Effectiveness of HPV vaccination in reducing infection among young Brazilian women

Persistent infection with high-risk Human Papillomavirus (HPV) is the main risk factor for cervical cancer [1]. This neoplasm is the fourth cause of cancer death in women, with 660,000 new cases and 350,000 deaths worldwide [2]. Cervical cancer is the third most common cancer in women in Brazil, causing more than 6,000 deaths in 2020 [3].

Among sexually transmitted infections, HPV infection is the most common worldwide and most sexually active individuals will probably have contact with at least one type of HPV in their lives [4, 5]. In Brazil, a meta-analysis showed that the general HPV prevalence in cervical samples was 25.4% [6]. Another study carried out in all Brazilian capitals revealed that the prevalence of HPV infection was 54.6% in women who had never had grade 2 or higher cervical intraepithelial neoplasia, aged 16 to 25, and high-risk viral types were present in 38.6% of participants [7]. In Ouro Preto, Minas Gerais, Brazil, 17.2% of women under age 30 and with normal cytology were infected with HPV. Furthermore, a higher frequency of infection by viral types with high risk was observed regardless of age group [8].

Cervical cancer prevention occurs mainly through HPV vaccination strategy. Three prophylactic HPV vaccines have been licensed and are available in several countries: bivalent, quadrivalent, and nonavalent [9, 10]. These vaccines protect against high-risk HPV16 and 18, responsible for 70% of cervical cancer cases worldwide. The quadrivalent vaccine also protects against HPV6 and 11, low-risk HPV which cause 90% of cases of genital warts. The nonavalent HPV vaccine provides immunity against the four types in HPV quadrivalent vaccine, in addition to high-risk types HPV 31, 33, 45, 52, and 58 [9, 11, 12]. In Brazil, quadrivalent HPV vaccine was introduced to the National Immunization Program in 2014. In the first years, the vaccine was only available free of charge for girls, and in 2017 boys were included in the vaccination program [13].

Clinical studies have demonstrated high efficacy of HPV vaccines [11]. However, there are potential factors that influence vaccination performance at a population level. Among these are age at which vaccination begins, compliance with the standard interval for receiving doses, regional differences, local prevalence of different HPV types, and most importantly, vaccination coverage [7, 14, 15]. Low coverage has been observed in several regions, especially in less developed ones [16]. In Brazil, vaccination coverage for girls reaches 76% for the first dose, but only 60% for the second dose, which is below World Health Organization´s (WHO) recommendation of 90% [17, 18].

HPV vaccination programs implemented in several countries have shown a reduction in HPV infection rates and, consequently, in diseases related to this infection [7, 10]. A meta-analysis evaluated the effectiveness of bivalent and quadrivalent vaccines in the population of high-income countries and showed a reduction in the prevalence of HPV 16 and 18 of 83% and 66% in girls aged 13–19 years and 20–24 years, respectively [19]. In Scotland, no cases of invasive cancer were recorded in women immunized with the bivalent HPV vaccine at age 12 or 13, regardless of the number of doses [20].

In Brazil, only one study evaluated HPV vaccine effectiveness in the population. This study demonstrated that quadrivalent vaccine reduced by 56.8% the infection with HPV 6, 11, 16, and 18 among women aged 16 to 25 [7]. In this context, given the importance of conducting additional populational studies to assess the impact of HPV vaccination in Brazil, the objective of this study was to evaluate the effectiveness of the vaccine in reducing prevalence and incidence of HPV infection among young women.

A total of 366 young women were interviewed between November 2018 and March 2021. However, 96 (26.2%) women did not attend the scheduled DNA-HPV test. Additionally, 21 samples were excluded because the HPV type could not be determined by the methods used. Thus, 249 young women were included at baseline, of which 89 (35.7%) were vaccinated against HPV. Among these, 71 (28.5%) received the complete HPV vaccination schedule – two or three doses according to the age at which vaccination began, while 18 (7.2%) received only one dose.

Table 1 shows sociodemographic and behavioral characteristics and gynecological history of the participants in this study. Most of the young women lived in urban areas (n=214, 85.9%). The mean age was 20.8±1.7 years old, and 43.0% (n=107) of participants were aged between 18 and 19 years old. Most women had high school education (n=170, 68.3%), per capita family income ≤US$131.00 (n=113, 53.6%), and were single (n=126, 50.6%). A significant difference was observed between vaccinated and unvaccinated groups in terms of age and education. In addition, a decrease in vaccination rates was observed among women aged 20 years or older (p<0.001), since they were not in the age range for HPV vaccination, according to the National Immunization Program. Considering that women in the vaccinated group were younger, their education levels were lower (p=0.002) when compared to those who were not vaccinated.

Sexual behavior showed the mean age at first sexual intercourse was 15.7±1.7 years old, ranging from 12 to 21 years old. The mean number of sexual partners was 4.3±4.5. Pregnancy was reported by 25.9% (n=63) of the participants. Moreover, 8.1% (n=20) of the young women said they had been previously diagnosed with one or more sexually transmitted infections, such as HPV, genital herpes, syphilis, trichomoniasis, and gonorrhea. More than half of the young women (n=137, 55.0%) had already taken the Pap smear. Additionally, 59.4% (n=148) of the participants used hormonal contraceptives, and only 23.7% (n=59) used condoms regularly. Significant differences were observed in the number of sexual partners, pregnancy history, and previous Pap smear when comparing vaccinated and unvaccinated young women (Table 1).

This population-based study evaluated the effectiveness of the HPV vaccine among vaccinated and unvaccinated young women, five years after the introduction of the quadrivalent vaccine into the National Immunization Program in Brazil. The results demonstrated a lower prevalence of infection by the HPV types contained in the quadrivalent vaccine among young women, with an effectiveness of 64.0% regardless of the viral type.

None of the young women immunized with at least one dose was identified with high-risk HPV16 or 18. HPV 6/11 was detected in only one woman at baseline. However, there was no persistence of infection after 12 to 18 months of follow-up. To date, only one study has evaluated the effectiveness of the HPV vaccine at a population level in Brazil [7]. The authors analyzed the prevalence of HPV infection in young people aged 16 to 24, recruited in all Brazilian capitals, and demonstrated a decline of 56.8% in HPV 6, 11, 16, and 18 among vaccinated participants, corroborating with the results of this study.

At baseline, a higher prevalence of infection by non-vaccine types was identified among vaccinated young women. Furthermore, a higher prevalence of infection with high-risk HPV types, excluding HPV 16 and 18, was observed among vaccinated young women compared to unvaccinated women, with emphasis on HPV 33 and 45. Similarly, the study that evaluated the prevalence of HPV infection in all Brazilian capitals observed a significant increase in the prevalence of non-vaccine high-risk types among young women who were immunized [7]. In the United States, a study carried out with women aged 20 to 29 years old observed a higher prevalence of non-vaccine HPV types, including high-risk HPV, in immunized women compared to unvaccinated women, despite the age at vaccination and the number of doses [26]. In Stockholm, Sweden, a decade after the introduction of the quadrivalent vaccine there was an increase in HPV 39, 51, 52, 56, and 59, regardless of vaccination status. However, a significant reduction in high-risk HPV types 35 and 45 was identified among vaccinated women [27]. Studies that used clinical data or those with high vaccination coverage identified an increase in the prevalence of high-risk HPV, excluding types 16 and 18, among girls aged 13 to 19 years in the first four years of vaccination. However, this change was not maintained over a long period of follow-up and was not evident in different age groups [19].

Cross-protection for HPV 31, 33, and 45 was observed in studies that evaluated the effectiveness of bivalent and quadrivalent vaccines [28‐30]. However, this protection may vary according to the age at which vaccination begins, the time elapsed between immunization and protection assessment, vaccination coverage, the type of vaccine used, and the number of doses received [19, 26]. The present study, carried out five years after the introduction of the vaccine into the National Immunization Program, showed a higher prevalence of infection with HPV types 33 and 45 among vaccinated young women. On the other hand, a meta-analysis observed a significant reduction of 54% of HPV types 31, 33, and 45, after 5 to 8 years of vaccination, among women aged 13 to 19 years old. In the 20 to 24 age group, there was a non-significant decrease of 28% [19].

There is a greater reduction in the prevalence of HPVs 16 and 18, in addition to the non-vaccine types HPVs 31, 33, and 45, in a context of high vaccination coverage (≥50%) [19]. However, in this study a vaccination rate of less than 50% was observed, which may have compromised cross-protection by HPV types 33 and 45. In addition, other studies have demonstrated that the bivalent vaccine is more effective in terms of immunogenicity and against infection by HPV types 31, 33, and 45 compared to the quadrivalent vaccine [31, 32]. In the United States, it was demonstrated that there was no effectiveness of the quadrivalent vaccine in protecting against HPV types 31, 33, and 45 when comparing women vaccinated with one or more doses and those not vaccinated [26]. In the present study, a rise in the prevalence of HPV infection types 33 and 45 was observed among the vaccinated group, despite the majority of young women in this group having received two or three doses of the vaccine.

Studies have shown that the effectiveness of HPV vaccines does not differ depending on the number of doses [26, 33, 34]. Considering the vaccine HPV types, only one participant vaccinated with one dose had HPV6/11 infection at baseline. Data from research carried out in India showed that a single dose of HPV quadrivalent vaccine is immunogenic and provides lasting protection against infection with HPV 6, 11, 16, and 18 for a period of approximately four years [35]. This protection was maintained for at least seven years for HPV 16 and 18, with the immune response against HPV infection by types 6 and 11 not being evaluated during follow-up [34]. Two randomized clinical trials in Kenya (KEN SHE) and Tanzania (DoRis) with young women demonstrated robust and durable immunological responses against high-risk HPV 16 and 18 after receiving a single dose of bivalent or nonavalent HPV vaccine [36, 37]. Researchers from Scotland evaluated the incidence of cervical cancer by age, number of doses, and socioeconomic status, demonstrating that girls aged 12 and 13 years old who received one or two doses of the HPV vaccine had zero cases of cervical cancer. Among vaccinated women aged between 14 and 22 years old there was a significant reduction in this cancer and women with socio-economic deprivation were those who had the greatest reduction [20]. Our study found that only 7.4% (n=20) of the young women selected received one dose, which made it impossible to analyze effectiveness in relation to the number of doses. The Brazilian National Immunization Program adopted a single-dose HPV vaccination schedule for children aged 9 to 14 in April 2024 [18].

The quadrivalent vaccine was found to be effective against all types of HPV after approximately 1.3 years of follow-up. Similarly, in Norway, five years after implementing the vaccine, a 42% decrease in infection with any type of HPV was observed when comparing a cohort of 17-year-old women who received the three-dose vaccination schedule with a cohort of non-vaccinated young people of similar age [38]. Following the present study, no immunized young woman was detected with HPV 6, 11, 16, or 18, indicating good protection against these viral types [38]. In Belgium, use of the quadrivalent vaccine, in the first three to seven years of vaccination implementation, was 67% effective for infections associated with HPV 16, 93% for HPV 18, and 100% for HPV 11, among women under age 30, in addition to 71% protection against infections related to the combination of HPV 16 and 18. However, for HPV 6, no significant protection associated with vaccination was observed [39].

Because the National Immunization Program targets young women and the study was conducted with women vaccinated at the beginning of the vaccine rollout in Brazil, the non-vaccinated group was consisted of slightly older women, which may have introduced selection bias, which is a limitation of this study. To minimize this potential bias, the final model was adjusted for age, even though age was not statistically significant. Therefore, selection bias can be ruled out in explaining the observed vaccine’s effectiveness.

More populational studies should be carried out to look for evidence of cross-protection for non-vaccine HPV types in the population; the impact of vaccination on non-immunized groups (herd protection); monitor the impact of the single-dose regimen; check the occurrence of substitution of viral types; and evaluate the cost-benefit and possible impacts of incorporating the nonavalent HPV vaccine into the Immunization Program. In addition, it is necessary to verify the best public health strategies for screening cervical cancer and other cancers associated with HPV infection in the vaccination era.

Effectiveness of the quadrivalent HPV vaccine was observed considering infection with all viral types among young women. At baseline, a higher prevalence of infection by non-vaccine viral types, including high-risk HPV, was detected, making it important to maintain surveillance. During follow-up, this trend continued, although not significantly, making it necessary to still maintain surveillance. Observing the behavior of HPV infection in this population is essential in order to assess the impact of long-term vaccination on public health strategies related to HPV infection.