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3.5 Ebola Virus
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potential Nglycosylation sites, respectively[138]. Most of them are rather conserved [139], suggesting that in addition to their role in protein structure and
activity, they could serve as vaccine candidates. A heterodimer complex is formed
by E1 and E2 on the viral particle, enabling HCV entry with involvement of E2
glycans[140]. Notably, the E2 glycoprotein includes the receptorbinding domain
(RBD) that interacts with cell surface entry receptors [141, 142] and is also the
major target for neutralizing antibodies[143]. Carbohydrates decorating HCV,
especially the conserved E2 oligosaccharides, form a nonevolving glycan shield
that protects underlying protein epitopes[144]. The E2 glycoprotein binds strongly
to the lectin DCSIGN (dendritic cellspecific intercellular adhesion molecule
grabbing nonintegrin), which may mediate viral infection in hepatocytes[145].
This is in line with the predominance of highmannose glycans in this protein[146], which signals the potential of carbohydratebinding agents (CBAs) as
antiHCV drug candidates that can disrupt glycan–protein interactions required
for HCV entry and infection.
Thus, several mannosespecific CBAs targeting the oligomannosecontaining
E1E2 heterodimer have been developed that bound to envelope glycans and inhibited capture of HCV by DCSIGN and viral entry [147]. Moreover, the lectin
c
yanovirinN was also found to inhibit HCV infection, likely due to interaction with
HCV envelope glycoproteins[148], highlighting the promise of CBAs as powerful
lead drugs for blocking HCV at the cell entry phase.
In addition to enabling the screening of CBAs with antiHCV activity, the abundance of conserved highmannose glycans in the E1/E2 glycoproteins suggests the
prospect of targeting these carbohydrate epitopes for the challenge of developing a
sofar elusive HCV vaccine that can fight against the highly heterogeneous HCV
genotypes. Nonetheless, some strategies based on recombinant HCV E2 protein
have been investigated that can induce bnAbs against most HCV genotypes. For
instance, an hyperglycosylation approach leading to an engineered subunit viral
vaccine with distinct glycan patterns was employed to mask suboptimal epitopes
associated with non-neutralizing antibodies, resulting in a more immunogenic
HCV E2 protein that generated a more epitopefocused and protective neutralizing
antibody response in mice[149].
91
3.5 Ebola Virus
Ebola virus (EBOV) is among the most lethal human pathogens, causing one of the
deadliest infectious diseases in the world (Ebola hemorrhagic fever, or EBOV disease). It was first described in 1976in Zaire (currently the Democratic Republic of
the Congo), followed by various subsequent outbreaks, predominantly in Central
Africa[150]. EBOV belongs to the Zaire ebolavirus species within the Ebolavirus
genus of the family Filoviridae[151]. The last Ebola epidemic caused by EBOV in
West Africa (2013–2016) reported over 28 000 cases of infected people and 11 000
deaths[152].
3 Carbohydrate-Based Antiviral Vaccines
92
3.5.1 Glycoprotein-Based Vaccines
The envelope glycoprotein (GP) on the viral surface plays a key role in viral entry,
being responsible for the interaction with hostcell receptors[153], and is the key
target of neutralizing antibodies and protective immunity. It is highly immunogenic
and has, therefore, been used as an immunogen in the development of Ebola vaccines. At present, two major vaccines exist against the Zaire ebolavirus species: the
®
FDAapproved rVSVZEBOV (called Ervebo
)[154] and the twocomponent Ad26.
ZEBOV/MVABNFilo vaccine, authorized by the European Commission [155].
Mature GP is formed by GP1 and GP2, which are presented as trimers of disulfide
linked GP1–GP2 heterodimers. The GP1 subunit comprises two highly variable
regions, the glycan cap and the mucinlike domain (MLD), that contain many N and
Olinked glycans[156]. Some of these Nglycans may serve as attachment points to
host cells, for instance, via mannosebinding Ctype lectins, which provides additional therapeutic opportunities (see below)[157]. Both heavily glycosylated domains
can prevent neutralizing antibodies fr om binding the GP by protecting critical
underlying epitopes[158]. Some research studies have investigated the influence of
GP glycosylation, showing that mutation of two Nglycosylation sites on GP1 (388,
415 sites) may increase immunogenicity, presumably by exposing protective antibody epitopes, whereas deletion of the mucin region led to reduced protective efficacy in mice[159]. Because GP antibodies are mainly generated against the least
conserved MLD, another study used a construct devoid of this domain for mouse
vaccination, which resulted in the induction of crossspecies immunity due to unmasking of more conserved regions by the immune system[160].
3.5.2 Monoclonal Antibodies and Carbohydrate Antiviral Agents
asTherapeutics
Currently, there are two therapeutic options approved in 2020 by the FDA to treat
Ebola, which are based on monoclonal antibodies that target the GP, blocking entry
of the virus into the host cell[161, 162]. In addition to these antibodybased strategies, some smallmolecule antivirals have been developed and tested in clinical trials, such as the broadspectrum nucleoside analogs BCX4430 (Galidesivir)
[163, 164] and Remdesivir[165], which act by inhibiting the viral RNA polymerase.
A general strategy exploited for the development of antiviral compounds involves
the inhibition of viral transmission through blockade of DCSIGN. This lectin interacts with highly mannosylated glycoproteins in a multivalent manner, including the
EBOV GP[166], and is one of the most important pathogenrecognition receptors,
being an important target for Ebola infection[167]. Consequently, a variety of multivalent carbohydrate structures have been developed with controlled glycan
valency, size, and shape[168] that mimic the glycan presentation on the GP surface.
Notably, some of these synthetic systems could block DCSIGN and were able to
inhibit infection by EBOV[169]. In a representative example, Davis and coworkers
used a proteic platform (multimeric Qβbased viruslike particles) for conjugation of
mannose glycodendrons through CuAAC click chemistry, assembling multivalent
3.5 Ebola Virus
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glycodendrimeric nanoparticles that displayed >1600 monosaccharides in a
homogeneous manner[170]. These glycoconjugates showed potent antiviral activity, preventing DC infection by pseudotype Ebola by competitively inhibiting the
binding of DCSIGN at low nanomolar/picomolar concentrations. Subsequently,
Martin and collaborators efficiently synthesized a watersoluble multifullerene
based dendritic structure decorated with 120mannose units using click chemistry
(Figure3.4), providing nanosized globularshaped multivalent macromolecules that
blocked DCSIGN and inhibited EBOV infection in the subnanomolar range[171].
The high inhibitory potencies of these antiviral constructs open the door to investigating whether these multivalent systems could induce potent antibody responses
invivo that might potentially neutralize some of the relevant glycan–protein interactions operative at the virus–cell interface. Moreover, the modular nature and full
chemical control enabled by this synthetic approach raise the possibility of creating
dual/bifunctional structures that can incorporate immunogenic elements recognized by the immune system, leading to prospective novel molecular vaccines for
inducing immune responses against EBOV.
93
Figure3.4 Glycofullerene “superballs” substituted with up to 120mannose units[171].
3 Carbohydrate-Based Antiviral Vaccines
94
3.6 SARS-CoV-2 Virus
COVID19has become a major pandemic and a global public threat since its first
outbreak in China in December 2019. It is caused by a novel coronavirus called
SARSCoV2 (WHO 2020) [172]. Coronaviruses are enveloped, singlestranded
positivesense RNA viruses that have a spike glycoprotein (Sprotein) that plays a
critical role in pathogenesis and in host immune response induction[173]. In addition to the spike glycoprotein, three other different proteins make up the SARS
CoV2 structure: an envelope protein (E), membrane protein (M), and nucleocapsid
protein (N)[174]. The SARSCoV2 spike has two functional subunits (i.e. S1 and
S2) and contains 22 putative Nlinked glycosylation sites and 4 potential Olinked
glycosylation points[175, 176]. The function of the S1 subunit is associated with
receptor binding, and the S2 subunit is responsible for membrane fusion[177]. As
with many viral envelope glycoproteins, the carbohydrates around the spike form a
SARSCoV2 glycan shield that helps evade the immune system. In addition to
shielding, two Nglycans (N165 and N234) have been found to play a structural role
in modulating the conformation of the RBD that binds to the angiotensin
converting enzyme (ACE2) hostcell receptor, priming the virus for infection[178].
Despite the structural similarity between SARSCoV2 and the first SARSCoV
virus, 5–6key amino acid residues of the RBD implicated in ACE2 recognition are
changed[179, 180], indicating distinct antigenic sites in the two viruses. The existence of different key epitopes points to the need to develop new therapeutic agents
and vaccines that are specific for COVID19[181, 182]. In this context, the SARS
CoV2 S protein serves as the main immunogen and a key target of neutralizing
antibodies[183], representing an area of focus for vaccine development[184]. In
particular, the spike glycan shield emerges, and its vulnerabilities [185] can be
exploited for smallmolecule drug development as well as for the design of potential
carbohydratebased vaccines to combat the COVID19 pandemic[186, 187].
3.6.1 Prospective Vaccine Constructs Based on α-Gal Epitope
As mentioned in the end of Section3.3.1.2 on influenza virus vaccines, endogenous
human antiGal antibodies might also be exploited for increasing SARSCoV2 vaccine immunogenicity by glycoengineering αGal epitopes on inactivated SARS
CoV2 or on Sprotein subunit vaccines[188]. Presentation of these αGal epitopes
would enable formation of antiGal/SARSCoV2α
or antiGal/Sproteinα
Gal
Gal
immune complexes, resulting in higher APC targeting and uptake via specific receptor interactions and, as a result, enhanced immunogenicity and vaccine efficacy.
This glycoengineering strategy would convert the native, proteinmasking glycan
shield into an αGalmodified carbohydrate coating that effectively directs the engineered vaccine to APCs via antiGal antibodies. Despite its promise, this αGal vaccine approach needs to be further demonstrated in a COVID19 setting to fully
assess its potential to boost antiSARSCoV2 immune responses, both in terms of
neutralizing antibody titers as well as Tcell immunity.
3.6 SARS-CoV-2 Virus
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3.6.2 RBD-Based Constructs for Vaccine Development
The RBD glycoprotein within the Sprotein trimer mediates viral infection by binding to ACE2 and represents a key target for the design of vaccines able to elicit neutralizing antibodies against SARSCoV2[189]. In a notable example, a recombinant
monomeric RBD vaccine adjuvanted with alum was shown to elicit a potent and
protective antibody response in laboratory animals after invivo SARSCoV2 challenge[190]. With a view to increasing immunogenicity and favoring presentation of
the key RBD motif surface in search of enhanced neutralizing antibody induction,
VérezBencomo and coworkers chemically linked the recombinant RBD to the
highly immunogenic protein carrier TT in a siteselective manner[191]. The resulting multivalent RBD–TT conjugates induced a robust IgGneutralizing antibody
and cellular response in mice when coadministered with alum, which prompted
advancement of this conjugate vaccine candidate to clinical trials[192].
In an effort to guide the development of semisynthetic carbohydratebased RBD
vaccines, Wang and coworkers recently investigated the role of precise glycan structures on this domain (at T323, N331, and N343) by preparing homogeneous RBD
glycoproteins using chemical synthesis and recombinant protein engineering[193].
Leveraging their homogenously glycosylated RBDs, they found no differences
between various synthetic glycoforms in terms of ACE2 binding and revealed the
influence of discrete RBD glycosylation on antiSARSCoV2 RBD monoclonal antibody binding. In addition to deciphering carbohydrate structure–activity relationships, these studies have provided chemically defined glycosylated constructs as
potential epitope mimics for further immunological evaluation invivo, opening the
door to the prospective rational development of synthetic glycanbased immunogens for future antiSARSCoV2 vaccines and therapeutics.
95
3.6.3 Saponins as Carbohydrate-Based Adjuvant Candidates for
COVID-19 Vaccines
The identification of novel vaccine adjuvants that can potentiate humoral, cellular,
and memory immune responses to prevent COVID19 infection is emerging as a
frontline strategy in vaccine development against COVID as well as other infectious
diseases[194, 195]. Triterpenoid and steroidal saponin natural products show antiviral activity against different viral groups. Aqueous extracts from the Chilean soapbark tree Quillaja saponaria Molina contain many physiologically active triterpenoid
saponins, some of which show high adjuvant activity, potentiating the immune
response against the coadministered antigen[196]. Purified saponin fractions (specifically QS21), either alone or integrated as part of immunostimulating complexes
(ISCOMs) and adjuvant systems, have been demonstrated to be powerful adjuvants
inducing both antibody and cellular immunity in several vaccine clinical trials
[197, 198]. AS01 is a potent adjuvant combination recently approved in herpes and
malaria vaccines that includes two immunostimulants, 3Odesacyl4′
monophosphoryl lipid A (MPLA) and the naturally derived purified saponin fraction
(QS21), in a liposomal formulation[199]. Both immunopotentiating substances in
3 Carbohydrate-Based Antiviral Vaccines
96
this system appear to be critical for the stimulation and activation of antigenspecific
cellular and humoral immune responses. The proprietary, saponinbased Matrix
M™ adjuvant has shown potent and welltolerated immunostimulatory effects by
inducing the influx of APCs into the site of injection and enhancing antigen presentation in the lymph nodes[200, 201]. Notably, MatrixM has been licensed as part of
Novavax recombinant nanoparticle subunit vaccine (NVAXCoV2373) derived from
the Sprotein, acting by boosting Bcell and Tcell immunity for elicitation of more
potent immune responses while also enabling dosesparing[202]. NVXCoV2373has
been successfully evaluated in clinical trials, demonstrating high vaccine efficacy
against several SARSCoV2 variants with an acceptable safety profile [203, 204],
which has led to its recent approval by the European Medicines Agency. This saponin
adjuvanted proteinbased vaccine highlights the promise of saponin adjuvants and
subunit vaccines to prevent not only traditional but also emerging viral diseases,
including COVID19 and potential new pandemics associated with further coronavirus infections.
3.7 Conclusions and Outlook
Viral glycosylation is a process mediated by the hostcell machinery that decorates
the surface proteins of several pathogens with cell glycans, including the envelope
glycoprotein (Env) of HIV1, hemagglutinin glycoprotein (HA) of influenza virus,
the envelope glycoproteins (E1 and E2) of HCV, the glycoprotein (GP) of EBOV,
the coronavirus glycoprotein spike (S), and others. This protein glycosylation is
characterized by high structural variation and is essential for the viral lifecycle
and pathogenesis, playing a key role in specific viral functions such as hostcell
attachment and entry, infectivity, and replication. Moreover, these viral carbohydrates form a glycan shield that has important implications for host immune
responses to infection, protecting internal protein epitopes from immune recognition while also exposing potential targets for vaccine and drug development. For
instance, the conserved oligomannosetype Nglycans of some envelope glycoproteins involved in transinfection and immune evasion also serve as neutralizing
antibody epitopes or binding receptors for CBAs to fight against viral infection.
Despite significant recent research on the development of carbohydrate vaccines
and therapies against viral diseases, much further work is needed for the translation
of additional glycanbased candidates into clinical applications in humans.
Increased knowledge of viral glycobiology and sitespecific protein glycosylation, as
well as a better understanding of the immunological basis that drives viral diversity,
will aid in guiding the rational design of nextgeneration vaccines and antiviral therapeutics in the future.
Acknowledgments
Funding from the European Research Council (ERC2016STG716878 “ADJUV
ANT VACCINES”) and the Spanish Ministry of Science and Innovation/State
References
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Research Agency (MCIN/AEI) (CTQ201787530R, RYC201517888 to A.F.T.;
PRE2018085772 to A.P.) is gratefully acknowledged. We thank Dr. Iñaki Bastida for
assistance with the preparation of the manuscript. A F.T. thanks Raquel Fernández
for inspiration.
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