Role of literacy, fear and hesitancy on acceptance of COVID-19 vaccine among village health volunteers in Thailand.

BACKGROUND: The roles of literacy, fear and hesitancy were investigated for acceptance of COVID-19 vaccine (AV) types among village health volunteers (VHVs) in Thailand.
MATERIALS AND METHODS: A cross-sectional study was conducted using an unidentified online questionnaire to assess literacy, fear and hesitancy of COVID-19 vaccine acceptance among Thai VHVs between 1 and 15 October 2021. The questionnaire was developed based on the HLVa-IT (Health Literacy Vaccinale degli adulti in Italiano) for vaccine literacy (VL), using an adult Vaccine Hesitancy Scale (aVHS) for COVID-19 vaccine hesitancy (VH) and Fear of COVID-19 scale (FCoV-19S) for the distress of COVID-19 vaccine. The effects of VL, VH and vaccine fear (VF) on AV were estimated using multivariable logistic regression.
RESULTS: A total of 5,312 VHVs completed the questionnaire. After adjustment with variables in the multivariable analysis, the VL score was insignificantly associated with increased vaccination (aOR = 1.002; (95%CI: 0.994-1.01)), while VF and VH significantly decreased the chance of vaccination, aOR = 0.966 (95%CI: 0.953-0.978) and aOR = 0.969; (95%CI: 0.960-0.979), respectively and VF and VH were negatively associated with AV for all types of vaccine preference, with VL showing a reverse relationship only for mRNA-based vaccines.
CONCLUSION: VL may not increase AV among VHVs. To increase attitudes toward receiving COVID-19 vaccination in Thailand, the government and health-related organizations should instigate policies to significantly reduce VF and VH among Thai VHVs.

Introduction

Coronavirus disease 2019 (COVID-19) is a communicable sickness caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) [1]. COVID-19 was officially declared widespread by the World Health Organization (WHO) on 11 March 2020 [2]. Case numbers and deaths from the disease are still increasing globally [3]. COVID-19 vaccines have shown promise as a prophylactic measure for protection against infection, preventing severe symptoms and slowing the rapid spread of the disease [4-6]. As of conducting research in October 2021, global vaccination coverage was 34%, with 23% in Thailand, far below the level of herd immunity [7]. The target of vaccination in Thailand is 70% [8]. However, current vaccination coverage in May 2022 is 70.3% [7].

Previous studies reported that the acceptance rate of the COVID-19 vaccine varied by countries and different time points [9]. Vaccine acceptance rate was 37.40% in Jordan, 61.16% in Bangladesh, 56.90% in the EU, 80.00% in the USA and 63% in Africa [10-14]. Known factors contributing to the acceptance of vaccine (AV) were vaccine literacy (VL), vaccine hesitancy (VH) and vaccine fear (VF). VH and VF had a negative impact on AV, while VL [15, 16] showed a positive impact [17, 18]. Low health literacy impacts VH and may result in refusal or delay in AV [19]. A study among French adults showed that high health literacy scores were associated with the intention to get vaccinated with minimal VH [17], while U.S. college students showed higher score, were positively associated with greater willingness for COVID-19 vaccination [20]. Rapid transmission of the COVID-19 pandemic has increased the fear of virus transmission in the community. A recent study in Vietnam demonstrated that health literacy modified the effect of fear; however, on quality of life [21].

Sirikalyanpaiboon et al. conducted a survey among Thai physicians. They found that preference for particular vaccines was independently associated with VH, especially for the mRNA vaccine [22]. Another study surveyed the general population and reported the AV rate at 41.8%. As well as adenovirus-based and mRNA-based vaccines, an inactive vaccine type is also available in Thailand. Acceptance rate increased from 89.0% to 91.3% if people could select the vaccine brand and 80.7% to 83.2% for brands recommended by healthcare professionals [23].

To combat the outbreak of COVID-19 in Thailand, the Ministry of Public Health recruited 1.04 million village health volunteers (VHVs) throughout the nation to help contain the spread of the disease. The emphasis was on humanizing and updating people about the cause, prevention and treatment of diseases. The first COVID-19 vaccine arrived in Thailand in February 2021 and the Thai Prime Minister encouraged VHVs to boost public confidence in this vaccine. Later, novel variants of COVID-19 and new vaccines arrived in Thailand. The VHVs assisted in communicating vaccine information to the public [24, 25] and encouraged the acceptance of the vaccine as a positive way to reduce the spread of the disease.

As aforementioned, few studies have examined the relationship between VL, VF and VH on AV, particularly by vaccine types, while no studies have been conducted in Thailand, especially among VHVs who are at the frontline of all community health matters and influence vaccine perceptions of community members. Therefore, this research investigated the consequences of VL, VF and VH on AV among VHVs in Thailand.

Research methodology

Study design and settings

We conducted a cross-sectional study between 1 and 15 October 2021 via the online platform of VHVs in Thailand.

Study samples and data collection

Eligible participants in this study were VHVs aged over 18 and registered in the mobile application SMART VHV. The total number of Thai registered mobile application SMART VHVs aged over 18 in 2021 was 254,743 people [26], with 137,782 records available for contact. A nonprobability snowball sampling method was adopted based on the 137,782 registered SMART VHVs through the social platforms Line and Facebook as the two most popular social media platforms in Thailand and used by VHVs to communicate and coordinate with each other.

First, we asked for cooperation with VHV leaders according to their responsible health areas. We uploaded our questionnaire to their social media and the representative VHV leaders forwarded the questionnaire to Line or Facebook groups for completion by their VHVs. The study subjects were screened for inclusion criteria including age and registration of mobile application SMART VHV. Eligible participants were asked to sign an informed consent form by clicking on it. After signing the informed consent, the structured questionnaire appeared on their screens. The participants completed and submitted the questionnaire via the online platform Google Form. They were free to withdraw at any time and the survey took approximately 10 minutes to complete. All completed questionnaire was stored via Google Form. SMART VHVs who lack of address information and incomplete filling questionnaire were excluded. A total of 5,312 VHVs responded to our survey (Fig 1).

Fig 1

Flow chart of sample collection.

Instruments and measurements

The questionnaire was designed and pretested by the researchers after an extensive literature review. Our questionnaire was self-rated and asked about demographic characteristics, VL, VF, VH and AV. Details of instruments, tools and measurements are presented below.

Demographic data

Demographics included the following data: sex, age, educational level, marital status, religion, occupation, medical condition, family income and work experience.

Vaccine literacy (VL)

A self-rated VL questionnaire including three domains as functional, communicative and critical was developed. The VL questionnaire was adapted from the Health Literacy Vaccinale degli adulti in Italiano (HLVa-IT) [27]. The VL questionnaire was composed of 12 items (questions) including functional VL (items L1 to L5), for example, “I did more research on the COVID-19 vaccine”, “I know where to find information on the COVID-19 vaccine”, communicative VL (items L6 to L10), for example, “I have consulted or received advice regarding the COVID-19 vaccine from a doctor, nurse or healthcare professional”, “I can analyze the quality or accuracy of the information I find on the COVID-19 vaccine” and critical VL (items L11 to L12), for example, “I pass on the correct information about the COVID-19 vaccine to others”. Answers were supplied by the interviewees according to a Likert scale with four possible choices (4-never, 3-rarely, 2-sometimes and 1-often). Scores were calculated using the mean value of each scale response ranging from 1 to 4, with higher values indicating greater VL.

Vaccine fear (VF)

A 5-item questionnaire was conducted to estimate the fear of COVID-19 vaccine, with a four-point Likert scale used to examine whether or not people were apprehensive of vaccination, ranging from 1 to 4 as 4-never, 3-rarely, 2-sometimes and 1-often. Examples of items included, “I am very afraid of having to get vaccinated against COVID-19”, and “I am afraid of dying from vaccination against COVID-19”. The aggregate score was the total scores of the 5 items ranging from 5 to 20, with a higher total demonstrating greater fear of the COVID-19 vaccine.

Vaccine hesitancy (VH)

Our VH questionnaire was adapted from Akel Kb et al. as the so-called Hesitancy Scale (aVHS) [28]. The VH had 7 items with a five-point Likert scale as answer choices, ranging from 1 to 5 as 5-strongly disagree, 4-disagree, 3-neutral, 2-agree and 1-strongly agree. Examples of the items included “The COVID-19 vaccine is very important to me”, and “The COVID-19 vaccine currently in use in Thailand is effective”. The aggregate score was the total of each item score ranging from 7 to 35, with a higher total demonstrating greater hesitancy toward the COVID-19 vaccine.

Acceptance of COVID-19 vaccine (AV)

The AV had two choices (1: yes, 0: no). The purpose was to collect evidence on the tolerability of COVID-19 inoculation. For example, “Do you accept to be vaccinated against COVID-19”. If the answer ‘yes’ was selected, a choice of vaccine types was available in Thailand. These included 2 doses of inactive types (Sinovac and Sinopharm), 2 doses of adenovirus-based (AstraZeneca), 2 doses of mRNA-based vaccine (Pfizer and Moderna) and Cocktail (mixed type).

All questionnaire was written in the Thai language and the generated items were evaluated for content validity. Three experts as one doctor, one nurse and one researcher with extensive experience in the area of health literacy were invited to review the questionnaire for content validity. Content rationality determines whether the content of a scale is capable of calculating what it is planned to satisfy the research objective. Content validity and reliability were first tested for 30 participants and assessed using the index of item objective congruence (IOC). The IOC value was more than 0.7 for the whole questionnaire, while Cronbach’s alpha coefficients were 0.85, 0.86 and 0.85 for VL, VH and VF, respectively. Mean scores and standard deviations (SD) of 5,312 VHVs were VL 33.83 (SD: 7.55), VF 11.35 (SD: 4.58) and VH 24.72 (SD:7.45), with Cronbach’s alpha coefficients for VL, VH and VF 0.89, 0.91 and 0.90, respectively.

Ethical approval and consent to participate

The study was reviewed and approved by the Institutional Ethical Review Board of the Faculty of Public Health, Chiang Mai University (IRB No.ET033/2021). Consent from the participants was obtained by asking them to sign an informed consent form by clicking on it. No animals were used in this research. All human research procedures were in accordance with the ethical standards of the committee responsible for human experimentation (institutional and national) following the Helsinki Declaration of 1975, revised in 2013.

Statistical analysis

Definite facts were stated as figures and proportions, while incessant facts were summarized as means with standard deviations or medians with ranges (minimum: maximum) when continuous variables showed non-normal distribution.

The associations between VL, VF, VH, various demographic variables and AV were examined using logistic regression, with the outcomes stated as crude odds ratio (OR) and adjusted odds ratio (aOR) at 95%CI. VL, VF, and VH score were summed up individually and treated in models as a continuous independent variable. Significant features in the univariate analysis were employed as candidate variables in the initial model of multivariable analysis using backward elimination. The associations between VL, VF, VH, various demographic variables and AV were also examined by vaccine preference types in separate models using both univariate and multivariable analyses. A random effect by province was expected; however, low intraclass correlation coefficient results were recorded (ICC: 0.0535), and random effects were not assessed in this study. Statistical significance was set at p<0.05. All examinations were conducted using Stata version 15.

Results

Demographic features

A total of 5,312 Thai VHVs completed the questionnaire via Google Form. Most VHVs who responded to our study were female (84.19%), aged 50–60 years old (36.09%), with work experience of less than 10 years (47.27%). Approximately 50% of VHVs had a high school education, a career in agriculture and no comorbidity. Most had an average monthly income of less than 10,000 baht and were couples (73.89%) and Buddhist (84.58%). Median VHV scores of VL, VF and VH were 2.92, 2.40 and 3.43, respectively.

Of the VHVs who accepted vaccination, a higher proportion (column percentage) preferred mRNA (56.52%), were female (85.22%), aged 50–60 years old (36.31%), had a high school education (54.34%), were couples (74.16%), Buddhist (86.09%), had a career in agricultural (46.88%), had no comorbidity (60.51%), had average monthly income of less than 10,000 baht (45.66%) and work experience of less than 10 years (45.66) (Table 1).

Table 1

Demographic, literacy, fear and hesitancy vaccine scores of Thai village health volunteers.

Variable	Vaccinated n (%)	Unvaccinated n (%)
Preferred type of vaccine
None	-	2200 (100)
Inactivated	503 (16.16)	-
Adenovirus	665 (21.37)	-
mRNA	1759 (56.52)	-
Cocktail	59 (1.90)	-
Any	126 (4.05)	-
Sex
Male	460 (14.78)	380 (17.27)
Female	2652 (85.22)	1820 (82.73)
Age
<40	472 (15.17)	377 (17.14)
40–50	989 (31.78)	608 (27.64)
50–60	1130 (36.31)	787 (35.77)
≥ 60	521 (16.74)	428 (19.45)
Education
Illiterate	12 (0.39)	19 (0.86)
Elementary School	1020 (32.78)	940 (42.73)
High School	1691 (54.34)	1038 (47.18)
Vocational Certificate	389 (12.50)	203 (9.23)
Marital status
Single, widowed	804 (25.84)	583 (26.50)
Couple	2308 (74.16)	1617 (73.50)
Religion		-
Buddhist	2679 (86.09)	1814 (82.45)
Christian	54 (1.74)	34 (1.55)
Islam	379 (16.00)	352 (12.18)
Occupation
Agriculture	1459 (46.88)	1004 (45.64)
Own business	533 (17.13)	380 (17.27)
Freelancer	826 (26.54)	578 (26.27)
Government officer	26 (0.84)	13 (0.59)
Private employee	32 (1.03)	29 (1.32)
Unemployed	236 (7.58)	196 (8.91)
Comorbidity
None	1883 (60.51)	1275 (57.95)
Diabetes	239 (7.68)	228 (10.36)
Hypertension	452 (14.52)	295 (13.41)
Hyperlipidemia	129 (4.15)	90 (4.09)
Obesity	61 (1.96)	56 (2.55)
Bone and skeletal disorder	64 (2.06)	56 (2.55)
Other	284 (9.13)	200 (9.09)
Income per month
< 10,000 baht	2173 (69.83)	1722 (78.27)
≥ 10,000 baht	939 (30.17)	478 (21.73)
Work experience
<10 years	1421 (45.66)	1090 (49.55)
≥10 < 20 years	1031 (33.13)	618 (28.09)
≥20 years	660 (21.21)	492 (22.36)
Vaccine literacy score median (IQR)	2.92 (0.75)
Vaccine fear score median (IQR)	2.40 (1.60)
Vaccine hesitancy score median (IQR)	3.43 (1.57)

Effect of literacy, fear and hesitancy scores on recognition of COVID-19 inoculation

Table 2 shows the literacy, fear and hesitancy scores for AV. The univariate analysis results showed that each incremental unit of VL score significantly increased AV by 1.4% (OR = 1.014; 95%CI: 1.006–1.021), while, by contrast, fear and hesitancy scores significantly decreased AV by 4.4% (OR = 0.956; 95%CI: 0.944–0.967) and 3.7% (OR = 0.963; 95%CI: 0.954–0.971), respectively. After adjustment by variables in the multivariable analysis including sex, age group, education, religion, income and work experience, the VL score had a non-significant but modest effect on AV (aOR = 1.002; 95%CI: 0.994–1.01), while VF and VH significantly decreased the chance of AV (aOR = 0.966; 95%CI: 0.953–0.978) and 0.969 (0.960–0.979). Age group (40–50 years old vs <40 years old), education (high school, vocational certificate or higher level vs illiterate), religion (Islam and Buddhist), income (≥ 10,000 baht vs < 10,000 baht) and work experience (≥10 < 20 years, ≥20 years vs <10 years) were significantly associated with AV in the multivariable model.

Table 2

Effect of literacy, fear and hesitancy scores on acceptance of COVID-19 vaccine.

Variable	Crude OR	95%CI	Adjusted OR	95%CI
Vaccine literacy score	1.014	1.006–1.021	1.002	0.994–1.010
Vaccine fear score	0.956	0.944–0.967	0.966	0.953–0.978
Vaccine hesitancy score	0.963	0.954–0.971	0.969	0.960–0.979
Sex
Male	1		1
Female	1.204	1.037–1.396	1.123	0.963–1.309
Age group
<40	1		1
40–50	1.299	1.097–1.538	1.288	1.076–1.541
50–60	1.147	0.974–1.350	1.168	0.970–1.407
≥ 60	0.972	0.807–1.171	1.001	0.805–1.246
Education
Illiterate	1		1
Elementary School	1.718	0.829–3.558	1.427	0.675–3.017
High School	2.579	1.246–5.335	2.145	1.015–4.535
Vocational Certificate	3.034	1.444–6.374	2.404	1.118–5.165
Marital status
Single, widowed	1		-	-
Couple	1.035	0.914–1.171	-	-
Religion
Buddhist	1		1
Christian	1.075	0.697–1.658	1.130	0.723–1.765
Islam	0.729	0.623–0.852	0.571	0.688–0.797
Occupation
Agriculture	1		-	-
Own business	0.965	0.827–1.126	-	-
Freelancer	0.983	0.860–1.123	-	-
Government officer	1.376	0.703–2.691	-	-
Private employee	0.759	0.456–1.263	-	-
Unemployed	0.829	0.674–1.017	-	-
Comorbidity
None	1		-	-
Diabetes	0.710	0.584–0.862	-	-
Hypertension	1.037	0.881–1.221	-	-
Hyperlipidemia	0.971	0.734–1.282	-	-
Obesity	0.738	0.509–1.067	-	-
Bone and skeletal disorder	0.774	0.536–1.115	-	-
Other	0.961	0.791–1.167	-	-
Income per month
< 10,000 baht	1		1
≥ 10,000 baht	1.557	1.371–1.767	1.385	1.213–1.581
Work experience
<10 years	1		1
≥10 < 20 years	1.280	1.126–1.453	1.252	1.092–1.434
≥20 years	1.029	0.893–1.184	1.030	0.899–1.233

-: variable did not reach statistical significance in univariate analysis and was not included in the multivariable model

Association of literacy, fear and hesitancy scores on acceptance of COVID-19 vaccination by preference type

The impact of VL score on AV differed for vaccine preference type (Table 3). The VL score showed a significant reverse effect on AV among VHVs who preferred mRNA vaccine (aOR = 0.984; 95%CI: 0.969–0.998), while VL scores increased the chance of AV in the remaining types of vaccines but not significantly. VF score was significantly associated with reduction of AV in VHVs who expected inoculation with inactive and adenovirus vaccines (aOR = 0.933; 95%CI: 0.901–0.966) and (0.917; 95%CI: 0.899–0.935), respectively. VH scores had a significant reverse effect on AV for most preference vaccine type in VHVs. The aOR values were 0.937 (95%CI: 0.912–0.963) for inactive vaccine, 0.947 (95%CI: 0.933–0.961) for adenovirus vaccine and 0.963 (95%CI: 0.945–0.982) for mRNA vaccine. The effects on other variables adjusted in the multivariable model by vaccine preference type are shown in the (S1 Table).

Table 3

Effect of literacy, fear and hesitancy scores on vaccine acceptance by preference type.

	Vaccine types
	Inactive a		Adenovirus b		mRNA c		Cocktail d
	aOR	95%CI	aOR	95%CI	aOR	95%CI	aOR	95%CI
Vaccine literacy score	1.000	0.980–1.020	1.010	0.994–1.018	0.984	0.969–0.998	1.013	1.000–1.027
Vaccine fear score	0.933	0.901–0.966	0.917	0.899–0.935	0.990	0.965–1.016	0.993	0.972–1.014
Vaccine hesitancy score	0.937	0.912–0.963	0.947	0.933–0.961	0.963	0.945–0.982	0.986	0.971–1.002

a: adjusted odds ratio (aOR) of literacy, fear and hesitancy scores for sex, age, occupation and comorbidity

b: adjusted odds ratio (aOR) of literacy, fear and hesitancy scores for sex, age, income and work experience

c: adjusted odds ratio (aOR) of literacy, fear and hesitancy scores for sex, age and income

d: adjusted odds ratio (aOR) of literacy, fear and hesitancy scores for sex, age, religion, comorbidity and income

Discussion

Several studies have investigated influencing factors connected with the reception of COVID-19 vaccination; however, few considered VL, VF and VH as predictors for AV, while none were conducted among VHVs in Thailand. Therefore, this study investigated the effect of VL, VF and VH on rapid contagious disease vaccination acceptance. The acceptance rate among Thai VHVs was 58.6%. After adjustment for demographic variables, VF and VH were significantly associated with decreasing VA, while VL was not significant in increasing vaccination of VHVs.

The AV rate of VHVs was moderate compared with the general population in other countries, ranging from 37.4% to 90% [10-14]. Vaccination acceptance was lower than among healthcare workers. A previous study of physicians in a university-based teaching hospital in Thailand found that better VL was inversely related to VH (aOR 0.34; 95% CI 0.13–0.9; p = 0.029) [22]. Parents with higher VL preferred to vaccinate their children compared to those with lower VL [29]. This is implying the role of VL in reducing VH and increasing AV. In the univariate analysis of our study, VHVs with high VL had stronger AV. There has been considerable discussion about the relationship between VL and the adoption of the COVID-19 vaccine. Numerous studies have suggested that high levels of VL contribute to AV. People with low VL have difficulty accessing health information, leading to poor vaccine decision-making. Individuals with high VL are able to access, comprehend, analyze, assess and disseminate vaccine information to others [30]. Therefore, encouraging individuals to have high levels of overall health literacy and VL would have a positive effect and improve access to and use of health information. Thus, understanding overall health literacy, as well as VL, is important for specific immunization situations [31]. However, analysis of variables in the multivariable analysis indicated that VL was not statistically significantly related to AV, while AV was influenced by other factors apart from VL [17]. After adjustment with variables in the multivariable analysis, the VL score was non-significantly positively associated with AV, implying that AV was influenced by other factors and not VL per se.

We also investigated the association between VH and AV among VHVs and found a significant negative association between hesitancy and acceptance, implying that an increase in VH may reduce AV. VH is a long-standing phenomenon that poses a severe threat to global health and some infectious illnesses have recently resurfaced [32]. The WHO defines vaccination apprehension as ‘delay in acceptance or refusal of vaccination despite the availability of vaccination services’, while vaccine acceptance refers to the likeliness to get vaccinated [33, 34]. VH has long been a serious global issue [35], while COVID-19 inoculation indecision may be the tip of the iceberg of overall serum uncertainty in Thailand.

Among VHVs, higher fear levels were related to lower acceptance of COVID-19 inoculation. VF was the foremost cause of non-acceptance and had an undesirable impact on COVID-19 inoculation recognition in line with other previous findings [36, 37]. Fear is defined as an unfriendly expressive state produced by the insight of a threatening incentive [38]. As a result, increasing epidemic length heightens the qualms of the public and impacts their happiness and psychological health [38, 39]. Several studies reported that more cultured and knowledgeable people suffered less distress from COVID-19, highlighting the necessity of teaching and transparent public health policies. VHVs are intermediate communicators between healthcare professionals and people in the community; thus, the studying findings are generalized and limited to these groups.

The impact of VL, VF and VH on AV was further investigated for preferred vaccine types available in Thailand as inactive, adenovirus, mRNA and cocktail. Previous studies suggested that VL increased AV, [40, 41]. Our results indicated that VL insignificantly increased the chance of vaccination with inactive (OR = 1.002; 95%CI: 0.982–1.022), adenovirus (aOR = 1.011; 95%CI: 0.999–1.022) and Cocktail types (aOR = 1.008; 95%CI: 0.994–1.021). VL had a borderline impact on VHVs who wished to be vaccinated with the adenovirus-based type. The adenovirus has long been developed, manufactured and used in the real world for preventing diseases such as highly pathogenic avian influenza and Ebola [42-44]. The adenovirus vaccine showed an acceptable efficacy of 76%, higher than the inactive type (Sinovac had an efficacy of 51%) [45]. Hence, increasing VL may lead VHVs to seek, judge and decide to choose adenovirus. The effect of VL was reversely significant on those who preferred mRNA type, while the mRNA vaccine was associated with an increase in VH (aOR 8.86; 95% CI 1.1–71.54; p = 0.041) [22]. The mRNA showed promising efficacy in COVID-19 prevention and is comparatively new compared with the inactive and adenovirus-based types. In the past in Thailand, fake news about the safety or efficacy of vaccines has been released with details unconfirmed by experts [46]. This has impacted the trust and acceptance of vaccines by some Thai people. Those with higher VL may have the ability to source information and decide to not select mRNA, instead choosing previously demonstrated vaccine types such as adenovirus-based.

Both VF and VH were associated with acceptance or willingness to receive the vaccination [47-50], while broadly based studies revealed that fear of the disease encouraged vaccination [48, 51, 52]. Our team also investigated the impact of VF and VH on AV. Results showed that both VF and VH were associated with decreasing AV in all types of vaccines. VF and VH caused vaccination refusal from the fear of adverse side effects, safety and efficacy concerns and the short duration of clinical trials, with more information desired on vaccine approval mechanisms [53, 54]. Other studies also reported that vaccine hesitancy and refusal occurred due to concerns about safety, general lack of trust and doubts about the efficiency and provenience of the vaccine [55, 56].

From the public health viewpoint, our study was conducted on Thai VHVs as intermediate mediators between government health professionals and the public. We believe that convincing this group of people will encourage people in the community to receive COVID-19 vaccines. Based on our findings, the government should not pay attention to the VL of VHVs but instead focus on minimizing VF and VH to convince VHVs to accept vaccination as worthwhile.

This study had certain limitations. First, our study was conducted among Thai VHVs, with results generalized to health volunteers or healthcare workers. Data were not collected among VHVs in all provinces, and did not take into account random effects by province; however, the study participants included representatives of each region in Thailand. Second, the participation rate was low compared to the total eligible number of VHVs because no compensation or rewards were offered to those who completed the questionnaire. Further studies should attract more samples by providing remuneration for those who completed the survey. Third, the study results did not reflect true vaccination numbers because vaccines available in Thailand were restricted to inactivated types. Therefore, AV was only related to preference vaccine types. Finally, online data collection relates to population samples and their non-random nature. The researchers had no control over who and how many people filled out the questionnaire. As a result, most of the samples were women and this caused the data to be skewed. In Thai society, men are the main income earners of the family, while women stay at home or work at home. Therefore, more women apply for work as VHVs to perform community healthcare duties, working mostly during the day.

Conclusions

Our cross-sectional study revealed that VL may not be a factor contributing to the acceptance of COVID-19 vaccination among VHVs in Thailand. Increasing VL obstructed VHVs who accepted to be vaccinated with the mRNA-based vaccine. To boost their vaccination acceptance, the government or health-related departments should focus on reducing VF and VH in Thailand.

Effect of literacy, fear and hesitancy vaccine score on acceptance by COVID-19 vaccine types: Univariate and multivariable analysis.

(DOCX)

Click here for additional data file.

(XLSX)

Click here for additional data file.

8 Mar 2022

A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'.

A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'.

An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'.

If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter.

If applicable, we recommend that you deposit your laboratory protocols in protocols.io to enhance the reproducibility of your results. Protocols.io assigns your protocol its own identifier (DOI) so that it can be cited independently in the future. For instructions see: https://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols. Additionally, PLOS ONE offers an option for publishing peer-reviewed Lab Protocol articles, which describe protocols hosted on protocols.io. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols.

We look forward to receiving your revised manuscript.

Kind regards,

Wenping Gong, Ph.D.

Academic Editor

PLOS ONE

Journal Requirements:

When submitting your revision, we need you to address these additional requirements.

1. Please ensure that your manuscript meets PLOS ONE's style requirements, including those for file naming. The PLOS ONE style templates can be found at

https://journals.plos.org/plosone/s/file?id=wjVg/PLOSOne_formatting_sample_main_body.pdf and

" ext-link-type="uri" xlink:type="simple">https://journals.plos.org/plosone/s/file?id=ba62/PLOSOne_formatting_sample_title_authors_affiliations.pdf"

2. Please provide additional details regarding participant consent. In the ethics statement in the Methods and online submission information, please ensure that you have specified what type you obtained (for instance, written or verbal, and if verbal, how it was documented and witnessed). If your study included minors, state whether you obtained consent from parents or guardians. If the need for consent was waived by the ethics committee, please include this information.

Once you have amended this/these statement(s) in the Methods section of the manuscript, please add the same text to the “Ethics Statement” field of the submission form (via “Edit Submission”).

For additional information about PLOS ONE ethical requirements for human subjects research, please refer to http://journals.plos.org/plosone/s/submission-guidelines#loc-human-subjects-research.

3. Thank you for stating the following in the Acknowledgments Section of your manuscript:

"This research is supported by the Center of Excellence in Community Health Informatics, Chiang Mai University. The authors would like to acknowledge the village health volunteer network in Thailand for distributing the online survey. "

We note that you have provided funding information that is not currently declared in your Funding Statement. However, funding information should not appear in the Acknowledgments section or other areas of your manuscript. We will only publish funding information present in the Funding Statement section of the online submission form.

Please remove any funding-related text from the manuscript and let us know how you would like to update your Funding Statement. Currently, your Funding Statement reads as follows:

"This study was granted by the Center of Excellence in Community Health Informatics, Chiang Mai University, Chiang Mai, Thailand."

Please include your amended statements within your cover letter; we will change the online submission form on your behalf.

4. We note that you have indicated that data from this study are available upon request. PLOS only allows data to be available upon request if there are legal or ethical restrictions on sharing data publicly. For more information on unacceptable data access restrictions, please see http://journals.plos.org/plosone/s/data-availability#loc-unacceptable-data-access-restrictions.

In your revised cover letter, please address the following prompts:

a) If there are ethical or legal restrictions on sharing a de-identified data set, please explain them in detail (e.g., data contain potentially sensitive information, data are owned by a third-party organization, etc.) and who has imposed them (e.g., an ethics committee). Please also provide contact information for a data access committee, ethics committee, or other institutional body to which data requests may be sent.

b) If there are no restrictions, please upload the minimal anonymized data set necessary to replicate your study findings as either Supporting Information files or to a stable, public repository and provide us with the relevant URLs, DOIs, or accession numbers. For a list of acceptable repositories, please see http://journals.plos.org/plosone/s/data-availability#loc-recommended-repositories.

We will update your Data Availability statement on your behalf to reflect the information you provide.

5. Your ethics statement should only appear in the Methods section of your manuscript. If your ethics statement is written in any section besides the Methods, please move it to the Methods section and delete it from any other section. Please ensure that your ethics statement is included in your manuscript, as the ethics statement entered into the online submission form will not be published alongside your manuscript.

6. Please include captions for your Supporting Information files at the end of your manuscript, and update any in-text citations to match accordingly. Please see our Supporting Information guidelines for more information: http://journals.plos.org/plosone/s/supporting-information.

[Note: HTML markup is below. Please do not edit.]

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Partly

**********

2. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: No

**********

3. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: No

**********

4. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: No

**********

5. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: The authors use cross-sectional data collected from a large and diverse sample of Thai village health volunteers to determine what factors are associated with COVID vaccination intentions. Results indicate that vaccine hesitance and fear are both associated with lower likelihood of getting vaccinated. The theoretical contribution is small, but there is considerable value in studying health behaviors in non-WEIRD (western, educated, industrialized, rich and democratic) countries. However, the manuscript has important shortcomings. There are data limitations, analytic errors, and the writing is unacceptable (e.g., there are numerous grammatical errors). These problems appear to be fixable, though doing so will require considerable effort.

Given the numerous opportunities for improvement, I organize my review in the order in which I first observed each problem.

- The introduction is unfocused and often off topic. This manuscript promises to make a modest empirical contribution, documenting attitudes associated with vaccine acceptance in Thailand. The introduction should explain this succinctly, summarizing what is known about other part of the world and explaining why readers might expect Thailand to be different.

- The description of the sample (page 4 line 100-) and of the procedures for collecting data (page 6 line 163-) do not appear entirely consistent. For example, the former implies that participants were registered users of a mobile app called “SMART VHV.” The latter says that participants were recruited using a form of snowball sampling via social media (Facebook and Line). I encourage the authors to combine these two sections and to carefully edit the content for clarity and consistency.

- There are important details missing from the description of the sampling. For example, how many individuals were invited to participate? See the AAPOR guidelines for reporting survey data.

- The authors imply that the sample is diverse and largely unbiased, but descriptive feature (page 7 line 195) suggest that it is highly skews (e.g., 84% female)

- Figure 1 is missing

- The description of the measures (starting on page 5) appears to contain many errors. For example, how can a 12-item scale include items numbered 11-15? And how can the same item numbers be used in several scales?

- When describing a scale, the authors should also report the M, SD, and alpha.

- What the authors describe as vaccine literacy appears to tap several different ideas, include efficacy. If this is an established scale, a cite would help.

- What the authors describe as vaccine hesitancy includes questions about effectiveness and perceived importance. If this is an established scale, a cite would help.

- The authors reject the use of a random effect based on the ICC (page 7 line 189). They should report the ICC.

- In the text, the authors say that participants were asked to specify their preferred vaccine if they indicated willingness to be vaccinated (page 6 line 148). However, Table 1 reports vaccine preference among those who do not wish to be vaccinated.

- The occupation categories in Table 1 are not mutually exclusive (e.g., employee and private employee).

- If the authors want to demonstrate that the association between vaccine fear and acceptance is conditioned on the individual’s vaccine preference, it would be more appropriate to test whether preference moderates the influence of fear when estimating acceptance.

- The discussion is too long and covers too many topics (including several that we not mentioned in the results section). As with the introduction, the manuscript would be more compelling if the authors restricted their comments to their most important contributions.

=== Potential PLOS policy violations ===

The authors checked the box indicating that the data will publicly available, but then write, “The datasets used and /or analyzed during the current study are available from the corresponding author on reasonable request.”

Participants were not allowed to submit the questionnaire if they skipped questions (page 7 line 175). Every US-based IRB that I have worked with requires that participants be allowed to refuse to answer questions.

**********

6. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: No

[NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.]

While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org. Please note that Supporting Information files do not need this step.

18 Apr 2022

Thank you very much for your fruitful comments. We have revised the manuscript following your suggestions and comments. We hope our revision would satisfy your expectation. Please find our point-by-point response below.

Comments to the Author

Reviewer #1: The authors use cross-sectional data collected from a large and diverse sample of Thai village health volunteers to determine what factors are associated with COVID vaccination intentions. Results indicate that vaccine hesitance and fear are both associated with lower likelihood of getting vaccinated. The theoretical contribution is small, but there is considerable value in studying health behaviors in non-WEIRD (western, educated, industrialized, rich and democratic) countries. However, the manuscript has important shortcomings. There are data limitations, analytic errors, and the writing is unacceptable (e.g., there are numerous grammatical errors). These problems appear to be fixable, though doing so will require considerable effort.

Given the numerous opportunities for improvement, I organize my review in the order in which I first observed each problem.

1. The introduction is unfocused and often off topic. This manuscript promises to make a modest empirical contribution, documenting attitudes associated with vaccine acceptance in Thailand. The introduction should explain this succinctly, summarizing what is known about other part of the world and explaining why readers might expect Thailand to be different.

Ans: We have re-written the whole introduction following your suggestions. (Page 3, line 51-91)

2. The description of the sample (page 4 line 100-) and of the procedures for collecting data (page 6 line 163-) do not appear entirely consistent. For example, the former implies that participants were registered users of a mobile app called “SMART VHV.” The latter says that participants were recruited using a form of snowball sampling via social media (Facebook and Line). I encourage the authors to combine these two sections and to carefully edit the content for clarity and consistency.

Ans: We totally agreed. We have combined the two sections. We first described about the registered SMART VHV, for these user group use social media (Line and Facebook). After that we described how we inform and distribute our online questionnaire. (page 4, line: 91-112)

3. There are important details missing from the description of the sampling. For example, how many individuals were invited to participate? See the AAPOR guidelines for reporting survey data.

Ans: We have revised the manuscript stated that “A nonprobability sampling so called the snowball sampling was adopted based on the 137,782 registered SMART VHV in our study through the social platform (Line and Facebook) in that these two social media are the most popular in Thailand and numbers of VHV use it to communicate and coordinate with each other.” (Page 4, line: 100-102)

4. The authors imply that the sample is diverse and largely unbiased, but descriptive feature (page 7 line 195) suggest that it is highly skews (e.g., 84% female)

Ans: This research is online data collection, and we did not specify the respondent. We understand that it will cause the data to be skewed. We therefore consider it a limitation of the present studies. (page 15, line 318-323). Moreover, Thai society men need to be the main income earner of the family and have to work outside while women are at home or working at home. Therefore, it is more likely that women will apply for VHV, which is obliged to perform community health care duties, which work mostly during the day.

5. Figure 1 is missing

Ans: We have submitted the Fig 1 (separate file).

6. The description of the measures (starting on page 5) appears to contain many errors. For example, how can a 12-item scale include items numbered 11-15? And how can the same item numbers be used in several scales?

Ans: We sincerely apologize for misunderstood in the use of characters. We explain that we planned to utilize the letter l (lowercase l) for the questions in the Vaccine Literacy (VL), which resembles the number 1. So, for the questions in this category, we've changed it to capital L for clarification. (page 5, line 127, 129 and 131-132).

7.When describing a scale, the authors should also report the M, SD, and alpha.

Ans: Thank you for your suggestions, we have reported the mean, SD and alpha as written in page 8 line 184-187. “Based on the present study, the mean score and standard deviation (SD) of VL was 33.83 (SD: 7.55), VF was 11.35 (SD: 4.58), and VH was 24.72 (SD:7.45). Cronbach’alpha coeffiecnt for VL, VH and VF were 0.89, 0.91 and 0.90, respectively.” (Page 6, line: 164-166)

8. What the authors describe as vaccine literacy appears to tap several different ideas, include efficacy. If this is an established scale, a cite would help.

Ans: The VL questionnaire was adapted from Vaccine Literacy Questionnaire-Italy (HlVa-IT) of Biasio LR. et al. (2020). We have added this reference in the Methods section. (Page 5, line 125-126)

9. What the authors describe as vaccine hesitancy includes questions about effectiveness and perceived importance. If this is an established scale, a cite would help.

Ans: The VH questionnaire was adapted from Hesitancy Scale (aVHS) of Akel HT. et al. (2021). We have added this reference in the Methods section. (Page 6 line: 144-145)

10. The authors reject the use of a random effect based on the ICC (page 7 line 189). They should report the ICC.

Ans: We have reported the ICC which was 0.053570. (page 7, line 186)

11. In the text, the authors say that participants were asked to specify their preferred vaccine if they indicated willingness to be vaccinated (page 6 line 148). However, Table 1 reports vaccine preference among those who do not wish to be vaccinated.

Ans: We have noted and corrected our mistaken of reporting number in table 1. (Page 9)

PS: we also re-checked our results and have corrected the number report in Table 2 and Table 3 of adjusted OR.

12. The occupation categories in Table 1 are not mutually exclusive (e.g., employee and private employee).

Ans: Thank you very much for your comments. We have changed the word from employee to freelancer in all Tables.

13. If the authors want to demonstrate that the association between vaccine fear and acceptance is conditioned on the individual’s vaccine preference, it would be more appropriate to test whether preference moderates the influence of fear when estimating acceptance.

Ans: Thank you very much for your idea about testing of whether preference moderates the influence of fear when estimating acceptance. We did try to analyze but it is impossible to do so, since our questionnaire design was that for those who only chose accepted to get vaccine can later choose the preference types. Therefore, it cannot take the preference type as a covariate in the logistic model.

Accept to get shot

Preference type of vaccine No Yes

No 2,200 0

Inactivated 0 503

Adenovirus 0 665

mRNA 0 1,759

Cocktail 0 59

Any 0 126

Total 2,200 3,112

As a result, we decided to analyze the association between VL, VF, VH, and AV in different model based on each preference type of vaccine, adjusted by other variables. We have showed in our univariate, the effect of fear itself on acceptance by vaccine types were not different according to the Odd ratio in the univariate analysis.

14 The discussion is too long and covers too many topics (including several that we not mentioned in the results section). As with the introduction, the manuscript would be more compelling if the authors restricted their comments to their most important contributions.

Ans: Thank you very much for your suggestions. We have revised our discussion follow our main aim and results. We arranged the discussion to follow first the result of factors associated with overall acceptance (Table 2) then factors associated with preferences types of vaccine (Table 3). Implication limitation and conclusion. (Page 12-15, line 234-330)

=== Potential PLOS policy violations ===

The authors checked the box indicating that the data will publicly available, but then write, “The datasets used and /or analyzed during the current study are available from the corresponding author on reasonable request.”

Ans: All relevant data are within the paper and its Supporting Information files.

Participants were not allowed to submit the questionnaire if they skipped questions (page 7 line 175). Every US-based IRB that I have worked with requires that participants be allowed to refuse to answer questions.

Ans: We would like to extend our meaning of the sentence “Participants were not allowed to submit the questionnaire if they skipped questions” and make it clearer that is participants can allow to refuse to answer the question, or don’t participate, or stop doing the questionnaire at any time. There is a function of google form that you need to answer all question before submitting. We select this function, for we can protect an incomplete missing data. However, there are still have some variable or questions (We did not set up the function) that were incomplete as show in Figure 1.

Submitted filename: Response to reviewer.docx

Click here for additional data file.

1 May 2022

3 May 2022

Thank you very much for your fruitful comments. We have revised the manuscript following your suggestions and comments. We hope our revision would satisfy your expectation. Please find our point-by-point response below.

Review Comments to the Author

Reviewer #2:

The authors have done a thorough revision of the manuscript based on previous comments. However, there are some parts still need to be revised further to make the manuscript better. Please find below a few comments for your consideration.

Introduction

1. Authors presented the vaccination coverage in Thailand as of October 2021. It would be better if the figures for the current vaccination coverage in the country is presented.

Ans: We have stated the current vaccination coverage in May 2022 is 70.3%. (Page 3; line: 58-59)

2. In the introduction, the authors presented the COVID-19 acceptance rates around the world. To make this information complete, the status in Africa could be added. For instance: https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0260575

Ans: We have added the recommended reference as in the sentence “Vaccine acceptance rate was 37.40% in Jordan, 61.16% in Bangladesh, 56.90% in the EU, 80.00% in the USA and 63% in Africa [10-14]”. (Page 3; line: 62)

3. The introduction still needs to be revised further for grammatical and presentation errors.

Authors should include the month in 2021 when the first batch of the COVID-19 vaccines arrived Thailand.

Ans: The first COVID-19 vaccine arrived in Thailand in February 2021 and the Thai Prime Minister encouraged VHVs to boost public confidence in this vaccine. Later, novel variants of COVID-19 and new vaccines arrived in Thailand (Page 4; line: 81)

Methods

4. “Questionnaires” should be rewritten as “questionnaire” all through the manuscript.

Ans: We have rewritten from questionnaires to questionnaire.

5. The authors have not stated the exclusion criteria used in the selection of the participants.

Ans: SMART VHVs who lack of address information and incomplete filling questionnaire were excluded. (Page 4-5; line 110-111)

6. Authors should provide the citations/references of the extensive literature used in this study.

Ans: We have provided citations/references of literature as recommendation.

7. Authors did not explain how the literacy, fear, and hesitancy scores were calculated before being used in the univariate and regression analysis. Ideally, this explanation should appear under the statistical analysis section.

Ans: VL, VF, and VH score were summed up individually and treated in models as a continuous independent variable. (Page 7, line: 181-182)

Results

8. In Table 1, the heading of the first row should be: Vaccinated n (%) Unvaccinated n (%)

Ans: We have revised accordingly.

Discussion

Has been improved upon.

Reviewer #3:

Paper by Dr. Wungrath et al. treated social and psychological factors associated with acceptance of COVID-19 vaccine in Thailand. I would like to present comments to improve the manuscript.

[Major]

1. Introduction section may be relatively lengthy. To introduce readers to Methods and Results, shorter introduction may be effective.

Ans: We shorten the introduction part as recommend.

2. As a reader, I would like the authors to explain vaccine literacy score, vaccine fear score, and vaccine hesitancy score, briefly.

Ans: We have briefly explained all scores as mentioned in the methods part. (Page 5-6; line: 124-150)

3. Table 3: I am interested in the results of pooled analysis of varied types of vaccines.

Ans: The pooled analysis result (all type of vaccines) have been shown in Table 2.

4. Table 3: Showing the results of the results of non-adjusted analysis may increase the understanding of this study results.

Ans: Thank you very much for your suggestions. We totally agree. However, we also concern about containing too many tables. Therefore, we put the overall results, showing both non-adjusted and adjusted results in the manuscript (Table 2). We provide the non-adjusted and adjusted full results varied by vaccine types in supporting information (S1 Table).

[Minor]

5. Many abbreviations may interrupt readers to smoothly read the manuscript. Key abbreviations could be spelled out.

Ans: We have reduced some abbreviations. However, according to the journal regulation about abbreviations stated that “Do not use non-standard abbreviations unless they appear at least three times in the text”. Therefore, we keep other key abbreviations in the manuscript.

Submitted filename: Reponse to Reviewers.docx

Click here for additional data file.

2 Jun 2022

Role of Literacy, Fear and Hesitancy on Acceptance of COVID-19 Vaccine among Village Health Volunteers in Thailand

PONE-D-22-04125R2

Dear Dr. Jukkrit Wungrath ,

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

Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication.

An invoice for payment will follow shortly after the formal acceptance. To ensure an efficient process, please log into Editorial Manager at http://www.editorialmanager.com/pone/, click the 'Update My Information' link at the top of the page, and double check that your user information is up-to-date. If you have any billing related questions, please contact our Author Billing department directly at authorbilling@plos.org.

If your institution or institutions have a press office, please notify them about your upcoming paper to help maximize its impact. If they’ll be preparing press materials, please inform our press team as soon as possible -- no later than 48 hours after receiving the formal acceptance. 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.

Kind regards,

Wenping Gong, Ph.D.

Academic Editor

PLOS ONE

14 Jun 2022

PONE-D-22-04125R2

Role of Literacy, Fear and Hesitancy on Acceptance of COVID-19 Vaccine among Village Health Volunteers in Thailand

Dear Dr. Wungrath:

I'm 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 let them know about your upcoming paper now to help maximize its impact. If they'll be preparing press materials, 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.

If we can help with anything else, please email us at plosone@plos.org.

Thank you for submitting your work to PLOS ONE and supporting open access.

Kind regards,

PLOS ONE Editorial Office Staff

on behalf of

Dr. Wenping Gong

Academic Editor

PLOS ONE