HIV vaccine research and development

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1 HIV vaccine research and development What is an HIV vaccine and how does it work? An HIV vaccine is a substance given to the body to teach it to defend itself against HIV. A successful preventative HIV vaccine will teach the body to recognise HIV, preparing the person s immune system to fight back if exposed to HIV at a later date, through, e.g., unsafe sex. A successful therapeutic HIV vaccine will boost the immune response of people who are already infected with the virus. This way, their immune system can fight HIV better and stop or slow disease progression. Each potential HIV vaccine is tested in different stages taking a number of years. These stages include initial laboratory work, followed by testing the vaccine in animals, and then in human clinical trials. HIV vaccine trials can be either preventative or therapeutic. Preventative HIV vaccine trials include HIV-negative volunteers to test if the vaccine stops infection, or slows HIV disease progression if infection occurs. Therapeutic HIV vaccine trials include HIV-positive volunteers to test if the vaccine strengthens their immune response to HIV to stop, or slow HIV disease progression. Currently researchers are testing mostly preventative HIV vaccines. What is a successful HIV vaccine? Graph 1, shows the normal progression of HIV infection when there is no antiretroviral treatment or a successful HIV vaccined used. The viral load goes up over time while the CD4 count goes down. This weakens a person s immune system and they start to get opportunistic infections (OIs). Once the immune system is very weak, the person is usually said to have AIDS, and may die from the OIs. Graph 1: CD4 count and viral load in a normal HIV infection NORMAL HIV INFECTION Graph 2 below, shows what researchers want as a first prize, or a primary end-point for a preventative HIV vaccine a vaccine that will prevent HIV infection in all those who are vaccinated. This is called sterilising immunity. Graph 2: Sterilising Immunity However, currently there is no vaccine in public use that works completely in everyone who gets it. Also, we may not find a preventative HIV vaccine that prevents infection in everyone who is immunised. So, the next best prize for a preventative HIV vaccine would be: a vaccine that helps the immune system control HIV infection if infection occurs. As in Graph 3, this means that the person s viral load will become undetectable. Their CD4 count will also be normal; or, a vaccine that keeps HIV under better control if a person is infected. - As in Graph 4, this would cause a lower viral load setpoint, and a lower viral load that remains lower for longer than in an HIV-positive person who has not had a successful HIV vaccine and/or antiretroviral treatment. - If a person has been immunised with a successful HIV vaccine, their CD4 count should recover after initial HIV infection. It should also stay at that level for longer, and decline slower than in an HIV-positive person who has not had an HIV vaccine and/or antiretroviral treatment. In both the above cases, a preventative HIV vaccine would either stop or slow down HIV disease progression. Graphs 3 and 4: Viral setpoint The lowest level the viral load falls to once the immune system brings the initial HIV infection under control. Graph 3 Graph 4

2 HIV vaccine research and development cont. A successful therapeutic HIV vaccine would boost or strengthen the immune response in a person who is already infected with HIV. As in Graph 4, this should reduce the person s viral load and keep it low, or keep it low for longer than without the HIV vaccination. It should also allow their CD4 count to recover, and to stay at that level or to reduce gradually over time. An undetectable, or lower viral load, means that a person may not progress to AIDS or may progress to AIDS slower. He or she is also less likely to infect others with HIV. This will reduce the number of new HIV infections in the general public, which is called herd immunity. This in turn, may result in better control of HIV disease in the general population. What HIV vaccine designs are there? Most vaccines in public use today are based on one of the following designs: Whole-killed/inactivated vaccine design: Here researchers disable or kill the germ using heat or chemicals. But it can still cause a strong immune response. Examples of this type of vaccine are the influenza (flu) and the rabies vaccines. Live-attenuated vaccine design: Here researchers change the germ in some way, e.g., by removing one or more of its genes so it cannot cause disease. But they keep some characteristics from the original germ so it will still trigger an immune response. Examples of vaccines like this are the measles and mumps vaccines. Researchers cannot use the above designs for HIV vaccines as they could cause HIV infection. So, HIV vaccines only include one or more laboratory-made proteins, or peptides or genes from HIV, which on their own cannot cause HIV infection. However, our body still sees these as foreign and should create a B- and/ or T-cell immune response to this false infection. In preventative HIV vaccines, the aim is to create memory B- and/or T-cells that stay on guard in the body, causing a quick immune response if the person is exposed to HIV at a later stage.this response should be quicker than if the person was not vaccinated and could prevent HIV infection. Or, it could lead to better control of the infection, if it occurs, thereby lowering the viral load and stopping or slowing HIV disease progression. In therapeutic HIV vaccines the false infection also sets off B- and/or T-cells to strengthen the immune response to HIV and to stop or slow HIV disease progression. The following HIV vaccine designs are more commonly used and all aim to cause vaccine-made immunity: Recombinant subunit protein vaccine (one of the subunit approaches) Researchers include one or more laboratory-made HIV proteins in the vaccine for example, proteins from the envelope surface of HIV, like gp120. The body should see these are foreign, leading to an immune response. Vector vaccine Researchers put one or more laboratory-made HIV genes into another type of germ, e.g., a virus or bacteria. They change the germ in the laboratory so it cannot cause harm and use it to carry one or more HIV genes into the body. The germ used to carry the HIV gene into the body is called a vector. Once in the body, the HIV genes produce proteins that researchers hope will lead to an anti-hiv immune response. DNA vaccine design Researchers stitch one or more laboratory-made HIV genes into a ring of DNA from another germ to form plasmids. When the plasmids enter the body, they cause the production of proteins that researchers hope will trigger an immune response. A DNA vaccine may need to be used in combination with another HIV vaccine design to get the most effective immune response. Laboratory-made HIV proteins from the envelope surface Vector vaccines are like a car that is carrying a passenger. Vector vaccine using a bacteria that is changed DNA vaccine design HIV gene/s stitched into a ring of DNA from another germ Currently, there are recombinant subunit protein, peptide, vector, DNA, replicon, and virus-like particle HIV vaccine designs.

3 Sometimes two different vaccines are given one after the other. This is called the prime-boost approach. Researchers think that this approach may cause a stronger immune response than giving just one vaccine design. Can an HIV vaccine cause HIV infection? HIV vaccines do not contain any whole or live HIV and therefore cannot cause HIV infection or AIDS. An HIV vaccine is like a car, which has no engine. You can still recognise it as a car, but without an engine, it cannot drive, i.e. cause HIV infection. An HIV vaccine is like a car, which has no engine. It has no whole or live HIV, so it cannot drive, i.e. it cannot cause HIV infection. Four different stages of HIV vaccine development Is there an HIV vaccine available? Currently there is no effective preventative or therapeutic HIV vaccine available. However, there are several possible vaccines that may work and are being tested in clinical trials. Testing a vaccine takes a long time to ensure that it is safe and effective. It has taken at least 10 to 20 years to bring most vaccines into public use. What are the different stages of HIV vaccine development? HIV vaccines follow the same four stages of development as any new drug or vaccine. These include: Stage 1: Stage 2: Stage 3: Stage 4: 3: Stage 1 is called Discovery and includes research, and development of HIV vaccine designs in the laboratory. In 1981, several rare illnesses, now known as symptoms of AIDS were brought to the attention of doctors and researchers. They then began to search for the cause of these illnesses as part of a process called discovery. It was only in 1984 that researchers finally found the cause of AIDS, namely HIV. Even today researchers do not completely understand HIV and this is partly why it has taken so long to develop potential HIV vaccines. Researchers are constantly learning more about HIV and use this knowledge to develop and improve on HIV vaccine designs. Stage 2 includes animal studies. Once researchers complete Stage 1, they test the new HIV vaccine design in small and then larger animals. This is to make sure that the vaccine is safe, to measure its potential toxic effects and to ensure that it shows a promising immune response against HIV. Stage 1 and 2 are called preclinical studies. If preclinical studies show that the vaccine is safe and promising, the Sponsor can submit a research protocol, or plan, for approval for the vaccine to be tested in human clinical trials. They send the protocol to the regulatory authorities, e.g., in South Africa, to the Medicines Control Council (MCC) and the relevant research ethics committee/s (RECs). If approved, the clinical trial must be registered with the Department of Health (DOH) to begin. Stage 3 includes clinical trials in humans. What are the different phases of clinical trials in humans? Each phase of clinical trials is done in exact order from phase I-IV. The results of each phase must show that the specific test HIV vaccine is promising. Only then can sponsors apply to the relevant parties to approve the next phase of clinical trials. Phase I: Safety Aims? To test if the vaccine is safe in humans. How many trial participants? 40 to 120 participants. Preventative HIV vaccine trials involve healthy, HIV-negative participants over 18 years of age, who are at low risk of infection. In South Africa, the MCC usually requires that they have at least 12 years of education. Therapeutic HIV vaccine trials involve HIV-positive trial participants over 18 years in age. How long does it take? The trial lasts 12 to 18 months. This is followed by 3 to 4 months to analyse the data.

4 Phase III: Efficacy, and always safety Phase I Phase II: Safety, the best way to give the vaccine and whether it triggers an immune response Aims? Still to test the vaccine for safety. To find the best way to give the vaccine; and, To see if it triggers an immune response. How many trial participants? Hundreds of trial participants. The requirements to join the trial are the same as phase I, except that preventative trials involve people at low and high risk of HIV infection. How long does it take? Usually 1 to 2 years. This is followed by 4 to 6 months to analyse the data. Aims? To test for efficacy if the vaccine protects people against HIV infection or if it slows disease progression to AIDS. Vaccine safety is always tested. How many trial participants? It involves several thousand people. The criteria to join the trial are the same as phase I, except that preventative trials involve people at high risk of HIV infection. How long does it take? It takes about 3 to 4 years, and another 12 to 18 months to analyse the data. Those who become HIV positive during a preventative HIV vaccine trial will be followed up. This may take another 3 to 4 years. If a successful HIV is found, those in the placebo group should be offered the vaccine. The Sponsor usually appoints an independent Data Safety Monitoring Board (DSMB) to analyse data collected during phase IIb and III clinical trials. This usually includes interim data analysis at a certain point during the trial. The results from the interim analysis will show, for example, whether there are any safety concerns. The results should be used to decide whether to continue with the trial. Stage 4 is about Public implementation. It includes registration and licensure, and large-scale manufacture for public use. Phase II Phase IIb clinical trials Sometimes there is a phase IIb trial. It includes fewer participants, e.g., 2000 to 3000, than a phase III trial. However, it produces enough safety and efficacy (whether it works) data to guide future research, e.g., to help decide whether to take the vaccine into a phase III trial. Phase IIb trials cost less and are a good way to manage limited resources. Criteria for trial participants is the same as in phase I, except that preventative trials involve people at high risk of HIV infection. Hopefully at the end of phase III there will be an HIV vaccine that is safe and effective. Researchers can then apply to the MCC to register and licence the vaccine. If application is successful, the vaccine can be marketed and manufactured on a large scale for public use. Phase IV studies can then begin. Phase III

5 Phase IV trials post-licensure or field studies Aims? To test whether the vaccine is effective - how well it works in the general public and in real-life conditions. To check for rare adverse drug reactions. To test how well the vaccine does when it is stored, transported and distributed on a large scale. To see if the vaccine reduces the number of new HIV infections or stops or slows HIV disease progression in members of the general public. How many trial participants? The general public. How long does it take? It takes a few years to see what effect the vaccine is having in the general public. These studies may show that health care providers need more training, or that better storage facilities are needed to improve the performance of the vaccine, etc. What is Good Clinical Practice (GCP)? The research protocol includes a statement that says that the researchers agree to do the trial according to the protocol, Good Clinical Practice (GCP) and other regulatory requirements. GCP is the minimum standards or requirements that must be followed in a clinical trial. These include standards for how the trial should be carried out, monitored, analysed and reported. GCP ensures that the data and results from the trial are reliable and accurate. GCP also aims to protect the rights, integrity, and confidentiality of trial participants. In South Africa, local GCP requirements are written into a document called The Guidelines for Good Practice in the Conduct of Clinical Trials with Human Participants in South Africa. Researchers in South Africa must also follow: the Constitution (1996), the National Health Act (2003), and, the Department of Health Guidelines: Ethics in Health Research: Principles, Structures and Processes (2004). Research that is done or funded by the South African Medical Research Council (MRC) must follow the MRC Guidelines on Ethics for Medical Research (2002). In South Africa, the following guidelines also exist for HIV vaccine research and development: What is a research protocol? Before starting a clinical trial, the Sponsor must write up and submit a research protocol, or plan, to the regulatory authorities and the RECs. The protocol contains a detailed plan and procedures for the research. It includes information on: what the research is about; where it will take place; when and how it will take place; and; possible risks and benefits to the trial participants. The relevant parties must approve the protocol, and the trial must be registered with the DOH before it can begin.

6 What parties are involved in approving, running and monitoring or quality assuring clinical trials? Parties involved in APPROVING clinical trials. The Sponsor The Regulatory Authority, e.g., the Medicines Control Council (MCC) and the Genetically Modified Organisms (GMO) Council. The Research Ethics Committees (RECs) The Department of Health (DOH) Roles and responsibilities Takes responsibility for initiating, managing and/or financing the clinical trial. Submits the trial protocol to the correct parties for approval. The MCC reviews the protocols to ensure that the research is scientifically sound. They must give approval for the trial to proceed. The GMO Council approves or rejects the testing, in clinical trials, of HIV vaccine designs that include genetically modified parts. It ensures responsible development, production, and use of GMOs in South Africa. Reviews protocols to ensure that the research is ethical and that the rights, safety and well-being of trial participants are protected. They must give ethical approval for the trial to proceed. With whom the clinical trial must be registered. Parties involved in RUNNING clinical trials. The Sponsor Trial site staff led by the Principal Investigator (PI), e.g., the trial site coordinator, doctors, nurses, counsellors, laboratory staff, administrative staff, community outreach team, etc. The Community Advisory Group (CAG) Roles and responsibilities Appoints qualified staff to design the protocol, to supervise the trial, to manage and analyse data, and to write trial reports. The PI is appointed by the Sponsor and takes sole or joint responsibility for designing, carrying out, analysing and reporting on the clinical trial. The PI ensures that approval is given by the regulatory authorities and the RECs before starting the trial. He or she ensures that the trial is registered with the DOH and that all the staff, facilities and equipment are in place. Represent the community s interests and concerns. The CAG form an ongoing communication and advisory link between the researchers and the community. They should participate in all decision making to do with the trial that affects the community. Parties involved in QUALITY ASSURING clinical trials. The Sponsor The Regulatory Authority RECs The Monitor The Auditor The independent Data Monitoring Committee (IDMC) or Data and Safety Monitoring Board (DSMB) CAG Roles and responsibilities Implements and maintains quality assurance and quality control systems. This includes appointing a Monitor, sometimes an independent Data Monitoring Committee (IDMC) or Data and Safety Monitoring Board (DSMB), and sometimes the Auditor. Can do on-site inspections at any time. Compares the practices of the trial site with the protocol and reports sent to the MCC. Do ongoing review and monitoring of the trial from an ethics and human rights point of view. Mainly oversees and reports on the progress of a trial. They visit the trial sites regularly to ensure that the trial is carried out and reported according to the protocol, Standard Operating Procedures (SOPs) and appropriate legislation. They also inform the Sponsor and trial management of any problems at the trial sites or laboratories. Does an in-depth examination of the trial to see that it meets the protocol, GCP, Good Laboratory Practice (GLP) and Good Pharmacy Practice (GPP), and all regulatory requirements. Reviews data at various points during the trial to assess progress. They can recommend that a trial continues, is paused or closed based on results from the data analysis. They are also a mechanism to ensure that any human rights issues and other personal concerns raised by the community are addressed.

7 How are trial sites chosen? Researchers choose a trial site by looking at baseline information facts and figures about the community that are relevant to the research, e.g., population and number of new HIV infections in the area. They also look at certain practical and logistical information, e.g., whether there is access to public transport, and whether clinical and laboratory facilities are available in the area. Where are clinical trials happening? Phase I, II and III HIV vaccine trials have been happening around the world. Currently most of the trials are phase I and II studies, although there have been one or two phase IIb and phase III trials. So far, most of the clinical trials in South Africa have been for preventative HIV vaccines. There has also been at least one therapeutic trial in South Africa while further trials are planned. Please visit the following websites for updates on where there are HIV vaccine clinical trials: SAAVI: IAVI database of clinical trials: US National Institutes of Health (NIH) clinical trials registry: EuroVacc Programme website: HVTN webpage on global trial sites: Sweden I Denmark I Finland I, II Russian Federation I Germany I, II Canada II, IIb, III USA I, II, IIb, III Netherlands III UK I, II Belgium I, II Switzerland I, II France I, II Italy I, II China I Cuba I Jamaica I Haiti I, II, IIb Dominican Republic I, IIb Puerto Rico I, II, III Trinidad & Tobago II Peru I, II, IIb Brazil I, II Spain I, II Gambia I Guinea-Bissau I Israel II Malawi I Zambia II Botswana I India I Uganda I, II Kenya I, II Rwanda I Tanzania I, II Thailand I, II, III Australia I, II, IIb American Samoa II South Africa I, II, IIb HIV vaccine trials completed or started up to 2010 The above map is based on information from two sources: the International AIDS Vaccine Initiative (IAVI) Trials Database and the US National Institutes of Health (NIH) clinical trials registry. It includes preventative and therapeutic HIV vaccine trials and shows where phase I, II, IIb and III trials have, or are being held.

8 HIV Vaccine Info-Line: 080 VACCINE SAAVI was established in 1999 as an initiative of the South African government with initial funding from Eskom, the Departments of Health and of Science and Technology. SAAVI is a lead programme of the South African Medical Research Council (MRC). It coordinates and supports the research, development and testing of HIV vaccines in South Africa with the aim to find a safe, affordable, effective and locally relevant HIV vaccine. SAAVI funds the activities of investigators at a number of South African academic institutions. These activies have included: development of potential HIV vaccines; laboratory science; immunology; development of a South African clinical infrastructure; testing of HIV vaccines; biostatistics; ethical, socio-behavioural, human rights and legal research; and, community involvement in HIV vaccine research and development. SAAVI is currently funded by the National Department of Health (NDOH), and by the Italian Cooperation with the technical support and collaboration of the Istituto Superiore di Sanita (ISS) or the Italian National Health Institute. SAAVI works and collaborates with key national and international partners to achieve its aims. SAAVI is proudly sponsored by: Department of Health