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


ABSTRACT

There are a number of specific characteristics to be considered when developing and manufacturing vaccines. This article discusses specific requirements to be fulfilled for three attenuated live bacterial vaccines (LBVs) including Mycobacterium bovis BCG vaccine against tuberculosis, Salmonella typhi Ty21a vaccine against typhoid fever, and Vibrio cholerae CVD 103-HgR vaccine against cholera. Special characteristics for these vaccines comprise the appropriate level of attenuation, the balance between safety and immunogenicity, the genetic stability of the organisms combined with environmental risk assessment, the challenge of old-fashioned upstream and downstream methods in combination with quality control of the final product, and the release requirements.


(Crucell NV)
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.1–3 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 cGMP requirements are increasing to guarantee the safety of vaccines being developed and produced. Using raw material of animal origin is avoided in the early-stages of research and development. Only few techniques such as nanofiltration and chromatography steps are applicable to viral removal. For viral inactivation, only formaldehyde treatment and beta-propiolactone inactivation are approved. The worldwide ban of preservatives such as thiomersal raised the standard for sterile production and supported the trend to monodose presentations.

To date, vaccines based on three different technologies are registered for human use: (1) whole inactivated vaccines containing entire killed bacteria or viruses, (2) subunit vaccines, containing only the relevant antigens of the pathogens in a highly purified form, and (3) live attenuated vaccines. The quality and safety requirements are even higher for live attenuated vaccines than for the killed and subunit vaccines. In this article, we will describe how vaccine developers and manufacturers solve the challenges related to manufacturing live attenuated vaccines.

Live Attenuated Vaccines

Live attenuated vaccines are among the most widely used vaccination technologies. Attenuated vaccines consist of bacterial or viral strains, which are weakened by stable mutations that allow the bacteria or viruses to infect humans only transiently. This transient infection elicits immune responses, while the vaccine strains are designed in such a way that they will not cause the symptoms of natural infection by the wildtype pathogen. There are a number of advantages of live attenuated vaccines in comparison to killed and subunit vaccines: (a) they mimic natural infection, therefore eliciting immune responses that are highly specific, effective, and long-lasting (b) they can prevent infection by the pathogen, not just disease symptoms, (c) in comparison to highly purified subunit vaccines, they are relatively cheap to produce and administer, and do not require sophisticated downstream processing or formulation with adjuvants, and (d) several live attenuated vaccines can be administered orally, which has a higher acceptance and better safety profile than injection with syringe and needle, and mimics natural infection better.


Table 1. Attenuated live bacterial vaccines licensed for human use
Three attenuated live bacterial vaccine (LBV) strains are currently licensed for human use: Mycobacterium bovis strain Bacille Calmette-Guerin (BCG), Salmonella typhi Ty21a, and Vibrio cholerae CVD 103-HgR. M. bovis BCG is the vaccine strain in the parenteral vaccine against human tuberculosis, S. typhi Ty21a represents the only oral vaccine against typhoid fever, and Vibrio cholerae CVD 103-HgR is the orally administered live vaccine against cholera (Table 1).4–6


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