Knowledge gaps and acquisition about HPV and its vaccine among Brazilian medical students.

OBJECTIVE: To analyze factors associated with knowledge gaps and acquisition about HPV and its vaccine among medical students.
METHOD: Cross-sectional and analytical study conducted at the University of São Paulo Medicine School, in 2016. A convenience sample of students completed a data collection instrument containing questions on knowledge about HPV and its vaccine, and vaccine acceptability. The level of knowledge and acceptability established as a "good level" was 80% of correct answers on the questionnaire. Internal validity was calculated with Cronbach's alpha value (α) = 0.74. Bivariate and multiple analyzes were performed using the Stata® program (Stata Corp, College Station, USA) 14.0.
RESULTS: To evaluate the internal consistency of the instrument applied, the Cronbach's alpha equation was used, obtaining the alpha value (α) = 0.74 for this population. This value attests that the consistency of the answers obtained with this questionnaire is considered substantial and acceptable. Among the 518 medical students who completed the survey, the majority were men 312 (60.4%) with a mean age of 23 (± 2.8) years old; 199 (38.3%) of the students were in the final years of graduation (5th and 6th years). Students in the first, second and third year of study had a 51% higher risk of a knowledge gap when compared to students in the final years of graduation [PR 1.51 (1.3:1.8); p <0.001]. Men were at 22% higher risk of unsatisfactory knowledge than women are [PR 1.22 (1.07: 1.39). There was no knowledge acquisition during medical school in the following questions (p <0.05), indication of vaccine for individuals with HIV and contraindication in pregnant patients.
CONCLUSION: Male medical students, in the first year of medical school, and those who were not vaccinated had significant knowledge gaps about HPV. The novelty of the study includes the finding of non- acquisition of knowledge during the medical school graduation on safety and vaccination schedule and vaccine administration in specific populations.

Introduction

Knowledge acquisition about HPV, its clinical repercussions, and its vaccine is developed throughout the graduate years of medical education in developed and developing countries [1,2]. The skills and competences acquired by these students will be used for men's and women's health care, especially for HPV-induced cancer (cervical, oropharynx, anus, rectum and penis) and precursor lesions at different levels of care, including health counseling and education, prevention, diagnosis, treatment and recovery [2,3].

As future health care providers, these medical students will perform preventive actions (HPV vaccination) and promotion of cervical cancer screening [4], which is a high prevalence and mortality disease in Brazil and worldwide, representing a public health problem [5,6]. In Brazil the HPV vaccine is available in the National Immunization Program for female population aged nine to 14 years old, male population aged 11 to 14 years old [7].

The attitude of non-recommendation of HPV vaccine by health professionals is related to their own understanding of HPV and the vaccine [8]. Berenson et al. (2015) [9] found that senior medical students had insufficient basic knowledge about HPV epidemiology and HPV vaccine.

The identification of knowledge gaps and barriers of acceptance during medical education can support proposals for improving the content delivered to students, reduce negative beliefs, and promote HPV vaccines recommendation [10]. Thus, medical students should be encouraged to receive education about HPV, prevention and vaccination, to enable them to deliver effective vaccine recommendations, guiding their patients and accurately responding to questions [9-11]. The objective of this research was to analyze factors associated with knowledge gaps and acquisition about HPV and its vaccine among medical students.

Method

Study design, place and date

This was a cross-sectional study conducted at the University of São Paulo Medicine School, São Paulo, Brazil, 2016.

Participants

The population was the 900 students enrolled in the Medicine School of the University of Sao Paulo. The appropriate sample size for the study, based on parameters [12] of 5% error, 95% confidence level, and 80% test power was estimated to 270 individuals. A convenience sample of both sexes’ students over the age of 18 from the first to sixth year of medical school were invited to participate voluntarily in the research, whit no financial incentive offered to the respondents, who signed the Informed Consent Form.

Non-inclusion criteria. Individuals with cognitive problems or any interest that may influences the answer to the questions contained in the data collection instrument.

Data collection procedure

Data collection was performed by undergraduate medical students previously trained to administer the instruments with the support and supervision of the researcher. To minimize selection bias, data collection occurred in student classrooms, between classes, on breaks in clinical rotations or in housing units. After completing the instrument, accurate information about HPV was provided and questions answered.

Instrument

The instrument (Box 1) is a previous study developed and applied in similar populations. In addition to socio-demographic questions, there were 31 questions divided into six sections [13,14]:

Box 1. Instrument: HPV knowledge and acceptability questionnaire

Domain 1: Knowledge about HPV

1. Do you know what HPV is?

(  )no (  )yes (  )not sure

2. Is HPV a virus?

(  )no (  )yes (  )not sure

3. Is HPV a sexually transmitted disease?

(  )no (  )yes (  )not sure

4. Can HPV cause cervical cancer?

(  )no (  )yes (  )not sure

5. Can HPV cause changes in the Pap (screening for cervical cancer)?

(  ) no (  ) yes (  ) not sure

6. Is cervical cancer a major cause of cancer in women?

(  )no (  )yes (  )not sure

7. Can smoking increase the risk of cervical cancer?

(  )no (  )yes (  )not sure

Domain 2: Knowledge about HPV vaccine

8. Does the HPV vaccine prevent cervical cancer?

(  )no (  )yes (  )not sure

9. Should the HPV vaccine be given before the first sexual intercourse?

(  )no (  )yes (  )not sure

10. Can the HPV vaccine be given to people who have had sex?

(  )no (  )yes (  )not sure

11. Can HPV vaccine be harmful to health?

(  )no (  )yes (  )not sure

12. Can the HPV vaccine cause HPV infection?

(  )no (  )yes (  )not sure

13. Is the HPV vaccine provided by the Government?

(  )no (  )yes (  )not sure

14. Is the HPV vaccine part of the girls’ immunization record?

(  )no (  )yes (  )not sure

15. Where did you hear about the HPV vaccine?

(  )School (  )Friends (  )TV/radio (  )Internet (  )Health professional (  )Others_____

16. Are 3 doses required for complete vaccination?

(  )no (  )yes (  )not sure

17. Does the HPV vaccine lessen the chance of having genital warts?

(  )no (  )yes (  )not sure

18. Does the HPV vaccine decrease the chance of having Pap (cervical cancer screening) changes?

(  )no (  )yes (  )not sure

Domain 3: HPV Vaccine Barriers

19. Do you think the HPV vaccine would stimulate the onset of sexual life earlier?

(  )no (  )yes (  )not sure

20. Do you think that after the HPV vaccine you still need to use a condom?

(  )no (  )yes (  )not sure

21. Do you think that after the HPV vaccine you still need to have the pap (cervical cancer screening)?

(  )no (  )yes (  )not sure

Domain 4: Acceptability of HPV vaccine

22. Do you know anyone who has already had the HPV vaccine?

(  )no (  )yes (  )not sure

23. Have you taken the HPV vaccine yet?

(  )no (  )yes/ If yes (  )public services (  )particular services (  )not sure

24. Would you recommend the HPV vaccine for a child, friend, or relative to take?

(  )no (  )yes (  )not sure

Domain 5: Personal Background

Answer only if you are female

25. Have you ever had pap (cervical cancer screening)?

(  )no (  )yes (  )not sure

26. Have you ever had cervical cancer?

(  )no (  )yes (  )not sure

27. Have you ever had genital warts?

(  )no (  )yes (  )not sure

Domain 6: Health professionals

Answer if you are a health professional

28. Patients living with HIV can take the vaccine?

(  )no (  )yes (  )not sure

29. Am I confident to indicate HPV vaccination for patients?

(  )no (  )yes (  )not sure

30. Do I feel confident giving information about HPV to patients?

(  )no (  )yes (  )not sure

31. Can pregnant women take the vaccine?

(  )no (  )yes (  )not sure

The Domain 5: Personal background was not considered in this study as it concerns medical personal information.

Variables

The dependent variables were gender, age, marital status, number of children, year of medical study, education, income, grade, and vaccination status. The independent variables were the total scores for each of the themes: knowledge about HPV, knowledge about HPV vaccine, barriers to HPV vaccination, acceptability of HPV vaccine and specific knowledge of health professionals.

The good level of knowledge was classified as adequate when the percentage of correct answers exceeded 80% and was based on the previously published score in a similar population [14]. Knowledge acquisition was considered when students in 1st, 2nd and 3th years of medical school achieved less than 80% correct answers and students in 5th and 6th years reached more than 80%. This shows that throughout the course the student gained knowledge about HPV and its vaccine.

Data analysis

Data was entered into Excel and analysis performed by two researchers (EFSS and ASC). All analyzes were performed using the Stata program (Stata Corp, College Statiom, USA) 14.0. The dataset is available on the Harvard Dataverse, https://doi.org/10.7910/DVN/IR3UJO [15].

Knowledge acquisition exists when the percentage of correct answers in the basic cycle (1st, 2nd and 3rd year of medical study) is less than 80% and in internship cycle (5th and 6th year of medical study) is higher than 80% limit. This shows that throughout the course, the student acquired knowledge about HPV and its vaccine.

For descriptive data analysis, quantitative variables were computed for measures of central tendency (mean, median and quartiles) and dispersion measures (variance, standard deviation and interquartile range), according to the data adherence to Gaussian distribution. And the Shapiro-Wilk test.

Qualitative variables were expressed as absolute and relative frequencies. Confidence intervals of the respective measurements were calculated.

For bivariate analysis of categorical variables, the chi-square test was used and for multiple analysis, Poisson regression was performed. Values were considered statistically significant with two-tailed p-value <0.05 with a 95% confidence interval.

Non-responding was represented as missing and did not exceed 5% of question-by-question responses. The response rate of the variables (questionnaire questions) was an average of 99.2% (SD 0.9%).

Ethical aspects

The research followed the rules of the National Health Council and was approved by the Faculdade de Medicina–Universidade de Sao Paulo Research Ethics Committee under opinion No. 1,938,072.

Results

To evaluate the internal consistency of the instrument applied, the Cronbach's alpha equation was used, obtaining the alpha value (α) = 0.74 for this population. This value attests that the consistency of the answers obtained with this questionnaire is considered substantial and acceptable [16].

Of the 520 medical students who answered the questionnaire, the majority of respondents were male 60.2% (312), 63.8% (332) aged 20–24 years, 98.9% (489) of the respondents were single and two students reported having children (Table 1).

Table 1

Medical students sociodemographic characteristics, medical school of the university of Sao Paulo, Brazil, 2016.

Characteristics	N (520)	% (CI 95%)*
Sex
Male	312/518	60.2 (56 : 64)
Female	206/518	39.8 (36 : 44)
Age
≤ 19 years old	46	8.8 (6.0 : 12)
20–24 years old	332	63.8 (60 : 68)
25–29 years old	131	25.2 (22 : 29)
≥ 30 years old	11	2.1 (1 : 3)
Marital Status
Singles	489/494	99.0 (97 : 99)
Stable Union	5/494	1.0 (0.4 : 2.4)
Children
Yes	2/516	0.4 (0.1 : 1.5)
No	514/516	99.6 (98 : 100)
Year of graduation
1st, 2nd and 3th	321	61.7 (58 : 46)
5th and 6th	199	38.3 (34 : 43)
HPV vaccinated
No	419/514	81.5 (78 : 85)
Yes	95/514	18.5 (15 : 22)
Family Icome**
>R$ 9.745,00	255/511	49.9 (45 : 54)
de R$ 7.475,00 a R$ 9.745,00	116/511	22.7 (19 : 26)
de R$ 1.734,00 a 7.475,00	40/511	7.8 (5.8 : 10)
de R$ 1.085,00 a 1.734,00	9/511	1.8 (0.9 : 3.3)
< R$ 1.085,00	91/511	17.8 (15 : 21)

*CI 95%: Confidence Interval of 95%

**1 American dólar ($) = 4,07 Brazilian currency (R$)

According to grade 61.7% (321) students were in 1st, 2nd and 3th year of medical study and 38.2% (199) were in 5th and 6th year of medical study. Of the participants, 81.5% (419) were not vaccinated for the HPV vaccine (Table 1).

Table 2 shows the factors associated with the knowledge gap about HPV, its clinical repercussions and its vaccine among students considering the variables: gender, age group, marital status, graduation period, having been vaccinated and income. Multivariate analysis showed a difference in knowledge by gender (p <0.01) and year of study (p <0.01). Men had a 22% higher risk of having unsatisfactory level of knowledge than the women interviewed [PR 1.2 (1.1: 1.4)]. It is observed that there was a difference in students by grade with first, second and third year students having a 51% risk of having a knowledge gap than students in the final cycle [PR 1.51 (1.3:1.8)] (Table 2). Students who were not vaccinated against HPV were 41% more likely to have a knowledge gap than vaccinated students [PR 1.41 (1.12: 1.78)].

Table 2

Factors associated with knowledge gap about HPV, its clinical repercussions and its vaccine among medical students at the medical school of university of São Paulo, Brazil, 2016.

Variables	Total PR (95% CI)*	P-value
Sex
Male	1.0
Female	1.2 (1.1 : 1.4)	<0.01
Age
≤ 19 years old	1.0
20–24 years old	0.9 (0.6 : 1.2)	0.41
25–29 years old	0.8 (0.6 : 1.0)	0.11
≥ 30 years old	0.8 (0.6 : 1.1)	0.14
Marital Status
Singles	1.0
Stable Union	0.5 (0.2 : 1.6)	0.26
Período de graduação
Basic cycle**	1.0
Final cycle***	1.5 (1.3 : 1.8)	<0.01
HPV vaccinated
No	1.0
Yes	1.4 (1.1 : 1.8)	<0.01
Family Income †
>R$ 9.745,00	1.0
de R$ 7.475,00 a R$ 9.745,00	0.8 (0.5 : 1.4)	0.40
de R$ 1.734.00 a 7.475.00	1.1 (0.9 : 1.3)	0.23
de R$ 1.085.00 a 1.734.00	1.0 (0.8 : 1.1)	0.70
< R$ 1.085.00	1.0 (0.8 : 1.1)	0.65

*PR (95%CI): Prevalence Ratio (Confidence Interval of 95%) calculated by Poisson regression.

**Basic cycle: 1st 2nd and 3th graduation year

***Final cycle: 5th and 6th graduation year

† 1 American dólar ($) = 4,07 Brazilian currency (R$)

Differences in knowledge of HPV and its vaccine between men and women (p <0.05) were identified in the questions “Can smoking increase the risk of cervical cancer?” [0.87 (0.79: 0.97)], "Can the HPV vaccine be given to people who have had sex?" [0.93 (0.87: 0.99)], "Can the HPV vaccine cause HPV infection?" [0.82 (0, 73: 0.92)], “Is the HPV vaccine part of the girls' immunization records?” [0.77 (0.67: 0.89)], “Are 3 doses required for complete vaccination?” [0, 57 (0.49: 0.67)], “Does the HPV vaccine decrease the chance of having changes in the Pap smear test?” [0.90 (0.82: 0.98)], “Do you think the HPV vaccine will stimulate the onset of sexual activity at an earlier age?”[0.94 (0.89: 0.98)], (S1 Table).

Table 3 highlights the knowledge acquisition (not acquired / acquired) and the knowledge level (adequate / inadequate) of participants by class level. There was no knowledge acquisition and the level of knowledge was inadequate in the fists years of study in the following questions (p <0.05): “Can smoking increase the risk of cervical cancer?” [0.65 (0.57 : 0.75)]; “Can HPV vaccine be harmful to health? [0.66 (0.53: 0.83)]; “Is the HPV vaccine part of a girls' vaccination card?” [0.75 (0.66: 0.86)]; “Are 3 doses required for full vaccination?” [0.76 (0.65: 0.90)]; “Can patients living with HIV get the vaccine?” [0.56 (0.44:0.71)]; "Can pregnant patients get the vaccine?" [0.50 (0.25: 1.00)].

Table 3

Acquisition and level of knowledge about HPV and its vaccine among medical students, according to grade, at the medical school of university of São Paulo, Brazil, 2016.

Questions	Grade		PR (CI95%)***	p-value	Knowledge Acquisition		Knowledge Level
	1st, 2nd and 3th year*	5th and 6th year**
1. Do you know what HPV is?	303 (94.4)	198 (99.5)	1.9 (0.9 : 1.0)	<0.01	not acquired		Suitable
2. Is HPV a virus?	320 (99.7)	199 (100)	1.0 (1.0 : 1.0)	0.32	not acquired		Suitable
3. Is HPV a sexually transmitted disease?	193 (97.8)	301 (93.8)	0.9 (0.9 : 1.0)	0.01	not acquired		Suitable
4. Can HPV cause cervical cancer?	199 (100)	315 (98.1)	1.0 (1.0 : 1.0)	0.01	not acquired		Suitable
5. Can HPV cause changes in Pap smear	276 (86.2)	199 (100)	0.9 (0.8 : 0.9)	<0.01	not acquired		Suitable
6. Is cervical cancer a leading cause of death in women?	278 (86.6)	192 (97)	0.9 (0.8 : 0.9)	<0.01	not acquired		Suitable
7. Can smoking increase the risk of cervical cancer?	159 (49.7)	150 (75.4)	0.6 (0.6 : 0.7)	<0.01	not acquired		Not suitable
8. Does the HPV vaccine prevent cervical cancer?	211 (66.1)	165 (83.8)	0.8 (0.7 : 0.9)	<0.01	adquirida		Suitable
9. Should the HPV vaccine be given before the first sexual intercourse?	232 (72.3)	149 (74.9)	1.0 (0.9 : 1.1)	0.51	not acquired		Not suitable
10. Can the HPV vaccine be given to people who have had sex?	265 (82.5)	183 (92)	0.9 (0.8 : 0.9)	<0.01	not acquired		Suitable
11. Can the HPV vaccine be harmful to your health?*	101 (31.6)	94 (47.2)	0.7 (0.5 : 0.8)	<0.01	not acquired		Not suitable
12. Can the HPV vaccine cause HPV infection?*	193 (60.3)	161 (80.9)	0.7 (0.7 : 0.8)	<0.01	Acquired		Suitable
13. Is the HPV vaccine provided by the government?	258 (80.6)	175 (88.4)	1.0 (0.8 : 1.0)	0.01	not acquired		Suitable
14. Is the HPV vaccine part of the girls' immunization records?	172 (53.6)	140 (70.7)	0.7 (0.7 : 0.9)	<0.01	not acquired		Not suitable
16. Are 3 doses required for complete vaccination?	151 (47.6)	122 (61.9)	0.8 (0.7 : 0.9)	<0.01	not acquired		Not suitable
17. Does the HPV vaccine decrease the chance of having genital warts?	210 (66.2)	127 (64.8)	1.0 (0.9 : 1.2)	0.74	not acquired		Not suitable
18. Does the HPV vaccine decrease the chance of having changes in the Pap smear test?	237 (75.2)	160 (81.6)	0.9 (0.8 : 1.0)	0.84	Acquired		Suitable
19. Do you think the HPV vaccine will stimulate the onset of sexual activity at an earlier age?*	290 (91.8)	184 (93.4)	1.0 (0.9 : 1.0)	0.49	not acquired		Suitable
20. Do you think that you still need to use a condom after HPV vaccination?	316 (100)	196 (100)	1.0	1.00	not acquired		Suitable
21. Do you think that you still need to have a Pap smear test after HPV vaccination?	314 (99.4)	196 (100)	1.0 (1.0 : 1.0)	0.16	not acquired		Suitable
22. Do you know anyone who has already received the HPV vaccine?	190 (59.9)	119 (60.4)	1.0 (0.8 : 1.1)	0.92	Not applicable		Not applicable
23. Have you received the HPV vaccine yet?	70 (22.1)	25 (12.7)	1.7 (1.1 : 2.6)	0.01	Not applicable		Not applicable
24. Would you recommend the HPV vaccine for a child, friend, or relative?	259 (82)	186 (94.4)	0.9 (0.8 : 0.9)	<0.01	Not applicable		Not applicable
28. Patients living with HIV can take the vaccine?	86 (27.4)	94 (48.4)	0.6 (0.4 : 0.7)	<0.01	Acquired / not acquired	Suitable/ Not suitable
29. Am I confident to indicate HPV vaccination for patients?	204 (65)	147 (75.8)	0.8 (0.8 : 1.0)	0.01	Not applicable	Not applicable
30. Do I feel confident giving information about HPV to patients?	140 (44.6)	147 (76.6)	0.6 (0.5 : 0.7)	<0.01	Not applicable	Not applicable
31 Can pregnant patients get the vaccine?	14 (4.5)	17 (8.8)	0.5 (0.2 : 1.0)	0.05	Acquired / not acquired	Suitable/ Not suitable

*Basic cycle: 1st 2nd and 3th graduation year

**Final cycle: 5th and 6th graduation year

***PR (CI 95%): Prevalence ratio (Confidence Interval of 95%) calculated by Poisson regression.

Suitable knowledge level was considered at 80%

The questions “should HPV vaccine be applied before first sexual intercourse?” And “does HPV vaccine reduce the chance of genital warts?” [0.96 (0.86: 1.07)]; [1.02 (0.89: 1.16)], respectively, did not show significance in the comparison between the basic and hospitalized cycle, however, showed that both groups did not have a good level of knowledge and there was no knowledge acquisition during graduation.

The main sources of information about HPV and its vaccine shown in Fig 1 and reported by participants were: “Healthcare Professionals” (40%, n = 207), “Media (TV / radio)” (28%, n = 146) and “School” (26% n = 136).

Fig 1

Sources of information on HPV and its quadrivalent vaccine among medical students.

Discussion

This study analyzed actors associated with the HPV knowledge gap and HPV vaccine acceptability among medical students. Results can support medical education given the importance of the subject in public health and the introduction of the vaccine into Brazil’s National Immunization Program in 2014 [17]. We found that males had attended first, second and third year of medical study and had not been vaccinated against HPV are related factors to gap of knowledge.

Knowledge gaps between males and females about HPV and its vaccine has been found in both medical students [18-21] and in the non-university population, corroborating our data [22,23]. While the higher level of knowledge found in females in this study is a function of the personal and individual experiences, since medical students of both sexes are exposed to the same amount of theoretical concepts before graduation [3]. In addition, a study shows that male parents underestimate the effects of HPV in males and prioritize the vaccine for women [24]. It is necessary to disseminate correct information to parents and to emphasize the fact that they are not actively involved and open to dialogue when it comes to their children's sexual education [25].

Regarding the undergraduate period, it was evidenced that students in the fists years of graduation have a greater knowledge gap than students in the final cycle. Similar results were found in the research by Yam et al, (2017) [26] and Silva et al, (2017) [27], which showed that senior medical students (3rd grade or above) have a higher level of knowledge than junior medical students (below 3rd grade). This is expected as senior students experience greater exposure to HPV classes and content.

The results show that not having been vaccinated against HPV was associated with lower levels of knowledge. Other studies have found low HPV vaccination rates among medical students was related to lack of knowledge about vaccine safety and efficacy, religious and cultural issues, and lack of government programs that cover the age range of students [28-31]. In addition, vaccination rates are higher in countries with national HPV vaccination programs [3]. Vaccinated students have been found to be more willing to recommend HPV vaccination and clarify patient questions and are more likely to follow the recommendations and take every opportunity to offer HPV vaccine [30,31].

For the question “Can smoking increase the risk of cervical cancer?” there was no knowledge acquisition throughout medical school and there was a knowledge gap between the students in the first and and last study years. Silva et al, (2017) [27] found different results in their research, showing that medical students understand that cervical cancer is associated with behavioral patterns such as smoking. Exposure, age at onset and frequency of cigarette smoking are factors that influence the incidence of cervical intraepithelial neoplasia (CIN) and cervical cancer [32]. The relation between smoking and cervical cancer should be reinforced in the medical school curriculum since smoking is a public health problem and interferes with the health-disease process.

In the question, “Should the HPV vaccine be given before the first sexual intercourse?”, Although there was no significant difference in knowledge between students of the basic and final cycle, it was observed that both have insufficient level of knowledge. This theme should be reinforced during the undergraduate years as it can be a barrier to vaccination because it is a sex-related theme and can be taboo in specific populations.

There was no acquisition of knowledge along the graduation to the question "The HPV vaccine may be harmful to health?". The vaccine is safe and approved by the World Health Organization Global Vaccine Safety Advisory Board [33]. Vaccine safety needs to be included in the undergraduate subjects, since it is in universities that the professionals responsible for transmitting information to the population are trained and thus become informers of this new technology introduced in the health system.

Programs for successful implementation of HPV vaccination include factors such as intersectoral involvement (across the education and health sector), as well as collaboration between institutions in the health, education and financial sectors. The future efforts should focus on programs that can be implemented within health care settings, such as reminder and recall strategies and physician-focused efforts, as well as the use of alternative community-based locations, such as schools [34,35].

In Brazil, in 2014, vaccine implementation had been used together with the education sector in public and private schools [33,35], bringing benefits in terms of vaccine coverage rates. Our study reinforces the themes that must be addressed during medical training in order to strengthen the physician's action in providing information and patient’s counseling. In the questions, “Are 3 doses required for full vaccination?” And “Is HPV vaccine part of the girl’s vaccination calendar?” There was no knowledge acquisition during the medical course and a knowledge gap was verified between the students of the basic cycle and the final cycle. The HPV vaccine was implanted in Brazil by PNI in March 2014, and then the vaccination schedule was modified with adjustment in the number of doses required and changes in the target population [19]. During graduation, the importance of reviewing the National Immunization Program and its updates contained in the National Health System (NHS) should be reinforced.

In the question, “Does HPV vaccine decrease the chance of having genital warts?” no knowledge acquisition occurred, and it remained inadequate in both periods. Studies show substantial effects of HPV vaccine in reducing anogenital warts and precancerous lesions [36-38].

The students in this research have significant knowledge gaps in specific questions to health professionals; as the indication of the vaccine for people with HIV and the contraindication in pregnant patients. Diverging from our results, Silva and Monteiro (2016) [39] identified in another Brazilian region that medical students demonstrated knowledge about the need for cervical cancer screening in HIV-positive women. Studies show that health professionals are important in vaccine counseling [40]. Moreover, the relationship of trust between the healthcare professional and the patient exists through clear and accessible and sometimes culturally appropriate communication and information about the HPV vaccination program [41]. This relationship is reflected in “healthcare professionals” being the main sources of information about HPV and its vaccine, followed by “Media (TV / radio)” and “School”. Williams et al, (2013) [40] points out that health care providers play a more active role in recommending HPV vaccines, and recent studies show that a patient receiving a doctor's recommendation is 4–5 times more likely to get vaccinated. Our results on information sources reinforce the importance of creating spaces on health topics for medical student self-care.

It is worth mentioning that the phenomenon called vaccine hesitation (which consists of delay in accepting or refusing vaccines, despite the availability of vaccination services) [41,42], is a fundamental determinant for low HPV vaccination rates. Studies show that potential determinants of vaccine hesitation are communication and preventive attitudes. Health professionals act as a key factor in reducing vaccine hesitation [43,44].

Studies [45-47] demonstrate the importance of the physician in primary health care setting and vaccination counseling. Furthermore, the authors describe care practices based on the patient's medical relationship and health promotion interventions based on the individual care. Our study shows information and knowledge gaps that must be acquired during the medical graduation so that the student can exercise health education and individual counseling of his patients.

Limitations of the study include the cross-sectional design which does not allow understanding over time how and when individuals gained knowledge about HPV, it is not possible to distinguish whether knowledge acquisition was a cause or a consequence according to the student's level of education, neither the individual acquisition of each student. The instrument did identify other possible associated factors such as ethnicity, culture and religion that may be associated. The data collection took place in an internationally recognized University by convenience sample and findings may not be representative of other Brazilian medical schools.

Integration between health professionals and the population is key to ensuring adequate vaccine coverage and ensuring promising vaccine results. The encouragement of information, counseling and continuing education is recommended as a strategy to broaden the acceptance of the vaccine in order to settle its implementation and ensure its effectiveness in reducing future cervical cancer cases [41,42].

Thus, our study brings the novelty of the non-acquisition of knowledge during medical school, especially among unvaccinated males on the important issues in women's and men's health. Other areas of minimal knowledge is the relationship between tobacco use and cervical cancer, the safety of vaccine, schedule and schedule used by the NHS, being allowed to administer the vaccine in HIV patients and not indicated among pregnant women.

Conclusion

Female and students in 5th and 6th years are more knowledgeable about HPV and its vaccine. Males, the basic cycle and not being vaccinated are factors associated with knowledge gaps among medical students.

The gaps in knowledge acquisition during graduation occur on the themes: relationship of tobacco with cervical cancer, safety and vaccination scheme in special populations such as immunosuppressed and pregnant women should be reinforced in the contents of medical training programs.

Knowledge about HPV and its quadrivalent vaccine among medical students by gender, medical school of university of São Paulo, Brazil, 2016.

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3 Jan 2020

PONE-D-19-33466

KNOWLEDGE GAPS AND ACQUISITION ABOUT HPV AND ITS QUADRIVALENT VACCINE AMONG MEDICAL STUDENTS

PLOS ONE

Dear Dr. Esposito Sorpreso,

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Reviewer #1: This paper examines factors associated with knowledge about HPV infection, related diseases and vaccine among medical students at the University of São Paulo, Brazil.

I am afraid that I have to recommend rejecting the present manuscript as it stands. I detail below what my reasons for doing so are and encourage the authors to improve their manuscript.

First of all, and I think this is the main problem of the paper, I noticed substantial grammar/language/syntax mistakes in the manuscript and tables. I kindly suggest you to have your paper proof read by a native speaker, if necessary multiple times, before you submit. Moreover, there is a lack of clear contribution in the present manuscript.

Title

I suggest to delete in the title and in the introduction the word “quadrivalent”. The survey questions generically explored HPV vaccine.

Introduction

In the first paragraph, the authors stated “The skills and competences acquired by these students will be used for women's health care…” Long-lasting infections with high-risk HPVs can cause cancer in different parts of the body, such as oropharynx, anus, rectum, penis, and not only in the cervix, vagina, and vulva. In developed countries, high-risk HPVs cause 3% of all cancers in women and 2% of all cancers in men. Please, clarify that the competences acquired by medical students will be also useful to protect men's health care.

I suggest to add a brief description of what the Brasil’s National Immunization Program recommend regarding HPV vaccination.

Methods

The authors described how the sample size was calculated, but the reference used for sample size calculation to estimate the prevalence was not included.

It would seem that “did not accept” to participate in the study was an ineligibility criterion, but the number of subjects who refused to answer the survey, represents a fraction of people in the total sample.

In the Instrument paragraph, no. 6), and throughout the manuscript, I suggest to replace health professionals with medical students.

Please, clarify the abbreviation “NTC”.

What the rationale of exclusion of the 4th year of medical school was? Please, specify.

I suggest to move the obtained Cronbach’s alpha value in the results section.

I suggest to delete the Bias paragraph: it is redundant since data recording is described in the Data analysis and the attempt to minimize selection bias in the Data Collection procedure.

I suggest to replace “year of graduation” with “year of medical study”.

The selection of the participants, as indicated in the Methods, reflects a classic example of a convenience sampling. Hence, the sample could be biased and not a truly random sample. This is a major limitation that undermines the validity of this study and suggests that the obtained sample could not be representative. The selection bias would have affected the external validity in terms of generalizing the findings to the wider population, and I am not sure if the attempt of the authors to minimize the selection bias was enough.

The authors should mention whether or not an incentive was offered for completion of the questionnaire.

Statistical analysis

No information is given about non-responding, if any.

Results

Please, clarify what the response rate was.

To avoid misunderstanding, I suggest to clarify what “RR” is. I suppose it refers to a ratio between two prevalences to analyse the association since the design of the study is cross-sectional (rate ratio), but it could be confused with a "relative risk".

The p- value of gender and year of study in the description of model 1 have been repeated twice. It is unnecessary p-value if the CIs were reported.

Discussion

The authors do not properly delineate discussion. The discussion is to analyze the meaning of the results, and to make them meaningful. It seems that the literature review to generate a well structured discussion and better define the theoretical framework of the research was not deep enough.

The study findings showed that male gender is a factor associated with knowledge gaps among medical students. I suggest, to comment the role of parents of male adolescents and acceptability of vaccination also among young males. The following paper have to be cited and commented: Hum Vaccin Immunother. 2014;10(9):2536-42, Hum Vaccin Immunother. 2016 Jun 2;12(6):1504-10, Hum Vaccin Immunother. 2016;12(1):47-51.

I suggest to add a comment about potential determinants of “vaccine hesitancy”, e.g. according to the WHO Strategic Advisory Group of Experts (SAGE) on Immunization. The following studies have to be cited and commented: Bianco et al. Vaccine 2019;37:984-999 and Napolitano et al. Hum Vaccin Immunother. 2018 Jul 3;14(7):1558-1565.

The authors should address the pivotal role of healthcare providers in promoting HPV vaccination in different setting and in specific risk groups. I suggest to cite and comment other studies (e.g. Napolitano F, et al. PLoS One. 2018 Mar 29;13(3):e0194920; Landis K et al. Vaccine. 2018 Jun 7;36(24):3498-3504; D’Alessandro et al. Hum Vaccin Immunother 2018;14:1573-1579; etc..).

In the limitations of the study, the authors did not mention the main limits of the cross-sectional survey.

In all Tables, please include only one decimal number.

Reviewer #2: The author provided an important topic for the paper; however, there are concerns in the manuscript.

1.Study title needs to add setting (Brazil). Title and study purposes need to revise based on study variables. For example, sources of HPV information were also explored in this study.

2.Introduction: Literature review needs to be more focused and related to the study variables and population. Please add HPV vaccination guidelines and insurance coverage in Brazil. Please add prevalence and mortality data of cervical cancer and other HPV-related diseases among men and women in Brazil.

3.Method: make eligibility and non-inclusion criteria more concise. Eligibility needs to add age criteria. Instrument- use table to list all 31 questions. It’s not clear about why 80% of correct answers was used to determine “adequate.”

4.Results: please clarify why odds ratios were performed in Table 1.

5.Discussion: Need to add more citations related to evidence-based practice and policy recommendations. Please also add study settings and location for citations.

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Reviewer #1: No

Reviewer #2: No

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6 Feb 2020

Dear Editor,

We are grateful for the considerations about our manuscript, "Knowledge Gaps and Acquisition About HPV and its Quadrivalent Vaccine Among Medical Students" (Manuscript ID: PONE-D-19-33466), to PLOS ONE.

This response letter contains a point-by-point reply to the peer reviewer’s comments, outlining the changes we have made.

Reviewer 1

Comment 1:

- Title

“I suggest to delete in the title and in the introduction the word “quadrivalent”. The survey questions generically explored HPV vaccine.”

Answer to Comment 1: We kindly appreciate the suggestion and made the necessary changes to the manuscript:

“Knowledge gaps and acquisition about HPV and its vaccine among medical students”

Comment 2:

- Introduction

“ In the first paragraph, the authors stated “The skills and competences acquired by these students will be used for women's health care…” Long-lasting infections with high-risk HPVs can cause cancer in different parts of the body, such as oropharynx, anus, rectum, penis, and not only in the cervix, vagina, and vulva. In developed countries, high-risk HPVs cause 3% of all cancers in women and 2% of all cancers in men. Please, clarify that the competences acquired by medical students will be also useful to protect men's health care.”

Answer to Comment 2: We kindly appreciate the suggestion and made the necessary changes to the manuscript:

“…The skills and competences acquired by these students will be used for men's and women's health care, especially for HPV-induced cancer (cervical, oropharynx, anus, rectum and penis) and precursor lesions at different levels of care, including health counseling and education, prevention, diagnosis, treatment and recovery”

Comment 3:

- Introduction

“I suggest to add a brief description of what the Brasil’s National Immunization Program recommend regarding HPV vaccination.”

Answer to Comment 3: We kindly appreciate the suggestion and made the necessary changes to the manuscript:

“As future health care providers, these medical students will perform preventive actions (HPV vaccination) and promotion of cervical cancer screening4, which is a high prevalence and mortality disease in Brazil and worldwide, representing a public health problem. In Brazil the HPV vaccine is available in the National Immunization Program for female population aged nine to 14 years old, male population aged 11 to 14 years old.”

Comment 4:

- Method

“The authors described how the sample size was calculated, but the reference used for sample size calculation to estimate the prevalence was not included.”

Answer to Comment 4: We agreed and made the inclusion

Reference: Agranonik, M., & Hirakata, V. N. (2011). Cálculo de tamanho de amostra: proporções. Clinical & Biomedical Research, 31(3).

Comment 5:

- Method

“It would seem that “did not accept” to participate in the study was an ineligibility criterion, but the number of subjects who refused to answer the survey, represents a fraction of people in the total sample.”

Answer to Comment 5: We kindly appreciate the suggestion

We considered inclusion only the student who agreed to participate in the research or signed the consent form and answered the questionnaire. There were no individuals who signed the term and did not respond the questionnaire.

Please consider to check our response rate per student on method.

Comment 6:

- Method

“In the Instrument paragraph, no. 6), and throughout the manuscript, I suggest to replace health professionals with medical students.”

Answer to comment 6: We kindly appreciate the suggestion and made the necessary changes to the manuscript.

Comment 7:

- Method

“Please, clarify the abbreviation “NTC”.”

Answer to Comment 7: We kindly appreciate the suggestion and made the necessary changes to the manuscript:

We replaced “NTC” with “NS (not sure).

Comment 8:

- Method

“What the rationale of exclusion of the 4th year of medical school was? Please, specify.”

Answer to Comment 8: We kindly appreciate the suggestion.

The main reason was to eliminate bias, as students in the fourth year of medical study are considered transitional, with knowledge acquired from basic cycle and also already acts as an senior student.

Comment 9:

- Method

“I suggest to move the obtained Cronbach’s alpha value in the results section.”

Answer to Comment 9: We kindly appreciate the suggestion and made the necessary changes to the manuscript.

Comment 10:

- Method

“I suggest to delete the Bias paragraph: it is redundant since data recording is described in the Data analysis and the attempt to minimize selection bias in the Data Collection procedure.”

Answer to Comment 10: We kindly appreciate the suggestion and made the necessary changes to the manuscript.

Comment 11:

- Method

“I suggest to replace “year of graduation” with “year of medical study”.”

Answer to Comment 11: We kindly appreciate the suggestion and made the necessary changes to the manuscript:

We replaced “year of graduation” with “year of medical study”.

Comment 12:

- Method

“The selection of the participants, as indicated in the Methods, reflects a classic example of a convenience sampling. Hence, the sample could be biased and not a truly random sample. This is a major limitation that undermines the validity of this study and suggests that the obtained sample could not be representative. The selection bias would have affected the external validity in terms of generalizing the findings to the wider population, and I am not sure if the attempt of the authors to minimize the selection bias was enough.”

Answer to Comment 12: We kindly appreciate the suggestion.

We consider our convenience sample as representative because it is a closed and known population. We included only students enrolled and attending a known and specific school curriculum. Still, the questionnaire was not applied in the disciplines that talked about the theme. The questionnaire was applied at the convenience and availability of the interviewers and interviewees, it was not scheduled. The interviewers were students, that is, there was no presence of the Professor that could intimidate or induce the students' response.

Under these conditions the convenience sample was applied and this will be included as a limitation in the discussion.

“Limitations of the study include the cross-sectional design which does not allow understanding over time how and when individuals gained knowledge about HPV. The instrument did identify other possible associated factors such as ethnicity, culture and religion that may be associated. The data collection took place in an internationally recognized University by convenience sample and findings may not be representative of other Brazilian medical schools.”

Comment 13:

- Method

“The authors should mention whether or not an incentive was offered for completion of the questionnaire.”

Answer to comment 13: We kindly appreciate the suggestion and made the necessary changes to the manuscript.

“A convenience sample of students from the first to sixth year of medical school were invited to participate voluntarily in the research whit no financial incentive offered to the respondents.”

Comment 14:

- Method, Statistical analysis

“No information is given about non-responding, if any.”

Answer to comment 14: We kindly appreciate the suggestion and made the necessary changes to the manuscript.

“Non-responding were represented as missing and did not exceed 5% of question-by-question responses.”

Comment 15:

- Results

“Please, clarify what the response rate was.”

Answer to comment 15: We kindly appreciate the suggestion and made the necessary changes to the manuscript.

“The response rate of the variables (questionnaire questions) was an average of 99.2% (SD 0.9%).”

Comment 16:

- Results

“To avoid misunderstanding, I suggest to clarify what “RR” is. I suppose it refers to a ratio between two prevalences to analyse the association since the design of the study is cross-sectional (rate ratio), but it could be confused with a "relative risk".”

Answer to comment 16: We kindly appreciate the suggestion and made the necessary changes to the manuscript. In fact, the “RR” represents the prevalence ratio and we will insert this into the statistical analysis in the method. We replaced relative risk (RR) for prevalence rate (PR).

Comment 17:

- Results

“The p- value of gender and year of study in the description of model 1 have been repeated twice. It is unnecessary p-value if the CIs were reported.”

Answer to comment 17: We kindly appreciate the suggestion and made the necessary changes to the manuscript. We agree and we will report only the CIs at supplementary material.

Comment 18:

- Discussion

“The authors do not properly delineate discussion. The discussion is to analyze the meaning of the results, and to make them meaningful. It seems that the literature review to generate a well structured discussion and better define the theoretical framework of the research was not deep enough.”

Answer to comment 18:

we appreciate the comment. The authors included new references and references suggested by the reviewers listed above:

References:

1- Cinar O, Ozkan S, Aslan GK, Alatas E. Knowledge and Behavior of University Students toward Human Papillomavirus and Vaccination. Asia Pac J Oncol Nurs. 2019;6:300-7.

2- Bianco A, Pileggi C, Iozzo F, Nobile CG, Pavia M. Vaccination against human papilloma virus infection in male adolescents: knowledge, attitudes, and acceptability among parents in Italy. Hum Vaccin Immunother. 2014;10(9):2536-42.

3- Napolitano F, Napolitano P, Liguori G, Angelillo IF. Human papillomavirus infection and vaccination: Knowledge and attitudes among young males in Italy. Hum Vaccin Immunother. 2016 Jun 2;12(6):1504-10.

Comment 19:

- Discussion

“The study findings showed that male gender is a factor associated with knowledge gaps among medical students. I suggest, to comment the role of parents of male adolescents and acceptability of vaccination also among young males. The following paper have to be cited and commented: Hum Vaccin Immunother. 2014;10(9):2536-42, Hum Vaccin Immunother. 2016 Jun 2;12(6):1504-10, Hum Vaccin Immunother. 2016;12(1):47-51.”

Answer to comment 19: We kindly appreciate the suggestion and made the necessary changes to the manuscript:

“While the higher level of knowledge found in females in this study is a function of the personal and individual experiences, since medical students of both sexes are exposed to the same amount of theoretical concepts before graduation1. In addition, a study shows that male parents underestimate the effects of HPV in males and prioritize the vaccine for women2. It is necessary to disseminate correct information to parents and to emphasize the fact that they are not actively involved and open to dialogue when it comes to their children's sexual education3.”

References:

1- Cinar O, Ozkan S, Aslan GK, Alatas E. Knowledge and Behavior of University Students toward Human Papillomavirus and Vaccination. Asia Pac J Oncol Nurs. 2019;6:300-7.

2- Bianco A, Pileggi C, Iozzo F, Nobile CG, Pavia M. Vaccination against human papilloma virus infection in male adolescents: knowledge, attitudes, and acceptability among parents in Italy. Hum Vaccin Immunother. 2014;10(9):2536-42.

3- Napolitano F, Napolitano P, Liguori G, Angelillo IF. Human papillomavirus infection and vaccination: Knowledge and attitudes among young males in Italy. Hum Vaccin Immunother. 2016 Jun 2;12(6):1504-10.

Comment 20:

- Discussion

“I suggest to add a comment about potential determinants of “vaccine hesitancy”, e.g. according to the WHO Strategic Advisory Group of Experts (SAGE) on Immunization. The following studies have to be cited and commented: Bianco et al. Vaccine 2019;37:984-999 and Napolitano et al. Hum Vaccin Immunother. 2018 Jul 3;14(7):1558-1565.”

Answer to comment 20: We kindly appreciate the suggestion and made the necessary changes to the manuscript:

“It is worth mentioning that the phenomenon called vaccine hesitation (which consists of delay in accepting or refusing vaccines, despite the availability of vaccination services)1, is a fundamental determinant for low HPV vaccination rates. Studies show that potential determinants of vaccine hesitation are communication and preventive attitudes. Health professionals act as a key factor in reducing vaccine hesitation2,3.”

References:

1- The Lancet Child Adolescent Health. Vaccine hesitancy: a generation at risk. Lancet Child Adolesc Health. 2019 May;3(5):281.

2- Bianco A, Mascaro V, Zucco R, Pavia M. Parent perspectives on childhood vaccination: How to deal with vaccine hesitancy and refusal? Vaccine. 2019 Feb 8;37(7):984-990. doi: 10.1016/j.vaccine.2018.12.062. Epub 2019 Jan 14.

3- Napolitano F, D'Alessandro A, Angelillo IF. Investigating Italian parents' vaccine hesitancy: A cross-sectional survey. Hum Vaccin Immunother. 2018 Jul;14(7):1558-1565.

Comment 21:

- Discussion

“The authors should address the pivotal role of healthcare providers in promoting HPV vaccination in different setting and in specific risk groups. I suggest to cite and comment other studies (e.g. Napolitano F, et al. PLoS One. 2018 Mar 29;13(3):e0194920; Landis K et al. Vaccine. 2018 Jun 7;36(24):3498-3504; D’Alessandro et al. Hum Vaccin Immunother 2018;14:1573-1579; etc..).”

Answer to comment 21:

We appreciated your comments and included the following paragraph:

“It is worth mentioning that the phenomenon called vaccine hesitation (which consists of delay in accepting or refusing vaccines, despite the availability of vaccination services), is a fundamental determinant for low HPV vaccination rates. Studies show that potential determinants of vaccine hesitation are communication and preventive attitudes. Health professionals act as a key factor in reducing vaccine hesitation.

Studies demonstrate the importance of the physician in primary health care setting and vaccination counseling. Furthermore, the authors describe care practices based on the patient's medical relationship and health promotion interventions based on the individual care. Our study shows information and knowledge gaps that must be acquired during the medical graduation so that the student can exercise health education and individual counseling of his patients.”

Comment 22:

- Discussion

“In the limitations of the study, the authors did not mention the main limits of the cross-sectional survey.”

Answer to comment 22: We agree and we will include a comment at discussion.

Limitations of the study include the cross-sectional design which does not allow understanding over time how and when individuals gained knowledge about HPV, it is not possible to distinguish whether knowledge acquisition was a cause or a consequence according to the student's level of education, neither the individual acquisition of each student.

Comment 23:

- Discussion

“In all Tables, please include only one decimal number.”

Answer to comment 23: We kindly appreciate the suggestion and made the necessary changes to the manuscript.

Reviewer 2

Comment 1:

- Title

“Study title needs to add setting (Brazil). Title and study purposes need to revise based on study variables. For example, sources of HPV information were also explored in this study.”

Answer to comment 1:

We kindly appreciate the suggestion and the changes were made according to recommendations of all reviewers: “KNOWLEDGE GAPS AND ACQUISITION ABOUT HPV AND ITS VACCINE AMONG BRAZILIAN MEDICAL STUDENTS”

Comment 2:

- Introduction

“Literature review needs to be more focused and related to the study variables and population. Please add HPV vaccination guidelines and insurance coverage in Brazil. Please add prevalence and mortality data of cervical cancer and other HPV-related diseases among men and women in Brazil.”

Answer to comment 2:

We appreciated your comments and included the following paragraph:

“The skills and competences acquired by these students will be used for men's and women's health care, especially for HPV-induced cancer (cervical, oropharynx, anus, rectum and penis) and precursor lesions at different levels of care, including health counseling and education, prevention, diagnosis, treatment and recovery2,3.”

Comment 3:

- Method

“Make eligibility and non-inclusion criteria more concise. Eligibility needs to add age criteria. Instrument- use table to list all 31 questions. It’s not clear about why 80% of correct answers was used to determine “adequate”.”

Answer to comment 3:

We appreciated your comments and resumed the eligibility and non-inclusion criteria paragraphs as follow:

“…A convenience sample of both sexes students over 18 years old from the first to sixth year of medical school were invited to participate voluntarily in the research, whit no financial incentive offered to the respondents, who signed the Informed Consent Form.

Non-inclusion criteria: Undergraduate students with cognitive problems or any interest that influences the answer to the questions contained in the data collection instrument.”

Furthermore the 31 questions were presented in a table.

We apologize and we clarify:

The good level of knowledge was classified as adequate when the percentage of correct answers exceeded 80% and was based on the previously published score in a similar population at reference:

Pereira JEG, Gomes JM, Costa AS, Figueiredo FWDS, Adami F, Santos EFS, Sorpreso ICE, Abreu LC. Knowledge and acceptability of the human papillomavirus vaccine among health professionals in Acre state, western Amazon. Clinics (Sao Paulo). 2019;74:e1166.

Comment 4:

- Results

“Please clarify why odds ratios were performed in Table 1.”

Answer to comment 4:

We apologize, the odds ratio was not used in Table 1 or in our study. The prevalence ratio was described in tables 2, 3 and supplementary material. The changes were made according to the comments of the other reviewers.

Comment 5:

- Discussion

“Need to add more citations related to evidence-based practice and policy recommendations. Please also add study settings and location for citations.”

Answer to comment 5:

We appreciated your comments and included the following paragraphs:

“Programs for successful implementation of HPV vaccination include factors such as intersectoral involvement (across the education and health sector), as well as collaboration between institutions in the health, education and financial sectors. The future efforts should focus on programs that can be implemented within health care settings, such as reminder and recall strategies and physician-focused efforts, as well as the use of alternative community-based locations, such as schools.

In Brazil, in 2014, vaccine implementation had been used together with the education sector in public and private schools, bringing benefits in terms of vaccine coverage rates. Our study reinforces the themes that must be addressed during medical training in order to strengthen the physician's action in providing information and patient’s counseling.”

We added the references below:

1) Niccolai LM, Hansen CE. Practice- and Community-Based Interventions to Increase Human Papillomavirus Vaccine Coverage: A Systematic Review. JAMA Pediatr. 2015;169(7):686-92.

2) Brotherton JML, Bloem PN. Population-based HPV vaccination programmes are safe and effective: 2017 update and the impetus for achieving better global coverage. Best Pract Res Clin Obstet Gynaecol. 2018;47:42-58.

3) Baker ML, Figueroa-Downing D, Chiang ED, Villa L, Baggio ML, Eluf-Neto J, Bednarczyk RA, Evans DP. Paving pathways: Brazil's implementation of a national human papillomavirus immunization campaign. Rev Panam Salud Publica. 2015;38(2):163-6.

Sincerely,

Isabel Cristina Esposito Sorpreso

Professor Doutor

Disciplina de Ginecologia

Departamento de Obstetrícia e Ginecologia

Faculdade de Medicina da Universidade de São Paulo

CV: http://lattes.cnpq.br/9672065408641518

ORCID: 0000-0002-5475-5957

Submitted filename: Response to reviewers.docx

Click here for additional data file.

18 Feb 2020

PONE-D-19-33466R1

KNOWLEDGE GAPS AND ACQUISITION ABOUT HPV AND ITS VACCINE AMONG BRAZILIAN MEDICAL STUDENTS

PLOS ONE

Dear Esposito Sorpreso,

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Kind regards,

Italo Francesco Angelillo, DDS, MPH

Academic Editor

PLOS ONE

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Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

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Reviewer #1: All comments have been addressed

Reviewer #3: (No Response)

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Reviewer #1: Yes

Reviewer #3: Yes

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Reviewer #1: Yes

Reviewer #3: Yes

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Reviewer #1: Yes

Reviewer #3: Yes

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Reviewer #1: Yes

Reviewer #3: Yes

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Reviewer #1: (No Response)

Reviewer #3: The topic addressed in the manuscript is important in terms of public health. It seems to me that the authors addressed properly all comments raised by the previous reviewers. The paper may be published and I have only some minor comments.

1) In the abstract, the Cronbach's alpha value of 0.74 should be reported in the results section.

2) In the results section the paragraph concerning the internal validity of the questionnaire should be at the beginning and not at the end of the section.

3) There is an error in the reporting of 95% CI of the PR concerning the year of study, both in the abstract and in the result section.

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Reviewer #1: No

Reviewer #3: No

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19 Feb 2020

Dear Reviewers,

We are grateful for the considerations about our manuscript, "Knowledge Gaps and Acquisition About HPV and its Quadrivalent Vaccine Among Medical Students" (Manuscript ID: PONE-D-19-33466), to PLOS ONE.

This response letter contains a point-by-point reply to the peer reviewer’s comments, outlining the changes we have made.

Reviewer #1

Comment 1: No comments

Reviewer #3

The topic addressed in the manuscript is important in terms of public health. It seems to me that the authors addressed properly all comments raised by the previous reviewers. The paper may be published and I have only some minor comments.

Comment 1:

“In the abstract, the Cronbach's alpha value of 0.74 should be reported in the results section.”

Answer to Comment 1: We kindly appreciate the suggestion and made the necessary changes in the abstract:

“Results: To evaluate the internal consistency of the instrument applied, the Cronbach's alpha equation was used, obtaining the alpha value (α) = 0.74 for this population. This value attests that the consistency of the answers obtained with this questionnaire is considered substantial and acceptable.”

Comment 2:

“In the results section the paragraph concerning the internal validity of the questionnaire should be at the beginning and not at the end of the section.”

Answer to Comment 2: We kindly appreciate the suggestion and put the paragraph concerning the internal validity of the questionnaire at the beginning of the section Results.

Comment 3:

“There is an error in the reporting of 95% CI of the PR concerning the year of study, both in the abstract and in the result section.”

Answer to Comment 3: We kindly appreciate the correction and made the necessary changes in the abstract and in the results section:

Abstract: “Students in the first, second and third year of study had a 51% higher risk of a knowledge gap when compared to students in the final years of graduation [PR 1.51 (1.3:1.8); p <0.001].”

Results: “It is observed that there was a difference in students by grade with first, second and thrid year students having a 51% risk of having a knowledge gap than students in the final cycle [PR 1.51 (1.3:1.8)]”

Sincerely,

Isabel Cristina Esposito Sorpreso

Professor Doutor

Disciplina de Ginecologia

Departamento de Obstetrícia e Ginecologia

Faculdade de Medicina da Universidade de São Paulo

CV: http://lattes.cnpq.br/9672065408641518

ORCID: 0000-0002-5475-5957

Submitted filename: Response to reviewers 19.02.2020.docx

Click here for additional data file.

21 Feb 2020

KNOWLEDGE GAPS AND ACQUISITION ABOUT HPV AND ITS VACCINE AMONG BRAZILIAN MEDICAL STUDENTS

PONE-D-19-33466R2

Dear Dr. Esposito,

We are pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it complies with all outstanding technical requirements.

Within one week, you will receive an e-mail containing information on the amendments required prior to publication. When all required modifications have been addressed, you will receive a formal acceptance letter and your manuscript will proceed to our production department and be scheduled for publication.

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With kind regards,

Italo Francesco Angelillo, DDS, MPH

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Reviewers' comments:

5 Mar 2020

PONE-D-19-33466R2

Knowledge Gaps and Acquisition about HPV and Its Vaccine Among Brazilian Medical Students

Dear Dr. Sorpreso:

I am pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department.

If your institution or institutions have a press office, please notify them about your upcoming paper at this point, to enable them to help maximize its impact. If they will be preparing press materials for this manuscript, please inform our press team within the next 48 hours. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information please contact onepress@plos.org.

For any other questions or concerns, please email plosone@plos.org.

Thank you for submitting your work to PLOS ONE.

With kind regards,

PLOS ONE Editorial Office Staff

on behalf of

Professor Italo Francesco Angelillo

Academic Editor

PLOS ONE