. Their initial focus is on countries that already have active vaccination programs and also high levels of HPV disease burden, which currently includes India, Peru, Vietnam, and Uganda, but even in these countries there are substantial barriers to vaccination. "While there may be vaccine programs on the books aimed at adolescents, only a tiny proportion of girls and boys in those age groups are reached," says Jacqueline Sherris of PATH. In some regions of India less than 10% of adolescent girls are receiving the recommended tetanus toxoid vaccine.
PATH is also working on a proposal to the Global Alliance for Vaccines and Immunization (GAVI) to explain why funding should be allocated for the purchase of HPV vaccines. The price for the Merck or GSK vaccines won't be set until after they receive approval but according to a report from the American Academy of Microbiology (Vaccine Development: Current Status and Future Needs), the HPV vaccine could well be prohibitively expensive for use in developing countries. "We expect to look at a range of strategies to encourage an affordable supply," says Sherris.
New research into the epidemiology of HPV infection by region may also be an important consideration in the implementation of these vaccine programs, but without a doubt introducing these vaccines in developing countries "could have a tremendous impact on mortality," says Kahn.
Both companies are also looking at ways to make the vaccine widely available while ensuring a return on their investment, which according to the Wall Street Journal could be profits that exceed US $1 billion annually. Neither company is exploring advance market commitments (see If you build it, they will pay, IAVI Report 9, 3, 2005) as a mechanism for making the vaccine available throughout the world, but both are looking to form public-private partnerships with organizations like GAVI or the United Nations Children's Fund (UNICEF) to get the vaccine to those in need. "It's very exciting to have this vaccine that works so well, but there is still much work to be done," says Feinberg.