Antibacterial and antifungal vaccines based on synthetic oligosaccharides - Carbohydrate Chemistry: Chemical and Biological Approaches - page 580

in mice than shorter synthetic oligosaccharide sequences. 117 Conjugates
of 33 induced anti-LPS antibodies that protect passively administered
naive mice from Sf2a infection 118 and represent a promising alternative
for vaccine development. 119 Here again, the need to include various
serotypes in a vaccine increases the level of complexity. A broad serotype-
coverage vaccine containing a limited number of serotype-specific anti-
gens has been proposed. 120 It has also been postulated that immunizing
with antigens corresponding to S. flexneri serotypes 2a, 3a and 6 could be
sucient to protect against almost all S. flexneri serotypes. 121 Almost all
serotypes have the same tetrasaccharide backbone consisting of a tetra-
saccharide -2)-a- L -Rhap-(1-2)-a- L -Rhap-(1-3)-a- L -Rhap-(1-3)-b- L -GlcpNAc-(1-
and differ only by O-acetyl substituents and monosaccharide branches.
In looking for broad spectrum coverage for synthetic antigens, the con-
formation of polysaccharides from serotypes 1a, 1b, 2a, 2b, 3a, 3b, 4a, 4b,
5a, 5b, X and Y have been studied 122 by molecular dynamic simulations
and nuclear magnetic resonance (NMR), which showed that all PS stud-
ied except 1a and 1b shared a favored backbone conformation.
3.2 Shigella dysenteriae type 1 (Sdt1)
S. dysenteriae is also an important cause of diarrhea and dysentery, mainly
in the poorest part of the world. The lipopolysaccharide of serotype 1 has a
tetrasaccharide repeating unit shown in formula 34.Oligosaccharides
having from 1 to 4 RU were prepared. 123 Simplification of the synthesis
was needed for such complex molecules. The stepwise oligomerization of a
tetrasaccharide unit, using acyl-type protecting groups in one of the tet-
rasaccharide building blocks, shows better eciency. 124
Similar to the finding for Sf2a, four RUs (a hexadecamer, 35) were re-
quired for maximal immunogenicity in mice. 125 Two other factors were
found to impact on the immunogenicity and specificity of antibodies for
the natural LPS: the carbohydrate loading onto the protein and the choice
of terminal non-reducing end. 126 The copious amount of data accumu-
lated will probably lead to a vaccine candidate for human trials.
3.3 Vibrio cholerae serotype 1 (VcO1)
Since the 19th century, seven cholera pandemics have been described, and
the currently ongoing one began in 1961. 127 This pandemic is caused by
the V. cholerae O1 biotype El Tor. V. cholerae is classified into different
serogroups according to differences in its O side chain of the LPS. Although
the O antigen presents a vast diversity of variants, only the O1 and O139
variants are known to cause epidemic or pandemic outbreaks. 128 The
O1-polysaccharide chain has the structure represented by formula 36.The
O1 serogroup can be further classified into Ogawa and Inaba serotypes by a
difference in terminal non-reducing D-perosamine residue that is O-
methylated in Ogawa serotype. 129 Our laboratory reported the first synthesis
of terminal mono and disaccharide fragments 37 from the VcO1 Ogawa and
Inaba and demonstrated that anti-Ogawa antibodies were directed to the
terminal methylated monosaccharide. 130 This finding was later confirmed
by the crystal structure of a disaccharide showing that most interactions
were made with the terminal monosaccharide (Scheme 12). 131