Important note: Information in this article was accurate in April 2001. The state of the art may have changed since the publication date. IAVI Report - April / June 2001
GlaxoSmithKline, the British-based pharmaceutical company and one of the world's leading vaccine makers, gave the first public presentation on its AIDS vaccine candidate at the Second International Conference on Vaccine Development and Immunotherapy in HIV (San Juan, 22-25 May). Lead scientist Gerald Voss reported on two rhesus macaque studies of its recombinant protein-based vaccine, containing the HIV Nef and Tat regulatory proteins (as a single "fusion protein" designated NefTat) along with gp120. The Nef and Tat proteins are derived from a laboratory-adapted clade B HIV isolate, the gp120 from a Dutch clade B isolate (ACH320) that is dual-tropic (able to infect T-cells via both CCR5 and CXCR4 co-receptors). The vaccine is delivered in a proprietary adjuvant developed by the former SmithKline Beecham (then called SBAS-2, now known as ASO2A), characterized by Voss as a mixture of a novel oil/water emulsion, 3D-MPL and QS21.
The first study involved six groups of four macaques each. Three groups received either all proteins, NefTat or gp120, all in AS02A. Another two groups received either all proteins or NefTat in a related adjuvant, AS06, while controls received adjuvant alone. All recipients of NefTat (in both studies) were also given SIV nef separately. Animals were immunized at months 0, 1 & 3 and then challenged intravenously one month later with SHIV89.6P. Voss reported that animals vaccinated with all proteins in ASO2A recovered CD4 T-cell counts after an initial dip and controlled viral replication out to 18 months. In contrast, three of four controls as well as all animals given gp120 or NefTat alone rapidly lost CD4 cells, developed symptoms of simian AIDS and were euthanized. The group receiving all proteins in ASO6 remained healthy, although three had persistently high viral loads. Voss reported a statistically significant difference between this group and controls in terms of CD4 count and viral load endpoints.
Attempting to confirm these results, Jonathan Heeney's group (the Biomedical Primate Research Center, Rijswijk, The Netherlands) immunized and challenged macaques (described by Voss as "genetically unrelated" to the first set of animals) on a similar schedule, using four groups of six animals each. After challenge, five of six animals receiving all three proteins showed relative preservation of CD4 cells but one animal experienced a clear decline. Control of viral load was variable and less robust than in the first experiment. Further confounding the results, none of the six control macaques experienced the "crash" in CD4 cells typically seen with SHIV89.6P challenges, and four ultimately controlled their viral loads. Overall, the study did not yield statistically significant differences in outcome between vaccinees and controls.
Voss also presented limited data on pre-and post-challenge immune responses. Neutralizing antibodies were detected only in one animal prior to challenge, indicating that they did not play a role in this model. T-helper cell proliferative responses to vaccine antigens were detected but declined post-challenge. CTLs are being investigated in ongoing experiments. Phase I human trials of the vaccine are slated to start later this year through the HIV Vaccine Trials Network (HVTN).
John G. Curd, MD, has left his position as Senior Vice President for Medical and Regulatory Affairs at VaxGen, Inc., where he oversaw clinical testing of the company's envelope-based vaccine candidate, AIDSVAX™. In that capacity he helped plan and launch the world's first Phase III AIDS vaccine trials, now ongoing in North America, Europe, and Thailand and collectively involving about 7500 high-risk volunteers. The search for his replacement is underway at VaxGen.
On 1 May 2001, Curd assumed the newly-created position of Senior Vice President, Clinical Development at Maxygen, Inc., a biotechnology company specializing in the optimization of genes and proteins for commercial uses, including therapeutics and vaccines. The company recently announced the start of an HIV vaccine research program in partnership with IAVI and DBLV LLC, an entity established and financially supported by the Rockefeller Foundation. Curd will be responsible for overseeing the clinical development of Maxygen's lead products.
Every year since 1997, when then-US President Bill Clinton challenged the world to develop an AIDS vaccine within a decade, the Washington, DC-based AIDS Vaccine Advocacy Coalition (AVAC) has released a critical assessment of progress towards this goal. Released on 18 May, the anniversary of Clinton's declaration (commemorated as World AIDS Vaccine Day), this year's report—"Six Years and Counting: Can a Shifting Landscape Accelerate an AIDS Vaccine?"-highlights the sense of optimism that has begun to permeate the field, while cautioning that "this moment of confidence must not be squandered, but used to confront the considerable challenges ahead." AVAC lays out seven principles it believes should guide vaccine development, and makes targeted recommendations for advancing the effort, emphasizing community involvement, coordination between stakeholders and government leadership. The full report can be read online at: http://www.avac.org/readings/newestreprt.htm or ordered by calling +1 (202) 387-5517.
Attempting to fill a gap that has plagued the AIDS vaccine field, several groups plan to release collections of information on human AIDS vaccine trials. Both IAVI and the Vaccine Research Center (Bethesda) seek to include all AIDS vaccine trials worldwide, both ongoing and completed. IAVI's information (www.iavi.org) is available as a searchable database with descriptions of the vaccine product and trial protocol and information on community contacts for enrollment. Barney Graham, Clinical Director at NIH's new Vaccine Research Center (see article) and director of NIH's previous Phase I and II AIDS vaccine trials network (the AIDS Vaccine Evaluation Group), has compiled a table listing the trials along with a scientific description (www.vrc.nih.org). Later this year, amfAR (the American Foundation for AIDS Research; www.amfar.org) will release a directory of ongoing trials.
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©2001. The IAVI Report.
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