Review ArticleSpotlight on the role of human papillomavirus vaccines
Introduction
Human papillomavirus (HPV) is one of the most common sexually transmitted disease worldwide. It is estimated that more than 14 million new genital infections occur every year [1]. HPV is considered the main risk factors for developing cervical cancer. Cervical cancer is the fourth most frequent cancer in women with an estimated 570,000 new cases in the year 2020 [2]. Approximately 90% of deaths from cervical cancer occurred in low- and middle-income countries.
HPV is a non-enveloped, double-stranded DNA virus, belonging to the Papillomaviridae family. The genome of HPV is enclosed in a capsid, composed of major (L1) and minor (L2) structural proteins [2]. The peak incidence of HPV infection occurs within 5–10 years from the first intercourse (age 15–25 years) with a lifelong risk of contracting HPV estimated to be 80–90%, in sexually active population [2,3].
The prevalence of HPV tends to slowly decline after the age of 25 because of the immune response, the decrease in sexual partners and the decrease in susceptibility of the cervical tissue [4]. However, a less evident secondary peak is described in perimenopausal women (between age 40 and 50), related to new sexual partner, especially in countries with high divorce rate [2,4]. Although the immune system clear spontaneously most HPV infections in few months or years, women with persistent infection (5–10%) are at high risk for developing cervical intraepithelial neoplasia (CIN) and, in a minority of cases, cancer [3].
Currently, the genomes of more than 220 different types of HPV have been identified, but only a relatively small number of these – those considered high-risk (HR) - have been recognized as a causal factor for cervical cancer (and of the majority of ano-genital and oropharyngeal tumors) [5]. The International Agency for Research on Cancer (IARC) working group identified 13 types of HPV classified as HR viruses [1]. They included: the alpha-5 type 51; alpha-6 types 56 and 66; alpha-7 types 18, 39, 45 and 59; and alpha-9 types 16, 31, 33, 35, 52 and 58 [1].
Persistent infection with HR HPV infection is accountable for almost all cervical cancers, but it is also involved in the pathogenesis of some types of vaginal, vulvar, penile, anal and oropharyngeal cancers. Among HR HPV, the main oncogenic types are HPV 16 and HPV 18. It is estimated that they are responsible for 70% and 90% of cervical cancer and oro-pharyngeal cancer, respectively. Types 6 and 11, on the other hand, are known to be responsible for genital warts and recurrent respiratory papillomatosis [1,5].
Most HPV-related lesions are asymptomatic and self-limited, and a large proportion of those infections are associated with low-grade dysplasia, that tends to regress spontaneously. Conversely, persistent HR HPV infection is the main risk factor for the progression of lesions to high-grade dysplasia and cancer. HPV infection is a crucial and necessary (albeit not sufficient) element in the natural history of cervical cancer. HR HPV types infect the epithelial cells of the lower genital tract and, in association with microtrauma and/or erosions, penetrate inside the basal layer. In the basal layer, the viral genome is poorly expressed. Viral replication takes place in supra-basal layers and is tied to the epidermal differentiation process. HPV causes morphological modifications in the surrounding epithelium, including koilocytosis. Then, HPV is released in desquamated cells, originating from the superficial layer [1,6].
It is of paramount importance to point out that cervical cancer rarely occurs in women without HPV. The time interval between the acquisition of a new HPV infection and malignant progression is usually at least 10 years, but it may be shorter in immunocompromised women [7]. The long-term time interval between HPV infection and the risk of developing high-grade dysplasia and cancer allows to apply safe secondary prevention to reduce incidence and treatment-related morbidity of cervical cancer. Cervical cancer represents an ideal target for secondary prevention (ie, screening program). In 1968, the World Health Organization (WHO) published guidelines on the Principles and practice of screening for disease, which often referred to as Wilson and Jungner criteria [8]. Cervical cancer screening fulfilled all the criteria. Of note, those criteria included: (i) The condition should be an important health problem (ii) a latent stage of the disease, (iii) There should be a test or examination for the condition. (iv) The natural history of the disease should be adequately understood [8].
Especially in high income countries, organized population-based screening programs have reduced the incidence and mortality from cervical cancer [9]. However, cervical cancer still represents a major health concern, being the third most common malignancy among women aged <39 years, and the second most common cause of death for cancer among females between 20 and 39 years in the US [10]. The adoption of secondary prevention aims to eradicate the occurrence of cervical cancer by detecting lesions at precancerous stage taking advantage of their slow malignant degeneration.
Moreover, cervical cancer remains the most common cancer in low- and middle-income countries, where the unavailability of resources and infrastructures makes the organized population-based screening programs difficult adoptable, and HPV prophylactic vaccination not affordable for costs. In the present investigation we aimed to review current evidence on vaccines against HPV and their implication in clinical practice.
Section snippets
The effect of HPV vaccination on various subjects
HPV vaccination has different efficacy rates across subjects' types. Although the scientific community agree that having vaccination before starting sexual activity is cost-effective, researchers are discussing about the potential role of vaccination among other classes of individuals.
Conclusions
Cervical cancer is preventable in most cases by secondary prevention, identifying and treating preinvasive and microinvasive disease. The introduction of primary prevention by means of vaccination against HPV may further reduced the incidence of cervical cancer. The effectiveness of vaccination is directly related to the whole coverage of the populations (due to herd protection) and number of doses administered (two or three doses according to age). Secondary prevention (ie, screening program)
Author contributions
Conceptualization: GB, FR, FS, Methodology: All authors.; Data Collection: //; Project administration: FR. FS; Supervision: FS, FR.; writing - original draft: GB, FS; writing - review & editing: all authors.
Funding
No funding sources supported this investigation.
Declaration of Competing Interest
The Authors declare no conflicts of interest.
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