In the present study, we compared the prevalence of histology confirmed high-grade cervical abnormalities (CIN2+, CIN3+) between an HPV-vaccinated group and unvaccinated group. As a result, the risk of high-grade cervical abnormalities was significantly lower in the vaccinated group as compared to the unvaccinated group.
Population-based studies are also conducted in many countries [13-19]. In Scotland, the risk for CIN3+ following bivalent vaccine at age 20 years was reduced by 86% in women who were vaccinated at the age of 12-13 years old [19]. In Sweden, the risk for CIN2+ and CIN3+ following quadrivalent vaccine was reduced by 75% and 84% in women who were vaccinated before the age of 16 years old [14]. These results were based on vaccination in women with 3 doses [14, 17], while our results were based on vaccination with at least one dose, because we did not have information on the number of doses. Several studies focused on the effectiveness of the number of doses received on CIN occurrence [24, 25]. In a case-control study from Australia, vaccine effectiveness for CIN2+ was observed in both 2- and 3-dose recipients (VE=46% in the 3-dose recipients, VE=21% in the 2-dose recipients) [25]. In the database linkage study from Australia, the vaccine effectiveness against high-grade was observed in the 3-dose recipients (hazard ratio=0.86, 95% CI: 0.78-0.94) and, women who were vaccinated before the age of 16 years old, trends of effectiveness were observed in less than 3-dose recipients [24]. A recent publication from India reported a rate of CIN1+ of 4.5% (5/132) in unvaccinated group, while there were no case (0/24) in vaccinated women (2- and 3-dose) [26]. These studies suggest that less than 3-dose regimens of HPV vaccine are effective against CIN.
In the recent reports from Denmark and Australia (with high coverage), one-dose regimen showed similar effectiveness than 3-dose regimen [27, 28].
Considering the results of these studies, it is reasonable to support that high effectiveness of vaccine was observed in the present study (although coverage was not so high). Moreover, distribution of HPV sub-types in Japanese women is also associated with high effectiveness in the present study. A previous study reported that prevalence of HPV-16/18 varied in accordance with age, prevalence of HPV-16/18 was highest in those aged 20-29 (53.8% and 90% in patients with CIN2/3 and cervical cancer, respectively) [29]. The HPV type distribution in Japanese women aged 20-25 enrolled in a clinical trial showed that HPV-16 was often found in HSIL cases (57.1%, 4/7) and CIN2+ cases (83.3%, 5/6) [30]. In short, detection rate of HPV-16/18 is high in young Japanese women, vaccination against HPV-16/18 is therefore considerably effective to prevent cervical cancer [31].
Several limitations of this study should be acknowledged. First, HPV vaccination status is self-reported and may be affected by recall bias. Japan has neither national vaccine registry nor national screening registry. Therefore, it is difficult to collect history of vaccination and screening results of individuals, and to link these data is even more difficult [32]. Deployment of the epidemiological surveillance at the national level is one of the most important challenges in the public health policy in Japan. Second, because screening uptake of cervical cancer in Japan is low, representativeness cannot be guaranteed, however we collected the linked data of 37,505 women, this is the largest study ever in Japan. Previous studies were based on limited sample size, and on cytology results solely [20, 21]. Our previous study using the data of 22,743 women from JCS showed the effectiveness of the vaccine against CIN2 + only [22]. This time, we can report the high effectiveness of vaccine against both CIN2+ and CIN3+.
In Japan, MHLW suspended proactive recommendation for the vaccine, as a result, uptake rate for HPV vaccine was plummeted from 70 percent to 0.3 percent [10]. Evidence of effectiveness and safety of vaccine has been accumulated, the recommendations have not yet been resumed. Additionally, screening uptake of cervical cancer younger than 30 is considerably low. Therefore, incidence rate is increasing especially among Japanese women aged 20-29 years old (5.1% per year between 1985 to 2012) [33].
In Ireland, uptake rate for HPV vaccine has also declined due to concerns about vaccine safety, however the uptake rate has recovered owing to efforts such as social media and governmental campaigns [34]. Since cervical cancer is a preventable disease [35], it is important to take steps to improve the HPV vaccination uptake rate in order to discontinue the increase in incidence and mortality from cervical cancer.