\documentclass[10pt]{article}

\usepackage{fullpage}
\usepackage{setspace}
\usepackage{parskip}
\usepackage{titlesec}
\usepackage[section]{placeins}
\usepackage{xcolor}
\usepackage{breakcites}
\usepackage{lineno}
\usepackage{hyphenat}





\PassOptionsToPackage{hyphens}{url}
\usepackage[colorlinks = true,
            linkcolor = blue,
            urlcolor  = blue,
            citecolor = blue,
            anchorcolor = blue]{hyperref}
\usepackage{etoolbox}
\makeatletter
\patchcmd\@combinedblfloats{\box\@outputbox}{\unvbox\@outputbox}{}{%
  \errmessage{\noexpand\@combinedblfloats could not be patched}%
}%
\makeatother


\usepackage{natbib}




\renewenvironment{abstract}
  {{\bfseries\noindent{\abstractname}\par\nobreak}\footnotesize}
  {\bigskip}

\titlespacing{\section}{0pt}{*3}{*1}
\titlespacing{\subsection}{0pt}{*2}{*0.5}
\titlespacing{\subsubsection}{0pt}{*1.5}{0pt}


\usepackage{authblk}


\usepackage{graphicx}
\usepackage[space]{grffile}
\usepackage{latexsym}
\usepackage{textcomp}
\usepackage{longtable}
\usepackage{tabulary}
\usepackage{booktabs,array,multirow}
\usepackage{amsfonts,amsmath,amssymb}
\providecommand\citet{\cite}
\providecommand\citep{\cite}
\providecommand\citealt{\cite}
% You can conditionalize code for latexml or normal latex using this.
\newif\iflatexml\latexmlfalse
\providecommand{\tightlist}{\setlength{\itemsep}{0pt}\setlength{\parskip}{0pt}}%

\AtBeginDocument{\DeclareGraphicsExtensions{.pdf,.PDF,.eps,.EPS,.png,.PNG,.tif,.TIF,.jpg,.JPG,.jpeg,.JPEG}}

\usepackage[utf8]{inputenc}
\usepackage[ngerman,english]{babel}



\usepackage{float}








\begin{document}

\title{Effectiveness of prophylactic HPV vaccine for cervical abnormalities and
HPV infection in Japan: the Japanese Human Papillomavirus Disease
Education and Research Survey (J-HERS) 2021}



\author[1]{Toshiyuki Sasagawa}%
\author[1]{Yoshihiko Saeki}%
\author[2]{Takuya Irie}%
\author[3]{Fujiko Itoh}%
\author[4]{Akiko Enatsu}%
\author[5]{Hiroko Komura}%
\author[6]{Miho Fujii}%
\author[7]{Ryota Fujii}%
\author[8]{Natsuko Hidaka}%
\author[9]{Toshiyuki Maehama}%
\author[10]{Nobuhiko Shirasu}%
\author[11]{Tomoo Waseda}%
\author[1]{Takeo Shibata}%
\author[1]{EMI TAKATA}%
\author[1]{Kazuki Mibe}%
\author[1]{Jinichi Sakamoto}%
\author[12]{Sousuke Yamada}%
\author[1]{Masahiro Takakura}%
\affil[1]{Kanazawa Ika Daigaku Igakubu}%
\affil[2]{Ladies Clinic}%
\affil[3]{Kokusai Central Clinic}%
\affil[4]{Four Seasons Ladies Clinic}%
\affil[5]{Koumura Women’s Clinic}%
\affil[6]{Caress Sapporo Tokeidai Memorial Hospital}%
\affil[7]{Koyodai Clinic}%
\affil[8]{Aoba Women’s Clinic}%
\affil[9]{Yuuai Medical Center}%
\affil[10]{White Ladies Clinic}%
\affil[11]{Anju Ladies Clinic}%
\affil[12]{Kanazawa Ika Daigaku}%


\vspace{-1em}



  
  \date{June 15, 2024}


\begingroup
\let\center\flushleft
\let\endcenter\endflushleft
\maketitle
\endgroup





\selectlanguage{english}
\begin{abstract}
\textbf{Objective:} This study investigated the efficacy of the
prophylactic human papillomavirus (HPV) vaccine started at 2009- 2013 in
Japan. \textbf{Materials and Methods:} The study involved 1529 eligible
women aged 16 to 39 years who visited 11 outpatient clinics for various
reasons in Japan. All these patients underwent an examination of HPV
genotype and a Pap test using cervical cell samples. Two hundred
ninty-nine women (19.6\%) received the prophylactic HPV vaccine
(bivalent :quadrivalent vaccine ratio = 2:1). Of the 5062 participants
in the Japanese Human Papillomavirus Disease Education and Research
Survey (J-HERS 2011), which was conducted in the pre-vaccination era,
3236 eligible participants were included as controls. \textbf{Results:}
In the present study (J-HERS 2021), highest rate for HPV vaccination
(53\%) was observed in 22- to 27-year-old patients. Vaccinated ones
showed 49\% protection against low-grade intraepithelial lesions (LSIL)
and atypical squamous cells not excluding high-grade squamous
intraepithelial lesions (ASCH) or worse (LSIL/ASCH+), and 100\%
protection against high-grade squamous intraepithelial lesions (HSIL) or
worse (HSIL+). The prevalences of HPV16 and HPV18 infections also
significantly decreased (HPV16; 95\% and HPV18; 100\%), but there were
no differences in HPV6 and HPV11 infections by the vaccination. The
prevalences of HPV51 and HPV59 increased with vaccination, although
these changes were not confirmed in the comparative study with J-HERS
2011. Comparisons between the pre-vaccination period (J-HERS 2011) and
post-vaccination period (J-HERS 2021) revealed reduction rates of 43\%,
51\%, 88\%, and 62\% were observed for HPV16, HPV18, HPV16/18, and
HPV31/58 infections, respectively. Similarly, reduction rates of 62\%
and 71\% for LSIL/ASCH+ and HSIL+, respectively. The reduction rate for
LSIL/ASCH+ was 88\% in 16- to 21-year-old patients, whereas the rate for
HSIL+ was 87\% in 28- to 33-year-old patients. C \textbf{onclusion:}
Bivalent or quadrivalent vaccines provided 100\% protection against
high-grade squamous cell lesions (suggestive of CIN2 or CIN3) in young
women aged \textless{} 39 years at 9 to 12 years after initiation of the
first nationwide HPV vaccination program in Japan. Cross-protection
against HPV31 and HPV58 is likely to occur, although some HPV type
replacements are inconsistent across vaccination regimens. This
demonstrates a high effectiveness of HPV vaccine. In contrast, we worry
about no reduction of cervical cancer in younger generation (born in
1997-2007) who are rarely vaccinated due to long term suspension of this
vaccine recommendation in Japan.%
\end{abstract}%



\sloppy


\textbf{Introduction}

Cervical cancer has the fourth highest mortality (7.5\%) among all
cancers in women. Additionally, it has the third highest incidence rate
(7.9\%) (1). A trend for both the morbidity and mortality associated
with cervical cancer are increasing in Japan. An average number of the
incidence from 2016 to 2019 were 2816 (might be more than 3000 if
uterine cancer of unknown origin were accounted), and that of the
mortality from 2012 to 2021 were 2816 in Japan. The peak of age for the
incidence was 45-49 and 65-69 years old. Annual numbers of death of
women aged 20-49 years being in the reproductive age or are mothers
taking care of young children are 479 -- 656 (average was 503) in 2012
-- 2021. Therefore, many young women are suffered from cervical cancer,
and about one third (32\%) (2016-2021) annually die in Japan (2). The
increased prevalence of cervical cancer among young women appears to be
driven by social factors.

More than 90\% of cervical cancer cases are caused by human
papillomavirus (HPV) (3). Among more than 200 types of HPV identified
thus far, 13 to 14 are considered to cause cervical cancer; these types
are regarded as high-risk HPV types. Among them, HPV16 and HPV18 are the
most widespread; they have been identified in approximately 70\% of
women with cervical cancer in Western countries (4) and in 50\% to 68\%
of women with cervical cancer in Japan (5, 6). The World Health
Organization has declared that cervical cancer would be eliminated
within this century if 90\% of women received HPV vaccination, 70\%
underwent cervical cancer screening, and 90\% received treatment for
cervical premalignant lesions (7). Nationwide reductions in high-grade
cervical intraepithelial neoplasia (CIN2 and CIN3) after administration
of the bivalent vaccine were reported in Scotland (8). Additionally,
decreases in cervical cancer after bivalent or quadrivalent HPV
vaccination were reported in Australia (9), Sweden (10), and the United
Kingdom (11). The prevalences of cervical cancer caused by HPV16 and
HPV18 infections, which are targeted by any types of prophylactic HPV
vaccines, have considerably decreased in several countries (9, 12--16).
Cross-protection against HPV16- and HPV18-related types has been
suggested (9--16), but there has been no increase in infections caused
by non-vaccine HPV types (15, 16).

In Japan, the bivalent HPV vaccine was licensed in October 2009, and the
quadrivalent vaccine was licensed in July 2011 (Fig.1). A special
funding program with 50\% support from the Japanese government and 50\%
from local governments was implemented in October 2010 in Japan.
Beginning in April 2013, the bivalent and quadrivalent HPV vaccines were
both included in the Japanese National Immunization Program for girls
aged 12 to 16 years. However, after the Japanese media published
sensational reports of so-called ``diverse symptoms,'' the Japanese
Ministry of Health, Labour and Welfare suspended proactive
recommendations for the HPV vaccine in June 2013---only 2 months after
implementation of the national HPV vaccine program. Thereafter, vaccine
coverage dramatically decreased from \textgreater{} 70\% to \textless{}
1\% among girls eligible for free vaccination. The vaccine crisis from
2013 to 2019 is expected to result in an additional 24,600 to 27,300
cases and 5000 to 5700 deaths over the lifetime of cohorts born from
1994 to 2007, compared with a scenario where coverage remained at
approximately 70\% since 2013 (17). Beginning in April 2022, Japan
reinstated the recommendation for nationwide HPV vaccination (18).
Nevertheless, a substantial effort will be required in Japan to raise
vaccine coverage among girls aged 12 to 16 years and among women aged 16
to 26 years in 2023---these women belong to the catch-up generation born
between April 1, 1997 and April1, 2007. The vaccine coverage for this
age group must be improved from its previous level, which ranged from
68\% to 76\% (18).

Importantly, some women within this age group received bivalent or
quadrivalent prophylactic HPV vaccines in Japan. Therefore, several
studies have evaluated the efficacies of these vaccines (19--21).
Reductions in the prevalences of HPV16 and HPV18 after vaccination were
reported in Akita Prefecture, Japan (19). Reductions in the prevalences
of HPV31, HPV45, and HPV52 after vaccination were also observed in a
cross-sectional study of individuals in Niigata, Japan, suggesting
cross-protection against these types (21). Moreover, lower incidences of
CIN2/3 or adenocarcinoma in situ among patients who tested positive for
HPV16 or HPV18 were reported in a nationwide case--control study (22).

We previously conducted a population-based study to investigate the
prevalences of HPV and abnormal cytology from 2011 to 2013 in Japan
{[}Japanese HPV Disease Education and Research Survey (J-HERS){]} (23).
Here, we performed a similar study, the J-HERS 2021, to explore the
prevalences of HPV infection and cervical abnormalities after
implementation of the national HPV vaccination program. This is the
first Japanese study to investigate the efficacy of HPV vaccination in
reducing the prevalences of cervical abnormalities and HPV infection
through comparisons between pre-vaccination and post-vaccination
periods.

\textbf{Materials and methods}

\textbf{Patients}

Among 1534 patients who participated in this study from April 2021 to
November 2022, 1529 eligible women aged 16 to 39 years (mean age, 30.4 \selectlanguage{ngerman}±
5.5 years) underwent evaluation. The patients visited 11 outpatient
clinics (9 private clinics and 2 hospitals) in 7 districts in Japan
(Hokkaido, Tokyo, Kanagawa, Aichi, Ishikawa, Osaka, and Okinawa) for
various reasons. All patients provided written informed consent prior to
participation in this study. All medical facilities received approval to
participate from their respective independent ethics
committees/institutional review boards. This study was conducted in
accordance with the ethical guidelines for epidemiological research and
the ethical principles of the Declaration of Helsinki.

The present study was performed using the same approach implemented in
the J-HERS performed from October 2010 to March 2012 (21) (Fig. 1).
Therefore, the present study was designated ``J-HERS 2021'' and the
previous study was designated ``J-HERS 2011.'' The J-HERS 2011 study was
conducted concurrently with the Japanese national and local governments'
special HPV vaccination program, as depicted in Figure 1. Consequently,
a limited number of participants underwent vaccination during that
study. The interval between the periods included in these two studies
varied from 9 years 1 month to 12 years 1 month.

Analysis of HPV vaccination rates among J-HERS 2021 participants
revealed that the rate was highest among women aged 22 to 27 years.
Therefore, the following age groups were established in the present
study: 16 to 21, 22 to 27, 28 to 33, and 34 to 39 years. Women were
excluded if they had past or present malignant diseases, lacked a
uterus, or had no history of sexual intercourse. The reasons for the
patients' visits were as follows: cervical cancer screening; follow-up
for abnormal Pap test results, including diagnosis of CIN1/2; and
obstetrics or gynecology consultations including pregnancy diagnosis,
menstrual disorders, sexually transmitted infections, endometriosis,
adenomyoma, uterine leiomyoma, and benign ovarian cysts (Table 1).

We evaluated the age-adjusted data of the 5062 patients who participated
in the previous J-HERS 2011 study for comparison with the patient
population in the present study. We intended to assess the prevalences
of cervical lesions and HPV infection, thus enabling examination of HPV
vaccination effectiveness in the context of the nationwide HPV vaccine
program in Japan, 9 to 12 years after initial implementation. The age
distribution did not differ between the two studies; however, the rates
of visiting for CIN follow-up and obstetrics or gynecology consultations
were significantly higher in J-HERS 2011 than in J-HERS 2021. To avoid
bias related to the different backgrounds between the two studies, only
patients who visited for cervical cancer screening were included in the
analysis (J-HERS 2021, n = 1130; J-HERS 2011, n = 3236).

\textbf{Pap test, HPV test, and histological diagnosis of cervical
disease}

All patients underwent Pap tests and HPV tests using liquid-based
cytology samples. Scraped cell samples were collected with a
Cervex-Brush (Rovers Medical Devices, Oss, Noord-Brabant, The
Netherlands) and placed in liquid-based cytology solution. Sample
collection was performed by an experienced obstetrician or gynecologist.
Pap tests were performed according to the Bethesda system by
cytotechnologists, and the results were verified by pathologists.

Abnormal Pap test results included atypical squamous cells of
undetermined significance (ASCUS), atypical squamous cells not excluding
high-grade squamous intraepithelial lesions (ASCH), low-grade squamous
intraepithelial lesions (LSIL), high-grade squamous intraepithelial
lesions (HSIL), and squamous cell carcinoma. In Japan, women with
high-risk HPV type-positive ASCUS, ASCH, and LSIL or worse undergo
colposcopy; histological examination is performed based on the
colposcopy findings. Histological diagnosis in this study was based on
the World Health Organization classification. Pap test results was
evaluated in the present study, since histology data had not been
available. Abnormal cervical Pap test results were defined as LSIL or
ASCH or worse (LSIL/ASCH+) and HSIL or worse (HSIL+). HPV genotypes were
determined using Genosearch-31 (MBL Life Science, Tokyo, Japan), which
is a novel genotyping system based on the polymerase chain reaction
reverse sequence-specific oligonucleotides Luminex® method (Luminex,
Austin, TX, USA) with HPV type-specific primer pairs (21). This system
is able to detect 31 HPV genotypes (HPV6, 11, 16, 18, 26, 31, 33, 35,
39, 42, 44, 45, 51, 52, 53, 54, 55, 56, 58, 59, 61, 62, 66, 68, 70, 71,
73, 82, 84, 89, and 90). This test was performed in a commercial
laboratory (LSI Medience, Tokyo, Japan).

\textbf{Statistical analysis}

Prevalence data were analyzed using Fisher's exact probability test in
JMP 14 software (SAS Institute, Cary, NC, USA). P-values \textless{}
0.05 were considered statistically significant. Odds ratios (ORs) and
95\% confidence intervals (95\% CIs) were calculated using PRISM 9
software (MDF, Tokyo, Japan).

\textbf{Results}

\textbf{Characterization of patients in present study (J-HERS 2021)}

The age distribution of the included patients is shown in Table 1. Most
patients (74\%) visited the clinics for cervical cancer screening, 14\%
visited for examinations of abnormal cytology results or follow-up
regarding a history of CIN, and 12\% visited for common obstetrics and
gynecologic disorders or follow-up regarding benign diseases. Two
hundred and ninety-nine patients (20\%) underwent prophylactic HPV
vaccination (Table.1). Among them, 54 (19\%) received bivalent vaccines,
28 (10\%) received quadrivalent vaccines, 5 (1.8\%) received nonavalent
vaccines, and 191 (69\%) did not know the type of vaccine they had
received. There was no so much difference in the rate of HPV vaccination
according to the reason for the clinic visit (Table 1). Aveilable data
showed that 156 subjects (79\%) received the HPV vaccine at 12 to 16
years of age.

\textbf{Efficacies of prophylactic HPV vaccination for cervical
abnormalities and each type of HPV infection in J-HERS 2021}

None of the vaccinated patients had ASCH+ or HSIL+. Comparison with
unvaccinated patients suggested that the prevalences of ASCH+ and HSIL+
(CIN2 or 3) had both decreased by 100\% (Table 1). There was no
significant difference in LSIL (CIN1), although a marginally decreased
prevalence was observed for LSIL/ASCH+ (CIN1, 2) among vaccinated
patients versus unvaccinated patients.

Regarding cervical HPV infection, the prevalences of HPV16 and HPV18
were 0.33\% and 0.0\%, respectively, among vaccinated patients, while
those in unvaccinated were 6.6\% and 2.7\%, respectively (Fig. 2). This
finding suggests that HPV vaccination reduced the prevalence of HPV16 by
95\% (OR, 0.05; 95\% CI, 0.0047--0.273; P \textless{} 0.0001) and HPV18
by 100\% (OR, 0.00; 95\% CI, 0.000--0.458; P = 0.0013) among vaccinated
patients, compared with unvaccinated patients. The reduction rate of
either HPV16 or HPV18 (i.e., HPV16/18) was 97\% (OR, 0.03; 95\% CI,
0.0034--0.191, P\textless{}0.0001). In contrast, the prevalences
increased for HPV51 (OR, 2.14; 95\% CI, 1.23--3.64; P = 0.0086) and
HPV59 (OR, 3.73; 95\% CI, 1.77--7.54; P = 0.0006) (Fig. 2A). However,
there were no differences in other high-risk, probable high-risk, and
low-risk HPV types (Fig.2B), including HPV6 and HPV11 (Fig.2A), which
are the target types of the quadrivalent vaccine.

Among the different age groups, the prevalence of HPV16 significantly
decreased in the 22- to 27-year and 28- to 33-year age groups after
vaccination, whereas the prevalence of HPV18 infection decreased, but
not significant in any age group (Fig. 3). The prevalence of HPV58
increased in the vaccinated 22- to 27-year age group (P = 0.0189), and
the prevalence of HPV59 increased in the 28- to 33-year age group (P =
0.0025). No difference in the prevalences of HPV51 were observed in any
age group.

\textbf{Changes in the prevalences of cervical cell abnormalities and
HPV infection between pre-vaccination and post-vaccination periods in
Japan}

We compared the prevalences of cervical abnormalities and HPV infection
between the J-HERS 2011 and J-HERS 2021 study periods. The nationwide
HPV vaccination program supported by both the Japanese national and
local governments was implemented in the same period as the start of
J-HERS 2011 (Fig. 1); the time interval between this period and the
present study (J-HERS 2021) was \textasciitilde{}10 years (range: 9
years 1 month to 12 years 1 month) (Fig. 1). There was no difference in
age distribution between the two studies (Table 2). The HPV vaccination
rate in J-HERS 2011 ranged from 3.6\% to 6.1\% (average, 4.9\%), whereas
the rate in the present study (J-HERS 2021) ranged from 3.8\% to 53.0\%
(average, 20.0\%) (Fig. 2). This finding suggests that HPV vaccine
coverage was higher among J-HERS 2021 participants. In the J-HERS 2021
study, HPV vaccine coverage was highest in the 22- to 27-year age group;
in the J-HERS 2011 study, coverage did not differ among age groups (Fig.
2).

Significant reductions in LSIL (OR, 0.22), LSIL/ASCH+ (OR, 0.38) and
HSIL+ (OR, 0.28) were observed in J-HERS 2021 compared with J-HERS 2011
(Table 2), suggesting that HPV vaccination reduced LSIL by 78\%,
LSIL/ASCH+ by 62\% and HSIL+ by 72\% for 10 years after implementation
of the national HPV vaccination program. Significant reductions were
confirmed in 22- to 27-year and 28- to 33-year for LSIL (ORs of 0.13 and
0.13, respectively), the 16- to 21-year, 22- to 27-year, and 28- to
33-year age groups for LSIL/ASCH+ (ORs of 0.12, 0.18, and 0.25,
respectively), and the OR for HSIL+ was 0.12 in the 28- to 33-year age
group (Table 2). These findings suggest that HPV vaccination reduced
LSIL by 87\% in 22- to 27-year and 28- to 33-year age grops, LSIL/ASCH+
by 88\%, 82\%, and 74\% in the 16- to 21-year, 22- to 27-year, and 28-
to 33-year age groups; it reduced HSIL+ by 88\% in the 28- to 33-year
age group.

The comparison of HPV genotypes between J-HERS 2011 and J-HERS 2021 also
revealed decreased prevalences of HPV16, HPV18, HPV31, and HPV58
infection, as well as a marginal reduction in HPV52 infection (Fig. 4A).
There were no differences in HPV6 or HPV11, which are the target types
for the quadrivalent HPV vaccine. The prevalence of high-risk HPV
infection also decreased, but there were no differences in the
prevalences of probable high-risk or low-risk HPV types (Fig.4B).

The reduction rates of HPV16 and HPV18 in J-HERS 2021 were 43\% and
51\%, respectively; the ORs were 0.57 (95\% CI, 0.399--0.799) for HPV16
and 0.49 (95\% CI, 0.265--0.899) for HPV18. The reduction rate of either
HPV16 or HPV18 (i.e., HPV16/18) was 44\% (OR, 0.56; 95\% CI,
0.408--0.756), whereas the rate for HPV31/58 was 42\% (OR, 0.58; 95\%
CI, 0.558--0.863). Among 22- to 27-year-old patients (who had the
highest vaccination rate), the reduction rates were 88\% for HPV16/18
(OR, 0.12; 95\% CI, 0.045--0.299) and 62\% for HPV31/58 (OR, 0.38; 95\%
CI, 0.208--0.702).

\textbf{Discussion}

A retrospective population-based study of a bivalent HPV vaccine in
Scotland showed reduction rates of 89\% for CIN3 or worse, 88\% for CIN2
or worse, and 79\% for CIN1 (12). Younger age at vaccination was
associated with increasing vaccine effectiveness: 86\% for CIN3 or worse
among girls vaccinated at age 12 to 13 years compared with 51\% among
girls vaccinated at age 17 years. Nationwide data demonstrated that the
incidence and mortality of cervical cancer were reduced by more than
half in 2014 and 2015, respectively, in Australia, where the national
HPV vaccine program (quadrivalent vaccine) began in 2007 for girls aged
12 to 13 years (13). Nationwide registry data regarding cervical cancer
in Sweden demonstrated that the age-adjusted incident ratio of
vaccinated women (quadrivalent vaccine) compared with unvaccinated women
was 0.57, whereas the ratio adjusted for other demographic variables
(adjusted incident ratio) was 0.37 (14). Intriguingly, the adjusted
incident ratio in women vaccinated before 17 years of age was 0.12,
whereas it was 0.47 in women vaccinated between 17 and 30 years of age.
This result suggests that younger age at vaccination increases efficacy,
as indicated by reduction rates of 88\% (\textless{} 17 years of age)
and 53\% (17--30 years of age). The efficacy of HPV vaccination
(bivalent vaccine) was also observed in the United Kingdom, where the
estimated relative reductions in cervical cancer rates according to age
at vaccination were 34\% for 16 to 18 years, 62\% for 14 to 16 years,
and 87\% for 12 to 13 years. The corresponding risk reductions of CIN3
according to age at vaccination were 39\% for 16 to 18 years of age,
75\% for 14 to 16 years of age, and 97\% for 12 to 13 years of age.

The present study is the first to show high efficacy of prophylactic HPV
vaccination, demonstrating 100\% protection against HPV18 and 95\%
against HPV16 in Japan (Table 1). Similar reductions were found in
Scotland (13), and efficacies of 75\% and 81\% for CIN2+ and CIN3+,
respectively, were found in the other Japanese study (18). Most patients
in the present study received the HPV vaccine at 12 to 16 years of age
(156/198, 79\%), suggesting that vaccination at a younger age is
important for efficacy.

In the present study, a reduction in abnormal cervical cytology among
vaccinated patients was confirmed by a decrease in prevalence during the
9 to 12 years after vaccination (i.e., the J-HERS 2021 period) (Table
2). Population-based reductions of 78\%, 62\% and 72\% were observed for
LSIL, LSIL/ASCH+ and HSIL+, respectively. Age-dependent reductions of
87\% were also observed for LSIL in 22- to 33-year-old patients, 74\% to
88\% for LSIL/ASCH+ in 16- to 33-year-old patients, and a reduction of
87\% was observed for HSIL+ in 28- to 33-year-old patients (Table 2).
The reduction rates of HSIL after vaccination are higher than expected
because the prevalences of HPV16- and HPV18-related CIN3 in Japanese
women reportedly range from 25\% to 45\% (5, 6).

In the present study, the reduction rates of HPV16 and HPV18 infection
were 95\% and 100\%, respectively, among vaccinated patients. These
findings clearly demonstrate that the bivalent or quadrivalent vaccine
is highly protective against HPV16 or HPV18 infection in vaccinated
Japanese women aged \textless{} 39 years. Population-based reductions of
HPV16 and HPV18 infection were also confirmed by comparison between
patients in J-HERS 2021 and J-HERS 2011 for 9 to 12 years after
implementation of the national HPV vaccination program (Fig. 5).
However, significant (for HPV31 and HPV58) and marginal (HPV52)
decreases in prevalence were observed in J-HERS 2021, compared with
J-HERS 2011. When we evaluated these HPV types according to age, we
found that the prevalences of HPV16, HPV18, HPV31 and HPV58 decreased in
the 22- to 27-year age group, whereas the prevalence of HPV52 decreased
in the 16- to 21-year age group (Fig. 5). The decreases in HPV31 and
HPV58 infections may have been related to cross-protection from the
bivalent or quadrivalent vaccines because the decreases occurred in the
22- to 27-year age group, which had the highest vaccination rate.
However, no explanation was found for reduction of HPV52 in the 16- to
21- year group (Fig. 5). Previous studies have revealed cross-protection
from bivalent and quadrivalent vaccines for HPV16-related (HPV31, HPV33)
and HPV18-related (HPV45) types in European countries (12, 13) and
HPV16-related (HPV31, HPV52) and HPV18-related (HPV45) types in a
Japanese study (21). Other studies demonstrated that cross-protection
from these vaccines is more likely for HPV16-related types (HPV31) than
for HPV18-related types (HPV45) (14--16). Our data may support a
decrease in HPV16-related types (HPV31) after HPV vaccination (14--16),
but not a decrease in HPV18-related types (HPV45) (12, 13, 21). HPV52
and HPV58 are the most common high-risk HPV types in Japan (5, 6).
Therefore, reductions of these types are reasonable and would be welcome
among the Japanese population. In the present study, the
population-based reduction rate of HPV16 or HPV18 (HPV16/18) in all
patients after vaccination was 44\%, whereas the rate of
cross-protection against HPV31 or HPV58 (HPV31/58) was 42\%.
Additionally, the reduction rates were 88\% for HPV16/18, 62\% for
HPV31/58 and 67\% for HPV16/18/31/58 among 22- to 27-year-old patients;
these patients had the highest rate (53\%) of HPV vaccination. These
results suggest that protection against HPV16/18 and cross-protection
against HPV31/58 may both contribute to reductions of high-grade
cervical lesions in Japan.

Notably, vaccination had no effect on the prevalences of HPV6 and HPV11
in the present study. This result may have been related to the lower
rate of vaccination with the quadrivalent vaccine than with the bivalent
vaccine (bivalent: quadrivalent vaccine = 2:1) at the start of the
national HPV vaccination program. The lower prevalences of cervical HPV6
(n = 30) and HPV11 (n = 5) infections than HPV16 (n = 82) and HPV18 (n =
33) infections may be another reason, limiting the statistical power.
Increasing prevalences of HPV51 and HPV59 were observed among vaccinated
patients in the present study; however, these changes were not confirmed
in the comparative study between J-HERS 2011 and J-HERS 2021.
Furthermore, there was no increase for HPV51 and HPV59 among 22-to
27-year age group who were highly vaccinated (Fig.3). Such inconsistent
results do not support the notion of HPV type replacement according to
HPV vaccination, contrary to previous studies (14--16). Analyses of
larger numbers of patients are needed to obtain more definitive
conclusions.

\textbf{Funding}

This study was supported in part by a research grant from the
Investigator-Initiated Studies Program of Merck Sharp \& Dohme, LLC. The
opinions expressed in this paper are those of the authors and do not
necessarily represent the opinions of Merck Sharp \& Dohme, LLC.

\textbf{Figure legends}

\textbf{Fig. 1. Schematic presentation for background of this study}

\textbf{Fig. 2. The prevalence of HPV type (A) and HPV risk-group (B) in
HPV-vaccinated and unvaccinated subjects}

\#; Statistically marginal different; 0.05\textless{}P\textless{}0.1

\textbf{Fig. 3. The prevalence of HPV type in HPV-vaccinated and
unvaccinated subjects in different age groups}

\textbf{Fig. 4. The prevalence of HPV type (A) and HPV risk-group (B) in
J-HERS2011 and J-HERS2021}

\#; Statistically marginal different; 0.05\textless{}P\textless{}0.1

\textbf{Fig. 5. The prevalence of HPV type for age-group in J-HERS2011
nnd J-HERS2021}

\#; Statistically marginal different; 0.05\textless{}P\textless{}0.1

\textbf{References}

\begin{enumerate}
\tightlist
\item
  Ferlay J, Soerjomataram I, Dikshit R, Eser S, Mathers C, Rebelo M,
  Parkin DM, Forman D, Bray F. Cancer incidence and mortality worldwide:
  Sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer
  2015; 136: 359--86.
\item
  National Cancer Center Cancer Control Information in Japan.
  https://ganjoho.jp/reg\_stat/statistics/stat/cancer/17\_cervix\_uteri.html
\item
  Crosbie EJ, Einstein MH, Franceschi S, Kitchener HC. Human
  papillomavirus and cervical cancer. Lancet 2013; 382: 889--99.
\item
  Small W Jr, Bacon MA, Bajaj A, Chuang LT, Fisher BJ, Harkenrider MM,
  Jhingran A, Kitchener HC, Mileshkin LR, Viswanathan AN, Gaffney DK.
  Cervical cancer: A global health crisis. Cancer 2017; 123: 2404--12.
\item
  Sakamoto J, Kamiura S, Okayama K, Okodo M, Shibata T, Osaka Y, Fujita
  S, Takata E, Takagi H, Takakura M, Sasagawa T. Single type infection
  of human papillomavirus as a cause for high-grade cervical
  intraepithelial neoplasia and invasive cancer in Japan. Papillomavirus
  Res 2018; 6: 46--51.
\item
  Onuki M, Yamamoto K, Yahata H, Kanao H, Yokota H, Kato H, Shimamoto K,
  Takehara K, Kamiura S, Tsuda N, Takei Y, Shigeta S, Matsumura N,
  Yoshida H, Motohara T, Watari H, Nakamura K, Ueda A, Tasaka N,
  Ishikawa M, Hirashima Y, Kudaka W, Taguchi A, Iwata T, Takahashi F,
  Kukimoto I, Yoshikawa H, Yaegashi N, Matsumoto K; MINT Study Group.
  Human papillomavirus vaccine effectiveness by age at first vaccination
  among Japanese women. Cancer Sci 2022; 113: 1428--34.
\item
  WHO. A cervical cancer-free future: First-ever global commitment to
  eliminate a cancer. 17 November 2020
\item
  Palmer T, Wallace L, Pollock KG, Cuschieri K, Robertson C, Kavanagh K,
  Cruickshank M. Prevalence of cervical disease at age 20 after
  immunisation with bivalent HPV vaccine at age 12-13 in Scotland:
  Retrospective population study. BMJ 2019; 365: l1161.
  https://doi.org/10.1136/bmj.l1161
\item
  Patel C, Brotherton JM, Pillsbury A, Jayasinghe S, Donovan B,
  Macartney K, Marshall H. The impact of 10 years of human
  papillomavirus (HPV) vaccination in Australia: What additional disease
  burden will a nonavalent vaccine prevent? Euro Surveill 2018; 23:
  pii=1700737. https://doi.org/10.2807/15607917
\item
  Lei J, Ploner A, Elfström KM, Wang J, Roth A, Fang F, Sundström K,
  Dillner J, Sparén P. HPV vaccination and the risk of invasive cervical
  cancer. N Engl J Med 2020; 383: 1340--8.
  https://doi.org/10.1056/NEJMoa1917338
\item
  Falcaro M, Castañon A, Ndlela B, Checchi M, Soldan K, Lopez-Bernal J,
  Elliss-Brookes L, Sasieni P. The effects of the national HPV
  vaccination programme in England, UK, on cervical cancer and grade 3
  cervical intraepithelial neoplasia incidence: A register-based
  observational study. Lancet 2021; 398:
  2084--92.\emph{https://doi.org/10.1016/S0140-6736(21)02178-4}
\item
  Drolet M, Bénard É, Boily MC, Ali H, Baandrup L, Bauer H, Beddows S,
  Brisson J, Brotherton JM, Cummings T, Donovan B, Fairley CK, Flagg EW,
  Johnson AM, Kahn JA, Kavanagh K, Kjaer SK, Kliewer EV,
  Lemieux-Mellouki P, Markowitz L, Mboup A, Mesher D, Niccolai L,
  Oliphant J, Pollock KG, Soldan K, Sonnenberg P, Tabrizi SN, Tanton C,
  Brisson M. Population-level impact and herd effects following human
  papillomavirus vaccination programs: A systematic review and
  meta-analysis. Lancet Infect Dis 2015; 15: 565--80.
  https://doi.org/10.1016/S1473-3099(14)71073-4
\item
  Donken R, King AJ, Bogaards JA, Woestenberg PJ, Meijer CJLM, de Melker
  HE. High effectiveness of the bivalent human papillomavirus (HPV)
  vaccine against incident and persistent HPV infections up to 6 years
  after vaccination in young Dutch women. J Infect Dis 2018; 217:
  1579--89. https://doi.org/10.1093/infdis/jiy067
\item
  Gargano JW, McClung N, Lewis RM, Park IU, Whitney E, Castilho JL,
  Pemmaraju M, Niccolai LM, Brackney M, DeBess E, Ehlers S, Bennett NM,
  Scahill M, Cleveland AA, Querec TD, Unger ER, Markowitz LE; HPV-IMPACT
  Working Group. HPV type-specific trends in cervical precancers in the
  United States, 2008 to 2016. Int J Cancer 2023; 152: 137--50.
  https://doi.org/10.1002/ijc.34231
\item
  Covert C, Ding L, Brown D, Franco EL, Bernstein DI, Kahn JA. Evidence
  for cross-protection but not type-replacement over the 11 years after
  human papillomavirus vaccine introduction. Hum Vaccin Immunother 2019;
  15: 1962--9. https://doi.org/10.1080/21645515.2018.1564438
\item
  Saccucci M, Franco EL, Ding L, Bernstein DI, Brown D, Kahn JA.
  Non-vaccine-type human papillomavirus prevalence after vaccine
  introduction: No evidence for type replacement but evidence for
  cross-protection. Sex Transm Dis 2018; 45: 260--5.
  https://doi.org/10.1097/OLQ.0000000000000731
\item
  Simms KT, Hanley SJB, Smith MA, Keane A, Canfell K. Impact of HPV
  vaccine hesitancy on cervical cancer in Japan: A modelling study.
  Lancet Public Health 2020; 5: e223--34. https://doi.org/10.1016/S2468
  2667(20)30010-4
\item
  Information of HPV-vaccine program from April 2022; Ministry of
  Health, Labour and Welfare, Japan.
  https://www.mhlw.go.jp/content/10906000/000911549.pdf
\item
  Karube A, Saito F, Nakamura E, Shitara A, Ono N, Konno M, Tamura D,
  Nagao D. Reduction in HPV 16/18 prevalence among young women following
  HPV vaccine introduction in a highly vaccinated district, Japan,
  2008-2017. J Rural Med 2019; 14: 48--57.
  https://doi.org/10.2185/jrm.2986
\item
  Ikeda S, Ueda Y, Hara M, Yagi A, Kitamura T, Kitamura Y, Konishi H,
  Kakizoe T, Sekine M, Enomoto T, Sobue T. Human papillomavirus vaccine
  to prevent cervical intraepithelial neoplasia in Japan: A nationwide
  case-control study. Cancer Sci 2021; 112: 839--46.
  https://doi.org/10.1111/cas.14682
\item
  Kudo R, Yamaguchi M, Sekine M, Adachi S, Ueda Y, Miyagi E, Hara M,
  Hanley SJB, Enomoto T. Bivalent human papillomavirus vaccine
  effectiveness in a Japanese population: High vaccine-type-specific
  effectiveness and evidence of cross-protection. J Infect Dis 2019;
  219: 382--90. https://doi.org/10.1093/infdis/jiy516
\item
  Matsumoto K, Yaegashi N, Iwata T, Yamamoto K, Aoki Y, Okadome M,
  Ushijima K, Kamiura S, Takehara K, Horie K, Tasaka N, Sonoda K, Takei
  Y, Aoki Y, Konnai K. Reduction in HPV16/18 prevalence among young
  women with high-grade cervical lesions following the Japanese HPV
  vaccination program. Cancer Sci 2019; 110: 3811--20.
  https://doi.org/10.1111/cas.14212
\item
  Sasagawa T, Maehama T, Ideta K, Irie T; Fujiko Itoh J-HERS Study
  Group. Population-based study for human papillomavirus (HPV) infection
  in young women in Japan: A multicenter study by the Japanese human
  papillomavirus disease education research survey group (J-HERS). J Med
  Virol 2016; 88: 324--35.
\end{enumerate}

The English in this document has been checked by at least two
professional editors, both native speakers of English. For a
certificate, please
see:\emph{http://www.textcheck.com/certificate/1v9Kxo}

\textbf{Hosted file}

\verb`J-HERS Fig final2 BW.pptx`  available at \url{https://authorea.com/users/676526/articles/674042-effectiveness-of-prophylactic-hpv-vaccine-for-cervical-abnormalities-and-hpv-infection-in-japan-the-japanese-human-papillomavirus-disease-education-and-research-survey-j-hers-2021}

\textbf{Hosted file}

\verb`Tables-final.xlsx`  available at \url{https://authorea.com/users/676526/articles/674042-effectiveness-of-prophylactic-hpv-vaccine-for-cervical-abnormalities-and-hpv-infection-in-japan-the-japanese-human-papillomavirus-disease-education-and-research-survey-j-hers-2021}

\selectlanguage{english}
\FloatBarrier
\end{document}

