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Introduction

DEVELOPMENT OF SALMONELLA VACCINE Abstract There are a number of specific characteristics to be considered when developing and manufacturing vaccines. Special characteristics for these vaccines comprise: 1. The appropriate level of attenuation, the balance between safety and immunogenicity, 2. The genetic stability of the organisms combined with environmental risk assessment, 3. The challenge of old-fashioned upstream and downstream methods in combination with quality control of the final product, and 4. The release requirements. Vaccination has proven to be the most efficient, cost-effective means for preventing a wide variety of infectious diseases. Vaccine development and manufacturing, however, poses several challenges. Inherent to all biological systems is the difficulty to achieve robust production processes guaranteeing reproducible efficacy and safety of the products. Highly automated bioprocess systems or advanced analytical systems used for closed-loop control may be a solution to overcome this. Yet these techniques are still not standard in the industrial environment or cannot be applied to vaccine production processes because of historical reasons, as some of the vaccines have been developed early in the previous century. Because vaccines are administered to healthy people, the efficacy and safety of vaccines are most important. Regulatory GMP (Good Manufacturing Practices) requirements are increasing to guarantee the safety of vaccines being developed and produced. ...read more.

Middle

Hence, vaccines have to undergo careful pre- and post licensure safety studies. 1. Regulatory Hurdles The vaccine must achieve the right balance between safety and immunogenicity. Additional issues include the potential for genetic reversion to partial or full pathogenicity, gene transfer into and out of the vaccine cells, and the potential risks for humans and the environment. For many vaccine candidates, the appropriate balance of attenuation and immunogenicity could not be met, and development of such candidates was consequently discontinued at an early stage of clinical evaluation. Hence, these safety issues have to be addressed very carefully during preclinical and clinical development. 1. Determining Safety and Efficacy In the case of Ty21a, safety and efficacy of the vaccine were demonstrated in a large number of clinical trials, with over 500,000 vaccinated children and adults in the US, Europe, Africa, Latin America, and Asia. Excellent tolerability and an overall protective efficacy of 67?80% were demonstrated for up to seven years in large field trials. The safety and tolerability profile of Ty21a was further confirmed in more than 200 million vaccinees during its more than 25-years of use worldwide. Recent post marketing surveillance has identified only mild and infrequent adverse events associated with Ty21a. ...read more.

Conclusion

Pharmacopoeia monographs are in place for the release testing of Ty21a. However, after internal testing and release by the vaccine manufacturers, each vaccine batch must undergo additional quality-control testing by regulatory authorities before it can be commercialized. Conclusion Live attenuated vaccines have numerous advantages over killed and subunit vaccines. However, they also have higher requirements regarding safety and quality. We have highlighted the challenges faced during preclinical and clinical development, as well as manufacturing and release testing for three attenuated live bacterial vaccines registered for human use?M. bovis BCG, S. typhi Ty21a, and V. cholerae CVD 103-HgR. When generating attenuated vaccines, attention must be given to the appropriate balance of attenuation and immunogenicity. We have demonstrated the progress in attenuation approaches from the empirical approach of the M. bovis BCG strain to the targeted attenuation of Ty21a and CVD 103-HgR. In the absence of correlates of protection of the vaccine, large Phase-3 field trials need to be conducted. Apart from ethical considerations caused by exposure of the trial participants to pathogens, potential side effects and safety issues are most prominent topics during the development and clinical trials of a vaccine. The orally administered Ty21a vaccine exhibits an excellent tolerability with an incidence rate of only 0.002% in addition to the absence of reversion to wildtype during the 30 years since its development. This clearly demonstrates the advantage of oral vaccination with a live attenuated vaccine. ...read more.

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