ISS T-003 ISS T-003 ISS T-003 THERAPEUTIC HIV VACCINE CLINICAL TRIAL

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1 ISS T-003 HIV vaccine clinical trial ISS T-003 Program to support the Ministry of Health of South Africa in the implementation of a national program of global response to HIV & AIDS QUESTIONS & ANSWERS ISS T-003 THERAPEUTIC HIV VACCINE CLINICAL TRIAL A Phase Il, Randomized, Double-Blind, Placebo-Controlled Trial to evaluate the Immunogenicity and Safety of a Therapeutic, Recombinant, Biologically Active HIV-1 Tat Protein Vaccine in HIV-Infected, Anti-Tat Negative, ARV-Treated Adult Volunteers 1. What is the ISS T-003 clinical trial? ISS T-003 is the short name for a phase II clinical trial to test a therapeutic vaccine based on the HIV-1 Tat protein. The aim of this trial is to test the immunogenicity (whether it causes or induces an immune response) and safety of the vaccine in HIV infected persons already on antiretroviral (ARV) treatment, and who have not developed antibodies against the HIV Tat protein. The study will take place in South Africa and involves the recruitment of 200 participants between 18 and 45 years of age. The total amount of time required for participation in this study will be a maximum of 51 weeks (approximately one year). Participants will be asked to visit the research clinic at least 12 times during the study including administration of the Tat vaccine, or placebo on 3 occasions, at 4-weekly intervals. 2. Who is conducting this clinical trial? The ISS T-003 clinical trial is part of a wider cooperation project between the governments of Italy and South Africa named Program to support the Ministry of Health of South Africa in the implementation of a national program of global response to HIV & AIDS. This Program, funded by the Italian Ministry of Foreign Affairs, Directorate General of Development Cooperation (MAE-DGCS), is implemented by the National AIDS Centre (CNAIDS) of the National Institute of Health of Italy (Istituto Superiore di Sanità or ISS), in cooperation with the South African National Department of Health (NDOH) supported by the South African Medical Research Council through its lead programme, the South African AIDS Vaccine Initiative (MRC-SAAVI). The ISS is the Sponsor for this clinical trial. 1

2 QUESTIONS & ANSWERS The ISS is the leading technical and scientific public body of the Italian National Health Service, with tasks of research, control, training and consultation in the interest of the protection of public health in Italy. CNAIDS of the ISS coordinates studies on HIV and other AIDS-related viral infections and cancers and has conducted research for over 13 years on HIV/AIDS vaccines, focusing its efforts on the HIV-1 Tat vaccine candidate, based on the HIV-1 Tat protein. The Center has sponsored and conducted phase I and phase II clinical trials testing the Tat vaccine in Italy. To learn more about the ISS and about the Tat-based vaccine strategy please visit and The trial will be conducted by researchers and staff at the Medunsa Clinical Research Unit (MeCRU), of the University of Limpopo - Medunsa Campus in Ga-Rankuwa, Gauteng Province. The Cooperation Program also envisages inclusion of an additional trial site in Mthatha, Eastern Cape, namely the Walter Sisulu University, HIV Vaccine Research Unit (WSU HVRU) once development of this site is complete. The site is expected to be ready to conduct the T-003 Tat HIV vaccine trial towards the end of The South African Medical Research Council (MRC) is a statutory organisation established by an Act of Parliament in Its mission is to improve the nation s health and quality of life through promoting and conducting relevant and responsive health research. The South African AIDS Vaccine Initiative (SAAVI) was established by the South African government in 1999 to co-ordinate the research and development of an affordable, effective and locally relevant HIV vaccine for southern Africa. SAAVI is a lead programme of the South African MRC. The MRC-SAAVI has been indicated by the NDOH as the local operational partner of ISS in the implementation of the ISS T-003-related activities. As part of this cooperation, SAAVI contributes towards the development of the infrastructure to conduct the clinical trial at the designated trial sites. 3. What is a vaccine? A vaccine is a substance that is introduced to the body to teach it to recognise and defend itself against germs, like bacteria and viruses that cause disease. A vaccine causes a response from the immune system (the body s defence system) helping it to fight when exposed to these germs again. A successful vaccine can cause the body to stop or disable an invading virus or bacteria. 4. What is a preventative vaccine? A preventative vaccine aims at preventing an infection or a disease in an uninfected individual. 5. What is a therapeutic vaccine? A therapeutic vaccine aims to cause or boost a specific immune response to a virus or bacteria in individuals already infected with this germ. It aims to reduce the impact or progression of the disease or infection. 6. What is a vaccine clinical trial? Each potential new vaccine is tested in various stages taking a number of years. These stages include initial laboratory work, followed by testing the vaccine in animals, and then humans. Testing the vaccine in humans is done in clinical trials. There are three main phases of clinical trials in testing a new vaccine phase I, II and III clinical trials. Phase I includes a small group of trial participants, usually below 100 people and tests mainly for safety of the vaccine. Phase II involves hundreds of trial participants and tests for an immune system response, different doses and ways to give the vaccine and for safety. Phase III involves thousands of participants and tests to see if the vaccine works does it work to reduce new infections or to treat and or reduce the impact of a disease. Other trials may also occur between phases to collect additional data to guide future research. 2

3 7. What kind of candidate or study vaccine, is being tested in the ISS T-003 clinical trial? The vaccine tested in the ISS T-003 therapeutic clinical trial is the Tat protein vaccine, manufactured in Italy by Diatheva-Avitech Srl and bottled and labelled by Injectalia Srl, in accordance with Good Manufacturing Practice (GMP) regulations. The HIV-1 Tat protein plays a central role in HIV infection, virus replication, transmission from cell to cell in infected individuals, and progression of the disease. This is why it is called a regulatory protein. The Tat protein has more conserved regions than the envelope or structural proteins of HIV used in most candidate HIV vaccines tested so far. This means that the parts of the Tat protein recognized by the immune system do not change much over the course of infection compared to changes in the envelope proteins over the same period. These parts of the Tat protein are also very similar across different patients, different continents including Africa, and different viral strains. The T-003 study will compare the effects of the HIV-1 Tat protein vaccine with those of a placebo. The placebo looks the same as the vaccine but it is an inactive substance that has no action or effect on the body. Participants will be randomly allocated to either the group that gets the vaccine, or the group that gets the placebo. The number of people who receive the study vaccine and the number of people who receive the placebo will be the same. QUESTIONS & ANSWERS The study is also double-blinded, which means that neither the participants nor the investigators will know which group the participants are in. Using a randomised, double-blind clinical trial helps to ensure that the information gathered during the study is accurate. In case of an emergency, however, it will be possible for the investigator to follow a procedure to find out if a participant received the vaccine or the placebo. The study vaccine (30µg of HIV-1 Tat protein) or the placebo will be administered by intradermal injection (injection within or between the layers of skin) at weeks 0, 4 and 8. Administration will be done at the research sites. 8. Is the Tat vaccine safe? The Tat vaccine has shown to be safe both in animal studies and in phase I and phase II clinical trials conducted so far in Italy. Nevertheless, as with most vaccines in clinical use, the Tat vaccine can induce side effects (adverse events) such as pain, redness or swelling at the site of injection. The possibility of more serious adverse events as a result of the vaccine will, however, be evaluated on an ongoing basis for all Tat vaccine clinical trials. 9. What does the Tat vaccine do? In a therapeutic HIV vaccine trial, the Tat vaccine aims to help restore healthy functioning of the immune system in HIV-infected individuals in order to reduce their HIV disease progression. 10. Why is this trial being done? This is a phase II trial, meaning its main purpose is to assess the immunogenicity of the vaccine (the capability of the vaccine to induce a specific immune response). The safety and tolerability of the vaccine also will be strictly monitored throughout the trial. 11. Who is eligible to participate in the ISS T-003 clinical trial? Each participant will be screened prior to trial enrolment and must meet certain criteria to be eligible (to qualify) to participate in the trial. Participants must be HIV-1 infected adults who are between 18 and 45 years old, and who are currently receiving ARV treatment. Participants must also have very low levels of HIV-1 replication (i.e. less than 50 copies/ml of HIV-1), a CD4+ T-cell count equal or above 200 cells/µl, and should be anti-tat antibody negative. 3

4 QUESTIONS & ANSWERS Potential participants will be asked for their medical history and will have a physical examination. They will also have blood and urine samples taken for routine testing. They will be asked about their sexual behaviour and alcohol or drug use. Females who want to join the trial will be given a pregnancy test. Those who are pregnant or breastfeeding will not be eligible to join. Any female who is able to become pregnant must agree to use effective birth control starting at least 21 days before the first injection of the clinical trial and continuing until the last clinic visit. 12. When and where is this trial being conducted? ISS T-003 is a national clinical trial, which will be conducted in South Africa only. The trial will be conducted by researchers and staff at the Medunsa Clinical Research Unit (MeCRU), of the University of Limpopo - Medunsa Campus in Ga-Rankuwa, Gauteng Province. Start up of the enrolment phase is planned within the first half of The Cooperation Program also envisages inclusion of an additional trial site in Mthatha, Eastern Cape, namely the Walter Sisulu University, HIV Vaccine Research Unit (WSU HVRU) once development of this site is complete. The site is expected to be ready to conduct the T-003 Tat HIV vaccine trial towards the end of How will the safety and rights of trial participants be protected? The Sponsor (ISS), the trial sites and SAAVI will work hard to protect the safety and rights of the trial participants. Before they join the trial, through a process of informed consent, volunteers will be given information about HIV vaccine trials, the reasons for the trial, possible risks and benefits of participating in the trial, and details of the trial procedures. It is important for participants to understand that any new study vaccine may have both medical and nonmedical risks. The clinic staff will allow plenty of time to explain the information to the volunteers and to answer their questions.they will give the information to the volunteers in writing, in language that the volunteers can understand. Volunteers will also be given time to think about whether they want to participate. They may also take the written information home to decide whether to participate. If a volunteer decides to participate, he or she will be asked to sign an informed consent form. This form will be signed before they are screened for eligibility and before being enrolled in the trial. The informed consent form helps confirm that trial participants have made an informed decision about joining the trial. They may decide not to take part. If they do take part, they may leave the trial at any time without losing the benefits of their standard medical care. During the trial, the clinic staff will monitor trial participants to check if they are experiencing any problems that may be related to the study vaccine or to their participation in the clinical trial. Participants will be given any new information that could affect whether they want to stay in the study. They will be reminded regularly that being in a therapeutic vaccine trial does not mean that they will necessarily get better, or that they will stop transmitting HIV infection. They will be counselled throughout the study on the importance of adhering to their ARV treatment, on HIV risk reduction and on the prevention of pregnancy. Community Advisory Boards or Groups (CAB/Gs) are also a mechanism to advise on any human rights and community-related issues. 14. How long will it take to find out if this vaccine works? It will take several years to test if the Tat vaccine is immunogenic and safe in this phase II clinical trial. This includes 51 weeks (about one year) for participation, plus an additional period for data analysis and 4

5 the final trial results. If these results are positive, the study may then move to a phase III clinical trial. In phase III, the vaccine will be administered to a larger number of patients, in the dose regimen that has been determined to be the safest and most effective in previous clinical trials. Given the higher number of participants, the researchers can collect more information than that received in the previous phases, especially concerning adverse events and vaccination of people who already have other rare diseases. This phase tests the large-scale effectiveness of the vaccine (whether it works). A phase III trial can last about 2-4 years followed by data analysis. In the case of positive results, this could lead to registration and availability of the vaccine to the public. 15. Who reviewed, approved and will monitor this clinical trial? All clinical trials to be conducted in South Africa must be reviewed and approved by the South African Medicines Control Council (MCC) and the Health research ethics committees of the participating institutions. The T-003 clinical trial has been reviewed and approved by the MCC and the Health research ethics committees of each participating research institution. The Provincial Department of Health (PDOH) offices relevevant to the participating sites will also have reviewed the study protocol before the clinical trial begins. The Health research ethics committees will be involved in reviewing any changes to the clinical protocol from an ethics and human rights point of view. Ethical concerns about the trial can also be directed the above bodies. QUESTIONS & ANSWERS The Protocol Team (the people who designed the trial) carefully reviewed the information about the study vaccine before deciding to conduct the trial. The ISS T-003 Protocol Team involves experts of the ISS, MRC-SAAVI, and the Investigators of the participating sites. Community members, for example, by way of Community Advisory Boards or Groups (CAB/Gs) are involved throughout the trial to advise on whether the research is acceptable to the community, and to advise on any human rights and community-related issues. The safety of the participants will be primarily ensured by the presence of an independent Data Safety Monitoring Board (DSMB), composed of specialists with experience in HIV/AIDS-related clinical research and evaluation of investigational product safety issues. Additional subject area experts may be consulted to provide expertise if requested by the DSMB. Further support to the Sponsor will be given by the International Advisory Board (IAB), an independent committee, including scientists with expertise in virology and immunology. The IAB s role is to advise the Sponsor regarding the different aspects of the clinical trial, and on critical aspects and key decisions that may arise during the conduct of the trial. In addition to the above, the trial will be monitored throughout by a Clinical Research Organisation (CRO) who has been appointed by the Sponsor, ISS. 16. How many patients have received the Tat vaccine? To date, 180 HIV-positive trial participants have been vaccinated with the Tat HIV vaccine. Of these, 27 were enrolled in phase I trials of the vaccine while the remaining 153 are enrolled in the ISS T-002 clinical trial. Eighty-seven of the 153 participants, have been included in the interim analysis published in PLoS ONE (Ensoli et al., PLoS One 2010). The total number of participants who will receive the vaccine in the T-002 trial is expected to be 160 people. For more on the PLoS One publication, please see 5

6 QUESTIONS & ANSWERS 17. What are the main results of studies previously completed with the Tat vaccine? Previous pre-clinical studies in animals and phase I clinical trials indicate that Tat vaccination is safe and causes a specific and durable immune response against the HIV Tat protein. 18. What are the main interim results of the phase II trial currently ongoing in Italy in participants on ARV treatment? Interim data of the phase II ISS T-002 study, ongoing in Italy, confirm that administration of the Tat vaccine is safe. In addition, the data indicate that vaccination with Tat is associated with an increase in the number of CD4+ T-cells and B-cells (cells that can produce antibodies), and a decrease in the harmful ongoing activation of the immune system caused by HIV infection. HIV infection causes imbalanced activation of the immune system and even with successful ARV treatment, a certain level of activation and imbalance has been shown to remain. This causes stress in the body that, long-term, can be associated with various symptoms including premature aging. The interim data from ISS T-002 indicate that the Tat vaccine enhances the capability of ARV treatment to restore the proper behaviour of cells of the immune system by reducing the immune activation and imbalance caused by HIV infection. Use of the Tat vaccine may therefore reduce the risk of developing symptoms including premature aging in participants on ARV treatment. 19. On the basis of the available results, can one say that the Tat vaccine is effective? Further studies are still needed to determine whether the therapeutic Tat vaccine is effective in slowing HIV disease progression. This is usually determined by way of a phase III clinical trial. 20. Can the Tat vaccine replace ARV therapy? To date, therapeutic trials to test the Tat vaccine have been done in HIV-infected individuals receiving ARV treatment, who have very low ( suppressed ) HIV viral loads. The scientific publication regarding the interim data analysis of the T-002 study (Ensoli et al., PLoS One 2010) thus examines potential implications of the possible synergy of vaccination and ARV treatment. Additional studies are needed to determine if the Tat vaccine can replace ARV therapy. 21. For more information About the DGCS: About the NDOH: About the ISS: About the Tat-based vaccine: About the MRC: About SAAVI: SAAVI Info-Line:

7 22. Positioning statements DGCS DGCS (Direzione Generale per la Cooperazione allo Sviluppo) is one of the Directorates of the Italian Ministry of Foreign Affairs and is responsible for the Italian ODA (Official Development Assistance). In South Africa, DGCS currently finances several initiatives, some directly managed, and some others implemented by partner institutions like ISS and Non-governmental Organisations (NGOs). Health in South Africa is the main sector of support with HIV-AIDS and TB as the present priority areas. Within the HIV project implemented by ISS, the DGCS, in conjunction with the NDOH, will ensure the monitoring and evaluation of the whole Program. Furthermore, DGCS will finance the United Nations (UN) agency charged with the coordination of the International Scientific Advisory Committee (ISAC). ISS The ISS is the leading technical and scientific public body of the Italian National Health Service, with tasks of research, control, training and consultation in the interest of the protection of public health in Italy. CNAIDS of the ISS coordinates studies on HIV and other AIDSrelated viral infections and cancers and has conducted research for over 13 years on HIV/AIDS vaccines, focusing its efforts on the HIV-1 Tat vaccine candidate, based on the HIV-1 Tat protein. The Center has sponsored and conducted phase I and phase II clinical trials testing the Tat vaccine in Italy. NDOH The National Department of Health (NDOH) is the custodian of health care in the Republic of South Africa. The provision of strategic leadership and stewardship, guided by the core values enshrined in the Constitution and the National Health Act, ensure that high quality health care is provided to all citizens of the Republic of South Africa. The Department provides high quality services through an over arching framework, which consists of the following: 1. Providing strategic leadership and the creation of a social compact for better health outcomes 2. Implementing National Health Insurance 3. Improving the quality of health services 4. Overhauling the health care system and improving its management 5. Improving human resource planning, development and management 6. Revitalizing infrastructure 7. Accelerating the implementation of HIV AND AIDS and Sexually Transmitted Infections National Strategic Plan , and increasing the focus on TB and other communicable diseases 8. Implementing mass mobilization for better health among the population 9. Reviewing the Drug Policy 10. Strengthening research and development QUESTIONS & ANSWERS The Negotiated Service Delivery Agreement (NSDA) is intended to further strengthen activities toward the following four outputs: Increasing life expectancy Decreasing Maternal and Child mortality Combating HIV and AIDS and decreasing the burden of diseases from Tuberculosis Strengthening Health System Effectiveness The involvement of the Department in the Program to support the Ministry of Health of South Africa in the implementation of a national program of global response to HIV & AIDS is to further strengthen health outcomes, improve quality of life and ensure a responsive and well functioning health care system. MRC-SAAVI The South African Medical Research Council (MRC) is a statutory organisation established by an Act of Parliament in Its mission is to improve the nation s health and quality of life through promoting and conducting relevant and responsive health research. The South African AIDS Vaccine Initiative (SAAVI) was established by the South African government in 1999 to co-ordinate the research and development of an affordable, effective and locally relevant HIV vaccine for southern Africa. SAAVI is a lead programme of the South African MRC. The MRC-SAAVI has been indicated by the NDOH as the local operational partner of ISS, in the implementation of the ISS T-003-related activities. MeCRU, University of Limpopo Medunsa Campus The Medunsa Clinical Research Unit (MeCRU) was established at the University of Limpopo - Medunsa Campus, Department of Medical Microbiology in July 2005, as a collaboration with the Department of Virology and the Medunsa Institute of Community Outreach Services (Medicos). The Unit conducts a variety of clinical trials on HIV/AIDS vaccines, the Human Papillomavirus (HPV) and opportunistic infections. It is strategically located at the University of Limpopo - Medunsa Campus where there is wide spectrum of qualified researchers from various fields of the health fraternity and is adjacent to Dr George Mukhari Hospital (DGM), a 1400-bed tertiary hospital. 7

8 QUESTIONS & ANSWERS The Unit has a contract Research laboratory to support the clinical trials which is 500m away from the trial site in the Research Section of the Department of Microbiological Pathology. The laboratory is accredited by SANAS from 2004 to date (Molecular Biology section, Serology, Bacteriology). It provides a variety of support to the clinical trials, including Peripheral Blood Mononuclear Cells (PBMC) isolation and a bulk specimen storage system. It is in close proximity to the SANAS-Accredited NHLS-Microbiology, Virology, Chemistry, Haematology, Anatomical Pathology (Histology, Cytology) facility. MeCRU was established with the support of the South African Medical Research Council (MRC) through its lead programme, the South African AIDS Vaccine Initiative (SAAVI). MeCRU is one of the sites which will conduct the ISS T-003 Tat HIV vaccine clinical trial. HIV Vaccine Research Unit, Walter Sisulu University Walter Sisulu University (WSU) is a developmental, comprehensive university focusing on urban renewal and rural development. It may be characterized as scientific, technological, innovative and responsive to local community needs, the requirements of commerce and industry and the socio-economic niche areas of national government. Operating across four campuses in the Eastern Cape: Mthatha, Butterworth, Buffalo City (East London) and Queenstown, WSU has a student population of over 24,000 and offers diplomas, degrees and post-graduate studies in four faculties: Health Sciences; Education; Science, Engineering and Technology and Business, Management Sciences and Law. The Faculty of Health Sciences recently celebrated 25 years of Socially Accountable medical education and is a leader in Problem- Based Learning (PBL), Community-Based Education (CBE) and Community Partnerships in Africa. One of its core principles is developing an appropriate curriculum that is based on the primary health care approach and guided by health and social needs. The Faculty is headquartered at the Mthatha Campus but has an Academic Health Service Complex that spreads throughout the Eastern Cape including Mthatha Hospital Complex, East London Hospital Complex, Port Elizabeth Hospital Complex, about 15 District Hospitals mainly in the North Eastern Region of the Eastern Cape, and seven Community Health Centres. The HIV Vaccine Research Unit (HVRU) falls under the WSU Faculty of Health Sciences. Development of the site began in 2006 with funding from the South African AIDS Vaccine Initiative (SAAVI), a lead programme of the South African Medical Research Council (MRC) via SAAVI s grant from the National Department of Health (NDOH). Since 2009, the site has been funded via the Program to support the Ministry of Health of South Africa in the implementation of a national program of global response to HIV & AIDS. This Program is funded by the Italian Ministry of Foreign Affairs, Directorate General of Development Cooperation (MAE-DGCS), and is implemented by the National AIDS Centre (CNAIDS) of the National Institute of Health of Italy (Istituto Superiore di Sanità or ISS), in cooperation with the South African National Department of Health (NDOH) supported by the MRC-SAAVI. Since November 2009 the HVRU has embarked on employment and training of several trial site staff as well as the purchase of relevant furniture and equipment. Renovations of an existing building in the old Mthatha Hospital grounds should be complete by mid The site is expected to be ready to conduct the T-003 Tat HIV vaccine trial towards the end of This clinical trial is being implemented in association with HIV Vaccine Research Unit 8