Fully Synthetic Self-Adjuvanting α-2,9-Oligosialic Acid Based Conjugate Vaccines against Group C Meningitis

Abstract

α-2,9-Polysialic acid is an important capsular polysaccharide expressed by serotype C Neisseria meningitidis. Its protein conjugates are current vaccines against group C meningitis. To address some concerns about traditional protein conjugate vaccines, a new type of fully synthetic vaccines composed of oligosialic acids and glycolipids was explored. In this regard, α-2,9-linked di-, tri-, tetra-, and pentasialic acids were prepared and conjugated with monophosphoryl lipid A (MPLA). Immunological studies of the conjugates in C57BL/6J mouse revealed that they alone elicited robust immune responses comparable to that induced by corresponding protein conjugates plus adjuvant, suggesting the self-adjuvanting properties of MPLA conjugates. The elicited antibodies were mainly IgG2b and IgG2c, suggesting T cell dependent immunities. The antisera had strong and specific binding to α-2,9-oligosialic acids and to group C meningococcal polysaccharide and cell, indicating the ability of antibodies to selectively target the bacteria. The antisera also mediated strong bactericidal activities. Structure–activity relationship analysis of the MPLA conjugates also revealed that the immunogenicity of oligosialic acids decreased with elongated sugar chain, but all tested MPLA conjugates elicited robust immune responses. It is concluded that tri- and tetrasialic acid–MPLA conjugates are worthy of further investigation as the first fully synthetic and self-adjuvanting vaccines against group C meningitis.

Synthesis and Immunological Studies of Oligosaccharides that Consist of the Repeating Unit of Streptococcus pneumoniae Serotype 3 Capsular Polysaccharide

“…However, larger oligosaccharides may not necessarily be better haptens than their shorter analogues, as the TT conjugates of ST3 CPS penta‐ and hexasaccharides 1 and 2 were proven to induce much stronger immune responses than that of hepta‐ and octasaccharides 3 and 4 . Similar results were also observed with other oligosaccharides, the reason for which is not clear but has no relation to the vaccine dose used in immunization . Worthy of additional investigation is the question of whether the number of sugar chains in the conjugates played a role.…”

Carbohydrate Conjugates in Vaccine Developments

“…MPLA can also serve as a vaccine carrier and a built-in adjuvant when conjugated with antigens covalently. Herein we discuss examples of fully synthetic vaccines containing MPLA as the carrier (Wu and Guo, 2006;Wang et al, 2011;Zhou et al, 2014Zhou et al, , 2015Liao et al, 2016).…”

“…In addition to the aforementioned cancer vaccines, a Group C meningitis vaccine has been reported by conjugating MPLA and α-2,9-oligosialic acid containing di-, tri-, tetra-and pentasialic acid (Liao et al, 2016). The resulting liposomal vaccines with various MPLA-oligosialic acid conjugates induced strong immune responses as revealed by high total antibody titers.…”

Preparation and in vivo evaluation of glyco-gold nanoparticles carrying synthetic mycobacterial hexaarabinofuranoside

“…A number of bacterial glycans [1,2] are specific markers for the detection and the serological identification of microorganisms [3][4][5] and are widely used as antigenic components of vaccines [6][7][8][9][10][11][12][13][14][15][16][17][18][19][20][21][22][23]. The use of gold nanoparticles (GNPs) [24][25][26] as carriers for glyco-epitopes is becoming an important alternative [15, to the traditional conjugation with proteins, synthetic polymers and other carriers [15,17,38,[49][50][51][52][53][54][55].…”