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Being “False Positive”: An “Inconvenience”? Debates and Questions Regarding the Notion of Vaccine-Induced Seropositivity (VISP) in the Recruitment of Healthy Volunteers for a Preventive Anti-HIV Vaccine Trial

Couderc, Mathilde

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JAIDS Journal of Acquired Immune Deficiency Syndromes: October 1, 2018 - Volume 79 - Issue - p S20-S29
doi: 10.1097/QAI.0000000000001814
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Abstract

In 1992, the year when the first HIV vaccine trials were conducted in France, the National AIDS Council (Conseil National du Sida) made the following recommendation regarding the recruitment of volunteers in an appeal to the public through the media: “It is absolutely essential that healthy volunteers are protected from the confusion which exists between seropositivity of vaccine origin and seropositivity connected with a viral infection.” It was therefore necessary to highlight one of the specific features of prophylactic HIV vaccine research: the development of seropositivity, without the person coming into contact with the virus, due to the stimulation of the production of HIV antibodies caused by the injection of the vaccines. This ethical recommendation relied on article L.209-14 of the French Public Health Code, which states that “biomedical research with no direct individual benefit must not include any serious, foreseeable risk for the health of the people participating in it.” Since the initial vaccine trials conducted by the ANRS, volunteers' understanding of this specific risk has been made part of the selection criteria (in the “Psychological criteria” section) in the same way as sociodemographic, clinical, and biological characteristics. In this way, volunteers “are able to understand the nature of the trial and the characteristics of the injected drugs, which do not provide protection from HIV and which induce seropositivity without the virus”.1 In the international scientific community, this phenomenon is referred to by different terms: “false seropositivity” (VISP), “vaccine-induced seropositivity [vaccine-induced HIV seropositivity (VISP)],” or “vaccine-induced seroreactivity (vaccine-induced seroreactivity)” (VISP). This list, which is not exhaustive, shows a change in the terminology over time. Most of all, it indicates that how difficult it is to explain this complex notion by means of a single term.

In 2014, ie, over 20 years after these recommendations, in a context which has changed considerably in terms of HIV/AIDS treatment, the results of a study on the reasons for engagement in a preventive vaccine trial (PVT) conducted in France on healthy volunteers (the ANRS-VRI01 trial) show that false seropositivity continues to be questioned and continues to give rise to resistance on the part of potential volunteers.2 One year previously, the issue of VISP had been included in the agenda of the Global HIV Vaccine Enterprise as “an emerging and growing concern, given the still highly complex nature of existing and future test vaccines and large-scale efficacy trials”(http://www.vaccineenterprise.org/content/timely-topic-VISP), thereby demonstrating the urgency and relevance of this research topic.

To better understand the prevalence of this hindrance to participation, this chapter attempts to put into perspective the manner in which information about VISP was conveyed in the recruitment campaign of the ANRS-VRI01 trial and the volunteers' perceptions of this. It examines how these volunteers understood this biomedical concept and the extent to which this influenced their decision to take part. It is essential to understand which aspects of medical research may constitute an obstacle to participation to develop recruitment campaigns, especially in a context which is unfavorable overall: crisis of confidence in vaccination in France; the trivialization of HIV in the young population targeted; and less interest in the general population in the fight against the epidemic.

PURPOSE, CONTEXT, AND METHODOLOGY

The recruitment for prophylactic vaccine trials for HIV/AIDS gave rise to studies on the volunteers' reasons for participating, the social impact of their participation, and the methods of administering informed consent.3,4 Most of this work concerns phase-III efficacy trials, which pose very different scientific and ethical problems from those of phase I/II. This is because phase-III trials concern volunteers who are highly exposed to the risk of HIV infection5 and because the trials are conducted in developing countries with very different situations in terms of sanitation, epidemiology, the economy, politics, and ethics.6–8 As for works in the human and social sciences that specifically concern the recruitment of healthy volunteers for phase-I/II PVTs, these are rare1,9 or they are qualitative studies in epidemiology concerning specific populations.10,11 This lack of interest is surprising when one considers that these volunteers are highly sought after, are exposed to constraints and potential secondary effects, and receive no direct individual benefit in return.12 Of these, the risk of developing a seropositivity involves a number of specific factors and disadvantages, which are very difficult to explain to volunteers.

First, from a biomedical point of view, the occurrence of seropositivity induced by the vaccine is not systematic. In clinical studies, the frequency of cases where VISP develops varies considerably depending on the characteristics of the candidate vaccine in particular13 (In the case of the ANRS-VRI01 trial, only 1 of the 3 test vaccine combinations is capable of inducing VISP). Moreover, the duration of a “false positive” status is also highly variable. In some cases, the responses of the HIV antibodies persisted for over 20 years after vaccination [It should be noted that long-term false seropositivity is primarily associated with protein vaccines (ie, vaccines that use protein with a whole envelope). In the case of the ANRS-VRI01 trial, two-thirds of the vaccines tested code for structural protein fragments, not envelope fragments. They generate very few antibodies but rather a “cellular” response]. A recent study assessed its persistence at approximately 17 years.14 However, it should be noted that to distinguish VISP from a real and recent HIV infection, “confirmation” tests need to be conducted in addition to the routine screening tests [A VISP may be similar to a positive enzyme-linked immunosorbent assay (ELISA) test (which gives a quantitative antibody response). In this case, we would conduct a confirmation test (Western blot or viral load) that gives a qualitative response as to the presence of antibodies directed against different HIV proteins, thereby distinguishing VISP from a true HIV infection]. For some authors, the occurrence of VISP makes it more difficult to detect a true HIV infection.13,14

Furthermore, no relationship was established between the occurrence of VISP and the age or sex criteria of the participants.15 Finally, from a social point of view, these results may have implications for the participants in terms of discrimination and limitations in their daily lives (problems obtaining a visa for certain countries or insurance, temporary ineligibility to donate blood, sperm, or organs, etc.)3,16 or psychological and social consequences.14,17 In the scientific literature, the issues surrounding VISP therefore mainly concern 3 aspects: the development of new diagnostic tools, particularly for the countries of the South, the need to inform volunteers about VISP and its social implications, and the establishment of measures to prevent or mitigate these implications.13 However, studies specifically concerning the perceptions of VISP by potential participants are rare.

“Pseudoseropositivity,” “seropositivity without the virus,” and “vaccine-induced HIV seropositivity” are names given to this phenomenon, which reveals the absence of a standardized terminology in the scientific community [This specific point was addressed during an international conference organized in 2013 by the Global HIV Vaccine Enterprise entitled “Building consensus for a terminology for HIV vaccine-induced sero-positivity (VISP)/sero-reactivity (VISR)” http://www.vaccineenterprise.org/content/timely-topic-VISP]. Some of these names contribute to the blurry distinction between real HIV infection and a postimmunization response (To remedy this, less stigmatizing terms, ie, which do not include the words “positive” or “seropositivity,” were proposed such as: “vaccine antibody response” and “vaccine-associated reactivity”). The first works on this topic report that false seropositivity was understood by participants to be a sign of the presence of the virus in the body and was therefore a “true seropositivity,” which logically resulted in a fear of infection3,18 [It should be noted that these works were produced in a specific context (the launch of the first vaccine trials, the recent discovery of the first triple therapies, and a perception of AIDS as associated with death)]. As such, we can see that one of the main issues of the recruitment process for PVTs lies in the information conveyed by the sponsor, both in terms of the knowledge that needs to be transmitted to potential volunteers and in terms of the communication tools used.19 The challenge is to translate complex scientific concepts into an intelligible message for an a priori lay public, especially regarding the risks and benefits.20 Studies in the social sciences have shown that the population's understanding of the scientific concepts of “placebo,” “randomization,” and “informed consent” posed problems. Although these studies mostly concern developing countries,21–23 a lack of knowledge and understanding of the principles and objectives of a trial is not specific to the countries of the South because they have been observed in developed countries.24,25 This chapter specifically examines the phenomenon of vaccine-induced HIV seropositivity—a problem specific to HIV vaccine research—by looking at the way in which it is treated, understood, and interpreted by researchers and potential volunteers.

This anthropological study was conducted from February 2014 to March 2015. It relies on 2 data collection tools: semistructured interviews conducted with 43 volunteers [26 participants (volunteers included in the PVT), 10 volunteers (any person who showed an interest in the PVT but was unable to take part for medical, biological, psychological, or availability reasons), and 7 unwilling (volunteers who showed an interest in the PVT but abandoned the recruitment process at some stage)] (These 3 definitions are the author's definitions) and the observation of 16 preinclusion consultations. As Fillieule points out in this article, although “the ‘motivations’ for engagement are usually recorded a posteriori,” our study was conducted in parallel with recruitment, before, during, or after the volunteers officially joined the PVT. This investigation procedure made it possible to access all the individuals who expressed an interest in the recruitment campaign at some stage and to report what they said here without distinguishing between eligible and noneligible individuals in terms of the selection criteria of the research protocol (particularly, the requirement of “low risk of HIV infection”). Access to the “unwilling” required close collaboration with all the participants involved in the recruitment process [medical staff of 2 investigation sites (Immunology Department of H. Mondor Hospital and Cochin Pasteur Clinical Investigation Centre for Vaccinology in Paris), coordinators of the communications agency, and manager of the telephone platform], so that they could be identified and contacted. Recruitment was also defined in this case as a dynamic process, from initial contact by volunteers and all the sources information regarding the trial (poster, website, an announcement in free press outlets, etc.) to interactions with a series of individuals, both internal and external to the PVT, who all possessed specific skills, information, and attitudes relating to the trial, as well as the preinclusion visit. The latter is distinctive for its bioethical approach, which often limits the definition of recruitment to the informed consent process.

INFORMATION, WARNING, AND REASSURANCE (WITHOUT TRYING TO PERSUADE): THE DISCOURSE OF THE RECRUITMENT CAMPAIGN WITH REGARD TO VISP

A multitude of methods are used to recruit participants, which will depend in part on the principle of the trial (preventive study or therapeutic trial), the target population (healthy volunteers or people with the disease), and the local research culture and/or the individual judgements of the researchers as to the best way to proceed.26 The main objective of the ANRS-VRI01 trial is to evaluate the biological efficacy of 3 candidate vaccines combined in pairs and the tolerance of a vaccine never before tested in humans, in subjects not infected with HIV. The purpose of this phase-I/II trial is not to test for any protective effect against HIV infection. Of the specific characteristics of this prophylactic vaccine research for HIV, we will retain the following three: (1) The absence of any direct individual benefit for the participants; (2) one of the 3 vaccine combinations tested could induce VISP; and (3) the “theoretical” risk of increasing the sensitivity of cells to HIV infection in the event of exposure to the virus (mentioned in the informational memorandum).

These characteristics will entail discussions and specific practices on the part of the PVT's team to ensure that they include individuals in the ANRS-VRI01 trial who are at low risk of infection, are already educated (recruitment targeted at faculties of medicine; preselection during the appeal to the French National AIDS Helpline Service), and are highly motivated (for example, volunteers who did not attend their first appointment were not called back). The investigators defend the position that “it is not about persuading people” since this approach is considered to be a waste of time and incompatible with the economic, scientific, and organizational purposes of the PVT.

A “TARGETED” COMMUNICATION CAMPAIGN UNDER MULTIPLE CONSTRAINTS

The phenomenon of false seropositivity was described as “problematic” to recruit volunteers once the first anti-HIV vaccine trials were launched.1,18,27 This has been recognized by the investigators of the ANRS-VRI01 trial, who have considered it as part of the complex vocabulary of the research protocol and of the information to be given to volunteers ever since the first meetings with the communications agency to develop the recruitment campaign. The best approach is targeted communication, which can “reach the people who are most receptive or already aware about the topic” (5 “target populations” were initially identified: qualified internet users, students, hospital nurses, eligible former volunteers, and supporters of HIV/AIDS-related associations) and who are therefore considered to be “qualified” volunteers (taken from an internal document of the communications agency). The aim is to recruit individuals who are able to understand what is involved in their participation as well as to apply a filter to avoid too much work for the investigation centers. To ensure comparability with other PVTs conducted internationally, the target population is young (20–40 years old) and differs from the volunteers targeted previously, particularly through the “Network of Volunteers for a Vaccine” of the ANRS. Finally, it was necessary for the message conveyed by this recruitment campaign not to be confused with that of a campaign for prevention, raising awareness or donations for HIV research, which are often conducted to appeal to the general public. These multiple constraints guided the format of the recruitment campaign (Fig. 1), which was developed jointly with a communications agency specialized in institutional communications.

FIGURE 1.
FIGURE 1.:
The recruitment process for the ANRS-VRI01 trial [diagram (Figure 1) by the author].

The recruitment process that was developed makes use of various media combining simple and educational content for the general public and scientific content that makes use of complex, biomedical terms. It provides for interactions of the volunteers with heterogeneous participants, both external and internal to the PVT (coordinators from the communications agency, SIS respondents, medical team, friends, colleagues, and family members).

ACTIONS TO REDUCE THE POSSIBILITY OF SOCIAL DISCRIMINATION AGAINST PARTICIPANTS WITH VISP

In the recruitment process, false seropositivity appears for the first time in the section “Your health and your safety” (this source was consulted by the 3 categories of volunteers) (Fig. 2), which uses various terms:

“Falsely positive? Certain tested vaccines may cause the production of anti-HIV antibodies, which sometimes result in a falsely positive result when tested for the AIDS virus. This false seropositivity or seropositivity without a virus has no repercussions on health, but it may have repercussions when subscribing to an insurance contract or travelling abroad”.

FIGURE 2.
FIGURE 2.:
Screenshot of the website of the PVT.

On the website, the consequences of VISP are limited to financial concerns and explicitly and categorically exclude “health” consequences. This first mention of VISP is immediately followed by information on measures that anticipate the potential concerns of volunteers: possessing a personal card explaining the holder's temporary seropositivity, the possibility of obtaining a certificate of participation, and specific tests conducted by accredited laboratories to distinguish between false and true seropositivity. Because it is impossible to predict the frequency and duration of VISP before conducting a trial, these measures aim to prevent or mitigate the risks of social stigmatization of participants who have VISP.

Of an international effort, initiated by the Global HIV Vaccine Enterprise (http://www.vaccineenterprise.org/sites/default/filesA/ISP%20Meeting%20Report_FINAL_0.pdf), which aims to develop a coordinated and consistent approach to the understanding of VISP, thereby abandoning the practices of sponsors who each develop their own approaches, standards, and principles (http://www.vaccineenterprise.org/sites/default/filesA/ISP%20Meeting%20Report_FINAL_0.pdf. We observe very different measurements from one clinical trial to another: information about VISP in the informational memorandum and during counseling; development of informational brochures for doctors, researchers, and participants; screening tests to determine serological status throughout the trial and at the end of the trial; issue of an ID card to participants and creation of a hotline; issue of a certificate of participation; support for participants who encounter problems in their day-to-day lives, etc).

It should be noted that expressions such as “may generate” or “sometimes causes” indicate the unpredictable nature of VISP and prevent any argument from having classic scientific authority: they induce the idea of uncertainty on the part of the trial investigators and can therefore give rise to doubt, although the content of this web page is dominated by the association between the education, health, and safety of the volunteers. At the very top of the page, the “risk of infection by the AIDS virus” appears explicitly and is the first item on the list about safety.

VISP then appears in the section “Risks and benefits” [the other risks are described as “local” (discomfort at the injection site and general signs) and “theoretical”] of the informational memorandum (The entire passage dedicated to the issue of false seropositivity in the informational memorandum can be viewed in the Appendix 1). Its consequences are described therein as a “potential inconvenience”:

The latter were recently the subject.

“Some vaccines are capable of provoking the production of HIV antibodies. This may cause a false-positive result for the ELISA HIV screening test and may, in this case, cause potential inconveniences in certain circumstances (eg, when subscribing to an insurance contract or travelling abroad) and in the event of a medical emergency because it may persist for months or even years.”

The “health consequences” are not absent, despite their absence in the website's text. We also note that although new information was provided regarding the duration of VISP, it was only very general and was not based on a scientifically grounded explanation.

At the same time, both the website and the informational memorandum concern the issue of prevention, which they present in an expert and prescriptive manner: “It is imperative that you protect yourself from all risks of infection, especially during sex. You will not be effectively protected from HIV by the candidate vaccines being tested. The only way to protect yourself during sex is still to use a condom” (extracted from the informational memorandum). Thus, the combination of this information with the information about VISP may be interpreted in an ambivalent manner by volunteers because they simultaneously aim to eliminate any risk of infection within the vaccine trial, to warn about any risk of infection outside the vaccine trial, and to inform and provide reassurance as to the possibility of a false infection due to VISP.

Finally, in all the preinclusion visits observed, when the question of VISP was raised by the MECs (Médecin d'Etude Clinique), this mainly concerned problems relating to the donation of blood, or it was an element of responses to the volunteers' questions about the known secondary effects, the consequences of seroconversion, or the possibility of travelling abroad. This information was systematically combined with information on the measures taken by the medical team to mitigate the problems caused by VISP, whereas information on its duration remained unclear.

Thus, the preinclusion visit was not used by the MECs as particular channel to convey more detailed information about VISP, probably because, as was reported to us by one of the investigators, “false seropositivity is not an issue in VRI01” because the probability of its occurrence is low. In fact, when the issue of VISP was raised by the volunteers themselves, the latter were mostly individuals who were already educated about vaccine research or who held qualifications in HIV/AIDS research. While this shows that the target population had been reached, questions remained regarding VISP even though the people concerned were qualified.

VOLUNTEERS' PERCEPTIONS OF VACCINE-INDUCED HIV SEROPOSITIVITY: FROM BIOLOGICAL RISK TO SOCIAL RISK

For the volunteers who were interviewed, the risks associated with their participation are the composition of the test vaccine, the short-term and long-term consequences of the vaccine, the fear of infection, and the fear of the occurrence of false seropositivity, which was mentioned by one-third of the volunteers (ie, 12 people: 4 participants/26; 5 unwilling/7; and 3 volunteers/10). Of the latter, the PVT participants who raised the issue of VISP (all of whom had higher qualifications in health care) highlighted: the difficulty for someone not familiar with medical research to understand VISP; concerns regarding the duration of VISP in the body; a fear of developing VISP; or that the information provided about VISP in different stages of the recruitment process was satisfactory. For the volunteers who dropped out of the process (“unwilling”), we shall see that the argument of VISP was mentioned repeatedly as a reason for this decision.

THE PROBABILITY OF “TESTING POSITIVE”: A RISK RECEIVED IN A VARIETY OF WAYS

The risk of developing VISP is sometimes tolerated, seen as ambiguous, or rejected by the volunteers.

A Nonrisk

First of all, there are volunteers who were informed about the occurrence of VISP and all the corrective measures but did not see them as a cause for concern:

“What intrigued me was the fact that one tests seropositive during the trial, which seems like it could be a potential cause for concern if there is an accident. But that was the extent of my concern. I talked to the person on the phone about it and she told me that they would give me a card to prove I was taking part in the vaccine trial so that I could travel in countries which would prohibit me from entering” (Michelle, 37 years old, employed by an HIV/AIDS association, woman who has sex with other women, volunteer).

“I remember that we could test positive in certain tests and that we would have a personal card to prove our participation in the trial, etc. I did wonder about that but it didn't scare me at all, on the contrary. Because I understood what the principle of a vaccine is, adapted for the HIV virus” (Peggy, 26 years old, employee in an anti-HIV/AIDS association, heterosexual, volunteer).

Both say that they mainly remembered the information about “false-positive” status after reading the website and the informational memorandum. Each of them spontaneously mentions the information on the PVT card, which seems to have reassured them as intended.

These 2 respondents have a similar profile: women younger than 40 years who work in organizations that seek to spread information and prevent HIV/AIDS. We can therefore assume that they are well informed and have a positive perception of the world of HIV research and that they are already aware of the notion of VISP.

Distinguishing True Seropositivity From False Seropositivity: A Complex Task for the Laypeople

VISP seems to be a source of confusion for other volunteers such as Jean-Marc and Sébastien. Both are “unwilling” although they have a profile that complies with the inclusion criteria at the time of the interview:

“What is false seropositivity? Is it possible to tell me at any given moment whether I have a true or a false seropositivity? I thought, so basically, in the 2 years, I won’t know if it's false or true! I thought to myself that they might tell me it's false, but would they prove it? […] All in all, my fear was more dominant. That's what decided it for me […] At the end of the day, I'm a complete novice, I have no medical knowledge so I don't understand at all” (Jean-Marc, 39 years old, project manager, sexual orientation not specified, unwilling).

“My first understanding was: what are they going to inject into me, what will the consequences be, and if I want to be tested, how will they tell if I'm truly positive or falsely positive” (Sébastien, 30 years old, employed in a public health auditing firm, man who has sex with men, unwilling).

These 2 senior managers express strong apprehension as to the ability of members of the medical team to distinguish true seropositivity from a false seropositivity, despite the information contained in the informational memorandum. For the first volunteer, this confusion generates anxiety and leads the volunteer to abandon his plan to participate because his level of medical knowledge does not permit him, in his view, to be free of doubt. In the case of the second volunteer, although his apprehension was attenuated by consulting other people considered to be experts, such as a friend working in an anti-HIV association, herself a volunteer, and a doctor from the team of the PVT contacted by telephone, he decided nevertheless not to participate.

REASONS FOR ABANDONMENT CONNECTED WITH A FEAR OF FALSE SEROPOSITIVITY

Our study identified 3 reasons for dropping out that are specifically connected with the volunteers' interpretation of VISP.

A Lack of Information as to the Definition, Duration, and Feasibility of Testing for VISP

A number of volunteers believe that they did not receive satisfactory answers regarding the implications of VISP at some stage of the recruitment process.

“The research seemed to be highly complicated in terms of its impact on my sex life […] She (person on the telephone platform) warned me that I would have to protect myself, that it could lead to a… I can't remember the exact word… To a change in positivity… But it's true that later on, I didn't really receive any more information about this topic. But then later on, I was still afraid […] Although I had plenty of information from documents or online, I didn't really have a specific person to talk to […] You are faced with terms which you don't necessarily understand” (Maxime, 41 years old, manager in a public function, heterosexual, unwilling).

Maxime's journey in the recruitment process is limited to 2 stages: the call on the telephone platform and his viewing of the website. He phoned again after consulting the website to clarify whether it was also obligatory to wear a condom in the event of a false seropositivity. Sébastien returned to obtain information about VISP from the website and the informational memorandum because he was not satisfied with the answers he received during his phone call on the platform:

“And the only question I would have liked an answer to was, can you get a false positive result when you do a classic test […] I told myself I would phone and that this would be simpler. They were unable to tell me. I would have liked to talk directly to the person responsible for everything, ie, the doctor” (Sébastien).

These 2 interviews' extracts show that an inability to understand VISP is a reason for volunteers to search for additional information. They want to know how the recruitment process is organized and, in particular, they question the absence of any interaction with a health care professional earlier in the recruitment process.

The relative lack of clarity regarding the characteristics of VISP (its duration or how accessible “specific tests conducted by the accredited laboratories” are in terms of cost, time, and availability) also gives rise to requests for additional information, including from trial participants:

“I don't like the idea of having to deal with a lab response time which is 6 times longer than normal because the test to prove that I'm false positive is a little complicated. It might look capricious, but if a problem were ever to happen…” (Vadim, 28 years old, psychotherapist, bisexual, unwilling).

“The booklet said clearly that false seropositivity could occur. Also, after my first vaccination, I was given a little card to keep with me at all times, which explains the situation. But the answer to my question, which is: after the study, once it's over, will I stay false positive after the end of the study or not? At the end of the day, I never got the answer” (Nino, 25 years old, biological engineer, man who has sex with men, participant).

Furthermore, a belief that taking part would definitely lead to VISP may have constituted a hindrance for potential volunteers, despite the reassuring information repeated by the investigators:

“The fact that there were all these things behind it: ‘If you want to travel to certain countries where a control is conducted upon entry, we will support you. We will give you a certificate saying that you are taking part in…’ That showed me that it was very serious. That frightened me even more. The basic question for me was: if I do this, I'm going to be diagnosed seropositive and it will last for 2 years […] Because at some point you have to ask yourself: am I taking a risk or not by participating in this?” (Jean-Marc, 39 years old, contractor, sexual orientation not specified, unwilling).

Thus, the existence of a card explaining the status of “false seropositivity” led this volunteer to conclude that he would definitely become false positive and that he would be taking a risk. He therefore stopped the process before his preinclusion visit, like all the other “unwilling.”

Can a False Seropositivity Hide a Seroconversion?

In the case of volunteers for whom the information shared by the PVT about prevention (obligation to wear a condom for the entire duration of the trial) conflicted with their personal prevention strategies for sex, the probability of developing VISP is associated with putting others at risk. Thus, a refusal to take the smallest risk seems to be a reason for dropping out:

“In fact, it was never clear, and since I never got an answer about whether I could become false HIV-positive, I don't want to put those around me at risk. I know how you catch it. Isn't it just by simply having sex […] I was told that it was better to protect yourself for the entire duration of the trial anyway. This wasn't feasible for me and I also didn't really understand the reason for it if it was supposed to be a false seropositivity. So I wasn't sure, and out of precaution, I didn't continue with the process” (Maxime, 41 years old, manager in a public function, heterosexual, unwilling).

A feeling of receiving contradictory information also contributed to Maxime's abandonment of the process. In this case, the person's interpretation of VISP depends on the consistency of all the information provided about the topic. The same motivations are shared by Vadim. To return to his case and understand why he was concerned about the delayed response to the serostatus test, his social context must be taken into account. In addition to his job, Vadim is an occasional sex worker. Although he does not consider himself to be “a risky partner,” because the sex he has with multiple partners “is only with people who have been tested and who have the same type of ethics as he does,” the fact of having to wait for an indefinite period without knowing if he has a false or true seropositivity is a problem. In terms of his behavior, Vadim adopts a prevention strategy based on his subjective selection of partners and which is different from “prevention mainly based on the use of a condom,”28 which is recommended by the PVT. In his case, the occurrence of VISP is incompatible with the preventive measures he takes when having sex:

“I couldn't allow myself to be seropositive all the time because I wouldn’'t be able to detect a real infection if one were to occur. So I would have put people in danger, unless I took a more precise test regularly” (Vadim).

Although Vadim could imagine various solutions for risky behavior outside the PVT (regular screening tests, probably followed by postexposure treatment), he saw his participation as a risk for others and VISP as an inconvenience that could hide the occurrence of seroconversion. In his understanding, VISP poses an objective problem because it can expose him to the loss of the chance of early treatment. Although Vadim did not perceive anything “risky or which would have made him drop out” during his journey through the recruitment process (awareness of the recruitment campaign through a free press insert, SIS phone call, reading the informational memorandum), he “declined the offer” to participate in the PVT after a long period of reflection. We can hypothesize that if Vadim had continued with his plan until the preinclusion visit, and provided that he disclosed his sexual practices to the MEC, he would not have been included because he does not meet the inclusion requirement of “at low risk of infection by HIV.” In this context of a trial with no direct individual benefit, the investigators were very careful to ensure that the volunteers were not exposed to any risks.

Refusal to Disclose Participation in the Trial

Maxime has been aware of the fight against HIV/AIDS since the death of a relative at the very start of the epidemic, and in his youth, he visited what he calls “alternative nightclubs” (gay clubs and bars, mixed dating clubs). He is heterosexual and has been living with his partner for the past 15 years. She does not want him to take part in any medical research. His personal history causes him to see his plan to take part in the PVT as “a personal and intimate choice” and the fact of having to inform his partner, because of the compulsory use of condoms, is experienced as problematic because it prevents him from keeping his participation a secret:

“The big problem for me, since I am in a relationship, is that doing the proposed follow-up would lead to… Not seropositivity… I don't know the technical term… But you could be identified as HIV-positive. And you would have to use a condom when having sex. And this was complicated for me because I didn't want to talk about it” (Maxime).

In his case, the decision to drop out must be associated with the impact of his participation on his relationship, and therefore with his ability to fulfill his commitments as a participant. Thus, for both Vadim and Maxime, their social and affective environment influenced their decision.

DISCUSSION

These analyses clearly show a discrepancy between the manner in which VISP is approached in the discourse of the recruitment campaign and how it is interpreted in the testimonies of the volunteers. First, although the information on the website very explicitly excludes the slightest health consequence, and then explains at length the potential problems linked to the occurrence of VISP (by explaining the practical measures taken to mitigate the social consequences), it is the latter which seem to be secondary in the opinion of volunteers. Second, although the probability of VISP is described in the informational memorandum as an “inconvenience,” it is a source of concern and doubt for volunteers and is the main reason why the “unwilling” refuse to take part. For the latter, the probability of a false seropositivity presents multiple problems from an organizational point of view (the need to undergo additional screening tests and waiting for the results) as well as a psychological (anxiety about the uncertainty of whether seropositivity is true or false) and sexual point of view (endangering others, obligation to wear a condom). Half of the volunteers who mentioned VISP are active, either as a paid employee or a volunteer, in the health care sector or the fight against HIV/AIDS. The other half of the volunteers comprise individuals with the following common characteristics: professions outside the health care sector and men who have sex with other men. Thus, it is insufficient to analyze the perceptions of VISP as a hindrance to participation solely in terms of a “lack of knowledge”23 or an inaccurate understanding because our survey shows that doubts also persist among qualified volunteers. Although a lack of familiarity with biomedical vocabulary is a cause of misunderstanding, other structural and social factors must be considered: a lack of mediation about the consequences and duration of VISP, individual preventive sexual practices of volunteers, and persistent fear surrounding HIV/AIDS. Thus, the reasons for dropping out cannot be limited to a personal evaluation of the risk. They are in fact part of a process that combines volunteers' personal history, social relationships, interactions that might involve relatives or a larger community,29 and the journey of volunteers through the recruitment process and their representations of HIV/AIDS.

CONCLUSIONS

The information presented above confirms the difficulty of conveying information about a risk (no matter how minimal it may be) or something perceived to be a risk that is subject to a probability and that is as yet not entirely understood, without compromising the adherence of potential participants in the clinical trial concerned. It also highlights the objective nature of the “social risk” (discovery of a secret, sexual, and preventive practices) and “biological risk” perceived by volunteers (loss of the chance of early treatment) to be associated with the occurrence of false seropositivity and that are not solely psychological. As such, it shows that false seropositivity is not interpreted in isolation but in a semantic network, which combines it with other information (eg, the “context” of sexual relations, ie, in relation to the PVT's safety guidelines) according to relations that may be defined differently by the researchers and the potential participants in these clinical trials. The study also highlighted the impact of volunteers' perceptions of VISP, which function like a sorting mechanism with some volunteers excluding themselves prematurely from the recruitment process, although a number of them presented with characteristics that were not contrary to the inclusion criteria.

For future recruitment campaigns for PVTs, especially PVTs that favor the development of persistent VISP in the participant (which was not the case for the ANRS-VRI01 trial), it would be beneficial to supplement the information on the probability and implications of VISP, eg, by offering counseling in the earliest stages of the recruitment campaign and not just information about the trial's conditions, duration, diagnostic tools, and the proposed follow-up during and after the trial.

APPENDIX 1. ANRS VRI01, Informational Memorandum, Version 4.0 of December 20, 2013

In accordance with the law, no compensation may be paid to you.

The samples provided may not be sold.

To manage the samples, the EVISP uses a digital file authorized by the French Data Protection Authority (Commission nationale de l'informatique et des libertés, CNIL). This file contains anonymous data, which can be used to identify the samples.

VIII. RISKS AND BENEFITS

Expected Benefits

The aim of this trial is to study the different vaccination strategies for HIV and to achieve a better understanding of how to stimulate the immune system against this infection. These results will be interesting for the further development of preventive vaccines or for other vaccination trials in people infected with HIV.

No direct benefit is expected on an individual level.

Risks

All injections are intramuscular or intradermal. As with most vaccinations (tetanus and polio), there are local risks that can generally be described as discomfort at the injection site (pain, redness, swelling, hardening of the skin, sensitivity to touch, itching, irritation, and blistering) as well as some general signs (fever, fatigue, headache, muscle pain, and joint pain). These secondary effects are usually of a short duration and generally do not require any specific medical treatment.

The MVA HIV-B candidate vaccine developed by the ANRS was never tested in humans; so, it is possible that adverse events occurred and were not described. As such, MVA candidate vaccines of the same type have already been present in humans and were well tolerated.

Some vaccines are capable of provoking the production of HIV antibodies. This may cause a “false-positive” result for the ELISA HIV screening test and may, in this case, cause potential inconveniences in certain circumstances (eg, when subscribing to an insurance contract or travelling abroad) and in the event of a medical emergency because it may persist for months or even years. To resolve these potential problems, you will be given a bilingual plastic card (in French and English) bearing your last name, first name, photograph, trial identification number, and the following text: “Vaccine volunteers” of the VRI. The holder of this card is taking part in an HIV vaccine trial and was immunized by candidate vaccines which may, in exceptional cases, cause a “false positive” result in routine HIV testing.

You are advised to keep this card with you at all times, together with your identity documents. In the event of a medical emergency, a telephone number is indicated on the card, which can be used 24 hours a day to confirm your participation in a vaccine trial. On the written request of the investigators, it will be possible to provide any person or institution that you consider requires the information with a certificate of participation in the present trial confirming that the seropositivity, if it occurs, is connected with the vaccine trial.

However, specific tests performed by the accredited laboratories of each clinical center of the trial can distinguish between a “false-positive” result after an HIV vaccination and a “positive” result after an HIV infection.

In addition, if you are a donor of blood or human tissue (bone marrow, organs, etc.), you will no longer be able to donate for 4 months after the trial and, possibly, until you have obtained a negative ELISA test.

In the current state of the development of the research, certain theoretical risks remain although they cannot be proven conclusively.

However, it is conceivable that these vaccine combinations may induce an unexpected activation of the immune system (eg, autoimmune responses). This is why an autoantibody assay will be conducted at the preinclusion visit (S-4) and during the trial, at visits S10, S22, and S30 (groups 1 and 2); and S14, S22, and S30 (groups 3 and 4). By way of precaution, subjects who presented with autoantibodies in the preinclusion test were excluded from the trial.

However, we cannot exclude that these vaccines, like any other stimulation of the immune system, may increase the sensitivity of cells to infection by HIV in the event of exposure to the virus. This theoretical risk is an additional reason for protecting oneself from all HIV infection during and after the trial.

Monitoring

Throughout the trial, scientific committees monitor the occurrence of adverse effects in particular. These committees monitor the safety of the participants and the proper execution of the trial. If necessary, they may decide to terminate the trial (eg, for safety reasons).

IX. WHAT HAPPENS AFTER THE TRIAL IS OVER?

The overall results of the trial (results for all the participants) will be shared on request after the end of the trial.

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Keywords:

medical research; vaccine; prevention; recruitment; healthy volunteers; risks; vaccine-induced HIV seropositivity

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