Cervical cancer develops in the cervix, which is the lower part of the uterus that connects to the vagina [1]. Cervical cancer is the fourth most common malignancy in women worldwide, with an estimated 604,000 new cases and 342,000 deaths reported in 2020 [2]. In South Korea, cervical cancer is the tenth most common cancer in women, with 2,998 new cases and 810 deaths in 2020 [3,4]. Almost all cervical cancer cases are caused by the human papillomavirus (HPV), which is sexually transmitted [5-7]. After HPV infection, cervical cancer develops over a latent period of 10-20 years [8]. All forms of cervical cancer can be caused by 15 different HPV strains [9], of which HPV 16 and 18 are responsible for approximately 70% of cervical cancer [10]. Thus, vaccination against HPV types 16 and 18 substantially reduces the risk of developing cervical cancer, and HPV vaccination is the most cost-effective public health intervention for the prevention of cervical cancer [11].

Currently, three HPV vaccine types are authorized for use. Cervarix, a bivalent vaccine against HPV types 16 and 18, has been in use since 2008. Additionally, Gardasil, a quadrivalent vaccine against HPV types 6, 11, 16, and 18, has been administered since 2007. The nine-valent vaccine known as Gardasil 9, introduced in 2016, is also effective against HPV types 31, 33, 45, 52, and 58, extending the coverage of the original quadrivalent Gardasil vaccines. All three vaccines showed 92%-100% prophylactic effects against HPV 16 and 18 [12]. All three vaccines have a relatively similar effectiveness in preventing cervical cancer [13]. The World Health Organization (WHO) does not endorse the preference for any specific HPV vaccine. However, the HPV nine-valent vaccine has greater HPV-type coverage, and only nine-valent vaccines have been available in the United States since 2017 [14]. The Centers for Disease Control and Prevention (CDC) in the United States recommend HPV vaccination for individuals aged 9-26 years, with a two-dose schedule administered 6-12 months apart for those up to 14 years of age, and a three-dose schedule administered within 6 months for those aged 15-26 [15]. The WHO recommends a two-dose schedule for girls aged 9-14 years and a three-dose schedule for those above the age of 15, similar to the recommendation of the U.S. CDC [16]. In April 2022, the vaccination recommendations were revised based on recent studies showing that a single dose of HPV vaccination can provide an efficacy similar to that of a two-dose schedule [17-19]. The WHO Strategic Advisory Group of Experts (SAGE) now recommends a one- or two-dose schedule for girls up to 20 years of age, including the primary target group of 9-14 year-olds, and a two-dose schedule with a 6-month interval for those aged 21 years or older [20].

In South Korea, HPV vaccination has been implemented as a national vaccination program since June 2016. Annually, two doses of bivalent and quadrivalent vaccines at intervals of six months are administered to 12-year-old girls. In the first year of the program, 61.8% and 54.9% of the subjects completed the first and second vaccinations, respectively. While the vaccination rate barely reached the halfway mark, it exhibited an increase each subsequent year until 2021, when nearly 90% of females had received their first vaccination, and about two-thirds had completed the full vaccination regimen. Starting in 2022, the vaccination efforts were expanded, with the target age range for vaccination extended to include individuals between the ages of 12-17 years. Adolescent females up to the age of 17 years who were not vaccinated before the age of 12 years prior to 2021 were eligible to receive the vaccine. Considering the vaccination age and operation period of the national vaccination program, it is difficult to anticipate a short-term cancer prevention effect in the entire population, although it may be of great help in the distant future. Thus, to gauge the short-term future effect of the national vaccination program, it is necessary to assess the prevention of cervical cancer among individuals in their 20s and 30s.

Therefore, this study aimed to evaluate the effectiveness of the national HPV vaccination program in South Korea by projecting the potential reduction in cervical cancer cases in the entire female population, especially in younger women, over the next 20 years through this vaccination program. Additionally, this study aimed to predict and compare the effects of vaccination programs against cervical cancer using an alternative scenario based on the vaccine type.

We predicted the development of cervical cancer over the next 20 years (2021-2040), with and without the national HPV vaccination program. Moreover, we predicted the development of cervical cancer under alternative scenarios of the vaccination program over the same period. The incidence rate of cervical cancer per 100,000 persons has continued to decrease from a crude incidence rate (CR) of 18.047 and an age-standardized incidence rate (ASR) of 15.508 in 2001-2005 to a CR of 13.234 and an ASR of 9.397 in 2016-2020. Additionally, the incidence rate over the next 20 years showed a decreasing trend. The CR was predicted to continue to decrease to 10.693 in 2036-2040, while the ASR was predicted to continue to decrease to 7.923 in 2031-2035 and subsequently slightly increase to 8.011 in 2036-2040 (Fig. 1, S4 Table).

The effect of the national HPV vaccination program did not differ from that of not introducing the program until 2021-2025. However, from 2026-2030, the effect of the vaccination program was predicted to gradually appear, and the effect would be slightly greater from 2036-2040. The current national HPV vaccination program is estimated to prevent 818 cases of cervical cancer over the next 20 years. The incidence of cervical cancer is projected to be reduced by 4.13% (PIF, 4.13%; 95% CI, 1.82% to 6.43%) for CR and 8.79% (PIF, 8.79%; 95% CI, 6.23% to 11.36%) for ASR in 2036-2040. When the nine-valent vaccine was used instead of the current 2- and quadrivalent vaccines, the number of preventable cervical cancers over the next 20 years was predicted to reach 1,016 cases. It was predicted to reduce the incidence of cervical cancer by 5.13% (PIF, 5.13%; 95% CI, 2.84% to 7.42%) for CR and 10.93% (PIF, 10.93%; 95% CI, 8.41% to 13.46%) for ASR in 2036-2040. This is more effective than the current national vaccination program by 1% for CR and 2% for ASR. In the scenario that expanded the target population from the initiation of the vaccination program to individuals aged 9 to 17 years old, including 9 to 14 years old, which is the first target in the WHO recommendation, the projected number of preventable cervical cancers over the next 20 years substantially increased to 2,486. Moreover, it was predicted to reduce the incidence of cervical cancer by 10.93% (PIF, 10.93%; 95% CI, 8.41% to 13.46%) for CR and 18.57% (PIF, 18.57%; 95% CI, 16.21% to 20.93%) for ASR in 2036-2040. This indicates an effect that is more than twice as large as that of the current national vaccination program (Table 2, Fig. 2).

When limited to their 20s and 30s, the preventive effect was predicted to be greater. It was predicted to prevent 560 cases of cervical cancer in 2036-2040, which is approximately 30% of cervical cancer cases in the 20s and 30s (PIF, 30.12%; 95% CI, 25.16% to 35.07% for CR). When age-standardized, it was predicted that approximately 34% of cervical cancer cases in the 20-30 age group could be prevented in 2036-2040 (PIF, 33.51%; 95% CI, 28.42% to 38.61% for ASR). In addition, in the alternative nine-valent vaccination scenario, the preventive effect was predicted to be slightly greater than that of the current vaccination program, and approximately 40% of cervical cancer cases in the 20-30 age group is predicted to be prevented in 2036-2040 (PIF, 37.45; 95% CI, 32.86% to 42.03% for CR and 41.67; 95% CI, 37.01% to 46.32% for ASR). Regarding the alternative vaccination scenario for expanding the target age, the preventive effect was predicted to be even greater, and over 60% of cervical cancer cases in the 20-30 age group were predicted to be prevented in 2036-2040 (PIF, 61.17; 95% CI, 57.83% to 64.51% for CR and 61.56; 95% CI, 58.03% to 65.10% for ASR) (Table 3, Fig. 3).

When examining the 20s age group, the preventive effect was predicted to be much greater in each vaccination scenario. The detailed values for each scenario are listed in the S5 Table.

We predicted the incidence of cervical cancer over the next 20 years, and calculated the potential impact of the Korean National HPV Vaccine Program. It was estimated to prevent approximately 4.13% of cervical cancer cases in the total population in 2036-2040. Additionally, when age-standardized, it was predicted to prevent 8.79% of cervical cancer cases in the entire population over the same period. We calculated the potential impact of the alternative vaccination scenarios on the national vaccination program. The scenario using a nine-valent vaccine was predicted to prevent 5.13% of cervical cancer cases in the total population and 10.93% of cervical cancer cases when age-standardized in 2036-2040. In another scenario, by expanding the vaccination age to 9-17 years, the preventive effect was predicted to reduce 10.19% of cervical cancer cases in the total population and 18.57% of cervical cancer cases when age-standardized during the same period.

When the age range was limited to the 20-30 age group, the current national HPV vaccination program was predicted to exhibit an earlier and greater predictive effect than in the entire population. It is estimated to prevent approximately 30% of cervical cancer cases, and about one-third in 2036-2040 when age-standardized. In the nine-valent vaccination scenario, cervical cancer was predicted to be reduced by 37.4% regardless of age, and by 41.7% when age-standardized in 2036-2040. In the scenario where the vaccination age is expanded, cervical cancer was predicted to decrease by approximately 60%, both with and without age-standardization. This suggests that the preventive effect of the cervical cancer vaccine becomes apparent in young women in their 20s and 30s, which corresponds to 10 years or more after vaccination.

This study is the first to estimate the number of cervical cancers that can be prevented in the future through Korea’s national HPV vaccination program by calculating PIFs. Kim et al. [24] suggested the potential impact of HPV vaccines; however, they only presented data on the distribution of HPV types among cervical cancer cases in South Korea and failed to consider the effect of the national HPV vaccination program. It is difficult to confirm the direct success of vaccination programs in preventing cervical cancer. The targeted vaccination group comprises girls, and a certain span of time is required before the HPV infection manifest as cancer. Moreover, the national HPV vaccination program has been implemented only recently. To overcome these limitations, we predicted the effect of disease prevention by making several assumptions using a cancer prediction model. When using a cancer prediction model, if the attributable fraction of the risk factors that cause cancer is well known, the cancer prevention effect can be predicted according to the scenario in which the risk factors are removed. Although their study was not on cervical cancer, Olsen et al. [30] predicted the number of melanoma cases that could be prevented by each intervention scenario if the number of people who regularly applied sunscreen increased. Similarly, we attempted to predict the cancer-prevention effects of the national HPV vaccination program based on the concept proposed by Olsen et al. [30]. We made some assumptions based on general facts and the results of previous studies on HPV and cervical cancer. Based on these assumptions, we predicted the cancer incidence effect for the next 20 years by specifically estimating the number of preventable cancer cases, considering the cohort effect of the age group at which vaccination was administered.

As of October 2020, 110 countries worldwide have implemented national HPV vaccination program [31,32]. At the population level, there is evidence of a reduction in high-grade cervical abnormalities among young women [33-35] and vaccination significantly reduces the prevalence of high-risk HPV types among young women [36]. Several studies have investigated the cost-effectiveness of HPV vaccines against cervical cancer in various countries [37]. Despite different methodologies and assumptions, most studies have consistently shown that HPV vaccination has an economic effect, and many countries have introduced it as a national vaccination program. The WHO also targets 90% HPV vaccination of girls under the age of 15 years by 2030, along with cancer screening and treatment, as targets for cervical cancer elimination [38].

Our predictive analysis showed that the nine-valent vaccine introduction scenario had a slightly higher cervical cancer prevention effect than the current national vaccination program. Specifically, in young women in their 20s-30s, it is predicted to prevent cervical cancer by approximately 7%-8% compared to the current vaccination program in 2036-2040. The nine-valent vaccine covers 5 additional HPV types (31, 33, 45, 52, and 58) that cause cervical cancer. This provides 15%-20% additional coverage than bivalent or quadrivalent vaccines, thereby preventing 90% of the HPV types related to cervical cancer [39]. Therefore, these vaccines are expected to prevent cervical cancer. In developed countries, such as the United States [14] and Australia [40], bivalent or quadrivalent vaccines have been replaced by a nine-valent vaccine in their national vaccination program. In addition, several clinical trials have shown that it is as safe as bivalent or quadrivalent vaccines [41]. While we cannot definitely assert that the nine-valent vaccines are more cost-effective than those being used in the current national vaccination program, their inclusion is also worth considering if there are no cost-related barriers.

In the predictions for each scenario, the scenario in which the age was expanded from the beginning of the project to 9-17 years old, including the WHO-recommended age (9-14 years old), was observed to have a much greater preventive effect over the next 20 years than the current scenario. The current national vaccination program has expanded the vaccination age to 12-17 years old, starting in 2022, where it was previously conducted for 12-year-olds. Expanding the target age broadens the impact of the vaccination program by increasing the proportion of vaccinated people, particularly among younger age groups, thereby advancing the effectiveness of the vaccination initiative over an extended period and enhancing its short-term effects. In particular, if the age group of 9-11 years is included in the vaccination target population, along with the WHO recommendations, vaccination coverage in the population can be further increased. The vaccine uptake was highest in this age group before the age of 13 years, and beyond that, the uptake gradually decreased with age [42,43]. Additionally, the HPV vaccine is most effective before HPV infection because there is little sexual activity before the age of 12 [44]. Thus, expanding the vaccination age to include younger individuals can increase vaccination coverage and further enhance the preventive effect, making it worthy of consideration in future policy deliberations.

Based on recent studies indicating that the efficacy of a single vaccination dose is comparable to that of a full dose, we conducted a predictive analysis based on first-dose vaccination statistics rather than second-dose vaccination statistics. Kreimer et al. [17] examined HPV 16/18 infections and antibody responses in a cohort of 1,783 individuals aged 18-25 in Costa Rica who received at least one dose of the HPV16/18 vaccine, along with a control group matched 1:1 by sex and region, over an 11-year period. The study found that single-dose vaccine efficacy (VE) against HPV16/18 infection remained high, and the levels of HPV16/18 antibodies remained stable. In another study, Basu et al. [18] enrolled 17,729 girls aged 10-18 from multiple centers in India who received one or more doses of the vaccine and followed them for 10 years. The study showed that a single dose of the HPV vaccine provides similar protection against persistent infection from HPV 16 and 18 as two or three doses. Furthermore, Barnabas et al. [19] recruited 2,275 Kenyan females aged 15-20 years and randomly assigned them to three groups: one receiving a nine-valent HPV vaccine, another receiving a bivalent HPV vaccine, and a third receiving a meningococcal vaccine. Eighteen months after vaccination, the levels of HPV 16/18 antibodies were measured. The results indicated that a single dose of either bivalent or nine-valent HPV vaccine demonstrated a 97.5% preventive effect, highlighting the efficacy of a single dose for cervical cancer prevention. However, a study by Toh et al. [45] in 2015 involving 200 Fijian girls aged 15-20 years, who were assessed for HPV antibody response 6 years after receiving the HPV4 vaccine showed that the HPV antibody levels in girls who received only one dose were significantly higher than those in unvaccinated individuals, but statistically lower than those who received two or three doses. Although the equivalence of one dose to two remains controversial, almost all studies have shown that a single dose provides a much higher long-term cervical cancer prevention effect than no-vaccination. In addition, even if a statistically significant difference exists between single-dose and two-dose vaccinations, the magnitude remains relatively small. Thus, omitting the attenuation due to only one vaccination would have a minimal impact on overestimating the prevention effect. Hence, we deemed it preferable to prioritize the prediction of the cervical cancer prevention effect by utilizing the first-dose vaccination rate.

The latency period was not considered in this analysis. The latency period between initial HPV exposure and the development of cervical cancer varies; but is known to be 15-20 years on average, according to the WHO [13]. Although overestimation of the prevention effect may occur because the latency period was not considered, our analysis is expected to predict cervical cancer in the age group under the age of 40 years, given the age at vaccination, the time at which the national vaccination program starts, and the projection period in the future. In South Korea, as of 2020, the number of cases of cervical cancer was the highest in the age group of 50-54 years. The age-specific incidence showed an intermediate peak at 8.8 per 100,000 population in the age group of 50-54 years and subsequently decreased, only to increase again in the age group of 75-79 years, reaching 9.4 per 100,000 population, and peaking in the age group of 85 years and above at 12.6 per 100,000 population. Cervical cancer is rare in young individuals, particularly those in their 20s. This could be attributed to the short interval between exposure to HPV after sexual activity and cancer development, suggesting a shorter latency period than the commonly known latency period. Had we incorporated the latency period in our analysis, explaining the occurrence of cancer among individuals in their 20s after the initiation of the national vaccination program would have posed challenges. Therefore, we did not consider the latency period as a critical factor in predicting the prevention effect among individuals aged 20-30 over the next 20 years.

We assumed that the age at which HPV infection begins is 19 years because the HPV infection rate is highest in the late teens and early twenties. According to domestic surveys, women aged 18 to 29 had the highest HPV infection rate at 49.9% [46]. While HPV infection can occur at earlier ages, the occurrence of cervical cancer in this age group is shallow. Therefore, we believe that it would not have had a significant impact on our predictions.

We did not consider individual vaccinations prior to the national HPV vaccination program. Before the national vaccination program, no precise statistics were available regarding pre-vaccination coverage rates. However, based on a 2013 survey conducted by the Korea Centers for Disease Control and Prevention, which reported a vaccination coverage rate of 12.6% among individuals aged 19 years and older, it can be estimated to be approximately 10%-15% [47]. Our predictions did not account for this, which may have led to an overestimation of the projected number of cervical cancer cases. Nevertheless, considering that the national vaccination program primarily targets young girls and personal vaccinations within that age group are likely to be limited, we believe that this would have a minimal impact on the future incidence of cervical cancer among younger age groups.

In addition, factors such as HPV screening and individual sexual behavior related to the incidence and prevention of cervical cancer in the future were not considered. Additionally, it was impossible to obtain or include these data in the analytical model. Failure to consider factors related to cervical cancer development may lead to a bias in the predicted number of incident cases of cervical cancer. We assume that the HPV vaccination program did not affect the need for cancer screening. HPV screening plays an important role in preventing cervical cancer and is recommended by the WHO [48]. However, HPV screening is an ongoing program; and screening rates have remained relatively consistent. Therefore, it is unlikely that this had a significant impact on our estimation of the effects of the national HPV vaccination program on cervical cancer prevention. Similarly, while there is a lack of data on individual sexual behavior, it is challenging to ascertain whether there have been significant societal changes in the sexual behavior of young women before and after the introduction of the HPV vaccination program. Therefore, we believe that such factors are unlikely to have influenced our predictions.

The main limitation of this study is that the preventive effects were estimated using assumptions for HPV and cervical cancer. Assumptions regarding the contribution of HPV risk, VE, and the prevalence of HPV 16 and 18 in the Korean population are based on known data and are not expected to be variable. However, the other assumptions may affect the results. However, a sensitivity analysis cannot be performed individually for all these assumptions. Another limitation is the omission of vaccination rates in non-eligible populations. According to a 2013 survey that revealed a vaccination rate of 15.9% among women aged 27-39 years [47], it is evident that a significant number of women aged above the eligible population age range are opting for HPV vaccinations. Our study did not account for this, which could lead to overestimating the effectiveness of the national HPV vaccination program. Lastly, the prediction model projected the incidence of cervical cancer only for the next 20 years. Considering that the national vaccination program has only recently been introduced, the prediction was limited to fully understanding the effects of the vaccine. However, if more data are accumulated over time, we believe that future predictive studies will compensate for these limitations and be fully aware of the effects of the vaccine.

Despite these limitations, this study is the first to quantitatively predict and evaluate the cancer prevention effects of an HPV vaccination program. While existing cost-effectiveness studies have not considered the incidence of cervical cancer, our study used existing cervical cancer incidence data and prediction models to calculate future preventable cancer cases, thereby enhancing the reliability of the analysis and enabling the approach from a more public health perspective. Despite the relatively short duration since the national vaccination program was implemented, its effectiveness has been validated in young women. This study confirmed the effectiveness of the national HPV vaccination program and provided important evidence for the future expansion of the national vaccination project in South Korea.

In this prediction, the current national HPV vaccination program is estimated to prevent approximately 4.1% of the crude incidence and 8.8% of the age-standardized incidence of cervical cancer in the overall population in 2036-2040. Assuming that the nine-valent vaccine was implemented in the national vaccination program, the vaccination effect appeared to be slightly greater. In addition, when the target age for vaccination was expanded, the effect appeared to increase considerably as population coverage increased. Although the potential impact within the next 20 years is not great in the general population, the effect was found to be significant even within the next 20 years in younger age groups, especially those in their 20s-30s, when considering the age at vaccination and time to HPV infection. Although the incidence of cervical cancer has been decreasing even before the implementation of the national vaccination program, it is conceivable that the program will help accelerate this trend. If national vaccination continues for a significant period, it is thought to contribute to a substantial reduction in cervical cancer, not only among young individuals, but also across all age groups, and may potentially eliminate cervical cancer.