Developing and Manufacturing Attenuated Live Bacterial Vaccines - Specific requirements must be met during preclinical and clinical development, as well as manufacturing and release testing of LBVs. -

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Developing and Manufacturing Attenuated Live Bacterial Vaccines
Specific requirements must be met during preclinical and clinical development, as well as manufacturing and release testing of LBVs.


BioPharm International Supplements


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. On the other hand, the issues of performing field studies in absence of the pathogen were highlighted with the example of CVD 103-HgR.

The challenges of manufacturing vaccines originating from the last century were demonstrated with the example of the BCG vaccine. Although novel manufacturing techniques may exist, their implementation will probably require new field trials, and hence, vaccine manufacturers are likely to stick to the historical technologies.

There are several requirements to be fulfilled during the development and cGMP manufacturing of live attenuated vaccines. We have listed the most important challenges and provided examples of how they can be met.

At the time when this article was written, GUIDO DIETRICH was vice president of operations at Berna Biotech AG, Berne, Switzerland. He currently is the director of bulk technologies at GlaxoSmithKline Biologicals, Wavre, Belgium, ANDRE COLLIOUD is the vice president of industrial development at Crucell NV, Berne, Switzerland, and SIMON A. ROTHEN is the CEO of Sartec GmbH, Thoerishaus, Switzerland, +32-10-85-3625,

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