Introduction

A conjugate vaccine is a substance that is composed of a polysaccharide antigen fused (conjugated) to a carrier molecule. This enhances the stability and the effectiveness of the vaccine.

During the last three decades, the development and commercialization of conjugate vaccines against Haemophilus influenzae type b (Hib), pneumococcus, and serogroups C, A, W, and Y of meningococcus contributed to the virtual elimination of bacterial meningitis caused by the bacteria included in the vaccines and to the prevention of diseases that used to cause more than a million deaths annually.

History

Conjugate vaccines have been developed to induce a robust immune response against bacterial capsular polysaccharides (CPSs). CPSs are long polymers composed of many repeating units of simple sugars and serve as a protective external layer for many bacteria. Depending on the chemical composition of the repeating unit (usually composed of one to seven monosaccharides). Bacteria can synthesize hundreds of chemically and immunologically different polysaccharides. Antibodies against the polysaccharides of many pathogenic bacteria, such as meningococcus, Hib, and pneumococcus, protect people from disease. Vaccines composed of purified polysaccharides against meningococcus and pneumococcus were developed in the 1970s.

Mechanism of action

Briefly, after immunization, polysaccharides or conjugate vaccines are taken up by dendritic cells and transported to lymph nodes where, to induce an immune response, they need to engage both B and T cells and start the formation of germinal centers (GCs). GCs are sites within lymph nodes and the spleen where mature B cells proliferate, differentiate, and mutate their antibody genes through somatic hypermutation. To form GCs, three main cells are necessary: the polysaccharide-specific B cells expressing the antibody on their surface as a receptor [B cell receptor (BCR)]; the follicular helper T (Tfh) cells, which recognize the protein carrier antigen presented on the surface of B cells; and follicular dendritic cells (FDCs), which contain and present the antigen to the B cells. The GC reaction produces higher-affinity antibodies and switches the class of antibodies (e.g., from IgM to IgG) during a normal immune response to an infection or after vaccination. The actions occur in spatially distinct regions of the GC called the light and dark zones. B cell selection and activation occur in the light zone, and the proliferation and mutation of the antibody genes occur in the dark zone. Usually, B cells bind and extract protein antigens from the FDCs in the light zone and then internalize the antigens into the endosome, process them into small peptides, and load the peptides into the cavity of the major histocompatibility complex (MHC), which exposes the peptide on the surface of the B cells so that it can be recognized by the receptor of Tfh cell. The activated Tfh cell then provides help to the B cell by direct cell–cell interaction and by secreting cytokines. B cells retrieve the antigen by applying tensile force so that the stronger the BCR’s affinity for the antigen is, the larger the amount of antigen retrieved will be and the more intense the help received from the Tfh cells will be. Tfh cells also sense the affinity for the antigen loaded in the MHC, and the higher the affinity is, the higher the intensity of help provided to the B cells in the light zone will be and, thus, the selected B cells will undergo more cycles of replication in the dark zone and will have a more efficient affinity maturation.

Conclusion

If the Tcarb hypothesis is the primary mechanism to engage T cells in conjugate vaccines, we should be able to improve their immunogenicity by increasing the number of covalent junctions between the protein and the polysaccharide. Testing this hypothesis can be an opportunity to optimize the novel chemical or biological conjugation technologies that have been recently described.

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