Production of the Viruses and the Components of Viral Vaccines

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Chapter: Pharmaceutical Microbiology : The Manufacture And Quality Control Of Immunological Products

Viruses replicate only in living cells, so the first viral vaccines were necessarily made in animals: smallpox vaccine in the dermis of calves and sheep, and rabies vaccines in the spinal cords of rabbits and brains of mice.


PRODUCTION OF THE VIRUSES AND THE COMPONENTS OF VIRAL VACCINES

 

Viruses replicate only in living cells, so the first viral vaccines were necessarily made in animals: smallpox vaccine in the dermis of calves and sheep, and rabies vaccines in the spinal cords of rabbits and brains of mice. Such methods are no longer used in advanced vaccine production; the only intact animal hosts that are still used are embryonated hens’ eggs. Almost all the virus that is needed for viral vaccine production is obtained from cell cultures infected with virus of the appropriate strain.

 

i)  Growth of viruses

 

Embryonated hens’ eggs are still the most convenient hosts for growth of the viruses that are needed for influenza and yellow fever vaccines. Influenza viruses accumu-late in high titre in the allantoic fluid of the eggs, and yellow fever virus accumulates in the nervous system of the embryos. A few bacterial vaccines, e.g. against rickettsial and chlamydial agents, are also prepared in embryonated eggs. It is important to use eggs from disease-free flocks and emphasis is placed on screening the latter for various avian viruses. The allantoic fluid or embryos must be harvested under conditions that minimize extraneous microbial contamination.

 

Where cell cultures are used for virus production, they must be of known origin, obtained from validated sourcesand shown to be free of extraneous agents. The mediaused in their production should not contain componentsof human or animal origin, unless the latter are from TSE-free sources.

 

ii) Processing of viral harvests

 

The processing of the virus-containing material from infected embryonated eggs may take one of several forms. In the case of influenza vaccines the allantoic fluid is centrifuged to provide a concentrated and partially purified suspension of virus. This concentrate is treated with organic solvent or detergent to split the virus into its components when split virion or surface antigen vaccines are prepared. The chick embryos used in the production of yellow fever vaccine are homogenized in sterile water to provide a virus-containing pulp. Centrifugation then precipitates most of the embryonic debris and leaves much of the yellow fever virus in an aqueous suspension. Further purification can then be performed as required.

 

Cell cultures provide infected fluids that contain little debris and can generally be satisfactorily clarified by filtration. Because most viral vaccines made from cell cultures consist of live attenuated virus, there is no inactivation stage in their manufacture. There are, however, two important exceptions: inactivated poliomyelitis virus vaccine is inactivated with dilute formaldehyde or β-propiolactone and rabies vaccine is inactivated with β-propiolactone. The preparation of these inactivated vaccines also involves a concentration stage—by adsorption and elution of the virus in the case of poliomyelitis vaccine and by ultrafiltration in the case of rabies vaccine. When processing is complete the bulk materials may be stored until needed for blending into final vaccine. Because of the lability of many viruses, however, it is necessary to store most purified materials at temperatures of −70°C.

 

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