Book 5: Potential harms

The nature, magnitude, and probability of all potential harms resulting from participation in an HIV preventive vaccine trial should be specified in the research protocol, as fully as can be reasonably done. Active steps must be taken to reduce potential risks to a minimum. Such steps must be specified in the protocol, and should include provision of the highest level of care to participants who experience adverse reactions to the vaccine and compensation for research-related injury, and psychosocial and legal support as necessary.

9.1 Participation in HIV preventive vaccine research may involve physiological, psychological and social risks.

9.2 Potential physiological risks The purpose of an HIV preventive vaccine is to induce an immunological response to counteract the HI virus if it enters the human body, or to prevent it from entering at all.

9.2.1 Vaccines currently being considered for human trials in South Africa are not based on live attenuated approaches, and are not capable of causing HIV infection, i. e. they do not include replicating HIV. 2

9.2.2 Several candidate HIV vaccines have been tested in laboratories, and some have been tested in human participants. Not all of these candidate vaccines are the same, and not all candidate vaccines carry the same harmful potential. So far, however, significant adverse biological effects have not been observed.

9.2.3 Nevertheless, some of the potential physiological risks of participating in vaccine research include:

1. A person who has received a candidate vaccine and is then exposed to HIV may, in theory, be more susceptible to infection, or to more rapid progression once infected, than if the vaccine had not been administered, although this potential harm has not been observed in trials thus far; 3
2. An HIV vaccine may require that several injections be given over months or years, resulting in pain, occasional skin reactions, and possibly other adverse biological events, such as fever and malaise; and
3. Injuries may be sustained due to research-related activities during the course of the trial.

9.3 The potential for adverse reactions to the candidate vaccine, as well as possible injuries related to HIV vaccine research, should be described in the research protocol and fully explained in the informed consent process.

9.4 There must be fair compensation for research-related injury, as laid out in the South African GCP Guidelines (see Book 1, 11.4.4. iv and Book 1, Appendix IV). The protocol must describe the nature of medical treatment to be provided for injuries, as well as compensation for harm due to research-related activities, and the process by which it is to be decided whether an injury will be compensated. This must also be fully explained in the informed consent process (see Point 12.4).

9.5 HIV infection acquired during participation in an HIV preventive vaccine trial should not be considered an injury subject to compensation unless it is directly attributable to the vaccine itself, or to direct contamination through research-related activities.

9.5.1 Every effort must be made to counsel volunteers against misplaced belief in vaccine efficacy, and to ensure that volunteers understand that the vaccine is experimental and may not afford protection (see Points 9.7, 12.4 and 14).

9.5.2 Every effort must be made to provide participants with optimal risk reduction counselling and interventions to prevent HIV infection (see Point 14).

9.5.3 Every effort must be made to ensure that counsellors involved in consent and risk reduction procedures understand the potentially harmful consequences of participants' mistaken belief that they may be protected from HIV infection (see Point 14.6.6).

9.6 Potential psychosocial risks These include:

1. Stress related to participation in a complicated, lengthy trial involving intensely intimate matters, and repeated HIV testing;
2. Anxiety related to exposure to culturally different scientific and medical concepts;
3. Stress that may result between partners in a relationship as a result of the participation of one partner in a trial;
4. Stigma and discrimination that may result if volunteers' participation becomes publicly known, and they are perceived to be HIV-infected or at high risk of HIV infection;
5. A 'false-positive' HIV test that may result in the same negative social consequences that exist for those actually HIV-infected. 4 Some participants may develop a positive HIV test after receiving a candidate HIV vaccine, even though they are not truly infected with HIV; and
6. Stigma attached to participating communities that may be identified as high risk.

9.7 Risk minimisation measures

9.7.1 Active steps must be taken to reduce potential risks to a minimum (see Book 1, 9.12.4.7).

9.7.2 The protocol must describe potential risks, and steps that will be taken to reduce these risks to minimum.

9.7.3 Participants must be informed of and should understand the risks and risk minimisation measures that will be taken, and these measures should be included in the informed consent form (see Point 12).

9.7.4 Risk minimisation measures that should be taken include:

9.7.4.1 Counselling participants against the belief that the experimental HIV vaccine will necessarily afford them protection, and ensuring that participants are provided with optimal risk reduction interventions (see Point 14).

9.7.4.2 Rigorous and ongoing monitoring of potentially harmful consequences of trial participation (such as discord with family members or co-workers if a participant discloses participation, increase in highrisk behaviour over the course of a trial, or trial-related stigma or discrimination: see Point 9.7.4.4);

9.7.4.3 Provision of supportive counselling for the duration of the trial, and appropriate referral after the trial is completed;

9.7.4.4 Provision of measures to anticipate and offset trial-related stigma and discrimination, including:

1. Provision of documentation to participants to indicate that they are participating in research, that their false-positivity is research-related, or that facilitates access to trial personnel for assistance. Such documentation could take the form of an identification card. Any such documentation must take into account confidentiality or stigma concerns related to the terms 'HIV' or trial phase;
2. Provision of differential testing, for as long as false-positivity persists. Investigators must ensure that participants will not have to bear the financial burden of differential testing for HIV infection; and
3. Provision of legal support for trial-related negative consequences, such as discrimination attendant on false-positivity.

9.7.4.5 Ensuring, once the trial is complete, that participants will have access to support services for trial-related negative consequences, and that participants are informed of where such services may be obtained;

9.7.4.6 Ensuring that the research takes place in communities where confidentiality can be maintained; and

9.7.4.7 Ensuring access to an ombudsperson who can intervene with outside parties, if necessary and requested, on behalf of participants.

9.8 In non-therapeutic research, such as trials of HIV preventive vaccines, healthy volunteers should be subject to no more than minimal risk as a result of participation, even if the particular research will be of great benefit to humanity (Book 1, 9.12.4.4.2). Minimal risk is defined as a small chance of a trivial reaction or a very remote chance of serious injury or death (Book 1, 9.12.4.3.2). The risk should be justifiable in relation to the value of the information being sought.

9.9 Research ethics committees must consider whether risks inherent in the proposed research are at an acceptable level, whether they have been reduced to the minimum necessary to achieve the research objective, and are outweighed by the probable benefits (see Book 1, 9.12.4.7-9 and Point 6).

9.10 Prior and ongoing consultation with community representatives should take place to assess potential risks that should be brought to the attention of investigators (see Point 5).