Conjugate Vaccine Adjuvants

A Conjugate Vaccine Adjuvants consists of a covalently conjugated antigen to a carrier protein. 

To elicit an immune response against protein/peptide antigens lacking T-cell epitopes, or against non-peptidic antigens, such as oligosaccharides, there is a need to conjugate these compounds covalently to a protein carrier that can supply T-cell epitopes in order to create a conjugate vaccine which triggers an effective immune response. Polysaccharides are not processed by “antigen presenting cells” or APCs, i.e. dendritic cells and macrophages, but they interact with B cells triggering antibody production in the absence of T cells, thus called T-independent antigens. Oligosaccharides are usually linked to a carrier protein to form conjugate vaccines, such as different inactivated bacterial toxins or toxoids, e.g. tetanus and diphtheria toxoids, to yield glycoconjugates, which are better immunogens than the oligosaccharides alone. Conjugation of the oligosaccharides to the carrier proteins would depend on their carbohydrate composition, for instance saccharides that carry carboxyl or amino groups can be conjugated to a protein using carbodimides. If the saccharide has only neutral sugars, it can be linked to a protein after a mild treatment with periodate to oxidize cis-hydroxyl groups and yield aldehyde groups, which can be linked to a protein’s amino group by reduction alkylation in the presence of cyanoborohydride. Alternatively, the saccharide can be linked to the protein by using either 1,1-carbonyldiimidazole (CDI) or 1-cyano-4-dimethyaminopyridinium (CDAP), to yield urethane and isourea bonds, respectively. However, while the conjugations with CDI need to perform in organic solvents that limit the saccharides’ solubility, conjugations with CDAP can be carried out in aqueous media, which allows good solubility for saccharides. As indicated before, peptides lacking T-cell epitopes can be linked covalently to proteins having those epitopes, such as serum albumin, edestin, thyroglobulin or KLH, using the carbodiimide method, alternatively, if the carrier protein has a carbohydrate it can be treated with periodate to oxidize the sugars and form an aldehyde, which can be linked by a primary amino group to the peptide. However, a potential problem of the periodate method is the formation of carrier protein aggregates, which may lead to insoluble aggregates.

Another type of useful conjugate vaccine is that made by covalently linking a protein or peptide to an immune modulating agent or adjuvant; where the adjuvant moiety can be a CpG oligonucleotide, a lipid A derivative, a polysaccharide such as a mannan, or some other type of immune stimulatory agent that can be linked to the antigen. Depending on the nature and size of the antigen and the adjuvant it would be possible to use one of the conjugation methods available. Advantages of antigen-adjuvant conjugates are i) a more focused immune response, as the antigen and adjuvant would stimulate the same APC, thus requiring less amount of adjuvant and reducing the toxic effects associated with these compounds, ii) better specific-antigen antibody titers, and iii) depending on the antigen-adjuvant combination, they may overcome some genetic restrictions imposed on an antigen’s immune response. However, the benefits of using this type of conjugates would depend on the antigen and adjuvant used, which may limit the scope of this application.

Reference

Goldblatt, D. (2000). Conjugate vaccines. Clinical and Experimental Immunology, 119(1), 1–3. http://doi.org/10.1046/j.1365-2249.2000.01109.x