Mass production of viruses for vaccines

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The production of the types of vaccine discussed so far (live attenuated, inactivated, subunit and live recombinant) requires large quantities of virions; for most viruses these are produced in cell cultures. John Enders demonstrated in 1949 that poliovirus can be grown in primary monkey cell culture and this led to procedures for the mass production of poliovirus for the Salk and Sabin vaccines. It was subsequently found that some monkey cell cultures used for vaccine production had been harbouring viruses, including simian virus 40 (Section 22.3). It was therefore recommended that human cell cultures should be used for the production of vaccines for human use, though cell lines of monkey origin, such as Vero cells (African green monkey cells), are used for the production of some.

Another preference is for the use of diploid cell lines, rather than heteroploid cell lines that have been derived from tumours, as there are perceived risks associated with tumour-derived cells. Examples of human diploid cell lines used for production of vaccine viruses are MRC-5 (developed by the Medical Research Council in the UK) and WI-38 (developed by the Wistar Institute in the US). Both of these cell lines were derived from human lung fibroblasts.

Most of the cells are grown on surfaces such as parallel plates and small plastic particles. The virus inoculum is added to the cell culture at 0.1-10 pfu per cell and the maximum titre is usually reached 12 - 24 hours after inoculation. The manufacturer might expect a virus yield up to 100 000 times the inoculum.

Some viruses are mass-produced in chick embryos (Figures 2.1 and 24.4), either because no suitable cell culture system is available, or because such a system has been developed only recently. Influenza and yellow fever vaccines are produced in chick embryos that are inoculated by automatic systems. The yield of virus from each embryo provides sufficient virus for a few doses of vaccine.

For influenza virus vaccines, decisions have to be made each year as to which H and N subtypes of the virus to include, as new influenza strains with altered subtypes are constantly arising through antigenic drift (Chapter 20). New strains are monitored and characterized by Collaborating Centres for Influenza Reference and Research around the world, and the World Health Organisation recommends the strains that should be produced for the next batches of vaccine.

Newly isolated strains of influenza virus rarely grow well in chick embryos, so a reassortant (Section 20.3.3.c) between each new strain and a high-yielding strain is produced. A high-yielding strain that is commonly used is strain A/Puerto Rico/8/34 (an influenza A virus isolated in Puerto Rico in 1934). This strain evolved during passage in the laboratory; it has roughly spherical virions and it replicates well in chick embryos, in contrast to many wild-type strains, which have filamentous virions and replicate poorly in chick embryos. For vaccine production reassortants are selected that have the H and N genes of the new strain and the remaining genes of the high-yielding strain.

Table 24.1 Examples of viruses that are mass produced for vaccine manufacture

Vaccines for humans

Vaccines for animals


Foot and mouth disease


Marek's disease


Newcastle disease


Canine distemper




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