Questions and Answers - vaccine trials
3 November 2003

What is the 040 vaccine trial?
HVTN 040 is a phase I trial to look at the safety and immune response of an experimental HIV vaccine. The term ‘HVTN 040’ is the name that the HIV Vaccine Trials Network (HVTN) uses to refer to this trial. The candidate vaccine is called AVX101, and it is an alphavirus replicon vaccine. Scientists designed this candidate vaccine to teach the human body how to fight off HIV infection. The hope is that a vaccine can eventually keep people from becoming infected with HIV.

This is a phase I study to assess the safety of this new HIV vaccine technology in people in the United States and South Africa. In addition, the study will measure the immune response generated by the vaccine. The vaccine candidate will be tested in healthy, HIV-uninfected volunteers.

How does this candidate vaccine work?
This vaccine is made to work by entering a few special human cells that are involved in the immune response. The genetic material in the vaccine will reproduce once it is in these cells, causing these particular cells to produce the same HIV protein carried by the vaccine. In animal experiments, production of this protein elicits both a humoral immune response (production of antibodies against the HIV protein) and cell-mediated immune response (the ability to kill HIV?infected cells). Therefore, it is hoped that the humans who receive this vaccine will have the same result as the animals and be able to produce an immune response.

Can this candidate vaccine cause HIV?
No, this candidate vaccine cannot cause HIV infection. The vaccine does not contain killed or weakened HIV. It contains only a copy of a small section of genetic material from HIV, known as the gag gene. Later versions of the test vaccine could include additional genes. The gag gene is only a small part of HIV. Therefore there is no possibility of the vaccine causing HIV infection. It does not include parts of HIV that would be needed to produce live HIV.
This vaccine is NOT made from live virus or from HIV-infected human cells, so there is NO possibility that it contains live or killed HIV virus. Therefore, it is NOT possible that someone can get HIV infection or AIDS by receiving this vaccine.

Has this candidate vaccine been tested (in humans or animals)?
This vaccine has been tested in animals and in a few human volunteers. Animal studies have shown significant humoral (antibody) and cell-mediated (T cell) immune responses. Investigations using an early prototype of the vaccine in monkeys showed reduced viral load and improved clinical outcomes. The vaccine candidate has been tested in a small number of human volunteers in the USA and no safety concerns have been identified to date.

Why is this approach being studied?
VEE has several characteristics that make it attractive as a vector for an HIV vaccine. First, it is easy to make the VEE vector carry HIV genes, while avoiding the potential for VEE itself to infect a trial volunteer. Particles made from VEE are able to target the immune system and to express the immunising genes they carry at very high levels (in large amounts). Research showing that this can create a highly effective vaccine in animals suggests that VEE can stimulate the desired immune response in humans.

Who is running this trial?
The trial will be run by the HIV Vaccine Trials Network (HVTN), a global partnership dedicated to conducting international clinical HIV vaccine trials. The HVTN is funded by the National Institute of Allergy and Infectious Diseases (NIAID), of the US National Institutes of Health (NIH).

Collaborating organisations in the design of this vaccine product and the conduct of the clinical trial are AlphaVax, Inc., the US NIH and its HVTN, the University of North Carolina at Chapel Hill, the South African AIDS Vaccine Initiative (SAAVI) under the auspices of the South African Medical Research Council, the University of Cape Town, and the South African National Institute for Communicable Diseases.

The principal investigators are Dr Don Burke at Johns Hopkins in Baltimore and Dr Glenda Gray at the University of the Witwatersrand in South Africa. Additional participating trial sites are Columbia University, the University of Rochester, and Vanderbilt University in the United States and the HIV Vaccine Research Unit in Durban, South Africa.

What is the design of the trial?
Forty-eight people will be enrolled in the trial, 24 in South Africa and 24 in the US. These people will randomly be divided into two groups of 12 people each. This is a double-blind, placebo-controlled trial – meaning that some of the participants will receive the test vaccine and some will receive a harmless substance which resembles the vaccine known as a placebo. Double-blind means neither the clinicians or the volunteers know which group they are assigned to in order to eliminate any bias. The two groups are then compared to see if the vaccine has made any difference.

Ten of these people will receive the candidate vaccine and two will receive the placebo. There will be two dosage amounts of vaccine candidate: the first group of 12 in each country will receive the lower dose, and the second group in each country will receive the higher dose. The trial will last approximately two years, with one year of participation expected from each volunteer. Participation will include nine clinic visits, three injection dates, and seven blood draws.

Who produced the vaccine candidate?
The vaccine was developed and produced by a biotechnology company called AlphaVax, Inc., based in North Carolina, USA. The vaccine was developed together with South African scientists from the University of Cape Town.

Who is funding the trial?
This trial is funded by the Division of AIDS (DAIDS), a part of the National Institute of Allergy and Infectious Diseases (NIAID) of the National Institutes of Health (NIH), which is within the US Department of Health and Human Services (DHHS). AlphaVax, Inc. made the product and is sponsoring the trial.

Who approved the trial, and what was the approval process?
The study protocol, which outlines everything that will happen in the trial, went through extensive independent review by the Institutional Review Board, Institutional Ethics Committee and Bio-Safety Committee of each institution involved. The HVTN 040 trial has been reviewed by at least six such committees.

It has also been approved by the governmental authorities, the US Food and Drug Administration (FDA) and the South African Medicines Control Council (MCC).

The candidate vaccine is considered investigational, meaning that the FDA and the MCC will allow its use only in research with a small number of participants (i.e. a phase I trial). The candidate vaccine has been made according to the guidelines established by the FDA and MCC, and has been reviewed by both agencies.

Finally, the Community Advisory Groups (at the various trial sites), which act as a link between the researchers and the community, while not part of the official approval process, give regular input into the trial design and proceedings.

When and where is this trial being run?
This trial began in July 2003 in the United States and in November 2003 in South Africa. The US clinical trial sites are Columbia University in New York City, New York; the University of Rochester, Rochester, New York; Johns Hopkins University, Baltimore, Maryland; and Vanderbilt University, Nashville, Tennessee. The South African sites are the HIV Vaccine Research Unit at the Medical Research Council (MRC) in Durban and the HIV/AIDS Vaccine Division of the Perinatal HIV Research Unit, University of the Witwatersrand, based at Chris Hani Baragwanath Hospital in Soweto, South Africa.

Why is this vaccine candidate being tested in South Africa?
This vaccine candidate has been developed based on HIV subtype C, which is the strain of HIV most prevalent in southern Africa (estimated to be responsible for over 90% of new infections in South Africa). HVTN 040 is based on subtype C with the intent of developing a vaccine that has a good chance of preventing future infections in South Africans. The gag gene which is inserted is based on gene sequences from viruses circulating in South Africa.

Scientists do not know yet if a vaccine might work better if it is matched to a local clade or virus type, so they are studying different variations to further understand the issue. At present there is insufficient evidence and further testing is needed. This vaccine candidate allows scientists to establish baseline safety information that could lead to additional studies to help in answering this important question.

What other candidate vaccines are being tested in South Africa?
This is one of the first candidate vaccines to enter a phase I trial in South Africa. A second candidate, the HIVA.MVA, has also received regulatory approval to enter a phase I trial in South Africa shortly. This trial will be run by the International AIDS Vaccine Initiative. In addition, there are other South African developed candidate vaccines that are currently in the pre-clinical phase and could enter clinical trials during 2004. The aim would be to have a number of candidates in phase I trials simultaneously so that the most promising approaches can quickly be identified and can proceed to later trials.

What are the possible risks with this vaccine candidate?
Any experimental vaccine carries possible risks, but based on the information they have, researchers do not expect that there will be serious safety issues. In addition to the HIV gag gene, the vaccine contains parts of a weakened (attenuated) strain of another virus called Venezuelan equine encephalitis (VEE) virus. The VEE is in the form of a replicon – it is not a normal virus structure. A different weakened (attenuated) strain of VEE has been used successfully in another vaccine product in humans for decades. Vaccine candidates using VEE have been tested extensively in experimental animals without causing any significant side-effects or infection. The candidate vaccine does not contain live HIV virus, and therefore there is no way for it to cause HIV infection.

The vaccine has already been administered to a small number of US volunteers as part of the HVTN 040 trial, so some very early safety data is available before it is given to South African volunteers. However, until the HVTN 040 trial, this candidate vaccine had never been tested in humans. While scientists believe that there are no serious safety risks, there is always the possibility that there could be problems that no one expected. This is why this candidate vaccine, like any new drug or vaccine, needs to be tested for the first time in a few volunteers in a controlled clinical setting.

Many people, from scientists and doctors to community members, looked carefully at the information about the candidate vaccine to make sure that they thought it was safe enough to begin the trial. In addition to the protocol team, the HVTN has a central Safety Monitoring Board, which will watch carefully to make sure nothing goes wrong. If there are any problems, the trial will be interrupted for careful review. After additional review by persons not involved with the study, the trial can be resumed or permanently stopped, based on the review.

What is VEE?
In addition to a synthetic piece of the HIV virus called the gag gene, this vaccine candidate contains parts of a weakened (attenuated) strain of another virus known as VEE (Venezuelan equine encephalitis) virus. The gag gene is the part of the candidate vaccine that should make the immune response specifically tailored to fight HIV.

The natural VEE virus typically infects horses, although occasional human infections occur. VEE infections in humans are rare. In these cases the VEE virus usually produces flu-like symptoms. For this vaccine, VEE has been designed so that it cannot reproduce itself. Infection cannot occur with a replicon because all the structural genes are removed. When a virus cannot reproduce it no longer can cause an infection, and therefore this vaccine candidate is not expected to cause VEE infections. As a further safety measure, the type of VEE virus used has been changed so that it is weakened, lessening its ability to cause harm. It is not expected that serious illness will result from the use of the VEE vector, but there is a very, very small chance that this could happen. Procedures are in place to monitor volunteers just in case an illness related to VEE does develop.

The altered VEE virus is the carrier or vector for a particular piece of HIV (the gag gene of HIV) that is put into the RNA of the VEE virus using standard scientific methods. The gag gene is synthetically made, is only a small part of the HIV virus, and cannot cause HIV infection. The VEE virus vector carries the gag gene into the cells, where it will cause the cells to make gag proteins. These proteins might be part of what would one day help the body fight off real HIV.

How will trial volunteers be protected during this trial?
Before deciding to enter the trial, potential volunteers are provided with the following: information about HIV and AIDS; the reasons for the trial; possible risks and benefits of participation; and, a description of the trial procedures. They are also informed that any new, experimental vaccine may have unknown risks. These may include side-effects due to injection of the vaccine, and issues of stigmatisation associated with taking part in HIV studies. Volunteers will be reminded frequently that being part of this trial does not mean that they are less likely to become infected with HIV. Volunteers are provided with risk-reduction counselling at each visit, explaining current proven ways to avoid HIV infection (including, for instance, abstinence and correct and consistent condom use).

Volunteers who are eligible and willing to participate after the study has been fully explained to them will be asked to give informed consent before they enroll in the study and on an ongoing basis throughout the study. Volunteers will be given plenty of time to consider whether or not they want to participate. Volunteers do not have to join the study and can leave the study at any time.
The role of the volunteer in HIV vaccine clinical trials is essential. Those involved in the design of the trial have considerable respect for trial volunteers, and are dedicated to the continued support of these volunteers.