In recent years, the vaccine market has experienced significant growth following the introduction of several novel bacterial
vaccines—more specifically conjugate vaccines—addressing unmet medical needs. These conjugate vaccines are safe and effective
against bacterial diseases and have been used in humans for many years. Although several serious bacterial infections, such
as Streptococcus pneumoniae and some Meningococcal strains, are prevented using conjugate vaccines, the underlying process of development and manufacture
has limited their scope. The method used for developing and manufacturing conjugate bacterial vaccines is based on chemical
conjugation technology. It is a complex chemistry-based process that, depending on the pathogen or serotype, is time-consuming
and expensive. A new approach has been developed to conceive and produce conjugate vaccines by employing recombinant DNA technology.
This technology enables the development and manufacture of conjugate vaccines, called bioconjugates, and addresses the limitations
of the current chemical conjugation process.
BACTERIAL CONJUGATE VACCINES: AN IMPORTANT MARKET IN BACTERIAL INFECTIOUS DISEASE
The vaccine market experienced significant growth over the past decade, with global revenues forecast to exceed USD $24 billion
in 2010 (1). Within the growing market, conjugate vaccines for the prevention of bacterial infections today account for over
25% of the total market. In 2009, two of the four leading vaccines by sales were the bacterial conjugate vaccines Prevnar
(Pfizer) for pneumococcal disease and Menactra (Sanofi Pasteur) for meningitis serogroups A, C, W-135, and Y. Together, these
two products alone accounted for 12% of global vaccine sales.
Despite the success of glycoconjugate vaccines, several important bacterial infections lack a vaccine. These pathogens are
responsible for significant morbidity, mortality, and cost to healthcare systems. Key pathogens that lack vaccines include
Staphylococcus aureus and Pseudomonas aeruginosa, both causing nosocomial infections; Neisseria meningitides type B; and many diarrheal pathogens such as Shigella sp., enterotoxigenic Escherichia coli (ETEC), and Salmonella sp.
THE LIMITATIONS OF CURRENT CONJUGATE VACCINE TECHNOLOGY
The conjugate is a large glycoprotein molecule consisting of a protein linked or conjugated to a polysaccharide. The sugars
are surface-exposed bacterial antigens to which the body will develop an immune response. The protein carrier is responsible
for eliciting a long-lasting immune response against the polysaccharide, leading to better protection against the target disease,
especially in young children (2). In chemical conjugation, the bacteria producing the polysaccharide and the protein carrier
are grown separately, then purified through multiple steps. The polysaccharide is then chemically bound to the protein carrier
(see Figure 1). This method faces the following challenges and limitations:
- Because the polysaccharide is produced by toxic bacteria, specialized and costly containment facilities are required. Moreover,
several purification steps are necessary to obtain an acceptable purity of the product, thus resulting in loss of material
throughout the process and decreased yields.
- Chemical coupling between the polysaccharide and the protein carrier results in a heterogeneous product which may still contain
some free polysaccharide that may interfere with the immune response to the conjugates. Any small change in the mixture affects
the characteristics of the vaccine, so the same mixture must be maintained throughout scale up and production—a manufacturing
and regulatory challenge.
- Chemical conjugation can change the structure of both the polysaccharide and the carrier protein, thus making them less immunogenic,
or in some cases, not immunogenic. Toxic polysaccharides must be chemically detoxified, often leading to further loss of immunogenicity
or increased safety concerns.
The net result is that chemical conjugate vaccines are restricted to certain targets, may induce suboptimal efficacy, are
difficult to develop, and are costly to produce. In addition, the growing resistance to antibiotics, the ever-increasing standard
of safety, and high development costs required to bring a product to market emphasize the need for new technologies to address
these challenges and fulfill the worldwide need for new vaccines.
Figure 1: Chemical method currently used for production of conjugate vaccines. (ALL FIGURES ARE COURTESY OF THE AUTHOR)