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2 Antifungal Glycoconjugate Vaccines
OH
Robust immune response but not protective
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66
OH
HO
O
O
HO
HO
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OH
COOH
OH
HO
HO
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HO
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GXM polysaccharide–TT conjugate 8
Immunogenic and protective in mice
OH
O
O
O
OH
OH
OH
HO
HO
OH
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HO
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N
S
TT
OH
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OH
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AcO
HO
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immunofluorescence the surface of serotype B and D strains,
but failed to provide protection in mice challenge model
OH
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O
OH
OH
O
O
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NH
OH
COOH
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O
GXM heptasaccharide IX–HSA conjugate 9
Elicited anti-GXM antibodies recognizing in
O
OH
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(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
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
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HO
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RHN
n
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RHN
n = 0–5
α-(1,4) biotinylated glucosamines 12
R = Ac or H
OH
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Generate antibodies recognizing α-(1,3) glucans on A. fumigatus surface
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α-(1,3) pentaglucoside conjugate to BSA 11
H
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N
Biotin
OH
OH
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HO
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OH
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H
OH
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H3N
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AcHN
n = 2 or 3
H
N
OH
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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
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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
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
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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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3
Carbohydrate-Based Antiviral Vaccines
Adrián Plata1 and Alberto Fernández-Tejada
1
CIC bioGUNE, Basque Research and Technology Alliance (BRTA), Chemical Immunology Lab, Biscay Science and
Technology Park, Building 801A, Derio, Biscay 48160, Spain
2
Ikerbasque, Basque Foundation for Science, Euskadi Plaza, 5, Bilbao, Biscay 48009, Spain
1,2
3.1 Introduction
Carbohydrates play a critical role in numerous infections caused by viruses that are
responsible for many diseases, including common cold, influenza[1], the more serious acquired immune deficiency syndrome (AIDS) [2], and different forms of the
severe acute respiratory syndrome (SARS), best exemplified by the current, devastating coronavirus disease 2019 (COVID19) pandemic due to the severe acute respiratory syndrome coronavirus2 (SARSCoV2) virus [3]. In addition to infectious
diseases caused by viral infections, some viruses are at the origin of several human
cancers, most notably liver cancers resulting from chronic infections by hepatitis B
and C viruses[4] and cervical cancers associated with longlasting infection with the
human papillomavirus (HPV)[5]. To fight against these serious diseases, the importance of safe, potent vaccines and therapeutic approaches is clear, contributing to
the prevention and treatment of such viral infections for global health. A number of
antiviral vaccines containing liveattenuated or inactivated viruses have been very
effective in combating and even eradicating several viral infectious diseases in
recent history, e.g. polio, measles, mumps, rabies, varicella, and smallpox [6].
However, this traditional approach has not been fully successful for some chronic
and reemerging viral diseases, such as HIV, influenza, or hepatitis C. As such, the
development of modern subunit vaccines based on purified and structurally defined
immunogenic elements of a specific virus has become a preferred preventative strategy due to their improved safety and more precise immune targeting[6].
Carbohydrates are ubiquitous on many viral surface proteins and are crucially
involved in viral pathobiology. Viral protein glycosylation plays pivotal functional
roles in the infectious process[7], from initial adherence of the virus and tissue
invasion to protection from the immune system, by mimicking the hostcell “self”
73
Carbohydrate-Based Therapeutics, First Edition. Edited by Roberto Adamo and Luigi Lay.
© 2024 WILEY-VCH GmbH. Published 2024 by WILEY-VCH GmbH.
3 Carbohydrate-Based Antiviral Vaccines
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74
glycans, particularly Nglycans [8], by hijacking cellular glycosylation. Thus, in
addition to the own viral genome information, the biosynthetic machinery and glycan processing events within the infected cell have important implications for shaping viral protein glycosylation. This provides further structural diversity for the
virus beyond that arising from potential mutations occurring during virus evolution, impacting their virulence, infectivity, and immunogenicity[9].
Thus, realizing the importance of viral glycosylation and diversity in driving viral
pathogenesis has provided fertile ground to exploit carbohydrates on the virus surface for the development of antiviral vaccines and therapeutic strategies using
chemical approaches. In this chapter, we describe key and recent developments in
synthetic carbohydratebased vaccines against representative viral diseases (e.g.
HIV, influenza, hepatitis, Ebola, and COVID19), while also providing some examples of glycanbased immunoadjuvants and therapeutic agents.
3.2 Human Immunodeficiency Virus
Human immunodeficiency virus type 1 (HIV1) is the causative agent of AIDS, a
pandemic that has affected more than 76
over 33
million deaths (680 000 of them in 2020) because of AIDSrelated diseases[2]. As such, the development of an effective and safe prophylactic vaccine
against HIV1 is of critical importance for global health. However, only a few clinical trials over the last decade have shown a positive outcome in terms of preventing
HIV1. The most successful results correspond to the RV144 efficacy trial, which
used a replicationdefective canarypox vector (ALVAC) together with the recombinant AIDSVAX B/E HIV1 gp120 protein. Despite its promise, the protected efficacy
of this vaccine was around 31%, mainly attributed to the synergistic contribution of
both humoral and cellular immune responses[10, 11]. Therefore, the development
of a successful HIV1 vaccine still poses a significant scientific challenge, whereby
induction of both neutralizing antibodies and Tcell responses should be ideal for
optimal vaccine efficacy[12].
The HIV1 virus surface is covered by a dense sugar coat, with the envelope glycoprotein (Env) spike being extensively glycosylated with hostsynthesized carbohydrates that mask the protein antigens from immune recognition[13]. This, together
with the high level of genetic diversity of the virus due to its high tendency to
mutate, promotes viral escape from the host immune system. The HIV1 Env is a
trimer composed of three gp120–gp41 heterodimers consisting of the gp120 surface
glycoprotein noncovalently associated with the gp41 transmembrane glycoprotein.
Gp120 is heavily glycosylated with an extensive array of Nlinked carbohydrates that
constitute more than 50% of its total mass. These oligosaccharides form a dense
glycan shield that covers the protein surface and contributes to immune evasion by
hindering immune recognition of the underlying peptide epitopes by naturally
induced broadly neutralizing antibodies (bnAbs) [14, 15]. Recent reports have
shown that around 20% of HIV1infected individuals have circulating bnAbs,
million people since its onset in 1981, with
3.2 Human Immunodeficiency Virus
which are characterized by special, uncommon features (e.g. extensive somatic
hypermutation, long heavychain third complementaritydetermining regions
[CDRH3], and/or self or polyreactive nature) that make it difficult to induce such
bnAbs by a designed HIV vaccine [16]. Notably, all bnAbs isolated sofar target
specific, conserved regions of vulnerability of the HIV1 Env, particularly within
established glycan/peptide domains corresponding to the gp120 variable loops 1/2
(V1V2) and 3 (V3), the CD4binding site (CD4bs) on gp120, the bridging region
between gp120 and gp41, and the gp41 membraneproximal external region
(MPER)[17]. Therefore, these bnAb epitopes represent promising targets for HIV1
vaccine design, with the main goal of inducing such type of bnAb with the ability to
neutralize multiple, diverse HIV1 strains.
Given the key role of the HIV1 glycans in viral transmission and infection as well
as in masking the protein antigens for immune escape, the Env surface glycans are
a primary target for the design of effective HIV1 vaccines[13, 18]. In this context,
the development of carbohydratebased synthetic immunogens as minimal structural mimics of several bnAb epitopes has emerged as an important strategy in an
attempt to develop vaccines capable of inducing bnAbs with safer and more precise
immune targeting. This section describes the most significant milestones in the synthesis and immunological testing of glycanbased epitope mimics as promising targets for the development of bnAbeliciting HIV1 vaccine candidates[19, 20]. We
summarize recent advances on carbohydratebased minimal immunogen design for
the induction of glycanrecognizing bnAbs that target three key domains on gp120:
the outer domain highmannose glycan cluster around N332 and the conserved
glycopeptidedependent epitopes in the V1V2 and V3loops, respectively.
75
3.2.1 Vaccine Constructs Derived from gp120 High-Mannose
N-Glycan Cluster
3.2.1.1 Surface Oligomannose Cluster-Targeting bnAb: 2G12 Antibody
The monoclonal antibody 2G12was the first bnAb identified to bind the HIV1 glycan shield. It was isolated from an HIV1positive patient and has been found to
neutralize an array of HIV1 virions[21] as well as to protect against simianhuman
immunodeficiency virus (SHIV) via passive immunization in macaques[22, 23]. As
shown by epitope mapping studies, 2G12 recognizes a conserved highmannose carbohydrate cluster on the gp120 surface that includes primarily Nglycans at the
N295, N332, and N392 positions [24]. Moreover, the Manα1→2Man disaccharide
terminus was identified as a critical motif for binding[25]. The crystal structure of
2G12 showed an unusual assembly of two Fab (fragment antigen binding) regions
into an interlocked V
domainswapped dimer, yielding an extended multivalent
H
binding surface for the glycan cluster[26].
Additional binding analysis using welldefined carbohydrate antigens provided
further details on glycan specificity. These studies showed that a Man
or even a Man
structure mimicking the D1 arm of native Man9GlcNAc2[28] pre-
4
GlcNAc[27]
9
sented the highest binding affinities with this bnAb [29–31], emphasizing the
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