Polysaccharide conjugate vaccine protein carriers as a “neglected valency” – Potential and limitations

The development of vaccines against polysaccharide-encapsulated pathogens (e.g. Haemophilus influenzae type b, pneumococci, meningococci) is challenging because polysaccharides do not elicit a strong and long-lasting immune response (i.e. T-cell independent). This can be overcome by conjugating the polysaccharide to a protein carrier (e.g. tetanus toxoid, cross-reacting material 197 [CRM]), which vastly improves the immune response and induces memory to the polysaccharide (T-cell dependent). Although it is well documented that protein carriers additionally induce an immune response against themselves, this potential “additional valency” has so far not been recognized. The only exception is for the protein D carrier (derived from non-typeable Haemophilus influenzae [NTHi]) used in a pneumococcal conjugate vaccine, which may have a beneficial impact on NTHi acute otitis media. In this review, we describe the immunogenicity of various protein carriers and discuss their potential dual function: as providers of T-cell helper epitopes and as protective antigens. If this “additional valency” could be proven to be protective, it may be possible to consider its potential effect on the number of required immunizations. We also describe the potential for positive or negative interference between conjugate vaccines using the same protein carriers, the resulting desire for novel carriers, and information on potential new carriers. The range of conjugate vaccines is ever expanding, with different carriers and methods of conjugation. We propose that new conjugate vaccine trials should assess immunogenicity to both the polysaccharide and carrier. Ultimately, this so-far “neglected valency” could be an exploitable characteristic of polysaccharide conjugate vaccines.