Human papillomavirus (HPV) is not only a sexually transmitted agent responsible for cervical cancer, but it is also incriminated in the appearance of anogenital and oropharyngeal diseases, affecting both women and men. Persistent infections with HPV are virtually responsible for all diagnosed cervical cancers. Among all the HPV strains, high-risk strains predispose carriers to a significant risk of developing cancers associated with HPV infection. Especially noteworthy are the strains 16 and 18 of HR-HPV (high-risk HPV), responsible for 70% of cervical carcinomas. Moreover, we must take into account that the high-risk 45 strain reaches a percentage of over 90% of cervical cancer cases(1). Also, strains 16 and 18 are responsible for the appearance of 90% of anal carcinoma cases.
Available vaccines against HPV
In the context of the frequent presence of human papillomavirus among oncological patients, vaccines have been created with the aim of preventing the acquisition of human papillomavirus and, subsequently, the development of associated infections. Today, there are three different types of vaccines, the factor that differentiates them being the number of HPV strains that enter in their composition, respectively that they target. The first vaccine which appeared on the market was the bivalent vaccine (Cervarix®) that addresses strains 16 and 18. Subsequently, the tetravalent vaccine (Gardasil® or Silgard®) was also released on the market, which additionally addresses low-risk strains 6 and 11, and the variant which is currently being marketed is Gardasil 9®, the nonavalent vaccine that targets strains 6, 11, 16, 18, 31, 33, 45, 52 and 58.
It is also worth mentioning the variant developed in China of the bivalent vaccine, Cecolin®.
Depending on the age at which vaccination is started, the Centers for Disease Control and Prevention (CDC) proposes two vaccination schemes.
For those who are given the first dose at 11-12 years old, even though the vaccination can be started at 9 years old, a second dose is administered 6-12 months after the first one, but not earlier than five months is sufficient.
In contrast, for people who start vaccination over 15 years of age, the recommendation is to use three doses, at 0, 2 and 6 months(2), respectively.
After the last update of the recommendations for HPV vaccination, these vaccines were recommended in adults up to the age of 26. Regarding adults over 27 years of age to 45 years old, the conduct should be individualized according to the case. HPV vaccines are not approved for administration in individuals older than 45 years of age(3).
Kreimer and collaborators have investigated the effectiveness of administering a single dose of the bivalent vaccine in the population of Costa Rica compared to the administration of two or three doses. Patients were tracked over a median period of 11.3 years, and the efficiency was evaluated at 80.2% in case of women vaccinated with three doses, 83.8% among women vaccinated with two doses, respectively 82.1% in the case of women vaccinated with one dose. However, a statistically significant difference was evidenced in the case of antibody titer, which was significantly lower in patients vaccinated with a single dose, although there was no marked decrease in antibody titers between the fourth and the eleventh year of follow-up in all patients(4).
A similar study was made in Kenya by Barnabas and collaborators who tried to prove the effectiveness of a single dose of the HPV vaccine. The patients included in the study were randomized into three different groups. The patients included in the first group were given a dose of nonavalent vaccine, those distributed in the second group were given a dose of bivalent vaccine, and the members of the third group were vaccinated with a dose of meningococcal vaccine. They were tracked from December 2018 to June 2021, with persistent infections 18 months after administration being identified in 38 patients, 36 being patients included in the third group, respectively one patient belonging to the first two groups. Also, vaccination with a single dose of HPV vaccine was found to have an efficiency of 97.5% in the case of the first two groups, with a statistically significant p<0.0001 value(5).
Optimal vaccination age
Considering the benefit that the administration of these vaccines can have, both from the point of view of the public health system, regarding the impact of cancer-related HPV, but also from an economic point of view, the question arises regarding the optimal age of their administration, but also regarding the age on which the benefit brought justifies the costs necessary to carry out immunization.
Naturally, the administration at an early age generates a more significant immune response, hence the justification for administration at the age of 11-12 years old, in addition to the logical argument represented by the definition of prophylaxis itself that involves the administration of vaccines before the primoinfection, in this case after the beginning of sexual life.
Looking to the other end of the age range, the question arises regarding the age at which the benefits of administration of the prophylaxis no longer justify the costs involved.
Thus, various studies have sought to find arguments in favor of extending the age range at which immunization is justified. It was found that the probability of developing CIN2+ lesions decreases with age among patients infected with 16/18 high-risk strains of HPV, the opposite phenomenon appearing in patients who have tested positive for non-16/18 high-risk HPV strains, in which the evolution from low-grade precancerous lesions to high-grade lesions and towards neoplasia is slow(6). The presence of type 16 high-risk HPV strains is more significantly associated with the diagnosis of precancerous lesions in young women than in those of older age(7). Also, the prevalence in the population of high-risk HPV 16 strain seems to decrease with age, and cancers related to the presence of strains 16 and 18 appear to occur five years earlier than those related to other high-risk HPV strains(8).
Similar results were reported by Munoz and his collaborators, who found that the incidence of high-risk strains has a bimodal evolution, while the incidence of low-risk strains gradually decreases with age(9). Also, the infection with high-risk strains lasted longer compared to the infection with low-risk strains (14.8 months versus 11.1 months)(9).
The study carried out in France by Elies et al. revealed the benefits of vaccinations in patients over 14 years of age, which is associated with a reduction in the risk of conization at ages between 19 and 30 years old. Although the percentage of vaccinated women out of the 42,452 included in the study was small, it increased as catch-up vaccination was implemented, from 0% in patients born in 1983 to 31% in patients born in 1991. Thus, the results revealed a conization rate of 1% in the entire population and a reduction in the risk of conizations in patients aged 19 to 30 years old, with a hazard rate of 0.59 (95% CI; 0.39-0.90; p=0.043)(10).
The prevention of cervical lesions at more advanced ages or latent HPV infections at these ages, as well as the prevention of other conditions related to HPV infection, such as the existence of vulvar and vaginal carcinomas, are all arguments in favor of extending the age of HPV vaccination. On the other hand, the low rate of cervical neoplasia after the age of 45, the lower frequency of vaginal and vulvar carcinomas, compared to that of cervical cancer, as well as the slower evolution of neoplasia in people of older ages and the better immune response in young people are the counterarguments to be considered when making recommendations for HPV vaccination. Therefore, the guidelines recommend individualized conduct with regard to vaccination at more advanced ages, as well as a judicious analysis of the costs and benefits arising from immunization at these ages.
At the same time, we cannot overlook the beneficial effects that have been demonstrated among UK patients who have been vaccinated against HPV. The effects were much more favorable when the earlier vaccination was carried out. In line with the results published by Falcaro et al., there was a 34% reduction in the cervical cancer rate in girls aged 16-18 years old at the time of vaccination, a reduction of 62% in girls aged 14-16 years old, respectively a reduction of 87% in girls vaccinated at 12-13 years old. The results for the rate of occurrence of CIN 3 lesions were similar, the percentages decreasing with 39%, 75% and 97%, respectively, in accordance with the smaller age of the patients at the time of vaccination. Estimates show that immunization led to a reduction of 448 cases in the number of cervical neoplasia, respectively by 17,235 in the number of cases of high-grade dysplasia. Thus, it is considered that the introduction of this vaccine into the vaccination scheme has led to the successful elimination of cervical cancer in patients born after 1 September 1995(11).
Vaccination of patients treated for HPV infections
There are several situations in which the vaccination against this virus in patients who already have a history of infection that has been treated can be a solution.
Although the effectiveness of the vaccine in HPV lesions already present could not be proven, the question was raised regarding the benefit that immunization could bring in patients with residual post-excision intervention disease. It also raises the issue of preventing recurrences, both in patients with residual disease, such as those with positive margins or with the persistence of the virus, and in the case of patients who could be reinfected from the HPV-positive partner. The risk of recurrence in patients treated by electrosurgical loop excision procedure (LEEP) is 10-14% globally. At five years, 6% of CIN 3 lesions, respectively 16.5% of CIN 2+ lesions have reappeared, therefore current guidelines recommend the monitoring of these patients at least 25 years after excision.
The prevention of other sites of HPV infection related diseases should not be neglected either, hence the pro-vaccination argument for the entire population, not just for the vaccination of the female population. And, finally, one can also consider the psychological argument, the appeasement of patients and their relatives.
The study conducted by Kang et al. showed that the absence of HPV vaccination is an independent risk factor for the recurrence of CIN 2-3 lesions (HR=2.840; 95% CI; 1.335-6.042; p<0.01). Of the 737 patients included, 2.5% of the patients vaccinated after excision experienced recurrence, compared to 7.2% of unvaccinated patients(12). Similar results were also reported in the meta-analysis conducted by Di Donato et al. They compared two batches of patients already treated for HPV infection, the first of whom was given the perioperative vaccine, and the second batch was only given surgery. Recurrence of lesions of type CIN 1+ (OR 0.45; 95% CI; 0.27-0.73; p=0.001), CIN 2+ (OR 0.33; 95% CI; 0.20-0.52; p<0.0001), CIN 3 (OR 0.28; 95% CI; 0.13-0.59; p=0.0009) was lower in the group of vaccinated patients, immunization also leading to a reduction in the risk of developing intraepithelial neoplasia (p=0.005), respectively recurrent respiratory papillomatosis (p=0.004). However, no differences were detected between the two groups in terms of the appearance of anogenital warts and vulvar intraepithelial neoplasia(13).
Vaccination in special populations
Several special categories of populations were considered in order to assess the effectiveness and appropriateness of immunization against HPV. Of these, patients with autoimmune diseases have shown a special interest, since they are subjected to immunosuppressive treatments, which increase their risk of developing dysplastic lesions associated with the HPV infection. It has been shown that patients with systemic lupus erythematosus have a higher risk of developing CIN 3 lesions or even cervical neoplasm, along with patients with rheumatoid arthritis; moreover, they are at risk regardless of the chosen therapeutic conduct.
Another category of interest is represented by patients diagnosed with inflammatory bowel disease. In the case of these patients, an increased risk of developing dysplastic lesions could not be demonstrated, with specific immunosuppressive therapy not leading to an increase in the risk of developing HPV-related lesions. Known patients with HIV infection are also a group of interest.
Immunizing these categories of patients has been shown to be safe. Although they do not develop antibody titers as robust as patients in the general population, seroconversion occurs and is considered to be relatively stable. Currently, it is recommended to repeat the vaccination with the nonavalent variant in patients already vaccinated with the tetravalent variant, considering that these patients are more frequently affected by the additional strains included in the new vaccine. It can also be considered useful to administer a fourth dose in these patients.
Considering the existing data, there is currently no longer any doubt about the need, efficacy and safety of vaccines against HPV. The only uncertainties that exist are related to the maximum use of this prevention tool, namely the exact definition and the characteristics of the people to whom immunization should be addressed for a maximum benefit. In Romania, at this moment, the reluctance towards this vaccine is still high, but the trend is towards an increase in the number of vaccinated people. The target that remains is represented by the eradication of cervical cancer, and a vaccination program targeting the right people at the right time, followed conscientiously, is the best method to achieve it.
Conflict of interests: The authors declare no conflict of interests.