Ethical Challenges Posed by HIV-Vaccine Induced Seropositivity for the Informed Consent Process and HIV Testing Practices in Maputo City,Mozambique

Abstract

Mozambique has a robust HIV control program and currently conducts HIV vaccine trials. One measure of a vaccine's success is development of antibodies, the vaccine-induced seropositivity(VISP). This study assesses the understanding and practices regarding VISP from trial participants and healthcare providers, as well as ethical challenges encountered during the informed consent. We conducted in-depth, semi-structured interviews using open and closed-ended questions with three categories of participants: healthcare professionals [n = 26], researchers [n = 5] and trial participants [n = 20]. For qualitative data, content analysis was performed and thematic axes were assigned. For quantitative analysis, descriptive analysis was performed. Trial participants had a better understanding of VISP's implications than front-line healthcare professionals. 53.8% healthcare professionals interviewed, stated that they would test the trial participants using an HIV rapid test, and initiate antiretroviral therapy immediately if positive. VISP may result in HIV misdiagnoses for trial participants when its broader pratical implications are not well understood.

Keywords

vaccine induced seropositivity (VISP)human immunodeficiency virus (HIV)testing informed consent ethics

Introduction

Human immunodeficiency virus (HIV) infection continues to be a significant global public health threat, with Mozambique identified as one of the most affected countries in the world in terms of absolute numbers of infections (Controlling the HIV Epidemic in Mozambique | Abt Global, n.d.). Mozambique HIV prevalence, as of 2021, was reported to be 12.5% among persons aged 15 to 49 years of age, with an overall incidence of 4.3 cases per 1,000 persons in that age range (ICAP, 2023).

Current HIV-control strategies in Mozambique include frequent testing of all patients at health facilities; antiretroviral therapy (ART) for people living with HIV to diminish viral load and subsequent transmission; pre-exposure prophylaxis (PrEP) for high-risk people at risk of contracting HIV; male circumcision; counseling to reduce high-risk behaviors; and distribution of condoms or other barrier devices (Dawson-Rose et al., 2016; HIV Risk and Prevention Estimates | HIV Partners | CDC, n.d.; Jaiantilal et al., 2015). Despite the relative success of these global strategies in recent years, the number of new HIV infections remains high across Mozambique, reinforcing the urgency to develop an effective vaccine to prevent HIV infection (Controlling the HIV Epidemic in Mozambique | Abt Global, n.d.; Hooft et al., 2021; Hsu & O’Connell, 2017)

Over the past 35 years, several candidate HIV vaccines have been developed and tested. (Cooper et al., 2010; Dispinseri et al., 2022; Esparza, 2013; Hsu & O’Connell, 2017). Mozambique has participated as a vaccine trial site country since 2013 (Centros e Unidades Satélites | Instituto Nacional de Saúde, n.d.). Even though no candidate vaccines have been deemed effective as of yet, Mozambique's experience in their testing has contributed to valuable insights and identification of new challenges that must be considered as the field continues to advance. One such challenge is posed by the induction of vaccine-induced seropositivity (VISP) in HIV vaccine trials, which is defined as the detection of vaccine-induced antibodies to HIV in serologic tests (Cooper et al., 2010; Couderc, 2018; Espy et al., 2023; Voronin et al., 2015). VISP is a desirable outcome of vaccine trials, yet it has the potential to cause harm in settings with a large HIV burden, many of which are in the midst of implementing aggressive programs for HIV testing and ART (Couderc, 2018). The primary concern is that study participants who develop VISP may subsequently experience negative consequences if their vaccine-induced antibodies are misinterpreted as a true HIV infection in subsequent HIV testing, especially if testing is carried out by someone who does not understand the nature of VISP or what it means to be in a vaccine trial (Fatola et al., 2022; Voronin et al., 2015).

In 2013, VISP was included on the agenda of the Global HIV Vaccine Initiative, as a growing concern given the complexity of vaccines in existing clinical trials and those to be used in future large-scale efficacy trials. This initiative includes efforts to develop tests that detect non-vaccine antibody responses or viral components and that are adaptable to low-resource settings (Voronin et al., 2015).

Mozambiqués HIV care and treatment program has been active since the early 2000's, with support from large-scale international programs such as the President´s Emergency Plan for AIDS Relief (PEPFAR) and the Global Fund to fight AIDS, Tuberculosis, and Malaria (PEPFAR-U.S. Embassy in Mozambique, n.d.). To accelerate progress towards achieving UNAIDS’ 95-95-95 goals - where 95% of people living with HIV know their status, 95% of those who know their status receive ART, and 95% of those receiving ART achieve viral suppression – health facilities across Mozambique have adopted several strategies. These strategies include targeted and widespread provider-initiated HIV testing, followed by aggressive treatment protocols aimed at initiating ART on the same day as diagnosis (PEPFAR-U.S. Embassy in Mozambique, n.d.; MISAU, 2015). In this scenario, knowledge and understanding about VISP is important, both for the study participant as well as for healthcare professionals who might attend to them in a context that heavily prioritizes test-and-treat strategies (Rautenbach et al., 2015)

Biomedical research in Mozambique faces many challenges, especially with regard to the informed consent process (Magaço et al., 2023). The population's low literacy rate, reported at 63.4% in 2021, is further complicated by linguistic diversity (Literacy in Mozambique: education for all challenges - UNESCO Digital Library, n.d.). Mozambique's 40 local languages/dialects, in addition to Portuguese as the official language, make it difficult for investigators to ensure that all trial participants can learn about, discuss and understand the objectives, procedures, and risks of individual research projects (Agu et al., 2014; Kass et al., 2015; Ossemane et al., 2018; Rajaraman et al., 2011). Despite these barriers, research teams and study sponsors must ensure that vaccine trial participants provide voluntary informed consent based on adequate, accurate, and appropriately transmitted and understood information prior to enrollment (Agu et al., 2014; Association, 2013). Some possible measures to overcome these barriers would be the inclusion of a translator to assist in the informed consent process using the participant's preferred language, the use of a comprehensive tests to ensure that the potential participant understood everything explained, and the use of simplified tools with images and illustrations to facilitate the explanation of complex concepts. Then, if all these measures do not ensure the participant's understanding, the research team should consider not including this individual in the study (Flory & Emanuel, 2004; Rautenbach et al., 2015; Vaswani et al., 2020).

This study sought to examine the ethical challenges posed by VISP in Mozambique as a result of clinical trials for HIV vaccines. We assessed the current state of understanding about VISP among vaccine trial participants and healthcare professionals who are likely to be involved in provider-initiated HIV testing strategies. We also explored the knowledge, attitudes and practices of trial participants and investigators within the context of vaccine trials’ informed consent processes.

Methods

Study Design

We conducted a cross-sectional descriptive study with both quantitative and qualitative data collection, using a semi-structured questionnaire with both open- and closed-ended questions. The in-dept interviews with frontline healthcare professionals and investigators were performed one-on-one in a private room in either the health facility or the research site. Interviews were conducted after normal work hours to avoid interruptions and the presence of healthcare professional's direct superiors. Interviews were conducted with trial particicpants in their homes or at a location they chose (public garden or snack bar). Data were collected from May to August 2022.

Study settings and population

This study was conducted in Maputo city at the Polana Caniço Research and Health Training Center (Centro de Investigação e Treino em Saúde de Polana Caniço, CISPOC), a research site of the Mozambican National Institute of Health (Instituto Nacional de Saúde, INS) that conducts clinical trials of infectious diseases such as HIV, Tuberculosis, and other vaccine- preventable illnesses. In addition, this study included five health facilities that provide comprehensive HIV care and treatment services. These facilities are located within the catchment area of CISPOC and represent facilities where vaccine trial participants may go to access routine care ( Figure 1 ).

Figure 1.

Map showing the location of the CISPOC research center (1) and five health facilities where the study was implemented: (2) 1° de maio health facility, (3) mavalane health facility, (4) alto maé health facility, (5) maxaquene health facility, (6) polana cimento health facility. Map designed by Katherine A. Gruber.

The study enrolled three categories of participants considered key informants for this study: 1) Participants from two HIV vaccine trials conducted in Maputo city in the last five years, who had given permission to be contacted for future studies; 2) Research investigators involved in the informed consent process for HIV-vaccine trials conducted at the CISPOC research site; and 3) Frontline healthcare professionals from the five health facilities located in proximity to CISPOC and who perform HIV counseling and testing and that the participants could potentially go to for care. The sample size was determined for all three categories of participants by our research questions, the range of responses that we expected to collect from key informants, the mechanisms and resources that were available for accessing the key informant population and their willingness to participante in the study. We determined that using a purposive sampling method would allow us to approach and solicit input from a diverse group of experts expected to be knowledgeable about the specific issues explored in relation to VISP.(Creswell & Poth, 2017; Etikan, 2016). For the participants from HIV vaccine trials and for the frontline healthcare professionals due to the larger population, we considered having at least 20 participants per category. In contrast, due to a small population of research investigators and challenges of accessing this group, we considered conveniently a smaller sample size of at least 5 researchers.

Recruitment Procedures

Participants from two different HIV vaccine trials were selected using a non-random purposive sampling approach. The lists were organized by the participant's identification number and contact number, in the order in which they were enrolled in the study. Individuals were contacted by telephone, in order, from an available list of 68 trial participants, and asked if they had been a participant in a HIV vaccine clinical trial and whether they would like to participate in our study. No names were asked for until they accepted to participate in the study. After they accepted the invitation to participate, an interview appointment was scheduled for a place and time of the participant's preference. On the day of the interview, study details were provided to the participant and those interested in taking part in the study provided their written informed consent to be interviewed and to have the interview recorded.

For recruitment of vaccine trial investigators, staff at CISPOC generated a list of study personnel engaged in the HIV vaccine trials’ informed consent process, and five individuals were randomly selected from this list to be recruited for participation in our study.

Finally, we aimed to recruit at least one frontline health worker (physician, nurse, counselor, or psychologist) from each of our participating health facilities. To accomplish this we used personnel lists generated by each health facility to identify staff engaged in HIV counseling and testing (services we recruited from included: HIV counseling and testing services; Maternal and child health services; Adolescent and youth friendly services; and Triage services). Frontline health workers were then randomly selected from the generated list for recruitment into the study. Once individuals agreed to participate in our interviews, we scheduled a convenient time and place to carry out the informed consent process and subsequent study interview.

Study Tools and Variables

Three interview guides with both qualitative and quantitative questions were developed by the study investigators to collect data from each of the three different participant groups. The interviews were performed by the study principal investigator and one well-trained sociologist hired to assist. The variables and constructs used in each interview guide are described in Table 1 .

Table 1.

Variables and Constructs Used in Interview Guides by Participant Type.

Section	Variables/Constructs
Frontline Healthcare Providers N = 26
Social demographics	1. Age 2. Gender 3. Education Level, (All quantitative) 4. Occupation, 5. Time in current position, 6. 6. Institution;
2. Questions related to knowledge about vaccines, clinical trials and VISP	Have you ever heard about clinical trials of HIV vaccines? (quantitative) Where did you hear about them? (quantitative) What do you understand about HIV vaccine trials? (qualitative) Do you know any institution in Mozambique that conducts clinical trials? If yes, where? (qualitative) Have you ever heard about VISP? What do you understand about VISP? (qualitative)
3. Questions related to HIV vaccine trial participants’ attendance in health facilities to perform HIV testing in the context of VISP	If someone comes to the health facility and you think they should be tested for HIV, but they say they have participated in an HIV vaccine trial, how should you proceed? (qualitative) If you perform an HIV test and the result is positive, what does it mean? (qualitative) Do you think this person needs to start ART? Why? (qualitative) What type of HIV test is most appropriate for someone who has participated in an HIV vaccine trial? (qualitative) In your opinion, what strategies should be implemented in health facilities to support participants in HIV vaccine trials? (qualitative
Vaccine trial Investigators N = 5
4. Social Demographics	1. Age 2. Gender 3. Education Level (Quantitative) 4. Occupation,
5. Questions related to knowledge about vaccines, clinical trials, and VISP	What do you know about clinical trials and VISP? (qualitative) What are the implications of VISP on the lives of the participants? (qualitative)
6. Questions related to the informed consent process considering VISP	What aspects of VISP do you feel participants have the most difficulty understanding? (qualitative) What barriers do you encounter in the informed consent process that impact participants’ decisions? (qualitative) In your experience, do clinical trial participants fear the possibility of VISP? (qualitative) In your experience, do participants ask many questions about VISP before agreeing to participate in the study? If so, which questions do you remember most? (qualitative) Based on your experience, if you could change/adapt the information given to participants about VISP, what would you change/adapt? Why? (qualitative) What information do you think is important for healthcare professionals who will encounter your clinical trial participants regarding VISP and vaccine trials? (qualitative)
Participants in HIV vaccine trial=20
7. Social Demographics	1. Age 2. Gender 3. Education Level (Quantitative) 4. Occupation 5. How long had participant been in a HIV vaccine trial.
6. Questions related to motivation and participation in HIV vaccine trials, knowledge about VISP obtained in the informed consent process.	How long ago did you participate in a HIV vaccine trial? (quantitative) What was your motivation? (qualitative) Have you heard about VISP? What do you understand about it? (qualitative) Do you know the implications of VISP? (qualitative) In your opinion, is VISP a good or bad thing to have as a study participant? (qualitative) At the time you enrolled in the study, do you think you understood the implications of VISP? (qualitative)
7. Questions related to participants’ attitudes towards HIV testing outside research centers.	Have you ever been to a health facility to get an HIV test since enrolling in the study? (quantitative) Can you describe the experience? (qualitative) If the test comes back positive, how would you proceed? (qualitative)
8. Questions related to your feelings and experiences as a participant and the risk of VISP.	Did you talk to your spouse (or family member) about participating in an HIV vaccine study? What was their reaction? (qualitative) Based on your experience, is there anything you wish had been explained better about VISP? (qualitative)

Data Collection and Management

Interviews were conducted in Portuguese and were audio recorded and subsequently transcribed. The quotes to be used in the manuscript (Suplement file 1) were translated into English using online tools (Google Translate) and reviewed by two investigators fluent in both Portuguese and English for data quality assurance. Qualitative data were entered into Microsoft Excel. Quantitative data, such as participants’ sociodemographics and responses to the closed-ended questions, were input into a secure Research Electronic Data Capture (REDCap) database maintained on a server at University Eduardo Mondlane (UEM) in Maputo. Only the research staff had access to REDCap. To protect participants’ confidentiality, identifying information was removed from the interview transcripts and each respondent was assigned a study code. For quality control, data were verified by a person different from the one who entered the information into REDCap.

Data Analysis

Qualitative data: For content analysis, thematic axes were assigned to each participant's responses in the audio-recorded interviews. Related ideas were categorized and coded using concise labels—limited to a maximum of four words—to reduce duplication. After coding, two-word subthemes were generated by grouping content with similar meaning. These subthemes were then organized into overarching thematic axes. Once the thematic axes were established, analyses were conducted to determine the frequency of each response across participants. For quality assurance, two independent reviewers verified the transcriptions and the thematic axes (Creswell & Poth, 2017). A flowchart of procedures for qualitatice data analysis was presented in Figure 2 .

Figure 2.

Flowchart of procedures for analyzing the qualitative data from the study.

Specifically, to determine good or poor understanding of VISP a codebook was used to assess the interview's explanation. Participants were deemed to have good understanding if they defined VISP using at least one of the following inclusion criteria:

Result of vaccine-induced antibodies.

Not a true HIV-infection.

Rapid tests appears as positive/ false-positive.

Need for the use of HIV specific testing to confirm the diagnosis.

Able to identify some clinical or social implications.

Participants were deemed to have poor understanding if they demonstrated at least one of the following :

Discussed HIV generally without stating any of the above points.

Confused VISP with a true HIV infection.

Made statements that reflects misinformation (example: VISP is because the vaccine contains the virus)

Quantitative data: We performed descriptive statistical analysis of frequencies, proportions, and central tendencies using SPSS version 20.0.

Results

Demographic Characteristics

Healthcare Professionals

A study investigator contacted 30 frontline healthcare professionals from lists provided by the health facility who were engaged in HIV couselling and testing at health facilities where HIV vaccine study participants could potentially go for care. Twenty-six accepted the invitation to be interviewed, while four were unavailable to participate in the study because they were out of office. The majority of healthcare professional participants were female (58%), with a median age of 32 years [interquartile range (IQR): 26,35]. Fourteen (54%) had completed a minimum education level of either technical school or university. The majority (80%) were Counselors, a specific professional role predominantly responsible for providing HIV counseling and testing, though they also provide education and couseling related to other health conditions ( Table 2 ).

Table 2.

Sociodemographic characteristics of frontline healthcare professionals included in the study.

Sociodemographic Characteristics (N = 26)	N (%)
Age
18–25 years	5 (19%)
26–35 years	15 (58%)
36–45 years	5 (19%)
>45 years	1 (4%)
Gender
Female	15 (58%)
Male	11 (42%)
Highest Education Level Achieved
Secondary school	12 (46%)
Technical school (health sciences)	3 (12%)
University	11 (42%)
Occupation
Medical Doctor	3 (12%)
Nurse	1 (4%)
Counselor*	21 (80%)
Medical Technician**	1 (4%)
Time in current position
<3 months	1 (4%)
3-months to 1-year	6 (23%)
1-year to 3-years	7 (27%)
>3-years	12 (46%)
Institution
Maxaquene Health Facility	5 (19%)
Polana Cimento Health Facility	6 (23%)
May 1^st Health Facility	6 (23%)
Mavalane Health Facility	5 (19%)
Alto Mae Health Facility	4 (16%)

*Counselor = Healthcare professional predominantly responsible for HIV counseling and testing; **Medical Technician = Equivalent to a Clinical Officer, healthcare professional responsible for providing direct patient care to HIV-patients.

A list of thirteen researchers from the CISPOC who actively participate in the informed consent process for HIV vaccine trials was provided to the study team. The researchers were contacted randomly from the list and the first five that accepted the invitation were subsequently interviewed. Four (80%) of the 5 researchers interviewed were female and an equal proportion reported “university” as their highest level of education (Table 3).

Table 3.

Sociodemographic Characteristics of CISPOC's Researchers Included in the Study.

Sociodemographic Characteristics (N = 5)	N (%)
Age
26–35 years	2 (40%)
36–45 years	2 (40%)
>45 years	1 (10%)
Gender
Female	4 (80%)
Male	1 (20%)
Highest Education Level Achieved
Secondary school	1 (20%)
University	4 (80%)
Occupation
Medical Doctor	2 (40%)
Counselor	1 (10%)
Psychologist	2 (40%)

*All the interviewees had worked at CISPOC for at least 3 years.

Participants of HIV Vaccine Trials

From the list of 68 volunteers who participated in one of two different HIV vaccine trials, twenty-eight were contacted, of which twenty accepted to be interviewed. Seven were unreachable (contact number unavailable) and one declined to be part of the study. The majority were female (80%), with a median age of 26 years [IQR: 25,29]. The amount of time that participants had been involved in the HIV vaccine trial was evenly split, with 50% having been enrolled for more than two years and 45% having been enrolled for two years or less ( Table 4 ).

Table 4.

Sociodemographic Characteristics of HIV Vaccine Trial Participants Included in the Study.

Sociodemographic Characteristics (N = 20)	N (%)
Age
18–25 years	8 (40%)
26–35 years	8 (40%)
36–45 years	4 (20%)
Gender
Female	16 (80%)
Male	4 (20%)
Highest Education Level Achieved
Primary	5 (25%)
Secondary	14 (70%)
Technical	1 (5%)
Occupation
Unemployed	5 (25%)
Student	2 (10%)
Employed	13 (65%)
How long had participation been in a HIV-vaccine trial
<1-year	3 (15%)
1-year to 2-years	6 (30%)
>2-years	10 (50%)
Don’t know	1 (5%)

Motivations for Participating in an HIV Vaccine Trial

We asked HIV vaccine trial participants about their motivation for participating in the trial, and several key factors emerged as primary drivers of their decision to participate ( Figure 3 ). The most frequently cited reason for participation, mentioned by eight participants (40%), was the desire to contribute to the development of a vaccine to prevent HIV (n = 8, 40%).

Figure 3.

Distribution of motivations for participating in an HIV vaccine trial.

Knowledge and Perceptions Related to HIV-Vaccine Trials and VISP

Healthcare Professionals

From the 31 healthcare professionals interviewed, 22 (71%) had previously heard about HIV-vaccine trials, including 17 frontline healthcare professionals and all five of the HIV vaccine trial investigators. Twelve of the seventeen (70.6%) had heard about HIV vaccine trials through a communication platform (radio, TV, internet), two (11.8%) had heard about them from a patient, and four (23.5%) had previously participated in a training session or seen a presentation on HIV-vaccines studies at their workplace. Of the four who had received training, three were counselors and one was a medical doctor. Of the 17 frontline healthcare professionalss who reported that they were previously aware of HIV vaccine trials, eight (41,7%) reported prior awareness of VISP, and of these, four (50%) could correctly describe what VISP was during the interview ( Table 5 ).

Table 5.

Study Participants' Knowledge about HIV Vaccine Trials and Vaccine-Induced Seropositivity

Participant	Knowledge About HIV Vaccine Clinical Trials N (%)		Knowledge About VISP N (%)
Participant	Yes	No	Yes	No
Vaccine study investigator	5/5 (100%)	–	5/5 (100%)	–
Vaccine study participant	N/A	N/A	15/20 (75%)	5/20 (25%)
Frontline health professional	17/26 (65%)	9/26 (35%)	8/26 (31%)	18/26 (69%)

Quotes from participants’ responses to interview questions are excerpted below in English. Original Portuguese responses are included in Supplemental File 1.

Illustrative quotes showing good understanding of VISP from healthcare professionals:

“…because of the vaccine reaction, after a certain time, the person could test and be positive. But not because the person is positive, the person is positive because of the vaccine reaction.”Healthcare professional-005

“…this could lead to a result that is not real [ positive], but it is not the real state of the patient, because the vaccine activated some cells in their body…” Healthcare professional-016

Illustrative quotes showing poor understanding of VISP from healthcare professionals:

“…Vaccine-induced seropositivity, in my words it would be, let's suppose, injecting [HIV] positive blood into a certain person, that is, passing from person to person, the… seropositivity.” Healthcare professional-005

“… But thinking about the actions of the vaccine… the vaccine uses the virus, if they are putting the virus in me without being positive, I run the risk of becoming positive…”

Healthcare professional-010

Of the five HIV vaccine investigators, all demonstrated good knowledge of the concepts of both HIV vaccine trials and VISP.

Illustrative quotes showing understanding of clinical trials and VISP from vaccine trial investigators :

“… a clinical trial is a study in which we are going to test a new product, a medicine, a vaccine, or something that is a new product that is not yet commercialized. So, vaccine-induced seropositivity is the presence of antibodies, which are tested for, for example, in the case of HIV, a test is positive without the person actually being infected by the virus, but a person who received the vaccine produced some antibodies, so these antibodies are detected by the test.” Vaccine trial investigator-002

“Regarding clinical trials, I would say they are studies that involve the participation of humans, in which a form of treatment or diagnosis of pathology may be evaluated that envolves intervention… Vaccine-induced seropositivity, I understand is a volunteer who participated in a clinical trial presenting a positive rapid test for HIV, having received a vaccine, with the aim of producing antibodies…” Vaccine trial investigator-001

Perceived Challenges in the Informed Consent Process for HIV Vaccine Trials

Of the 20 HIV vaccine trial participants interviewed, 15 (75%) had a good working knowledge of VISP, while five (25%) were unable to provide an explanation when asked “what is VISP?”.

Illustrative quotes showing good VISP understanding among vaccine trial participants:

“…we could have this risk, when getting vaccinated, when participating in the study we could have this risk that, if by chance we took an HIV test outside, it could come back positive due to… this vaccine that was given to us….” Trial participant-006

“…after the vaccine is applied, in the case of tests, those rapid tests that are carried out in health units, that HIV test could give a positive result in this case, but it does not mean in this case that you are a carrier of HIV/AIDS, but because of the vaccine…” Trial participant-018

Illustrative quotes showing poor VISP understanding among vaccine trial participants:

“We were going to be given the vaccine and the vaccine was supposed to be effective and cure HIV.” Trail participant-007

“They explained a lot of things. That this vaccine depends on the person, whether it suits them or not…” Trial participant-014

Perceived challenges in the informed consent process for HIV vaccine trials

We assessed the perspectives of the vaccine trial investigators in relation to what they perceived as barriers/challenges for study participants with regards to VISP and the informed consent process. Four vaccine trial investigators (80%) described that study participants often struggled to grasp that a positive HIV-test result due to VISP may not be a true positive, but rather a vaccine-induced effect.

“…I believe that they understand, but they don’t imagine the dimension of living in a scenario in which they may perfom the test and the test can be positive…” Vaccine trial investigator-001

“…It is a concept that often confuses some participants, because unfortunately, even though they have been with us for a long time, and we always expain, there are many who have not assimilated this knowledge well.” Vaccine trial investigator-002

Of the vaccine trial investigators interviewed, two (40%) additionally stated that the participants’ overall lower level of education interferes with their understanding of the research's goals, as well as their ability to fully understand the implications of their participation, as illustrated in the quotes below.

“ We are in an environment where people are not used to, or do not know what research is and why they should be participating in research. They feel that participating in research is like being a guinea pig, and not realizing that research helps solve health problems… I think the main barrier in the informed consent process is the volunteer understanding what role they have in the research.” Vaccine trial investigator-001

“…the first thing is education, right? I think that their education does not allow (full understanding), and when I say education, I do not mean just reading and writing, but in terms of being able to understand what and where the participant is getting involved. This is the first barrier…” Vaccine trial investigator-002

Attitudes Toward HIV Testing and VISP Care Among Frontline Healthcare Professionals

Frontline Healthcare Professionals’ Attitudes

We next explored the attitudes of frontline healthcare professionals with regards to performing HIV-testing of HIV vaccine trial participants when they sought care at their local health facility. In response to the question: [Question: If someone comes to the health facility and you think they should be tested for HIV, but they say they have participated in an HIV vaccine trial, how should you proceed?], 15 (58%) frontline healthcare professionals reported that they would follow the national HIV-testing protocol and test the HIV vaccine trial participant with an antibody detection-based rapid HIV test ( Figure 4 ).

“I would personally advise the person to take the test, first to understand what the result will be after the HIV vaccine.” Healthcare professional-002

“… Testing is voluntary. Clinically, I think the person needs to do it… I believe… I think we need to do an HIV test. If the person refuses, that's it… I'm not going to insist, the person refused. We continue to do the symptomatic treatments, what he is feeling, and what the other tests say, except for the HIV test. I accept the patient's decision.” Healthcare professional-010

Figure 4.

Attitudes of frontline healthcare professionals towards HIV testing of participants in HIV vaccine trials.

We further questioned frontline healthcare professionals as to what they thought was the appropriate type of HIV test to administer to a participant in an HIV vaccine trial. Five frontline healthcare professionals (19.2%) were able to respond correctly that the appropriate test would be an HIV DNA-based polymerase chain reaction (PCR) test.

We next followed up with questions about how they would interpret the results of a positive rapid HIV test. Six of the frontline healthcare professionals (24%) were able to state correctly that a positive result on an HIV rapid test could be due to the patient's VISP, and not due to an active HIV infection. Another nine (35%) stated that they belived that a positive HIV rapid test for these patients would still indicate that they were HIV-infected.

Moreover, 17 (65.4%) frontiline healthcare professionals responded that an HIV-vaccine study participant who tested positive using a rapid HIV test should be started on ART at that visit.

Illustrative quotes showing that the healthcare professionals would start treatment:

“I would suggest starting treatment. First, it is a trial. So in this trial anything is possible, so in this case the possibility was a positive test result.”Healthcare professional-003

“If you tested positive, you tested and started the treatment. Unless there is some other criteria related to the study… But here, we have to follow the protocol.”

Healthcare professional-018

Illustrative quotes showing healthcare professionals who would not start treatment:

“The participant is not elegible to take ART, but to [not] do so, he/she would need to show their study ID card.” Healthcare professional-005

“No, because you are not sure of the real result, so I would ask for some time for the person to test again…” Healthcare professional-006

HIV Vaccine Trial Participants' Experiences with HIV-Testing

We questioned HIV vaccine trial participants about their experiences in accessing care and whether they had received testing for HIV at any point after their participation in the HIV vaccine trial. A total of nine vaccine trial participants reported that they had been given an HIV test, including one who received the test as part of routine pre-natal care. None reported a negative experience, such as being discriminated against or being asked to start ART. Additionally, nine (45%) of the HIV vaccine trial participants appropriately described what they should do if offered a test and it happened to come back positive. The participants described that they would contact the study site for clarification and ask for the right test.

Illustrative quotes showing participants who know what to do if their HIV test comes back positive in the health facility:

“ Approach CISPOC, or get in touch with the professionals, explain the situation, and they could perform the new test.” Trial participant-002

“I already knew, that in fact it was normal to test (positive). If I had done it there and it was positive, I would ask to do again at CISPOC. Yes, to be able to see if in fact, it was really positive.” Trial participant-003

Illustrative quotes showing participants who do not know what to do if the HIV test comes back positive in the health facility:

“ If the test was positive, all you had to do was continue with the treatment, the pills, because it is not a fatal disease.” Trial participant-005

“They didn’t give any explanation, they said that if I wanted to do the test, I had to ask there in the study.”Trial participant-006

Perception of Stigma and Discrimination

We next questioned HIV vaccine participants about their understanding of the potential implications of VISP when accessing healthcare in the future. Sixteen HIV vaccine trial participants (80%) responded that VISP could cause them to be given an incorrect diagnosis of HIV infection; three participants (15%) responded that it could interfere with their ability to donate blood; three participants (15%) reported that it could complicate their future pre-natal care; and one (5%) reported an inability to receive the HIV rapid test in the future. All HIV vaccine trial participants ackowledged that a wrong HIV diagnosis due to VISP could result in stigma, discrimination, and social harm to themselves. When participants were asked whether VISP was a good or bad thing in their perception, eight (40%) stated that it was a good thing because it is a reaction to the vaccine or because their participation in the study was worth it, seven(35%) stated that was a bad thing because VISP could cause stigma and stress when trying to figure out if the result is the right one, and five (25%) were neutral or didn’t respond.

Illustrative quotes showing vaccine trial participants who think VISP is a good thing:

“For those of us who are in the study, it (VISP) is good… because in the study it is possible to know whether I am producing antibodies or not…” Trial participant-011

“I can say that it is good, because I felt comfortable, because with that I can… even having sexual relations or being with someone infected, that can…can protect me-Trial participant-002

Illustrative quotes showing participants that think VISP is a bad thing:

“I don’t think it's [VISP] a good thing, because after a while I started feeling uncomfortable. I think the first time they explained it to me I didn’t really understand, but when they explained it to me the second time I was worried.” Trial participant-006

“For me it's a bad thing (laughs). Because I'm going to do the test outside and it turns back positive, right… so that implies that they're going to give me…the pills and everything else, while it was nothing.” Trial participant-003

“I think it's bad… Because maybe I’m at school, they force us to take a test, and it comes back positive, while it's not…” Trial participant-001

Discussion

Despite the implementation of multiple HIV vaccine trials in Mozambique over the last decade, the local health system continues to face considerable challenges related to frontline healthcare professionals’ understanding of key clinical trial-related concepts (Malahleha et al., 2023). One of the most pressing—and often underrecognized—issues is the limited awareness among frontline healthcare professionals, especially those involved in HIV counseling and testing, regarding the nature of HIV vaccine trials and the phenomenon of VISP(Voronin et al., 2015). These professionals often serve as the first point of contact for individuals re-engaging with the health system after trial participation, making their knowledge vital for ensuring appropriate care and support. This limited knowledge among frontline healthcare professionals compared to the greater knowledge of the participants may be due to lack of exposure to VISP and vaccine trial concepts during their formal training, while participants are informed about VISP during the initial informed consent process and, on an ongoing basis throughout the study.

This issue is especially critical in high HIV prevalence settings like Mozambique, where aggressive HIV testing strategies are in place as part of the country's commitment to the UNAIDS 95-95-95 targets. In such settings, large-scale routine testing can amplify the risks of VISP-related misdiagnosis if frontline providers are not adequately informed (Msafiri et al., 2022; Rautenbach et al., 2015). Our findings align with previous research conducted in South Africa, which similarly reported widespread misunderstanding about VISP among key stakeholders—including healthcare professionals, community members, and even some trial participants (Malahleha et al., 2023).The potential for individuals who have received an HIV vaccine to test false-positive due to vaccine-induced antibodies—and to then be inappropriately initiated on lifelong ART—is a serious concern and can be considered a serious ethical problem (Couderc, 2018; UNAIDS, 2021). Beyond clinical mismanagement, this scenario can cause lasting social harm, including stigma, discrimination, and a loss of trust in both health services and HIV vaccine research (Van Braeckel et al., 2011; Voronin et al., 2015)

A relevant finding in this study was that, although most of the frontline healthcare professionals interviewed did not have a clear understanding of VISP, or how to intervene in a case of VISP, none of the vaccine trial participants reported having had a negative experience related to HIV testing in a health facility. This may be due to the small sample size, and may not be representative of the pratices of frontline healthcare professionals, or experiences of all HIV vaccine trial participants.

Another notable finding was that, although trial participants were not able to clearly articulate the concept of VISP, they could describe its practical implications. This indicates that they held some understanding of VISP and its potential impact on their lives, suggesting that this awareness may have informed their decision to consent to the study.

Educational Implications

Building and maintaining public trust requires proactive communication and education strategies to clarify the implications of VISP (Fatola et al., 2022). In our study, most of the frontline healthcare professionals interviewed were HIV counselors rather than clinicians. These counselors—often laypersons with limited formal medical training—play a crucial role in guiding patients through HIV testing processes and, in some cases, initiating linkage to care (MISAU, 2015). Given Mozambique's extensive HIV testing infrastructure, these individuals operate at the heart of national case-finding efforts. It is therefore essential that they be equipped with a clear understanding of exceptions to standard diagnostic protocols, particularly when managing the care of individuals who have received an HIV vaccine in a clinical trial (Msafiri et al., 2022).

Our findings revealed a significant training gap: few frontline healthcare professionals had received formal training related to HIV vaccine trials or VISP. This lack of training is especially concerning given their limited clinical background and the complexity of VISP-related scenarios. Addressing this gap through targeted, context-appropriate educational interventions integrated into routine HIV services is critical. Ongoing reinforcement of VISP-related concepts in both pre-service and in-service training will safeguard patient well-being, prevent unnecessary initiation of ART, and maintain trust in ongoing and future HIV vaccine efforts—especially in countries striving to meet ambitious global HIV targets (Chinyenze et al., 2023).

Best Practices

Information on the number of successful VISP cases managed in previous HIV vaccine trials was limited. Existing literature indicates that approximately 41.7% of vaccine recipients developed vaccine-induced seropositivity (VISP), and the effectiveness of managing VISP varies considerably across studies and settings, highlighting its strong context-dependence (Voronin et al., 2015).

Several insights from this study suggest practical steps that can be considered best practices in managing the challenges of VISP in resource-limited, high-prevalence settings. First, HIV vaccine trials in Mozambique demonstrated that it is possible for participants—even in low-literacy contexts—to develop strong comprehension of VISP through a carefully designed informed consent process (Flory & Emanuel, 2004; Magaço et al., 2023; Rautenbach et al., 2015). Clear, repeated communication strategies, use of local languages, and culturally adapted explanations appear to have been effective in ensuring participants’ understanding.

Second, continuous engagement with participants beyond initial enrollment may strengthen comprehension and retention of critical information (Ssali et al., 2015). Study participants reported adequate knowledge of what to do if they tested positive outside of the trial setting, indicating that reinforcement of VISP-related counseling during follow-up visits was a successful approach. In contrast, healthcare professionals—particularly counselors—demonstrated lower levels of understanding, underscoring the need to extend similar educational strategies to the broader health workforce.

Third, participants’ motivation and family support emerged as influential factors in their decisions to enroll in HIV vaccine trials. Best practices must therefore include not only individual-focused education but also community and family engagement, which can help reduce stigma, dispel misconceptions, and support ethical participation in research (Ubisse Capitine et al., 2024)

Research Agenda

As HIV vaccine candidates continue to improve in immunogenicity, the likelihood of VISP increases, necessitating greater preparedness at all levels of the health system. Policymakers and researchers should prioritize studies that:

Evaluate educational interventions: Future research should assess the effectiveness of different models of provider education—such as digital modules, onsite workshops, and mentorship programs—in improving frontline healthcare professionals’ knowledge of VISP.

Test alternative HIV testing algorithms: Implementation studies should explore how existing HIV testing protocols can be adapted to account for VISP, including referral pathways for confirmatory nucleic acid-based testing.

Examine participants’ long-term experiences: Longitudinal research following vaccine trial participants after study completion could provide insights into how VISP affects healthcare access, social dynamics, and trust in research institutions over time.

Study community perceptions: Community-based participatory research could illuminate how broader socio-cultural environments influence trial participation and responses to VISP-related stigma (Chinyenze et al., 2023).

Strengthen informed consent models: Further research should test innovative, literacy- and linguistically-appropriate consent approaches to ensure that participants in low-resource settings can fully understand trial implications, including VISP.

Investment in the informed consent process for HIV vaccine trials should be continuous, throughout the course of the study and not limited to enrollment. Strategies should prioritize simple, accurate, and transparent communication tailored to Mozambique's linguistic and educational landscape, ensuring participants can make truly informed decisions (Vaswani et al., 2020).

Limitations

This study has several limitations that should be considered when interpreting the findings. First, the cross-sectional design limits our ability to draw causal inferences or assess changes in perceptions and practices over time. Second, although we employed a non-random purposive sampling strategy to recruit a diverse group of participants, the overall sample size was relatively small and limited to a single urban area (Maputo City), which may affect the generalizability of the findings to other settings in Mozambique or sub-Saharan Africa. To avoid bias due to sampling, the lists used to select the participants were generated by an impartial individual apart from the study. Third, the reliance on self-reported data during interviews introduces the potential for recall bias or social desirability bias, particularly among frontline healthcare professionals and research study staff who may have had incentives to provide responses perceived as favorable. To avoid this bias the interviewer provided a safe non-judgmental environment and assured participant's confidentiality and anonymity. Fourth, although qualitative interviews provided valuable insights, we may not have captured the full range of perspectives from all relevant stakeholders, particularly trial participants who declined to participate or who were unreachable. Additionally, participants were drawn from a pool of individuals already involved in HIV vaccine research or related healthcare services, which may limit the applicability of findings to more general populations unfamiliar with research settings. Despite these limitations, the study offers important contextual insights into perceptions surrounding HIV vaccine trials and VISP in a high HIV-burden setting.

Conclusions

While HIV vaccine trial participants and research investigators in this study demonstrated a relatively strong understanding of VISP, the frontline healthcare professionals who are the most likely to encounter VISP cases in clinical practice, showed limited knowledge. This highlights the urgent need for systematic educational initiatives that target HIV counselors and other non-clinical staff who are central to the country's testing and treatment infrastructure.

This study also demonstrated that a good informed consent process should be tailored to the literacy level of the community in which the study will be implemented to enable participants to develop and retain key knowledge about VISP.

Future studies should evaluate educational interventions for healthcare providers, adapt HIV testing algorithms to account for VISP, and follow participants longitudinally to understand their experiences beyond trial completion. Community-level research and innovative consent strategies will be critical for ensuring ethical, effective, and sustainable HIV vaccine research in high-prevalence, low-resource settings.

Supplemental Material

sj-docx-1-jre-10.1177_15562646261448776 - Supplemental material for Ethical Challenges Posed by HIV-Vaccine Induced Seropositivity for the Informed Consent Process and HIV Testing Practices in Maputo City, Mozambique

Supplemental material, sj-docx-1-jre-10.1177_15562646261448776 for Ethical Challenges Posed by HIV-Vaccine Induced Seropositivity for the Informed Consent Process and HIV Testing Practices in Maputo City, Mozambique by Emilia Fumane, Khatia Munguambe, Graça Salome, Troy D. Moon, Elizabeth Heitman and Esperança Sevene in Journal of Empirical Research on Human Research Ethics

Footnotes

Acknowlegments

We would like to express our gratitude to the healthcare professionals and vaccine trial participants who took part in this study. Additionally, we especially thank our colleagues at University Eduardo Mondlane and the Mozambican National Institute of Health for the technical support that made this research possible.

ORCID iDs

Emilia Fumane

Elizabeth Heitman

Ethical Approval and Informed Consent Statement

The protocol for this study was reviewed and approved by the Inter-institutional Committee for Bioethics for Health (Comité Inter-institucional de Bioética para Saúde, CIBS) of the UEM Faculty of Medicine/Maputo Central Hospital, under registration number CIBS FM&HCM/080/2021. The study was conducted in compliance with the Belmont Principles, CIOMS guidelines, the 2013 Declaration of Helsinki and other applicable regulatory principles. Written informed consent was given by all the study participants.

Author Contibution

EF, ES, TM, EH, KM, GS conceived the study, contributed to the development of the proposal. ES, TM, EH, GS provided mentorship. EF recruited the participants, performed the interviews and conducted the analysis. ES supervised the data collection and analysis. All authors contributed to writing of the manuscript.

Funding

The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported by the Fogarty International Center of the United States National Institutes of Health under award number R25TW009722. The funder had no role in study design, collection, management, analysis, interpretation of data, writing of the report, and the decision to submit the report for publication, including whether they will have ultimate authority over any of these activities.

Declaration of Conflicting Interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Data Availability Statement

Due to participant privancy, excerpts from participant interviews can be made available upoin reasonable request to the corresponding author.

Supplemental Material

Supplemental material for this article is available online.

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