By Kristen Jill Kresge
First Phase II AIDS Vaccine Trial Begins in South Africa
A clinical trial evaluating the safety and immunogenicty of tgAAC09, a recombinant adeno-associated virus (AAV) vector-based vaccine containing clade C HIV antigens, recently began at three sites in South Africa, including clinics in Soweto, Cape Town, and Medunsa. The randomized, placebo-controlled, double-blind trial will evaluate two inoculations with the candidate at three different doses and two dosing intervals. This is the country's first Phase II AIDS vaccine trial and investigators will enroll and follow 78 volunteers over a period of 18 months.
Preliminary safety data on the candidate administered at lower doses was established in a joint, multi-country Phase I trial conducted in Belgium, Germany, and India. The candidate was designed by Philip Johnson at the Columbus Children's Research Institute in Ohio and Children's Hospital of Philadelphia and developed and manufactured by Targeted Genetics Corporation in Seattle.
The South African trial is a collaboration between Targeted Genetics and IAVI and is an important advancement in a country where 25 million people are currently estimated to be HIV infected. Other arms of this Phase II trial will occur in Zambia and Uganda, after receiving final regulatory approval in these countries.
South Africa is now also hosting another important HIV prevention trial involving the microbicide candidate PRO 2000, a vaginal gel consisting of a synthetic polymer that binds to HIV and acts as a fusion inhibitor, preventing the virus from infecting target cells. This placebo-controlled Phase III trial will enroll over 10,000 women volunteers in South Africa, Uganda, Tanzania, and Zambia, making it the largest microbicide trial to date. The trial began enrolling volunteers recently in Johannesburg and is being coordinated by the UK Medical Research Council.
Rwanda Starts First AIDS Vaccine Trial
A Phase I AIDS vaccine trial to evaluate the safety and immunogenicity of a prime-boost vaccine regimen recently began enrolling volunteers at a site in Kigali, Rwanda. The two candidates, a DNA plasmid vaccine followed by an adenoviral vector vaccine, were developed by the Vaccine Research Center (VRC) of the US National Institutes of Health (NIH). This is the first AIDS vaccine trial to take place in Rwanda and is being conducted by the NIH, IAVI, and Project San Francisco, a research organization that has been working in Kigali for almost 20 years.
Volunteers in this placebo-controlled, double-blind trial (IAVI V001) will be randomized to receive either the multi-clade adenovirus serotype 5 (Ad5) candidate alone or the DNA/Ad5 candidates in a prime-boost sequence. The naked DNA vaccine is comprised of a fused gag/pol/nef construct from subtype B, the primary viral clade found in Europe and North America, and HIV env genes from subtypes B as well as A and C, which are the most common subtypes in Africa and parts of Asia. The boost vaccination is an Ad5 recombinant vector containing gag, pol, nef, and env genes. The adenovirus vector was developed by the VRC in collaboration with GenVec, who also manufactured the vaccine. The DNA components were manufactured by the California biotechnology company Vical.
This Phase I trial will also soon begin enrolling volunteers in Kenya and the prime-boost approach will be evaluated in HVTN 204, an ongoing Phase II trial at HVTN sites in North and South America, Haiti, Jamaica, Botswana, and South Africa. The DNA/Ad5 candidates will also be tested in other Phase I/II trials that are expected to begin soon at other clinical trials sites in Uganda, Kenya, and Tanzania in partnership with the US Military HIV Research Program.
New Public Private Partnerships for AIDS Vaccine Development
Two new partnerships between private sector companies and non-profit organizations were recently established to focus on the development of novel AIDS vaccine candidates. The first between IAVI and Transgene, a French biopharmaceutical company, will focus on the development and manufacturing of an AIDS vaccine candidate using an adenovirus serotype 35 (Ad35) vector.
Two currently ongoing trials are using Ad5 as a vector, including Merck's Phase IIb "test of concept" trial and the DNA/Ad5 prime-boost strategy being evaluated by the VRC. However, the immune responses induced by Ad5-based vaccines could be limited by pre-existing immunity to the viral vector in some populations. Researchers have therefore focused their efforts on the development of novel candidates based on other adenovirus serotypes, including Ad35, which naturally infect fewer people worldwide.
The vaccine candidate will be manufactured at Transgene's facility near Strasbourg, France for eventual evaluation in clinical trials. IAVI has worked with Transgene in the past on the manufacturing process of modified vaccinia Ankara (MVA) constructs and on other characterization studies.
A second partnership between GlaxoSmithKline (GSK) Biologicals in Rixensart, Belgium and the Institut Pasteur in Paris will concentrate on developing an AIDS vaccine candidate using the measles vaccine as a vector to carry HIV antigens. Researchers hope that this vaccine concept will induce similarly strong and persistent immune response to HIV as it does for measles. The measles vector technology will be licensed from Institut Pasteur to GSK and the initial project, which includes manufacturing the vaccine candidate and evaluating its safety and immunogenicity in two clinical studies, is supported by a grant from the European Union.
GSK is also working with IAVI on other AIDS vaccine vectors based on non-human primate adenoviruses. Several other public private partnerships have also recently been established to research and develop other vaccines, including collaborations between GSK and Aeras Global TB Vaccine Foundation for tuberculosis vaccines and GSK and the Malaria Vaccine Initiative to complete development of an advanced malaria vaccine candidate.
WHO and UNAIDS Release Update that Focuses on HIV Prevention
The Joint United Nations Programme on HIV/AIDS (UNAIDS) and the World Health Organization (WHO) recently released their annual report on the global AIDS epidemic. It highlights the progress made by some countries in lowering HIV infection rates despite a continued increase in the total number of people infected with HIV throughout the world, which now is estimated at 40.3 million. The report, AIDS Epidemic Update 2005, was released in advance of World AIDS Day on December 1 and focused on the importance of HIV prevention efforts and the need to increase and improve efforts that focus on behavior change throughout the world.
Kenya and Zimbabwe are two African countries where behavioral changes, such as an increase in the uptake of voluntary counseling and testing (VCT), a delay in the initiation of sexual contact, and a reduction in the number of sexual partners, are linked with a decline in HIV prevalence over the past few years. National prevalence rates among adults in Kenya dropped to 7%, while Burkina Faso also witnessed a decline in prevalence among young pregnant women in urban areas.
But there were still nearly 5 million new infections in 2005 and more than 3 million AIDS-related deaths. Sub-Saharan Africa was the hardest hit region globally, accounting for 64% of all new infections or more than 3 million newly HIV-infected people. Infection rates continued to rise in Mozambique, Swaziland, and South Africa.
Eastern Europe and Central Asia saw the sharpest rise in infection rates where a 25% increase in total infections now accounts for 1.6 million infected individuals. In these areas as well as in East Asia and Latin America—where there were 200,000 new infections—the epidemic is now being fueled by both injection drug use and heterosexual transmission. Pakistan and Indonesia are also now facing explosive epidemics among both injection drug users (IDUs) and sex workers. The only region that didn't have an increase in the number of new HIV infections was the Caribbean, where there has been an increase in VCT services and condom use among sex workers.
"We really are failing to prevent this epidemic in most parts of the world," says Jim Kim, director of WHO's HIV/AIDS program. "And we have real opportunities to scale up prevention." He said one of those opportunities is ensuring that some of the momentum created around access to HIV treatment programs in developing countries, including more available funding, is extended to HIV prevention efforts. This can help bolster existing programs, allowing countries to scale up VCT programs and focus on preventing mother-to-child transmission of HIV.
Efforts must also be made to improve the number and reach of harm reduction programs such as methadone maintenance therapy for IDUs and Kim says progress is also being made on this front. "China is committed to scaling up harm reduction in every province by 2008," he says.
The greatest obstacles to expanding treatment programs are the need for more funding to increase the number of prevention workers and overcoming the stigma that is associated with accessing VCT and harm reduction programs in many countries.