Human papillomavirus vaccine effectiveness by age at first vaccination among Japanese women

Abstract In Japan, the National Immunization Program against human papillomavirus (HPV) targets girls aged 12‐16 years, and catch‐up vaccination is recommended for young women up to age 26 years. Because HPV infection rates increase soon after sexual debut, we evaluated HPV vaccine effectiveness by age at first vaccination. Along with vaccination history, HPV genotyping results from 5795 women younger than 40 years diagnosed with cervical intraepithelial neoplasia grade 2‐3 (CIN2‐3), adenocarcinoma in situ (AIS), or invasive cervical cancer were analyzed. The attribution of vaccine‐targeted types HPV16 or HPV18 to CIN2‐3/AIS was 47.0% for unvaccinated women (n = 4297), but 0.0%, 13.0%, 35.7%, and 39.6% for women vaccinated at ages 12‐15 years (n = 36), 16‐18 years (n = 23), 19–22 years (n = 14), and older than 22 years (n = 91), respectively, indicating the greater effectiveness of HPV vaccination among those initiating vaccination at age 18 years or younger (P < .001). This finding was supported by age at first sexual intercourse; among women with CIN2‐3/AIS, only 9.2% were sexually active by age 14 years, but the percentage quickly increased to 47.2% by age 16 and 77.1% by age 18. Additionally, the HPV16/18 prevalence in CIN2‐3/AIS was 0.0%, 12.5%, and 40.0% for women vaccinated before (n = 16), within 3 years (n = 8), and more than 3 years after (n = 15) first intercourse, respectively (P = .004). In conclusion, our data appear to support routine HPV vaccination for girls aged 12‐14 years and catch‐up vaccination for adolescents aged 18 years and younger in Japan.


| INTRODUC TI ON
The Japanese government initiated an HPV vaccination program for girls aged 12-16 years in 2010. In Japan, a bivalent vaccine against HPV16 and HPV18 was licensed in October 2009, and a quadrivalent vaccine against HPV6, HPV11, HPV16, and HPV18 was licensed in July 2011. Recently, a next-generation 9-valent vaccine, which extends coverage to HPV31, 33, 45, 52, and 58, was licensed in July 2020. Currently, the Japanese National Immunization Program against HPV includes bivalent and quadrivalent HPV vaccines but not yet the 9-valent HPV vaccine. In the Japanese guidelines, catch-up vaccination is recommended up to age 26 years for women not previously vaccinated. 1 Human papillomavirus vaccination prevents new HPV infections but does not treat pre-existing HPV infections or HPV-related diseases. 2 Because HPV infection rates increase soon after first sexual intercourse, 3 HPV vaccination is recommended by the WHO for routine immunization in 9-to 14-year-old girls in most countries. For instance, the current target ages for girls in the National Immunization Programs are 11-12 years in the US, 12-13 years in Australia, [11][12][13] years in the UK, 11-14 years in France, and 9-14 years in Germany. [4][5][6] In Japan, adolescents aged 15-16 years are also included as a target population for routine vaccination. 1 However, few studies have addressed the differences in the effectiveness of HPV vaccines based on age at first vaccination in Japan.
To our knowledge, the MINT study is the largest nation-wide study monitoring HPV vaccination impact and HPV genotypespecific disease incidence in Japan. [7][8][9] We selected changes in HPV16/18 prevalence among young women with cervical diseases as the primary end-point because: (a) a decrease in HPV16/18 prevalence is expected to occur quickly as the earliest measure of vaccine impact; and (b) monitoring HPV genotypes detected in cervical lesions can distinguish vaccine impact from screening effects and changes in lifestyle factors and sexual behaviors. During the earlier years of this project, we reported the preliminary results on vaccine effectiveness according to age at vaccination, 9 but the analysis had limitations due to the small sample size of vaccinated women. 10 Using a larger sample size over a longer surveillance period, we updated the previous findings and provided new data regarding age at first sexual intercourse. Our additional data support greater vaccine effectiveness among Japanese girls vaccinated at a younger age. This age information is very important because the Japanese government has recently decided to resume proactive recommendation of HPV vaccination in April 2022, along with a catch-up vaccination program for women who missed routine HPV vaccination at age 12-16 years. Our findings
In conclusion, our data appear to support routine HPV vaccination for girls aged 12-14 years and catch-up vaccination for adolescents aged 18 years and younger in Japan.

K E Y W O R D S
adenocarcinoma in situ, cervical cancer, cervical intraepithelial neoplasia, human papillomavirus, vaccination have important implications for the optimal target age population for routine and catch-up HPV vaccination in Japan.

| Study design
We undertook a collaborative hospital-based study (MINT studies I and II) to monitor the long-term population-level impact of HPV vaccination in Japan. Details regarding the design and methods have been provided elsewhere. [7][8][9] Briefly, study participants consist of all women aged 16-39 years (age at registration) newly higher (CIN2+) because CIN2 is the standard threshold for immediate treatment. [11][12][13][14][15][16][17][18] In the present study, we also focused on data analyses from women with CIN2-3/AIS.
Both studies relied on self-reported information regarding vaccination status because official vaccination records were not available to determine vaccination status. In the present study, women with at least one HPV vaccine dose were defined as "vaccinated".
Information on sexual history, sexually transmitted disease history, and smoking status was obtained from a self-administered questionnaire in the MINT study II but not collected in the MINT study I. Data from the questionnaires were self-reported and not validated.
Institutional ethical and research review boards of the participating institutions have approved the study protocol. The MINT studies I and II were registered in the UMIN Clinical Trials Registry as UMIN000008891 and UMIN00038883, respectively.

| Human papillomavirus genotyping procedures
Human papillomavirus genotypes in cervical samples were determined using the LA assay (Roche Molecular Systems) in the MINT study I and the PGMY-CHUV assay in the MINT study II. Both assays are L1 consensus primer-based PCR methods that use a primer set designated as PGMY09/11. 19 Details of these HPV genotyping assays have been provided elsewhere. 20  All HPV DNA assays were carried out by individuals masked to the results and clinical profile of each patient.

| Statistical methods
Positive rates for vaccine types HPV16 or HPV18 were analyzed according to disease severity, HPV vaccination history (HPV vaccine status and age at vaccination), and age at first sexual intercourse.

| RE SULTS
The present analysis included 4466 women with CIN2-3/AIS who had HPV genotyping results and vaccine history information; their characteristics are summarized in Table 1. Of 4466 women with CIN2-3/AIS, 3319 and 1147 women were registered in the MINT studies I and II, respectively. The vaccine uptake rate was 3.8% (169/4466).
We evaluated HPV vaccine effectiveness by age at first vaccination. The youngest age at time of first vaccination was 12 years.
Unfortunately, information regarding age at first dose was unavailable for five vaccinated women. The attribution of vaccine-targeted types HPV16 or HPV18 to CIN2-3/AIS was 47. In the MINT study II, information on age at first sexual intercourse was obtained from a self-administered questionnaire in 69.8% (801/1147) of those with CIN2-3/AIS. The median age at first sexual intercourse was 17 years (range, 9-30 years) among those with CIN2-3/AIS (Figure 2). The cumulative proportion of sexually active women was 9.2% by age 14, 47.2% by age 16, and 77.1% by age 18.
Information regarding both age at first vaccination and sexual debut was obtained from 39 women with CIN2-3/AIS. When the data were analyzed according to the timing of vaccination in relation to sexual debut, HPV16/18 prevalence in CIN2-3/AIS was 0.0%, 12.5%, and 40.0% among women vaccinated before (n = 16), within 3 years after (n = 8), and more than 3 years after (n = 15) first sexual intercourse, respectively (P =.004) (Figure 3).

| DISCUSS ION
Human papillomavirus vaccination effectiveness is highly dependent on age at the first immunization. [13][14][15][16][17][18] In this study, we reported the greater effectiveness of HPV vaccination among Japanese girls aged 18 years or younger at first vaccination outside clinical trial settings. Similar findings have been observed in other countries. Recently, several registry-based studies reported HPV vaccine effectiveness against invasive cervical cancer in a real-world setting. [13][14][15] In a UK study, the relative risk reduction for invasive cervical cancer was 87%, 62%, and 34% for women vaccinated at 12-13 years, 14-16 years, and 16-18 years, respectively, compared TA B L E 1 Characteristics of human papillomavirus (HPV)-typespecific analysis cohorts with those unvaccinated. 13 The risk of invasive cervical cancer was remarkably reduced among women vaccinated at age 16 years or younger in a Denmark study 14 and at age 17 years or younger in a Swedish study. 15 In another Swedish study, HPV vaccination effectiveness against CIN2+ was statistically significant for women aged 19 years or younger at first vaccination but not those aged 20 years or older at first vaccination. 16 Similarly, a US population-based casecontrol study of over 25 000 women showed significant protection against CIN2+ in women who received their first HPV vaccine dose at 14-20 years old but not for women aged 21 years or older at first vaccination. 17 In Scotland, the protective effect of three-dose catchup vaccination against CIN2+ was significant among women first vaccinated at age 14-17 years but not those first vaccinated at age 18 years or older. 18 Our findings were consistent with these realworld data reporting the greater effectiveness of HPV vaccination at a younger age; [13][14][15][16][17][18] however, the magnitude of this effect and the age range of women who benefit from HPV vaccination could vary from country to country.

History of HPV vaccination
Because HPV acquisition generally occurs soon after first sexual activity, 3 data regarding age at first intercourse, especially among women who develop CIN2+, are crucial to optimize the HPV vaccination strategy. However, in Japan, few studies have assessed the sexual behaviors of women who developed cervical diseases to date.
In the present study, 9.2% of women with CIN2-3/AIS were sexually active by age 14 but the proportion quickly increased to 47.2% by age 16 and 77.1% by age 18 (Figure 2). The percentage of sexually experienced women in our study population increased more rapidly cervical cancer and precancer. 23,24 Our data revealed complete protection against HPV16/18positive CIN2-3/AIS among girls vaccinated before 15 years old or sexual debut and higher HPV vaccine effectiveness among those vaccinated at 18 years old or younger. Furthermore, the proportion of sexually active females was less than 10% at age 14, but rapidly F I G U R E 2 Age at first sexual intercourse among Japanese women with cervical intraepithelial neoplasia grade 2 or 3 or adenocarcinoma in situ (CIN2-3/ AIS). Black bars and left axis show the number of women who experienced first sexual intercourse at age indicated on the X axis; red line and right axis indicate the cumulative proportion of women who experienced first sexual intercourse at the indicated age. Blue and red dotted lines show 10% and 50% of the cumulative proportion of women who experienced first sexual intercourse, respectively. Median age at first sexual intercourse was 17 years (range, 9-30 years)

F I G U R E 3
Attribution of human papillomavirus type 16 (HPV16) and HPV18 to cervical intraepithelial neoplasia grade 2 or 3 or adenocarcinoma in situ (CIN2-3/AIS) by the timing of HPV vaccination relative to first sexual intercourse. Prevalence of HPV16/18 in CIN2-3/AIS was 0.0% among women vaccinated before first sexual intercourse (FSI) (n=16), 12.5% among those vaccinated within 3 years after FSI (n = 8), and 40.0% (n = 15) among those vaccinated more than 3 years after FSI (n = 15) (P = .004). Error bars indicate 95% confidence intervals increased to 50% by 16 years old and to 80% by 18 years old. These results indicate that HPV vaccination should be initiated before 14 years of age for the National Immunization Program in Japan and support the Japanese guideline recommendations of HPV vaccination mainly for girls aged 14 years or less. 1 Furthermore, Japanese physicians, pediatricians, and gynecologists should be aware of these data when discussing the optimal time point of HPV vaccination with female adolescent patients and their parents.
Our data also suggested the limited effectiveness of catch-up vaccination in women older than 18 years. However, the present study might have evaluated only HPV vaccine effectiveness against cervical precancer caused by HPV infections acquired at young ages. 25 The effectiveness of catch-up vaccination against CIN2+ for women older than 18 years is one of the most important issues in HPV vaccination, especially in Japan, because the vaccination rate in women born in or after 2000 is extremely low (less than 1%) due to the Japanese government's suspension of the vaccination recommendation in 2013. 26,27 In the present study, the attribution of HPV16/18 to CIN2-3/AIS was reduced by 10%, even among women vaccinated at age older than 18 years compared with unvaccinated women, although the difference did not reach statistical significance. To determine the upper age limit for effective HPV vaccination among Japanese women, long-term surveillance studies in real-world settings are warranted.
The present study has several limitations. First, our study included only women who developed cervical diseases under the age of 40 years, but not women with normal cytology. As mentioned above, sexual activity of our study subjects appears to be higher than that previously reported among Japanese women. 21 19 Fourth, the response rate to the self-administered questionnaire regarding sexual activity was approximately 70%. Accordingly, 420 women lacking data collected from self-reports were excluded from the analysis of age at first intercourse. Although demographic characteristics and HPV type distributions were similar between the included and excluded women (data not shown), this rate of loss could have influenced the results. Fifth, we were unable to exclude the effects of confounding factors, such as changes in sexual behaviors, oral contraceptive use, and smoking rates. However, these changes are less likely to affect the rates of HPV16/18 detected from cervical lesions compared with the incidence rates of cervical lesions. Finally, despite the larger sample size over the longer surveillance period of the present study compared with our previous report, 8,9 the small sample size might still have influenced the research outcomes.
In conclusion, the present study updated HPV vaccine effectiveness information related to age at first vaccination and provided additional data on age at first sexual intercourse among Japanese women with CIN2-3/AIS. Our data indicated complete protection against HPV16/18-positive CIN2-3/AIS among girls vaccinated before 15 years old or sexual debut (most were likely HPV naïve at vaccination) and the greater HPV vaccine effectiveness among girls and adolescents vaccinated at age 18 years or younger. The proportion of sexually active females was approximately 10% at age 14 years but rapidly increased to 50% by age 16 years. Taken together, our data support routine HPV vaccination for girls aged 12-14 years and catch-up vaccination for adolescents aged up to 18 years in Japan.
However, to address the benefits of HPV vaccination at older ages and determine the optimal target age group for HPV vaccination, further research is warranted.