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The Cancer Journal - Volume 6, Number 1 (Januay-February 1993)


Why is an AIDS vaccine taking so long?

We are now almost completely certain that AIDS is an infectious disease, that the micro-organism responsible is a verus called HIV, of which two very similar variants, HIV1 and HIV2, have been identified. However, attempts to develop a vaccine which would protect against a first infection and, if possible, increase the natural immunity of sero-positive patients against the continuous presence of the virus have so far been unsuccessful.

Most effective antiviral vaccines are live attenuated viruses, the best known being the original vaccination which reduced smallpox epidemics and later allowed the disease to be completely wiped out. Smallpox was a highly infectious acute illness, often fatal, caused by a virus which was genetically stable and which disappeared from the organism in survivors.

In the case of AIDS, the genetic instability of the virus, and the fact that it remains after a first infection in (almost) all sero-positive subjects mean that vaccination is a very difficult problem, but not an unsurmountable one. From the beginning, two directions of research were followed: 1) the search for a highly immunogenic antigen common to the innumerable mutants of HIV; 2) the use of a live attenuated virus capable of inducing a first infection which is strongly immunizing but nonpathogenic, which would protect against all the variants of the virulent HIV.

This second approach has been abandoned for fear of the risks involved in using live attenuated viruses for preventive immunization: resurgence of virulence because of the high mutation rate of HIV and the risk of persistent infection with the attenuated virus causing a disease as serious as "natural" AIDS, especially in sero-positive subjects.

In a paper published in Science in December 1992, which was also the subject of a commentary in the same issue, Daniel et al. (1) report a protective effect obtained after immunization with a live attenuated virus against SIV (Simian Immunodeciency Virus), a virus similar to HIV which causes fatal immunodeficiency in the rhesus monkey. By doing so they re-opened the way towards protective or curative immunization with a live attenuated virus against AIDS, after a six or seven-year gap.

What happened during this period to prompt renewed research into attenuated viruses? The failure of the first strategy chosen and the resulting frustration were the main reasons. By using an SIV attenuated by deletion, Daniel et al. have avoided the risk of a reversion to virulence. Of course, the innocuity of the attenuated virus can be demonstrated in the case of SIV, because the virulent form of SIV brings about a fatal disease in the monkeys. An attenuated strain can therefore be characterized. At the moment this is not possible for HIV, because no direct animal model exists.

The attenuated SIV was obtained by Daniel et al. by means of the deletion of one of the non essential accessory genes of SIV: the nef gene. Four other non essential accessory genes exist: vif, vpr, vpx and vpu.As for nef, a loss of function of one of these genes does not prevent the virus from replicating. These genes are also found in HIV. It seems that when deprived of a functional nef gene SIV becomes attenuated and suitable for immunization against the virulent wild-type strains of SIV.

If this result is confirmed, it is now possible to imagine the development of an live attenuated anti-HIV vaccine. This calls for some serious thinking about strategy and an open debate on the various possibilities and their ethical implications.

One burning question remains: could this course have been taken in 1986? Were non essential accessory genes known and would it have been possible to prepare attenuated HIV? I invite my readers to perform a short literature survey which will enlighten them on this point. Why has the live attenuated vaccine approach been ignored up to now?

What were the factors which led to this option being abandoned from the beginning? Could it be that the modern trend of preferring sophisticated techniques worked against a research direction considered too "old-fashioned"?

Did the scientific decision-makers evaluate the risks correctly? The worst thing we can do in this case is to unjustifiably rewrite history. However, it is difficult not to bring into question the way in which such decisions are made, while whole-heatedly supporting scientists who have the courage to dissociate themselves from ready-made ideas.

Jean-Claude Salomon
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1- Daniel MD, Kirchhoff F, Czajak SC, Sehgal PK, Desrosiers RC. Protective effects of a live attenuated SIV vaccine with a deletion in the nef gene. Science 258, 1938-1941, 1992.