Effects of different educational interventions on cervical cancer knowledge and human papillomavirus vaccination uptake among young women in Japan: Preliminary results of a cluster randomized controlled trial

Yuko Takahashi; Yukifumi Sasamori; Risa Higuchi; Asumi Kaku; Tomoo Kumagai; Saya Watanabe; Miki Nishizawa; Kazuki Takasaki; Haruka Nishida; Takayuki Ichinose; Mana Hirano; Yuko Miyagawa; Haruko Hiraike; Koichiro Kido; Hirono Ishikawa; Kazunori Nagasaka

doi:10.1371/journal.pone.0311588

. 2025 Jan 7;20(1):e0311588. doi: 10.1371/journal.pone.0311588

Effects of different educational interventions on cervical cancer knowledge and human papillomavirus vaccination uptake among young women in Japan: Preliminary results of a cluster randomized controlled trial

Yuko Takahashi ¹, Yukifumi Sasamori ¹, Risa Higuchi ¹, Asumi Kaku ¹, Tomoo Kumagai ¹, Saya Watanabe ¹, Miki Nishizawa ¹, Kazuki Takasaki ¹, Haruka Nishida ¹, Takayuki Ichinose ¹, Mana Hirano ¹, Yuko Miyagawa ¹, Haruko Hiraike ¹, Koichiro Kido ¹, Hirono Ishikawa ², Kazunori Nagasaka ^1,^*

Editor: Lucy W Kivuti-Bitok³

PMCID: PMC11706404 PMID: 39774513

Abstract

The incidence and mortality rates of cervical cancer are increasing among young Japanese women. In November 2021, the Japanese Ministry of Health, Labour, and Welfare reinstated the active recommendation of the human papillomavirus (HPV) vaccine, after it had been suspended in June 2013 due to reports of adverse reactions. However, vaccine hesitancy is prevalent in the younger generation in Japan. To identify obstacles to vaccine uptake, we conducted a randomized study using different methods to provide educational content to improve health literacy regarding cervical cancer and HPV vaccination among Japanese female students. We surveyed 188 Japanese female students, divided into three groups according to the intervention: no intervention, print-based intervention, and social networking service-based intervention. Twenty questionnaires and the Communicative and Critical Health Literacy scales were used as health literacy scales. Participants’ knowledge and health literacy improved regardless of the method of education. In fact, participants acquired proper knowledge when given the opportunity to learn about the importance of the disease and its prevention. Therefore, medical professionals in Japan must provide accurate scientific knowledge regarding routine HPV vaccination and the risk of cervical cancer in young women to improve their health literacy and subsequently increase HPV vaccination rates in Japan, which may lead to cervical cancer elimination.

Trial registration number: UMIN000036636.

Introduction

Cervical cancer is the fourth most common cancer among women globally, with an estimated 604,000 new cases and 342,000 deaths reported in 2020 [1]. Cervical cancer is the 10^th most common cancer among women in Japan and the second most common among women aged 15–44 years [2]. Human papillomavirus (HPV) causes cervical as well as vaginal, vulvar, and head and neck cancers [3–7].

The Japanese government approved the HPV vaccine in October 2009. Public funding was provided for HPV vaccination in April 2013, targeting students from the sixth grade of elementary school to the first year of high school (approximately aged 11–16 years, in accordance with the World Health Organization recommendation) as a project to promote emergency measures for vaccination against cervical cancer [8]. However, the government withdrew its active recommendation for the vaccine on June 14, 2013, due to reports of post-vaccination adverse reactions, such as chronic pain and motor dysfunction [9]. Consequently, although the HPV vaccination rate for girls born between 1994 and 1999, who were eligible for vaccination during the public subsidy period, reached approximately 70%, it declined markedly for girls born after 2000; the rate plummeted to below 1% for those born after 2002 [10–13].

The Japanese Ministry of Health, Labour, and Welfare (MHLW, Tokyo, Japan) reinstated the official active recommendation for HPV vaccination in November 2021. In addition, a catch-up HPV vaccination program was launched in April 2022 for women who missed the HPV vaccination opportunity. Nevertheless, without improved health literacy on cervical cancer and the HPV vaccine, young women are less likely to receive vaccination [12, 14–16]. Awareness regarding the risk of cervical cancer should be raised, and people should be educated on the benefits of vaccination to overcome this issue [17–20]. Social media interventions may or may not improve vaccine uptake. Some studies have indicated that increased awareness is not always related to increased vaccine uptake [21–23]. Cooper et al. [24] demonstrated that various digital interventions, including those using social media, have been developed over the past decade to enhance vaccine acceptance and uptake. In low socioeconomic status (SES) families, the campaign reduced uptake by 10%, whereas in low-medium SES families, uptake increased by 6% [25]. HPV promotion campaigns on social media might be a double-edged sword, depending on the target population [25]. Despite the tremendous advantage of implementing HPV vaccination programs for young women, there has been insufficient progress in addressing this issue worldwide, including in Japan.

Therefore, we used different health information delivery methods to enhance the understanding of cervical cancer and HPV vaccination. To the best of our knowledge, this is the first randomized trial to examine whether knowledge and HPV vaccination rates increased after presenting HPV information.

Materials and methods

Study design

This study, conducted in our laboratory at Teikyo University between May 1, 2019, and March 31, 2024, implemented a cluster, randomized, parallel cluster randomized group trial involving three groups: Group 1, no intervention (control); Group 2, print-based educational intervention; and Group 3, social networking service (SNS)-based educational intervention. These groups were compared to identify potential educational effects (S1 Fig). The study employed cluster-level randomization; however, due to factors such as the small sample size and the non-randomized recruitment process, the design does not fully conform to the characteristics of a traditional randomized controlled trial (RCT). Despite these limitations, the design was chosen to assess the effectiveness of the interventions while considering ethical constraints and practical challenges.

Study settings and participants

This study enrolled students from 17 private universities (S2 Fig). Students were assured that study participation was voluntary and would not interfere with their academic activities. We included female students aged 18–26 years who could access and use print-based or SNS-based educational programs and complete the follow-up questionnaire comprising 20 questions and the Communicative and Critical Health Literacy (CCHL) scale. We excluded students who experienced mental and physical challenges during the study. According to the research protocol, students with mental or physical challenges were to be excluded. However, in practice, the study only included students who volunteered to participate, and no students with psychological or physical difficulties were actually enrolled. This exclusion criterion did not affect the study’s outcome, as no participants in the study were found to meet this criterion. The universities were selected based on logistical considerations and feasibility. While the focus on private universities facilitated recruitment and ensured voluntary participation, this choice may limit the generalizability of the findings. Due to funding constraints and logistical challenges, the recruitment pool was not expanded beyond these institutions.

Estimation of the participant number required

The proportion of high health literacy in the competing hypotheses was P1 (intervention group) = 0.60 and P2 (control group) = 0.30, indicating a significant difference between the groups. The within-class correlation, mean cluster size, two-sided significance level, and power were 0.100, 200, 0.05, and 0.80, respectively.

Intervention

Medical information and educational tools on cervical cancer and HPV vaccination were developed by the principal investigator and distributed to the female students every 6 months. Students were randomly assigned to three arms: arm 1, no intervention (control); arm 2, information was mailed in an envelope containing print-based educational material; and arm 3, information was distributed through electronic materials on websites using social networking sites (LINE, Facebook, and Twitter) (S1 Fig). Students in all three arms were followed up for 15 months, during which, interventions in arms 2 and 3 were conducted three times at 6-month intervals. At the time of recruitment, it was explained to participants that if they were assigned to arm 1, they would only be registered to participate and would not be provided with any information.

Allocation method

Allocators prepared an allocation table using stratified block randomization with medical and non-medical institutions (Teikyo University and Teikyo Institute of Advanced Nursing Studies, Tokyo, Japan, along with Teikyo Heisei University, Tokyo, Japan) as two stratification factors. The study was an open-label randomized trial, indicating that both allocators and participants were aware of group assignments.

Data collection

A questionnaire was sent to individuals randomly allocated across the no intervention, print-based educational intervention, and SNS-based educational intervention groups at baseline. All groups received the subsequent survey questionnaires via email, including a questionnaire regarding affiliation, age, diet, HPV vaccination history, the presence of a family healthcare provider, smoking habits, voluntary exercise, physician visits, and routine and HPV vaccinations (S1 Method), as well as a questionnaire regarding knowledge about cervical cancer (S1 Table). In total, five surveys were administered during the study period.

Measurements

For the questionnaire about knowledge regarding cervical cancer (S1 Table), "0" was set for the answer "I know" and "1" for "I did not know," and the total score of the 20 items was used as the objective number. Health literacy was measured using the CCHL scale (S2 Table). This scale measures health literacy beyond the functional level, focusing on the ability to access, understand, and use health information; its reliability and validity have been previously confirmed [26]. Participants responded to five questions on the CCHL scale, with scores ranging from 1 (very easy) to 5 (very difficult), focusing on HPV vaccination and cervical cancer screening. The within-individual health literacy score was calculated as the mean of the scores for these five questions. A score of ≤3 was considered ’highly health literate’ because it represented participants who had significant knowledge within both groups. The number of participants classified as “high” and “low” will be approximately half at the time of the first survey. As the total number of participants was smaller than expected, we considered it would be difficult to find significant between-group differences if the participant number was skewed toward one group or the other. On the CCHL scale, the average of the 1–5 rating scale was used as another objective rating figure.

Outcomes

Outcome measures pertained to the cluster level and individual participant level.

Primary outcome

The primary outcome was increased knowledge regarding susceptibility to cervical cancer, disease severity, and the benefits of vaccination, as assessed using the reliable and valid health belief model [26]. The primary endpoint was the proportion of participants with high health literacy scores immediately after the delivery of the third educational session at 12 months.

Secondary outcome

We investigated how participant backgrounds and family environments affected the sum of their questionnaire responses regarding knowledge of cervical cancer and the mean value of the CCHL scale score.

Efforts to avoid possible sources of bias

Bias may have been introduced due to the self-selection of survey participants. Thus, we asked all students to enter this research voluntarily through a public post in the university or other notices, such that every student had access to the information. To avoid biases related to student environments, the allocation of participants to the three groups was conducted using an allocation table.

Main analysis

A mixed-effect logistic model was used for data analysis, with the dichotomous variable indicating high or low health literacy serving as the outcome variable. The model calculated the odds ratio to determine the effect of the intervention on high health literacy, considering various factors, including the experimental group, institution, and medical and non-medical background as population effects, and cluster as the variable effect. An odds ratio that was significantly higher than 1 indicated that the intervention positively influenced health literacy. Age and prior knowledge were optional adjustment factors that could be incorporated into the model based on the discretion of the statistical analyst and principal investigator. A significance level of 0.05 was set for all statistical tests. The one-way analysis of variance was performed for continuous variables, and the Chi-square test was performed for categorical variables in the subgroup analysis. For the sub-analysis, we examined the literacy level in each cluster by collecting the total scores of the first 20 questionnaires returned for each cluster in the first survey. In the questionnaires, participants responded with “Yes, I know,” or “No, I don’t know” to each item, which were scored as 0 or 1, respectively. These scores were summed; a lower total score indicated that the respondents were more knowledgeable about HPV, cervical cancer, and HPV vaccination. It is important to note that, unlike typical scoring systems where higher scores reflect better knowledge, in this study, a lower score reflects higher knowledge. Statistical analyses were performed using JMP Pro version 17.0.0 (SAS Institute Inc., Cary, NC, USA).

Ethical considerations

This study was approved by the Institutional Review Board of Teikyo University (protocol code 18-195-3; date of approval: March 22, 2019). Although a data-monitoring committee was not deemed necessary for this feasibility study, as we did not anticipate any adverse events, any unintended consequences of the interventions were diligently recorded. All students and their parents provided written informed consent before participation.

Results

Participant selection

Overall, 15,400 young female students were targeted and recruited to participate in the study. Consequently, due to student behavioral restrictions at the university, 267 participants met the eligibility criteria and 79 did not; thus, the data of 188 participants were included in the analyses. The invitation to participate was only posted in front of the educational affairs division due to the challenge of making direct contact with students.

Participant characteristics

Of the 267 participants, 188 completed all questionnaires 3 times (S3 Table). The mean age was 21 (standard deviation 1.67) years. Participant affiliations included Nursing (27.1%), Medicine (23.9%), Pharmaceutical (20.7%), Medical technology (14.9%), Literature (8.0%), Economics (2.7%), Law (1.6%), Foreign Language (0.5%), and Science and Technology (0.5%). Those who had any medical professionals in their family accounted for 38.3%. Non-smokers accounted for 98.8%, and 67.6% were aware of the importance of a balanced diet. Regarding exercise frequency, 60.6% did not exercise, and 15.4%, 19.7%, and 2.66% exercised once a week, two or three times a week, and daily, respectively. A total of 80.3% had not consulted an obstetrician or gynecologist before; 81.9% had routine vaccinations conducted in accordance with Japanese law; 56.9% had not been vaccinated for HPV; and 9.6%, 7.4%, and 25.5% had received an HPV vaccination once, twice, and thrice, respectively.

Questionnaire

Each participant was randomly assigned to one of three groups. Questionnaires were sent out at enrolment (baseline) in the manner assigned to the groups. The survey was conducted in three rounds, and the results from the 141 participants who completed all three rounds are presented in S4 Table. Responses to Item 11 in the questionnaire indicated a significant improvement in the participants’ knowledge. Specifically, participants became more aware that malignant findings in the cervix and procedures including conization could increase the risk of imminent miscarriage and premature birth. The responses to Item 16 also illustrated a significant improvement in understanding regarding the efficiency of “catch-up vaccination.”

However, responses to Items 2 and 8 demonstrated that a lower percentage of participants had knowledge of HPV types, including high-risk HPV, and the mortality rate of cervical cancer in both the first and third surveys than in the others, indicating that students had difficulty finding the exact figures related to cervical cancer (S5 Table). Despite the common belief that early detection of cervical lesions is necessary for treatment, surprisingly, approximately half of the participants were unaware of the perinatal risks associated with surgery involving the uterus.

CCHL scale

The CCHL scale results are presented in Table 1. There were no inquiries from participants about the questions. In the first and second survey rounds, most students rated the five items on the scale as “easy” or “slightly easy.” However, many students responded “very difficult” to Items 3 and 4, which were related to being able to understand and communicate information related to the HPV vaccine and cervical cancer screening to others and being able to determine which information is reliable or not.

Table 1. Results of the Communicative and Critical Health Literacy Scale in the first, second, and third survey rounds.

	Degree of difficulty ^*N (%) (N = 141)
	Very easy	Slightly easy	Intermediate	Slightly difficult	Very difficult
1) I can collect information related to the HPV vaccine and cervical cancer screening from various sources, such as newspapers, books, television, and the Internet.	1^st
	45 (31.9)	61 (43.3)	18 (12.8)	14 (9.9)	2 (1.4)
	2^nd
	35 (24.8)	58 (41.1)	23 (16.3)	23 (16.3)	0 (0)
	3^rd
	29 (20.6)	71 (50.4)	28 (19.9)	13 (9.2)	0 (0)
2) I can extract the information you are looking for from a large selection of information related to the HPV vaccine and cervical cancer screening.	1^st
	11 (7.8)	52 (36.9)	36 (25.5)	35 (24.8)	6 (4.3)
	2^nd
	16 (11.3)	50 (35.5)	28 (19.9)	39 (27.7)	6 (4.3)
	3^rd
	13 (9.2)	55 (35.5)	35 (24.8)	34 (24.1)	4 (2.8)
3) I can understand and communicate the obtained information related to the HPV vaccine and cervical cancer screening to others.	1^st
	8 (5.7)	33 (23.4)	35 (24.8)	44 (31.2)	20 (14.2)
	2^nd
	12 (8.5)	29 (20.6)	48 (34.0)	32 (22.7)	16 (11.3)
	3^rd
	9 (6.4)	36 (25.5)	38 (27.0)	46 (32.6)	11 (7.8)
4) I can judge the credibility of the information related to the HPV vaccine and cervical cancer screening.	1^st
	6 (4.3)	23 (16.3)	37 (26.2)	55 (39.0)	19 (13.5)
	2^nd
	9 (6.4)	30 (21.3)	38 (27.0)	47 (33.3)	15 (10.6)
	3^rd
	9 (6.4)	40 (28.4)	36 (25.5)	46 (32.6)	11 (7.8)
5) I can make decisions about plans and actions for improving my health based on information related to the HPV vaccine and cervical cancer screening.	1^st
	12 (8.5)	37 (26.2)	44 (31.2)	36 (25.5)	11 (7.8)
	2^nd
	13 (9.2)	52 (36.9)	36 (25.5)	30 (21.3)	7 (5.0)
	3^rd
	9 (6.4)	55 (39.0)	52 (36.9)	24 (17.0)	0 (0)

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HPV, human papillomavirus

*The number of participants who responded to these items.

Main outcome

The null hypothesis stated that the proportion of participants with high health literacy in Groups 1, 2, and 3 would be equal. Conversely, the alternative hypothesis posited that the proportion of participants with high health literacy in Groups 2 and 3 would be greater than that in Group 1, which was a one-sided hypothesis. Logistic regression analysis applying a mixed-effects model showed that the odds ratio for “high health literacy” was below 1 for the print-based and control groups. Interestingly, this difference did not reach statistical significance for the groups that seemed more interested in HPV vaccination: participants who had visited a gynecologist, received HPV vaccination, and completed three HPV vaccinations (Fig 1, S4 Table). Intriguingly, participants who were routinely aware of diet importance had an odds ratio of <1, suggesting that they have lower motivation for increasing their knowledge and collecting information on the HPV vaccine and cervical cancer (Fig 1).

Fig 1 — Odds ratio (OR) for being “highly health literate” in the third survey. Logistic regression analysis was used to estimate the adjusted ORs and 95% confidence intervals (CIs) for Communicative and Critical Health Literacy (CCHL) scale scores (response variable: 1 = CCHL “high” in the 3^rd survey, 0 = “low”).

Subgroup analyses

We found significant differences in the total scores of the questionnaire depending on whether participants were students at medical facilities and whether they had received HPV vaccinations before the study (Fig 2a–2d). However, no significant differences were found between the average CCHL scale scores obtained in the first survey between subgroups defined by HPV vaccination status (Fig 2e and 2f).

Fig 2 — a–d: There are significant differences in the total scores of the questionnaire depending on whether participants were students at medical facilities and whether they had received HPV vaccinations before the study. e, f: No significant differences were found between the average Communicative and Critical Health Literacy (CCHL) scale scores obtained in the first survey between subgroups defined by HPV vaccination. HPV complete group: those who had already completed three doses of the HPV vaccine at the start of the study.

We then examined participants’ knowledge improvement during the study period using the average of the differences in total scores between the first and third surveys, based on the first 20-item questionnaire completed about knowledge regarding cervical cancer, received in each cluster. No significant differences were found among the three education groups, whereas students in a non-medical faculty tended to show greater improvements compared with those in a medical faculty (S3 Fig).

We then compared each group based on the average of the differences in the CCHL scale scores between the first and third surveys. We found no significant difference among the three groups. Interestingly, in the print-based group, no improvement was observed; rather, a slight regression in literacy was noted (Fig 3a and 3b).

Fig 3 — a, b: Comparison of groups based on the average of the differences in the Communicative and Critical Health Literacy (CCHL) scale scores between the first and third surveys. There are no significant differences among the three groups. Interestingly, in the print-based group, no improvement can be observed; rather, a slight regression in literacy can be noted. c–e: Comparison of average CCHL scores in the first and third surveys, and the difference between the first and third surveys, in groups defined by the presence of family members in the medical profession. In the group of participants with medical professionals as family members, a slight regression can be observed in the difference in CCHL scale scores between the first and third surveys. c: First questionnaire. d: Third questionnaire. e: Difference between the first and third questionnaires. The difference is more pronounced in the negative, with a higher improvement observed when there is no family member in the medical profession.

Additionally, the group comparisons for whether participants had medical experts as family members yielded similar results. In the group of participants with medical professionals as family members, a slight regression was observed in the difference in CCHL scale scores between the first and third surveys (Fig 3c–3e).

Discussion

In this study, we surveyed the effect of an education intervention on Japanese female students’ knowledge regarding HPV vaccination and cervical cancer for the first time in Japan. We found that participant knowledge and health literacy improved regardless of whether correct education about the HPV vaccine and cervical cancer was presented through print material or SNS. The analysis comparing the responses to the first and third surveys in the three groups showed that health literacy increased substantially, even in the control group that received no specific educational intervention. The improvement in health literacy in the control group indicated that the realization of “not knowing” was an important factor, that can drive students to investigate, think, and learn further information on their own accord. Conversely, the analysis comparing the differences in CCHL scale scores showed no improvement in the print-based group but rather a slight regression over time. As presented in Fig 3a, health literacy in the print group tended to be slightly higher from the start. However, their improvement in scores was less than that in the other groups; thus, print is not read repeatedly or does not stimulate intellectual interest, even when it is handed out. Although the insufficient numbers hamper a definite conclusion, the initial health literacy was higher in the print-based group than in the other groups, which suggests that already health-literate participants were less likely to obtain further information. However, further research on this topic is required.

A previous study aimed at determining the factors that influence satisfaction with decision-making concerning HPV vaccination among female university students in Japan concluded that being vaccinated against HPV, having higher knowledge scores, and having lower awareness regarding the risk of sexually transmitted infections were significant influencing factors [27]. In Japan, the need to make appropriate decisions and behavioral choices according to scientific thinking and the correct judgment of health-related issues is discussed in the school education curricula [28]. Nevertheless, considering that the recommended target population for HPV vaccination is students from the sixth grade of elementary school to the first year of high school, the students, as well as their parents, should be targeted for intervention. Therefore, the family environment is an important factor in health literacy.

In our study, subgroup analyses of the groups with and without a family member in the medical profession showed that the mean CCHL scale score tended to be slightly higher for the first survey in the subgroup with a family member in the medical profession (Fig 3c). However, for the third survey, the mean CCHL scale scores were reversed, with greater improvement in the subgroup without a family member in the medical profession (Fig 3e). This indicates that, in modern Japan, people can absorb the correct information if they are alerted by their surroundings and are willing to learn independently.

A study of Swiss university students suggested that primary care has a high potential for increasing HPV vaccination coverage rates [29]. Unlike in countries in Europe and the United States, Japanese citizens, particularly the younger generation, do not have a “family doctor.” Therefore, the solution for vaccination uptake lies in the educational environment in the family, local community, and school. Social media platforms should be arranged so that young students and their parents can obtain appropriate and sufficient information, regardless of their situation.

In their investigation of strategies to debunk vaccine untruths, paradoxical effects were reported by Betsch and Sachse [30]. However, subsequent investigations failed to provide any scientific or epidemiological evidence supporting a causal relationship between the reported symptoms, such as pain and motor dysfunction, and HPV vaccination [31]. Consequently, the Ministry of Health, Labour and Welfare (MHLW) Adverse Effects Review Committee confirmed that these symptoms were functional physical symptoms [32, 33]. A nationwide epidemiological survey conducted by the Sobue Group of the MHLW also reported that similar symptoms to those reported post-vaccination were present among individuals without a history of HPV vaccination [34]. In a questionnaire survey of women born between 1994 and 2000 in Nagoya, no significant difference in the age-adjusted incidence of 24 symptoms was found between vaccinated and unvaccinated women, providing no evidence of a causal relationship between the symptoms and HPV vaccination [35]. The Japanese government’s decision to stop the active recommendation of HPV vaccination spanned 8 years, from June 2013 to November 2021 [36]. Meanwhile, Australia, Sweden, and Denmark published the results of the effects and safety of HPV vaccination, reporting that a substantial reduction was anticipated in the risk of invasive cervical cancer among vaccinated women [37–40]. Knowledge and awareness regarding cervical cancer and HPV vaccines in various countries have been analyzed, and the research in Japan remains limited [41–52]. The results of this study are expected to enhance knowledge and awareness regarding cervical cancer among young women in Japan.

Limitations

This study is limited by the relatively small sample size, which was partly due to the ethical care taken in the recruitment methods. Utmost care was taken to solicit voluntary participation without coercion or harassment against students. Recruitment was also affected by the COVID-19 pandemic when many students were not attending class. Thus, the number of participants was much lower than expected, resulting in a lack of statistically significant differences due to the low study power. Nevertheless, this study provides valuable information. Additionally, the study participants were recruited from young female university students who were asked to participate voluntarily. Therefore, the target population was limited to university students who were interested in this study; inevitably, this involved bias in terms of family environment, parental income, and access to information sources. Thus, the results may not be generalizable to all Japanese women. This study was a physician-initiated research project funded by an external agency. It is important to note that the funding agency had no influence over the study design, participant recruitment, data collection, or analysis. All participants were recruited voluntarily and were not selected based on the funding agency’s preferences. The funding agency had no impact on the study results or the interpretation of the findings. This transparency regarding the role of the funding agency reinforces the credibility of the study’s conclusions, ensuring that the study’s design and outcomes were independent of any external influence.

Conclusion

Our analysis indicated that participants’ knowledge and health literacy on cervical cancer and the HPV vaccine improved regardless of whether education was delivered by a print-based or SNS-based intervention; participants acquired proper knowledge and awareness regarding the importance of the disease and its prevention. These findings highlight the effectiveness of both traditional and digital educational methods in enhancing public health literacy. Moving forward, such interventions can be integrated into broader public health campaigns to improve cervical cancer prevention, especially in populations with limited access to healthcare education.

Supporting information

S1 Fig. Study procedure.

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S2 Fig. Study flowchart.

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S3 Fig. Comparison of average differences in total scores between the first and third surveys, based on the first 20-item questionnaire completed about knowledge regarding cervical cancer received in each cluster.

No significant differences were found among the three education groups, whereas non-medical students faculty tend to show greater improvements than did those in a medical faculty.

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S1 Method. Questions about your current life.

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S1 Table. Questionnaire about knowledge of cervical cancer and the human papillomavirus vaccine.

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S2 Table. Communicative and Critical Health Literacy Scale (CCHL).

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S3 Table. Baseline characteristics of the female students who participated in the study from three universities in Japan, 2019–2023 (N = 188: Number of participants).

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S4 Table. Factors related to “high” health literacy scores in the third survey.

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S5 Table. Distribution of knowledge regarding cervical cancer items and rate of the answer “I know” in the first, second, and third rounds (N = 141).

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pone.0311588.s009.pdf^{(29.3KB, pdf)}

Acknowledgments

The authors are grateful for helpful discussions with former colleagues Dr. Shiho Fukui, Dr. Yoshiko Kawata (Department of Obstetrics and Gynecology, University of Tokyo), and Prof. Kyoko Nomura (Department of Public Health, Akita University Graduate School of Medicine). We thank our students and colleagues at Teikyo University for their critical comments. For recruiting students to participate in the study, the teaching departments of Teikyo University, Teikyo Heisei University, and Teikyo Institute of Advanced Nursing provided tremendous support by displaying recruitment posters.

Data Availability

All relevant data are within the article and its Supporting information files.

Funding Statement

This research was funded in part by the Investigator-Initiated Studies Program of Merck Sharp & Dohme Corp. (Kenilworth, NJ, USA) and MSD K.K. (grant number 58246). The opinions expressed in this study are those of the authors and do not necessarily represent those of Merck Sharp & Dohme Corp. or MSD K.K. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. No other funding or sources of support were received during this study. There was no additional external funding received for this study.

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PLoS One. doi: 10.1371/journal.pone.0311588.r001

Decision Letter 0

Lucy W Kivuti-Bitok

15 Oct 2024

PONE-D-24-35490Effects of different educational interventions on cervical cancer knowledge and human papilloma virus vaccination uptake among young women in Japan: preliminary results of a cluster randomized controlled trialPLOS ONE

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Reviewer #1: Yes

Reviewer #2: Yes

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Reviewer #1: Yes

Reviewer #2: Yes

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Reviewer #1: Yes

Reviewer #2: Yes

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Reviewer #1: Yes

Reviewer #2: Yes

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Reviewer #1: I recommend this manuscript for publication with minor revisions and some significant concerns.

The sample size is a significant concern. The authors mention the small number of participants as a limitation, but the reasons provided are not sufficiently compelling. While I recognize the challenges posed by the COVID-19 pandemic, more effort could have been made to increase the number of participants. For instance, broadening the recruitment pool beyond private university students could have provided more robust data and increased generalizability. Additionally, the rationale for selecting only private universities is not clearly articulated. This raises questions about whether the findings of this study can be referred to as representative of the population. It also raises concerns about potential selection bias. Expanding on why these institutions were chosen and how this decision may affect the study’s applicability to other populations would strengthen the argument.

In the “Study settings and participants” section, it is noted that students facing mental or physical challenges were excluded, but there is no detailed explanation of what specific challenges were encountered or how their exclusion may have influenced the findings. The study would benefit from further elaboration on this point, including any possible connections between the excluded students’ challenges and the study’s outcomes. Clarifying this could help readers understand whether the exclusion of these participants had any significant impact on the study’s results.

Regarding the classification of the study as a randomized controlled trial (RCT), I have reservations. The study design, combined with the small sample size and the recruitment strategy, makes it difficult to categorize this work as an RCT. The control mechanisms seem more aligned with a case-control study, given the observational nature of the data and the lack of a fully randomized, robust sample size. The authors should reconsider framing the study as an RCT or, at the very least, revisit their conclusions to reflect the study’s limitations in this regard.

Lastly, while the authors declare that the funding agency did not influence the study design, data collection, or analysis, I would appreciate more discussion regarding the role of the funding body in the study’s limitations section. A transparent reflection on how the presence of a funder might have influenced certain study decisions would provide additional credibility to the work.

Overall, the paper has merit, and with the suggested revisions, it has the potential to strengthen its contribution to the field. I encourage the authors to consider these points and revise the manuscript accordingly.

Reviewer #2: Reviewer comments for the Manuscript Number PONE-D-24-35490

“Effects of different educational interventions on cervical cancer knowledge and human papilloma virus vaccination uptake among young women in Japan: preliminary results of a utcluster randomized controlled trial”

Kazunori Nagasaka et al

The manuscript is well written but a few areas need clarification . This way it will make it easier for the reader and enhance clarity and flow in the article.The attached file contains the areas that need attention

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Reviewer #1: Yes: Dr. Shamim Ahmed

Reviewer #2: No

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Attachment

Submitted filename: Reviewer comments for the article.docx

pone.0311588.s010.docx^{(17.4KB, docx)}

PLoS One. 2025 Jan 7;20(1):e0311588. doi: 10.1371/journal.pone.0311588.r002

Author response to Decision Letter 0

23 Nov 2024

Dear Reviewers,

We wish to re-submit the manuscript titled “Effects of different educational interventions on cervical cancer knowledge and human papillomavirus vaccination uptake among young women in Japan: preliminary results of a cluster randomized controlled trial.” The manuscript has been rechecked and the necessary changes have been made in accordance with the reviewers’ suggestions. The responses to all comments have been prepared and attached herewith.

Thank you for your consideration. I look forward to hearing from you.

Sincerely,

Kazunori Nagasaka MD, PhD

Reviewer #1: I recommend this manuscript for publication with minor revisions and some significant concerns.

→We appreciate the reviewer’s insightful feedback regarding the sample size and recruitment strategy. We acknowledge that the relatively small sample size could be seen as a limitation. While the COVID-19 pandemic presented significant challenges to participant recruitment and study expansion, we agree that more effort could have been made to increase the number of participants. Originally, we intended to broaden the recruitment pool beyond private universities and planned to collaborate with additional universities and educational institutions, including junior high schools and high schools in Tokyo. However, due to funding constraints and difficulties in securing cooperation from other institutions, we were unable to execute this broader recruitment strategy. Furthermore, public awareness of HPV vaccination was limited at the time due to government guidelines, which impacted participant engagement. Regarding the selection of private universities, our decision was influenced by several factors. First, the study aimed to ensure voluntary participation, particularly because students are a vulnerable population, and the Ethics Committee stressed the importance of preventing any undue influence from academic obligations. Recruiting from private universities helped to ensure that participation was voluntary and did not inadvertently pressure students due to academic requirements. Additionally, we considered the feasibility of recruitment within the limited time frame and the available resources. We recognize that this selection may limit the generalizability of our findings to the broader population, and we have added a more thorough explanation of these limitations in the manuscript. We agree that future studies should aim to include a more diverse and representative sample to strengthen the applicability of the findings to other populations. On lines 109-114, we have added the following statement: “The universities were selected based on logistical considerations and feasibility. While the focus on private universities facilitated recruitment and ensured voluntary participation, this choice may limit the generalizability of the findings. Due to funding constraints and logistical challenges, the recruitment pool was not expanded beyond these institutions.”

→Thank you for highlighting this point. The research protocol specifies that students with mental or physical challenges were to be excluded. However, in practice, the study only included students who volunteered to participate, and no students with psychological or physical difficulties were actually enrolled. We have clarified this in the text to ensure accurate understanding on the line 105-108: “According to the research protocol, students with mental or physical challenges were to be excluded. However, in practice, the study only included students who volunteered to participate, and no students with psychological or physical difficulties were actually enrolled. This exclusion criterion did not affect the study’s outcome, as no participants in the study were found to meet this criterion.”

→Thank you for this valuable insight. As the reviewer noted, this study’s design has inherent limitations that make it challenging to classify as an RCT. We have updated the manuscript to include these limitations in the "Study design" section and have carefully reconsidered the framing of the study’s design as below on line 91-96: “The study employed cluster-level randomization; however, due to factors such as the small sample size and the non-randomized recruitment process, the design does not fully conform to the characteristics of a traditional randomized controlled trial (RCT). Despite these limitations, the design was chosen to assess the effectiveness of the interventions while considering ethical constraints and practical challenges.”

→We are very grateful for this suggestion. In the "Limitations" section, we have reiterated that this was a physician-initiated study funded by the agency without influence over the design, recruitment, or analysis on line 453-460: “This study was a physician-initiated research project funded by an external agency. It is important to note that the funding agency had no influence over the study design, participant recruitment, data collection, or analysis. All participants were recruited voluntarily and were not selected based on the funding agency’s preferences. The funding agency had no impact on the study results or the interpretation of the findings. This transparency regarding the role of the funding agency reinforces the credibility of the study's conclusions, ensuring that the study's design and outcomes were independent of any external influence.”. All participants were voluntary and not selected based on funder preferences, and the funding agency had no impact on the results. We believe this additional clarification strengthens the transparency of our study.

Reviewer #2: Reviewer comments for the Manuscript Number PONE-D-24-35490

Kazunori Nagasaka et al.

The manuscript is well written but a few areas need clarification . This way it will make it easier for the reader and enhance clarity and flow in the article. The attached file contains the areas that need attention

Reviewer comments for the Manuscript Number PONE-D-24-35490

Kazunori Nagasaka et al.

Abstract

The abstract looks good and gives an overview of cervical cancer in Japan it could improve by providing more context about the adverse reactions that led to the suspension of the HPV vaccine could enhance understanding of vaccine hesitancy.

→Thank you for this helpful feedback. We have revised the abstract to include details on the adverse reactions that contributed to the suspension of the HPV vaccination, addressing the issue of vaccine hesitancy.

Introduction

This section is good. It can be improved by providing specific examples of how health literacy can be improved. Other areas the author needs to check are for instance;

Line 70 Cooper et al. [24]... the reference style is not consistent with the other references. Ensure that references are consistent and clearly formatted to improve readability of the article.

→We sincerely appreciate the reviewer’s suggestions. We have added specific examples of strategies to improve health literacy. We have also corrected the formatting inconsistency in Line 71 and will ensure that all references are consistently and clearly formatted throughout the article.

Materials and methods

This section looks good but the authors will need to check and make correction on the following.

Line 86 a cluster, randomized, parallel-group trial - This is a bit confusing. did you mean parallel cluster randomized group trial?

→ Thank you for your suggestion. We have modified the wording to "parallel cluster randomized group trial" on line 87 to improve clarity.

Line 121 Clusters were defined as a faculty or department and an allocation. This statement is not clear, is there some information missing?

→ Thank you for pointing this out. We did not conduct a cluster analysis in this study; thus, we have removed this sentence for accuracy.

The authors indicate that Analysis of variance with Scheffé test was performed for continuous variables, and the Chi-square test ….. Was the Scheffé technique utilised in the analysis? If they did were the results presented in the writeud?

→Thank you for highlighting this. We performed a one-way analysis of variance for continuous variables and did not use the Scheffé test. We have corrected the text to read, "The one-way analysis of variance was performed for continuous variables." on line 225. Also, we mentioned the level of significance used in the study on line 229.

189 performed for categorical variables in the subgroup analysis.

Line 148 -149 A score of ≤3 was considered “highly health literate” because this represented the number of participants in the two groups. this statement is not clear, what is the connection of the literacy score and the number of participants?

→ We apologize for the confusion. The sentence has been revised to clarify that "A score of ≤3 was considered 'highly health literate' because it represented participants who had significant knowledge within both groups." on line 185.

Line 179 logistic regression mixed-effect-Is this, ok? I guess you wanted to say mixed-effect logistic model

→ Thank you for pointing this out. We have updated the terminology to "mixed-effect logistic model" to ensure clarity on line 220.

On line 193 the authors state that, “these scores were summed, a lower total score indicated that the respondents were more knowledgeable ,. The researchers may need to reverse the score coding since most readers will associate high score to success. In this case it is in the opposite direction

→ Thank you for this valuable suggestion. We acknowledge that a lower score indicates greater knowledge, which is opposite to typical expectations. We have clarified this in the manuscript to avoid misunderstanding. We have added clarification on line 237: “It is important to note that, unlike typical scoring systems where higher scores reflect better knowledge, in this study, a lower score reflects higher knowledge.”

Line 264- 265, the alternative hypothesis is not clear. Was the alternative hypothesis one sided since the authors state that hat the proportion of participants with high health literacy in Groups 2 and 3 would be higher than that in Group 1

→ Thank you for pointing this out. The alternative hypothesis was indeed one-sided, as stated, and we have clarified this in the revised text on line 315: “Conversely, the alternative hypothesis posited that the proportion of participants with high health literacy in Groups 2 and 3 would be greater than that in Group 1, which was a one-sided hypothesis.”

line 365…, for the third questionnaire, ….do the authors mean the third survey here or what is the third questionnaire?

→ Thank you for requesting clarification. We used the same questionnaire at three different time points to assess knowledge development. The "third survey is a collection of responses" refers to the third questionnaire. We have revised the text for clarity on line 423.

On line 381 and 383 the authors use the abbreviations MHLW which is not clearly defined.

→ We apologize for this oversight. MHLW stands for “Ministry of Health, Labour and Welfare,” and we have added this definition at the first use on line 439 in the text.

Attachment

Submitted filename: Rebuttal_letter_20241117_resubmission.docx

pone.0311588.s011.docx^{(25.2KB, docx)}

PLoS One. doi: 10.1371/journal.pone.0311588.r003

Decision Letter 1

Lucy W Kivuti-Bitok

18 Dec 2024

Effects of different educational interventions on cervical cancer knowledge and human papillomavirus vaccination uptake among young women in Japan: preliminary results of a cluster randomized controlled trial

PONE-D-24-35490R1

Dear Dr. Nagasaka,

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PLoS One. doi: 10.1371/journal.pone.0311588.r004

Acceptance letter

Lucy W Kivuti-Bitok

26 Dec 2024

PONE-D-24-35490R1

PLOS ONE

Dear Dr. Nagasaka,

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

S1 Fig. Study procedure.

(TIF)

pone.0311588.s001.tif^{(1.5MB, tif)}

S2 Fig. Study flowchart.

(TIF)

pone.0311588.s002.tif^{(740.6KB, tif)}

No significant differences were found among the three education groups, whereas non-medical students faculty tend to show greater improvements than did those in a medical faculty.

(TIF)

pone.0311588.s003.tif^{(309.5KB, tif)}

S1 Method. Questions about your current life.

(PDF)

pone.0311588.s004.pdf^{(43.3KB, pdf)}

S1 Table. Questionnaire about knowledge of cervical cancer and the human papillomavirus vaccine.

(PDF)

pone.0311588.s005.pdf^{(40.9KB, pdf)}

S2 Table. Communicative and Critical Health Literacy Scale (CCHL).

(PDF)

pone.0311588.s006.pdf^{(45.9KB, pdf)}

S3 Table. Baseline characteristics of the female students who participated in the study from three universities in Japan, 2019–2023 (N = 188: Number of participants).

(PDF)

pone.0311588.s007.pdf^{(43.2KB, pdf)}

S4 Table. Factors related to “high” health literacy scores in the third survey.

(PDF)

pone.0311588.s008.pdf^{(26.6KB, pdf)}

S5 Table. Distribution of knowledge regarding cervical cancer items and rate of the answer “I know” in the first, second, and third rounds (N = 141).

(PDF)

pone.0311588.s009.pdf^{(29.3KB, pdf)}

Attachment

Submitted filename: Reviewer comments for the article.docx

pone.0311588.s010.docx^{(17.4KB, docx)}

Attachment

Submitted filename: Rebuttal_letter_20241117_resubmission.docx

pone.0311588.s011.docx^{(25.2KB, docx)}

Data Availability Statement

All relevant data are within the article and its Supporting information files.

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PERMALINK

Effects of different educational interventions on cervical cancer knowledge and human papillomavirus vaccination uptake among young women in Japan: Preliminary results of a cluster randomized controlled trial

Yuko Takahashi

Yukifumi Sasamori

Risa Higuchi

Asumi Kaku

Tomoo Kumagai

Saya Watanabe

Miki Nishizawa

Kazuki Takasaki

Haruka Nishida

Takayuki Ichinose

Mana Hirano

Yuko Miyagawa

Haruko Hiraike

Koichiro Kido

Hirono Ishikawa

Kazunori Nagasaka

Roles

Abstract

Introduction

Materials and methods

Study design

Study settings and participants

Estimation of the participant number required

Intervention

Allocation method

Data collection

Measurements

Outcomes

Primary outcome

Secondary outcome

Efforts to avoid possible sources of bias

Main analysis

Ethical considerations

Results

Participant selection

Participant characteristics

Questionnaire

CCHL scale

Table 1. Results of the Communicative and Critical Health Literacy Scale in the first, second, and third survey rounds.

Main outcome

Fig 1. Odds ratios for "high health literacy" in the third survey, adjusted for CCHL scale scores.

Subgroup analyses

Fig 2. Subgroup analyses of questionnaire total scores and CCHL scale scores.

Fig 3. Comparison of average differences in CCHL scale scores.

Discussion

Limitations

Conclusion

Supporting information

Acknowledgments

Data Availability

Funding Statement

References

Decision Letter 0

Lucy W Kivuti-Bitok

Roles

Author response to Decision Letter 0

Decision Letter 1

Lucy W Kivuti-Bitok

Roles

Acceptance letter

Lucy W Kivuti-Bitok

Roles

Associated Data

Supplementary Materials

Data Availability Statement

ACTIONS

PERMALINK

RESOURCES

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