Human Papilloma Virus Vaccines and Vaccination

Certain infectious agents are known to exhibit a strong relationship with malignancies. Harald zur Hausen¹ first discovered the link between human papillomavirus (HPV) and cervical cancer in the 1980s, and went on to win the Nobel Prize for Physiology or Medicine in 2008. HPV is one of the most common carcinogenic pathogens after Helicobacter pylori, constituting approximately 5% of all infection-attributable cancers worldwide.² HPV is the causative agent of almost all cases of cervical cancer, one of the most common cancers in women globally, with an estimated annual prevalence of 604 000 new cases and 342 000 deaths.³ It also plays an important role in the pathogenesis of many other cancers, including organs such as the anus, vagina, penis, oropharynx, vulva, oral cavity, and larynx. Some benign lesions such as cutaneous (genital and non-genital) warts, Bowen’s disease, epidermodysplasia verruciformis, condylomata acuminata, and respiratory papillomatosis also occur due to HPV infection. HPV is a small double-stranded DNA virus, infecting only humans by means of direct or sexual contact from another person. Approximately 80% of sexually active individuals are estimated to be exposed to HPV at least once up to the age of 45.

There are approximately 450 HPV types, 12 of which (types 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, and 59) are specifically associated with carcinogenesis. HPV types 16 and 18 are defined as high-risk HPV and are responsible for ~70% of all cervical and most anal cancer cases. The virus exhibits a tropism to cutaneous or mucosal epithelial cells. Its life cycle begins after passing through the epithelial barrier which has been broken by microtraumas. The process continues with basal cell layer infection, replication, and expressing capsid genes (L1 and L2). The epithelial transition zones, such as the junction of the endocervix/ectocervix and anorectal junctions, are areas which are more susceptible to carcinogenesis. Fortunately, the immune system eliminates most of HPV infections. However, ~3% of infections progress to cervical precancer/cancer within seven years by evading the immune system as a result of living exclusively in epithelial cells, modulating the intracellular signaling pathways, and preventing inflammatory reactions.⁴ The patient’s immune status, the oncogenic potential of the virus type, hormonal contraceptive use, smoking, the presence of any other sexually transmitted infections, number of births, and younger age at the time of first sexual intercourse are all facilitating and accelerating risk factors for cancer.

Vaccination plays a pivotal role in preventing HPV infections. HPV vaccines are mainly prophylactic and intended to prevent initial HPV infection and subsequent HPV-associated lesions before the virus is ever encountered. Although the presence of genital warts or any HPV infection and an abnormal Papanicolaou test do not constitute contraindications for HPV vaccination, the expected benefit from vaccination is less in individuals infected with any HPV vaccine type. Delayed immunization is advised because HPV-positive individuals may not be infected with all the HPV types in the vaccine, and HPV vaccination can protect against reinfection or reactivation of latent infections with same HPV types despite natural infections. HPV-type-specific neutralizing antibodies against the HPV L1 protein represent the basis of HPV vaccines. Second-generation nonavalent vaccine was introduced following first-generation bivalent and quadrivalent vaccines. The HPV vaccines currently available and licensed by the U.S. Food and Drug Administration (FDA) are bivalent (HPV types 16, 18; Cervarix®), tetravalent (HPV types 6, 11, 16, 18, Gardasil®), and nonavalent (HPV types 6, 11, 16, 18, 31, 33, 45, 52, and 58; Gardasil®). In addition to HPV types 16 and 18, the latest vaccine, Gardasil9®, also protects against oropharyngeal and other head and neck cancers caused by other HPV types. HPV vaccine has been included in the national immunization programs of 137 countries.⁵

Although the minimum antibody titer required to protect against infection is unclear, immunization with HPV vaccine results in higher type-specific antibodies than titers induced during natural infection. The antibody titers gradually decrease after vaccination, although it appears that protection is still present. Vaccines induce higher antibody titers in children under 16 than in older children and adults.⁶ All types of vaccine (9-valent, tetravalent, and bivalent) are highly immunogenic and yield satisfactory antibody responses with seroconversion rates up to 100% (between 90% and 100%) in females and males.^7-9 Antibody levels persist for up to 10 years after vaccination.¹⁰ HPV vaccination has been described as cost-saving and cost-effective in reducing the incidence of cervical cancer and the consequences thereof in most of parts of the world.^11-13 It was estimated that vaccinating all 12-year-old females in the USA would protect annually more than 200,000 girls against HPV infections and 3300 against cervical cancer every year.¹⁴ However, it must also not be forgotten that men are also a reservoir for HPV infection. The prevalence of HPV infection in men peaks between the ages of 25 and 29.¹⁵ Vaccination of men is as important and effective as that of girls in preventing HPV-related benign and malignant diseases. Vaccine efficacy for both boys and girls are highest when administered before any HPV infection occurs. Well-documented, large, randomized trials of all types of HPV vaccine have reported benefits against cervical, vaginal, vulvar, and anal cancers in males and females, in addition to efficacy against oropharyngeal disease, anogenital warts, and recurrent respiratory papillomatosis.^16-21 High vaccination coverage also contributes to herd immunity.¹⁷ All HPV vaccines are safe and well-tolerated, except for mild injection site reactions. HPV vaccines can be safely administered simultaneously with any other vaccines without reducing the immune response of any or increasing the possibility of adverse effects.

The Advisory Committee on Immunization Practices (ACIP), American Academy of Pediatrics (AAP), American Academy of Family Physicians, and International Papillomavirus Society recommend routine HPV vaccination for both females and males.^22-24 Based on the recommendations, the dosing schedule in different age groups can be summarized as follows:

• For individuals aged 9 to 14 years of age; two doses at an interval of six to 12 months.

• For individuals aged 15 to 26 or older; three doses, i) initially, ii) after one to two months, and iii) six months after the first dose.

• For immunocompromised patients; three doses at 0, 1-2, and six months, irrespective of age.

Although HPV vaccination is immunogenic, efficacious, and safe in women over 25, catch-up vaccination for individuals over 27 is not routinely recommended because of potential prior exposure to HPV vaccine types, and resulting reduced benefits and cost-effectiveness of HPV vaccination.^25,26 The decision to vaccinate members of this age group is therefore made on an individual basis, if there is no history of prior sexual experience, or only with a limited number of partners. The scarcity of data concerning the vaccination of individuals over 45 makes it impossible to offer any advice for this age group.

These recommendations are largely applicable to source-rich settings. In May 2018, the World Health Organization (WHO) declared cervical cancer to be a public health problem and aimed to eliminate it by 2030 by the help of full vaccination with the HPV vaccine of 90% of all girls under 15.²⁷ Unfortunately, a decline has been observed in global HPV vaccination coverage. First-dose coverage declined from 25% to 15% between 2019 and 2021.²⁸ The HPV – ‘cancer’ vaccine has many hurdles to overcome, including its high price, and low acceptance and coverage rates. It was subsequently concluded that vaccination rates could be improved by reducing the number of doses to one or two. A recent meta-analysis investigated the clinical effectiveness of intentionally or unintentionally administered one-dose HPV vaccination compared to that of two or three doses.²⁹ The results showed that the risk of HPV16 and HPV18 infection was higher among individuals receiving one HPV dose than in those given more doses. However, although some studies have reported that a single dose causes no decrease in the incidence of pre-cancer lesions and infection rates compared to unvaccinated individuals, more than half of studies have shown that one dose of HPV vaccine resulted in similar vaccine effectiveness to that of two or three doses. Protective antibody levels were also observed for at least four to eight years in women who received one-dose HPV vaccination.

Vaccinating young people, particularly in regions where cervical screening programs are inadequate, is particularly important. The WHO has revised its recommendations for resource-limited settings, primarily targeting sexually inactive girls aged 9-14, rather than boys and older females, in order to improve access to the vaccine and to increase the numbers of girls who are vaccinated.²⁸

• For girls aged 9-14 years; one or two doses.

• For females aged 15-20 years; one or two doses.

• For women older than 21 years; two doses at a six-month interval, if the vaccination is affordable and cost-effective.

The most important problem regarding the HPV vaccine is low coverage rates. In combatting this problem, health authorities should implement individualized practices based on the specific needs and characteristics of the country in questions. The causes should be investigated in detail. Some source-rich Western countries may have overcome low coverage rates by including the vaccine in their national vaccination programs.³⁰ Thinking that the vaccine is unnecessary, unsafe, or not recommended, a lack of information concerning the vaccine or disease, and believing that their daughters are not sexually active have been reported as reasons for parental reluctance to have their children vaccinated.³¹ The principal cited reasons for lack of receipt of the HPV vaccine in Türkiye, a low-income country, are that the vaccine is not covered by social security, a lack of information concerning it, and individuals not feeling at risk for HPV comorbidities.³²

Another problem against the low coverage rates that we face today is vaccine hesitancy. The basis of the concept of vaccine hesitancy in the world has started in England against mandatory vaccination during the smallpox epidemic in 1853.³³ Although this concerns most of the vaccines, it is also a major problem for the HPV vaccine. The increasing number of unvaccinated individuals decreases herd immunity and puts susceptible individuals at greater risk. Parents’ non-scientific hesitations or thoughts about ingredients in vaccines such as mercury, aluminum, etc. as dangerous and having a link to diseases such as autism, autoinflammatory diseases, or Guillain Barre syndrome, etc. and thinking that it is better to heal from diseases naturally or with natural products rather than protecting against them with vaccines were some of the reasons of vaccine hesitancy.³⁴ To overcome these arguments and fight with anti-vaccine movements, in addition to WHO and governments’ strategies to supply accurate and reliable information about vaccines and to raise public awareness, improved communication skills of physicians and healthcare workers with these hesitant parents and efficient use of the media and social media are important in increasing social awareness.

In conclusion, HPV vaccines are life-saving cancer vaccines for both sexes. They are highly effective and provide long-time protection. Few or no serious adverse effects represent another advantage. However, global HPV vaccination coverage rates are very low. It is imperative that all countries add these vaccines to their national immunization programs. In addition, specific measures, such as vaccination campaigns, social media promotion and marketing strategies, and physician (particularly family physician)-focused interventions are also needed to improve low vaccination coverages.