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While bacterial vaccines have been successfully developed by conjugation of
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extracted polysaccharides to carrier proteins, this approach proves challenging for
fungal sugars due to their complex organization and variable structure.
Given the challenge associated with fungal carbohydrate production, synthesis of
oligosaccharide structures has appeared as an attractive alternative. Several synthetic glycoconjugate vaccines have been prepared and studied for the fungal pathogens causing most invasive infections in humans (Candida, C. neoformans). For
Aspergillus fumigatus and C. neoformans, many efforts have been directed toward
the synthesis of oligosaccharide components of the CW for structural studies aiming to identify the chemical features responsible for immunogenicity. Recent findings based on the use of synthetic oligosaccharides are summarized in this chapter.
2.4 Glycoconjugate Vaccines Against Candida albicans/
Candida auris
The outer core of Candida albicans CW is essentially composed of mannans, forming
a network that functions as a scaffold for highly glycosylated proteins. This mannan
polysaccharide is characterized by a set of different structural motifs, namely antigenic factors, distinguished by size, type of the glycoside bond, presence of phosphodiester linkages, branching points, etc., and its composition varies depending on
species and strain of Candida microorganism. β‐(1,3)‐glucans, β‐(1,6)‐glucans, and
chitin are instead present in the inner core of Candida CW. These polysaccharides
are the main PAMPs that are recognized by PRRs.
Laminarin from the brown alga Laminaria digitata is composed of branched
β‐(1→3)‐(1→6)‐glucans and, due to its structural similarity with fungal sugars, has
been considered a source of carbohydrates to develop vaccines against Candida
infections[17, 22–29]. Other sources of β‐glucans, such as the fully linear β‐(1,3)
glucan Curdlan (from Alcaligenes faecalis bacteria) or the β‐(1,6) glucan Pustulan
from Umbilicaria papullosa, have been exploited to determine the structural features needed for optimal immunogenicity. These studies indicated that the antibodies raised against β‐(1,3) glucans were protective in a mouse model of systemic
candidiasis, while structures containing β‐(1,6) glucan side chains might induce
non-protective antibodies[22, 23].
β‐(1,3) glucan binds to the C‐type lectin‐like receptor Dectin‐1, which is expressed
on immune cells such as macrophages, neutrophils, and DCs[30, 31]. The binding
residues have been identified in Trp221 and His223 [32]. The polysaccharide is
structurally well organized[33], and its long form appears to assume a triple helical
conformation, as it has been demonstrated by conformational nuclear magnetic
resonance (NMR) studies[34] and also by combined static light scattering, dynamic
light scattering, and atomic force microscopy[35]. However, a structurally disordered hexamer seems sufficient to bind to Dectin‐1[34].
The protective role of β‐(1,3) glucans was thoroughly investigated by employing
synthetic oligosaccharides conjugated with different conjugation chemistries to the
carrier proteins in order to elucidate the optimal structure of the protective epitope
612.4 Glycoconjugate Vaccines Against Candida albicans/Candida auris
2 Antifungal Glycoconjugate Vaccines
62
and of the resulting glycoconjugate (saccharide/protein ratio, type of carrier, and
conjugation site). By comparing a linear 15‐mer with a branched 17‐mer (1), it was
observed that β‐(1→6) branches need to be separated by at least six β‐(1→3) residues
for efficient antibody production[22].
Following this, a CRM
‐conjugate of a synthetic linear β‐(1,3) glucan hexamer
197
(2) was tested invivo and showed to elicit in mice anti‐β‐glucan IgGs in a comparable manner to Lam‐CRM
[23]. This result well correlates with the findings that
197
mAb 2G8, which is protective in mice challenged with C. albicans, mostly targets
linear β‐(1,3) glucan sequences. Subsequently, the impact of the conjugation site on
CRM
was further investigated by preparation of the linear β‐(1,3) glucan hexamer
197
conjugates through site‐selective conjugation to tyrosines [24] via a newly developed 4‐phenyl‐1,2,4‐triazoline‐3,5‐dione linker or controlled conjugation at the surface‐exposed lysines [25] via active ester chemistry [36] (4). The resulting
glycoconjugates were compared to those obtained through traditional random conjugation chemistry for CRM
lysines[25]. All the constructs elicited a comparable
197
level of IgGs[26, 37], and sera from immunized mice were able to inhibit the adhesion of C. albicans to human epithelial cells[25]. Therefore, it was concluded that
four conjugation sites are sufficient to elicit a robust immune response in the animal
model. The potential as an antigen of β‐glucans was further confirmed by other
investigators who conjugated a synthetic linear octasaccharide to the protein carrier
Keyhole limpet hemocyanin (KLH) (3)[26]. The same team then investigated the
immunogenicity of synthetic nonasaccharides of β‐(1,3) glucans bearing β‐(1,6) or
β‐(1,3) branches. Both conjugates showed similar immunological properties to the
previously tested octasaccharide, and in addition to this, competitive ELISA experiments suggested that the majority of the induced antibodies were directed against
the linear β‐(1,3) backbone[37]. Overall, these studies suggested that β‐(1,3) glucan
oligomers could be promising candidates for antifungal vaccines and contributed to
the development of a well‐established synthetic route giving access to libraries of
β‐(1,3) glucan structures.
Due to its irregular structure, Candida mannan’s immunogenic properties are difficult to reproduce, which makes its use problematic for the vaccine design. Therefore,
the synthetic approach has been helpful in identifying the protective epitope to
ensure the immunogenicity of the corresponding glycoconjugate vaccines. Short oligomers ranging from di‐ to hexasaccharide were synthesized in order to investigate
the structure and size of the protective epitope based on the interaction with two
protective mAbs generated by hybridoma techniques from mice immunized with a
natural mannan–liposome preparation[16, 38]. Their findings indicated that a trisaccharide was recognized by both mAbs and, therefore, was a promising antigen for
further vaccine development[39]. The synthetic β‐(1,2)‐mannan trisaccharide conju-
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gated to TT (5) showed a robust secondary antibody response in rabbits but poor
immunogenicity in mice [40, 41]. In order to improve the immunogenicity of the
mannan trisaccharide, a synthetic conjugate was constructed using the 14‐mer peptide Fba (6), deriving from a C. albicans CW protein and prepared through solid‐
phase peptide synthesis. After being tested in mice, the conjugate elicited a strong
antibody response and offered protection against a lethal challenge of C. albicans
[42, 43]. β‐glucans act as immune potentiator molecules through Dectin‐1 activation,
and a hexamer has been shown to be sufficient to enhance the antibody response
against protein antigens[44]. This feature has been harnessed to generate a tricomponent β‐glucan and β‐mannan conjugate, where the sugars were both conjugated to
TT as carriers. This type of approach resulted in an enhanced antibody response to
the β‐mannan epitope of the conjugate while exploiting the proven targeting and
antifungal response of the β‐glucan conjugates[29]. Recently, a fully synthetic conjugate vaccine was constructed from a β‐(1,2)‐linked mannose trisaccharide conjugated
to a T‐cell peptide. This combined B‐ and T‐cell epitope was synthesized and subsequently conjugated by click chemistry to an asymmetric dendrimer component bearing four copies of a β‐(1,3)‐linked hexaglucan DC epitope, obtaining a conjugate
vaccine (7) that induced antibodies to all three epitopes of the fully synthetic construct. Unfortunately, the preparation of a synthetic dendrimer‐based immunogen
proved very challenging, discouraging the authors from continuing with further
work on fully synthetic vaccines[45].
Other researchers focused their attention on the α‐mannosides and studied the
immunological properties of a series of synthetic oligo α‐mannosides with and
without branches conjugated to bovine serum albumin (BSA) via squarate chemistry. According to reported results, the presence of branches does not correlate with
the induction of protective antibodies as measured by in vitro opsonophagocytic
assay, while the length does not seem to play a major role, suggesting that oligomannoside structure more than their length might influence the quality of the antibody
response and that the use of linear oligomannosides for vaccine design might be
preferable[46].
Recent research demonstrated the immunobiological activity of synthetically prepared biotinylated α‐mannooligosaccharides mimicking Candida antigenic factors.
Macrophage exposure to a set of eight structurally different mannooligosaccharide
conjugates induced the release of Th1, Th2, Th17, and Treg cytokine signature patterns, making these conjugates potential invitro immunomodulative agents suitable
for in vitro Candida diagnostics or prospectively for subcellular anti‐Candida
vaccine design[47] (Figure2.2).
632.4 Glycoconjugate Vaccines Against Candida albicans/Candida auris
2 Antifungal Glycoconjugate Vaccines
HO
Fully synthetic three-component vaccine 7
64
O
HO
HO
HO
HO
H
O
O
OH
HO
HO
O
H
HO
HO
O
H
HO
HO
HO
O
Robust immune response in mice model
HO
HO
HO
HO
O
HO
O
O
OH
3
OH
HO
O
HO
O
OH
minimal linear epitope of Laminarin
HO
HO
O
O
OH
O
OH
Hexa-CRM
O
O
4
OH
O
3
197
Octa-KLH 3
OH
O
O
HO
O
HO
HO
O
HO
O
HO
HO
O
β-(1,2)-mannan trisaccharide-TT 5
Robust antibody response in rabbit,
poorly immunogenic in mice
HO
HO
O
HO
S
3
2
O
O
O
OH
H
N
4
2
O O
O
O
N
H
H
N
S
3
4
2
O O
OH
HO
O
HO
HO
HO
HO
HO
HO
OH
O
HO
HO
OH
OH
O
HO
O
OH
O
HO
O
OH
H
N
CRM
KLH
H
N
O
O
HO
HO
O
O
OH
HO
OH
HO
O
HO
protective in a Candida mice model
TT
HO
O
OH
17-mer-Glucan-CRM
197
O
O
O
S
3
OH
O
O
OH
O
HO
HO
O
O
2
OH
1
197
4 copies of the glycan sufficient for robust Ab production
HO
HO
HO
Candida peptide
Protection against a lethal challenge of C. albicans
H
N
2
O
OH
OH
O
OH
HO
HO
∗
CRM
197
site-selective conjugation at tirosine or lysines
OH
O
HO
HO
HO
HO
Fully synthetic vaccine 6
Strong antibody response
TT
NH
N
N
N
NH
O
HO
O
O
OH
OH
O
N
HN
N
O
HO
HO
O
H
Hexa-CRM
O
O
O
HO
O
HO
HN
O
2
n
2-3
H
N
O
2
OH
O
O
O
HO
HO
O
O
OH
4
197
H
O
N
S
3
2
O
S
O
O O
N
N
O
OH
4
H
N
4
CRM
197
N
O
3
O
Figure2.2 Vaccine candidates against Candida infections.
2.5 Glycoconjugate Vaccines Against Cryptococcus
neoformans
The first fungal glycoconjugate vaccine was designed against C. neoformans, whose
capsular polysaccharide is an important virulence factor and is composed mostly of
glucuronoxylomannan (GXM), while galactoxylomannan (GalXM) and mannoproteins (MPs) are present to a lesser extent.
GXM has a very complex structure: it is a heteropolymer, not consisting of repeating
units as bacterial polysaccharides but rather of six different chemotypes, occurring in
various ratios depending on both strain and batch of the microbe and distributed
among four serotypes: A, B, C, and D[48]. NMR experiments aiming to elucidate the
structure of GXM concluded that this polysaccharide consisted of a linear α‐(1,3)
mannan trisaccharide backbone containing β‐1,2 and β‐1,4 xylose branches and a
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β‐1,2 glucuronic acid branch attached at different mannoses of the repeating unit.
Additional structural complexity and heterogeneity are introduced by O‐acetylation,
whose variability makes the identification of protective epitopes difficult.
GalXM represents about 7% of the capsular mass, and it is made of a α‐1,6galactan
backbone with potentially four short oligosaccharide branch structures. Other carbohydrates present in the CW of C. neoformans are α‐(1‐3) glucans, which anchor
the polysaccharide capsule to the CW, and β‐(1‐3) glucans.
Early attempts to make an anti‐Cryptococcal glycoconjugate vaccine have been
focused on GXM and resulted in a poorly characterized product, which showed
immunogenicity in mice but did not give a protective antibody immune response[49].
The first evidence that GXM can be regarded as a target for immunotherapy was
obtained using a natural polysaccharide conjugated with tetanus toxoid (GXM‐TT
conjugate 8), which resulted in immunogenicity and protection in mice[50, 51]. The
results of both active and passive protection experiments suggested that the presence
of GXM‐TT‐elicited antibodies during the first — four to six weeks of infection was
critical for the clearance of cryptococci from various organs, for limiting serum GXM
titers from reaching immunosuppressive levels, and ultimately for survival[51, 52].
Thanks to the availability of anti‐GXM mAbs isolated from mice infected with C. neo-
formans and mice immunized with GXM‐TT, the presence of protective as well as
nonprotective epitopes within GXM structure was demonstrated[53, 54].
Thus, further studies were directed toward determination of the protective epitope
structure using synthetic oligosaccharides to be used in the conjugated vaccine. First,
the synthetic heptasaccharide IX, representing the dominant putative epitope of
C. neoformans serotype A GXM, was synthesized with different O‐acetylation patterns and tested for binding against a library of seven mAbs. Both O‐acetylated and
nonacetylated forms of the heptasaccharide were strongly recognized by two mAbs
(13F1 and 7B13). The mono‐O‐acetylated synthetic serotype A heptasaccharide was
conjugated to human serum albumin (HSA) (9) and tested for immunogenicity in
mice with or without Freund adjuvant. Only the conjugate administered with adjuvant was able to elicit anti‐GXM antibodies, which unexpectedly recognized primarily and in an irregular manner the surface of serotype D and B strains in
immunofluorescence experiments[55]. In a subsequent study, the ability of the antibodies elicited by the above conjugate to protect mice against challenge with serotype
D C. neoformans was investigated, but unfortunately, no protection was observed[56].
To elucidate the oligosaccharide structure, which could be regarded as an efficient
ligand for vaccine development, a synthetic glycan array containing immobilized oligosaccharides related to GXM fragments, ranging from di‐ to octadecasaccharides, was
developed and the interactions of such oligosaccharides with available protective and
nonprotective mAbs were investigated. The screening revealed that a serotype A decasaccharide was recognized by several neutralizing mAbs, making this structure a promising candidate for anti‐C. neoformans conjugate vaccine development[57].
Another cell‐wall polysaccharide that has been considered as vaccine antigen is
GalXM, which was conjugated to BSA and to a protective antigen from Bacillus
anthracis as protein carriers (10), demonstrating its effectiveness to induce robust
652.5 Glycoconjugate Vaccines Against Cryptococcus neoformans
2 Antifungal Glycoconjugate Vaccines
OH
Robust immune response but not protective
66
OH
HO
O
O
HO
HO
O
OH
COOH
OH
HO
HO
O
O
O
O
HO
O
HO
O
GXM polysaccharide–TT conjugate 8
Immunogenic and protective in mice
OH
O
O
O
OH
OH
OH
HO
HO
OH
O
HO
O
O
H
HN
N
S
TT
OH
HO
OH
O
O
HO
HO
HO
OH
OH
O
HO
O
HO
O
O
HO
OH
OH
OH
O
HO
HO
HO
O
O
AcO
HO
HO
immunofluorescence the surface of serotype B and D strains,
but failed to provide protection in mice challenge model
OH
OH
O
OH
O
HO
O
OH
OH
O
O
O
O
OH
OH
HO
OH
O
OH
O
O
HO
O
HN
NH
OH
COOH
OH
O
HO
O
O
O
O
HO
O
GXM heptasaccharide IX–HSA conjugate 9
Elicited anti-GXM antibodies recognizing in
O
OH
O
O
OH
O
OH
O
OH
O
OH
O
O
OH
O
OH
OH
HO
O
O
O
HO
O
O
HO
OH
HO
O
O
(CH2)2NH
O
O
N
H
BSA
GalXM–BSA or GalXM–PA Bacillus anthracis conjugate 10
BSA or Bacillus anthracis PA
Figure2.3 Vaccine candidates against Cryptococcus neoformans.
immune responses in the animal model, although the antibody responses were not
protective[58, 59]. Further studies are, therefore, needed to clarify, possibly with the
use of synthetic glycans as done for GXM, whether there are protective epitopes
expressed on the polysaccharide (Figure2.3).
2.6 Glycoconjugate Vaccines Against
Aspergillus fumigatus
Similarly to other fungi, the CW of A. fumigatus, which is a main cause of pulmonary infections in immunocompromised patients, is dominated by carbohydrates,
and its general composition not only comprises β‐glucans crosslinked to chitin but
also an extracellular matrix (ECM) composed of polysaccharides, mainly α‐(1,3)
glucan and galactosaminogalactan (GAG), creating a cell surface structure that
is thought to be crucial to pathogenic expression. GAG consists of galactose
(Gal), galactosamine (GalN), and N‐acetylgalactosamine residues (GalNAc)[60].
The presence of α‐(1→3)‐glucans on their surface is shared by Cryptococcus and
OH
H
)COOH
Glucosaminoglycan structures 13 and 14
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Aspergilli. However, in the first case, they anchor the polysaccharide capsule to the
CW, whereas in A. fumigatus, α‐(1→3)‐glucans induce the aggregation of germinating fungal conidia[61].
The protective evidence of carbohydrate antigens from Aspergillus still needs to be
deeply investigated. To address this, many research groups have recently focused on
the synthesis of carbohydrate components of A. fumigatus to obtain synthetic oligosaccharides, which could aid to characterize structure–immunogenicity relationships of the cell‐wall glycans. Nifantiev and coworkers synthesized, in 2015, an
α‐(1,3) pentaglucoside and then conjugated it with BSA (11)[62]. Immunization of
mice with the BSA conjugate induced the generation of antibodies that recognize
α‐(1→3)‐glucan on A. fumigatus CW and distinguish its morphotypes [62, 63].
Recently, the same group directed their synthetic efforts toward the preparation of
oligo‐α‐(1,4) GalNs and their N‐acetylated derivatives (12)[64–66]. After biotinylation, synthetic glycans were used as molecular probes in glycoarrays against sera
from patients infected with pulmonary aspergillosis. Such investigations showed that
human IgGs recognized both acetylated and non‐acetylated oligo‐GalNs with a
degree of polymerization of at least 3. In the same direction, Codée, Barbero, and
coworkers synthesized GAG structures (13 and 14), identifying a synthetic methodology for the assembly of GAG‐oligomers capable of incorporating possible variations
672.6 Glycoconjugate Vaccines Against Aspergillus fumigatus
O
HO
HO
OH
O
O
HO
RHN
n
OH
O
HO
RHN
n = 0–5
R = Ac or H
α-(1,4) biotinylated glucosamines 12
OH
OH
O
HO
O
OH
OH
O
O
HO
O
OH
OH
O
O
HO
O
Generate antibodies recognizing α-(1,3) glucans on A. fumigatus surface
O
α-(1,3) pentaglucoside conjugate to BSA 11
H
O
N
Biotin
OH
OH
O
O
HO
O
OH
O
H
OH
O
O
HO
H3N
O
HO
AcHN
n = 2 or 3
H
N
OH
O
O(C5H10)COOH
n
HN
O
O
BSA
HO
H
OH
O
O
OH
H3N
O
O
HO
AcHN
O
HO
n = 1 or 2
OH
O
HO
O(C5H
10
n
Figure2.4 Vaccine candidates against Aspergillus fumigatus.
2 Antifungal Glycoconjugate Vaccines
68
of the natural structures[67]. The conformation of the synthesized oligosaccharides
was investigated by molecular dynamics and NMR experiments, and these glycans
may find application in future binding studies to establish GAG epitopes, which
can be used in the development of glycoconjugate vaccines against A. fumigatus
(Figure2.4).
2.7 Universal Fungal Polysaccharide Antigens
β‐glucans are present in a conserved layer of the CW across many fungal species
and, therefore, are an appealing target for the development of an effective “pan‐
fungal vaccine”[68]. The algae‐derived sugar Laminarin conjugated to the nontoxic
mutant of diphtheria toxin CRM
infection model against both systemic candidiasis and aspergillosis [17].
Saccharomyces cerevisiae β‐glucans induced a protective response to coccidioidomy-
cosis and aspergillosis[69–71] in a murine model, confirming the potential of these
carbohydrate antigens as tools for pan‐fungal vaccination.
Another potential target that has been studied for the potential development of a
vaccine targeting multiple fungi is the poly‐N‐acetyl‐1,6‐glucosamine (PNAG),
which has been detected on the surface of C. albicans. An anti‐PNAG mAb, mAb
F598, and polyclonal serum from mice immunized with a synthetic nonasaccharide, analog of deacetylated PNAG and conjugated to TT, provided protection in a
mouse model of C. albicans keratitis [72] and were able to kill A. fumigatus and
Fusarium solani in an opsonophagocytosis assay and to protect mice from A. fumig-
atus keratitis[73].
has been shown to induce protection in a murine
197
2.8 Conclusions and Future Prospects
IFIs are becoming an increasing threat in nosocomial settings due to increasing life
expectancy, especially in the presence of underlying medical conditions such as
cancer, HIV, or other immunosuppressive diseases. Current pharmaceutical treatments of fungal infections consist of a few old drugs with severe adverse events,
while some fungal pathogens are starting to represent a concern for the emergence
of antimicrobial‐resistant strains. Preventive therapies such as vaccination, relying
on the host immune response to fungal antigens, can represent an interesting alternative for IFIs in immunosuppressed patients and/or for recurrent mucosal infections in healthy people, such as vulvovaginal candidiasis. Polysaccharides are the
main component of the fungal CW and are, therefore, regarded as potential vaccine
antigens upon conjugation to carrier proteins, providing the T‐cell help needed for
the formation of memory B cells. However, the complexity of the fungal CW makes
it very difficult to establish a correlation between oligosaccharide structures and
immunogenicity. For this reason, many attempts have been made over the years to
elucidate the glyco‐epitopes expressed on the CW polysaccharides with the aim of
References
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designing glycoconjugate vaccines able to induce a robust and protective immune
response. This task has been mainly in the hands of synthetic organic chemists,
who have focused over the years on the preparation of glycans from three fungal
pathogens (Candida spp., C. neoformans, and A. fumigatus). Synthetic well‐defined
oligosaccharide fragments conjugated to carrier proteins or peptides helped to
highlight the saccharide structural requirements to induce functional antibodies in
animal models. Moreover, the availability in the last few years of mAbs targeting
fungal glycans has allowed the screening of libraries of oligosaccharide structures
by glycoarray, helping to identify the length and the branches needed for epitope
optimization. Synthetic glycoconjugate vaccines require the optimization of synthetic methods for complex oligosaccharide chain assembly. In particular, over the
years, many research groups have developed efficient chemistries for the preparation of β‐glucans and to achieve stereoselective 1,2‐cis glycosylation, which are
needed for the β‐mannosylation essential to prepare Candida mannans and for the
α‐glucosylation for Aspergillus α‐glucans[74]. Advances in synthetic methodologies together with the application of techniques that can map the interactions
between oligosaccharides and proteins (glycoarray, surface plasmon resonance,
NMR, and X‐ray crystallography) can aid the rational structural design of modern
and safe antifungal glycoconjugate vaccines. In addition to this, formulation technologies and adjuvants are also important factors in modulating the immune
response.
69
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