Development of vaccines
Modified live (mlv) and inactivated viral vaccines have a long history. In recent years, however, it has become customary to start developing and producing vaccines as soon as a new virus has been identified and adapted to growth in cell culture. In my view, this has resulted in a number of useless, if not dangerous vaccine preparations. One remarkable example is the field application of a modified live African Swine Fever (ASF) virus vaccine in Spain and Portugal, which almost led to the perpetuation of ASF on the Iberian peninsula ([12], and references therein).

Another example is the case of a canine coronavirus (CCV) vaccine. Although no disease could be associated with CCV infection [26], much effort was invested into developing a vaccine. To demonstrate its efficacy, immunized and control dogs were treated with dexamethasone after challenge, which resulted in diarrhoea in most (80%) control animals, as well as in some (15%) vaccinees [9]. Using this approach it was shown that dogs could be protected from a disease that does not even exist in nature.

The influenza viruses - much underestimated in veterinary virology - may serve as a third example. Between 1985 and 1991, several subtype H1N1 influenza A viruses had been isolated from patients in Mongolia. Characterization by sequence analysis [3] showed that these isolates were most closely related to strains isolated from diseased camels in the same region at the same time. The camel viruses were apparently derived from a UV-inactivated reassortant vaccine (PR8/USSR/77) that had been prepared for humans (in Leningrad, 1978) and used in the Mongolian population. The evidence was convincing: a reassortant between two human influenza virus strains had caused severe epizootics in camels, a species previously unknown to be a natural host for influenza A viruses.

Which lessons should we take home from these incidents? I suggest the following: (i) there is a need for better vaccines (Tab. 2) (ii) vaccine development should take the natural co-evolution of viruses and their hosts into account (iii) results obtained in model studies should be interpreted with caution (iv) it is very clear that mistakes have occurred in the past and more are bound to happen in the future. However, these mistakes should not discourage us. Vaccine development should continue with prudence and forethought, keeping the Japanese proverb in mind: "Vision without action is a daydream. Action without vision is a nightmare".

Indeed, progress has recently been achieved in developing novel vaccination strategies, epitomized by DNA or RNA vaccines (reviewed in [15]) and by the BAC-VAC principle [25]. BAC-VAC refers to an artificial bacterial chromosome harbouring the entire genome of herpes simplex virus type 1 (fHSVDpac), with minor deletions. The most important deletion concerns the signals for packaging of the viral DNA into virions. This bacterially cloned viral DNA is infectious and leads to replication, protein synthesis and virus particle formation upon gene gun application. However, the progeny is not infectious, because the viral DNA cannot be packaged. This single-cycle replication was found to induce cytotoxic T-cells (CTL), antibodies, and protection in a manner almost indistinguishable from immune reactions after mlv immunization - and it proved superior to inactivated or conventional DNA vaccines. Specifically, 1.5 mg of fHSVDpac coated to gold particles yielded the same amount of CTLs as 10⁹ TCID₅₀ of DISC HSV-1 [17], but five times higher antibody titers and antibodies of all isotypes; gB-specific CTLs could even be measured without previous restimulation in vitro. BAC-VAC immunized mice were protected against an intracerebral (i.c.) challenge infection with 200 LD₅₀ of HSV-1, which leads to disease and death in control animals. Protection was cell-mediated, since serum transfer had no effect.

Apart from its potential to induce an immunity similar to that after infection, BAC-VAC is intrinsically safe: if ever the packaging signals would be restored by recombination during co-infection with a wild type virus, the immune system would profit from a lead over the multiplication of the recombinant, and development of disease or even spread of the vaccine virus would be quite unlikely.

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