By Roberto Fernandez-Larsson, Ph.D.*
Disappointing results from DNA/ MVA AIDS vaccine candidates
Interim safety and immunogenicity data from clinical trials of two AIDS vaccine candidates was presented at the AIDS Vaccine 04 conference which took place 30 August to 1 September in Lausanne, Switzerland. The candidates, DNA.HIVA and MVA.HIVA, were developed as a prime-boost pair by a partnership led by the International AIDS Vaccine Initiative (IAVI). The partnership includes the University of Oxford/UK Medical Research Council, the University of Nairobi/Kenya AIDS Vaccine Initiative and the Uganda Virus Research Institute. DNA.HIVA is a bacterial plasmid containing the p17 and p24 regions of the HIV gag gene, plus 25 cytotoxic T lymphocyte epitopes from across the HIV genome. MVA.HIVA consists of a copy of the same HIV genetic material inserted into a modified vaccinia Ankara (MVA) virus vector. The HIV sequences were derived from an HIV subtype A, the subtype which accounts for most infections in East Africa.
The data presented at Lausanne involved 205 volunteers in small-scale Phase I clinical trials in Kenya, Uganda and the United Kingdom. Generally, the two vaccines were safe and well tolerated. However, only about a quarter of all volunteers showed HIV-specific cellular immune responses, and these were not long-lasting. Immune responses in volunteers were assessed by interferon (IFN)– ELISPOT assays conducted at the trial sites on fresh peripheral blood mononuclear cells.
Clinical trials of the same two vaccine candidates that have already started will be completed over the next few months. These trials, currently taking place in Kenya and the United Kingdom, are studying the highest dose of MVA.HIVA and the administration of a third dose of MVA.HIVA. The trials will also measure vaccine-induced immune responses using multiple laboratory tests in addition to IFN-γ ELISPOT assays. Emilio Emini, IAVI’s Senior Vice President for vaccine development, has said that unless there are new data on immune responses that are dramatically different IAVI will not develop DNA.HIVA and MVA.HIVA further.
Seven European countries demand push on AIDS vaccine
In Paris last June, health ministers and representatives from seven European countries (United Kingdom, France, Germany, Italy, the Netherlands, Spain, and Sweden) plus representatives of the European Union's Commission and the EuroVac consortium issued a joint call for better coordination in the development of an AIDS vaccine. The meeting, hosted by French Health Minister Philippe Douste-Blazy, aimed to formulate a single European view before a Group of Eight (G8) meeting in the US that same week (see Enterprise article below).
The representatives fell short of committing more funding to the AIDS vaccine effort, but did call for strengthening research collaboration among vaccine scientists and working together to attain a critical mass to push prototype vaccines through the lengthy, costly process of clinical trials. The statement described an AIDS vaccine as “an absolute necessity.” Attendees formulated a European “scientific diary” under the authority of a scientific committee that Michel Kazatchkine, director of the French ANRS, outlined: to identify and prioritize the best candidate vaccines for testing in clinical trials; to establish a network of research laboratories and centers of clinical evaluation for Phase II trials in particular; to support collaboration with developing countries to take part in Phase III trials; to mobilize private sector vaccine research in Europe.
Crucell grants IAVI exclusive license to use AdVac technology for AIDS vaccine
Dutch biotechnology company Crucell NV has signed an agreement with IAVI whereby Crucell will develop AdVac vectors for use in IAVI’s AIDS vaccine development program.
Earlier this year Crucell and IAVI entered into an exclusive license agreement to develop an AIDS vaccine based on Crucell’s AdVac technology. The AdVac vectors are developed from adenovirus serotypes 11 and 35 and have shown promising results as vectors for AIDS vaccines in a series of studies by Crucell in collaboration with Harvard Medical School. The technology is also being used by Crucell in the development of a malaria vaccine in collaboration with GlaxoSmithKline, Walter Reed Army Institute of Research and the US National Institute of Allergy and Infectious Diseases, and a tuberculosis vaccine in collaboration with the Aeras Global TB Vaccine Foundation.
With the AdVac technology agreement, Crucell adds to the AIDS vaccine candidate collaboration it already has with Merck & Co. “Our technologies are now supporting two of the programs best positioned to bring an AIDS vaccine to the market,” Crucell’s Chief Scientific Officer Jaap Goudsmit said in a statement.
ANRS launches new clinical trials of preventive AIDS vaccine candidates
The French National Agency for AIDS Research (ANRS) announced the launch of a new trial of a candidate preventive AIDS vaccine at the AIDS Vaccine 04 Conference in Lausanne, Switzerland. The Phase I trial ANRS VAC16 will compare the intramuscular and intradermal (ID) routes of injection of a vaccine preparation of lipopeptides to determine safety and immunogenicity. Enrollment for this trial started in July at six sites in France; the target is a total of 70 non-infected volunteers. This is the first time that the ID route is being assessed for this type of vaccine preparation. Encouraged by results obtained in macaques, the investigators hope that the ID route may enhance the production of HIV-specific cytotoxic T lymphocytes (CTLs).
The vaccine candidate, LIPO-4T (LPHIV-1), is a mixture of 4 lipopeptides containing CTL epitopes from HIV-1 subtype B proteins (from strains MN and LAI). The epitopes are from Gag, Pol-RT, Pol and Nef. Each epitope contains a CD4+ T cell epitope from tetanus toxin in colinear sequence, and a monopalmitoyl group at the N-terminal position to form the lipopeptide. The vaccine is manufactured by Biovector SA.
A second trial involving a lipopeptide vaccine candidate started enrollment in September. The Phase II ANRS VAC18 trial will test the safety and compare the cellular immunogenicity of three doses of the LIPO-5 candidate versus placebo in 132 non-infected volunteers in 6 sites in France. LIPO-5, manufactured by Aventis Pasteur, is a mixture of 5 lipopeptides containing CTL epitopes from HIV-1 subtype B (Gag, Pol and Nef). Each peptide is modified in the C-terminal position by the addition of a lipid moiety to form the lipopeptides.
The LIPO-5 vaccine is currently being tested in a different trial in the United States. Earlier this year the US National Institute of Allergy and Infectious Diseases in collaboration with the ANRS began the Phase I/II trial HVTN 042/ANRS VAC19 to evaluate LIPO-5 combined with a canarypox vector (vCP1452). This trial is based on preliminary results obtained from the ANRS Phase I trial VAC10, which suggested that the combination of lipopeptides and canarypox vector could induce a significant cellular immune response. For more information on these and other trials, visit the IAVI database of AIDS vaccines in human trials.
Global HIV Vaccine Enterprise Scientific Plan Meeting
The Coordinating Committee of the Global HIV Vaccine Enterprise met on 21 October in Washington, DC to finalize the scientific plan that will outline the priorities needed to achieve the goal of developing a safe and effective AIDS vaccine and to discuss its implementation. A total of 52 participants from 16 countries attended the meeting, including the Joint United Nations Programme on HIV/AIDS (UNAIDS), the World Health Organization (WHO), the European Commission, as well as other stakeholders. Also present were leaders of the six working groups that helped draft the scientific plan.
The Global HIV Vaccine Enterprise arose from a concept and broad proposal developed by Richard Klausner, from the Bill and Melinda Gates Foundation, and other scientists and advocates. The proposal was published in the journal Science in June 2003 and was endorsed by the G8 nations during their meeting in Sea Island, Georgia last June.
In general terms, the Enterprise is an alliance of independent agencies and groups who are working to jointly develop the scientific plan, which will be published early next year. The idea is to identify and prioritize the most critical scientific problems and encourage donors to deploy resources to solve them. There will be common standards for assessing laboratory and clinical research results and an emphasis on the sharing of data, resources, and expertise.
Participants at the meeting discussed the best ways the Enterprise could help address critical areas needed for the development of a vaccine. The major components of the plan are fourfold. First, encouraging the development of AIDS vaccine development centers or AIDS vaccine consortia, analogous to the Vaccine Research Center at the US National Institutes of Health or IAVI’s Neutralizating Antibody Consortium, to develop and test novel candidate vaccines that can elicit enhanced humoral and cellular immunity. Second, standardization of the laboratory and clinical assays and parameters used to evaluate preclinical and clinical immunogenicity of candidate vaccines, so that the collected laboratory and clinical data can be compared even if trials are conducted in different geographical locations and with different vaccine candidates; the goal is to develop a fully integrated clinical trials system. Third, to improve the utility of non-human primate models in fundamental research efforts to better define immunological parameters associated with protection. Fourth, ensuring that increased, dedicated vaccine manufacturing capacity is available for use once an effective AIDS vaccine has been licensed.
The Coordinating Committee will also develop plans for a support framework for the Enterprise. This will comprise four major elements: a permanent secretariat; expert working groups that will provide guidance to steer the scientific plan; a forum for engaged funders willing to devote additional resources to the scientific plan; and a broader stakeholders’ forum to enable engagement of the wider community and provide a mechanism for feedback and dialogue. The Coordinating Committee will be meeting again in the first quarter of 2005 to discuss progress.
*Roberto Fernandez-Larsson, Ph.D., is the IAVI Report Web editor.