302 Subject Vaccine development

Furthermore, by comparing the gene expression profdes of healthy clinical subjects with those clinical subjects who experienced adverse reactions after administration of the vaccine, it will be possible to find differences in their immune responses and to identify biomarkers for these adverse reactions. These biomarkers can then be utilized in future vaccine development, diagnosis, and risk calculations. 

Chicz, R.M. and Urban, R.G. (1994). Analysis of MHC presented peptides applications in autoimmunity and vaccine development. Immunology Today, 15, 155-160 good review on a complicated subject. 

The safety of the cocaine vaccine TC-CD in former cocaine abusers has been evaluated in a Phase I clinical trial, and it was determined that the vaccine was well tolerated with dose-related increases in antibody levels.65 Two Phase II clinical trials have now been conducted.66,67 The vaccine was again well tolerated and subjects reported a reduction in cocaine s reinforcing effects. The antibody levels were detectable after the second dose, peaked at 8 to 12 weeks, and remained elevated for up to 6 months preliminary findings indicated a negative association between antibody level and cocaine use. Other anti-cocaine vaccines in development include a blocking antibody (ITAC-cocaine) and a monoclonal catalytic antibody (15A10). 

Some additional subunit vaccines are being developed, based upon internal viral polypeptides, particularly the p24 core protein. This was chosen as it is known to contain epitopes capable of eliciting a T cell response, and core proteins are generally less subject to antigenic drift than envelope proteins. 

Finally, technical models for approval of vaccines that cannot be tested on human subjects for efficacy and must rely on animal studies are only now being developed empirically. 

There are many countries that still use first-generation brain tissue rabies vaccine because of limited financial resources and where neurological complications after immunization still occur. The neurological effects produced by this type of vaccine are very variable. Sometimes a peripheral neuropathy occurs, while other vaccinees develop encephalomyelitis, dorsolumbar myelitis, ascending myelitis, hemiplegia, or general subjective neurological symptoms, such as stiffness of the neck or physical weakness. 

In this chapter the subject of scale-up is reviewed, which is taking small laboratory cultures (e.g. 10 ml) to industrial-scale processes (e.g. 10 000 litre), i.e. a 1 000 000-fold scale-up The aim of such scale-up is to provide more cells, and more cell product, in as efficient and cost-effective a manner as possible. Cell cultures have been used since 1954 for the production of human (e.g. polio, measles, mumps, rabies, rubella) and then veterinary (e.g. FMDV) vaccines (Griffiths, 1990a). Interferon was the next most important product to be developed, followed by monoclonal antibodies and a range of recombinant proteins. 

The ground rules for cellular characterization were set with human diploid cells and these particular substrates for vaccines are subject to guidelines developed by the WHO (1997). In turn, WHO guidelines have provided the parameters for characterization of heteroploid cells (WHO, 1987). It is therefore a natural progression that this level of characterization should also provide the basis for the characterization of master and working cell banks (see Chapter 1, section 1.3), even though this does present problems. 

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