Young at risk-people in Maputo City, Mozambique, present a high willingness to participate in HIV trials: Results from an HIV vaccine preparedness cohort study.

INTRODUCTION: Vaccine efficacy testing requires engagement of willing volunteers with high disease incidence. We evaluated factors associated with willingness to participate in potential future HIV vaccine trials in Maputo, Mozambique.
METHODS: Adults aged 18-35 years without HIV and who reported at least two sexual partners in the 3 months prior to screening were enrolled into a 24-month observational study. They were asked at screening and exit if they would be willing to participate in a theoretical HIV vaccine study. Bivariate and multivariate logistic regression analyses were done between willingness to participate, demographic, sexual behavior, and motivational factors for screening visit data. Logistic regression with generalized estimating equations (GEE) was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for factors potentially associated with willingness to participate for data from both visits.
RESULTS: A total of 577 participants without HIV were eligible, including 275 (48%) women. The mean age was 22.2 (SD ± 3.9) years. At screening 529 (92%) expressed willingness to participate and the proportion remained stable at 378 (88%) of the 430 participants retained through the exit visit (p = 0.209). Helping the country (n = 556) and fear of needles (n = 26) were the top motive and barrier for willingness to participate, respectively. Results from the GEE binary logistic regression (screening visit and exit visit) showed that wanting to learn how to avoid risk behaviors (aOR 3.33, 95% CI: 1.61-6.86) and feeling protected against HIV infection (aOR 2.24, 95% CI: 1.07-4.7) were associated with willingness to participate in HIV vaccine studies.
CONCLUSION: The majority of our study population in Mozambique expressed willingness to participate in a theoretical HIV vaccine trial. Participation in a HIV vaccine trial was seen as a way to contribute to the fight against HIV but was associated with some unrealistic expectations such as protection against HIV. This reinforces the need for continuous mobilization and awareness of potential participants to HIV vaccine trial.

Introduction

The burden of the HIV epidemic in Mozambique, a country with almost 28 million inhabitants, is high [1]. HIV prevalence in Mozambique’s capital, Maputo City is 21.7% for women and 11.0% for men, aged 15–49 years [2].

Vaccines are considered one of the primary strategies for preventing infectious diseases. An effective HIV vaccine would prove a turning point on the path to achieving zero new HIV transmissions in Mozambique [3-5]. Mozambique has successfully conducted two HIV vaccine clinical trials, a phase I trial and a phase II trial, using HIV-DNA as a prime and modified vaccinia virus Ankara (HIV-MVA) as a boost [6,7], and is currently conducting additional vaccine trials [8] in a global effort to develop an HIV vaccine that is safe, affordable and efficacious for different populations [9].

A wide range of social and behavioral frameworks have been designed to improve the implementation of HIV preventive studies, resulting in a consensus that emphasis should be placed on socio-behavioral components, including the assessment of willingness to participate (WTP) in HIV vaccine studies [10-14].

Literature reviews have reported different hypothetical willingness to participate results from studies conducted in the same and/or different places, with the same and/or different populations. A myriad of factors such as safety of experimental HIV vaccines, distrust of those involved with clinical research, and risk of discrimination because of participation in HIV vaccine studies, have been identified as key factors influencing hypothetical willingness to participate. However, the importance of these factors also varies over time, populations, and contexts. Also important is the fact that, hypothetical willingness to participate, does not guarantee actual participation in a vaccine trial [15,16].

Identifying new factors and exploring underlying factors that can influence willingness to participate can help to explain the differences observed in willingness to participate in different communities [10,13]. This prompts for the need to continually evaluate whether individuals at risk for HIV infection would be willing to participate in HIV vaccine trials and to identify factors that could serve as barriers or facilitators for trial participation in a detailed and contextualized manner [17,18].

Relatively few willingness to participate studies have been conducted in low-income countries in Africa, including Mozambique. To our knowledge, there are no reports of willingness to participate studies conducted in Maputo city, which have assessed willingness to participate over a period of time with the same participants [15,16,19]. Therefore, we evaluated factors associated with willingness to participate in future HIV vaccine trials during a two-year HIV incidence cohort study in Maputo City, Mozambique.

Methods

Study design and population

The RV363 study was a prospective observational HIV-incidence cohort study. It was conducted between November 2013 and October 2017 at the Centro de Investigação e Treino em Saúde da Polana Caniço (CISPOC), a health research and training center of Instituto Nacional de Saúde (INS). CISPOC has experience in conducting HIV vaccine clinical trials and is located in a populated low-income suburban area of Maputo city, Mozambique [8]. Inclusion criteria for the cohort study were age 18–35 years and self-report of at least two sexual partners in the 3 months prior to screening. HIV status was assessed using the Alere Determine™ HIV-1/2 rapid test (Alere Inc, Waltham, USA) with reactive tests confirmed using the Uni-Gold™ Recombigen® HIV-1/2—for HIV 1 and 2 (Trinity Biotech, Bray, Ireland). Women of child-bearing potential were required to have a negative urine pregnancy test. Co-enrollment in any other HIV prevention study was not allowed. Participants who were eligible for the cohort study, were without HIV, and who answered the survey questions about willingness to participate in future HIV vaccine trials were included in these analyses.

Sample size

The sample size was calculated considering a hypothetical incidence of at least 3% and prevalence of 16.1%, and a response rate of 50%. The expected retention rate was 85% over a 2-year follow-up period.

Study procedures

Participants were evaluated every 3 months for up to 24 months, with HIV testing and extensive questionnaires as previously described [20]. Participants were required to pass a test of comprehension to confirm their understanding of the study procedures before signing the informed consent form. Paper-based questionnaires were administered to each volunteer by a trained staff member (face-to face interviews) at screening and at the exit visit 24 months later. Questionnaires collected data on participant demographics, sexual behaviors, and willingness to participate in future HIV vaccine trials.

Questionnaires

HIV vaccine knowledge

Participants were asked “if a vaccine is meant to prevent illness” (true/false) and if they had received information on HIV research (yes/no) prior to their participation in the study, including the source of information.

Willingness to participate questionnaire

First, the staff member would give a brief explanation of the purpose of HIV vaccine clinical trials to the participant before proceeding to the main question, “would you be willing to participate in such a study to test an experimental HIV vaccine?” (yes/no/someone else should decide/refused to answer/don´t know). Next, participants had to indicate factors that could influence participation in a HIV vaccine study. Participants were asked to select barriers for not wanting to participate in a HIV vaccine trial, and to select personal benefits of participating in a study of an HIV vaccine. Facilitators for participation in a HIV vaccine study were assessed with the question “how likely or unlikely would you be to enroll in a research study of a new experimental HIV vaccine”, and responses were collected on a 4-point Likert scale: very unlikely, somewhat unlikely, somewhat likely, and very likely. Motives for wanting to participate in a HIV vaccine study were assessed with the question “how important are the following factors in making a decision about participating in a research study of an experimental HIV vaccine”, with responses also collected on a 4-point Likert scale: not important at all, somewhat important, important, and very important. The last question was if the participant thought that an HIV vaccine would be useful in controlling HIV infection (yes/no). Participants could select all applicable answers for questions with more than one option. The questionnaire used can be found as S1 Table.

Statistical analyses

Demographic variables (age, gender, level of education, marital status, income, main occupation, history of blood transfusion, desire to get pregnant) [16,21] and sexual behavior variables (age of first sexual intercourse and perceived risk for HIV infection) [22,23] included in the analyses were selected based on literature review. Expressed Willingness to Participate was the dependent variable and was determined by a “yes or no” question, with “do not know” and “refused to answer” as the other options. Only 17 participants chose “do not know” as an option and 0 participants chose “someone else should decide” or “refused to answer”, but these were removed for bivariate and multivariate analysis. Likert scale questions were dichotomized from a set of 4 categories: “unlikely” (questionnaire responses “very unlikely” and “somewhat unlikely”) and “likely” (questionnaire responses “somewhat likely” and “very likely”); “not important” (questionnaire responses “not important at all” and “somewhat important”) and “important” (questionnaire responses “important” and “very important”). Frequencies and proportions for all variables were calculated. Two analytical approaches were employed, based on the status of the participants’ visit assessments. For the screening assessment, bivariate analysis was done between willingness to participate (yes/no), demographic, sexual behavior, and willingness to participate factors. Differences were assessed with Chi-square and Fisher’s exact test when appropriate. Willingness to participate factors that were statistically significant (p<0.05) in unadjusted logistic regression models were included in the adjusted logistic regression model at the baseline assessment. Analyses were performed among participants who stayed throughout the study, to identify factors associated with willingness to participate. McNemar’s exact test was used to assess the differences in responses within the participants, at screening and at the exit visit, and variables with p<0.05 were included in a generalized estimating equation (GEE) logistic regression for binary outcomes model. Analyses were performed using STATA 15.1 (StataCorp, College Station, TX).

Ethical approval

This study was approved by the National Health Bioethics Committee of Mozambique (IRB00002657), and by the Institutional Review Board Ethics Committee of the Walter Reed Army Institute of Research (IRB00000794). Administrative approval was granted by the Ministry of Health of Mozambique.

Results

Demographic and sexual behavioral characteristics

From 1150 screened volunteers, 577 were eligible for inclusion in this analysis, all of whom responded to the question about willingness to participate in a future HIV vaccine trial. Their characteristics are shown in Table 1. Briefly, 275 (48%) were female, the mean age was 22.2 (SD ± 3.9) years, 67% of the participants did not complete the secondary level of education. Most of the participants were single (82%) and 87% earned less than 5,000 meticais (~USD147) [24] per month, which is around the minimal national wage salary. Only 10% of the participants reported being older than 18 years of age when they had their first sexual intercourse, and almost all (94%) acknowledged that they had at least some risk of acquiring HIV. Of the 577 eligible participants who were also without HIV, 505 participants enrolled and of these 75 (15%) did not respond to the willingness to participate questionnaire at the exit visit. Independence test between levels of education revealed that participants with only primary school completed (p<0.001) were more likely to drop-out before the exit visit. The exit visit was completed by 430 participants who remained at risk for HIV.

Table 1

Selected demographic and sexual behavior characteristics of 577 eligible HIV negative participants by willingness to participate at screening in a HIV-incidence cohort study (RV363 study).

	Willingness to Participate (N = 577)
	No	Yes	Do not Know
Age (categorized), n (%)
18–20	14 (2)	225 (39)	2 (0)
21–24	14 (2)	191 (33)	5 (1)
25–35	10 (2)	113 (20)	3 (1)
Gender
Male	23 (4)	272 (47)	7 (1)
Female	15 (3)	257 (45)	3 (1)
Highest level of Education attained, n (%)
≤ Primary school completed	3 (1)	54 (9)	0 (0)
Secondary school not completed	23 (4)	306 (53)	2 (0)
≥ Secondary school completed	12 (2)	169 (30)	8 (1)
Marital Status, n (%)
Single	32 (6)	434 (75)	9 (2)
Cohabiting or married	5 (1)	77 (13)	1 (0)
Separated or divorced	1 (0)	17 (3)	0 (0)
Monthly income in metical’s, n (%)
≤ 5000	32 (6)	459 (79)	10 (2)
>5000	6 (1)	70 (12)	0 (0)
Main occupation, n (%)
Student	22 (4)	292 (50)	7 (1)
Occasional Work	4 (1)	26 (5)	0 (0)
Permanent work	10 (2)	146 (25)	0 (0)
N/A a)	68 (12)
Ever received blood transfusion, n (%)
No	35 (6)	506 (88)	9 (2)
Yes	1 (0)	20 (3)	1 (0)
N/A a)	5(1)
Desire to get pregnant in the next year (n = 275 females only), n (%)
No	8 (3)	227 (83)	2 (1)
Yes	4 (1)	30 (11)	2 (1)
N/A a)	2 (1)
Age (years) of first sexual intercourse, n (%)
< 15 years old	10 (2)	81 (14)	1 (0)
15–18 years old	20 (3)	368 (64)	5 (1)
≥ 18 years	6 (1)	49 (8)	3 (0)
N/A a)	34 (6)
Perceived risk for HIV infection, n (%)b)
No risk	3 (0)	25 (4)	0 (0)
Some risk	32 (6)	459 (80)	9 (2)
High risk	0	38 (7)	1 (0)
N/A a)	10 (2)

a) N/A—data not available. Only shown for variables ≥ 1% of data missing.

b) Question phrased as “How would you classify your risk for getting infected with HIV”.

WTP in a HIV vaccine study

Of the 577 HIV negative participants eligible at screening, 529 (92%) said they would be willing to participate in an HIV vaccine study, 38 (7%) were not willing and 10 (2%) indicated that they did not know (Fig 1). Participants who were not willing to participate, were single 32 (6%), reported a monthly income of less than 5,000 meticais 35 (6%) (Table 2). At the exit visit, 430 (75%) participants were still active in the study and willingness to participate in a HIV vaccine study remained high, with 378 (88%) willing to participate in an HIV vaccine trial, 35 (8%) not willing, and 17 (4%) who said that they didn’t know (Fig 1). Among the 430 participants who stayed throughout the duration of the study, 392 indicated willingness to participate in a vaccine trial at entry. Of these 392, 360 (92%) maintained their willingness, 19 (5%) became not willing, and 13 (3%) became undecided. Of the 28 participants who initially were not willing to participate, 14 (50%) maintained their unwillingness, 12 (43%) became willing, and 2 (7%) became undecided. For 10 participants who initially stated that they did not know if they would participate in a HIV vaccine trial, 6 became willing, 2 became unwilling and 2 stayed undecided.

Fig 1

Willingness to participate of 577 HIV negative participants at baseline, and of 430 HIV negative participants who completed the 24 months follow-up period.

Table 2

Association analysis between HIV vaccine knowledge, benefits, barriers, facilitators and motives with willingness to participate in HIV vaccine studies among the RV363 participants, by visit status.

Willingness to Participate Factors	Total Eligible N = 577	Visit Status		p-valuea
		Screening Visit (n = 430)	Exit Visit (n = 430)
Purpose of a Vaccine is to prevent illness—n/N (%)	546 (95) *	407(95) *	417 (97)	0.090
Had any previous information on HIV vaccine research, prior to participation—n/N (%)	223 (39)	175 (41)
Source of Previous information regarding HIV vaccine research—n/N (%)
Hospital/clinic/health worker	43 (7)	35 (8)	30 (7)	0.398
Radio/Tv	143 (25)	112 (26)	113 (26)	0.917
Friend/relative	71 (12)	56 (13)	42 (10)	0.016
Internet	12 (2)	10 (2)	30 (7)	<0.001
Poster	4 (1)	2 (0)	22 (5)	<0.001
Learned from a vaccine trial volunteer	3 (1)	3 (1)	4 (1)	0.706
Research center	7 (1)	7 (2)	24 (6)	0.002
Personal benefits of participating in Vaccine study- n/N (%)
Learn how to avoid risky behavior	529 (92)	398 (93)	352 (82)	<0.001
Feel protected from HIV infection	531 (92)	394 (92)	372 (87)	0.002
Get free HIV counselling and testing	496 (86)	369 (86)	273 (63)	<0.001
Receive updated information about HIV/AIDS	368 (64)	276 (64)	253 (59)	0.045
Get small reimbursement	83 (14)	67 (16)	18 (4)	<0.001
Be tested for sexually transmitted infection	527 (91)	389 (90)	311 (72)	<0.001
Receive regular health care related to research	373 (65)	289 (67)	206 (48)	<0.001
Get free pregnancy test every 3 months (N = 275 females)	195 (71)	137 (50)	63 (23)	<0.001
Barriers that could make you not participate in a vaccine study- n/N (%)
Fear of needle	26 (5)	22 (5)	23 (5)	0.847
Fear of getting HIV	1 (0)	1 (0)	5 (1)	0.103
Fear of side effects	15 (3)	10 (2)	7 (2)	0.405
Fear of death	1 (0)	1 (0)	2 (0)	0.564
Fear of fetal abnormalities	10 (2)	9 (2)	7 (2)	0.480
Time required for visits	1 (0)	1 (0)	8 (2)	0.008
Fear of testing HIV positive	1 (0)	1 (0)	4 (1)	0.180
Fear of discrimination	2 (0)	2 (0)	1 (0)	0.564
How likely would you enroll in research study of a new experimental HIV vaccine if (likelyb)—n/N (%)
Required to come every 3 months to study center on a specific day	571 (99)	425 (99)	427 (99)	1.0000
Required to talk about study experiences with a nurse	571 (99)	425 (99)	427 (99)	1.0000
Required to test for HIV every 3 months	569 (99)	423 (98)	427 (99)	0.317
Required to be injected with a HIV study vaccine a few times	541 (94)	401 (93)	422 (98)	0.706
Required to give blood samples every time that you attend a study visit	554 (96)	413 (96)	422 (98)	0.564
The center was open for weekend visits	552 (96)	409 (95)	422 (98)	0.103
Required to use contraceptive during study participation (N = 275 females)	214 (78)	153 (56)	172 (63)	0.178
Which factors are important for your decision to participate in a study of an experimental HIV vaccine (motives) (importantc)—n/N (%)
Helping vaccine research	548 (95) *	405 (94) *	429 (100)	<0.001
Helping fighting HIV/AIDS	549 (95) *	408 (95) *	429 (100)	0.003
Positive family support	463 (80) *	343 (80) *	426 (99)	<0.001
Meet new people	488 (85) *	359 (83) *	426 (99)	<0.001
Helping the community	553 (96) *	408 (95) *	429 (100)	0.002
Helping the country	556 (96) *	412 (96) *	430 (100)	0.002
Helping research of HIV Vaccine	554 (96) *	411 (96) *	429 (100)	0.007
Perceived as HIV positive	16 (3) *	11 (3) *	237 (55)	<0.001
Perceive as High-risk person for HIV infection	9 (2) *	7 (2) *	233 (54)	<0.001
Unable to have sex intercourse	19 (3) *	11 (3) *	231 (54)	<0.001
People refusing contact	16 (3) *	10 (2) *	227 (53)	<0.001
Preventive vaccine will work—n/N (%)	573 (99) *	426 (99) *	428 (100)	1.0000

a. McNemar’s exact test.

n/N = numbers of participants who answered yes, likely or important/total numbers of participants who answered.

b. Likely = composite of somewhat likely and very likely.

c. Important = composite of important and very important.

* Data missing.

HIV vaccine knowledge

At baseline, 546 (95%) participants indicated that the purpose of a vaccine is to prevent illness and 223 (39%) indicated that they had received any information on HIV vaccine research prior to study participation. The main source of information was radio/television in (n = 143, 25%), followed by friends (n = 71, 12%) and hospital (n = 43, 7%) (Table 2). Friends/relatives became a less important source of information (n = 56, 13%) vs. n = 42, 10%), (p = 0.016) at the end of the study, in contrast the internet become a more significant source of information (n = 12, 2% vs. n = 30, 7%), (p = 0.001).

Factors that could influence HIV vaccine trial participation

Table 2 also shows the perceived personal benefits and motives that could influence decision to participate in an HIV vaccine trial for the 577 participants at screening. Feeling protected from HIV infection (n = 531, 92%), learning how to avoid HIV infection (n = 529, 92%), and free testing for sexually transmitted infections (n = 527, 91%) were the three most commonly reported personal benefits of vaccine study participation. Positive social motives for participants’ decision to participate in a HIV vaccine study were helping the country (n = 556, 96%), helping the research of HIV Vaccine (n = 554, 96%), and helping the community (n = 553, 96%). Negative social motives were unable to have sex intercourse (n = 19, 3%), perceived as HIV positive (n = 16, 3%) and people refusing sexual contact (n = 16, 3%). Perceived barriers to participation in an HIV vaccine study included fear of needles (n = 26, 5%), fear of side effects (n = 15, 3%) and fear of fetal abnormalities (n = 10, 2%). When comparing data from enrollment to the 24-month visit among participants who provided information at both time-points, the proportion of perceived personal benefits of study participation tended to decrease over time while the proportion of both positive and negative social motives for study participation increased (Table 2). No statistically significant differences over time were observed for barriers to participation. When presented with various theoretical study design elements, most participants self-reported being Very Likely to enroll in a research study for a new experimental HIV vaccine (Fig 2).

Fig 2

Self-reported likelihood of enrolling in a research study for an experimental HIV vaccine, by theoretical study design elements.

Asterisk (*) indicates for only female. Due to bar size, percentage values of less than 4% were not shown; only subjects who provided a valid response to the question were included.

Predictors of willingness to participate in HIV vaccine trial

Bivariate analysis among the participants at screening visit revealed that participants who had their sexual debut between the ages of 15–18 had an odds ratio (OR) of 2.27 (95% CI: 1.02–5.04) times more likely to be willing to participate in a HIV vaccine study when compared to those whose sexual debut was before age 15 (Table 3). Perceived personal benefits of participating in an HIV vaccine study that were significantly associated in analysis with WTP include learning how to avoid risky behavior (OR 9.37, 95% CI:4.42–19.89), and feeling protected from HIV infection (OR 7.17, 95% CI:3.31–15.50). We also found that HIV vaccine trial attributes, such as having to receive an experimental HIV vaccine (OR 14.84, 95% CI: 6.02–36.6), and being required to donate blood samples (OR 7.69, 95% CI: 2.53–23.35) were associated with WTP. Multivariate analysis was adjusted for variables with p<0.05 and age as controller (Table 3). Factors identified as significant in the bivariate analysis, such as aged of sexual debut being between the ages 15–18 (aOR 2.39, 95% CI: 1.01–5.66) wanting to learn how to avoid risk behavior (aOR 4.28, 95% CI: 1.40–13.07), and feeling protected from infection (aOR 3.41, 95% CI: 1.27–9.20), were also significant in the multivariate analysis (Table 3).

Table 3

Binary and multivariate logistic regression analysis of selected factors associated with willingness to participate in HIV vaccine studies, among participants of the RV363 study, at screening visit.

Variables	Willingness to participate
	Screening visit assessment (n = 567)a)
	Bivariate Analysis		Multivariate Analysisb)
	OR (CI 95%)	p-value	aOR (CI 95%)	p-value
Age (ref: 18–20 years)
21–24 years	0.85 (0.39–1.83)	0.675	0.93 (0.39–2.23)	0.876
25–35 years	0.70 (0.30–1.63)	0.412	0.95 (0.36–2.52)	0.921
Gender (ref: male)
Female	1.45 (0.74–2.84)	0.280
Education (ref: ≤ Primary school completed)
Secondary school not completed	0.74 (0.21–2.55)	0.632
≥ Secondary school completed	0.78 (0.21–2.88)	0.712
Age of first sexual intercourse (ref: < 15 years old)
15–18 years old	2.27 (1.02–5.04)	0.043	2.39 (1.01–5.66)	0.046
≥ 18 years	1.01 (0.35–2.95)	0.988	0.87 (0.27–2.84)	0.819
Perceived Risk for HIV infection (ref: No risk)
Some risk	1.72 (0.49–6.01)	0.395
Previous to this study did you received information regarding HIV Vaccine research (ref: No)
Yes	0.86 (0.44–1.68)	0.662
Which of these sources have you received information about HIV vaccine research? (ref: None)
Hospital/clinic/health worker	0.66 (0.22–1.95)	0.450
Radio/Tv	0.80 (0.39–1.66)	0.548
Friend/relative	1.21 (0.42–3.52)	0.724
Research center	0.42 (0.05–3.62)	0.433
Benefits of participating in Vaccine study (ref: No)
Learn how to avoid risky behavior	9.37 (4.42–19.89)	<0.001	4.28 (1.40–13.07)	0.011
Feel protected from HIV infection	7.17 (3.31–15.51)	<0.001	3.41 (1.27–9.20)	0.015
Get free HIV counselling and testing	2.81 (1.33–5.93)	0.007	1.00 (0.35–2.89)	1.00
Receive updated information about HIV/AIDS	1.69 (0.87–3.27)	0.121
Get small reimbursement	1.43 (0.49–4.13)	0.513
Be tested for sexually transmitted infection	5.26 (2.43–11.42)	<0.001	1.48 (0.47–4.70)	0.503
Receive regular health care related to research	1.76 (0.91–3.41)	0.094	1.29 (0.60–2.76)	0.513
How important are the following factors in making a decision about participating in a research study of an experimental vaccine? (ref: Not Important)
Helping vaccine research	0.82 (0.11–6.31)	0.848
Receiving support from family and friends	1.17 (0.49–2.76)	0.726
Meet new people	1.34 (0.54–3.36)	0.530
Helping the community	1.00 (0.13–7.78)	1.000
Perceived as HIV positive	0.94 (0.12–7.31)	0.949
Perceive as High-risk person for HIV infection	0.43 (0.05–3.6)	0.436

a) 10 participants who answered “Don’t know” were not included in analysis.

b) The multivariable analysis is a complete-case analysis, n = 534, and adjusted for all significant variables with p<0.05 and age as a controller.

OR Odds Ratio.

CI Confidence Interval.

aOR Adjusted Odds Ratio.

Among the 430 participants who stayed through the course of the study, results from the GEE binary logistic regression (screening visit and exit visit) showed that wanting to learn how to avoid risk behaviors (aOR 3.33, 95% CI: 1.61–6.86) and feeling protected against HIV infection (aOR 2.24, 95% CI: 1.07–4.7) were associated with willingness to participate in HIV vaccine studies. The perceived risk for HIV infection (aOR 1.90, 95% CI: 0.99–3.63) shows positive association, although remaining borderline significant (Table 4).

Table 4

Multivariate analysis using generalized estimation equation of factors associated with willingness to participate in HIV vaccine studies, among participants who complete the RV363 study (screening visit and exit visit).

Variables	GEE Analysis
	aOR (CI 95%)	p-valuec)
Age (categorized ref: 18–20 years)
21–24 years	0.88 (0.41–1.89)	0.743
25–25 years	0.77 (0.34–1.71)	0.515
Gender (ref: male)
Female	0.81 (0.42–1.58)	0.545
Age of first sexual intercourse (ref: < 15 years old)
15–18 years old	1.76 (0.77–4.05)	0.181
≥ 18 years	1.32 (0.41–4.21)	0.643
Perceived Risk for HIV infection (ref: No risk)
Some risk	1.90 (0.99–3.63)	0.053
Which of these sources have you received information about HIV vaccine research?
Friend/relative	1.61 (0.4–6.44)	0.503
Benefits of participating in Vaccine study (ref: No)
Learn how to avoid risky behavior	3.33 (1.61–6.86)	<0.001
Feel protected from HIV infection	2.24 (1.07–4.7)	0.032
Get free HIV counselling and testing	0.62 (0.27–1.44)	0.267
How important are the following factors in making a decision about participating in a research study of an experimental vaccine? (ref: Not Important)
Helping the community	2.62 (0.55–12.42)	0.225
Perceive as High-risk person for HIV infection	0.34 (0.06–2.01)	0.236
Unable to have sex intercourse	3.12 (0.76–12.85)	0.115
Not being able to contact people	2.17 (0.63–7.42)	0.217

a) Adjusted for age; gender; age of first sexual intercourse; perceived risk for HIV infection; which of these sources have you received information about HIV vaccine research?; benefits of participating in vaccine study; How important are the following factors in making a decision about participating in a research study of an experimental vaccine?

GEE Generalized estimation equation for binary logistic regression for screening and exit visit.

aOR Adjusted Odds Ratio.

CI Confidence Interval.

Discussion

Hypothetical willingness to participate in HIV vaccine studies was high among young adults at risk for HIV in a low-income peri-urban area in Maputo, Mozambique. This study reinforces the practicality of conducting HIV vaccine trials in Maputo. Also, we identified factors that are associated with willingness to participate over a period of time, with the same participants, which can be used for the development of communication and retention strategies of future HIV vaccine clinical trials to be conducted in Mozambique. In an HIV-incidence study cohort study with fishing communities, conducted in Uganda [25], 99.4% (n = 328) of the participants expressed their willingness to participate in a HIV vaccine trial. In contrast only 50.6% (n = 450) of young adults recruited at a youth clinic in Tanzania expressed their willingness to participate in a HIV vaccine trial [22]. These results are consistent with findings from Inugu et al. [16], where the authors concluded that willingness to participate in HIV vaccine trials varied by region and population.

Young adults and women tend to have a high incidence of HIV, and play an important role in the ongoing transmission of HIV [26,27]. This strengthens the need for HIV vaccine trials and willingness to participate studies to target the largest number of women and young volunteers [28-30]. Our population consisted of young adults most-at-risk for HIV infection, of whom almost half were women, identified and recruited from the general community, in contrast to other HIV vaccine preparedness studies which specifically targeted populations that are vulnerable and socially stigmatized such as MSM and FSW [17,22,23,31]. We found high rates of willingness to participate results for both males and females, while Meque, et al. [32] in a study conducted in another province in Mozambique, found that WTP was 77.8% (n = 1019) for females and 57.6% (n = 97) for males. In our study, the majority of our participants (both male and female) acknowledge at least some risk for HIV acquisition, which corroborates findings from other studies that perceived risk for HIV infection is related to willingness to participate [23,33,34]. Successful execution of an HIV vaccine efficacy trial requires recruitment and retention of a large number of individuals without HIV from a source population with a high incidence of disease [10], who recognize their own risk behaviors for HIV acquisition.

Altruism was the most frequently reported positive social motivator for WTP in our study, and much of the same results were reported in other studies [32,35,36], suggesting that study participation may be seen by participants as their contribution to the fight against HIV. Important to highlight, was the increase in the proportion of negative social motives. Being perceived as HIV positive was reported in a study conducted in the USA [23] and perceive as a high-risk person for HIV infection was reported in a study conducted in India [37]. In Tanzania [38] a major barrier to decline participation in phase I and phase II HIV vaccine trials was resistance from significant others, which could be related to being unable to have sex intercourse and/or people refusing contact. The ongoing presence of these factors in different contexts implies that it is necessary to define and implement recruitment strategies that address them, in order to minimize their impact. It should be noted that these variables did not rise to statistical significance in the multivariate or longitudinal modeling.

Perceived personal benefits of participating in HIV vaccine trial, such as feeling protected from HIV infection, learning how to avoid HIV infection, and free testing for HIV and STI have also been reported elsewhere [36]. The proportion of sources of information changed significantly from screening to exit visit, as information from friends and relatives dropped, but internet, poster and research center information increased. One hypothesis could be that, because of their participation in the RV363 study, participants learned how to use more accurate sources of information and, consequently, to discern what they thought was the more accurate information related to HIV vaccine research. The most common personal barrier was fear of needles, similar to other reported results [33]. We did not find fear of fetal abnormalities in other reported results. This is important, as it can impede young people who intend to have children from participating.

Willingness to participate remained high among the participants who completed the 24-month follow-up, but no assurance should be taken that actual WTP will be high. In a 2-year follow-up cohort study conducted in Kenya, Nyasani et al. [21] reported that 86 of 100 participants who expressed their willingness to participate in a HIV vaccine trial and were contacted afterwards, only 30% (n = 26) actually consented to participate in a phase-I HIV vaccine trial. As in our study, they also did not provide cohort participants with HIV vaccine research information. Asiki et al. [25], found that willingness to participate among high-risk men and women in Uganda decreased after the participants received information regarding HIV vaccine trials attributes. The principal barriers were number and duration of visits, being injected with an experimental vaccine, being required to delay pregnancy, and blood collection [21,25]. In our study, feeling protected against HIV infection, was associated with greater willingness, highlighting the need to consider our high rate of willingness to participate with caution. Paramount to highlight, is the erroneous perception that receiving an experimental HIV vaccine could provide protection against HIV, which can lead to alterations in risk behavior due to trial participation. This can be explained by the fact that no information was given on HIV vaccine research and its goal to prove the efficacy of experimental vaccines. Equally important was the fact that the rate of perceived benefits associated with willingness to participate decreased at the end of the study, despite wanting to learn how to avoid risky behavior being associated with greater willingness to participate. We theorize that this could be for several reasons: 1) participants felt that there was not more to learn, since they received counselling for HIV risk behavior reduction during the cohort study and 2) participants might have learned more about HIV vaccine trials and, especially the fact that there is no guarantee of protection from an experimental vaccine.

Although willingness to participate (hypothetical) was high and remained high, one-quarter of the participants did not complete the willingness to participate questionnaire at the final visit. This group had the highest proportion of individuals with the lowest levels of education. We postulate that these individuals who did not respond to the willingness to participate questionnaire at the final visit can reflect the rates and characteristics of drop-out individuals who are eligible for an actual HIV vaccine trial, making it an important group to characterize in order to identify potential factors associated with HIV trial non-adherence or hesitancy. In an HIV incidence study conducted in Kenya, Nyambura et al [39] found that being female and having a higher level of education was associated with greater risk for missing a study visit.

Limitations

There are a number of limitations to this study that should be considered. The findings are potentially limited by the high loss to follow-up from the cohort, which may lead to an overestimation of the rate of willingness to participate. This risks introduction of survivor bias into the analysis of our covariate associations, in terms of characterizing the overall cohort; however, to the extent that the intent is to characterize associations with willingness among participants who were able to complete the trial we argue that survivor bias is negligible.

Some aspects of the study may limit the generalizability of the results. Because the cohort participants were recruited based on their propensity towards high risk behaviors, they may not represent attitudes and values of a wider, lower risk or mixed-risk population. Additionally, due to the status of the CISPOC area as a high incidence population, numerous education, outreach, and testing interventions may disproportionately increase HIV awareness and willingness compared to what may be expected in areas with less outreach activity. However, within the context of high-risk behavior populations, which are those of most interest to HIV vaccine trials, we argue the results are likely generalizable. The corroboration in associations with willingness to participate in this study and the existing literature lends face validity to the generalizability of results; additionally, unlike other studies in the existing literature which limit their cohorts to small sub-populations (such as hospital-based recruitment, MSM or Trans only studies) the population-based nature of our cohort adds to the generalizability of our findings.

Participant recall bias may be an important mediator regarding reporting of previous information sources. As no information was collected on the length of time since exposure to the information source, participants who were presented with vaccine knowledge prior to screening, particularly from interpersonal sources, may not recall the incident at exit some two years later. Future studies may consider collecting time-relevant information to help address issues in recall bias as well as message permanency.

Lastly, there is a potential that social desirability bias may have influenced individual participant responses. While efforts were made to limit this tendency in participants through assurances of confidentiality of responses, neutral and impartial wording or phrasing, the potential remains that participant responses may have been influenced by the rapport developed over the cohort trial period. While it is unlikely this played a part in the knowledge-based responses (as these are more factual in nature), the potential influence of this bias should be considered when interpreting the social/personal benefits and barriers to results.

Conclusion

A large proportion of at-risk young adults in Maputo City have expressed and maintained their WTP in future trials and should therefore be considered as participants in future trials. Young age and altruism are factors associated with willingness. However, there is a need to deepen knowledge about the associated factors, including the experimental HIV vaccine and its potential risks, to prepare better messages in order to avoid high rates of refusal during actual clinical trial recruitment.

The RV-363 HIV/AIDS awareness, vaccine knowledge and willingness to participate questionnaire.

(PDF)

Click here for additional data file.

6 Nov 2020

PONE-D-20-31594

Young at risk-people in Maputo City, Mozambique, present a high willingness to participate in HIV trials: results from an HIV vaccine preparedness cohort study

PLOS ONE

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Reviewer #1: Kudos for your success in enrolling and following this sizable cohort for 24 months.

INTRODUCTION

I note your statement that the importance of WTP factors varies over time and contexts (lines 67-68). How then should we assess the meaning of the findings of these interviews done between 2013 and 2017? Has the epidemic changed? Have attitudes changed?

The fact that 2 HIV vaccine trials have been conducted in Mozambique (including a Phase 2 trial) and more are currently under way seems like the best, most concrete demonstration of WTP (lines 57-60). Might there be information about enrollment and follow-up from those trials that would be relevant to the discussion of this WTP study?

RESULTS

The cohort comprises young people at substantial risk of HIV infection, the great majority of whom are aware of that risk. It seems like an ideal target for HIV vaccine trials. So the high WTP percentages are no surprise to me.

The low loss to follow-up (LFU) and the continued high WTP at the end of follow-up testify to a well-done study that treated the participants well!

Line 209: you state that motives for not participating increase during follow-up. I do not see the evidence for that.

Table 3: the OR for "required to receive the vaccine a few times" increased from 14.8 to 104.8 after adjustment. I have never seen an aOR that high! Can you look more deeply into the data to find out what is going on? Perhaps some major collinearity.

Table 3: The factor "required to use contraceptive" is associated with an increased WTP. In Table 2, that factor seems to reduce participants' WTP. (The Meque study also found that a family planning requirement would be a barrier for some women.) Can you examine that further? In Table 2, you show data for women only. Perhaps the results in Table 3 include the responses from both women and men?

DISCUSSION

Lines 264-265: you state that the cohort derives from the general population. I would reiterate that they are nevertheless at substantial risk of contracting HIV, as borne out by numerous prevalence and incidence estimations.

Line 282: rather than "the correct information" I would write "more accurate information."

Lines 283-285: I am not clear on your argument here. Table 2 shows that the perceived value or salience of the potential benefits of vaccine trial participation diminished during follow-up. But knowledge of the potential benefits would not go down, would it? Admittedly, in line 305 you write that no information was given to them on features of potential vaccine research. But I would say that their responses about possible personal benefits shown in Table 2 reveal a pretty clear idea of what a vaccine trial might offer.

Lines 321-325: your brief discussion of limitations made me curious whether there was a larger cohort that was created for RV 363, since you refer to the RV 363 incidence cohort in line 323. I looked at reference #19, but it describes only the cross-sectional findings from the baseline screening of 1125 participants. Was the larger cohort also followed for 24 months? If so, can you provide the LFU figure from the entire RV 363 study? That seems like a very relevant and important piece of data to help interpret these findings from a subset of participants. It could be inserted into the section Study Design and Populations, and then discussed in limitations. If only the 577 participants described here were followed prospectively, then these questions of mine are irrelevant.

Reviewer #2: General comments:

This study looks at the willingness to participate in a HIV vaccine trial among young adults at a suburban area in Maputo City, Mozambique. Authors assessed factors and barriers to WTP in a hypothetical HIV vaccine trial. This is quite an interesting manuscript, and the authors set out the aims quite clearly. However, there is a need to explore the uniqueness of the manuscript given that there is a relatively extensive literature on factors about WTP in HIV vaccine trial in different African populations as well as strengths form this study.

Some specific points need authors consideration:

Introduction

The authors mentioned that there are already studies conducted in Africa assessing factors associated with WTP, including in Mozambique; so, what is new about the current study that other studies did not assess? Authors may need to explore additional gaps to justify the need for this study.

Methods

Authors may need to provide additional description of all variables in the methods section.

Lines 120- 121: how many participants answering do not know, refused to answer, someone else should decided etc were removed from the analyses? This need to be specified.

Line 130: What are willingness to participate factors? Is this different from the willingness to participate (the dependent variable)? This is not clear ; How motives and barriers to WTP were assessed? This is not clear in the methods section

How the authors defined perceived risk for HIV infection? How was this explanined to the participants?

Results

Table1. How the authors define perceived risk for HIV infection? See comment above

Figure 1 is missing

Table 2: Do WTP factors the same as HIV vaccine knowledge? please see comment above on line 130

Table 3: Title … analysis of selected factors for willingness to participate… Please replace "for" by "associated" to make the title more clear.

How do the authors explain the finding of volunteers requiring to be injected with an HIV vaccine express WTP, and on the other hand, fear of needles a barrier?

Table 4: perceived risk for HIV infection was not significant. Authors may reconsider from including it as a factor associated with WTP in a vaccine trial

Discussion:

Lines 261-262- authors mentioned the need for WTP studies to target women… and line 267 – authors found high rates of WTP for men and women. Did the authors assess gender differences in the WTP in the current study? How WTP differs from men and women in the current study at screening and exit visits? Given that this study has a gender balance in participation authors may want to assess gender differences in factors and barriers to WTP in a vaccine trial.

Line 287: I am not entirely clear about this sentence, as the authors did not assess this factor in the current study. Did the authors find gender differences in assessing the barriers to participating in vaccine trials? Please see comment above.

Lines 312-314: A substantial percentage (25%) of the participants did not complete the WTP questionnaire at the exit visit. With such a considerable number of participants, the author may need to provide potential explanations and assess the characteristics of this group. How this group of participants (n=147) differ from the group who answered no to the WTP questionnaire at the exit visit? Could the authors discuss their similarities and differences?

Lines 322-324: The authors discussed the limitations of the study. Can the authors discuss the generalizability of this study? What % of participants came from different suburban areas other than Polana Caniço? This is a relevant issue in this study as if I understood the majority o participants are from Polana Caniço area.

Along these lines, it is also essential to discuss the strengths of the study as this can add more relevance to the study.

Reviewer #3: General Comments:

This study assessed factors associated with willingness to participate in potential HIV vaccine trials by conducting a 24-month observational cohort study among high-risk people in Maputo City, Mozambique. The analyses presented make use of data collected during a 24-month prospective HIV incidence study. As currently formulated, the analyses do not provide new insights into who might be interested – and who should be the focus of – future HIV vaccine trials. As in several studies, willingness to participate is most associated with HIV risk perception and/or altruism. The study could benefit from inclusion of HIV incidence (which I believe was the main outcome of the parent study) in models of WTP. In addition, some of the measures used in this study likely suffer from self-presentation bias. It might be more informative to compare likert scale response options (“very” likely versus other categories) than to simply collapse into bivariate variables. Finally, the authors should provide a more thorough discussion in the introduction and discussion sections about differences between “willingness” and actual behavior.

Introduction:

1) The authors should consider how to strengthen the introduction and justification for the research presented in this manuscript. Specifically, the introduction should address the idea that hypothetical “willingness” may not correlate with actual behavior and, to the extent possible, identify any factors that do strongly correlate between the two. Given that barriers and facilitators of trial participation vary widely over time, population and context, what can we learn from these kind of studies?

Methods:

2) Based on description of this study, participants enrolled in an HIV incidence study that did not entail receiving any kind of “vaccine-like intervention”. In order to interpret findings related to “willingness”, it would be useful to provide the actual script that described what participation in an HIV vaccine trial would entail.

3) What proportion of participants who joined the HIV incidence study responded to questions about willingness to participate in future HIV vaccine trials? (It is unclear whether the 570 of 1150 screened volunteers related only to the “willingness to participate” sample, or to the parent study in which these data were collected.

4) Were questions administered via tablet, or on paper? (I assume face-to-face interviews, correct?)

5) It looks like the main willingness question was bimodal. However, the “barriers” question with likert scale responses also seems to be to be more about willingness than barriers. If specific barriers to participation were assessed, please provide an idea about these items. The same would be useful for the “facilitators” items.

Results:

6) Given the lack of variation in the willingness to participate variable, the authors might consider focusing their analysis on the “barriers” variable instead, maintaining the 4 point likert response scale.

7) It is interesting that all perceived benefits of trial participation dropped between screening and exit. Do the authors have any ideas about why this is, or who participants were that have a decrease in perceived benefits over time?

8) Given the likelihood of self-presentation bias, it might be useful to examine and/or provide data for strongly agree category versus other categories related to willingness to participant if various tests, procedures required.

9) It appears that willingness to participate largely driven by risk perception for this study. How does this compare to other studies?

Discussion

10) The statement about the “practicality” of conducting willingness to participate studies seems overly positive. WTP studies are expensive and themselves may be considered interventions that drive incidence down – so promoting them as practical is not very convincing. It would be useful to show how such trials can help to better target the right kind of participants, recruit and retain them.

11) Line 254/page 18 – “study” redundant.

12) The discussion brings to mind that this study would be strengthened if the authors included HIV incidence as covariate in the models. Are those who are willing to participate also most likely to be at risk of HIV? It is particularly important to determine ways to recruit participants from the general population who are in fact most likely to be at risk of HIV – those who are altruistic are also likely to be at lower risk.

13) Changes in source of information – YES, of course. These studies are interventions in themselves. But, not a practical way to inform people about HIV vaccine trials.

14) Study limitations should identify self-presentation bias.

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Reviewer #1: No

Reviewer #2: No

Reviewer #3: No

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19 Apr 2021

Editor Comments

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.

R: Manuscript updated according to PLOS ONE’s style requirements.

2. Please provide a sample size and power calculation in the Methods or discuss the reasons for not performing one before study initiation.

R: We thank you for the comments. We added section regarding the calculation of the sample size added (Line 100-103) accordingly.

3. Please include additional information regarding the survey or questionnaire used in the study and ensure that you have provided sufficient details that others could replicate the analyses. For instance, if you developed a questionnaire as part of this study and it is not under a copyright more restrictive than CC-BY, please include a copy, in both the original language and English, as Supporting Information.

R: The questionnaire was developed by the study team. The questionnaire was not translated into Portuguese, but the study interviewers were trained to administer the questionnaire in Portuguese. Questionnaire added as S1 RV363-WTP_Questionnaire (line 133).

4. Please note that PLOS does not permit references to “data not shown.” Authors should provide the relevant data within the manuscript, the Supporting Information files, or in a public repository. If the data are not a core part of the research study being presented, we ask that authors remove any references to these data.

R: We thank you for the comments. The information has been removed from the manuscript.

5. 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.

R. Data Availability statement was updated when re-submitting. There are currently no ethical or legal restrictions on sharing the de-identified data set. The dataset supporting the conclusions of this article will be made available in the following Harvard Dataverse repository prior to publication of this article at the following link: https://doi.org/10.7910/DVN/RBTW80

6. One of the noted authors is a group or consortium [7 RV363 Study Group]. In addition to naming the author group, please list the individual authors and affiliations within this group in the acknowledgments section of your manuscript. Please also indicate clearly a lead author for this group along with a contact email address.

R: Thank you for your comment. We have included a list of individual authors and affiliations for the ‘RV363 Study Group’ to the Acknowledgements as suggested.

Reviewer#1 Comments

Kudos for your success in enrolling and following this sizable cohort for 24 months.

1. Introduction

a. I note your statement that the importance of WTP factors varies over time and contexts (lines 67-68). How then should we assess the meaning of the findings of these interviews done between 2013 and 2017? Has the epidemic changed? Have attitudes changed?

R: During the period 2013 and 2017, national reports indicate that HIV prevalence has remained stable. One of the principal findings of this study, is that the perceived personal benefits for wanting to participate in a HIV vaccine trial varied between the same period (table 2). This was also further discussed in the discussion section (line 306 – 313).

b. The fact that 2 HIV vaccine trials have been conducted in Mozambique (including a Phase 2 trial) and more are currently under way seems like the best, most concrete demonstration of WTP (lines 57-60). Might there be information about enrollment and follow-up from those trials that would be relevant to the discussion of this WTP study?

R: We agree that the data about recruitment and follow-up of previous participants of HIV vaccine clinical trials conducted in Mozambique would be relevant to the discussion, since it would represent actual reasons for participating or not in a HIV clinical trial conducted in Mozambique. However, both trials did not report the reasons for participating or reasons to withdraw from participating in HIV vaccine study.

2. Results

a. The cohort comprises young people at substantial risk of HIV infection, the great majority of whom are aware of that risk. It seems like an ideal target for HIV vaccine trials. So, the high WTP percentages are no surprise to me.

R: Although the high rates of willingness to participate are encouraging results, until the time of implementing the study it was not possible to know whether the willingness to participate would be high or low. A study carried out in Tanzania with young people with similar characteristics reported rates of willingness to participate below compared to the results reported in this article. Literature reviews also reported that willingness to participate varies.

c. The low loss to follow-up (LFU) and the continued high WTP at the end of follow-up testify to a well-done study that treated the participants well!

R: We appreciate this compliment. As part of a team effort, it was possible to retain most of the participants.

d. Line 209: you state that motives for not participating increase during follow-up. I do not see the evidence for that.

R: We updated the information. Instead of motives for not participating it should be important motives. We also added proportions to clarify (line 227-230).

e. Table 3: the OR for "required to receive the vaccine a few times" increased from 14.8 to 104.8 after adjustment. I have never seen an aOR that high! Can you look more deeply into the data to find out what is going on? Perhaps some major collinearity.

R: Thank you for this very insightful comment. Upon further investigation, we found that there were some variables which were moderately correlated with the outcome, namely “required to receive the vaccine a few times” and “required to donate blood samples”, so these were removed. Additionally, the model included two factors which were specific for women (“required to use contraceptive” and “get free pregnancy test every 3 months”), therefore, these were also removed which added men back into the multivariate model in Table 3. The 4-point Likert scale data pertaining to ‘How likely would you enroll in research study of a new experimental HIV Vaccine if’ are now presented as a stacked column chart in Figure 2.

f. Table 3: The factor "required to use contraceptive" is associated with an increased WTP. In Table 2, that factor seems to reduce participants' WTP. (The Meque study also found that a family planning requirement would be a barrier for some women.) Can you examine that further? In Table 2, you show data for women only. Perhaps the results in Table 3 include the responses from both women and men?

R: Data in Table 2 represent both men and women. The question of “required to use contraceptive” as well as “get free pregnancy test every 3 months” was only answered by women. For this reason, in our updated model for bivariate and multivariate analysis we removed these factors in Table 3. Table 3 now includes responses for both men and women.

g. Lines 264-265: you state that the cohort derives from the general population. I would reiterate that they are nevertheless at substantial risk of contracting HIV, as borne out by numerous prevalence and incidence estimations.

R: We agree with your comments. We clarified that our participants are young adults most-at-risk for HIV infection (Line 291-294).

b. Line 282: rather than "the correct information" I would write "more accurate information."

R: We thank you for the comments. Information updated in the manuscript as requested (Line 310).

c. Lines 283-285: I am not clear on your argument here. Table 2 shows that the perceived value or salience of the potential benefits of vaccine trial participation diminished during follow-up. But knowledge of the potential benefits would not go down, would it? Admittedly, in line 305 you write that no information was given to them on features of potential vaccine research. But I would say that their responses about possible personal benefits shown in Table 2 reveal a pretty clear idea of what a vaccine trial might offer.

R: In the discussion section we hypothesize that, the participants learned to obtain more accurate information from more reliable sources, simply because they participated in the study. However, a good part of the participants expected that by being injected with an experimental HIV vaccine, they could somehow get some protection against HIV infection. This phenomenon has been observed in other studies as well, as described in the discussion (Line 326 -339), and it also shows the importance of this study, because one of the recommendations is that detailed information regarding HIV vaccine trials should be clearer provided to study participants, to avoid high percentages of study withdraw (Line 325-326).

d. Lines 321-325: your brief discussion of limitations made me curious whether there was a larger cohort that was created for RV 363, since you refer to the RV 363 incidence cohort in line 323. I looked at reference #19, but it describes only the cross-sectional findings from the baseline screening of 1125 participants. Was the larger cohort also followed for 24 months? If so, can you provide the LFU figure from the entire RV 363 study? That seems like a very relevant and important piece of data to help interpret these findings from a subset of participants. It could be inserted into the section Study Design and Populations, and then discussed in limitations. If only the 577 participants described here were followed prospectively, then these questions of mine are irrelevant.

R: Data on the incidence study is yet to be published and will be published as a separate article. Only 577 participants were eligible and followed.

Reviewer#2 Comments

This study looks at the willingness to participate in a HIV vaccine trial among young adults at a suburban area in Maputo City, Mozambique. Authors assessed factors and barriers to WTP in a hypothetical HIV vaccine trial. This is quite an interesting manuscript, and the authors set out the aims quite clearly. However, there is a need to explore the uniqueness of the manuscript given that there is a relatively extensive literature on factors about WTP in HIV vaccine trial in different African populations as well as strengths form this study. Some specific points need authors consideration:

1. Introduction

a. The authors mentioned that there are already studies conducted in Africa assessing factors associated with WTP, including in Mozambique; so, what is new about the current study that other studies did not assess? Authors may need to explore additional gaps to justify the need for this study.

R: We appreciate the comments. We have edited the introduction section to make the objectives and justification for the study clearer.

2. Methods

b. Authors may need to provide additional description of all variables in the methods section.

R: We added the questionnaire, as requested (Line 133).

c. Lines 120- 121: how many participants answering do not know, refused to answer, someone else should decided etc were removed from the analyses? This need to be specified.

R: We appreciated the recommendation. Information updated in the manuscript as requested (line 140 – 142).

d. Line 130: What are willingness to participate factors? Is this different from the willingness to participate (the dependent variable)? This is not clear; How motives and barriers to WTP were assessed? This is not clear in the methods section

R: We thank you for the comments. We added information that clarifies the reasons for not being willing to participate, the benefits of being willing to participate, the barriers and facilitators to participate in an HIV vaccine study – Willingness to participate section (Line 116-133). Questionnaire also added.

e. How the authors defined perceived risk for HIV infection? How was this explained to the participants?

R: The question was: “How would you classify your risk for getting infected with HIV” – information added to Table 1 legend (Line 183).

3. Results

f. Table1. How the authors define perceived risk for HIV infection? See comment above

R: Please see response above.

g. Figure 1 is missing

R: Figure 1 was added as a separate file. We will review journal guidelines and make sure we comply with journal guidelines.

h. Table 2: Do WTP factors the same as HIV vaccine knowledge? please see comment above on line 130

R: HIV vaccine knowledge is different form WTP variable. Please see response above and refer to study questionnaire.

i. Table 3: Title … analysis of selected factors for willingness to participate… Please replace "for" by "associated" to make the title more clear.

R: Thank you for the suggested edits. We have updated the information accordingly.

j. How do the authors explain the finding of volunteers requiring to be injected with an HIV vaccine express WTP, and on the other hand, fear of needles a barrier?

R: We believe that because the participants did not receive a detailed information about HIV vaccine clinical trials attributes, they might have thought that an experimental HIV vaccine would at some point provide protection. We address this issue in the discussion section. (Line 327-339). We believe that with our results we can’t explain why fear of needles is a barrier. Other studies have also identified this as a barrier. We believe a more in-depth analysis with a qualitative study would provide the best answers.

k. Table 4: perceived risk for HIV infection was not significant. Authors may reconsider from including it as a factor associated with WTP in a vaccine trial

R: We thank you for your comments. The Perceived risk was borderline significant p=0.053. We believe this trend should be considered.

4. Discussion

l. Lines 261-262- authors mentioned the need for WTP studies to target women… and line 267 – authors found high rates of WTP for men and women. Did the authors assess gender differences in the WTP in the current study? How WTP differs from men and women in the current study at screening and exit visits? Given that this study has a gender balance in participation authors may want to assess gender differences in factors and barriers to WTP in a vaccine trial. –

R: We did not observe any difference in willingness to participate between male and female, but because of the high HIV infection among young and females we recognize the importance of them participating in HIV vaccine trials.

m. Line 287: I am not entirely clear about this sentence, as the authors did not assess this factor in the current study. Did the authors find gender differences in assessing the barriers to participating in vaccine trials? Please see comment above.

R: We appreciate your comments. We have updated the information and add “young people who intend to have children from participating (Line 314-316)”.

n. Lines 312-314: A substantial percentage (25%) of the participants did not complete the WTP questionnaire at the exit visit. With such a considerable number of participants, the author may need to provide potential explanations and assess the characteristics of this group. How this group of participants (n=147) differ from the group who answered no to the WTP questionnaire at the exit visit? Could the authors discuss their similarities and differences?

R: We recognize that it is important to characterize the lost to follow-up group. However, this information will be presented and discussed in the main article on HIV incidence. The team had discussed this issue and have addressed in the discussion.

o. Lines 322-324: The authors discussed the limitations of the study. Can the authors discuss the generalizability of this study? What % of participants came from different suburban areas other than Polana Caniço? This is a relevant issue in this study as if I understood the majority o participants are from Polana Caniço area.

R: We thank you for the comments. Data will be used in another manuscript (incidence paper).

p. Along these lines, it is also essential to discuss the strengths of the study as this can add more relevance to the study.

R: We thank you for the suggestions. Please refer to the discussion section for an update discussion regarding the study strengths (Line 279-284).

Reviewer#3 Comments

This study assessed factors associated with willingness to participate in potential HIV vaccine trials by conducting a 24-month observational cohort study among high-risk people in Maputo City, Mozambique. The analyses presented make use of data collected during a 24-month prospective HIV incidence study. As currently formulated, the analyses do not provide new insights into who might be interested – and who should be the focus of – future HIV vaccine trials. As in several studies, willingness to participate is most associated with HIV risk perception and/or altruism. The study could benefit from inclusion of HIV incidence (which I believe was the main outcome of the parent study) in models of WTP. In addition, some of the measures used in this study likely suffer from self-presentation bias. It might be more informative to compare likert scale response options (“very” likely versus other categories) than to simply collapse into bivariate variables. Finally, the authors should provide a more thorough discussion in the introduction and discussion sections about differences between “willingness” and actual behavior.

a. Introduction - The authors should consider how to strengthen the introduction and justification for the research presented in this manuscript. Specifically, the introduction should address the idea that hypothetical “willingness” may not correlate with actual behavior and, to the extent possible, identify any factors that do strongly correlate between the two. Given that barriers and facilitators of trial participation vary widely over time, population and context, what can we learn from this kind of studies?

R: Updated the introduction section with a clearer information that justifies why this study was conducted (please refer to reviewer 2 comments response). We agree that hypothetical willingness to participate does not correlated with actual willingness to participate and address it in the discussion section (line 299 – 303).

1. Methods

b. Based on description of this study, participants enrolled in an HIV incidence study that did not entail receiving any kind of “vaccine-like intervention”. In order to interpret findings related to “willingness”, it would be useful to provide the actual script that described what participation in an HIV vaccine trial would entail.

R: Information added to the section questionnaire. We added the questionnaire, as requested (Line 133).

c. What proportion of participants who joined the HIV incidence study responded to questions about willingness to participate in future HIV vaccine trials? (It is unclear whether the 570 of 1150 screened volunteers related only to the “willingness to participate” sample, or to the parent study in which these data were collected.

R: Only eligible participants who answered the questionnaire were included in the analyses. In totally 1150 participants were screened, of whom 577 eligible participants answered the questionnaire. Information updated in the methods sections (line 97-99).

d. Were questions administered via tablet, or on paper? (I assume face-to-face interviews, correct?)

R: Paper based questionnaires were administered face-to-face to the participants. Information updated (line 108 - 109).

e. It looks like the main willingness question was bimodal. However, the “barriers” question with likert scale responses also seems to be to be more about willingness than barriers. If specific barriers to participation were assessed, please provide an idea about these items. The same would be useful for the “facilitators” items.

R: Please see updated information regarding the methods and results section. Titles were updated, description of variables also. Table 2 was also updated.

2. Results

f. Given the lack of variation in the willingness to participate variable, the authors might consider focusing their analysis on the “barriers” variable instead, maintaining the 4-point likert response scale.

R: We appreciate the suggestion. But we believe that our results respond to the objective of this article.

g. It is interesting that all perceived benefits of trial participation dropped between screening and exit. Do the authors have any ideas about why this is, or who participants were that have a decrease in perceived benefits over time?

R: We agree that the results are interesting. We address it in the discussion section. (Line 311 – 316).

h. Given the likelihood of self-presentation bias, it might be useful to examine and/or provide data for strongly agree category versus other categories related to willingness to participant if various tests, procedures required.

R: We appreciate the suggestion. But we think it’s out the scope of this article.

i. It appears that willingness to participate largely driven by risk perception for this study. How does this compare to other studies?

R: The same results were reported in other studies. We address it in the discussion section. (Line 300 – 303).

3. Discussion

j. The statement about the “practicality” of conducting willingness to participate studies seems overly positive. WTP studies are expensive and themselves may be considered interventions that drive incidence down – so promoting them as practical is not very convincing. It would be useful to show how such trials can help to better target the right kind of participants, recruit and retain them.

R: Regarding practicality, we were referring to the practicality of conducting HIV clinical trials in Maputo (Line 280-281).

k. Line 254/page 18 – “study” redundant.

R: We appreciate the suggestions. Information updated.

l. The discussion brings to mind that this study would be strengthened if the authors included HIV incidence as covariate in the models. Are those who are willing to participate also most likely to be at risk of HIV? It is particularly important to determine ways to recruit participants from the general population who are in fact most likely to be at risk of HIV – those who are altruistic are also likely to be at lower risk.

R: Data on the incidence study is yet to be published and will be published as a separate article.

m. Changes in source of information – YES, of course. These studies are interventions in themselves. But not a practical way to inform people about HIV vaccine trials. –

R: We agree with your comments. However, we think that the results of this study can help inform future studies and recruitment and retention strategies, regarding what information should be provided to the participants. This study results made it clear that it is important to provide participants with clear and detailed information about HIV vaccine clinical trials before and during their participation.

n. Study limitations should identify self-presentation bias.

R: We recognize that how the participant feels can impact how he responds, and that’s a human phenomenon. We believe that with our current results, we don’t have enough evidence to discuss it.

Submitted filename: WTP_RV363_PlosOne-Comments.20.04.21.docx

Click here for additional data file.

27 May 2021

PONE-D-20-31594R1

Young at risk-people in Maputo City, Mozambique, present a high willingness to participate in HIV trials: results from an HIV vaccine preparedness cohort study

PLOS ONE

Dear Dr. Capitine,

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Reviewer #1: (No Response)

Reviewer #2: I again congratulate the authors for such an interesting paper that helps to advance evidence of HIV vaccines. I also thank the authors for addressing the majority of issues in the manuscript. However, there are still some issues that need authors consideration as they are relevant. I leave to the Editor to decide the paper's outcome, to accept as it is, or to request another revision based on the reviewer's findings.

1. One issue is related to the interpretation of a borderline/ non-significant result on table 4. Significance and non-significance are based on an arbitrary cut-off of 5% and as such one needs to interpret according to the study context. Although I understand authors need report their bordeline result, I still believe authors may not report it as it is a significant finding, without a further explanation. Instead, they may need to discuss the meaning of this finding in terms of their impact or so. This may be an issue with sample size, but the meaning needs to be discussed. On page 19 (see below the text extract), the authors report the same findings as purely significant. This in my view, needs attention.

"Among the 430 participants who stayed through the course of the study, results from the GEE

265 binary logistic regression (screening visit and exit visit) showed that perceived risk for HIV

266 infection (aOR 1.90, 95% CI: 0.99-3.63),… were associated with willingness to participate in HIV vaccine studies (Table 4)."

k.Table 4: perceived risk for HIV infection was not significant. Authors may reconsider

from including it as a factor associated with WTP in a vaccine trial

R: We thank you for your comments. The Perceived risk was borderline significant

p=0.053. We believe this trend should be considered.

2. The second issue is related to the limitations of the study that needs to be clearly addressed. In my previous revision, I raised the issue of the generalizability of the study that needed to be discussed. However, the authors mentioned that this issue would be addressed in another paper, not the current one (see below the authors’ answer). I still believe that the issue of generalizability needs to be mentioned in this paper. There are other issues that were postponed to a future paper, but are also important in the current paper.

o.Lines 322-324: The authors discussed the limitations of the study. Can the authors

discuss the generalizability of this study? What % of participants came from different

suburban areas other than Polana Caniço? This is a relevant issue in this study as if I

understood the majority o participants are from Polana Caniço area.

R: We thank you for the comments. Data will be used in another manuscript (incidence

paper).

3. The third issue is acknowledging the self-presentation bias that another reviewer (#3) had raised, but was not addressed by the authors. I also state that these type of studies are highly influenced by social desirability bias—this need to be considered in the limitations and actions to minimise it stated.

Reviewer #3: (No Response)

**********

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Submitted filename: Revision 2_ WTP paper.docx

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26 Jul 2021

R: We would like to take this opportunity to thank you for your comments and suggestions, which we believe will improve the manuscript. Please find the answers below.

1. One issue is related to the interpretation of a borderline/ non-significant result on table 4. Significance and non-significance are based on an arbitrary cut-off of 5% and as such one needs to interpret according to the study context. Although I understand authors need report their bordeline result, I still believe authors may not report it as it is a significant finding, without a further explanation. Instead, they may need to discuss the meaning of this finding in terms of their impact or so. This may be an issue with sample size, but the meaning needs to be discussed. On page 19 (see below the text extract), the authors report the same findings as purely significant. This in my view, needs attention.

"Among the 430 participants who stayed through the course of the study, results from the GEE 265 binary logistic regression (screening visit and exit visit) showed that perceived risk for HIV 266 infection (aOR 1.90, 95% CI: 0.99-3.63),… were associated with willingness to participate in HIV vaccine studies (Table 4)."

“k.Table 4: perceived risk for HIV infection was not significant. Authors may reconsider from including it as a factor associated with WTP in a vaccine trial R: We thank you for your comments. The Perceived risk was borderline significant p=0.053. We believe this trend should be considered.”

R: Thank you, this comment was well taken. We have clarified the marginally significant results by revising the text as follows:

“Among the 430 participants who stayed through the course of the study, results from the GEE binary logistic regression (screening visit and exit visit) showed that wanting to learn how to avoid risk behaviors (aOR 3.33, 95% CI: 1.61-6.86) and feeling protected against HIV infection (aOR 2.24, 95% CI: 1.07-4.7) were associated with willingness to participate in HIV vaccine studies. The perceived risk for HIV infection (aOR 1.90, 95% CI: 0.99-3.63) shows positive association, although remaining borderline significant (Table 4).”

2. The second issue is related to the limitations of the study that needs to be clearly addressed. In my previous revision, I raised the issue of the generalizability of the study that needed to be discussed. However, the authors mentioned that this issue would be addressed in another paper, not the current one (see below the authors’ answer). I still believe that the issue of generalizability needs to be mentioned in this paper. There are other issues that were postponed to a future paper, but are also important in the current paper.

“o.Lines 322-324: The authors discussed the limitations of the study. Can the authors discuss the generalizability of this study? What % of participants came from different suburban areas other than Polana Caniço? This is a relevant issue in this study as if I understood the majority o participants are from Polana Caniço area. R: We thank you for the comments. Data will be used in another manuscript (incidence paper).”

R: Our sincere apologies for not fully addressing the generalizability comment in the previous revision. We have now addressed the comment as suggested by including a paragraph on the generalizability of the study under a new ‘Limitations’ section of the manuscript.

3. The third issue is acknowledging the self-presentation bias that another reviewer (#3) had raised but was not addressed by the authors. I also state that these type of studies are highly influenced by social desirability bias—this need to be considered in the limitations and actions to minimise it stated.

R: We appreciate your comment, and our apologies for the oversight. The issue pertaining to self-presentation bias as well as social desirability bias have been addressed under the new ‘Limitations’ section of the manuscript.

Submitted filename: WTP_RV363_PlosOne-Response to Reviewers.25.07.21.docx

Click here for additional data file.

4 Nov 2021

Young at risk-people in Maputo City, Mozambique, present a high willingness to participate in HIV trials: results from an HIV vaccine preparedness cohort study

PONE-D-20-31594R2

Dear Dr. Capitine,

We are pleased to inform you that your manuscript has been judged potentially scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements. Please kindly note two final proposed comments from the Academic Editor.

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.

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Kind regards,

Karine Dubé, DrPH

Academic Editor

PLOS ONE

Additional Editor Comments:

We strongly encourage the authors to cite previous similar research in Mozambique ()https://pubmed.ncbi.nlm.nih.gov/25555105/).

The authors should adhere to the NIAID Language Guide (https://www.hptn.org/resources/HIVLanguageGuide). The expression 'HIV-infected' and 'HIV-uninfected' are now considered stigmatizing. We encourage person-first language as much as possible (e.g., people with HIV, people without HIV).

Reviewers' comments:

N/A

19 Nov 2021

PONE-D-20-31594R2

Young at risk-people in Maputo City, Mozambique, present a high willingness to participate in HIV trials: results from an HIV vaccine preparedness cohort study

Dear Dr. Capitine:

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.

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

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on behalf of

Dr. Karine Dubé

Academic Editor

PLOS ONE