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Mycobacterium tuberculosis genome sequence illuminates bug's biology
SCIENCE AND MEDICINE
NEWS HIV-1-vaccine-trial go-ahead reawakens ethics debate he US FDA has approved the first phase III trial of a candidate HIV1 vaccine, it was announced on June 3. VaxGen (South San Francisco, CA, USA) has been given the go-ahead for a placebo-controlled trial of AIDSVAX (panel) in 5000 healthy US volunteers, and hopes soon to win official approval for a further trial in Thailand. But the move has generated controversy, particularly because global ethics standards for HIV-1vaccine trials are still in development. UNAIDS has been holding a series of meetings this year to develop consensus ethics guidelines for such trials in developing countries. This effort will culminate in a meeting in Geneva
on June 25–26, just before the 12th World AIDS Conference. According to Jose Esparza, meeting organiser and UNAIDS vaccine development adviser, the meeting will review a draft of UNAIDS guidelines drawn up by Robert Levine (Yale University, New Haven, CT, USA), and consider modification of the International Guidelines for Biomedical Research Involving Human Subjects. Three of the central issues, says Esparza, are: the obligations of vaccine-trial sponsors to make any succesful vaccines available to the countries where they were tested; treatment for study participants who become infected; and the nature of HIV-1prevention programmes First HIV-1 vaccine in phase III trial that should be included VaxGen’s AIDSVAX consists of recombinant gp120 in trials. envelope antigens from two HIV-1 strains (figure). In Peter Lurie (Public earlier trials, AIDSVAX induced strong circulating Citizen Health Research antibody responses. Phase III trials will now find out Group, Washington, to what extent these antibodies protect against DC, USA) says it is HIV-1, says VaxGen. However, production of HIV-1essential that health specific cytotoxic T lymphocytes and/or mucosal authorities in developantibody responses may also be needed for ing countries get specific protection. Some scientists are sceptical about the guarantees from sponefficacy of AIDSVAX, and are concerned that trial sors before trials start. participants may be excluded from subsequent trials “These are rich compaof more effective vaccines, and that recruitment to nies. You have to get the future trials will thus be affected. Kelly Morris best deal possible.” Donald Francis,
T
VaxGen president, says that his company intends to make the vaccine as “inexpensive as possible for Thailand, including as much in-country production as possible”. The making of AIDSVAX gp120
Viral genome
Two HIV-1 strains
Recombinant gp120
+ aluminium adjuvant
Lurie says that trial sponsors have an ethical obligation to ensure that intravenous drug users in trials have access to clean needles. Francis notes that Thai health authorities do not have needle-exchange programmes, so VaxGen will not provide one. Lurie also cautions against doublestandards for treatment of seroconverters in the developed world versus the developing world. But Francis warns against such “therapeutic imperialism”, saying that Thai seroconverters will depend on their health-care system for treatment, but VaxGen will make a small donation to the Bangkok Municipal Administration. Peter Wehrwein, Kelly Morris
Mycobacterium tuberculosis genome sequence illuminates bug’s biology
K
nowing the complete genome sequence of Mycobacterium tuberculosis should help in the “conception of new prophylactic and therapeutic interventions” against tuberculosis, write Stewart Cole (Institut Pasteur, Paris, France) and coauthors in this week’s Nature (1998; 393: 537–44). The development of DNA vaccination, the use of secreted or surfaceexposed proteins as immunogens, and the attenuation of M tuberculosis for use in vaccines should all progress quickly now that the full sequence is known (http://www.sanger.ac.uk/). The complete genome sequence of 4·4 million basepairs was mostly elucidated at the Wellcome Trust Pathogen Unit (Sanger
THE LANCET • Vol 351 • June 13, 1998
Centre, Cambridge, UK), but scientists in France, Denmark, and the USA helped convert raw sequence data into information on the biology of M tuberculosis. 3924 open-reading frames have been identified, accounting for about 91% of the genome’s coding capacity. Precise functions have been assigned for about 40% of the predicted proteins by comparison with known sequences. Another 44% of the sequences have some similarity to known proteins. The remaining 16% are unique to M tuberculosis and may account for specific mycobacterial functions. 10% of the coding capacity of the genome encodes two large unrelated families of acidic, glycine-rich
proteins. The scientists speculate that these proteins could be “the principal source of antigenic variation” in M tuberculosis and that the glycine-rich proteins “might interfere with immune responses by inhibiting antigen processing”. Both these possibilities need to be considered when designing new vaccines. The usefulness of this new resource does not stop at vaccination. The genome contains many potential drug-resistance genes and numerous genes involved in cell-wall synthesis, all of which may be good drug targets. The sequence also indicates how M tuberculosis can persist in tissues for long periods of time. Jane Bradbury
1789
NEWS HIV-1-vaccine-trial go-ahead reawakens ethics debate he US FDA has approved the first phase III trial of a candidate HIV1 vaccine, it was announced on June 3. VaxGen (South San Francisco, CA, USA) has been given the go-ahead for a placebo-controlled trial of AIDSVAX (panel) in 5000 healthy US volunteers, and hopes soon to win official approval for a further trial in Thailand. But the move has generated controversy, particularly because global ethics standards for HIV-1vaccine trials are still in development. UNAIDS has been holding a series of meetings this year to develop consensus ethics guidelines for such trials in developing countries. This effort will culminate in a meeting in Geneva
on June 25–26, just before the 12th World AIDS Conference. According to Jose Esparza, meeting organiser and UNAIDS vaccine development adviser, the meeting will review a draft of UNAIDS guidelines drawn up by Robert Levine (Yale University, New Haven, CT, USA), and consider modification of the International Guidelines for Biomedical Research Involving Human Subjects. Three of the central issues, says Esparza, are: the obligations of vaccine-trial sponsors to make any succesful vaccines available to the countries where they were tested; treatment for study participants who become infected; and the nature of HIV-1prevention programmes First HIV-1 vaccine in phase III trial that should be included VaxGen’s AIDSVAX consists of recombinant gp120 in trials. envelope antigens from two HIV-1 strains (figure). In Peter Lurie (Public earlier trials, AIDSVAX induced strong circulating Citizen Health Research antibody responses. Phase III trials will now find out Group, Washington, to what extent these antibodies protect against DC, USA) says it is HIV-1, says VaxGen. However, production of HIV-1essential that health specific cytotoxic T lymphocytes and/or mucosal authorities in developantibody responses may also be needed for ing countries get specific protection. Some scientists are sceptical about the guarantees from sponefficacy of AIDSVAX, and are concerned that trial sors before trials start. participants may be excluded from subsequent trials “These are rich compaof more effective vaccines, and that recruitment to nies. You have to get the future trials will thus be affected. Kelly Morris best deal possible.” Donald Francis,
T
VaxGen president, says that his company intends to make the vaccine as “inexpensive as possible for Thailand, including as much in-country production as possible”. The making of AIDSVAX gp120
Viral genome
Two HIV-1 strains
Recombinant gp120
+ aluminium adjuvant
Lurie says that trial sponsors have an ethical obligation to ensure that intravenous drug users in trials have access to clean needles. Francis notes that Thai health authorities do not have needle-exchange programmes, so VaxGen will not provide one. Lurie also cautions against doublestandards for treatment of seroconverters in the developed world versus the developing world. But Francis warns against such “therapeutic imperialism”, saying that Thai seroconverters will depend on their health-care system for treatment, but VaxGen will make a small donation to the Bangkok Municipal Administration. Peter Wehrwein, Kelly Morris
Mycobacterium tuberculosis genome sequence illuminates bug’s biology
K
nowing the complete genome sequence of Mycobacterium tuberculosis should help in the “conception of new prophylactic and therapeutic interventions” against tuberculosis, write Stewart Cole (Institut Pasteur, Paris, France) and coauthors in this week’s Nature (1998; 393: 537–44). The development of DNA vaccination, the use of secreted or surfaceexposed proteins as immunogens, and the attenuation of M tuberculosis for use in vaccines should all progress quickly now that the full sequence is known (http://www.sanger.ac.uk/). The complete genome sequence of 4·4 million basepairs was mostly elucidated at the Wellcome Trust Pathogen Unit (Sanger
THE LANCET • Vol 351 • June 13, 1998
Centre, Cambridge, UK), but scientists in France, Denmark, and the USA helped convert raw sequence data into information on the biology of M tuberculosis. 3924 open-reading frames have been identified, accounting for about 91% of the genome’s coding capacity. Precise functions have been assigned for about 40% of the predicted proteins by comparison with known sequences. Another 44% of the sequences have some similarity to known proteins. The remaining 16% are unique to M tuberculosis and may account for specific mycobacterial functions. 10% of the coding capacity of the genome encodes two large unrelated families of acidic, glycine-rich
proteins. The scientists speculate that these proteins could be “the principal source of antigenic variation” in M tuberculosis and that the glycine-rich proteins “might interfere with immune responses by inhibiting antigen processing”. Both these possibilities need to be considered when designing new vaccines. The usefulness of this new resource does not stop at vaccination. The genome contains many potential drug-resistance genes and numerous genes involved in cell-wall synthesis, all of which may be good drug targets. The sequence also indicates how M tuberculosis can persist in tissues for long periods of time. Jane Bradbury
1789