Examining the effect of HPV vaccination in order to prevent cervical cancer – a systematic review

Introduction

Human papillomavirus (HPV) is a common sexually transmitted infection that is transmitted through skin-to-skin contact. There are about 40 types of HPV that spread through sex [1]. This disease is so common that 80% of sexually active people are infected with HPV. Often, a healthy immune system can fight off the virus [2], but some HPV infections do not go away [3]. High-risk types of HPV cause genital warts and cancers such as cervical cancer in women and penile cancer in men [4]. This is why getting the HPV vaccine is so important, because it is a safe and effective way to prevent dangerous disease in case of exposure to this virus [5].
HPV virus has low-risk and high-risk types. Genital warts are caused by infection with types 6 and 11 of these viruses. Types associated with cervical cancer risk include HPV 16, 18, 31, 33, 45, and 54, among others. It is noteworthy that these types, despite causing warts, are not associated with cervical cancer risk. Cervical cancer, which is one of the most common cancers among women, is often caused by HPV infection [6].
Cervical cancer is the second most common cancer among women under the age of 65 and the leading cause of cancer death in women worldwide. It is staged according to the extent of the disease and whether the cancer has spread beyond the cervix (classification using a globally accepted system called the International Federation of Gynecology and Obstetrics staging system). Stage I cervical cancer is confined to the cervix. Stage I is divided into stages IA and IB. Stage IA is the earliest stage of cervical cancer, in which the cancer is too small to be seen with the naked eye. Stage IA is further divided into stages IA1 and IA2 [7, 8].
Stage IA2 means that the cancer has grown 3–5 millimeters into the tissues of the cervix, but is still less than 7 millimeters wide. It is well established that survival rates decrease as the stage at which the disease is diagnosed increases. It has been reported that 95–98% of women with stage IA2 cervical cancer survive five years after diagnosis with standard surgery. For stage IA2 disease, surgery or radiation therapy has been/is the treatment of choice. Standard surgery includes radical hysterectomy and bilateral pelvic lymphadenectomy [9]. This procedure involves removing the uterus, cervix, upper part of the vagina, and tissues around the cervix (parametrial tissue) as well as lymph nodes (glands) in the pelvis (pelvic lymphadenectomy). Although this type of surgery has very good results, it can cause side effects such as organ damage (bladder, bowel, blood vessels, nerves) and long-term side effects such as sexual or bladder dysfunction, pelvic cyst formation, and lymphedema (swelling) in the legs. One of the main disadvantages of radical hysterectomy is that it leaves the patient unable to have children. Since cervical cancer is most common in women at the age of 25–35, this is a major concern for many women [10, 11]. Therefore, the aim of the present study was to evaluate the effect of HPV vaccination in order to prevent cervical cancer.

Material and methods

In the current study 63 articles published in 2010–2024 were reviewed with keywords including “cervical cancer”, “HPV”, and “uterine cancer” in PubMed, Web of Science, Scopus, Science Direct, Elsevier and Wiley databases based on PRISMA 2020-27-item checklist. The keywords were standardized in MeSH and used for searching. In addition, the reference list of the selected articles was screened to find relevant studies. The search strategy was as follows, at first, a list of titles and abstracts of all articles searched in the databases under review was prepared. This work was done independently by two researchers. Then articles with duplicate titles were removed. Next, the abstracts of the articles were checked to find suitable studies, all the searched studies were saved in the EndNote. X8 software, and the rest of the steps were performed by the software.
The initial search identified 63 articles. In the first step, 12 articles were eliminated due to duplicate records based on article titles. Studies that did not meet the inclusion criteria were excluded (n = 19) by reviewing the abstracts of 51 articles in the second step. In the third step, 16 articles with incomplete data or non-compliance with the inclusion and exclusion criteria were eliminated after examining the full texts of 32 articles. Ultimately, six articles were included in the present study (Fig. 1).

Results

One cross-sectional study and five retrospective cohort studies met the inclusion criteria and were included in the study. 973,518 HPV-vaccinated women and 13,627 unvaccinated women were evaluated. Other characteristics of the studies are summarized in Table 1.

HPV vaccination in order to prevent cervical cancer

The risk ratio of cervical cancer screening was 1.15 times (HR = 1.15; 95% CI: 0.18–2.21) higher among HPV-vaccinated women than unvaccinated women (Fig. 2). Consequently, the adoption of cervical cancer screening was significantly predicted by HPV vaccination. A low heterogeneity between studies was evident, I² = 0% (p = 0.99) (Fig. 1).
According to Table 2, the risk ratio of cervical cancer screening among women who received at least one dose of HPV vaccine was 1.25 (HR = 1.25; 95% CI: 0.16–2.34; I² = 0) than unvaccinated women. Women with two doses of HPV vaccine more likely to initiate screening (HR = 1.66; 95% CI: 0.43–2.89; I² = 0) and were more likely to screen than those receiving three doses (HR = 2.80; 95% CI: 1.57–4.07; I² = 0).

Discussion

AR vaccine is effective against strains of HPV that are likely to cause cancer. It is necessary to know that this vaccine does not provide protection against diseases caused by other types of HPV, other viruses and bacteria [18], and HPV infections that are already present in the person’s body.
The papilloma vaccine should be injected intramuscularly into the deltoid muscle (preferably in the non-dominant arm) or into the upper outer part of the thighs. Side effects of this vaccine can include redness, swelling, or pain at the injection site, but should disappear within a few days [19]. Headache is one of the common side effects of this vaccine, which usually does not last very long and is transient [20]. Other side effects include bruising and itching at the injection site, increased body temperature or feeling hot and shivering, nausea, and pain in the arms [21], hands, fingers, legs, or toes [22].
New evidence suggests that HPV vaccines protect against the development of cervical lesions in young women, particularly those vaccinated at the age of 15–26 [23]. This review also summarizes the findings on the harms of this vaccine that have been evaluated in randomized controlled trials. Most people who experience sexual contact will be exposed to HPV at some point in their lives. In most women, HPV infection is cleared by the immune system. When the immune system does not eliminate the virus, persistent HPV infection can cause abnormal cervical cells. These lesions are known as cervical pre-cancer, because if not treated over time, they can turn into cervical cancer [24]. There are different types of HPV and some of them are associated with the development of cervical lesions that can become cancerous and are known as high-risk types of HPV [25, 26]. Two of these high-risk types (HPV16 and HPV18) account for about 70% of cervical cancer cases worldwide. Vaccines have been developed that help the immune system to recognize certain types of HPV [27]. Since cervical cancer can take several years to develop, regulatory agencies and international health organizations such as the World Health Organization consider cervical lesions as the preferred endpoint for HPV vaccine trials [28]. The results of 26 studies in 73,428 women across all continents over the past eight years were summarized. Most of the women in these studies were under the age of 26, although three trials were conducted in women aged 25–45 [29–31]. The new vaccine, which targets nine HPV types, was not included in this review, because it has not compared with a placebo in any randomized controlled trial. The effects of the vaccine measured as a pre-cancer effect related to HPV16/18 and a pre-cancer effect regardless of the HPV type [32]. None of these studies followed participants long enough to determine the effect of these vaccines on cervical cancer. Instead, researchers have considered precancerous lesions of the cervix. They found that in young women who did not have HPV [33], vaccination reduced the risk of developing precancerous lesions. About 164 women out of 10,000 women who received the placebo and 2 out of 10,000 women who received the vaccine developed precancerous lesions [34]. The researchers also reviewed data from all participating women, regardless of whether they were at risk for HPV at the time of vaccination. Among women aged 15–26, the vaccine reduced the risk of cervical precancerous lesions caused by HPV16/18 from 341–157/from 341 to 157 per 10,000. HPV vaccination also reduces the risk of developing any precancerous lesions from 559–391/from 559 to 391 cases per 10,000 people. The HPV vaccine does not work as well in older women who are vaccinated at the age of 25–45. This may be because older women are more likely to be already at risk. Evidence also shows that the vaccine does not appear to increase the risk of serious side effects [35]. The rate of these complications in both vaccinated and control groups was about 7%. The researchers found no increased risk of miscarriage in women who became pregnant after vaccination [36]. However, they stress that more data are needed to be surer about very rare side effects and the effect the vaccines have on preterm birth rates and birth defects in those who became pregnant shortly before or after vaccination [37].
According to Arbyn et al., the findings of this review were combined with the numerous global survey studies carried out by the World Health Organization’s global advisory committee on vaccine safety since the vaccinations were licensed [3]. It is concluded that the risk-benefit profile of prophylactic HPV vaccines is favorable and expressed concern about unsubstantiated claims about the vaccine’s harms that lack biological and epidemiological evidence and could undermine public confidence [39, 40].
Vaccination aims to stimulate the immune system to produce antibodies that can stop natural HPV infections [41]. These data suggest that immunization against HPV infection protects against precancerous lesions of the cervix and is likely to reduce the incidence of cervical cancer in the future [40]. However, this vaccination cannot prevent all cervical cancers, and even if you are vaccinated, you should have regular screening. The development of cervical cancer can take years after being infected with HPV and causing/causes precancerous lesions [42]. Therefore, studies with long-term follow-up are needed to determine the effects of HPV vaccination on the rate of cervical cancer.
One of the doubts that many women have is whether the vaccine causes infertility [43]. It should be noted that this claim has not been clinically proven. Recently, some studies have stated that the injection of vaccine is effective in early ovarian failure and can reduce the reserves of immature eggs in the ovary because this vaccine contains aluminum and its deposition on the ovary is associated with the occurrence of such a complication [44, 45]. Also, you should not receive a new dose of the vaccine if you have had a life-threatening allergic reaction to any component of the vaccine or to a previous dose of the vaccine [46, 47]. Although there is no concern about the side effects of the vaccine for women, the HPV vaccine is not recommended for pregnant women [48, 49] because during pregnancy [49], the immune system of the mother’s body is naturally weakened a little [50], and after the injection of the vaccine [51], the body may not respond fully. For this reason, the severity of vaccine side effects in pregnancy may be milder than normal conditions [52].

Conclusions

According to the present results, HPV vaccination reduces the risk of cervical cancer because cervical cancer screening is performed 1.15 times more often in vaccinated women than in non-vaccinated women. Also, receiving at least one dose of HPV vaccination was associated with a higher rate of cervical cancer screening, which reduces the risk of cervical cancer by increasing the number of doses to two and three doses, and with more timely screening, cervical cancer can be detected.

Disclosures

1. Institutional review board statement: Not applicable.
2. Assistance with the article: None.
3. Financial support and sponsorship: None.
4. Conflicts of interest: None.

References