She was given three doses of the vaccine over a six-month period.
Her parents, Caroline and Patrick, thought it was "a good thing". The family stress that they are "not anti-vaccination".
Shannon and her three younger siblings have all had their shots, including the BCG and MMR, with no adverse side effects.
Looking back, her distressed mum describes the consent form as "the worst thing I've ever put my signature to - it has ruined Shannon and has left our family in turmoil".
After the first dose, Shannon had a high temperature and complained of a headache, but her parents say it was nothing out of the ordinary.
Following her second dose, a couple of months later, Shannon started vomiting and had diarrhoea.
"We thought it was a bug," said Caroline.
Then one morning, a few days after her third dose, Shannon fainted three times while trying to get from her bedroom to the bathroom. She was rushed to A&E at Mullingar General Hospital and then on to Tullamore Hospital to undergo further tests.
"She had an MRI, but it all came back clear. There was nothing they could find," Caroline said.
Up until her daughter began receiving the Gardasil vaccine, Caroline says she was "super fit" and "very sporty". She was a cross-country runner with Mullingar Harriers Athletic Club, played football for St Lomans GAA club, played tennis and did swimming lessons.
Now, her parents say she can't walk up the stairs without sitting down halfway and can't go outside the door by herself. Her family is desperately worried that Shannon won't be able to complete her Leaving Cert because of extreme anxiety.
When asked how certain she is that the vaccine is the root cause of Shannon's illness, her mother said: "It's so obvious. For a child to be so healthy and fit and to then suddenly become this unwell after her third dose - you don't need to be a doctor to know.
"I want it to be pulled off the market and for more research to be done - how many more victims do they want before they say stop?" she said.
HPV vaccine development: A case study of prevention and politics
Janelle L. GrimesCorresponding author
- E-mail address: firstname.lastname@example.org
- Keck Graduate Institute, Claremont, California 91711
- Keck Graduate Institute, Claremont, California 91711
An analysis of the development of human papillomavirus (HPV) vaccines requires a fundamental comprehension of the underlying science of the technology, as well as an appreciation for the business issues essential to successful commercialization. Students analyzing this topic must consider scientific challenges related to the development of these vaccines, as well as the implications for their commercialization. This case study describes the evolution of our understanding of HPV infection and its causative link to cervical cancer, the establishment of viable HPV vaccine candidates, and various issues related to HPV vaccine implementation. Study questions for use in generating class discussion are provided.
For as long as viruses have been infecting humans, they have been evolving mechanisms to evade detection. One of the most successful viruses in this respect is the human papillomavirus (HPV).11 As a result, HPV is currently the most common sexually transmitted virus, with ∼20 million people infected with the virus in the U.S. alone . More than 100 strains of HPV have been identified, with a wide range of manifestations and clinical implications. Several HPV strains have been linked to the development of cervical cancer in women. This represents one of the few instances in which the development of cancer has been conclusively linked to a definitive source, thus providing a discrete target for intervention. Both therapeutic and prophylactic vaccines against HPV are in development. Merck Pharmaceuticals and GlaxoSmithKline (GSK) Biologicals have released positive clinical trial results for their distinct prophylactic vaccines. Merck's vaccine will likely be approved for marketing by the Food and Drug Administration (FDA) by 2006, with GSK's vaccine not far behind. However, approval is just the first step in a long process of intervention. Many questions remain regarding the standards for use and distribution of vaccines. Advocacy groups have already raised concerns regarding the adverse impact that the vaccines might have on increasing sexual promiscuity in adolescents. The complexities of the issue require an in-depth probe to fully define the multifaceted argument, and in the process, separate the science from the politics.
HPV is a double-stranded DNA virus whose genome is divided into early and late stage genes corresponding to stages of viral infection (Fig. 1). Mucosal infections of the female cervix progress according to the expression of viral proteins associated with each infectious phase. The cervix is comprised of two stratified cell layers, an inner basal columnar epithelium and an outer squamous cell epithelium. Cell division occurs in the basal layer, and these cells differentiate into squamous epithelium, growing outward in the process. HPV initially infects the inner basal epithelial cells of the cervix through microtrauma to the skin, typically generated during sexual intercourse (Fig. 2). The virus sheds it capsid, or viral coat, and the DNA enters the basal cell nucleus. Infection may be latent, or may progress upon expression of the E6 and E7 genes. Through multiple mechanisms, proteins produced by these genes cause increased cell division and inhibit programmed cell death, notably through interference with cell cycle regulatory proteins including p53 and RB . As cells begin to differentiate, E1, E2, E4, and E5 HPV genes are expressed, which are involved in viral replication. When terminal differentiation of squamous cells is reached, L1 and L2 genes are expressed, resulting in production of viral capsid proteins. At this point, new viral particles may be completely assembled and are shed with dead skin cells at the mucosal surface (Fig. 3). The typical time from active infection to particle release is 3 weeks.
HPV is transmitted directly through skin-to-skin contact. Non-genital HPV infection with some strains of the virus can cause cutaneous lesions, or warts, generally on the skin of the hands and feet (e.g. strains 1, 2, 3, 4, 7, 10). Forty of the recognized strains are capable of infecting the mucosal areas of the upper digestive tract and anogenital region . These strains may be subcategorized into low risk and high risk strains, according to their propensity for developing into cervical cancer. Low risk strains, including 6, 11, and 42–44, are typically associated with subclinical lesions or clinically evident genital warts. High risk strains, including 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, and 68, are not associated with genital lesion development but can develop into cervical cancer if infection is allowed to progress untreated. These infections are sexually transmitted through intercourse or, more rarely, oral-genital contact. The virus can also be passed from mother to child during childbirth, although instances of this type of transmission are rare (on the order of 7% or less ).
LINKING HPV TO CERVICAL CANCER
The connection between HPV and the subsequent development of cervical cancer took many years, and innumerable contributors, to elucidate. Researchers from academia and industry alike collectively built a body of evidence that, although initially dismissed, proved irrefutable. In the late 1800s, both canine and human warts were linked with a viral causative agent. Researchers transferred ultrafiltered wart lysate between subjects, who exhibited subsequent clinical manifestations . Bacterial sources of infection were thus ruled out by size exclusion as most bacteria measure micrometers in diameter, whereas the HPV virus diameter ranges only from 40 to 57 nm. The first suggestion that these viruses were associated with cancer occurred in the 1930s, when cancer was shown to develop in domestic rabbits after injection of cottontail rabbit papilloma extracts . By the early 1970s, HPV was implicated as a possible causative factor in the development of mucosal cancers, such as cervical cancer. Harald zur Hausen, a German virologist, became one of the first investigators to suggest this connection . However, at the time, it was largely thought that the herpes simplex virus was the more likely causative agent, and there initially was much resistance to the growing evidence linking HPV to the eventual development of cervical cancer.
In 1977, Hausen became the Chair of the Institute of Virology in Freiburg, Germany, where he and his fellow researchers were able to isolate both HPV 6 and HPV 11 from genital wart samples. A student at the Institute, Mathias Durst, became the first to isolate and clone a new type of HPV, HPV 16, obtained from a biopsy from a cervical cancer patient. This discovery laid the framework for a larger scale study in which HPV 16 was identified in over half of all samples collected from various geographical regions .
Hausen's findings were corroborated in the early 1990s by a number of clinical and epidemiological studies. Two primary studies demonstrated that HPV infection results in virtually all diagnosed cases of cervical cancer and preinvasive cytopathologic precursors. In 1993, Schiffman and Hildesheim, together with their colleagues at the National Cancer Institute (NCI), were investigating HPV implications in changes to cervical cytology prior to invasive cancer development, defined as cervical intraepithelial neoplasia (CIN). The group was able to provide evidence that HPV infection causes most CIN . In 1995, using >1000 frozen tumor specimens from women in 22 countries, Bosch et al.  demonstrated that virtually all cases of invasive cervical cancer they investigated contained DNA of the same 13 oncogenetic HPV types. These specimens were collected with help from the International Agency for Research on Cancer . These developments resulted in a series of long term progressive studies to prove that HPV association was causative, and conversely, that the incidence of cervical cancer did not lead to increased carriage or detection of HPV .
HPV AND CERVICAL CANCER
For 90% of women, cervical HPV infection, as measured by the presence of HPV DNA, becomes undetectable within 2 years . The danger arises when infection with a high risk strain persists. In these situations, HPV infection can lead to the development of cervical cancer. The most common strains of HPV leading to cervical cancer are 16 (60%), 18 (10–20%), and 31 and 45 .
Globally, cervical cancer is the second most common cancer affecting women . There are ∼470,000 cases of cervical cancer diagnosed every year worldwide. Half of those diagnosed will die of the disease. Of this number, ∼10,000 cases are diagnosed in the U.S., with ∼3,700 deaths . Thus, the global burden of detection and intervention rests largely on the shoulders of developing countries.
Cervical cancer is very slow to develop and progresses through various stages of CIN, where CIN 1 is considered to be low grade neoplasia and CIN 3 is the highest grade, before transforming into full-blown cancer. Consequently, in developed countries such as the U.S., the use of screening measures such as the Papanicolaou (Pap) smear has reduced the cervical cancer incidence due to early detection and intervention. The Pap test detects abnormalities in cellular morphology and other precancerous changes, as well as the presence of infection or inflammation in cells sampled from the cervix (Fig. 4). Abnormal tissue can then be removed by ablation or excision before progression into cancer, with ∼90% efficacy rates . Common procedures include the loop electrosurgical excision procedure, conization, laser ablation, and cryotherapy . However, in developing countries where regular screening techniques are not widely available, cervical cancer remains the second leading cause of death in women .
Vaccines work by inducing an immune response against a particular antigen, such as a bacteria or virus. Following administration of the vaccine, the immune system produces antibodies specific to that antigen. As a result, these antibodies are available to bind and aid in the clearance of the invader in the event of future infection.
Vaccine development against HPV infection represents a promising area of intervention in halting the progression to cervical cancer. Two types of vaccines are currently being explored: therapeutic and prophylactic. Therapeutic vaccines would be administered to individuals already infected with HPV. Here, the hope would be that a vaccine could induce regression of precancerous or cancerous lesions, induce remission of advanced cervical cancer, control the spread of metastatic cancer, and/or prevent recurrences of cervical cancer after treatment . These vaccines are primarily designed to trigger the cell-mediated immune response of the body to react against the E6 and E7 proteins, which are expressed early (Fig. 1) and would allow for timely intervention during the infectious cycle. Prophylactic vaccines represent a preventative intervention, for those individuals not infected with the HPV virus. These vaccines are based upon the presentation of the L1 and L2 proteins of the HPV viral capsid to induce an antibody-mediated immune response against invading virion particles and the L1 and L2 proteins exposed on their surface. To obtain maximum efficacy, prophylactic vaccines would have to be administered prior to the initiation of sexual activity. This fact has placed their use, unlike the related therapeutic vaccines, at the center of a controversy, requiring an examination of their development, proposed implementation, and political baggage.
Both vaccines in development by Merck and GSK are based upon virus-like particle (VLP) technology. VLPs are comprised of recombinant HPV capsid proteins, which attain the exact capsid conformation of a viable HPV virion but are not infectious due to the lack of genetic material contained within. However, due to the foreign protein presentation, VLPs are capable of eliciting an antibody-mediated immune response upon injection. Conceived in the late 1980s and early 1990s, the technology emerged from the collective work of researchers around the globe. Different groups experimented with the VLP technology, utilizing an assortment of expression systems, as well as L1 or L1 and L2 proteins.22 In 1991, Zhou et al.  reported that HPV L1 and L2 proteins self-assemble into VLPs in solution. Through Dr. Ian Frazer, a collaborator of Zhou and coauthor of the 1991 publication, the University of Queensland in Australia received a patent for this technology in 1994 . The research was supported by Commonwealth Serum Laboratories (CSL), Australia's largest biotechnology company. In 1995, CSL licensed the technology from the University of Queensland. That same year, a license agreement was reached between CSL and Merck and Co. to use the technology in the development of a vaccine to prevent against cervical cancer and genital warts . Under this agreement, Merck obtained worldwide rights to the vaccine outside of Australia and New Zealand, and CSL retained the rights in these two countries.
In parallel with the efforts at the University of Queensland, researchers at the German Cancer Institute in Heidelberg, Georgetown University, and the University of Rochester made their own contributions to the development of VLP technology . Their efforts resulted in the construction of a VLP, whose use was validated utilizing a canine model . This technology was licensed to MedImmune, who demonstrated proof of principle in a small, Phase 1 trial in humans involving HPV 11, a strain that is implicated in the causation of genital warts. Once proof of principle was demonstrated, MedImmune initiated clinical evaluation with HPV-16/18 VLPs in humans . In 1997, MedImmune and GSK entered into a research and development license agreement for the development of a cervical cancer vaccine. According to this agreement, MedImmune was responsible for conducting Phase 1 and Phase 2 trials with the vaccine, whereas GSK was responsible for the final development, regulatory, manufacturing, and marketing activities related to the vaccine's production. In exchange for exclusive worldwide rights to MedImmune's HPV technology, GSK agreed to provide MedImmune with an upfront payment, equity investment, and research funding, as well as potential developmental and sales milestones and royalties on any product sales .
Additional contributors to the body of work involving HPV VLP technology included Drs. John Schiller and Doug Lowy at NCI's Center for Cancer Research . Through their research, it was determined that the L1 major capsid protein alone could induce immune response, whereas the L2 protein is required to envelop genomic DNA. Both prophylactic vaccines nearing approval utilize VLP technology comprising L1 protein alone. With all of the contributing technologies, it is not surprising that a patent dispute involving competing intellectual property claims arose between Merck/CSL and GSK/MedImmune. This dispute was partially settled with respect to HPV 18 in February of 2005 through a cross-licensing agreement. In exchange for the sublicense, GSK received an upfront payment and royalties from Merck from future sales of their HPV vaccine after development and launch. As a further result of this agreement, CSL will receive from GSK separately negotiated milestones and royalties related to GSK's development and sales of its HPV vaccine from GSK . Similarly, MedImmune's agreement with GSK was further amended to include receipt of royalties and certain milestone payments from Merck. Additional patent disputes are ongoing.
Merck's vaccine will be marketed under the brand name of Gardasil™. Gardasil™ contains L1 proteins incorporating subunits from HPV types 16, 18, 6, and 11, produced through recombinant yeast technology. As such, this vaccine is designed to provide protection both against the two most common strains of HPV leading to cervical cancer, implicated in 70% of all cases diagnosed, and against the two most common strains causing genital warts, implicated in 90% of all manifestations of genital warts. A Phase 2 clinical trial demonstrated 90% efficacy in reducing HPV 6-, 11-, 16-, or 18-related persistent infection or disease . Phase 3 trial data released in October of 2005 showed the vaccine to be 100% effective for 2 years after administration in preventing infection with HPV 16 and HPV 18. In the pivotal Phase 3 trial, Gardasil™ was given to 12,167 women between the ages of 16 and 26 in 13 countries; 6,082 women received three doses, at 0, 2, and 6 months, as compared with 6,075 women receiving placebo. In an intent-to-treat analysis, considering women who had received less than the required three doses, efficacy fell to 97% . Merck submitted its biologics license application for review to the FDA on December 5, 2005, with product launch projected in 2006, pending approval. The decision is expected to take anywhere from 6 to 12 months. Filing in the European Union (EU) and Australia is expected by the end of 2005.
GSK's vaccine will be marketed under the brand name of Cervarix™. Cervarix™ contains L1 proteins incorporating subunits from HPV types 16 and 18, produced through recombinant baculovirus technology. Thus, this vaccine is designed to provide protection against only the two most prevalent HPV types leading to cervical cancer. Phase 2 clinical studies with Cervarix™ showed 92% efficacy in preventing transient infection with HPV 16 and 18 and 100% efficacy in preventing persistent infection. Phase 3 clinical testing is underway, and regulatory filing is expected in 2006 in the EU, followed by U.S. filing, with launch in the EU expected in 2007.
MERCK AND GSK: A RACE TO THE FINISH
Analysts are predicting that the global HPV vaccine market could reach $4 billion by the year 2011 . A key assumption in this forecast is that these vaccines will be placed on a U.S. drug schedule leading to a government-funded vaccination program for teenage girls. Capturing a significant portion of this market is critical for Merck for several reasons. First, Merck is slated to lose patent protection on a primary source of revenue, Zocor®, in 2006. Additionally, claims related to Vioxx® lawsuits have been predicted to range upwards of $18 billion. Although Merck will file before GSK in the U.S., the window of opportunity to garner a first to market advantage in market share could be smaller than anticipated. This is due to the fact that GSK's application was granted fast-track status in the U.S., using Merck's registration packet as an educational primer for its own application. This could bring Cervarix™ to the U.S. market within 6 months of the filing date. Coupled to their first mover advantage in the EU, GSK stands to benefit significantly by utilizing this strategy.
REGULATORY APPROVAL OF VACCINES
In the U.S., vaccines are approved and regulated by the Center for Biologics Evaluation and Research at the FDA. Reviews are conducted by the Division of Vaccines and Related Product Applications with the Office of Vaccines Research and Review. The clinical development program for vaccines follows the same basic format as that for drugs and biologics. Preclinical safety studies in animals are required. Then, the vaccine manufacturer must file an Investigational New Drug application to initiate clinical trials in humans. Clinical trials are performed in three phases. Phase 1 studies are the initial studies performed to evaluate safety and immunogenicity of the dosing regimen in a small number of human subjects. Clinical evaluations will include both the injection site as well as any systemic side effects. Adverse events will continue to be monitored through follow-up visits for a predefined period of time. Laboratory testing to measure antibody titers and hematological values may also be assessed at this time. Phase 2 studies are larger and evaluate both safety and efficacy. It is at this stage that an ideal dosing regimen should be identified, including dose, formulation, schedule, and route of administration. Phase 3 studies are the pivotal studies that provide the bulk of the data required for vaccine approval. At this development stage, many patients are studied to evaluate the safety and efficacy of the proposed dosing regimen intended for commercial launch. Extended follow-up from these studies provides the data to assess the duration of the immunity conveyed by the vaccination. Following completion of the clinical studies, the manufacturer of the vaccine will file a biologics license application to the FDA to obtain approval to market the vaccine in the U.S. A multidisciplinary FDA review committee is assembled to review the data and determine whether the vaccine is adequately safe and effective for use in the intended population. The council of an advisory committee, which for HPV vaccines is the Vaccines and Related Biological Products Advisory Committee, may be solicited. In addition to basic safety and efficacy information, the manufacturer must also provide for appropriate product labeling to communicate the vaccine's proper use, benefits, and risks to physicians, parents, and patients alike .
Following approval, the FDA, along with the Center for Disease Control (CDC), continues to monitor the safety of approved vaccines through the Vaccine Adverse Event Reporting System (VAERS) . VAERS was established in 1990 and is maintained by the Department of Health and Human Services. Reporting by healthcare providers of vaccine adverse events within 30 days of the event was mandated by the National Childhood Injury Act of 1986, and these reports are entered into VAERS. FDA monitors adverse events reported to VAERS by both healthcare providers and vaccine manufacturers alike.
Several novel regulatory issues involved in HPV vaccine development and approval are worthy of note. One is the design of the clinical trial end points for the clinical trials. Cervical cancer cannot be used as a primary end point in HPV vaccine clinical trials as allowing development into cervical cancer from persistent infection would be unethical. In 2004, the FDA's Vaccines and Related Biologicals Advisory Committee concluded that the primary end point for vaccine licensure should be CIN 2/3, as well as cancer. Persistent infection with a high risk strain of HPV is considered to be required for development of infection into dysplasia and cancer if left untreated. As such, incidence of persistent infection is being used as a surrogate end point for cervical cancer development in clinical trials. The question remains, however, regarding what vaccine manufacturers will be able to claim on their label, and thus, what marketing claims they will be able to make regarding the HPV vaccines. Technically, the vaccines are providing protection against incidence of infection with particular strains of HPV. Although it is well recognized that HPV infection with certain strains can lead to cervical cancer, it will be interesting to see whether the FDA allows the companies to claim protection against the development of cervical cancer on their label, which would in turn affect the marketing campaigns for each vaccine.
An additional point of interest involves the use of adjuvants in the vaccines. An adjuvant is an immunological agent added to a vaccine to increase the antigenic response against the co-administered antigen. Adjuvants can operate in various ways, including increasing antibody titers, enhancing mucosal immune response, and enhancing cellular responses . Currently, the only adjuvants present in approved vaccines in the U.S. contain aluminum salts. These salts work primarily by creating a depot effect, precipitating smaller antigens and enabling them to remain longer near the injection site, which prevents transport to and subsequent breakdown by the liver before immunogenic effects can take place . Gardasil™ contains one such aluminum salt, aluminum hydroxyphosphate sulfate. Cervarix™ contains aluminum hydroxide, as well as a proprietary adjuvant, AS04, containing a bacterial lipid . As such, the chemistry, manufacturing, and controls section of the approval package will be more complex. It is unknown whether the FDA will have any additional issues with Cervarix™ as compared with Gardasil™, due to the addition of this novel, proprietary adjuvant.
PROBLEMS AND POLITICS OF VACCINATION
Approval of these vaccines is just the first step in implementing a worldwide intervention strategy that will truly have the force and momentum to significantly impact incidence of cervical cancer worldwide. Additional considerations that must be taken into account include the following.
Time of Vaccination—
To be effective, prophylactic vaccines will need to be administered before the onset of sexual activity. This time varies widely both in and outside of developed countries, but studies in the U.S. conducted by the CDC suggest that some adolescents initiate sexual activity prior to 13 years of age . Merck conducted a Phase 3 trial in 1,529 individuals that showed a significantly higher antibody level production in both boys and girls ages 10–15, as compared with women ages 16–23 . Based upon this timeframe, Merck plans to lobby that states require a vaccination for all 12-year-old children before they can enter the next school year. GSK plans to market the vaccine to girls as young as the age of 10 years . Alternatively, it may be easier to introduce the vaccine into populations of late teens and young women first, to provide the vaccine to an informed, interested population and get the general public more accustomed to the concept .
It has been debated whether or not to distribute the vaccine to both males and females or just females. Although rarer than the association with cervical cancer in women, HPV can cause anogenital cancers in men . However, HPV infection in males is often innocuous. Thus, although potentially providing some protection against the development of these types of cancers in men, the vaccine would primarily provide increased protection for their future partners. As stated above, Merck plans to provide the vaccine for both males and females, whereas GSK will market Cervarix™ strictly to females. It is likely that this is due to the fact that Cervarix™ provides protection against only the HPV strains associated with cervical cancer and not those associated with genital warts, as Gardasil™ provides for.
Merck is anticipating that Gardasil™ will cost around $100 per dose, with three doses required per regimen. GSK will likely charge $80 per dose, again for a three-dose regimen of Cervarix™. This makes the cost of this vaccine orders of magnitude higher than other traditional vaccine regimens, with the measles, mumps, and rubella vaccine costing just $34.73 in 2003 . However, with healthcare costs associated with screening and prevention, including doctor visits, Pap tests, and follow up, forecasted to reach upwards of $6 billion in 2005 , many argue that this is a more efficient use of healthcare dollars, particularly if vaccinations are initiated early in mid-to-late childhood. Screening might need to be less frequent, and positive tests would be more likely to indicate a clinically significant abnormal change in cytology .
Implementation in the Developing World—
The vast majority of the burden for cervical cancer prevention worldwide falls on developing countries due to lack of adequate screening programs. Concern abounds over the high cost of the vaccine and distribution of the vaccine to the countries where it is most desperately needed. Merck and GSK both plan to offer their vaccines at a discount to developing countries. However, the time that will be required to get the vaccine to those countries is an area of deep concern. Furthermore, most vaccines in the developing world are distributed through the World Health Organization Expanded Program for Immunization to children under the age of 2. Although this might seem the ideal strategy to pursue in these countries, immunity provided by the current HPV vaccines has so far only been demonstrated up to ∼4 years . As such, an alternative route of distribution that is not aligned with the standard vaccination paradigm must be considered, which could be a logistical challenge.
Effect on Current Screening Programs—
Another area of concern is the impact that vaccination might have on women's compliance with regular screening programs, particularly in developed countries such as the U.S. The problem here is that the current vaccines only protect from HPV infection for the two most common high risk types of HPV covering 70% of all incidence of cervical cancer. The vaccine provides no protection against the other high risk types of HPV leading to cervical cancer. Additionally, it is possible that some women might not develop antibodies to the virus even after vaccination, leading to a false sense of protection.
Vaccination versus Abstinence—
One argument already gaining momentum is the debate over promoting abstinence as a form of prevention, as opposed to prevention through a vaccine. Several advocacy groups, such as the Family Research Council, have voiced concern that the use of these vaccines in adolescents and teenagers will increase the incidence of teen promiscuity. An analogous issue has been raised in the case of Plan B, an emergency contraceptive that was recommended for approval for over-the-counter (OTC) use by a federal advisory committee. Final approval by the FDA, however, has been delayed indefinitely; many feel this delay is due to political pressure exerted by the current administration and various advocacy groups over concern that OTC availability will promote teen promiscuity, similar to concerns raised over implementation of the HPV vaccine. Plan B is a classic example where a drug has been proven safe and efficacious for OTC use, yet is delayed due to social concerns. The same issues could potentially cause a huge stumbling block in the approval of the HPV vaccines, unless Merck and GSK can find an effective way of satisfying the concerns of advocacy groups and political conservatives alike. Many feel this will require a massive educational program relaying the scientifically proven association between HPV and cervical cancer, which in turn could delay market acceptance, size, and dominance by one company over the other.
The pathway of the development of prophylactic HPV vaccines has not been an easy one, and although the end is in sight, many obstacles remain before the world will have access to a marketed HPV vaccine. The technical hurdles of the past have been replaced by the social and political hurdles of the present and the implementation hurdles of the future. Perhaps the future of these vaccines is even more precarious than prevailing thought would indicate. As recent developments surrounding Plan B have shown us, when science meets politics, anything is possible.
What should the FDA's role be in the drug approval process? Should the ethical and social implications of the approval be a factor in the decision?
Discuss the distribution of these vaccines in developing countries. How would you assure that these vaccines are reaching the people that are most burdened with disease resulting from HPV infection? How much would you charge?
What is the most appropriate age for a child to be vaccinated with the HPV vaccine? Do you think that a child will realize the implications of what they are being vaccinated against? Is it the parents' obligation share this information?
Divide the class into two groups and discuss the merits of prevention of HPV infection through abstinence versus vaccination. Do this from the U.S. perspective. Repeat the process from a developing country perspective. Do the arguments change?
Divide the class into two groups. One group will be in charge of the U.S. marketing for Gardasil™, the other in charge of the U.S. marketing for Cervarix™. Design a promotional campaign for each, making sure to address the concerns from all interested parties, including the sponsor company, FDA, advocacy groups, physicians, managed care entities, etc. Be sure to address the indication(s) for each drug, target patient population, slogan, or catch phrase and where and how this vaccine will be marketed (direct-to-physician, direct-to-consumer, etc.).
The author thanks Dr. Alan Cann of the University of Leichester, the CDC National Prevention Information Network, the Mayo Clinic, and Elsevier for the gracious use of figures pertaining to HPV structure, genome, infectious cycle, and etiology; Dr. Sheldon Schuster for recommendations regarding the manuscript; and Dr. Karen Moynihan for highly valuable advice and continuous support.
The abbreviations used are: HPV, human papillomavirus; FDA, Food and Drug Administration; GSK, GlaxoSmithKline; NCI, National Cancer Institute; CIN, cervical intraepithelial neoplasia; Pap, Papanicolaou; VLP, virus-like particle; CSL, Commonwealth Serum Laboratories; EU, European Union; CDC, Center for Disease Control; VAERS, Vaccine Adverse Event Reporting System; OTC, over-the-counter.
I. Frazer, Personal communication.
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- human papillomavirus;
- cervical cancer
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