Important note: Information in this article was accurate in October 2001. The state of the art may have changed since the publication date. IAVI Report - October - November 2001
Ian Grubb
With HIV vaccines based on canarypox poised to enter Phase III studies (see articles, Thailand, and HVTN ), a new prime-boost strategy using a related viral vector is just entering the clinical development pipeline. At the Bangkok and Melbourne meetings, researchers from an Australia-based consortium reported on their program to combine a DNA vaccine prime with a new HIV vaccine made from fowlpox, and possibly also with a cytokine (an immune-enhancing "messenger" molecule). The strategy is designed to work by inducing T-cell responses, with little or no contribution from antibodies.
With design and production work in full swing, the first Phase I study in HIV-negative volunteers is expected to begin in Sydney in August, 2002 using a "proof of concept" clade B construct. A second trial with a subtype E-based vaccine is planned for the following year in Thailand. A therapeutic trial of an HIV-fowlpox construct carrying the cytokine interferon-gamma was launched last year in Sydney and has so far enrolled 27 of a planned 36 newly HIV-infected people.
Led by David Cooper, director of the National Centre in HIV Epidemiology and Clinical Research (NCHECR) at Sydney's University of New South Wales (UNSW), the project is organized as a consortium of public and private sector collaborators, including several academic research centers, social researchers, a biotechnology company and community groups. Funding comes from a US$ 16.7 million grant from the National Institute of Allergy and Infectious Diseases (NIAID) under its HIV Vaccine Design and Development Team (HVDDT) program, which covers development and testing of the concept over five years (2000-2005). The Australian researchers are the only group outside the US to receive HVDDT funding so far, and the NIAID grant is among the largest ever for Australian biomedical research. Under the contract, no decision to commercialize the product, should it prove successful, can be made without consensus of all consortium members.
The DNA vaccine prime, developed by Ian Ramshaw's group at the Australian National University in Canberra (based on technology developed by Heather Davies and colleagues, and licensed to Coley Pharmaceutical Group) contains gag-pol sequences as well as the env, tat and rev genes. It also includes bacterial sequences called CpG motifs that are known to enhance immune responses.
The "boost" component is based on a recombinant fowlpox vector (rFPV) that has been used for several poultry vaccines. The fowlpox platform was developed by David Boyle and colleagues at Australia's Commonwealth Scientific & Industrial Research Organization (CSIRO), based outside Melbourne. The version used in the Sydney trial will contain gag-pol and env, and possibly a cytokine (interferon-gamma or IL-12). It may be further refined for the Thai trial.
In his ICAAP presentation, David Boyle (CSIRO Animal Health) described fowlpox as one of the largest known viruses, capable of accepting very large genetic inserts. It can be grown to higher titers than its relative, canarypox, but is also difficult to produce on a large scale. Both Boyle and Cooper expressed the view that there will eventually need to be head-to-head comparisons of these and other viral vectors.
For the sake of speed, the Australian group has tested the HIV vaccines directly in monkeys rather than constructing SIV equivalents, based on earlier work probing the utility of this approach for answering certain questions. Using this system, Stephen Kent (University of Melbourne) found that the prime and boost vaccines induce significant CTL and T-helper cell responses when given together, but not singly. He also showed that they protect macaques against acute infection after challenge with non-pathogenic HIV. Challenge studies with a pathogenic SHIV are now in planning.
Kent also described ongoing work in macaques to evaluate other potential vaccine components, including CpG motifs, additional HIV antigens, and cytokines (interferon-gamma or IL-12). The latter studies are based on a co-expression technology (Co-X-Gene™) with FPV) being developed under license from the CSIRO and the Australian National University by the Melbourne-based biotech firm Virax Immunotherapeutics, Inc. The outcome of these macaque studies, and of the ongoing therapeutic trial, should clarify whether to include a cytokine in the final vaccine design.
At the ICAAP meeting, Sean Emery (NCHECR), coordinator of the project's trials and laboratory monitoring, reported that the protocol for the Sydney study is almost ready for submission to Australia's Therapeutic Goods Administration (TGA), NIH and the Institutional Review Board at Sydney's St Vincent's Hospital Medical Centre, where the trial will take place.
The study will begin with a "vanguard" cohort of 8 low-risk volunteers, a requirement of the TGA, and then scale up to 42 participants divided into three arms: placebo (n=6); DNA prime + FPV boost (n=18); and DNA prime + rFPV/cytokine (n=18). DNA will be given at weeks 0 and 4, followed by FPV at week 8, and participants will be monitored for 52 weeks. Primary endpoints will be safety and immunogenicity, as measured by ELISPOT and lymphoproliferation assays, with other immune assays likely to be added. GMP manufacture of both the DNA component (under subcontract to the German firm Qiagen Inc.) and the rFPV vaccine (by IDT Limited in Melbourne) is complete. Design of the Thai study will be informed by the results from Sydney. The trial will be carried out under the banner of HIV-NAT, a partnership of HIV clinical researchers from the Netherlands, Australia and Thailand, together with the Thai Red Cross, with whom Cooper has an ongoing clinical study on anti-retroviral treatment in 1,000 volunteers.
The vaccine development consortium also includes the National Centre in HIV Social Research (NCHSR) at Sydney's UNSW and the Australian Federation of AIDS Organisations (AFAO), who will take the lead on socio-behavioral and ethical issues. Over the next few years, the NCHECR group plans to enroll up to 500 HIV-negative men in an open cohort vaccine preparedness study called "Health in Men (HIM)." The study will examine the relationships between trials and risk behaviors, help researchers understand what motivates people to join trials and guide AFAO--the national umbrella group for Australian AIDS NGOs--in developing future HIV prevention programs.
Beyond ensuring that the trials incorporate strong risk behavior prevention strategies, AFAO is collaborating with the project's biomedical researchers on community needs and ethical concerns. Outgoing AFAO Executive Director and ICAAP Co-Chair Robin Gorna also reported on plans to partner with a Bangkok NGO to support community participation in the Thailand trial.
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©2001. The IAVI Report.
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