By Michelle Rotchford Galloway, South African AIDS Vaccine Initiative
The South African Medicines Control Council (MCC) has approved the first human clinical trial for a phase I HIV vaccine trial in South Africa. This is a phase I human clinical trial of the AlphaVax replicon Vector (ArVTM) clade C candidate HIV-1 vaccine to assess the safety and immune system responses induced by this new vaccine technology. The trial will involve a small number of volunteers in the USA and South Africa.
ArV is cutting-edge vaccine technology that was awarded the World Technology Forum Award for biotechnology in 2001. It utilises virus-like particles, containing parts of an attenuated strain of Venezuelan equine encephalitis (VEE) virus and a gene from a South African strain of the HI virus, to deliver the vaccine to the immune system. This is the first trial of the ArV technology in humans.
The HIV Vaccine Trials Network (HVTN) is conducting the trial, which will take place at two clinical trial sites in South Africa – the Perinatal HIV Research Unit at the Chris Hani Baragwanath Hospital in Soweto and the SAAVI Vaccine Research Unit at the Medical Research Council in Durban. The US trial sites are Johns Hopkins University, Columbia University, the University of Rochester and Vanderbilt University.
As the vaccine contains only a copy of a small section of genetic material from HIV, and does not include the genetic elements needed to reconstitute live HIV, there is no possibility of the vaccine itself causing HIV infection. The vaccine material is also designed in such a way that its VEE components cannot generate VEE virus or cause VEE infection.
This ArV vaccine technology was originally developed by researchers at the University of North Carolina (UNC) and the US Army Medical Research Institute of Infectious Diseases, and has been applied to HIV by an international collaboration of researchers from UNC, the University of Cape Town, the Medical Research Council in South Africa, and AlphaVax, a North Carolina biotechnology company. The International AIDS Vaccine Initiative (IAVI) was also a key supporter of the programme earlier in the collaboration. The organisations involved in conducting and funding the trial in the US and SA include the US National Institutes of Health (NIH), the HIV Vaccine Trials Network (HVTN) and the South African AIDS Vaccine Initiative consortium partners in South Africa. The NIAID-funded HVTN is conducting the trial. AlphaVax developed the vaccine, produced the vaccine material, and submitted the regulatory applications in both countries.
A total of 96 participants will be involved in the trial – 48 in the US and 48 in South Africa. Twenty four volunteers are required at each South African site and recruitment activities are continuing in preparation for the first vaccinations. Volunteers will be healthy, HIV-negative adults who are willing and able to give informed consent. Intensive pre-recruitment educational and community awareness activities have been conducted at both sites in South Africa. The study that has been approved will begin by enrolling 12 volunteers in the US, and additional volunteers will be enrolled in the US and SA once initial safety data from these 12 volunteers has been reviewed.
Potential volunteers will be supplied with detailed information about the candidate vaccine. Volunteers will undergo intensive risk-reduction counselling and clinical monitoring on an ongoing basis throughout the trial to ensure their safety and that they do not expose themselves to unnecessary risk.
A phase I trial is a safety trial, which aims to confirm that the test vaccine does not produce significant side effects in human volunteers. Volunteers in this study will be closely monitored over a 12-month period. This test vaccine has already been extensively tested in laboratory and animal studies. The phase I clinical trial protocol has also been reviewed and approved by the US Food and Drug Administration (FDA) as well as by multiple ethics committees in South Africa and the USA.
Volunteers will be involved in the trial for about a year and with data analysis the trial will last approximately two years.
This is the first HIV vaccine trial to be approved in South Africa and the first in the world to test a subtype C vaccine.
More about the VEE candidate vaccine
The vaccine is based on alphavirus replicon vector technology. A vaccine vector is a biological delivery system for a vaccine. This is a replicon vaccine, which uses parts of the Venezuelan equine encephalitis virus (VEE). In replicons, the genes for the VEE viral structural proteins are removed and replaced with a gene or genes cloned from the HI virus. Instead of producing its own structural proteins, the VEE replicon RNA is used like a machine to produce large amounts of HIV protein in the person vaccinated. It is hoped that the HIV protein will induce immune responses protective against HIV infection.
To deliver the replicon RNA into the body, it is packaged into an artificial virus-like particle, a VEE vaccine replicon particle (VRP). The VRP is used as a vector for the HIV gene. In making this vaccine, the genetic material of the VEE virus is weakened and restructured. Important parts are removed to make a vaccine particle that can express the proteins from the inserted HIV gene but cannot make more VEE virus, and therefore cannot cause VEE infection. Multiple, layered safety features are designed into the system and rigorous safety testing of each vaccine batch ensures that VRP preparations are safe. This has been confirmed in various laboratory and animal studies.
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 derived from the clade C virus circulating in South Africa. It does not include the genetic elements needed to reconstitute live HIV. Therefore there is no possibility of the vaccine causing HIV infection.
This gene is a promising target for the cellular immune responses thought to be a prerequisite for a successful HIV vaccine. The gag gene selected conforms closely to the South African consensus sequence for this gene, and is therefore characteristic of the circulating clade C virus. A single gene was selected for the lead project to simplify the development and expedite initiation of clinical trials. Work on a multi-gene product is also proceeding with the hope of entering clinical trials by late 2004.
The same technology is also being studied in other disease models – including herpes and certain cancers.