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Introduction

Human papillomaviruses (HPV) infection is the most common sexually transmitted infection in the United States (US) and worldwide and may lead to significant morbidity and mortality. The World Health Organization (WHO) recognizes HPV-related diseases as a global public health issue. It is estimated that 50-80% of sexually active individuals will become infected with HPV in their lifetime.

HPV are members of the Papillomaviridae family of small, nonenveloped, double-stranded DNA viruses that target epithelial cells of skin, anogenital, and oral mucosa.

There are currently more than 200 HPV serotypes and than 40 are spread through direct sexual contact. There are more than 10 high risk HPV serotypes including HPV 16, 18, 31, 33, 34, 35, 39, 45, 51, 52, 56, 58, 59, 66, 68, and 70. The lower risk HPV serotypes 6 and 11 are associated with genital warts and in rare cases, recurrent respiratory papillomatosis.

In 1970s, HPV was first found to be associated with cervical cancer. In the 1980s, HPV was found to be associated with oropharyngeal cancer. Since that time, other malignancies have been found to be associated with HPV including, vaginal, vulvar, anal, and penile cancers.

Each year in the US, approximately 14 million people are infected with HPV. Of those 14 million, 27,000 develop HPV related cancers with a subsequent 4,000 deaths per year.

Pathenogenesis of Cancer Due to HPV

Only a small percentage of HPV infections result in cancer. Within 1-2 years, most (~90%) of HPV infections become dormant.

The HPV family of virus infects basal cells of the epithelium, which may subsequently lead to mutations and cancer. HPV proteins E6 and E7 are typically present early in infection. E6 interacts with P53 and E7 interacts with retinoblastoma proteins resulting in impairment in DNA checkpoints. DNA impairment leads to unregulated cell proliferation, chromosomal mutations, and eventual malignancy.

HPV replicates in differentiated cells. Additionally, HPV is present in the basal cells of the epithelium in a minute amount, therefore, exposes viral protein to the immune system. Seroconversion typically occurs with persistent HPV infection. Most women who develop cervical cancer typically test positive for a high-risk HPV serotypes 3-5 years prior to their cancer diagnosis.

Within 3 years of HPV infection, 68% of young women with untreated moderate grade dysplasia (CIN 2) will have regression of the lesion while 15-22% of CIN 2 will progress to high-grade dysplasia (CIN 3). A subsequent 0.2-4% of CIN 3 will progress to squamous cell carcinoma.

Epidemiology

Age

HPV infection is prevalent in ages less than 25 years. In some parts of the world, like the United States (US) a second peak occurs above 45 years.

In US ~79 million people age 15-59 years are infected with HPV. Half of 14 million new annual infections in US are seen in age 15-24 years. By age 45, 80% people in the US are infected with HPV.

Sex – Transmission from females to males is more common than males to females.

Route of transmission

Primary route of transmission is sexual behavior via anogenital or oral-genital contact causing infection of skin and mucous membranes. The incidence of HPV transmission is directly related to the number of sexual partners and sexual behavior of those partner(s).

Nonsexual transmission, such as from mother to infant, may occur, but is less common.

Time to Onset

The majority of new HPV infections are asymptomatic and occurs for a median duration of ~8 months.

New cervical infections related to HPV are cleared by 70% of people in 1 year, 90% in 2 years, and <3% result in epithelial dysplasia or cancer.

Persistence of the infection is related to the development of cancer and typically takes about 20 years from HPV infection to invasive cervical cancer.

HPV Associated Cervical Cancer

Cervical cancer is the most common HPV associated cancer in women. Additionally, cervical cancer is 4th most common cancer among women worldwide and is often preceded by persistent cervical dysplasia or cervical intraepithelial neoplasia (CIN) over the course of 20 years after the initial HPV infection. It is thought that latent infections or subclinical infections become more relevant when the individual is immunocompromised. In a vast majority of cases, individuals are asymptomatic.

Almost 95% of all cervical cancer cases are linked to HPV. There are 12 HPV genotypes shown to cause cervical cancer, but HPV16 and HPV18 responsible for 50% high grade cervical dysplasia and 70% of cervical cancer. Genotypes 31, 33, 45, 52, 58 accounts for additional 15% of cervical cancer.

Risk factors for HPV progression into cervical cancer include immune status, coinfection with other sexually transmitted disease, young age at first pregnancy, parity, and tobacco use.

Due to the screening effort for early detection of cervical dysplasia, there has been a reduction in cervical over the years where clinicians are able to intervene for CIN 2 and 3.

HPV and Other Cancers

HPV16 is predominantly responsible for vaginal, vulvar, penile, anal, and oropharyngeal cancers.

Head and neck cancer

In 1980s, HPV was found to be associated cancers of the tonsils, base of the tongue, and larynx. The rates of HPV associated head and neck squamous cell carcinoma (HNSCC) have increased by 50% since the time of its initial association with cancer, likely due to improved HPV detection.

Currently, HPV associated HNSCC account for ~ 36-50% of all HNSCC cases with HPV 16 being the predominant type.

On average, 2-8% of healthy adults have HPV infection of the oral cavity with HPV 16 being the most commonly identified genotype.

The prevalence of oral HPV is 4.5 times more common in males than females.

Anal cancer

Rates of anal squamous cell carcinoma has been increasing over the previous decades and accounts for ~35,000 cases per year. HPV genotypes 16 and 18 account for 87% of anal cancers. Anal squamous intraepithelial lesions occur at the anal transition zone where anal squamous and rectal columnar epithelium join and share cytologic features with cervical dysplasia.

Women with high risk HPV cervical infections had an odds ratio of 6.5 of displaying abnormal anal cytology compared to women without high risk HPV.

The prevalence is 2 times more common in females than males.

Vaginal cancer – HPV associated vaginal cancer accounts for 78% of cases and 86% of high grade vaginal intraepithelial neoplasia cases.

Vulvar cancer – The total incidence of HPV associated vulvar cancer is not clearly defined. However, there are reports of ~26-29% or ~35-77% of HPV associated vulvar cancer. HPV associated vulvar intraepithelial neoplasia (VIN) accounts for ~87% of cases.

Penile cancer – Due to the low incidence of penile squamous cell carcinoma in men, it is even more difficult to estimate the total cases related to HPV infection. However, some sources have estimated that oncogenic HPV cause ~50% of penile cancer.

HPV and Other Diseases

Genital warts – Genotypes 6 and 11 cause 90% of genital warts. These warts are considered to be benign lesions. However, the diagnosis of genital warts may have psychosocial effects, such as anxiety and depression.

Recurrent respiratory papillomatosis (RRP)

RRP may occur from vertical transmission from mother to infant at time of delivery and presents at a median age of 3 years with a presentation of warts in upper respiratory tract and larynx affecting airway requiring multiple treatments over prolonged period of time.

Adult onset RRP occurs in the third decade of life, typically from horizontal transmission during sexual activity.

Prevention Strategies

No pharmacologic therapy exists for the treatment of HPV infection. However, there are surgical methods for eliminating HPV infected precancerous cervical lesions using a cold knife cone excision, loop electrosurgical excision, electrofulgaration, cold-coagulation, and cryotherapy.

Since HPV infection is acquired soon after sexual activity, it is recommended to initiate vaccination with the HPV vaccine prior to any HPV exposure for the optimal effect. However, it is not a contraindication for an HPV positive individual to receive the HPV vaccine, as there may be benefit.

The risk of HPV infection can be decreased by condom use, having fewer sexual partners, having sexual partners who have not had any partners or fewer partners, and monogamy. Additionally, male circumcision is effective at preventing HPV transmission in male and female partners.

Prevention is key in reducing the incidence of HPV infections, however, vaccination rates remain low. Only 41.9% females and 28.1% males in recommended age group have received all recommended doses.

Percent of Individuals Vaccinated with HPV in U.S.

Screening Strategies

The only screening program that has been effectively shown to decrease HPV associated malignancy is cervical cancer screening. No other screening method currently exists for vaginal, vulvar, penile, anal, or HNSCC.

Additionally, all females should be screened regardless of HPV vaccination status.

All major guidelines including American Cancer Society (ACS), US Preventative Services Task Force (USPSTF), American College of Obstetricians and Gynecologists (ACOG), and Society of Gynecologic Oncology (SGO) recommend females receive cervical cancer screening starting at 21 years of age. If individuals are human immunodeficiency virus (HIV) positive or immunocompromised, cervical cancer screening may start at a younger age.

Cervical cancer screening with cytology should continue at a frequency of every 3 years from age 21-65. For women who want to extend the interval of cervical cancer screening, an HPV co-test with cytology can be performed every 5 years in women older than 30 years.

As an alternative to screening with cytology or co-testing, high risk HPV (hrHPV) testing may be used every 5 years for age 30-65. Some guidelines allow for hrHPV testing as a standalone test starting at age 25 at a frequency of every 3 years to replace screening with cytology.

Screening may stop once a patient is older than 65 years with adequate screening history and no results of CIN 2 or higher.

Types of HPV Vaccine

There are 3 HPV vaccines available worldwide, bivalent (2vHPV, Cervarix), quadrivalent (4vHPV, Gardasil), and nonavalent (9vHPV, Gardasil 9). These three vaccine types target 70-90% of HPV associated cancers. As of 2016, there is only 1 marketed HPV vaccine available in the U.S., which is the 9vHPV.

The first HPV vaccine that was approved by the food and drug administration (FDA) in 2006 was the quadrivalent HPV vaccine containing genotypes 6, 11, 16, and 18. This 4vHPV was originally approved for 3 total doses in females aged 9-26. The 4vHPV was eventually approved for males 9-26 in 2011 based on positive results from clinical trials in males.

The bivalent HPV vaccine was subsequently approved by the FDA in 2016 and contains genotypes HPV 16, 18 for a total of 3 doses in females 9-26 years of age. HPV 16 and 18 account for ~66% of cervical cancer in the US. The 2vHPV vaccine is not FDA approved for use in males.

The 9vHPV is currently the only available HPV vaccine in the US and it covers types 6, 11, 16, 18, 31, 33, 45, 52, and 58. The increased number of genotypes covered by the vaccine help target an additional 15% of HPV genotypes known to cause cervical cancer. Females derive the most benefit from the additional inclusion of high-risk HPV genotypes, however, males may have ~4% increased coverage from the additional genotypes.

HPV Vaccine Mechanism of Action

HPV vaccines works similarly to other approved vaccine products. The HPV vaccines contain inactivated HPV protein, L1, from high risk HPV subtypes (the actual number of subtypes depends on the marketed vaccine) produced in synthetically manufactured virus like particles (VLPs).

Unlike actual viruses, VLP is non-infectious since there are no viruses involved. Since VLPs resemble the HPV virus, the host’s antibodies are produced against VLPs and HPV virus. VLPs result in the production of high titers of of antibodies to the viral capsid, making it an effective agent against HPV viruses. This exposure to VLPs to produce an immune response leads to increased detection by the host when HPV is exposed. The immune system subsequently produces HPV antibodies to bind the HPV virus and prevent the interaction between the HPV capsid and host cell surface to prevent viral entry into the cells.

Vaccines provide enhanced immunogenicity compared to exposure to the L1 proteins from the actual HPV. Antibody titer is often higher with vaccination compared to exposure of the HPV virus alone, therefore, even individuals who are HPV positive may still benefit from vaccination due to the robust immune response.

Gardasil 9

The nonavalent HPV vaccine compared to the quadrivalent demonstrated non-inferiority antibody responses to all of the serotypes contained in the quadrivalent vaccine including, HPV 6, 11, 16, and 18. Additionally, studies have also demonstrated non-inferiority in males for immune responses with the comparison of the 9vHPV and 4vHPV vaccines.

The 9vHPV vaccine contains more than twice the antigenic load of the 4vHPV vaccine and has increased concentrations of protein L1 VLPs for HPV 16 and 18.

The safety profile was comparable for both the 9vHPV and 4vHPV vaccines. The 9vHPV vaccine demonstrated more injection site adverse events compared to the 4vHPV vaccine. However, the majority of injection site reactions were mild to moderate. Serious adverse events with 9vHPV are rare (less than 0.1%) and no vaccine related deaths have been reported.

The major benefit of 9vHPV vaccine compared to 4vHPV is the increase coverage of additional high-risk serotypes of HPV. However, based on study results, it is not recommended to administer the 9vHPV vaccine after completion of the 4vHPV vaccine series due to cost and efficacy. Results of the study demonstrated higher titers for HPV 16 and 18, however, other serotype titers (HPV 31, 33, 45, 52, 58) were low with 9vHPV vaccination after 4vHPV vaccination series.

Vaccination Recommendations: Age

Vaccination recommendations are from Advisory Committee on Immunization Practices (ACIP), Centers for Disease Control and Prevention (CDC), and American College of Obstetrics and Gynecology (ACOG).

The typical recommended ages are 9-26 years.

HPV vaccination is often recommended at age 11 or 12 years due to targeting individuals before HPV exposure and it may be administered at the same time as 2 other recommended vaccines, Tdap and meningococcal conjugate vaccines.

Vaccination can be started at age 9 years for individuals with a history of sexual abuse or assault based on ACIP recommendations.

Catch-up HPV vaccination is recommended for individuals through age 26 years who are not adequately vaccinated.

Age >27 years

Individuals 27-45 years of age are now eligible to receive the HPV vaccine due to the results of a 4vHPV clinical trial in women age 24-45 years. The study led to the FDA’s extended age approval of the HPV vaccine in females and males up to age 45 as of October 2018.

ACIP does not recommended routine HPV vaccination for all individuals age 27-45 years. Instead, it is recommended that a shared clinical decision be made as some individuals may derive benefit.

HPV vaccines are not approved for use in adults greater than 45 years.

Vaccination Recommendations: Dose

The number of doses recommended range from 2-3.

The number of doses recommended have changed throughout the past decade. The current recommendation for individuals age 9-14 years is 2 doses at 0 and 6-12 months.

A study comparing antibody response with 2 versus 3 doses demonstrated that individuals age 9-14 years who received 2 doses had noninferior immunogenicity and higher titers than the 16-26 age group who received 3 doses.

The minimal interval between the 2 doses is 5 months. If the second dose is administered prior to 5 months, a third dose is recommended to complete the series.

It is not recommended to allow an interval of greater than 12 months between doses in order to ensure that both doses are administered prior to the onset of sexual activity to gain the most benefit.

For individuals age 15 and older, 3 doses are recommended at 0, 1-2, and 6 months after the first dose.

Additionally, for individuals who have immunocompromising conditions, 3 doses are recommended regardless of age.

The vaccine series does not need to be restarted if there is a delay between the first and second dose or second and third dose. Once the vaccination series is completed, no additional doses are necessary, including booster vaccination.

Vaccination Recommendations: Special Populations

Pregnancy

HPV vaccination is not recommended during pregnancy and initiating the vaccine series should wait until after pregnancy. However, a pregnancy test is not routinely required prior to vaccination.

If the vaccine series has started prior to or during pregnancy, it should be interrupted until after pregnancy.

For individuals who were inadvertently vaccinated while pregnant, there have not been any reports of vaccine related adverse pregnancy outcomes.

Breastfeeding – Individuals who are breastfeeding or lactating are eligible to receive the HPV vaccine series.

History of HPV infection – Vaccination is recommended regardless of history of abnormal Pap test, positive results of HPV DNA, and/or history of genital warts.

Illness/fever – Individuals who are febrile should wait until illness improves before receiving the vaccine.

Immunocompromised – Immunocompromised individuals are eligible for HPV vaccination. Individuals diagnosed with human immunodeficiency virus (HIV) infection or organ transplantation may not have as a robust immune response, therefore, a 3-dose regimen is recommended regardless of age.

Adolescents – Adolescents should be directly observed for at least 15 minutes after vaccination due to a higher risk of fainting.

Vaccination Goals

The primary goal of HPV vaccination is for the prevention of HPV associated cancers, however, this effect may not be observed for several decades. Although the primary goal may not be observed at this point, there has been a decline in HPV-associated infections and clinical outcomes in the U.S. Additionally, there has been a decrease in anogenital warts at the since time the HPV vaccine has been approved.

In a study with national surveys, there appears to be a decline in cervical cancer in young women with HPV vaccine associated serotypes within the first 4 years of the vaccine’s approval. There was a 56% decrease in HPV vaccine types in cervical samples from individuals 14-19 years of age in the first 4 years. By 8 years after the vaccine approval, there was a 71% decline in HPV vaccine types in cervical samples.

More recent data demonstrated a continued decline in HPV associated infections. From 2013-2016, there was a decrease from 11.5% to 1.8% of HPV vaccine type infection in females age 14-19 and 18.5% to 5.3% in females age 20-24 years.

Despite the benefits of the HPV vaccine, vaccination rate still remains below the Healthy People 2020 target of 80% for adolescents. It was reported in 2017 that only 65.5% of individuals age 13-17 received at least 1 dose of HPV vaccine. Additionally, data shows 42% of females and 28% of males have completed the vaccine series.

Efficacy Data for Females

All 3 HPV vaccines are efficacious with durable responses. Since the evidence of cervical cancer may take a few decades to present, preinvasive disease and HPV infection have been used as markers to predict malignancies.

Prevention of HPV vaccine type infection in females have been reported to be 96% with 9vHPV at 4.5 years, which is comparable to the 4vHPV and 2vHPV, 97% at 3.7 years and 94.3% at 4 years, respectively. This benefit in prevention of HPV vaccine related infections have also been demonstrated in females previously exposed to HPV with an efficacy rate of 80.2% at 4.5 years, 42% at 3.7 years, and 76.2% at 4 years with the 9vHPV, 4VHPV, and 2vHPV vaccines, respectively.

Additionally, an analysis of 9 million females in a period of 8 years has demonstrated a decline in the incidence of high-grade cervical lesions from 14.4% to 8.3%. This decline was more prominent in the younger female population compared to females 30-39 years of age.

It was found in a clinical trial evaluating the 9vHPV vaccine in 14,000 females age 16-26 years that the vaccine was effective for the prevention of CIN 2+, vulvar intraepithelial neoplasia (VIN) 2 or 3, and vaginal intraepithelial neoplasia (VAIN) 2 or 3 that were caused by genotypes 31, 33, 45, 52, and 58.

Additional data comparing all 3 vaccines have shown that all 3 HPV vaccines are effective in the prevention of CIN 2 and 3 in cervical cancer in females less than 25 years of age and older than 25 years of age.

The 2vHPV had an efficacy rate of 62% for CIN 2+ and 93% for CIN 3+ in females 15-25 years of age. The 4vHPV had an efficacy rate of 22% for CIN 2+ and 43% for CIN 3+. The 9vHPV had an efficacy rate of 63% for CIN 2+ with no data for CIN 3+. Females older than 25 years of age also demonstrated a similar benefit for the 2vHPV vaccine with an efficacy rate of 91% and 4vHPV vaccine with an efficacy rate of 85%. Additionally, females in the younger and older than 25 years age group all benefited from a decrease number of colposcopies and cervical excisional therapies.

In the prevention of vaginal and vulvar VAIN 2 and 3 and VIN 2 and 3 related to HPV 16 and 18, both the 2vHPV and 4vHPV demonstrated an efficacy rate of 100%. There is no current data available yet for 9vHPV.

For females with a previous HPV infection, no difference was found for effectiveness between 4vHVP vs 9vHPV for cervical, vaginal, or vulvar disease.

For the prevention of oral and anal cancer related to HPV 16 and 18, there were no data for endpoints relating to 4vHPV vaccine or 9vHPV vaccine. However, the 2vHPV was 93% effective in the prevention of oral infections with HPV 16 and 18 in females age 18-25.

Efficacy in Males

In a systematic review of 5000 males, HPV vaccination showed low efficacy for infections related to HPV 16 and 18 with efficacy rates of 28-33.9% and 45.1-49.5% for anogenital infections.

A study using 4vHPV in males age 16-26 demonstrated an overall reduction of 85.6% in individuals with persistent HPV infections and 85.6% in individuals without evidence of HPV. This translated to an efficacy rate of 44.7-59.4% in the HPV exposed population and 78% in the HPV non-exposed population. This study demonstrated efficacy in the prevention of early endpoints of cancer, such as dysplasia.

The HPV vaccine was also shown to be 91% effective for oral infections related to HPV 16 and 18. Another study in 150 males age 27-45 years who completed the vaccine series for 4vHPV developed serum anti-HPV antibodies in the oropharyngeal areas, however, the clinical significance is unknown at time for cancer related endpoints.

Data in relation to HPV endpoints for penile and anal cancers are limited.

Cross-Protection from Vaccination

There is data to support that the HPV vaccines (2vHPV and 4vHPV) administered may have some cross-protection against other HPV serotypes not included in the vaccines.

A study in females analyzed the 2vHPV vaccine and found that there was a 31.5% efficacy rate at preventing CIN 2 lesions from HPV 31, 33, 45, 52, and 58. Other studies demonstrated similar results for partial cross protection against HPV 31, 33, and 45 with the use of both 2vHPV and 4vHPV vaccines.

A study in males showed similar results to the female population with 49.4% partial cross protection against HPV 31, 33, and 45.

Furthermore, there is data to support the efficacy of HPV vaccine for prevention of re-infection. A study in females found that after 2vHPV vaccination, there was a reduction in subsequent HPV associated CIN 2+ after surgical removal of the lesion, regardless of HPV serotype found in the lesion.

Long-term Protection

Long-term data is currently being monitored for HPV vaccines, but a booster vaccine is not recommended at this time.

Some studies have detected antibodies to HPV 10 years after vaccination with no waning protection after completion of vaccine series. It has been shown that antibody titers do not increase above the natural infection titers and providing full protection until after the second dose of the vaccine series. In individuals who only received 1 dose, there may be decreased long-term protection, however, additional data is needed.

Another study in females age 16-26 found both 2vHPV and 4vHPV to have long term protection with antibody concentrations detected at a 12 fold or higher than that of a natural infection at 9 years after vaccination. Data in older females age 25-45 years demonstrated non-inferior antibody titers compared to younger females age 16-26 years.

Long-term data for 9vHPV is limited and the majority of long term data for 9vHPV has been extrapolated from the 2vHPV and 4vHPV vaccines.

Vaccine Safety

Clinical trials including more than 15,000 individuals for each of 3 vaccines found the most prominent adverse events found were fever and injection site reactions.

There is ongoing monitoring after the approval of HPV vaccines using data from Vaccine Adverse Event Reporting System (VAERS), Clinical Immunization Safety Assessment Network, Vaccine Safety Datalink (VSD), and FDA Sentinel System. VAERS found syncope to be a reported adverse event of vaccination, however, it is an uncommon adverse event with vaccines in general. It is recommended to observe patients for 15 minutes after vaccination due to the potential for syncope. The FDA concluded that after 80 million doses of the 4vHPV vaccine administered post licensure, there were no safety concerns.

A meta-analysis found a higher incidence of injection site symptoms with HPV vaccines compared to hepatitis A and B vaccines. It was noted that the localized symptoms were transient and similar between the 2vHPV and 4vHPV vaccines. Additionally, the 9vHPV vaccine appears to have more injection site adverse events compared to the 4vHPV vaccine.

The most common adverse events include pain or redness at the injection site (63-90%), headache (9-10%), and fever (4-10%). Other less common (<3%) adverse events include dizziness, syncope, fatigue, nausea, abdominal pain, mouth pain, and induration or nodule at the injection site.

Global HPV Vaccination

In the first decade after the 4vHPV vaccine was approved, there were reports of up to 90% reductions for HPV 6, 11, 16, and 18 worldwide. In 9 countries with national HPV vaccination programs, it was found that there were significant reductions in genital warts (90%), low-grade cytological cervical abnormalities (45%), and high-grade cervical abnormalities (85%) in females.

The global impact of HPV vaccination depends on several factors including, vaccine coverage, age of vaccination, catch up programs, time between program initiation and measurement of its results, and length of follow up.

As of 2014, 68 countries and 12 territories adopted HPV vaccination programs and at least 118 million women have received 1 dose of HPV vaccine, which is ~3.5% of the world population.

The U.S. was the first country to adopt a gender neutral policy for routine HPV vaccine in 2011. Since then, only Australia, Canada, and Austria routinely vaccinate males for HPV.

There is a stark difference in cancer burden between low income and high income countries, representing the global disparity of care.

Cervical cancer exists at 40% in low and middle income countries, which is where the highest global cervical cancer burden occurs. Lack of resources including cervical cancer screening and national HPV vaccination programs make it difficult to decrease this cancer burden. Only 15% of these countries have adopted an HPV vaccination program.

The incidence of cervical cancer is slightly improved in upper middle income countries, which occurs at 30%. Only 7.2% of 10-20 year old females have completed the vaccine series.

In high income counties with HPV vaccine implementation, a systematic review and meta-analysis found a 68% decrease in HPV infections with serotypes 16 and 18 and a 61% decrease in anogenital warts in females 13-19 years of age.

Australia has a fully government funded HPV vaccination program. Studies in this country have shown reductions in vaccine type HPV infections by 86% in 18-24 year olds who completed the vaccine series and 76% in individuals who received 1 or 2 doses. There was also a 34% decrease in low-grade cervical dysplasia and 47% decrease in high-grade CIN and adenocarcinoma in situ. Additionally, Australia also has the greatest worldwide decline of anogenital warts of up to 92% for individuals under 21 years of age.

Global HPV Vaccination Herd Immunity

It was estimated that a population level impact would be seen if the female vaccination rate exceeded 50%. Studies in Scotland with cytology samples from cervical screening showed a decrease in HPV 16 and 18 infection and cross protection for HPV 31, 33, 45 in females who completed the vaccine series versus unvaccinated females. There was also a decrease in the prevalence of 5 HPV types in unvaccinated women, further indicating herd immunity.

Similarly, a Danish HPV vaccination program in females age 12-15 years and up to 27 years with a catch up program achieved vaccination coverage up to 91% for at least 1 dose. Due to the high vaccination rate, herd immunity was demonstrated with a decrease in genital warts in females up to 35 years of age and in unvaccinated Danish males 12-29 years of age.

However, in countries with vaccination rates less than 50%, there was still a reduction in anogenital warts and HPV infections in males and females, potentially indicating herd effect with a lower vaccination coverage rate. This may be due to potential cross protection of the 2vHPV and 4vHPV vaccines.

Barriers to Increased Vaccination

The current vaccination rate is lower that that of the target goal of Healthy People 2020 and can be attributed to several factors. These factors may include health system, providers, cultural beliefs, and cost.

Additionally, the effectiveness of the vaccine program is dependent on access and attitudes towards vaccination. There may a stigmatization of HPV as a sexually transmitted disease and parents may opt to delay vaccination until the child is about to be sexually active or after the child is sexually active. There may also be concerns about decreased cervical cancer screening in vaccinated females.

Multiple studies comparing the behaviors of vaccinated to unvaccinated adolescent girls have not found an increase in riskier sexual behaviors when assessing for pregnancy, condom use, or increase in total number of sexual partners.

Cost may a prohibitive factor for the health system as it is estimated to cost $1.49-18.94 per fully immunized female when initiating a vaccination program. Additionally, there may be a personal cost to the individual as well.

Furthermore, studies have found that providers recommended other vaccines more strongly than HPV vaccine and present the HPV vaccine as an optional choice for individuals less than 26 years of age.

Health Economic Analysis

The WHO estimates HPV vaccination could prevent 850,000 deaths and save 4 billion dollars in total economic cost. Additionally, a yearly direct medical cost of $1 billion for HPV related cancers was estimated in the U.S. in 2012. With additional costs of screening and treatment of other HPV related diseases, the total estimated cost was ~$8 billion in the U.S.

Cost effectiveness ratio for the current HPV vaccination program in the U.S. ranged from cost saving to ~$35,000 per quality adjusted life year (QALY) gained. Vaccination for individuals through age 26 was $178,000 per QALY. Additionally, with the age expansion to 45 years, it was found to have less favorable cost effectiveness ratios with the incremental cost per QALY for age 30-45 years to exceed $300,000.

It is estimated that the number needed to vaccinate to prevent 1 case of anogenital warts was 9, CIN grade 2 or worse was 22, and cancer was 202. With the expansion of the vaccination program through the age of 45 years, the number needed to vaccinate to prevent 1 case of anogenital warts, CIN grade 2 or worse, and cancer were 120, 800, 6,500, respectively.

Additionally, cost effectiveness analyses consistently indicated that all 3 doses prophylactic HPV need to provide protection against vaccine type specific HPV infection for at least 15 years or cervical cancer has only been postponed and not prevented. Long-term data for these results have not been presented.

Conclusion

HPV related infections might lead to morbidity and mortality, including several types of cancer. Since the approval of the first HPV vaccine, there have been many changes to the recommendations of the vaccination schedule. It is recommended for non-immunocompromised individuals to receive routine HPV vaccination up to the age of 26. Individuals 14 and younger may receive 2 doses while individuals 15 and older should receive 3 doses. Vaccination may also be considered for up to age 45. Additionally, the 9vHPV vaccine is the only FDA approved vaccine available for use in the U.S.

Data has indicated that HPV vaccination leads to decrease in cases of HPV related infections, anogenital warts, cervical cancer, and potentially other types of malignancies as well. There may also be evidence of cross protection for other serotypes not included in the HPV vaccine for females and males. Additional herd immunity may also be present, especially for countries with vaccination rates above 50%.

Global HPV vaccination rates are low and there is disparity in care in low income countries compared to higher income countries. There are also several factors that prohibit vaccination relating to cost, cultural beliefs, providers, and health system.

Health economic analyses have found cervical cancer and HPV related diseases to be a cost burden on the health system with the most cost effective approach to vaccinate individuals 26 years of age and younger.

Active Learning

ACOG Committee Opinion: The American College of Obstetricians and Gynecologists (ACOG) provides a succinct background on HPV infections and its clinical implications. ACOG also provides vaccination recommendations that follow CDC guideline recommendations for individuals younger than 26 years and up to 45 years. Additional information on the safety of vaccination is also provided. https://www.acog.org/Clinical-Guidance-and-Publications/Committee-Opinions/Committee-on-Adolescent-Health-Care/Human-Papillomavirus-Vaccination

References

Harper DM, DeMars LR. HPV vaccines – A review of the first decade. Gynecol Oncol. 2017 Jul;146(1):196-204. doi: 10.1016/j.ygyno.2017.04.004.

Immunization Expert Work Group, Committee on Adolescent Health Care. Committee Opinion No. 704: Human papillomavirus vaccination. Obstet Gynecol. 2017 Jun;129(6):e173-e178. doi: 10.1097/AOG.0000000000002052.

Centers for Disease Control and Prevention. Cervical cancer screening guidelines for average-risk women. https://www.cdc.gov/cancer/cervical/pdf/guidelines.pdf. Published 2018. Accessed October 10, 2019.

Meites E, Szilagyi PG, Chesson HW, et al. Human papillomavirus vaccination for adults: Updated recommendations of the Advisory Committee on Immunization Practices. MMWR Morb Mortal Wkly Rep. 2019 Aug 16;68(32):698-702. doi: 10.15585/mmwr.mm6832a3.

Human Papillomavirus (HPV) Vaccines. National Cancer Institute at the National Institutes of Health. https://www.cancer.gov/about-cancer/causes-prevention/risk/infectious-agents/hpv-vaccine-fact-sheet. Updated May 16, 2018. Accessed October 10, 2019.

Fu LY, Bonhomme LA, Cooper SC, Joseph JG, Zimet GD. Educational interventions to increase HPV vaccination acceptance: a systematic review. Vaccine. 2014 Apr 7;32(17):1901-20. doi: 10.1016/j.vaccine.2014.01.091.

Markowitz LE, Gee J, Chesson H, Stokley S. Ten years of human papillomavirus vaccination in the United States. Acad Pediatr. 2018 Mar;18(2S):S3-S10. doi: 10.1016/j.acap.2017.09.014.

Ogawa Y, Takei H, Ogawa R, Mihara K. Safety of human papillomavirus vaccines in healthy young women: a meta-analysis of 24 controlled studies. J Pharm Health Care Sci. 2017 Jul 11;3:18. doi: 10.1186/s40780-017-0087-6.

Harder T, Wichmann O, Klug SJ, van der Sande MAB, Wiese-Posselt M. Efficacy, effectiveness and safety of vaccination against human papillomavirus in males: a systematic review. BMC Med. 2018 Jul 18;16(1):110. doi: 10.1186/s12916-018-1098-3.

St Laurent J, Luckett R, Feldman S. HPV vaccination and the effects on rates of HPV-related cancers. Curr Probl Cancer. 2018 Sep;42(5):493-506. doi: 10.1016/j.currproblcancer.2018.06.004.

Maver PJ, Poljak M. Progress in prophylactic human papillomavirus (HPV) vaccination in 2016: A literature review. Vaccine. 2018 Aug 28;36(36):5416-5423. doi: 10.1016/j.vaccine.2017.07.113.

Braverman PK. HPV Vaccine in Adolescents. Pediatr Ann. 2019 Feb 1;48(2):e71-e77. doi: 10.3928/19382359-20190118-02.

Image graph: Academic Pediatrics 2018 18, S3-S10DOI: (10.1016/j.acap.2017.09.014)

Khan L. Human Papillomavirus and the HPV vaccine: Where are we today? Pediatr Ann. 2017 Jan 13;46(1):e2-e5. doi: 10.3928/19382359-20161216-01.

Arbyn M, Xu L. Efficacy and safety of prophylactic HPV vaccines. A Cochrane review of randomized trials. Expert Rev Vaccines. 2018 Dec;17(12):1085-1091. doi: 10.1080/14760584.2018.1548282.

Attia AC, Wolf J, Núñez AE. On surmounting the barriers to HPV vaccination: we can do better. Ann Med. 2018 May;50(3):209-225. doi: 10.1080/07853890.2018.1426875.