AIDS vaccines in clinical trials

A number of approaches are being assessed with regard to developing an effective AIDS vaccine. No safe attenuated form of the virus has been recognized to date, nor is one likely to be developed in the foreseeable future. The high level of mutation associated with HIV would, in any case, heighten fears that spontaneous reversion of any such product to virulence would be possible.

The potential of inactivated viral particles as effective vaccines has gained some attention, but again fears of accidental transmission of disease if inactivation methods are not consistently 100 per cent effective have dampened enthusiasm for such an approach. In addition, the stringent containment conditions required to produce large quantities of the virus render such production processes expensive.

Not withstanding the possible value of such inactivated viral vaccines, the bulk of products assessed to date are subunit vaccines. Live vector vaccines expressing HIV genes have also been developed and are now coming to the fore (Table 13.12).

Much of the preclinical data generated with regard to these vaccines entailed the use of one of two animal model systems: simian immunodeficiency virus infection of macaque monkeys and HIV infection of chimpanzees. Most of the positive results observed in such systems have been in association with the chimp-HIV model. However, no such system can replace actual testing in humans.

Most of the recombinant subunit vaccines tested in the first half of this decade employed gp 120 or gp 160 expressed in yeast, insect or mammalian (mainly CHO) cell lines. Eukaryotic systems facilitate glycosylation of the protein products. Like all subunit vaccines, these stimulate a humoralbased immune response but fail to elicit a strong T-cell response. The failure to elicit a cell-based

Table 13.12 Some putative HIV vaccines which have made it to clinical trials

Vaccine preparation

Developing company

Inactivated viral particles rgp 120 subunit vaccines rgp 160 subunit vaccines rp 24 subunit vaccines

Live vaccines based on viral vectors

Octameric V3 peptide

Immune Response

Genentech/Vaxgen, Biocine, Chiron/Ciba Geigy MicroGenes Sys. Inc., Immuno-Ag. MicroGenes Sys. Inc.

Biocine, Merck, Sanofi Pasteur, Targeted Genetics UBI

response, in particular a cytotoxic T-cell response (now seen as critical to mounting an effective immune response), explains at least in part why subunit vaccines were a clinical disappointment.

Several HIV vaccine systems based upon live vectors have also been developed in an attempt to stimulate a significant T-cell, as well as B-cell, immune response. Both envelope and core antigens have been expressed in a number of recombinant viral systems. The clinical efficacy of these remains to be established. Expression in engineered vaccinia has been undertaken, but its use as an HIV vaccine is likely precluded by the fact that the virus can apparently disseminate and cause fatal encephalitis in immunosuppressed infected individuals. Modified vaccinia Ankara, canarypox and fowlpox viruses have come to the fore as vectors. These likely can produce sufficient protein to initiate both a humoral and cellular immune response during an abortive replication cycle in humans. A vaccination schedule variation of potential interest entails the use of a vector-based primary dose (to induce a cellular response in particular) followed by a subunit-based booster (to induce mainly a humoral response). Whatever the schedule however, the induction of effective (i.e. broadly neutralizing) antibodies remains a challenge, as the regions of HIV envelope proteins that are most highly conserved seem to be shielded from antibody access by loop structures and sugar side-chains on these surface proteins.

Large-scale clinical trials are likely to be the only way by which any HIV vaccine may be properly assessed. In addition, a greater understanding of the molecular interplay between the virus and immune system may provide clues as to the development of novel vaccine and/or therapeutic products. For example, a small proportion of infected individuals remain clinically asymptomatic for periods considerably greater than the average 10-15 years. An understanding of the immunological or other factors that delay onset of ARC/full-blown AIDS in these individuals may aid in the design of more effective vaccines.

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