Article Published in the Author Account of

Diane M Harper

Prophylactic HPV Vaccines: Current Knowledge of Impact on Gynecologic Premalignancies

Abstract: Approaches for cervical cancer prevention are changing. Screening still remains the most effective method for cervical cancer prevention. Guidelines are moving to an older group of women to be screened less frequently with combinations of technologies that include biomarkers and cytology. HPV vaccination is an appropriate option for this older group of women as well, should the woman not wish to make her decision about vaccination until 21 years of age, the age of screening. Parents making decisions about HPV vaccination for their young adolescent daughters need to be fully informed that only continued screening prevents cervical cancer. HPV vaccination reduces the possibility of their daughter having an abnormal Pap test by 10% if the vaccines have not waned by the time the young adolescent becomes sexually active. HPV vaccine efficacy must last at least 15 years to contribute to the prevention of cervical cancers. At this time, protection against cervical intraepithelial neoplasia grade 2/3 (CIN 2/3) is 5 years for Gardasil and 8.4 years for Cervarix. The value of the current protection HPV vaccines offer will be viewed differently by different women. Physicians' ethical duties are to provide full explanation of the risks and benefits of adding HPV vaccination to the ongoing screening programs, and to support women in their personal choice for cervical cancer prevention.



Introduction

Gardasil dissemination programs in Andhra Pradesh and Gujarat, India were suspended in April 2010 by the Indian government (http, 2010g, http, 2010h) despite an annual cervical cancer incidence rate of 28 women per 100,000 (WHO/ICO, 2010), which is over three times that of the US (US Cancer Statistics Working Group, 2010) and seven times that of Finland (Arbyn et al., 2007). The most disquieting objection to the program, voiced by over 70 civil society groups, public health organizations, medical professionals, human rights organizations, women’s groups and others, was the lack of information provided to the public so that each participant could be afforded the opportunity for informed decision making about their cervical cancer protection. This desire for information is not limited to India.

In this era of HPV vaccines and multiple screening methods for cervical cancer, clear communication about the changes in screening recommendations and the expected benefits a screened woman will have from HPV vaccination is of paramount significance. This article will review the current information on cervical cancer prevention.

Benefits and Harms of Cervical Cancer Screening Programs

Given the current price of HPV vaccines in developed countries, regardless of limited or lifetime duration of vaccine efficacy, cervical cancer screening is more cost effective than either HPV vaccination alone or HPV vaccination in combination with cervical cancer screening for the 9-26 year age range of vaccinees (Barnabas et al., 2006; Chesson et al., 2008; Coupe et al., 2009; de Kok et al., 2009; Diaz et al., 2008; Ginsberg et al., 2009; Goldhaber-Fiebert et al., 2008; Goldie et al., 2004; Goldie et al., 2008; Jit et al., 2008; Kim and Goldie, 2008; Rogoza et al., 2008; Techakehakij and Feldman, 2008; Thiry et al., 2009). HPV vaccination alone or with screening is not considered cost savings for population health at current prices and for unknown duration of efficacy. Likewise, for any given population coverage, cervical cancer screening will always be able to detect more cervical cancers than HPV vaccination can prevent because the vaccines contain only a fraction of the HPV types that cause cervical cancer.

The natural history of HPV infection evolving into cervical cancer is very slow, allowing ample time for screening, early detection, and treatment. Ninety percent of HPV infections resolve on their own within 3 years, never becoming cervical intraepithelial neoplasia grade 2/3 (CIN 2/3). Five percent of persistent HPV infections after 3 years become CIN 2/3 with 20% of CIN 3 progressing to invasive cancer within 5 years and 40% of CIN 3 progressing to invasive cervical cancer within 30 years (McCredie et al., 2008; Schiffman and Rodríguez, 2008).

Using Finland as the gold standard for effectiveness of Pap testing programs, cervical cancer has declined a measurable 75% over the past 60 years (Finnish Cancer Registry, 2010a; Finnish Cancer Registry, 2010b), primarily because at least 70% of the population participates in Pap screening (Quinn et al., 1999; Peto et al., 2004). But when 20-29 year old unvaccinated women stopped attending Pap screening, a four-fold increase in cervical cancer occurred in this population within five years from screening cessation (Engeland et al., 1995; Laukkanen et al., 2003). This rebounding increase in invasive cancer underscores the need for continued screening, or potential personal and public health risk would elevate should women, vaccinated with a vaccine that wanes in less than 15 years, disregard regular screening (Harper et al., 2010).

While Pap testing is effective, there still remain five specific challenges. First, screening must be done repeatedly over most of the woman’s lifetime. Second, false negatives can occur; 30% of women developing cervical cancer having had a history of normal cytology screens (Sawaya and Grimes, 1999). Third, abnormal cytology causes much anxiety for many women (Rogstad, 2002). Fourth, for those women whose screening leads to a diagnosis of CIN 2/3, treatment with loop electrosurgical excision procedure (LEEP) can lead to an increased risk in subsequent pregnancies of preterm delivery, low birthweight infants, premature rupture of membranes, and operative delivery at a rate of 70-300% increase (Arbyn et al., 2008). Lastly, there is no lifetime protection from future HPV infections from her natural infection, leaving a woman at a 3-12 fold increased risk of other anogenital cancers about 10 years later (Edgren and Sparen, 2007).

Benefits of HPV Vaccinations as an option for Cervical Cancer Prevention

Primary efficacy

Cervarix has 20 micrograms each of HPV 16 and HPV 18 L1 proteins; Gardasil has 20 micrograms of HPV 6, 40 micrograms of HPV 11, 40 micrograms of HPV 16, and 20 micrograms of HPV 18 (Harper, 2009). Both are quite effective at preventing HPV 16/18 persistent infections and the associated CIN 2+ caused in women of 15-26 years old with no current HPV infection at the time of initial vaccination (Paavonen, 2009; Koutsky, 2007). However, if the girl/woman is currently infected with and producing the HPV 16 or 18 virus at the time of vaccination, the vaccines will not stop the HPV from progressing to CIN 2+, nor will the vaccines accelerate the progression to CIN 2+. They show no therapeutic efficacy against current infection (Garland et al., 2007; Hildesheim et al., 2007). In addition, there is early evidence suggesting that one of the vaccines will be nearly as effective (Cervarix at 89% efficacy) in the prevention of HPV 16/18 related CIN 2+ in women with prior exposure to HPV 16/18 (seropositive), but not having active infection (DNA HPV 16/18 negative) at the time of vaccination (Olsson et al., 2009; Poppe et al., 2009). This finding broadens the impact of vaccination to those women highly motivated to reduce any future infections.

Squamous cell carcinoma

HPV 16 and 18 are associated with 70% of the squamous cervical cancers (Smith et al., 2007), 50% of CIN 2/3 lesions (Smith et al., 2007), and 35% of low grade squamous intraepithelial lesions (LSIL) Clifford et al., 2005b), and occur in 2.5% of normal women (Clifford et al., 2005a). HPV 45, the next most common oncogenic HPV type, is associated with 5% of the squamous cervical cancers (Smith et al., 2007), 2.5% of CIN 2/3 lesions (Smith et al., 2007), and 5% of LSIL (Clifford et al., 2005b), and occurs in 0.5% of normal women (Clifford, 2005a). HPV 31 and 33 identify the fourth and fifth most oncogenic HPV types with each associated with another 4.4% of squamous cancers (Smith et al., 2007), with 12% and 7%, respectively, of the LSILs (Clifford et al., 2005b), and in 0.7% and 0.5%, respectively, of normal women (Clifford et al., 2005a). HPV 51 and 56 account for 2% of the squamous cervical cancers and 6.5% of the CIN 2/3 lesions (Smith et al., 2007), 11% and 9.7%, respectively of LSILs (Clifford et al., 2005b), and 1% of normal women (Clifford et al., 2005a). Although HPV 16/18 contribute to the majority of squamous cell carcinomas, the squamous cancer precursors are relatively easy to detect by a program of repeated cytology screening, thus making vaccination most important for the prevention of the precursor lesions, rather than cancers, in the screened populations.

Both Cervarix and Gardasil prevent about 10% of all abnormal Pap tests regardless of HPV causation (Paavonen et al., 2010; Munoz et al., 2010). In the HPV naive populations, Cervarix reduces colposcopies by 26% and LEEPs by 69% (Paavonen et al., 2010). Gardasil reduces colposcopies by 20% and LEEPs by 42% (Munoz et al., 2010).

Adenocarcinomas

Adenocarcinoma of the cervix, on the other hand, is more difficult to detect by cytology screening and colposcopic examination, and when detected, is usually at a later stage resulting in higher mortality (Gunnell et al., 2007). Adenocarcinomas comprise about 25% of the cervical cancers and peak in occurrence at a younger age than the squamous cancers (Smith et al., 2000). HPV 16 and 18 are associated with 74% of the adenocarcinomas of the cervix; HPV 45 is associated with 3.8%; and HPV 33 and 51 are associated with about 1.2% (0.6 each) (Castellsagué et al., 2006). Because screening cannot detect adenocarcinomas to any measurable degree, HPV vaccination for HPV 45, 33, and 51 prevention assumes supportive importance to HPV 16/18 coverage.

Protection among the naïve women seronegative and DNA negative for HPV 16/18 at the time of vaccination extends to persistent HPV 31 infection at 75% by Cervarix (96.1% CI:70, 85) and 46% by Gardasil (95% CI:15, 66) (Paavonen, 2009; Brown et al., 2009). However, significant protection for persistent HPV 45 and 33 infections is only seen by Cervarix at 82% and 42%, respectively (Paavonen, 2009). In order to remedy the lack of overall adenocarcinoma protection covered by Gardasil, a second generation pentavalent Gardasil vaccine with these missing types has been developed and is currently in clinical trials (http, 2010a; http, 2010b; http, 2010c). The Cervarix cross protection extends to type specific CIN 2+ prevention at 100% for HPV 45, 44% for HPV 31 and 55% protection against HPV 51 related CIN 2+ lesions (Naud et al., 2010). Overall, the updated adenocarcinoma protection is estimated to be 91% by Cervarix and 78% by Gardasil.

Noncervical lesions

Other HPV associated anogenital lesions will also be prevented by HPV vaccines (Joura et al., 2007). While this coverage is intellectually exciting, clinical reality shows that the incidence of abnormal Pap tests dwarfs the incidence of genital warts by tenfold (Hoy et al., 2009; Eversole et al., 2010), and the incidence of all noncervical HPV associated cancers is only 12% of all HPV associated cancers (Parkin, 2006a; Parkin and Bray, 2006b). Cervical cancer is 78 times more common than mouth cancer, 60 times more common than oropharyngeal cancer, 47 times more common than penile cancer, 30 times more common than vulvar and vaginal cancers combined, and 17 times more common than anal cancer. The economic burden of the noncervical cancers is tallied to be only 8% of the economic burden of all HPV related diseases (Myers, 2008), emphasizing that prevention of cervical cancer is the dominant clinical and economic force for vaccination.

Duration of immunity

The full duration of HPV vaccine efficacy is unknown. Phase II trials provide the longest follow-up data for Gardasil at 5 years and for Cervarix at 8.4 years (Villa et al., 2006; The GSK HPV Vaccine 007 Study Group, 2010). Modeling has shown that HPV vaccines must maintain their near 100% efficacy for a full 15 years, at minimum, in order for cervical cancers to be prevented (Barnabas et al., 2006). Until there are trials that assiduously track both immune titers and efficacy for at least 15 years, we will not know the immune titer necessary for protection. Vaccines function to induce immediate antibody responses to the directed antigen and provide a recall memory anamnestic response. As both 5 years and 8.4 years are insufficient durations of protection, the immunologic response to the vaccines is the only indicator to provide intermediate guidance on probability of duration of efficacy for policy guidelines.

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Figure 1. Vaccine induced anti-HPV 16 titers in women 15-26 years of age. a) Cervarix has induced sustained antibody titers for HPV 16 more than seven-fold higher than natural infection titers (Einstein et al., 2009) at 8.4 years after initial vaccination with 100% seropositivity maintained measured by the pseudovirion based assay (PBNA); and more than 11-fold higher than natural infection titer measured by ELISA with similar 100% seropositivity maintained (The GSK 007 Study Group, 2010). b) Gardasil has induced sustained antibody titers for HPV 16 more than ten-fold higher than natural infection titers (Olsson et al., 2007) at 5 years after initial vaccination with 98.8% seropositivity maintained measured by the competitive Luminex immunoassay (cLIA) in milliMerck units/ml (mMU/ml). The monovalent HPV 16 phase I pre-Gardasil vaccine maintains titers 1.8-fold higher than natural infection titers measured by cLIA with a decrease in seropositivity to 86% (Rowhani-Rahbar et al., 2009), meaning 14% of women had lost measurable antibodies to HPV 16 by 8.5 years. GMT, geometric mean titer; HPV, human papillomavirus; NIT, natural infection titer.

Antibody responses

Induced antibodies against the L1 VLP for HPV 16 are high and are sustained for both Cervarix and Gardasil for their 8.4 years and 5 years of protection, respectively (Figure 1). Induced antibodies for HPV 18 from Gardasil fall quickly after peak with 35% of women having no measurable antibody titers to HPV 18 at 5 years. Cervarix titers remain several fold above natural infection titer for HPV 18 (Figure 2). Much discussion has ensued about comparability of antibody titers due to different assay systems used to measure each antibody. Immunologic responses were measured in both the competitive Luminex immunoassay (cLIA) and the binding ELISA systems for both vaccines resulting in higher titers for HPV 16 and 18 induced by Cervarix than Gardasil in all measurement systems (Figure 3). Induced antibody titers for HPV 6 and 11 by Gardasil show very rapid return to natural infection titer levels for both genital wart types (Figure 4).

Gardasil trials showed that natural infection titers are not protective against future type specific infections (Olsson et al., 2009), implying a need for Gardasil booster shots to maintain protection against genital warts and HPV 18 lesions potentially as soon as 5 years after vaccination. The monovalent experimental HPV 16 Gardasil precursor vaccine even showed a loss of 14% of measurable antibodies to HPV 16 after 8.5 years (Rowhani-Rahbar et al., 2009), supporting the belief that Gardasil boosters will be necessary before the 15 year threshold for actual cancer prevention.

T and B cell responses

Because natural HPV infection evades the human immune system so well, it is highly unlikely that natural HPV infection, occurring in the intraepithelial space with limited access to sparse Langerhans cells and no direct access to blood or lymphatic channels, will induce an anamnestic response after vaccination. While some believe that HPV might respond as Hepatitis B does with a viremic natural infection challenge to produce an anamnestic response (But et al., 2008), we look to other immune parameters to provide evidence of sustained memory. T helper cells are important for B cell differentiation, sustained memory, activation of recall reactions, and anamnestic responses. Both vaccines were tested for their T helper responses. Cervarix induced higher T cell frequencies for HPV 16, 18, 31, and 45 than did Gardasil. Both Cervarix and Gardasil induced equivalent T cell frequencies for HPV 6 and 11 (Pacher et al., 2010). Further data indicate significantly superior cervicovaginal secretion antibody titer and memory B cell responses for HPV 16 and 18 by Cervarix than Gardasil both at month 7 and month 18 after the first vaccination (Table 1) (Einstein, 2010; Einstein et al., 2009).

These limited data indicate that Cervarix has a higher probability of longer duration of efficacy than Gardasil.

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Figure 2. Vaccine induced anti-HPV 18 titers in women 15-26 years of age. a) Cervarix has induced sustained antibody titers for HPV 18 more than four-fold higher than natural infection titers (Einstein et al., 2009) at 8.4 years after initial vaccination with 100% seropositivity maintained measured by the pseudovirion based assay (PBNA); and more than ten-fold higher than natural infection titer measured by ELISA with similar 100% seropositivity maintained (The GSK 007 Study Group, 2010). b) Gardasil has induced antibody titers for HPV 18 measured by the competitive Luminex immunoassay (cLIA) in milliMerck units/ml (mMU/ml) that return to natural infection titer levels at 18 months (Olsson et al., 2007) after initial vaccination with significant continued loss of seropositivity over time: 14% of women have lost measurable titers to HPV 18 at 18 months, 24% have lost measurable titers at 36 months, and 35% of women vaccinated with Gardasil have lost antibody titers by 5 years. Natural infection titers do not prevent future type specific infections (Olsson et al., 2009), leaving the woman at risk for new infections. GMT, geometric mean titer; HPV, human papillomavirus; NIT, natural infection titer.

Dangers of HPV Vaccination

The generally recognized maximum amount of foreign protein that the human body can tolerate in one injection is 200 micrograms before severe adverse events occur in most recipients. Given that Gardasil has 120 micrograms and Cervarix has 40 micrograms of highly antigenic foreign protein in the form of VLPs to different L1 genotypes, the amount of VLP antigens becomes important to monitor in both the current HPV vaccines as well as in second generation vaccines (http, 2010d; http, 2010e). In general, at this time both vaccines are considered safe for most women. However, there is no medicine or vaccine that is completely harmless. While national and international regulatory bodies continue to monitor surveillance safety data after millions of vaccinations, independent scientists are publishing reports of patients who have had autoimmune demyelinating neurologic sequelae after Gardasil administration, resulting in blindness, paralysis, and death (Sutton et al., 2009; CDC, 2008; Beller and Abu-Rustum, 2009; Marsee et al., 2008; Studdiford et al., 2008; Kang et al., 2008; Brotherton et al., 2008; Debeer et al., 2008; Das et al., 2008; Lower, 2008; Lawrence et al., 2008; Wildemann et al., 2009; McCarthy and Filiano, 2009; Cohen, 2009). The current postmarketing commitment between Merck and the FDA is to recognize a rate of serious adverse events that exceed 2/10,000 women in a cohort of 44,000 women who have received all three doses of Gardasil (http, 2010f). Yet, although autoimmune neurologic sequelae after Gardasil administration have occurred, because the frequency of autoimmune neurologic diseases is less than 2/10,000, regulatory authorities do not have to evaluate these reactions, such as Guillain-Barré Syndrome, as possible serious adverse events. Nevertheless, recognizing that these issues could be life-threatening to some girls, studies are registered, but not yet recruiting subjects, to evaluate the effect of Gardasil on young girls with systemic lupus erythematosus, inflammatory bowel disease, juvenile idiopathic arthritis, juvenile dermatomyositis, solid organ transplants, HIV/AIDS, and chronic illnesses (http, 2010c).

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Figure 3. Measurement of induced antibodies to HPV 16 and 18 by Cervarix and Gardasil one month after the 3rd dose (month 7) among 18-45 year old women. This figure shows that Cervarix induces a significantly higher antibody response after three doses of vaccine than Gardasil regardless of the measurement system (Dessy et al., 2010). ELISA, Enzyme-linked immunosorbent assay in ELISA units/ml (EU/ml); cLIA, competitive Luminex immunoassay in milliMerck units/ml (mMerckU/ml).

Additionally, fetal malformations and death were evaluated for both vaccines over various time intervals between conception and injection. Analysis of pregnancy events within 30 days of injection has evolved over two publications (Koutsky, 2007; Garland et al., 2009), indicating initial significant fetal anomalies within 30 days of Gardasil; however, upon the discovery of one additional fetal anomaly in the placebo group, differences were no longer statistically significant. The prevalence of schizencephaly and anencephaly in the general population is 1.5/100,000 and 1.1/10,000, respectively, with both events happening to fetuses of women who received Gardasil (Dana et al., 2009). Neither Cervarix nor Gardasil has been implicated in teratogenic adverse events to date, but they continue to be monitored via self-report pregnancy surveillance databases (Garland et al., 2009; Dana et al., 2009; McCune-Smith and Sawaya, 2009; Descamps et al., 2009; Wacholder et al., 2010). As was stated by an editorialist, “The current findings are fragile: analyses are interim, the total number of outcomes is small (especially in the placebo group), and the association [of reproductive effects] lacks clear biologic plausibility. Nevertheless, results from randomized trials suggesting harm warrant focused attention” (McCune-Smith and Sawaya, 2009).

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Figure 4. Induced anti-HPV 6 and anti-HPV 11 titers after three doses of Gardasil in women 16-26 years of age. a) HPV 6 titers overlap with natural infection titers at 18 months after initial vaccination. Women lose measurable seropositivity for HPV 6 by 2% at 18 months, 6% at 36 months, and 10% at 5 years (Olsson et al., 2007). At natural infection titers, women are susceptible for new infections of HPV 6 (Olsson et al., 2009). b) HPV 11 titers overlap with natural infection titers at 12 months after initial vaccination. Women lose measurable seropositivity for HPV 11 by 2% at 18 months, 4% at 36 months, and 9% at 5 years (Olsson et al., 2007). At natural infection titers, women are susceptible for new infections of HPV 11 (Olsson et al., 2009).

Conclusions

As data emerge on the relative risks and benefits of various methods for reducing cervical cancer, there is an increasing need for women to make informed decisions knowing all of their options. The current environment of changing Pap screening guidelines, direct marketing of vaccines to consumers, and general confusion about risks of cervical cancer provide an ideal opportunity to present women with clear options about risks and benefits of cervical cancer screening and HPV vaccination. Presenting factual information in ways that generate fear, such as advertising that 30 women per day in the U.S. get cervical cancer, serves women poorly. Factual framing that can be compared across options must be provided by physicians for the well being of their patients. For example, with cervical cancer screening in the U.S., 8/100,000 women get cervical cancer every year; whereas, with HPV vaccination without screening, assuming lifetime vaccine efficacy and all women being vaccinated, 9.5/100,000 and 14/100,000 women could get cervical cancer every year using Cervarix or Gardasil, respectively. Combining screening with vaccination does not significantly lower the number of women getting cervical cancer every year, but does decrease the number of women with abnormal screening tests. This may not be information that influences increased uptake of vaccination, but physicians’ goals are not to sell vaccine product. Physicians’ goals include providing full and open discussion guiding women to make a decision for their cervical cancer protection that is in line with the woman’s own personal values.

Disclosure

DMH: The institutions at which I have conducted HPV vaccine trials have received funding to support clinical trials on the vaccines discussed herein from Merck and GlaxoSmithKline.

I have also received honoraria for speaking and for participation on advisory boards from Merck and GlaxoSmithKline.

KBW: Nothing to disclose.

(Corresponding author: Diane M. Harper, M.D., M.P.H., M.S., Professor of Medicine, University of Missouri at Kansas City, Truman Medical Center Lakewood, 7900 Lee’s Summit Road, Kansas City, MO 64139, USA.)

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[Discovery Medicine; ISSN: 1539-6509; eISSN: 1944-7930. Discov Med 10(50):7-17, July 2010.]

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