PROOF-OF-CONCEPT STUDIES USING THE BIOCONJUGATE PLATFORM
The process to create new and efficacious bioconjugate vaccines in a cost-effective and efficient manner has potential, but
what is required is proof that such vaccines can be manufactured in commercial quantities, and that the vaccines produced
are safe and effective. The following are examples that demonstrate the potential of in vivo bioconjugate technology:
A bioconjugate against Shigella sp. was produced under GMP conditions and tested for the first time in humans. Shigella is an important pathogen responsible for serious diarrhea and dysentery, so a vaccine to prevent infection in the emerging
nations where it is present, as well as a vaccine for travellers, would provide a significant public health benefit. No vaccine
exists for Shigella, despite ongoing research in many laboratories for several years. Attempts at vaccine development, both conjugate and live-attenuated
bacteria, showed modest immunogenicity (8–11). Moreover, the technical hurdles to producing a conjugate vaccine with chemistry-based
methods are very high. The bioconjugate produced against the serotype, Shigella dysenteriae, was tested in 40 healthy volunteers and found to be well tolerated. Importantly, the vaccine demonstrated a significant
immunogenic response, and these immunogenicity data compare favorably to previous candidate vaccines tested against this pathogen.
This promising Phase I data provide clinical proof-of-concept that the bioconjugate produced under GMP conditions by an recombinant
DNA technology is safe and induces an immunogenic response in human.
The technology has been also applied for the development of a bioconjugate against Staphylococcus aureus. Nosocomial S. aureus infections represent up to 50% of all hospital infections. Moreover, methicillin-resistant S. aureus (MRSA) rates continue to increase dramatically. Despite significant research efforts undertaken by academic and pharmaceutical
laboratories to develop a successful vaccine, there has been no recorded sustained effectiveness against S. aureus has been generated by the experimental vaccines tested (12, 13). More recently, the DNA recombinant in vivo technology was able to conjugate, for the first time, the main polysaccharides of S. aureus to a selected protein carrier of the same pathogen (i.e, antigen protein of S. aureus). This bioconjugate vaccine has been tested in animals and produced functional antibodies inducing protection in mice bacteremia
and lethal pneumonia models (14). Although early, these results are promising considering recent clinical trial failures of
S. Aureus candidate vaccines. The combination of polysaccharide and protein antigen against the pathogen will increase the immunogenicity
of the vaccine at various stages and pathways of the infection, thus enhancing the possibility of protection.
These data demonstrate that this in vivo technology is a feasible approach for developing vaccines against challenging pathogens and offers the promise of improved
efficiency in general.
Antibacterial conjugate vaccines have become important tools for the public-health community to prevent serious bacterial
infections. However, the complex development and manufacturing process has limited the potential of this important class of
vaccine. This article describes a new in vivo process that incorporates a well-understood recombinant DNA technology in E. coli to manufacture bioconjugate vaccines. The process has demonstrated proof-of-concept in more than one bacterial pathogen,
including a first-in-man study. Research is currently in progress to develop additional vaccine candidates and advance them
into late-stage clinical trials.
Veronica Gambillara PhD is director of clinical and regulatory affairs at GlycoVacyn, Schlieren Switzerland, Veronica.Gambillara@glycovaxyn.com
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