Introduction

Vaccines are normally considered to be a class of biological medicines. The vaccine materials are produced by living biological systems or biotechnological processes, and usually also tested in biological systems. Preventive or prophylactic vaccines are designed to induce sterilizing immunity against pathogenic organisms, and thus reduce the disease burden in humans and domestic animals. In general, these vaccines deliver the antigenic components of microorganisms and viruses in a manner that simulates to some degree the natural infection; this in turn stimulates the immune system to develop neutralizing antibodies and protective T-cell responses that persist in the long term. The degree to which individual vaccines are effective for their intended purpose depends on a number of factors, including antigenic structure, live-attenuated versus killed vaccine, adjuvant effects, mode of delivery, age of recipient, and disease target. Efficacy is thus often difficult to predict or to measure accurately, especially at the nonclinical testing phase of vaccine development, and usually remains uncertain until substantial evidence for it accrues from clinical trials. Nevertheless, it is crucial that experimental testing ahead of clinical usage is carried out in order to assess both potential efficacy and safety. Suitable animal models are frequently the means of choice for determining efficacy and safety, but the great social debate on the use of animals in scientific research, and legal and economic pressure to reduce usage at all costs, has emphasized the need for appropriate, valid in-vitro testing methods.

While it is evident that some animal tests are difficult to justify and/or have serious shortcomings with regard to their prediction of efficacy in humans, it is very important that any in-vitro tests developed to replace or support them are scientifically validated, and do not themselves suffer shortcomings. For instance, for certain single-protein vaccines (e.g., hepatitis B virus vaccine) the amount of antigen (hepatitis B virus surface antigen {HBsAg}) may be determined by immunoassays [1]. The antigen concentration is then assumed to be a direct measure of the amount of immunogen. However, variable production methods of hepatitis B virus vaccine can lead to unexpected changes to the amount of antigen recorded in the immunoassay, without concomitant changes in immunogenicity of the vaccine [1, 2]. These cell-free tests appear also to be of little use for evaluating the efficacy of more complex vaccines, such as inactivated- and live-attenuated-viral vaccines. For example, several collaborative studies of the potency/efficacy of inactivated polio vaccines have attempted to relate the amount of antigen to immunogenicity in animal models and in humans, but have failed to identify a single antigen measurement method that can be applied to all of the different vaccines available [3, 4]. As alternatives, in-vitro tests in cell lines or primary tissues can sometimes yield informative data on potential efficacy. Here, the aim is to measure vaccine potency (or some other surrogate parameter) that can be linked to vaccine efficacy or correlates of protection.

There are three main scenarios where such testing might be appropriately carried out:

• The use ofmostly attenuated live viral vaccines and viral/plasmid vector vaccines expressing a foreign (heterologous) antigen(s). Suitable mammalian cell lines are infected/transfected with the vaccine, and the amount of the intended antigen(s) measured at selected time points.

• The testing of blood leukocytes from animals/humans following immunization with the vaccine. Estimations ofT-cell activation, for example, interferon-gamma (IFN-y) production, the generation of specific cytotoxic T lymphocytes (CTL), following antigenic stimulation in vitro are among the immunological tests carried out to assess whether a vaccine is effective, or not.

• A form of in-vitro immunization where lymphoid cells/tissues/organoids are exposed to the vaccine to stimulate quantifiable immune responses; this is more for consideration in the future.

This aim of this chapter is to consider the relevance and validity of in-vitro testing methods in evaluating the potential efficacy of prophylactic vaccines. Certain aspects of such testing also apply to therapeutic vaccines - vaccines administered after infection by pathogen or during disease progression, for example, the so-called "cancer vaccines" - but these will be considered only briefly. Specific examples are used to illustrate vaccination regimes and assay methods. Since one of the main current foci of vaccine development is in the human immunodeficiency virus type 1 (HIV-1) field, and because the types of cell-based assays used to evaluate potential preventative HIV-1 vaccines are applicable to several novel vaccines against other pathogens, this clinical research area will be used to provide and illustrate assay methods and discussion.

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