AIDS RESEARCH AND HUMAN RETROVIRUSES Volume 8, Number 8, 1992 Mary Ann Liebert, Inc., Publishers
Summary of the SIV Working Group ALAN M. SCHULTZ
for the simian immunodevirus (SIV) model in AIDS vaccine development had two major thrusts: one to debate a scientific question and the other to address a management issue. Representatives of over a dozen primate facilities, both domestic and European, which employ this model provided a full range of opinions. The scientific issue focused on the significance of a large body of successful SIV/macaque vaccine experiments which have employed whole inactivated virus as the vaccine. These experiments had been questioned by a presentation in the general session which showed that 50% of macaques could be protected from challenge by immunization merely with the cells that had been used to produce both the vaccine and the challenge virus, without requiring the presence of SIV antigens in the vaccine at all. This result suggested that immune responses in the immunized macaques to nonviral, cellular antigens common to the whole virus vaccine preparation and to the challenge virus stock could account for a major proportion of the highly successful protection experiments. At the workshop, these new experiments were described and critiqued in detail, and questions were raised concerning vaccine dose and schedule of administration and challenge. Several alternative explanations of the data were
Theficiency
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WORKSHOP ON MAJOR ISSUES
proposed. Vaccination of macaques with whole, killed vaccine preparations has certainly induced protection from lethal challenge with SIV in a very large number of experiments. What was at issue now is whether this body of evidence indicates that progress has been made toward obtaining a human vaccine against AIDS. For the SIV in these vaccines has always been grown in human T-cell lines, and similarly the SIV used for challenge of the immunized macaques has also been grown in either human T-cell lines or primary human lymphocytes. Thus both the vaccine and the challenge virus contain human cellular antigens that are "foreign" to the macaques. But humans are exposed to HIV from human cells. If macaque responses to the "foreign" antigens prove to be essential for protection, then it is not clear that this vaccine approach will be equally successful in humans. First, it was pointed out in the workshop that three other vaccine approaches in the SIV model have also been successful: an epitope-based recombinant vaccine, a live recombinant vaccinia virus coupled with boosting with recombinant subunit
Vaccine Research &
Development Branch. BRDP,
protein, and a transiently infectious SIV
molecular clone acting attenuated virus vaccine. None of these vaccines is compromised by the presence of human, nonviral antigens which could attribute their efficacy to this phenomenon. Thus, although only a few of these experiments have been performed so far, there is definite evidence from the SIV model that protection based on viral antigens alone is achievable by vaccination. Work on these and other vaccine approaches in the SIV model can continue without problems of interpretation caused by the presence of "irrelevant" human antigens. Second, it became clear that separating the contributions to protective immunity of nonviral and of SIV antigens in a whole, inactivated virus vaccine would be a daunting task. The major suggestion arising from the workshop was to avoid this dilemma and directly model the human situation in the macaques. If the inactivated SIV vaccine could be produced from macaque cells, and the SIV challenge likewise obtained from macaque cells, then any role of cellular antigens in the experiment would be the same as for an HIV vaccine produced in human cells and human exposure to HIV. It was agreed that the development of a CD4+ macaque cell line would be very valuable for this and other purposes. The second major issue regarded the future management of SIV model development. This model had developed as the result of several independent isolations of immunologically distinct strains of SIV. Consequently, work in the United States has proceeded with independent challenge stocks and virus strains which differ in biological properties. While this diversity has strengthened some aspects of the experimentation, it also has hampered cross-comparison of experimental results. For example, the different SIV strains will not grow well in all the same cell lines, thus limiting the usefulness of a number of assays. In contrast, a European Community initiative has distributed a common SIV,, challenge stock and a common pool of inactivated SIV and encouraged the development of reagents for this strain. A series of coordinated experiments now underway permits considerable latitude in the investigator's experimental design yet provides for a powerful cross-comparison of results among laboratories based on these common reagents. It was suggested in the workshop that a small number of common challenge stocks, defined and well-titered in as an
Division of AIDS. N1AID, Bethesda. MD.
1439
1440 macaques, would
SCHULTZ save
time and
resources
if it
were
done
centrally and made available. This would favor the development of common immunological assays, especially for neutralizing antibody, which would greatly benefit the whole field. Panels of infected animal sera as well as monoclonal and polyclonal antibodies for assay comparison at individual sites would also be valuable. Support for one or two central sites for analysis of sera from animals in all the different experiments was recommended. Major hurdles for the SIV model in the immediate future were agreed to be: development of mucosal challenge models (genital
Downloaded by Karolinska Institutet University Library from www.liebertpub.com at 02/02/19. For personal use only.
and rectal), the induction and measurement of local immune responses on mucosal surfaces, and a solution of the problem of
measuring neutralization and understanding why some SIV preparations appear not to be "neutralizable" in the current assays.
Address
reprint requests
to:
Alan M. Schultz Vaccine Research & Development Branch BRDP, Division of AIDS NIAID Bethesda, MD
Summary of the SIV Working Group ALAN M. SCHULTZ
for the simian immunodevirus (SIV) model in AIDS vaccine development had two major thrusts: one to debate a scientific question and the other to address a management issue. Representatives of over a dozen primate facilities, both domestic and European, which employ this model provided a full range of opinions. The scientific issue focused on the significance of a large body of successful SIV/macaque vaccine experiments which have employed whole inactivated virus as the vaccine. These experiments had been questioned by a presentation in the general session which showed that 50% of macaques could be protected from challenge by immunization merely with the cells that had been used to produce both the vaccine and the challenge virus, without requiring the presence of SIV antigens in the vaccine at all. This result suggested that immune responses in the immunized macaques to nonviral, cellular antigens common to the whole virus vaccine preparation and to the challenge virus stock could account for a major proportion of the highly successful protection experiments. At the workshop, these new experiments were described and critiqued in detail, and questions were raised concerning vaccine dose and schedule of administration and challenge. Several alternative explanations of the data were
Theficiency
Downloaded by Karolinska Institutet University Library from www.liebertpub.com at 02/02/19. For personal use only.
WORKSHOP ON MAJOR ISSUES
proposed. Vaccination of macaques with whole, killed vaccine preparations has certainly induced protection from lethal challenge with SIV in a very large number of experiments. What was at issue now is whether this body of evidence indicates that progress has been made toward obtaining a human vaccine against AIDS. For the SIV in these vaccines has always been grown in human T-cell lines, and similarly the SIV used for challenge of the immunized macaques has also been grown in either human T-cell lines or primary human lymphocytes. Thus both the vaccine and the challenge virus contain human cellular antigens that are "foreign" to the macaques. But humans are exposed to HIV from human cells. If macaque responses to the "foreign" antigens prove to be essential for protection, then it is not clear that this vaccine approach will be equally successful in humans. First, it was pointed out in the workshop that three other vaccine approaches in the SIV model have also been successful: an epitope-based recombinant vaccine, a live recombinant vaccinia virus coupled with boosting with recombinant subunit
Vaccine Research &
Development Branch. BRDP,
protein, and a transiently infectious SIV
molecular clone acting attenuated virus vaccine. None of these vaccines is compromised by the presence of human, nonviral antigens which could attribute their efficacy to this phenomenon. Thus, although only a few of these experiments have been performed so far, there is definite evidence from the SIV model that protection based on viral antigens alone is achievable by vaccination. Work on these and other vaccine approaches in the SIV model can continue without problems of interpretation caused by the presence of "irrelevant" human antigens. Second, it became clear that separating the contributions to protective immunity of nonviral and of SIV antigens in a whole, inactivated virus vaccine would be a daunting task. The major suggestion arising from the workshop was to avoid this dilemma and directly model the human situation in the macaques. If the inactivated SIV vaccine could be produced from macaque cells, and the SIV challenge likewise obtained from macaque cells, then any role of cellular antigens in the experiment would be the same as for an HIV vaccine produced in human cells and human exposure to HIV. It was agreed that the development of a CD4+ macaque cell line would be very valuable for this and other purposes. The second major issue regarded the future management of SIV model development. This model had developed as the result of several independent isolations of immunologically distinct strains of SIV. Consequently, work in the United States has proceeded with independent challenge stocks and virus strains which differ in biological properties. While this diversity has strengthened some aspects of the experimentation, it also has hampered cross-comparison of experimental results. For example, the different SIV strains will not grow well in all the same cell lines, thus limiting the usefulness of a number of assays. In contrast, a European Community initiative has distributed a common SIV,, challenge stock and a common pool of inactivated SIV and encouraged the development of reagents for this strain. A series of coordinated experiments now underway permits considerable latitude in the investigator's experimental design yet provides for a powerful cross-comparison of results among laboratories based on these common reagents. It was suggested in the workshop that a small number of common challenge stocks, defined and well-titered in as an
Division of AIDS. N1AID, Bethesda. MD.
1439
1440 macaques, would
SCHULTZ save
time and
resources
if it
were
done
centrally and made available. This would favor the development of common immunological assays, especially for neutralizing antibody, which would greatly benefit the whole field. Panels of infected animal sera as well as monoclonal and polyclonal antibodies for assay comparison at individual sites would also be valuable. Support for one or two central sites for analysis of sera from animals in all the different experiments was recommended. Major hurdles for the SIV model in the immediate future were agreed to be: development of mucosal challenge models (genital
Downloaded by Karolinska Institutet University Library from www.liebertpub.com at 02/02/19. For personal use only.
and rectal), the induction and measurement of local immune responses on mucosal surfaces, and a solution of the problem of
measuring neutralization and understanding why some SIV preparations appear not to be "neutralizable" in the current assays.
Address
reprint requests
to:
Alan M. Schultz Vaccine Research & Development Branch BRDP, Division of AIDS NIAID Bethesda, MD
