Comment AIDS vaccine research in the U K The UK Medical Research Council initiated a Directed Programme, aimed at developing vaccines for prevention and drugs for treatment o f H I V infection and AIDS, in April 1987. This is a single collaborative research programm e encompassing work in about 100 UK laboratories together with a small number in Europe and the USA. The third annual workshop for the programme, held at the University of Sheffield in September 1989, which brought together nearly 400 scientists, technical staff and students, as well as representatives o f other national A IDS research programmes, showed that the Directed Programme is now well established and productive, making important contributions to the worldwide effort to control AIDS.
Enabling research The Directed Programme's scientific strategy was set out in 19881 . Basic studies of human immunodeficiency viruses (HIVs) and their interaction with the immune system provide essential underpinning for the rest of the Programme's work, whether oriented to vaccines or drugs. Examples of this type of work include documenting the variability of the sequence of virus nucleic acid and exploring its biological significance; discovery of T cell epitopes on virus proteins, and studies on the function of HIV regulatory proteins (tat, rev, vii', etc.).
Production of virus antigens Isolated virus antigens are needed both for study of their immunogenic properties and for structural studies aimed ultimately at designing antiviral agents. Recombinant DNA technology is being used to prepare all the major HIV components in a variety of expression systems, including chinese hamster ovary (CHO) cells, the baculovirus insect cell system, Escherichia coli and yeast. Optimizing expression, developing suitable purification methods and scaling up production is proving to be a lengthy business, but rewards are now being reaped. Much of this work involves close collaboration
Dr J. Cope is at present head of the AIDS Secretariat, Medical Research Council, London W1N 4AL, UK 0264-410X/90/080003-02$03.00 ~;) 1990 Butterworth & Co. (Publishers) Ltd
with biotechnology or pharmaceutical companies such as Celltech Limited, British Biotechnology Limited, Evans Medical Limited and American Biotechnologies Inc.
Immunogenicity studies Small animals are being injected with HIV antigens to study the humoral immune response to individual HIV components and in particular to investigate the production of neutralizing antibodies. The significance of virus neutralization in vitro remains unclear though many scientists continue to believe it to be an important indicator of potential vaccine efficacy. Purifed antigens are also being used to raise monoclonal antibodies and polyclonal sera for use as laboratory reagents throughout the Directed Programme.
Two centres in the UK are using SIV in macaques (either cynomolgus or rhesus) and have demonstrated the occurrence of an AIDS-like illness in infected animals. The possibility of an HIV-2-cynomolgus model is also being explored. An important early experiment will be to test whether an inactivated whole virus vaccine can protect against infection in one of these models. While such a vaccine strategy would not be feasible foi" use against HIV in man, due to the difficulty of demonstrating 100% inactivation, it could provide evidence that protection is possible, and with it considerable encouragement for AIDS researchers. Work of this kind is also being undertaken in the US; close contact will continue to be maintained to make the best use of the resources available on both sides of the Atlantic.
Adjuvants Adjuvants have been somewhat neglected as a subject for research in the past. However, the advent of simple recombinant vaccines emphasizes the need for safe and effective adjuvants. Within the Directed Programme, such work is at an early stage but will evolve parallel with the production of HIV and SIV antigens and their evaluation in animals.
AIDS reagent project Animal models For preliminary studies of the possible protective efficacy of candidate vaccine materials an animal model system is needed. The most convenient type of model - a rodent susceptible to HIV infection - is not available at present although it appears that encouraging results are being obtained in the US with scid-hu transgenic mice. While keeping in touch with these developments the MRC programme is currently concentrating its efforts on development of model systems using simian immunodeficiency virus (SIV) and feline immunodeficiency virus (FIV).
An important feature of the AIDS Directed Programme is the Reagents and Resources Centre based at the National Institute for Biological Standards and Control (NIBSC) at Potters Bar. Its role is to provide scientists working within, or associated with, the programme, a broad range of basic and specialized research reagents including cell lines, virus strains, molecular clones, monoclonal antibodies, recombinant proteins and peptides. It also identifies new reagent needs and arranges centralized production and supply. Participants in the programme are asked to deposit reagents produced in the course of their MRC funded work.
Vaccine, Vol. 8, February 1990
3
Comment
Materials may sometimes be made available to scientists outside the MRC programme, but priority is given to those in the programme or collaborating closely with it. A catalogue of available reagents 2 was published in September 1989 and will be updated from time to time. The NIBSC reagent repository is one of three World Health Organisation (WHO) Reagent Centres, the others being at the National Institute of Allergy and Infectious Diseases (NIAID) in the US and the Institut Pasteur in Paris. A limited range of research reagents is offered by W H O on a worldwide basis through these three centres. NIBSC also provides a central laboratory facility for programme EVA, European Vaccine agent AIDS, a new initiative supported by the European Commission during 1989. The aim of this programme is to promote the development of AIDS research reagents and their use in vaccine-related research in Europe: the first call for proposals was issued in August 1989.
Collaborative research The philosophy of the AIDS Directed Programme is strongly collaborative.
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Vaccine, Vol. 8, February 1990
Laboratories participating in the programme are encouraged to work together and this is promoted through a number of specialist groups, which meet to discuss ideas and results. Newcomers to the programme must design their research projects not only to fit programme strategy but to complement other work in progress. Collaboration with pharmaceutical and biotechnology companies is promoted through the establishment of cooperative research agreements linking academic laboratories with commercial partners, as well as through the placing of contracts. A further dimension is added through international collaboration. Similar strategies for the development of vaccines and drugs are being pursued in a number of countries including the US, U K and others in Europe. Coordination and collaboration are essential to make the best use of the resources available. Formal collaborative agreements exist between the U K and France and West Germany while links with other countries are pursued through more informal contacts and a reciprocal travel agreement with colleagues in the US. The MRC also works closely with the W H O Global Programme on AIDS.
Clinical studies The MRC have been developing guidance documents on both the technical and ethical aspects of clinical trials of AIDS vaccines. These are freely available to interested parties on request and have been used as working papers at a World Health Organisation consultation 3. Preliminary studies of the safety and immunogenicity in man of potential vaccine antigens have been undertaken in a number of countries since 1987 though results to date have been disappointing. Such small-scale clinical studies will be useful for establishing methodology and producing some preliminary data. Studies of this kind are set to begin in the UK in 1990 though clinical trials of plausible candidate vaccines are still some years away.
References 1 AIDS Directed Programme Medical Research Council, London, UK, 1988 2 AIDS Reagent Project: Catalogue of Reagents Medical Research Council, London, UK, 1989 3 WHO Global Programme on AIDS: Statement from the consultation on criteria for international testing of candidate HIV vaccines 27 February-2 March 1989, Geneva, Switzerland. WHO/GPA/INF/89.8
Enabling research The Directed Programme's scientific strategy was set out in 19881 . Basic studies of human immunodeficiency viruses (HIVs) and their interaction with the immune system provide essential underpinning for the rest of the Programme's work, whether oriented to vaccines or drugs. Examples of this type of work include documenting the variability of the sequence of virus nucleic acid and exploring its biological significance; discovery of T cell epitopes on virus proteins, and studies on the function of HIV regulatory proteins (tat, rev, vii', etc.).
Production of virus antigens Isolated virus antigens are needed both for study of their immunogenic properties and for structural studies aimed ultimately at designing antiviral agents. Recombinant DNA technology is being used to prepare all the major HIV components in a variety of expression systems, including chinese hamster ovary (CHO) cells, the baculovirus insect cell system, Escherichia coli and yeast. Optimizing expression, developing suitable purification methods and scaling up production is proving to be a lengthy business, but rewards are now being reaped. Much of this work involves close collaboration
Dr J. Cope is at present head of the AIDS Secretariat, Medical Research Council, London W1N 4AL, UK 0264-410X/90/080003-02$03.00 ~;) 1990 Butterworth & Co. (Publishers) Ltd
with biotechnology or pharmaceutical companies such as Celltech Limited, British Biotechnology Limited, Evans Medical Limited and American Biotechnologies Inc.
Immunogenicity studies Small animals are being injected with HIV antigens to study the humoral immune response to individual HIV components and in particular to investigate the production of neutralizing antibodies. The significance of virus neutralization in vitro remains unclear though many scientists continue to believe it to be an important indicator of potential vaccine efficacy. Purifed antigens are also being used to raise monoclonal antibodies and polyclonal sera for use as laboratory reagents throughout the Directed Programme.
Two centres in the UK are using SIV in macaques (either cynomolgus or rhesus) and have demonstrated the occurrence of an AIDS-like illness in infected animals. The possibility of an HIV-2-cynomolgus model is also being explored. An important early experiment will be to test whether an inactivated whole virus vaccine can protect against infection in one of these models. While such a vaccine strategy would not be feasible foi" use against HIV in man, due to the difficulty of demonstrating 100% inactivation, it could provide evidence that protection is possible, and with it considerable encouragement for AIDS researchers. Work of this kind is also being undertaken in the US; close contact will continue to be maintained to make the best use of the resources available on both sides of the Atlantic.
Adjuvants Adjuvants have been somewhat neglected as a subject for research in the past. However, the advent of simple recombinant vaccines emphasizes the need for safe and effective adjuvants. Within the Directed Programme, such work is at an early stage but will evolve parallel with the production of HIV and SIV antigens and their evaluation in animals.
AIDS reagent project Animal models For preliminary studies of the possible protective efficacy of candidate vaccine materials an animal model system is needed. The most convenient type of model - a rodent susceptible to HIV infection - is not available at present although it appears that encouraging results are being obtained in the US with scid-hu transgenic mice. While keeping in touch with these developments the MRC programme is currently concentrating its efforts on development of model systems using simian immunodeficiency virus (SIV) and feline immunodeficiency virus (FIV).
An important feature of the AIDS Directed Programme is the Reagents and Resources Centre based at the National Institute for Biological Standards and Control (NIBSC) at Potters Bar. Its role is to provide scientists working within, or associated with, the programme, a broad range of basic and specialized research reagents including cell lines, virus strains, molecular clones, monoclonal antibodies, recombinant proteins and peptides. It also identifies new reagent needs and arranges centralized production and supply. Participants in the programme are asked to deposit reagents produced in the course of their MRC funded work.
Vaccine, Vol. 8, February 1990
3
Comment
Materials may sometimes be made available to scientists outside the MRC programme, but priority is given to those in the programme or collaborating closely with it. A catalogue of available reagents 2 was published in September 1989 and will be updated from time to time. The NIBSC reagent repository is one of three World Health Organisation (WHO) Reagent Centres, the others being at the National Institute of Allergy and Infectious Diseases (NIAID) in the US and the Institut Pasteur in Paris. A limited range of research reagents is offered by W H O on a worldwide basis through these three centres. NIBSC also provides a central laboratory facility for programme EVA, European Vaccine agent AIDS, a new initiative supported by the European Commission during 1989. The aim of this programme is to promote the development of AIDS research reagents and their use in vaccine-related research in Europe: the first call for proposals was issued in August 1989.
Collaborative research The philosophy of the AIDS Directed Programme is strongly collaborative.
4
Vaccine, Vol. 8, February 1990
Laboratories participating in the programme are encouraged to work together and this is promoted through a number of specialist groups, which meet to discuss ideas and results. Newcomers to the programme must design their research projects not only to fit programme strategy but to complement other work in progress. Collaboration with pharmaceutical and biotechnology companies is promoted through the establishment of cooperative research agreements linking academic laboratories with commercial partners, as well as through the placing of contracts. A further dimension is added through international collaboration. Similar strategies for the development of vaccines and drugs are being pursued in a number of countries including the US, U K and others in Europe. Coordination and collaboration are essential to make the best use of the resources available. Formal collaborative agreements exist between the U K and France and West Germany while links with other countries are pursued through more informal contacts and a reciprocal travel agreement with colleagues in the US. The MRC also works closely with the W H O Global Programme on AIDS.
Clinical studies The MRC have been developing guidance documents on both the technical and ethical aspects of clinical trials of AIDS vaccines. These are freely available to interested parties on request and have been used as working papers at a World Health Organisation consultation 3. Preliminary studies of the safety and immunogenicity in man of potential vaccine antigens have been undertaken in a number of countries since 1987 though results to date have been disappointing. Such small-scale clinical studies will be useful for establishing methodology and producing some preliminary data. Studies of this kind are set to begin in the UK in 1990 though clinical trials of plausible candidate vaccines are still some years away.
References 1 AIDS Directed Programme Medical Research Council, London, UK, 1988 2 AIDS Reagent Project: Catalogue of Reagents Medical Research Council, London, UK, 1989 3 WHO Global Programme on AIDS: Statement from the consultation on criteria for international testing of candidate HIV vaccines 27 February-2 March 1989, Geneva, Switzerland. WHO/GPA/INF/89.8
