- HPV causes virtually all cervical cancer, with 87% of deaths occurring in low- and middle-income countries. HPV vaccines can dramatically reduce HPV-related cancer incidence, and international efforts are underway to promote HPV vaccination.
- The structure and strength of local health care systems and infrastructure for vaccine delivery are key to HPV vaccine implementation, and approaches may require adaptations to existing delivery settings to provide effective vaccination programs.
- Given that health care provider recommendation is the strongest predictor of HPV vaccination,36-39 providers in the United States have a prime opportunity to promote HPV vaccination by pairing HPV vaccination with required vaccinations, such as tetanus-diphtheria-acellular pertussis (Tdap) and meningococcal vaccinations.36-39
- Although HPV vaccination is the primary tool in our fight to eliminate cervical and other HPV-related cancers, it does not replace cervical cancer screening, including screening of women who have received HPV vaccination or who are already infected with high-risk HPV.
Worldwide, high-risk HPVs are the cause of virtually all cervical cancer, with an estimated 520,000 cases and 266,000 deaths each year.1 Cervical cancer is a disease of the poor and underserved from a global and local perspective. Globally, the majority of women diagnosed with cervical cancer in high-income countries/regions are likely to survive, while in low- and middle-income countries (LMICs), women are more likely to die from this preventable disease.2-4 Approximately 85% of the incident cancers and 87% of deaths occur in LMICs, representing 12% of all cancers among women in those countries.1 However, even within a high-income country such as the United States, there is a direct association between cervical cancer and poverty where disproportionate cervical cancer incidence and mortality rates are observed in poor states and counties5,6 and even among subpopulations within these states and counties.7,8
The causal relationship between HPV and cervical cancer led the way to landmark innovations in cancer prevention—namely HPV-based vaccination and screening—yet access to these prevention strategies differs across regions of the world and within regions and settings despite their availability for more than a decade. These disparities are magnified by the fact that HPVs cause not only cervical cancer but also anal and oropharyngeal cancers (particularly those at the base of the tongue and tonsils) and can cause other genital malignancies including penile, vulvar, and vaginal cancers.7,9 Therefore, there is an urgent need to address disparities in the areas where the burden of disease is disproportionately high.
Development and Advancements of HPV Vaccines
Three prophylactic HPV vaccines are approved and recommended in the United States, Europe, and many regions and countries.10-19 The U.S. Food and Drug Administration (FDA) approved the quadrivalent formulation in 2006. This vaccine is highly efficacious in the primary prevention of infections by HPV16, 18, 6, and 11. HPV16 and 18 cause more than 70% of all invasive cervical cancer worldwide,20,21 and HPV6 and 11 cause approximately 90% of all genital warts.22 The bivalent formulation is highly efficacious in the primary prevention of HPV16 and 18. A nonavalent HPV vaccine was approved in 2014 after showing 97% efficacy against precancerous lesions caused by HPV31, 33, 45, 52, and 58 and equivalent immunity against the four HPV types included in the original quadrivalent vaccine formulation.17
As of June 2017, only the nonavalent HPV vaccine is available in the United States.22 An estimated 24,600 HPV-associated cancers are caused by HPV16 or 18, and 3,800 are caused by the five additional types prevented by nonavalent HPV vaccine in the United States. Almost all of the cancers caused by the five additional HPV types occur in women.16-19 Globally, near-complete population coverage with the nonavalent HPV vaccine is predicted to reduce up to 90% of HPV-related cancers.
Initially, the bivalent, quadrivalent, and nonavalent HPV vaccines were approved in most countries as a three-dose vaccine series; however, investigators subsequently showed that only two doses are as effective as three doses in young boys and girls. In alignment with the World Health Organization’s (WHO) recommendations for women and girls,23 many countries have recommended administering the bivalent, quadrivalent, and nonavalent HPV vaccines as a two-dose series to both male and female patients, making it easier to complete the vaccine series and reducing the global costs of effective HPV vaccination. Evidence supports that the number of recommended vaccine doses is based on the age at administration of the first dose. The U.S. Advisory Committee on Immunization Practices (ACIP) and public health authorities in other countries23-25 recommend that 9- to 14-year-old male and female patients receive two doses of HPV vaccine at least 6 months apart, rather than the previously recommended three doses under the 0, 1-2, and 6-month schedule. Teens and young adults who start the series later (i.e., between ages 15 and 26) need three doses of HPV vaccine to protect against cancer-causing HPV infections, as do immunocompromised individuals (e.g., patients with HIV). Data to support the efficacy of two doses in older teens and young adults is currently insufficient.
Efforts to Promote HPV Vaccination Uptake
Secondary HPV prevention through cervical screening remains important in vaccinated and unvaccinated women and is the priority among unvaccinated women for cancer prevention. But HPV vaccination is the optimal strategy for primary prevention of the vast majority of cancer-causing HPVs. Importantly, effective mass screening is not present in many countries, and there is no other preventive strategy that can substitute for vaccination.
HPV vaccines have undergone extensive safety evaluations, have a safety profile similar to that of other vaccines approved for adolescents, and have been evaluated and approved by the WHO Global Advisory Committee on Vaccine Safety. Their strong vaccine safety data also comes from numerous clinical trials and real-world safety data gathered from the administration of more than 200 million vaccine doses across a decade of HPV vaccine global implementation. Extensive data also shows that high vaccine coverage could reduce the vast majority of high-risk HPV types associated with a variety of cancers (i.e., cervical, oropharynx, anal, vulvar, vaginal, and penile carcinomas) by almost 90%. But despite all of this, HPV vaccination in the United States and in most countries remains low.26,27 Although HPV vaccination coverage varies greatly globally and as a whole is poor,27 evidence of reduced prevalence of HPV16 and 18 infections28 and HPV16- and HPV18-related CIN2/329 has been observed in several countries, including Australia,30 Denmark,31 and the United States.32
In 2015, U.S. surveillance data showed that 62.8%, 52.2%, and 41.9% of women and 49.8%, 39.0%, and 28.1% of men age 13 to 17 had received at least one, two, or three doses of the quadrivalent vaccine, respectively.26 Pointing to the low rates of HPV vaccination as a serious public health threat and acknowledging the rare opportunity that HPV vaccination could prevent more than 30,000 cases of HPV-associated cancers diagnosed annually in the United States, National Cancer Institute (NCI)–designated cancer centers issued a formal endorsement of the Centers for Disease Control and Prevention/ACIP vaccination recommendations for a two-dose vaccination of boys and girls age 9 to 14.33 The NCI-designated cancer centers’ plea to the nation was for: (1) all parents and guardians to have both their sons and daughters vaccinated against HPV; (2) young men (age 19 to 21) and young women (age 19 to 26) who were not vaccinated as children to complete the three-dose vaccine series to protect themselves against HPV; and (3) all health care providers to be advocates for cancer prevention by making strong recommendations for childhood HPV vaccination.
In support of global and U.S. efforts to prevent and treat HPV infections and cervical cancer in all, including resource-constrained, settings, ASCO took another important step by issuing three global cervical cancer–related guidelines25,34,35 and a domestically focused policy statement to provide the rationale and roadmap for increasing HPV vaccine uptake.34 ASCO’s resource-stratified guidelines addressed both primary and secondary cervical cancer prevention, as well as the treatment of women with invasive disease. Vaccine coverage is essential to achieve maximum reductions in HPV prevalence (i.e., circulating HPVs) in populations; however, in basic and limited settings, the highest priority is to prevent cervical cancer through high coverage of girls while still promoting safe sex to reduce transmission of HPVs and other sexually transmitted infections.25 The ASCO guideline states, “If sufficient resources remain after vaccinating girls age 9 to 14 years, girls who received one dose may receive additional doses between age 15 and 26 years. Maximal, enhanced, and limited settings: if ≥ 50% coverage in the priority female target population, sufficient resources, and cost effectiveness, boys may be vaccinated to prevent other noncervical human papillomavirus–related cancers and diseases. Basic settings: vaccinating boys is not recommended.”25
Barriers and Challenges of HPV Vaccine Implementation
The structure and strength of local health care systems and infrastructure for vaccine delivery are key to HPV vaccine implementation, and approaches may require adaptations to existing delivery settings to provide effective vaccination programs. For example, marked differences in HPV vaccine coverage in high-resource settings have been observed (e.g., the United States has lower HPV vaccination coverage than the United Kingdom and Australia), reflecting differences in delivery settings. These differences demonstrate that vaccine availability is not sufficient to promote uptake, as all of these settings have subsidized vaccines (e.g., the Vaccines for Children program in the United States).
An important feature of these health care systems is capacity building among providers, given that health care provider recommendation is the strongest predictor of HPV vaccination.36-39 In the United States, providers have a prime opportunity to promote HPV vaccination among those age 11 to 12 by pairing HPV vaccination with required vaccinations, such as tetanus-diphtheria-acellular pertussis (Tdap) and meningococcal vaccinations. Studies have shown that providers’ primary concerns about recommending HPV vaccination or delaying recommendation include time needed during the clinic visit to discuss the vaccine with parents (i.e., competing time demands), hesitancy in having an uncomfortable conversation about sex, and perceptions of parents’ reluctancy.40-42 However, results of a randomized trial comparing “announcements” or brief statements about the importance of HPV vaccination and a “conversational” approach with parents show that announcements are as effective as lengthier conversations, suggesting that brief, strong recommendations from providers are effective.43
Although there is overwhelming evidence that the benefits of vaccination for many infectious agents far outweigh any harms—which holds true for HPV vaccines—there are also barriers at the policy level. Unfounded HPV vaccine safety concerns can and have had deleterious effects on vaccine implementation and coverage at the local and country levels (e.g., in Denmark and Japan). With limitations acknowledged, regulatory agencies in many countries diligently investigate claims related to adverse events and vaccine safety with findings to date inconsistent with actions to modify HPV vaccine labels or recommendations for population delivery. Extensive data continue to accumulate, providing even more assurance of the safety of HPV vaccines. Surveillance and monitoring efforts remain important and must continue to be supported now and in the future.
To achieve high vaccine coverage and overcome barriers, education and communication strategies to support HPV vaccination must be targeted to the population to be vaccinated, developed at the regional and local levels, and adapted over time to address changes in population coverage and local needs and concerns.44 Throughout the world, strong recommendations for childhood HPV vaccination by governments, public health policymakers, and, most importantly, health care providers remain critical to successfully reducing HPV-related cancers.25,34,39,44,45 Efforts should include reminders for providers and parents; promotion of HPV vaccination through delivery with other childhood vaccines (e.g., Tdap); and dissemination of consistent evidence-based, culturally relevant messages among parents, agents of change (e.g., teachers or pastors), and providers, particularly with regard to the effectiveness and safety of HPV vaccines in preventing HPV-related cancers.25
Integration of Primary and Secondary HPV Prevention
Although HPV vaccination is the primary tool in our fight to eliminate cervical and other HPV-related cancers, it does not replace cervical cancer screening for the women who are already infected with high-risk HPV.34,35 Approximately 5% to 10% of women older than age 35 may carry HPV at a given time. Furthermore, until additional data are gathered, vaccinated cohorts must continue to be screened for the foreseeable future. Efforts are underway internationally to evaluate the effectiveness of adding HPV vaccine to screening for adult women up to age 45.
Many countries are still evaluating testing algorithms and intervals between cervical cancer screening tests. It is likely that the initial change in screening recommendations for vaccinated women will be to increase the age at which screening is initiated. However, it will be another decade before HPV-naive women vaccinated with the nonavalent HPV vaccine will reach the age of screening. For the present, women will have been vaccinated with only the quadrivalent or bivalent vaccines, which offer protection against two cancer-causing HPV types (HPV16 and 18) with some added benefit of cross-protection against HPV types that are phylogenetically related to the HPV vaccine types observed (e.g., protection against HPV31 and 33, which are closely related to HPV16, and HPV45, which is closely related to HPV18). However, the duration of protection against non-vaccine HPV types is unclear. Going forward, our challenge is uncovering how to successfully integrate HPV vaccination and screening and thereby maintain the effectiveness and cost-effectiveness of both interventions while establishing a good benefits-to-harms ratio for screening.
In addition to identifying screening strategies in the HPV era, some of the highest priority areas for the future include evaluating vaccine dose reduction, researching gender-neutral vaccination, and understanding which cohorts benefit from catch-up vaccination. Further attention to producing more efficient and predictive screening tests especially in vaccinated populations, less costly and more accessible vaccines, and developing a therapeutic vaccine remain worthwhile. Vaccination is seen as equity-promoting and therefore should be at the forefront of strategies to prevent HPV infections. Efforts are needed to make this a reality everywhere.
About the Authors: Dr. Wheeler is a public health scientist with the University of New Mexico (UNM) NCI–Designated Comprehensive Cancer Center and director of the UNM Center for HPV Prevention. She serves as an expert panel member for the Primary Prevention of Cervical Cancer: ASCO Resource-Stratified Guideline. Dr. Scarinci is a behavioral scientist and associate director for Globalization and Cancer at the University of Alabama at Birmingham Comprehensive Cancer Center. She serves as an expert panel member for the Primary Prevention of Cervical Cancer: ASCO Resource-Stratified Guideline. Dr. de Sanjosé is head of the Cancer Epidemiology Research Program at Institut Català d’Oncologia, Spain, and President of the International Papillomavirus Society. She is co-chair of the expert panel for the Primary Prevention of Cervical Cancer: ASCO Resource-Stratified Guideline. Dr. Arrossi is an official and researcher at the Instituto Nacional del Cancer, Argentina. She is co-chair of the expert panel for the Primary Prevention of Cervical Cancer: ASCO Resource-Stratified Guideline.