Descriptions of risks and benefits of HIV vaccine trials in low-and middle-income countries (LMICs): an integrative review

Abstract

Abstract

Human immunodeficiency virus (HIV) vaccine trials are needed in efforts to prevent infection and acquired immunodeficiency syndrome (AIDS). Like other types of research, HIV vaccine trials present benefits and risks that may or may not be anticipated by participants. Perceptions of risks and benefits often vary with contextual factors, such as sociocultural and economic variables, which are important in low- and middle-income countries (LMICs).

Aims

This integrative review aimed to determine the risks and benefits of HIV vaccine trial participation reported in the LMICs from 1995 to 2024. The risks and benefits were reported by participants and potential participants during trial preparations, recruitment, actual trial participation or after trial participation. In this review we assessed on how the risks and benefits were described by the authors of the reviewed studies. We also sought to categorize these risks and benefits, consider ethical implications, identify gaps for further research, and recommend actions for policy improvement.

Methods

The integrative review screened studies from four databases (CINAHL, Embase, MEDLINE and Web of Science). Studies were eligible if they involved interactions with human subjects and were written in English. Covidence software was used to organize the search outcomes.

Results and discussion

Twenty-five studies met inclusion criteria. Identified benefits included a sense of altruism, free healthcare, financial incentives and HIV education. Risks included stigma and discrimination associated with vaccine-induced seropositivity, perceived racism and fear of delayed harms. Important descriptions of risks and benefits (e.g., magnitude and likelihood) were missing. Free healthcare and financial incentives may render participants too influenced to enter consent, which is an important ethical concern in LMICs.

Conclusion

The literature was scant, highlighting a need for research on how participants in LMICs are informed about weighing risks and benefits of HIV vaccine trial participation. More in-depth description of risks and benefits is warranted. Standardized risk/benefit assessment frameworks tailored to the context of these trials in LMICs are needed.

Introduction

The human immunodeficiency virus (HIV) and acquired immunodeficiency syndrome (AIDS) continue to be a global public health concern, with nearly 40 million people living with the infection [1, 2]. Today, the brunt of the global burden of HIV and AIDS lies in low- and middle-income countries (LMICs) [2, 3]. Efforts by international research communities to find preventive vaccines, among other measures to curb the HIV/AIDS pandemic, are ongoing [2]. Historically, LMICs were lagging behind high-income countries (HICs) in research on preventive vaccines [4]. In recent decades, however, LMICs have made substantial efforts to advance scientific research on the prevention of HIV/AIDS. LMICs have been hosting several HIV vaccine trials to address the incidence and prevalence of the disease in these settings [2, 4]. In fact, most HIV vaccine trials have been implemented in a smaller part in HICs and in a larger part in LMICs, often within the same studies (multi-country collaborative trials). Because of the inevitable socioeconomic disparities between HICs and LMICs, implementation of such trials often involves in some way an increased risk of unintentional exploitation of LMICs. There is an increased chance that LMIC participants will face the risks and burdens of research participation more than HIC participants. There has also been a shift between HICs and LMICs in the numbers of research publications, which may indicate increased research activities in LMICs, although the funding for HIV vaccine research in LMICs often comes from HICs [5].

Since AIDS was first identified and the causative virus was discovered in the early 1980s, more than 187 HIV preventive vaccine trials have been conducted worldwide [6]. Moreover, more than 44,000 volunteers around the world have participated in HIV vaccine trials since 1987, and most of them are assumed to have received the trial vaccines [6, 7]. As in any research, HIV vaccine trials are associated with anticipated and even unforeseen risks, along with potential benefits. Because of the overwhelming need to find working solutions to curb HIV disease in LMICs, HIV vaccine trials and other HIV-related research studies, such as cure-based drug trials and pre-exposure prophylaxis trials, continue, despite the known and unknown risks. The safety and wellbeing of vaccine trial participants are of utmost importance. Assessment of risk/benefit ratios of these trials is considered essential for the protection of human participants [8–14]. A properly calculated risk-benefit balance helps to protect research participants from partaking in studies that may be unreasonably risky for them [9, 14–17].

Risk/benefit assessments ought to be conducted in a systematic and quantitative way that is evidence-based, consistent and objective [9, 11, 18–22]. However, this ideal has remained unrealized because individuals’ risk-perceptions often vary with social, economic, cultural and other contextual factors [23]. Lack of specificity in risk/benefit assessment of HIV vaccine trials can be even worse in places without adequate context-specific data to inform the researchers, institutional review boards (IRBs) and or research ethics committees (RECs).

Ideally, there should be adequate, context-specific and research-based facts about the risks and benefits of a particular HIV vaccine trial for people to make autonomous participation decisions [9, 12, 15–17]. A favorable balance between the risks and benefits is an essential ethical consideration for protection of research participants as outlined in ethical codes [16, 22]. Every effort should be made to describe the nature, magnitude and likelihood of the risks and benefits in as much detail as possible to inform researchers, IRBs/RECs and potential participants [8, 16].

We sought to understand whether and to what degree the risks and benefits of HIV vaccine trials in LMICs are addressed in the literature. Thus, the primary purpose of this integrative review was to determine what risks and benefits are identified in HIV vaccine trials conducted in LMICs. The risks and benefits were reported by participants and potential participants during trial preparedness studies, trial recruitment, actual trial participation or after trial participation. In this review we assessed on how the risks and benefits were described by the authors of the reviewed studies. We also wanted to make an initial effort to categorize the types of risks and benefits described in these studies and to consider the ethical implications of the findings, identify gaps for further research about risk/benefit assessment and recommend actions for policy improvement.

Methods

Design

An integrative review of the literature on the risks and benefits of HIV vaccine trials participation in LMICs was conducted. Integrative reviews allow gathering and evaluating evidence from various sources with diverse methodologies [24] and the findings inform new insights on a topic of interest. Moreover, an integrative review critiques and synthesizes information from the literature in an integrated way in order to identify patterns and generate frameworks and perspectives that guide practice in the area of interest [25–28]. This review followed conventional steps: identify the review question and determine the search concepts and strategy, critically appraise the search results, extract and reduce the data for analysis, synthesize the findings, report and disseminate the results [25, 26, 29]. Quantitative, qualitative and mixed-methods studies were included in order to capture a wide range of descriptions of the risks and benefits of HIV vaccine trials across LMICs.

Selection and screening of studies

We followed a systematic and rigorous process to select and screen the studies [25, 26, 29]. We searched for studies from MEDLINE, Web of Science, Embase and CINAHL databases. Key words/concepts searched were “risk,” “benefit,” “HIV vaccine trial” and “HIV vaccine trial participation.” After an initial search and review, we expanded the search to include additional terms: “HIV vaccine research,” “HIV vaccine studies,” “participation” and “experience.” Also, the names of all LMICs were added in order to capture the literature from this context. We used the variations of the search words and concepts in MeSH (Medical Subject Headings) terms (such as burdens and harms for risks) in order to capture as many relevant studies as possible. We used Boolean logic, such as AND, OR and NOT to narrow, expand or exclude the search outcomes. Studies published over a period of 29 years, from 1995 to 2024, were included. The length of the time was selected to establish patterns or paradigm shifts [24] in risk/benefit descriptions.

Quantitative, qualitative or mixed-methods [24, 26, 30–32] studies published from empirical research studies conducted in LMICs (per the current World Bank classification) to assess the risks and benefits of HIV vaccine trials were selected. Studies were considered eligible if they involved interactions with human subjects (i.e., participants or researchers or stakeholders of HIV vaccine trials) and were published in English in peer reviewed scientific journals. Studies that did not meet these criteria were excluded. Most of the excluded studies had unrelated outcomes, a few were non-empirical studies or not from LMICs; and some were excluded because we were not able to access the full text (Fig. 1).

Fig. 1.

Flow-chart of study search and screening process

Covidence systematic review software [33] was used to aid in sorting and organizing the searched studies. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) [34]framework was used to record the screening process as shown in Fig. 1.

The search yielded 186 studies in total after removal of duplicates. All 186 studies were included in the initial screening of titles and abstracts; 95 were irrelevant and hence removed. After the initial screening, 91 studies qualified for full-text screening. Sixty-six were excluded for reasons related to the outcome, setting, design and full-text non-availability. Thus, 25 studies met the inclusion criteria and were included in this integrative review.

Quality assurance and methodological rigor

To ensure quality and methodological rigor, the search and screening and review process was conducted by an interdisciplinary team. Disagreements between reviewers were effectively resolved through discussions and consensus. Also, the overall aim of the review was well explained at the beginning of the review, which was to appraise the authors’ description of HIV vaccine trial risks and benefits and the ethical implications in the context of LMICs. Specifically, this review answers the following questions: (a) what are the risks and benefits of HIV vaccine trials as documented in published studies from LMICs, (b) how were the risks and benefits described and (c) what are the ethical implications of the risks and benefits in the context of LMICs?

Data extraction and abstraction

The first author (JS) conducted the data extraction and abstraction, followed by discussion with all authors. Information from the reviewed studies included: study information (author, year and country); study methodology (study design and population); and empirical results (risks and benefits) as shown in Table 1.

Table 1.

Review results

Author, year, setting	Population	Study design	Outcome analyzed	Risks	Benefits
Celentano et al. (1995), Thailand [35]	2179 healthy volunteers	Quantitative	Willingness to participate (WTP) in AIDS vaccine trials	-Discrimination -Vaccine-induced seropositivity (VISP) -Partner rejection	-Health insurance -Altruism -Recognition -Financial gain
Jackson et al. (1995), Mombasa, Kenya [36]	201 male truck drivers and 206 female commercial sex workers (CSW)	Quantitative	Acceptance of a prophylactic HIV vaccine trial	-Risky behavior -VISP	-Reduced HIV incidence
Vieira de Souza et al. (2003), Rio de Janeiro, Brazil [37]	627 men who have sex with men (MSM)	Quantitative	WTP in HIV vaccine trials	-Risky behavior -Adverse effects -Perceived racism	-Protection from HIV
Jenkins et al. (2005), Thailand [38]	363 phase I/II HIV vaccine trial volunteers	Quantitative	Behavioral and social issues in phase I/II HIV preventive vaccine trial	-Stigmatization -Discrimination	-HIV knowledge -Heath checkups -Financial gain -Free counselling
Fincham et al. (2010), South Africa [39]	264 Black females	Quantitative	Inhibitors and facilitators of WTP in HIV vaccine trials	-Personal costs -Safety concerns -Stigmatization	-Personal gains
Essack (2010), South Africa [40]	14 stakeholders of in HIV vaccine trials	Qualitative	Issues of concern in HIV vaccine trials	-Perceived racism -Stigmatization -VISP	-Altruism -Post-trial access -Financial gain
Tarimo et al. (2010), Tanzania [41]	66 police officers	Qualitative	Reasons for participation in HIV vaccine trial	-Partner rejection -Fear of unknown effects -Incidental findings	-Altruism -Free healthcare
Nyblade et al. (2011), Kenya [42]	215 adults	Qualitative	Barriers to HIV vaccine research participation	-Stigmatization -Breach of confidentiality -Confidentiality burden
Tarimo et al. (2011), Tanzania [43]	35 former HIV vaccine trial participants	Qualitative	Volunteers’ experiences in a phase I/II HIV vaccine trial		-Safer sexual behavior -Free healthcare -Recognition for participation towards a common good
Essack et al. (2012), South Africa [44]	14 civil society organization representatives	Qualitative	Perspectives on negative biomedical HIV prevention trial results and implications for future trials	-Perceived racism -Emotional impact of negative results (disappointment, anger, distrust, misunderstanding)
Chakrapani et al. (2013), Chennai, India [45]	43 MSM	Qualitative	Mental models of candidate HIV vaccines trials	- VISP -Stigmatization -Perceived racism -Confidentiality breach
Gray et al. (2013), South Africa [46]	801 HIV vaccine trial participants	Quantitative	Change of risk behavior over time among participants in HIV vaccine efficacy trial	-Risky behavior
Tarimo et al. (2014), Tanzania [47]	33 volunteers who participated in HIV vaccine trials	Quantitative	Social harm among volunteers who had completed a phase I/II HIV vaccine trial employing HIV-1 DNA priming and HIV-1 MVA boosting	-Stigmatization -Discrimination	-Reduced risky behavior
Asiki et al. (2015), Uganda [48]	443 healthy volunteers	Quantitative	WTP in HIV vaccine efficacy trials	-Time, -Transport cost -Vaccine safety	-Free healthcare -HIV education -Protection -Recognition for participation towards a common good -Altruism
Doshi et al. (2017), Kenya [49]	70 MSM	Mixed methods	WTP in future HIV prevention trials	-Risky sexual behavior -Side effects -Guinea pig mentality	-Protection -Information access -Altruism
Nyaoke et al. (2017), Kenya [50]	281 healthy volunteers who participated in HIV vaccine trial	Mixed methods	Motivators of participation in HIV vaccine trials		-Healthcare -Financial gain -Altruism
Tarimo et al. (2019b), Tanzania [51]	67 volunteers who participated in phase I/II HIV vaccine trial	Qualitative	Harms and benefits of HIV vaccine trial participation	-Persistent misperception of being infected	-Healthcare access -HIV education
Tarimo et al. (2019a), Tanzania [52]	67 former HIV vaccine trial participants	Qualitative	Post-trial misperceptions of HIV vaccine trials	-Misperception of being infected with HIV
Mutisya et al. (2020), Kenya [53]	250 MSM and female CSW	Quantitative survey	WTP in HIV vaccine trials		-HIV education -Healthcare access -Altruism -Protection -Networking -To be busy
Iseselo et al. (2020a), Tanzania [54]	28 injecting drug users	Qualitative	Factors that motivate or hinder participation in hypothetical HIV vaccine efficacy trials	-Stigmatization -Side effects	-Altruism -Protection
Iseselo et al. (2020b), Tanzania [55]	24 volunteers who participated in the phase I/II vaccine trial between 2007 and 2010	Qualitative	Sexual behavior practices before and after participation in phase I/II HIV vaccine trial	-VISP -Risky behavior	-Safer sex practice -HIV testing
Ubisse-Capitine et al. (2021), Mozambique [56]	577 healthy adults	Quantitative	WTP in HIV vaccine preparedness cohort study	-Stigmatization -Side effects -Fear of unknown congenital abnormalities	-Protection -Knowledge -Free checkup -Altruism
Tarimo et al. (2022), Tanzania, [57]	4 volunteers who acquired HIV infection while participating in HIV vaccine trials	Qualitative case study	Personal experience in phase I/II HIV vaccine trials.	-Confidentiality breach -Stigmatization
Pancras et al. (2022), Tanzania [58]	29 adults	Qualitative	Benefits of HIV vaccine trials		-Ancillary care
Ubisse-Capitine et al. (2024), Mozambique [59]	577 adults	Quantitative	Experiences of participation in the first phase II HIV vaccine trial	-Partner rejection -Side effects -Fear of potential unknown congenital abnormalities	-Protection from HIV -Knowledge -Free healthcare -Altruism

Results

A total of 25 studies were included (Table 1). Twelve studies were qualitative, 11 were quantitative and the remaining two were mixed-methods studies. The study populations of the reviewed articles were consenting adults, including former volunteers in HIV vaccine trials, men who have sex with men (MSM), commercial sex workers (CSW), high-risk and low-risk men and women, police officers and military personnel. We did not find any studies that were specifically titled risk/benefit assessment of HIV vaccine trials in LMICs; however, we reviewed those that labeled the risks and benefits in several ways. These included terms such as motivators, positive experiences, facilitators and opportunities for benefits. Demotivators, barriers, challenges, negative experiences, harms and social harms were considered as risks.

Summary of results

Table 1 presents information from the reviewed studies. The studies did not necessarily directly assess risks and benefits. Some risks were derived from studies that assessed participants’ willingness to participate (WTP) in HIV vaccine trials. We looked for words that may signify risks,such as demotivators, barriers, challenges, negative experiences, harms, and social harms.Words such as motivators, positive experiences, facilitators and opportunities were considered as benefits.Also, the reviewed studies did not use any risk/benefit taxonomy to classify or categorize types of risks and benefits (e.g., physiological, psychological or social). Thus, we adhered to the terms for risks and benefits that were used by the authors of the reviewed studies. To maintain specificity, we present only the benefits and risks that pertained to individual trial participants. Other types of risks and benefits, such as those that pertained to society (e.g., generalizable knowledge) or to the researchers themselves (e.g. capacity building) are not included in this review.

Among the 25 reviewed studies, 19 assessed both risks and benefits and 6 studied either risks or benefits. Table 2 presents the risk and benefit categories, including social, psychological, economical, and physiological.

Table 2.

Four categories of risks and benefits and number of reviewed studies that assessed risks and benefits in those categories

Risks	Frequency (%); N = 21	Benefits	Frequency (%); N = 19
Social Stigma Breach of confidentiality Discrimination Partner rejection Perceived racism Burden of confidentiality Guinea pig mentality	9 (43%) 4 (19%) 3 (14%) 3 (14%) 3 (14%) 1 (5%) 1 (5%)	HIV education Knowledge Information access Networking To be busy	2 (11%) 3 (16%) 1 (5%) 1 (5%) 1 (5%)
Psychological Vaccine-induce seropositivity Increased risky behavior Fear of the unknown Fear of being infected Emotional impact of negative findings (disappointment, anger, distrust or misunderstanding)	5 (24%) 5 (24%) 3 (14%) 2 (10%) 1 (5%)	Altruism Protection from HIV Recognition Safe sexual behavior Safe sex practice Reduced risk behavior	10 (53%) 6 (32%) 3 (16%) 2 (11%) 2 (11%) 1 (5%)
Economical Personal costs Time Transport costs	1 (5%) 1 (5%) 1 (5%)	Free healthcare Free medical check up Financial gain Health insurance Free counselling Personal gain HIV testing Post-trial access Healthcare access Ancillary care	6 (32%) 3 (16%) 4 (21%) 1 (5%) 1(5%) 1 (5%) 1 (5%) 1 (5%) 1 (5%) 1 (5%)
Physiological Side effects Adverse effects Safety concern Vaccine safety Incidental findings	4 (19%) 1 (4%) 1 (4%) 1 (4%) 1 (4%)

Benefits of HIV vaccine trials in LMICs

The Belmont report (1979) defines research benefit as something that promotes the health and well-being of research participants [14]. Research benefits can be categorized in various ways, including those that are social, psychological, economical, legal or physiological. The benefits can be for individual trial participants or for society, such as the generalizable knowledge that may be obtained through a particular HIV vaccine trial. Individual benefits can be further sub-divided into direct benefits (e.g., physiological benefit) and perceived participation benefits (e.g., sense of altruism and recognition).

As shown in Table 2, altruism was the most prominent benefit, reported in 10 (53%) of the 19 reviewed studies that assessed benefits. Other reported benefits were free healthcare in six studies (32%); hope for protection from HIV in six (32%); financial gain in four (21%); free medical check-ups, recognition and HIV education in three (16%); knowledge, safe sexual behavior and safer sexual practice in two (11%); health insurance, information access, networking, to be busy, reduced risky behavior, free counselling, personal gain, HIV testing, post-trial access, healthcare access and ancillary care reported in one study for each (5%). A finding of interest was that participants in six of the studies mentioned a hope of being protected from HIV infection by the trial vaccines as a benefit of participating in the trials.

Risks of HIV vaccine trial participation in LMICs

The Belmont report defines research risk as a function of the likelihood and the magnitude of harm that a person may incur as a result of participation in research [14]. Harms from HIV vaccine trials may be categorized into two groups: direct and indirect, or those that come directly from the trial vaccine (e.g., side effects) and those that are linked to participation in the trial (e.g., social stigma). The reviewed studies simply mentioned the harms, with no attempt to categorize them. Also, no study assessed or described the magnitude or likelihood of the harms.

Stigma was the most prominent identified harm, reported in nine (43%) of the 21 reviewed studies that assessed risks. Other harms included VISP in five studies (24%), increased risky behavior in five (24%); breach of confidentiality in four (19%), side effects in four (19%); discrimination, partner rejection, perceived racism and fear of unknown in three (14%); fear of being infected in two (10%); burden of confidentiality, guinea pig mentality, time loss, transport costs, adverse effects, safety concern, personal costs, vaccine safety, incidental findings and emotional impact of negative findings (disappointment, anger, distrust and misunderstanding) in one for each (5%).

Discussion

HIV and AIDs remains a significant infectious disease worldwide and infection is more prevalent in LMICs [60, 61]. Efforts to design a vaccine to prevent HIV infection have made significant strides [62]. Even though these trials have not succeeded in producing a vaccine, preventing HIV is a global health priority, and researchers will continue to undertake such trials [62, 63]. However, people may be afraid to participate in these trials due to fear of risks and other concerns. Therefore, we undertook this integrative review to understand how the benefits and risks of HIV vaccine trials in LMICs have been described in the literature. Also, we categorized the risks and benefits into a basic initial framework: social, psychological, economical and physiological. Our discussion of the risks and benefits identified in this review uses these basic categories. Below we briefly discuss a particular harm or benefit, followed by ethical implications and recommendations for policy change or further research as appropriate.

Social benefits

The reviewed studies described the following benefits, which we categorized as social: education, knowledge and access to information about HIV and AIDS and other sexually transmitted infections (STIs). Knowledge and information sharing are provided at various stages of HIV vaccine trials. As a trial is being prepared for recruitment and launch, researchers make intensive efforts to educate and inform the target population as part of community sensitization, engagement and recruitment. After recruitment, a continuing focus on education and information sharing fosters transparency throughout the trial. For example, education and information is shared as part of the informed consent process and as an element of counselling. Thus, participants in the reviewed studies were being educated about HIV and preventive measures, including risk reduction. This is supported by a study about perception of beneficial social impacts among HIV vaccine trial participants, which reported education and risk-reduction counselling as social benefits [64]. Other social benefits such as networking arise spontaneously when people meet in one place repeatedly and with a shared interest. Some participants reported that simply having an activity to keep them busy was another benefit of participating in HIV vaccine trials. These participants may have been unemployed and in need of being involved in an ongoing effort.

Psychological benefits

The reviewed studies reported the following psychological benefits: altruism, protection from HIV, recognition, safe sexual behavior, safe sex practice and reduced risk behavior. Altruism was reported in more than half the studies. In this review, we defined altruism as both personal gratification for doing something good, as well as helping others [65], such as by eliminating HIV. Similar findings have been reported by many studies [65–69], and this is a common finding in other types of clinical trials [70]. However, altruism is often intertwined with expected tangible benefits, such as free healthcare and other incentives [23, 40, 48, 66].

Protection from HIV infection was the second prominent psychological benefit. Protection has two facets—one of which is a risk in disguise. The “good” facet is protection by an effective vaccine in case of trial success. Post-trial access to an effective vaccine is a benefit many participants would hope for. The second facet was the frequently held and false notion that the trial vaccine could protect the participants from acquiring HIV—regarded as a benefit, but actually a risk [37, 48, 49, 53, 59, 71]. In some of the reviewed studies, protection from HIV was reported as contributing to a person’s willingness to participate in the HIV vaccine trial [37, 49, 53]. These individuals would be motivated to participate in the hope of being protected from infection. This hope can be particularly attractive to high-risk populations, such as commercial sex workers and men who have sex with men (MSM). Hope of protection can be misleading given that vaccine trials are randomized, placebo controlled and double blinded. False hope of protection has been associated with increased risky sexual behavior and increased HIV infection among former HIV trial participants [36, 46, 49, 71, 72]. This finding highlights the need for more intensive education and increased transparency regarding what a trial vaccine cannot do for participants. Researchers should ensure that participants understand the concept of randomization and placebo use in HIV vaccine trials.

Economic benefits

The reviewed studies described several economic benefits: free healthcare, free medical checkups, financial gain, health insurance, free counselling, personal gain, HIV testing, post-trial access, healthcare access and ancillary care. These are all economic benefits, providing something of monetary value directly or indirectly to participants. Direct monetary gain comes in the form of financial gain and health insurance. Indirectly, free healthcare, free medical checkups, free counselling and ancillary care can save participants money, as they would otherwise pay for these services. Some of the reviewed studies that described economic benefits were assessing WTP in an HIV vaccine trial [48, 52, 55]. Participants may have been motivated by such economic benefits. Free healthcare and financial gain have been published by other studies as benefits of participating in research [69, 70].

Providing free healthcare through health insurance or ancillary care as well as financial incentives to participants is considered fair and necessary for HIV vaccine trial success in LMICs [14, 40, 48, 66, 73, 74]. However, such incentives are controversial. On the one hand, they can be viewed as facilitating participation and reciprocating participants for entering and continuing in the trial. But the risk of undue influence or even coercion and exploitation exist. Participants may perceive the incentives as too good to resist, in which case autonomous decisions will be impaired by undue influence. Patients who try to resist the economic incentives may feel coerced if they feel that not accepting them will make them worse off [75–77]. For example, participants may feel that their inability to access healthcare outside a trial will lead to worsening health. Incentives that are considered too enticing may impair voluntariness and damage authenticity of the informed consent process [75]. Exploitation occurs when participants who enter a study would not normally participate if their circumstances were different [75, 77]. Both undue influence and coercion may lead to exploitation especially if the trial comprises a risk of significant harm as it may be in some phase I and II HIV vaccine trials.

Economically less-privileged populations in LMICs are likely to be unemployed, less educated, uninsured and with poor access to healthcare alternatives [37]. Therefore, they may be more vulnerable to undue influence and coercion [20, 22, 77]—and exploitation. Balancing economic incentives with potential participants’ voluntariness is an important research issue; people desperate to meet their basic needs can be unduly influenced by virtually any amount of money or tokens [78–80]. There has been much discussion about the use of economic incentives in LMICs and the unequal reimbursement between participants in HICs and LMICs [16, 40]. The arguments about unequal reimbursement are beyond the scope of this review. We recommend further research to find appropriate incentives for research participants in LMICs and to assess their role in potential participants’ ability to assess the risks and benefits of a trial.

Risks

Social risks

For this review, we considered social harms as jeopardizing individuals’ social status and undermining their position in society, such as in their families and surrounding communities. The reviewed studies described several social harms: stigma, breach of confidentiality, discrimination, partner rejection and perceived racism. Stigma was the most frequently described social harm. Stigma is related to discrimination and to partner rejection, but we labeled them separately, as they were separately reported in the studies. All three were related to vaccine-induced seropositivity (VISP), which we categorized as a psychological risk, not a social one. When individual participants test HIV positive as a result of VISP, they feel that they are actually infected, leading to self-stigma. Also, false-positive results may lead to rejection by intimate partners. In the reviewed studies, discrimination mostly came from community members who were not familiar with vaccine trial issues. It is widely documented that discrimination regarding HIV vaccine trials is mostly attributable to those who are not part of the trial and are not knowledgeable or aware of how the trial vaccine works [7, 81, 82]. We recommend that education about HIV vaccine trials be extended to the surrounding communities rather than being focused exclusively on trial populations. Such education can be incorporated in health promotion programs, which are usually run by the health ministries in LMICs.

Another social harm was perceived racism. Some studies of HIV vaccine trial participation in LMICs noted that people may be troubled by pervasive feelings of being exploited by these trials. Feelings of being exploited may arise from various sources: a sense of less negotiation power, dependency on those conducting the trial, a lack of knowledge, and skills and uncertainty about post-trial access to the vaccine trial product [78]. Indeed, perceived racism was reported in Brazil, South Africa and India, where some communities reported a sense of being targeted and used as guinea pigs for the pharmaceutical industry in HICs [40, 42, 44]. A sense of being targeted could also result from repeated research on specific groups or in certain geographical settings, which may be associated with biased enrolment [78]. Biased enrollment signifies unfair selection of trial populations for non-scientific reasons. The reviewed studies did not indicate whether perceived racism had any impact on participant recruitment. Further research is required to document how perceived racism affects participation in HIV vaccine trials in LMICs.

Breach of confidentiality and the burden to maintain confidentiality were also among the social harms uncovered by this review. An individual’s HIV status or other health conditions may be revealed to others during the pre-trial screening process. For example, when a potential participant is excluded from the trial, some people may speculate about the reasons. From the reviewed studies, we learned that HIV vaccine trial participants often felt burdened by the need to hide their participation [42, 57]. The confidentiality burden may have been heavier in geographic areas and at times when HIV and AIDS were highly stigmatized. In those places and at those times, people were keen to know who was associated with HIV and AIDS programs, either research or simply care and counselling [42]. Trial participants made extra efforts to preserve their privacy and confidentiality. Such efforts may be complicated by factors other than place and time. Visits to the trial site when it is housed within an HIV clinic or receipt of home visits by trial staff may expose participation. Some scholars have suggested helping participants be comfortable with disclosing their participation and trying to normalize HIV/AIDS and related projects, such as HIV vaccine trials [83, 84].

Psychological harms

This review uncovered several psychological harms: VISP, increased risky behavior, fear of the unknown, fear of being infected and the emotional impact of negative findings (disappointment, anger, distrust and misunderstanding). VISP was the most frequently reported. When a trial participant tests HIV positive because of VISP, they may temporarily feel as if they are infected, with accompanying fear, despair and anger. If unchecked, VISP related discrimination (see above) can lead to rejection by intimate partners, family members and even uninformed healthcare workers [7, 81, 82]. Several strategies have been proposed to mitigate the impact of VISP, such as changes in HIV testing algorithms; changes in blood donation policies, which formerly excluded people with VISP; extensive education and information through seminars, workshops and symposiums; and community dissemination by physical and virtual means, such as TV, radio, newspapers and social media [7, 40, 45, 51, 71, 82, 85].

This review also uncovered a fear of unknown harms that might appear only after completion of the trial [42, 51]. Although the fear may be scientifically unfounded, it may cause apprehension and other psychological and emotional issues. The same may be said about the fear of being infected with HIV in the vaccine trials. It was unclear from the reviewed studies how much impact these fears had among individuals and families of former trial participants. We recommend further research to examine the extent and impacts of these types of fears on participants’ psychological well-being.

We also found that HIV vaccine trial participants were at risk of heightened risky sexual behavior, resulting from the false hope of protection from the trial vaccine [49, 55]. Similar findings over a long period of time have been widely documented [86–89]. As noted, pre-trial preparedness training should focus on this issue. It should also be considered as part of a long-term health promotion education package targeted to former HIV vaccine trial participants and communities at large.

The studies described emotional distress that may be experienced by participants of failed or of prematurely terminated vaccine trials. Participants and other lay people may not understand that negative results or undesired trial outcomes can contribute to valuable knowledge [55, 58, 59, 66]. How potentially disappointing information is communicated to participants may make a significant difference. Researchers should be mindful of the ethical dilemma of communicating such results.

Communication of potentially disappointing results requires balancing between honesty or transparency and sensitivity to participants’ emotions while maintaining trust. Lack of transparency may erode trust, while blunt truth about negative results may lead to negative emotional responses such as disappointment, feelings of betrayal and resentment. Studies have suggested that information about the outcome of negative results ought to be given early in the informed consent process [90]. Researchers must ensure transparency about such outcomes and possible emotional responses among participants. Sheets et al. suggested that researchers communicate about various possible HIV vaccine trials outcomes, such as positive or negative or undetermined results to avoid instilling participants with too much hope, which may set them up for disappointment [90]. Other scholars have suggested post-trial psychological counselling for participants [91]. Ongoing communication through community engagement, in which researchers explain the meaning of negative results and their implication for future research, was also found to foster trust among participants and communities [91]. Communication of negative results has been scantily explored, and further research on effective ways to disseminate negative results to lay people is needed.

Economic risks

The risks described in the reviewed studies, which we categorized as economic, were personal costs, loss of time and transport costs. Personal costs and time lost may be described as trade-offs that participants make in order to participate in vaccine trials. The trade-off involves foregoing some income generation activities and spare that time in order to participate. How much is lost in this trade-off may depend on many factors. Transport cost may be taken to mean fares to and from the vaccine trial centers. The economic harms were reported by only one (5%) of the studies that assessed risks, which may indicate that participants rarely suffer economic loss as a result of participation in HIV vaccine trials. Many trials reimburse participants’ transport costs, and many provide other financial incentives (see above).

Practical recommendation to policy makers, researchers and sponsors

Given the unique socio-economic contexts of populations in LMICs, a rigorous risk/benefit assessment is required to protect participants who volunteer their much-needed time and effort to HIV vaccine trials. Policy makers should attempt to create standardized risk/benefit assessment frameworks that are tailored to the context of HIV vaccine trials in LMICs. Frameworks should be designed to make risk/benefit assessment comprehensive by including all categories of risk. Frameworks should ensure systematic methodologies for identifying, analyzing and mitigating risks inherent in HIV vaccine trial participation, particularly those that may be augmented by socio-economic vulnerabilities. Other recommendations are below:

• Institutions should strengthen the capacity of their IRBs and RECs in the area of risk/benefit assessment of HIV vaccine trials.

• Researchers should carefully assess the risks and benefits of their vaccine trial protocols as a means to protect participants from a study that may be overly risky for them.

• Researchers should empower participants’ ability to assess the risks and benefits and use their judgment as basis for participation in a proposed vaccine trial.

• Researchers should foster transparency by strengthening education strategies to ensure that participants understand that trial vaccines may not be protective, and that randomization and placebo use in trials further diminishes any hope of protection.

• Policy makers must extend HIV vaccine trial education to the communities, rather than focusing only on trial populations. An education package that includes the nature and types of risks associated with an HIV vaccine trials can be incorporated into the health promotion programs, which are usually run by the health ministries in LMICs.

• Sponsors should increase research funds for independent research on the ethics of HIV vaccine trials, especially on informed consent and consideration of the risks and benefits of research participation.

Limitation

There are several limitations to this review. First, few studies specifically assessed benefits and risks directly. Most of the studies were intended to assess feasibility, preparedness, and peoples’ WTP in HIV vaccine trials. Second, most of the studies were nested in the main HIV vaccine trials and hence conducted by people who were part of the trial staff. As a result, the interpretation and implications might be skewed toward the feasibility of the trials rather than the description of the risks and benefits. We recognize that our review includes diverse sources of information on risks and benefits as it is important to capture a broad range of studies on the phenomenon of interest for integrative reviews. However, this also might have limited our ability to directly hone in on the risks and benefits specific to HIV vaccine research participants. Nonetheless, it provides important information for future study that has consequences for the ethical conduct of these trials and the recruitment and retention of research participants. In addition, we do not have any standardized scale or guide for risk/benefit studies developed for LMICs, thus, we were not able to assess the overall quality of the reviewed studies. Lack of quality assessment of our data sources may impair the dependability of the conclusions of this review.

Conclusion

This integrative review presents a critical appraisal of the description of risks and benefits of HIV vaccine trials in the literature published from LMICs. Risk/benefit assessment of HIV vaccine trials involves identifying, quantifying and weighing the balance between these two central concepts in research ethics. To conduct a thorough and systematic assessment of the research protocols, reviewers, researchers and potential research participants need detailed descriptions of these risks and benefits, such as magnitude and likelihood, that are context-specific. However, none of the reviewed studies included all the needed descriptions, which creates an information void. This warrants an urgent call for further research to describe risks and benefits of HIV vaccine trials in LMICs in order to enhance the objectivity of HIV vaccine trial protocol reviews. We recommend the development and use of a standardized scale for risk/benefit assessment for LMICs that would be useful for IRB members and researchers, as well as for those who volunteer to participate in these trials.

Abbreviations

AIDS

Acquired immunodeficiency syndrome

CSW

Commercial sex worker

HICs

High income countries

HIV

Human immunodeficiency virus

LMICs

Low- and middle-income countries

MSM

Men who have sex with men

VISP

Vaccine-induced seropositivity

Author contributions

DS. and JS. prepared the search concepts and searched the databases for the articles for this integrative review. JS imported the search results to Covidence software, performed the article screening, conducted the review and presented the review data to all the other authors. EL. CU. AA. DS. and JS. participated in the write-up of this review from the abstract, introduction, methods, discussion and conclusion. All authors actively participated in the critical review of the manuscript.

Funding

This review is part of a PhD study funded by Fogarty International Center, NIH International Research Training Grant, [D43TW011809].

Data availability

Data is provided within the manuscript.

Declarations

Ethics approval and consent to participate

Ethical approval to conduct this review was granted by research review committees of Muhimbili University of health and allied sciences and the national institute for medical research, Tanzania.

Consent for publication

Not applicable.

Competing interests

The authors declare no competing interests.