It beat smallpox. So now what else can it do?

Genetically altered, the anti-smallpox virus vaccinia can fight many other diseases, writes Bernard Dixon

Is smallpox vaccine due for a comeback? It may seem perverse to ask such a question in 1996. This is the 200th anniversary of Edward Jenner's successful vaccination of young James Phipps, which led to the widespread adoption of Jenner's method of preventing smallpox by infecting people with the related cowpox virus (vaccinia). Two centuries later, having eradicated smallpox using Jenner's technique, the World Health Organisation has announced that the two remaining laboratory stocks of the virus are to be destroyed.

With smallpox gone, there might seem to be little further use for vaccinia. But many other viruses continue to cause disease and death on a vast scale throughout the world. And one means of combating them may be to use genetically altered forms of vaccinia.

One expert who believes so is Enzo Paoletti. More than 10 years ago he discovered how to insert genes from other microbes into the DNA of vaccinia. In principle, if such an inserted gene normally produces a particular protein in the donor microbe, then it could do so in the cells of its new host too. And if that protein, in its original place, induced an infected animal to produce antibodies, the augmented vaccinia virus might do the same thing.

It worked. Scientists have since engineered several such "recombinant vaccines". One is a version of vaccinia designed to provoke immunity against rabies when taken by mouth. It has been distributed in several parts of Western Europe, injected into chicken heads left to be eaten by wild foxes, which can carry rabies. Many foxes took the bait and the disease is virtually extinct in Belgium.

Although such vaccines appear to be safe, scientists remain cautious about the prospects of using similar ones in humans, or in animals in contact with humans. First, the procedure is not trouble-free. At the injection site, vaccinia can cause unpleasant reactions, which are likely to be severe in individuals whose immune systems are impaired - by Aids, for example, or by drugs given to prevent the rejection of transplanted organs. Second, it is theoretically possible that a genetically altered vaccinia virus could pass from humans to wildlife, or interact with related viruses, with uncertain consequences.

Paoletti believes that an alternative approach may prove more acceptable and equally effective: to use viruses that have the advantages of the first generation of recombinant vaccines, but none of their disadvantages. Several are being developed which have virtually no side-effects, provoke immunity and, like conventional vaccinia, are "live"; they do not reproduce (or do so poorly) in recipients' cells and so cannot spread to other animals.

As a basis for one range of vaccines, Paoletti and colleagues have removed several regions of DNA from vaccinia that it require to multiply harmfully. Known as NYVAC, the resulting virus retains the capacity to grow normally in chick embryo cells, yet can scarcely grow at all in human and other animal cells. NYVAC does not produce inflammation at the injection site, and has negligible ill-effects, even in mice whose immune systems have been compromised. When researchers incorporated into NYVAC relevant genes taken from Japanese encephalitis virus and equine influenza virus, the resulting vaccines protected pigs and horses respectively against these infections.

Another strategy, pioneered by the Virogenetics Corporation, focuses on vaccinia-related viruses that normally infect birds. These too can be genetically altered so that they immunise various mammals against other microbes, even though the viruses do not multiply in mammalian cells. A modified canarypox virus, for example, has protected dogs and cats experimentally against rabies.

A recently recognised use for recombinant poxviruses is in cancer treatment. Many types of tumour cell have on their surface antigens - proteins characteristic of those tumours - which can induce the body to make antibodies. Unfortunately, the response of the immune system to such antigens is normally weak or non-existent. However, a poxvirus carrying not only a tumour antigen but also a cytokine (a natural substance that heightens the immune response) might provoke the production of sufficient antibody to attack a patient's tumour.

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