Human Papillomavirus (HPV) Vaccines: A Reproductive Health Perspective

WHEC Practice Bulletin and Clinical Management Guidelines for the healthcare providers. Educational grant provided by Women's Health and Education Center (WHEC).

New vaccines designed to prevent human papillomavirus (HPV) infection have the potential to reduce the incidence of serious illness and death worldwide among women, substantially reduce emotional suffering associated with abnormal Papanicolaou (Pap) test results and the diagnosis of cervical cancer, and save significant healthcare dollars. HPV vaccines are expected to significantly reduce HPV-associated morbidity and mortality. Overcoming barriers to vaccine acceptance will require reaching out to the patient community with accurate and pertinent information on both the risks of HPV disease sequelae and the benefits of HPV vaccines that provide coverage for the most common disease-causing HPV types. Improving individualized patient care and population health by preventing an important infectious disease is now a realistic goal. Potentially difficult as it might be to implement a vaccination program, vaccination and prevention of HPV-associated disease are still infinitely preferable to observation and treatment. In 2006, a quadrivalent human papillomavirus (HPV) vaccine was licensed, and another vaccine may be licensed soon. Although the vaccine may ultimately be indicated for both males and females, young girls, or girls and women aged 9-26 years, will be the initial candidates for the vaccine.

The purpose of this article is to review some of the barriers to HPV vaccine acceptance, with a particular focus on factors relevant to female patients, parents, and healthcare providers. It also explores avenues for service delivery of HPV vaccines and critical information gap that must be bridged in order to inform future sexual and reproductive health programming. It proposes the role that the sexual reproductive health community, together with immunization and cancer control programs, could have in supporting the introduction of HPV vaccines within the context of current health systems. The benefits of HPV vaccine may not be fully realized until the vaccine is accepted by patients, parents, and healthcare practitioners. Furthermore, there may be unique issues related to the acceptance of a vaccine designed to prevent a sexually transmitted infection that is poorly understood by many women.


Use of cervical cytology has reduced the incidence of cervical cancer by 70%. However, cervical cancer remains a leading cause of death in countries without screening programs. Vaccines that prevent these persistent HPV infections have the potential to further reduce the burden of disease. Papillomaviruses are highly prevalent, species- and tissue-specific non-enveloped double-stranded DNA viruses that infect epithelial cells. More than 100 different papillomavirus types have been identified that infect humans and are associated with a variety of benign and malignant epithelial lesions. HPV is the most common sexually transmitted infection in the United States, with an estimated 20 million people currently infected, and approximately 5.5 million new cases acquired annually (1). Because infections are often asymptomatic, the prevalence of HPV may be underestimated. Nonetheless, epidemiological studies have suggested that approximately three-quarters of all sexually active individuals will become infected with HPV at some point in their life. Newly active sexually adolescent populations are most at risk of acquiring HPV; approximately 74% of all new HPV infections are reported to occur in young people between 15 and 24 years of age, with cumulative rates of HPV up to 82%. More than 50% of sexually active adolescents will become infected with HPV within 3 years of initiating sexual activity. High prevalence rates of this virus underscore the need for the education of patients and their healthcare providers about HPV infection and HPV-associated sequelae.

HPV Infection:

Human papillomaviruses are small, non-enveloped viruses, whose circular genome encodes the encapsulating structural proteins, L1 and L2. The life cycle of the virus is integrally linked to the maturation of the keratinocyte. Initial infection occurs in the basal stem cell. Specific gene products are transcribed at every of differentiation of the squamous keratinocyte (2). HPV infection evades the immune system through a variety of mechanisms. It leads to down regulation of interferon expression and regulatory pathways, which subsequently prohibits the activation of cytotoxic T-lymphocytes. Specific HPV types are associated with squamous intraepithelial lesions. HPV 16, 18, 45, and 31 cause over half of the low grade lesions, and about 65% of the high grade lesions. HPV 6 and 11 cause 12% of low grade lesions and approximately 80% of genital warts. Up to 40% of patients are infected with more than one HPV type. HPV 16 and 18 are associated with approximately 50% and 20% of cervical cancers, respectively. HPV 45 and 31 are the next most common HPV types associated with cervical cancer, accounting for another 5% each. The fist peak of oncogenic HPV infection occurs between the ages of 15 to 25 years, with a secondary peak in the sixth grade (3). Approximately 75% to 90% of HPV infections will clear within a year of initial infection. Clearance is mediated mostly by the natural desquamation of epithelial cells, and in part, by low-levels of neutralizing antibody responses to the specific HPV L1 epitope. The importance of cellular immunity is clinically apparent in HIV-infected patients and in renal transplant patients, who have a higher incidence of HPV-related disease.

Population awareness of the risks associated with acquiring HPV and the consequences associated with infection is low. Numerous studies have demonstrated that most patients are unaware of HPV and its association with genital warts and cervical cancer. Furthermore, awareness has not improved in the past decade; approximately 33% of women and half of men surveyed have never heard of HPV (4). Nonetheless, there is a desire for more information about HPV. Women want to know how HPV is transmitted, including whether intercourse is required to transmit disease, and how they and their sexual partners can prevent becoming infected. Additional information of interest includes whether condoms protect against the virus, how HPV is detected, the likelihood of spontaneous resolution of infection, and the risk of cervical cancer. HPV infection induces a time-limited, type-specific immunity to HPV infections. Individuals who are infected with one HPV type may develop protective antibodies against future infection with that specific type, but remain immunologically naive to other HPV types. Thus vaccine design strategies need to incorporate the most common disease-causing HPV types in order to protect against the majority of cervical intraepithelial neoplasias and cervical cancers. The interval between acquisition of incident HPV infection and malignancy usually takes ten years or longer.

HPV Vaccines:

HPV vaccines are prepared from virus-like particles produced by recombinant technology. The quadrivalent vaccine (Gardasil, Merck and Co., Whitehouse Station, NJ, USA) has recently been licensed, and a bivalent vaccine (Cervarix, GlaxoSmithKline Biologicals, Rixensart, Belgium) is in advanced stages of clinical testing. These HPV vaccines are designed to prevent infection with and disease from HPV 16 and 18; the quadrivalent vaccine also protects against low-risk genotypes 6 and 11. The vaccines are not designed to treat people who have already been infected with these genotypes. The results of phase III trials of Gardasil, show that it provides almost 100% protection against moderate and severe cervical intraepithelial neoplasia (CIN 2 and CIN 3) caused by the genotypes in the vaccine among women who have not previously been infected with these genotypes (5). Gardasil has also been shown to protect against external genital lesions caused by types 6 and 11, which Merck hopes will make the vaccine more attractive to men as well as women. Trial data for both vaccines suggest they offer a minimum of 4-5 years' efficacy, of close to 100%, in preventing genotypes. The actual impact of vaccine will be highly dependent on country-specific parameters (6). On June 8, 2006, quadrivalent vaccine (Gardasil) was licensed by the US Food and Drug Administration (FDA), becoming the first licensed vaccine developed to prevent cervical cancer and other diseases in females caused by genital HPV infection. On June 29, 2006 the Advisory Committee on Immunization Practices (ACIP) voted to recommend use of the quadrivalent vaccine in females, ages 9 to 26 years of age. The vaccine is administered through a series of three intramuscular injections over a six-month period (at 0, 2, and 6 months).

HPV infects only the epithelium and does not have a viremic phase. As a result, HPV actively invades immune recognition. Therefore, it is unlikely, that in the individual host, there will be any antibody response with re-infection of type specific HPV. Protective antibody levels will be dependent on initial vaccine response or requisite booster shots. At this time, most alum-based vaccinations have booster shots recommended at 7 to 10 year intervals, to maintain disease protection. This concept is important for HPV disease since the benefits of vaccination are to prevent long-term cancer development, and not immediate epidemic protection as has been the standard for infectious diseases, such as pertussis, meningitis, or polio. Higher antibody titers have been reported with use of an ASO4 adjuvant system in the bivalent vaccine, which specifically primes antigen presenting cells (7). Vaccine efficacy for cervical caner is defined for several natural history events that all serve as surrogate markers for the development of cervical cancer: incident HPV infection; persistent type-specific HPV infection (>6 or >12 months); abnormal cytology; abnormal histologic changes. For the quadrivalent vaccine, immunogenicity data show no interference when hepatitis B vaccine is administered simultaneously. Administration of HPV vaccine in combination with other vaccines has not been tested nor have the vaccines been tested in people who are on long-term drug therapy. Bridging studies should address these issues (8).

Evaluation is required of the degree of flexibility in intervals between doses and the possibility of two doses being sufficient. Lack of safety and immunogenicity studies in infants or young children will hinder the integration of vaccines into the traditional Expanded Program on Immunization (EPI) schedule, which is tailored to childhood vaccination. Despite the successes of EPI there are several programmatic challenges in introducing HPV vaccines as part of the program in many countries. Given the limited data on the duration of protection of the HPV vaccines, and absence of clinical trails in children aged <9 years old, school entry would be too early for co-administration. School-based vaccination may be cost-efficient because children are already gathered in one place and accounted for. In countries where education is mandatory and/or accessible to all children, laws mandating vaccination before enrollment may increase vaccination rates by as much as four-fold. Parents usually trust healthcare recommendations made in a school setting, especially when they are endorsed by professionals involved in the settings, such as teachers. Where enrollment rates are high, school-based vaccination may be extremely successful in eliminating disease (9).

HPV Vaccine Acceptance:

Average age of first sexual intercourse in North America is approximately 16 years for both men and women. To provide the greatest public health benefit, HPV vaccines must be most effective must be administered prior to initiating sexual activity and hence would be most effective if offered during early adolescence. Historically, vaccine availability has not always translated to widespread use. Underestimates of both the level of risk and the severity of HPV-associated disease may become barriers to vaccine acceptance. Hence, physician, parent, and patient education about HPV and HPV vaccines will be crucial to effectively implement HPV vaccination programs.

Vaccine acceptability among healthcare professionals: Endorsement by professional organizations is a major predictor of HPV vaccine acceptance. Educational initiatives targeting healthcare professional have demonstrated effectiveness in fostering vaccine acceptance. These efforts aimed at healthcare professionals should include physician assistants and nurse practitioners, as well as physicians. Educating patients about HPV and the HPV vaccine will be time consuming, and the assistance these groups can provide will prove to be invaluable. Clinicians should provide information in an individualized fashion, tailoring educational sessions according to the patient's background, age and literacy level. An effort should be made to provide needed information to parents and adolescents without creating needless anxiety over the situation. Nonetheless, it is crucial that the high risk of infection, the frequent negative consequences associated with infection, and the importance of vaccinating in early adolescence, before the individual has become sexually active, be made clear to the parent.

Vaccine acceptability among parents: Vaccine acceptance among parents is not universal. Although, in general, overall confidence in vaccines remains high, many Americans distrust public health policy and refuse vaccination on these grounds. Concern over potential side effects from vaccines is a common barrier to vaccination. Parents may also object to vaccination for religious or philosophical reasons (10). The sexual nature of HPV infections may introduce unique barriers to parental consent not previously encountered with other vaccines. Parents may feel that consenting to a vaccine for a sexually transmitted disease my inadvertently encourage their adolescent children to engage in sexual intercourse. Similarly, parents may feel that vaccination at an early age will encourage earlier sexual debut. Acceptance of vaccine represents an acknowledgement of risk of infection, and some parents may have difficulty accepting the fact that their children are approaching an age at which sexual activity is often initiated. When parents who were undecided about HPV vaccination were provided with a basic information sheet about HPV and HPV vaccines, they became significantly more likely to support HPV vaccination. Physician endorsement and school requirements have also been identified as important catalysts for parental vaccine acceptance. Conversely, information acquired from friends, relatives, or advertisements had a marginal impact (11).

Vaccine acceptability among individuals: Attitudes regarding HPV vaccine acceptance can be assessed based on acceptability of previous vaccines and through questionnaires completed by patients, parents, and healthcare providers. Clearly, women are concerned about HPV and want to be better informed about prevention and the risk of the adverse consequences with infection; however, this concern and desire for information about HPV may or may not translate into widespread acceptance of HPV vaccines. Some to the potential obstacles to sexually transmitted infection vaccine acceptance that have been discussed include the stigma associated with sexually transmitted diseases and the possibility that acceptance of this vaccination might be seen as an admission of risky sexual behavior.

Health Systems and Policies: Considerations for introduction

The introduction of HPV vaccine into a national healthcare system will raise questions for all countries. It may be possible to implement simplified screening and vaccination programs as part of an integrated reproductive health strategy to reach girls and women if a coordinated effort is made by all stakeholders. Countries need to: use evidence to determine the age cohort to target, develop a service-delivery strategy, address the training needs of health professionals and other issues related to human-resource development, forecast the demand and supply of the vaccine, develop product-financing mechanisms and mechanisms for procurement and supply-chain management, and implement monitoring and evaluation programs. Evaluation of potential product financing and procurement mechanisms should be considered in the context of existing mechanisms used by organizations such as UNICEF, the GAVI Alliance, and the International Financing Facility for Immunization. The Global Immunization Vision and Strategy provides opportunities for engagement because it highlights the importance of introducing new vaccines, extending them to other age groups and linking vaccines with other interventions (12). Because global financing mechanisms for an HPV will depend on the cost of the vaccines, financing and procurement-related issues must be considered as soon as possible. Manufacturing limitations for HPV vaccines are unclear. Without 5-year estimates of purchasing demand, the industry is unlikely to invest in building manufacturing capacity or move towards cost structures that include lower profit margins. A business case for HPV vaccine production and procurement that is specific to developing countries must be developed.

Demonstration projects that will both inform industry using demand forecasting and provide models for introduction that maximize acceptability and access based on country-specific assessments are being implemented. During negotiations on pricing structures, ministers of finance and purchasing agencies must not lose sight of the costs of the service delivery. Ancillary costs, such as transportation and human resources (providers, educators and so forth), must be accounted for. Estimating these ancillary costs for cost-effectiveness models has proven difficult because they are country-specific. Countries must consider their pre-existing screening services, and/or expanded EPI programs, and the comparable costs of other priority health interventions.

Editor's Note:

Comprehensive prevention programs that offer screening and early treatment alongside new vaccine programs would allow an opportunity to provide community-based education regarding sexual and reproductive health in broader terms. The significant role of the sexual and reproductive health community in nurturing advocates to campaign for the adequate allocation of resources, nationally and internationally, must not be underestimated. Several studies have demonstrated that if parents understand the benefits of vaccination their apprehension about discussing issues of sexual health or acknowledging that their child may be, or may become, sexually active can be overcome. Evidence-based standardized information materials should be developed or identified for wide distribution by healthcare professionals. Since HPV is sexually transmitted, culturally appropriate information must be developed to avoid a negative reaction against vaccination or sexual and reproductive health services, particularly since young girls will be the ones who are vaccinated. It is also important to avoid the risk of a girl-only focus; even if only women and girls receive the vaccine, information must also be given to men and boys about cervical cancer and behavioral interventions to reduce HPV transmission. Educational initiatives targeted towards patient, parents, and healthcare providers will play key roles in fostering positive attitudes towards vaccination.The development of adolescent health programs are of utmost importance; developing user-friendly services that aim to provide counseling on sexual health that focuses on the prevention of pregnancy and sexually transmitted infections including HIV. The presence of a new intervention, such as an HPV vaccine, could extend the scope of these services and help to integrate other interventions, thereby making them more attractive to young people.

Suggested Reading:

  1. World Health Organization
    Preparing for the introduction of HPV vaccines: policy and programme guidance for countries (pdf)
    Human Papillomavirus and HPV vaccines: Technical information for policy makers and health professionals (pdf)
  2. Center for Disease Control and Prevention (CDC)
    HPV Vaccination
  3. US Food and Drug Administration
    Quadrivalent human papillomavirus (types 6, 11, 16, 18) recombinant vaccine, 2006 (product approval information: licensing action)


  1. Cox, JT. Introduction. Curr Opin Obstet Gynecol 2006;18 Suppl1:s3-s4
  2. Munger K, Howley PM. Human papillomavirus immortalization and transformation functions. Virus Res 2002;89:213-216
  3. Clifford GM, Gallus S, Herrero R et al. Worldwide distribution of human papillomavirus types in cytologically normal women in the International Agency for Research on Cancer HPV prevalence surveys: a pooled analysis. Lancet 2005;366:991-998
  4. Dell DL. Chen H, Ahmad F et al. Knowledge about human papillomavirus among adolescents. Obstet Gynecol 2000;96:653-656
  5. Villa LL, Costa RL, Petta CA et al. Prophylactic quadrivalent human papillomavirus (types 6, 11, 16, 18) L1 virus-like particle vaccine in young women: a randomized double-blind placebo-controlled multicenter phase II efficacy trial. Lancet Oncol 2005;6:271-278
  6. Lowndes CM, Gill ON. Cervical caner, human papillomavirus and vaccination. BMJ 2005;331:915-916
  7. Gianni, SL, Hanon E, Moris P et al. Enhanced humoral and memory B cellular immunity using HPV 16/18 L1 VLP vaccine formulated with the MPL/aluminium salt combination (ASO4) compared to aluminium salt only. Vaccine 2006;24:5571
  8. Pollack AE, Balkin M, Edouard L et al. Ensuring access to HPV vaccines through integrated services: a reproductive health perspective. Bulletin of the World Health Organization 2007;85:57-63
  9. WHO consultation on human papillomavirus vaccines. Wkly Epidemiol Rec 2005;35:299-302
  10. Diekma DS. Responding to parental refusals of immunization of children. Pediatrics 2005;115(5):1428-1431
  11. Zimet GD, Mays RM, Sturm LA et al. Parental attitudes about sexually transmitted infection vaccination for their adolescent children. Archives of Pediatrics & Adolescent Medicine 2005;159(2):132-137
  12. Bilous J, Eggers R, Gasse F et al. A new global immunization vision and strategy. Lancet 2006;367:1464-1466

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