Diane M. Harper

Currently approved prophylactic HPV vaccines.

Cervarix® and Gardasil® are two prophylactic HPV vaccines designed primarily for cervical cancer prevention. Cervarix is effective against HPV-16, -18, -31, -33 and -45, the five most common cancer-causing types, including most causes of adenocarcinoma for which we cannot screen adequately. Gardasil is effective against HPV-16, 18 and 31, three common squamous cell cancer-causing types. In addition, Gardasil is effective against HPV-6 and -11, causes of genital warts and respiratory papillomatosis. The most important determinant of vaccine impact to reduce cervical cancer is its duration of efficacy. To date, Cervarix’s efficacy is proven for 6.4 years and Gardasil’s for 5 years.

Prevention of human papillomavirus infections and associated diseases by vaccination: a new hope for global public health.

Cervarix® and Gardasil®, 2 human papillomavirus (HPV) vaccines, have been approved and implemented globally in young adolescent women with the hope of reducing the incidence of cervical cancer several decades hence. This program is dependent on the concept of ‘immunobridging’: antibody titers generated in young adolescents that are the same or higher than generated in HPV-naive 16- to 26-year-old women, the population in which efficacy is proven. Likewise, realizing a decline in cervical cancer from young adolescent female vaccination depends on the duration of vaccine efficacy, and the population coverage reached. While we patiently wait for results from our young adolescent vaccination programs, newly released data indicates that the immunogenicity and efficacy of the vaccines for young adult women with prior HPV exposure is equal or superior to that seen for young adolescents. This same concept of immunobridging supported by limited efficacy data offers the potential to reduce cervical cancer precursors within just a few years in our young sexually active adult women, a population secondary to our young adolescents. The HPV vaccines are not therapeutic. Neither vaccine will inhibit an already HPV-infected basal epithelial cell which continues to transform differentiated epithelial layers into cervical dysplasias. There is a clinical hope, though, already supported by early data, that the vaccines are capable of neutralizing HPV virions in host tissues from both auto-inoculated infections and infections in other organs than the cervix, thereby making it possible for these vaccines to prevent less common HPV-associated cancers of the penis, vagina, vulva, anus, oral cavity and oro-pharynx. Both vaccines have been shown to be generally safe in the phase II and phase III randomized controlled trials over 3–6.4 years. Post-marketing surveillance of Cervarix and Gardasil continues to show that they are safe for most women despite rarely occurring serious events.

Next Generation Cancer Protection: The Bivalent HPV Vaccine for Females

Nearly a half a million women throughout the world develop cervical cancer every year Parkin and Bray (“Chapter 2. The burden of HPVrelated cancers,” Vaccine, vol. 24, no. 3, pp. S11–S25, 2006); 80% of these women are in countries without a quality-assured cytology screening program. It is in this setting that Cervarix could reduce the incidence of cervical cancer to about 9.5/100,000 women. New evidence indicates that this might be able to be accomplished with a single dose of Cervarix, a great advantage to public health implementation programs Kreimer et al. (“Proof-of-principle evaluation of the efficacy of fewer than three doses of a bivalent HPV16/18 vaccine, The Journal of the National Cancer Institute, vol. 103, no. 19, pp. 1444–1451, 2011). In countries with screening programs, adenocarcinoma is the most difficult to detect and treat with later-stage presentation and higher mortality Smith et al. (“The rising incidence of adenocarcinoma relative to squamous cell carcinoma of the uterine cervix in the United States—a 24-year population-based study,” Gynecologic Oncology, vol. 78, no. 2, pp. 97–105, 2000) and Gunnell et al. (“A longitudinal Swedish study on screening for squamous cell carcinoma and adenocarcinoma: evidence of effectiveness and overtreatment,” Cancer Epidemiology Biomarkers and Prevention, vol. 16, no. 12, pp. 2641–2648, 2007). With additional cross-protection to HPV 31, 33, and 45 and protection against HPV 16 and 18 lasting at least 9.4 years, Cervarix may reduce adenocarcinomas in screened populations by more than 90%. This paper will detail the evidence about the efficacy, immunogenicity, and safety of Cervarix in the studied populations contrasting public health goals with individual health options.

Review of Gardasil.

Human papillomavirus (HPV) is necessary for the development of cervical cancer. Cervical cancer is the second most common cancer in women worldwide but 80% occurs in developing countries, not countries with Pap screening programs. Pap screening programs in industrialized countries have reduced the incidence of cervical cancer to 4-8/100,000 women. HPV vaccines may be a promising strategy for cervical cancer in women without access to screening programs. In industrialized countries, the benefit of HPV vaccines focuses on individual abnormal Pap test reduction not cancer prevention. The focus of this review is to cover the side effects of Gardasil in perspective with the limited population benefit cervical cancer reduction in countries with organized Pap screening programs. In addition, information about Gardasil benefits, risks and unknowns for individual patient decision making for vaccination is presented. Gardasil offers protection against CIN 2+ lesions caused by HPV 16/18 and against genital warts caused by HPV 6/11 for at least 5 years. Combining Gardasil with repeated cytology screenings may reduce the proportion of abnormal cytology screens and hence reduce the associated morbidity with the subsequent colposcopies and excisional procedures.

Preliminary HPV vaccine results for women older than 25 years

After prophylactic human papillomavirus (HPV) vaccina tion, cost-effectiveness models predict that a reduction in cervical cancer will occur decades from now, but only when 90% of all girls aged 11–12 years have been vaccinated for many years, assuming vaccines confer lifelong protection. Should prophylactic vaccination protect women for less than 15 years, the incidence of cervical cancer will shift to women older than 25 years, with no overall decrease in cervical cancers from early vaccination. Women older than 25 years would again be susceptible to oncogenic HPV types causing cervical cancer at the same rate as younger women, but now with seropositivity that is insufficient to confer immunity. Persistent HPV infections transcribe virions that repeatedly reinfect the genital mucosa. Prophylactic vaccination, however, could neutralise this auto-inoculation, reducing recurrent cancers over time. Long-term follow-up studies show that women with treated cervical intraepithelial neoplasia (CIN) have between three and 12 times the rate of redevelopment of new genital cancers over 10–20 years than does the general population. While we wait to see whether HPV vaccine efficacy will last more than 15 years, 93 million women worldwide have already been exposed to HPV 16 and 18. 83 000 women will develop cervical cancer every year despite ongoing organised screening programmes, and an additional 400 000 women per year in countries without screening will develop cervical cancer. Clearly, we need to understand the prophylactic benefit of HPV vaccines in women older than 25 years who fall into two groups: women without present HPV infections with low antibody titres (seropositive and PCR negative) and those naive to HPV 16 and 18 exposure (seronegative and PCR negative). Past work has clearly shown that the two commercially available HPV vaccines are prophylactic rather than therapeutic and will not hasten regression of present infections, or hasten their progression to invasive cancer. In The Lancet today, Nubia Muñoz and colleagues report on the effi cacy of the quadrivalent HPV vaccine for women aged 24–45 years, after 26 months of follow-up in populations in which black women were under-represented. Vaccine effi cacy, ranging from 31% in the intention-to-treat population to 91% in a per-protocol population, was determined by a composite endpoint comprising cervical or external genital disease or type-specifi c infection that had persisted for at least 6 months, not the cancersurrogate of CIN 2 or 3 disease. About 30% of women in the trial were seropositive and PCR negative for HPV 6, 11, 16, or 18, representing the population at highest risk for cervical cancer. But this group of women were not followed up for a suffi cient time for HPV 6, 11, 16, or 18 persistent infection to progress into any grade of CIN disease. Antibody titres maintained after 24 months, however, do allow immunobridging inferences of effi cacy to younger populations (fi gure). The high anamnestic titres provide great hope that the available HPV vaccines will be at least partially eff ective in prevention of new and recurrent infections in seropositive women vaccinated at older ages. This

The influence of free quadrivalent human papillomavirus vaccine (HPV4) on the timely completion of the three dose series

OBJECTIVE Economic incentives can positively influence social determinants to improve the health care of the uninsured and underserved populations. The aim of this study was to determine if free HPV4 vaccine would lead to on-time series completion in our safety net health care system in the US Midwest. METHODS A nested retrospective cohort study of females receiving HPV4 vaccine between 2006 and 2009 was conducted. Patient characteristics and payor source for each of the three HPV4 doses were abstracted from electronic records. Logistic regression was used to predict on-time completion rates. RESULTS The proportion of adolescent and adult females completing three on-time HPV4 doses was equal (21% (28/136) vs. 18% (66/358), respectively) from among the 494 females receiving 927 HPV4 doses in this study. No adolescent receiving free HPV4 vaccine completed three doses. Grant sponsorship of at least one HPV4 dose among adults did not predict three dose on-time completion (OR=1.56, 95%CI: 0.80, 3.06). Neither was adult grant sponsorship of HPV4 significant when analyzing exclusive payor sources vs. a combination of payor sources (OR=0.72, 95%CI: 0.10, 5.17). CONCLUSIONS Free HPV4 vaccine does not influence the on-time completion rates among adults.

Cross protection against HPV might prevent type replacement

www.thelancet.com/infection Vol 13 March 2013 195 1 Heitmann ER, Harper DM. Prophylactic HPV vaccines and prevention of cervical intraepithelial neoplasia. Curr Obstet Gynecol Rep 2012; 1: 95–105. 2 Khan MJ, Castle PE, Lorincz AT, et al. The elevated 10-year risk of cervical precancer and cancer in women with human papillomavirus (HPV) type 16 or 18 and the possible utility of type-specifi c HPV testing in clinical practice. J Natl Cancer Inst 2005; 97: 1072–79. 3 Malagon T, Drolet M, Boily MC, et al. Cross-protective effi cacy of two human papillomavirus vaccines: a systematic review and meta-analysis. Lancet Infect Dis 2012; 12: 781–89. 4 Wheeler CM, Castellsague X, Garland SM, et al, for the HPV PATRICIA Study Group. Cross-protective effi cacy of HPV-16/18 AS04-adjuvanted vaccine against cervical infection and precancer caused by nonvaccine oncogenic HPV types: 4-year end-ofstudy analysis of the randomised, double-blind PATRICIA trial. Lancet Oncol 2012; 13: 100–10. 5 Kahn JA, Brown DR, Ding L, et al. Vaccine-type human papillomavirus and evidence of herd protection after vaccine introduction. Pediatrics 2012; 130: 249–56. or greater (CIN2+). Additionally, Wheeler and colleagues showed that Cervarix provided cross protection against persistent infection or CIN2+ caused by HPV 51, 52, and 56 in HPV-naive populations. Estimates of the duration of cross protection of Cervarix are restricted over 9·4 years by loss of participants assigned to placebo from follow-up of trial populations, which makes it seem as though the substantial original cross-protection effi cacy decreases. On the basis of the 9·4 year data, whether effi cacy truly decreases is unclear, but the continuing existence of 9·4 year effi cacy is important. Findings from a 2012 study showed a 13·6% increase in the incidence of non-vaccinerelated HPV types in adolescents and women (aged 13–26 years) given Gardasil within 3 years of vaccination (ie, the postsurveillance period) by comparison with adolescents given Gardasil in the presurveillance period when vaccination had just been approved before implementation. This type replacement has not been studied for progression to CIN 3+ disease, but raises concerns about future cervical cancers. Cross protection could become important for the restriction of type replacement CIN 3+ disease. Populations are exclusively vaccinated with either Cervarix or Gardasil, so whether Cervarix’s better cross protection suppresses the typeplacement suggested by studies of Gardasil-vaccinated populations should become apparent.

Prophylactic HPV Vaccines and Prevention of Cervical Intraepithelial Neoplasia

Cervical cancer kills women of all ages. The irrefutable link to oncogenic human papillomavirus (HPV), a sexually transmitted infection, forever changed society’s attitude toward cervical cancer. The advent of HPV vaccines has brought the link of sexual practices and personal behavior to the forefront. The vaccines were aggressively marketed to parents, young girls, public health officials, physicians, and all payor sources before the scientific data defining their actual benefit could be delineated. At this early time, the HPV vaccines prevent persistent type-specific HPV infections, some abnormal Pap tests, some colposcopies, and some excisional procedures in women who are HPV-DNA negative before vaccination. Health-modeling exercises have demonstrated that duration of vaccine efficacy is the most important parameter for any long-term cancer prevention benefit. Implementation efforts have demonstrated that a three-dose series is difficult to achieve and results in a high vaccine wastage rate.

Women Have a Preference for Their Male Partner to Be HPV Vaccinated

Background Peer influence and social networking can change female adolescent and young adult behavior. Peer influence on preferences for male human papillomavirus (HPV) vaccination has not been documented. The primary aim of this study was to determine if women had preferences about male sexual partner HPV vaccination receipt. Methods and Findings A prospective survey of women 18–26 years of age was conducted at an urban university student health clinic. Education about the two HPV vaccines, cervical cancer and genital warts was provided. Women self-reported their demographic and medical history data, as well as their own preferences for HPV vaccine and their preferences for their male partner HPV vaccine using a 5 point Likert scale. 601 women, mean age of 21.5 years (SD 2.4), participated between 2011 and 2012. Nearly 95% of respondents were heterosexual; condoms and contraceptives were used in over half of the population. Regardless of the womans vaccination status, women had significantly higher (strongly agree/agree) preferences for the male partner being vaccinated with HPV4 than not caring if he was vaccinated (63.6% vs. 13.1%, p<0.001). This preference was repeated for sexual risk factors and past reproductive medical history. Women who received HPV4 compared to those choosing HPV2 had a significantly lower proportion of preferences for not caring if the male partner was vaccinated (13% vs. 22%, p = 0.015). Conclusions Women preferred a HPV vaccinated male partner. Peer messaging might change the male HPV vaccination uptake.

In a Safety Net Population HPV4 Vaccine Adherence Worsens as BMI Increases

Objectives Obesity adversely inhibits antibody response to vaccination. Three doses of HPV4 may or may not provide adequate long term protection against HPV 16/18 in obese females. The aim of this study was to determine whether adherence to HPV4 vaccination in a safety net population was reduced with increasing body mass index (BMI). Methods We designed a historical prospective study evaluating the number and dates of HPV4 dosing that occurred from July 1, 2006 through October 1, 2009 by the demographic characteristics of the 10–26 year old recipient females. The defined dosing intervals were adapted from the literature and obesity categories were defined by the WHO. Results 1240 females with BMI measurements received at least one dose of HPV4; 38% were obese (class I, II and III) and 25% were overweight. Females with normal BMI received on-time triplet dosing significantly more often than did the obese class II and III females (30% vs. 18%, p<0.001). Obese class II/III females have a significant 45% less chance of completing the on-time triplet HPV4 series than normal women (OR = 0.55, 95% CI: 0.37, 0.83). Pregnancy history has a significant influence on BMI and HPV4 dosing compliance in this safety net population where 71% had been gravid. Hispanic females were less likely to complete HPV4 dosing regardless of BMI (aOR = 0.39, 95% CI: 0.16, 0.95). Conclusions Obesity, as well as gravidity and Hispanic race, are risk factors for lack of HPV4 vaccine adherence among young females in a safety net population.