4.1

INTRODUCTION

Viral vaccines are usually cell-culture–based medicinal products. As human viruses

require a human host to replicate, vaccine researchers use the knowledge of animal-

cell technology to develop existing and future vaccines.

Since the mid-twentieth century, numerous viral vaccines were developed to meet

important medical needs such as poliomyelitis, measles, congenital disease related to

rubella, or gastroenteritis due to rotavirus. Millions of lives have been saved, and the

morbidity associated with those viral infections has been reduced substantially [1].

In the history of vaccines, animal-cell technology had been demonstrated as a key

technology by the beginning of the twentieth century. The early progress made in tissue

culture had led to the isolation of certain viruses, such as the yellow fever virus. In that

period, tissue culture was based on the use of chicken eggs; in effect, the embryonic

tissue of chickens. The first vaccines for yellow fever and influenza were developed with

embryonated chicken eggs in 1930s. Later on, primary cells such as chicken-embryo

fibroblasts were used. In the 1950s, cell cultures derived from monkey cells were de-

veloped to propagate poliomyelitis viruses; and this pioneering work led to Enders,

Weller, and Robbins receiving the Nobel Prize in 1954. In the 1960s, diploid cell lines

were isolated and considered as safe for use of human vaccine [2].

During the 1970s, the use of continuous cell lines was highly debated, because

oncogenes had been discovered, and the DNA of continuous cell lines was per-

ceived as a threat. Some continuous cell lines were approved for some vaccines,

thanks to additional requirements being met.

Molecular biology opened the field to recombinant products. Some cell lines

were quickly identified as expression systems for recombinant products, such as

Chinese hamster ovary (CHO) cells.

During all these decades of viral-vaccine development and manufacturing, the

safety of the products, including the cell lines, was a critical question. The safety of

the viral vaccine remains the top priority, even though some risks associated with

the use of viruses have been mitigated.

The aim of this chapter is to review which cell lines are useful for vaccine manu-

facturing, and how they are selected. The review includes information on viral safety and

associated regulatory guidance; and on the analytical considerations for determining cell

line quality with respect to vaccine safety and to its performance in general.

4.2

BASIC AND TECHNICAL CONSIDERATIONS

4.2.1

BASIC CONSIDERATIONS (INCLUDING VACCINE TYPES AND CELL LINES)

Vaccine development is based on a strong knowledge of the antigen and its im-

munogenicity. To identify antigen targets, immunologists are helped by an in-depth

understanding of the natural disease the vaccine is intended to protect against. This

knowledge drives the identification of key antigens, which are usually proteins in the

case of viruses. Hence, their selection is also driven by the anticipated/desired im-

mune response, which can be either humoral, or cell-mediated, or a combination of

both. In the case of a humoral response, neutralizing antibodies against the pathogen

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Bioprocessing of Viral Vaccines