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)
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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
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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
