By Roberto Fernandez-Larsson, Ph.D.*
IAVI and industry/academic partners begin two phase I HIV vaccine trials in December
IAVI, in partnership with industry and academic research centers, began two separate AIDS vaccine human trials in December 2003. The trials were designed to test two distinct investigational vaccine products for the prevention of HIV/AIDS in non-infected individuals.
The first trial is a collaboration of IAVI and the Aaron Diamond AIDS Research Center (ADARC), an affiliate of Rockefeller University. The vaccine being tested is a new DNA vaccine called ADVAX and contains genetic material from clade C, the most prevalent HIV strain in the world. Clade C HIV is largely distributed in China, India and in sub-Saharan Africa. This phase I trial will involve 45 healthy non-infected volunteer men and women over the next few months and will test the safety and immunogenicity of the vaccine. ADARC and IAVI have agreed that if ADVAX proves effective, it will be made available in developing countries at reasonable cost.
The second trial is currently underway in Belgium and soon to be in Germany, and is a collaboration of IAVI, Targeted Genetics Corporation and Columbus Children’s Research Institute. This candidate vaccine, called tgAAC09, containing clade C HIV sequences, uses Targeted Genetics’ rAAV (recombinant adeno-associated virus) and is designed to elicit both humoral and cell-mediated responses. In studies to date, non-human primates that received the rAAV-based vaccine showed robust and durable antibody and T-cell responses, and also had reduced viral load when challenged with a virulent strain of SIV, the non-human primate equivalent to HIV.
Merck AIDS vaccine researcher Emilio Emini joins IAVI
In January Merck’s Senior Vice President of Vaccine Research, Emilio Emini PhD, joined IAVI as Senior Vice President and Chief of Vaccine Development. Emini will spearhead IAVI product development activities and lead efforts to accelerate the most promising of these candidates into large-scale efficacy trials and eventual licensure. During his 20-year tenure at Merck, Emini helped lead the company’s AIDS vaccine program that brought several candidates into human trials and is currently focused on a candidate based on the replication-incompetent adenovirus (Ad)-5 vectors. Ad-5 candidate vaccines are currently being tested both alone and in combination in several ongoing clinical trials. Emini also led the Merck team that developed Crixivan (indinavir), the first protease inhibitor, a potent antiretroviral therapy against HIV.
Chiron starts phase I HIV vaccine trial
On 15 January, Chiron Corporation announced the initiation of its first phase I clinical trial of a preventive AIDS vaccine strategy. The study, HVTN 049, will be conducted by the US HIV Vaccine Trials Network (HVTN); it is funded by the US National Institute of Allergy and Infectious Diseases (NIAID) and Chiron. The trial will evaluate the safety and immunogenicity of a prime-boost strategy. The DNA priming immunization consists of clade B gagand env plasmids delivered in cationic polylactide coglycolide (PLG) microparticles. The study will boost with a novel oligomeric, V2-deleted gp140 with an MF59 adjuvant (used in an influenza vaccine licensed in Europe) designed to enhance the production of broadly neutralizing antibodies.
VaxGen announces results from Thai AIDSVAX trial
On 12 November 2003, VaxGen announced the preliminary results from its randomized, double-blind, placebo-controlled phase III clinical trial in Thailand to evaluate AIDSVAX B/E, an investigational vaccine (monomeric recombinant gp120) for the prevention of HIV infection. The study of 2,546 injecting drug users found that the vaccine offered no protection from HIV infection or disease. The North American and European phase III trial of a highly similar candidate also found no overall protection. Thailand recently launched another phase III trial that will test AIDSVAX B/E together with the canarypox candidate ALVAC vCP1521 in a prime-boost regimen (see below).
Thai prime-boost trial launches amid criticism
On 29 September 2003, the U.S. National Institute of Allergy and Infectious Diseases (NIAID) launched a phase III efficacy trial in 16,000 volunteers of a prime-boost regimen consisting of AIDSVAX B/E and Aventis Pasteur’s canarypox candidate ALVAC vCP1521 in Thailand. The US$119 million trial has since been the subject of criticism from a group of prominent scientists, including HIV co-discoverer Robert Gallo. Writing in the 16 January issue of the journal Science, the group expressed concern over the trial saying that while the original aims of the trial “remain fundamentally worth addressing, [they] doubt whether these immunogens have any prospect of stimulating immune responses anywhere near adequate [to] prevent infection and/or lead to the immune control of HIV-1 replication postinfection.”
The prime piece of the vaccine is the canarypox vector ALVAC from Aventis Pasteur, which these critics claim is “poorly immunogenic” as determined in “multiple phase I and II clinical trials. The AIDSVAX gp120 component has shown no efficacy to date in two independent phase III trials in the United States and Thailand.” Dr. Prasert Thongcharoen, chairman of the Thai National AIDS Commission's subcommittee on HIV Vaccine Development, told the Associated Press that their aim in this trial is to test the effect of the two vaccine components in combination.
John McNeil of the Walter Reed Army Institute of Research and a key player in the current Thai trial, told Science last November that in small human trials, the prime-boost approach has triggered a "much broader" immune response expanding HIV-specific CD4+ T helper cells. NIAID is preparing a formal rebuttal to the letter for publication in Science.
*Roberto Fernandez-Larsson, Ph.D., is the IAVI Report Web editor.