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able of contents1. Carbohydrate-based vaccines: challenges and opportunities...................................................................... 1
Bibliography...................................................................................................................................................... 24
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Document 1 of 1
Carbohydrate-based vaccines: challenges and opportunitiesAuthor: Huang, Yen-LinProQuest document link
Abstract:Advances in the synthesis of oligo- or polysaccharides and new technologies developed inglycobiology studies have opened a new avenue in carbohydrate vaccine design. In principle, various types of
cell-surface epitopes, characteristic of the invading organism or related to aberrant growth of cells, can be
applied to develop vaccines. Numerous promising carbohydrate-based vaccine candidates have been prepared
in recent years. This article, primarily for general readers, briefly presents the recent advances involving
carbohydrate-based vaccines, including antibacterial, antiparasite, anticancer and antivirus vaccines.
Full text: Figure 1. Current licensed Haemophilus influenzaeserotype b conjugate vaccines. CRM: Diphtheriatoxin mutant; OMPC: Neisseria meningitidisserogroup B outer membrane protein complex; PRP: Poly-ribosyl
ribitol phosphate; TT: Tetanus toxoid. Adapted from [26-30].
(Figure omitted. See article PDF.)
Figure 2. Glycosylphosphatidylinositol-based antimalaria vaccine. GPI: Glycosylphosphatidylinositol; KLH:
Keyhole limpet hemocyanin. Adapted from [32,35].
(Figure omitted. See article PDF.)
Figure 3. Synthesis of lipophosphoglycan-based antileishmania vaccine. A)Synthetic antileishmania vaccinewith different phosphoglycan structures conjugated to TetC. B)Synthesis of Leishmania donovanicaptetrasaccharide glycoconjugate with influenza HA. GPI: Glycosylphosphatidylinositol; HA: Hemagglutinin; LPG:
Lipophosphoglycan; TCEP: Tris(2-carboxyethyl)phosphine; TetC: Tetanus toxin fragment C. Adapted from [39-
41].
(Figure omitted. See article PDF.)
Figure 4. Monovalent clustered keyhole limpet hemocyanin-conjugated vaccines. (c): Cluster; Gb3:
Globosyltriaoside; KLH: Keyhole limpet hemocyanin; MUC5Ac: Mucin 5, subtypes A and C; Tn: 2-6--N-
acetylgalactosamine. Adapted from [61-64].
(Figure omitted. See article PDF.)
Figure 5. Unimolecular pentavalent vaccine conjugate. The construct contains: Globo H, STn, Tn, TF and GM2
antigens conjugated to KLH and pentavalent MUC1 to KLH. Globo H: Globohexaosylceramide; GM:
Gangliosidoses; KLH: Keyhole limpet hemocyanin; MUC: Mucin; STn: Sialyl 2-6-- N-acetylgalactosamine; TF:
Thomsen-Friedenreich; Tn: 2-6--N-acetylgalactosamine. Adapted from [68-70].
(Figure omitted. See article PDF.)
Figure 6. Fully synthetic multiple-component vaccines. A)Tn glycopeptides conjugated with Pam3Cys. B)Thetwo-component vaccine contains: Tn-, TF- or STF-modified MUC1 glycopeptide and Pam3CysSK4. C)Thetrimeric branched vaccine contains: unglycosylated Tn, TF-linked MUC1 glycopeptide and a Th epitope,
PADRE. D)The three-component vaccine contains: Tn antigen, Pam3CysSK4 built-in adjuvant and a Thepitope. E)The four-component vaccine contains: Tn-RAFT cyclic peptide, Pam adjuvant, CD8+T-cell epitopeand CD4
+T-cell eitope. MUC: Mucin; OVA: Ovalbumin; PADRE: Pan HLA-DR-binding epitope; Pam: Palmitic
acid; Pam3Cys: Tripalmitoyl-S-glyceryl-cysteinylserine; Pan-DR: CD4+T-helper epitope peptide; RAFT:
Regioselectively addressable functionalized template; SK4: Serine-lysine-lysine-lysine-lysine; STF: Sialyl
Thomsen-Friedenreich; TF: Thomsen-Friedenreich; Th: T helper; TLR: Toll-like receptor; Tn: 2-6--N-acetylgalactosamine. Adapted from [73-78].
(Figure omitted. See article PDF.)
Figure 7. Synthetic anti-HIV glycoconjugates. A)GlcNAc2Man
9bivalent glycopeptides OMPC conjugate, B)
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Man9glycodendron BSA conjugate, C)template-assembled of 6-fluorine-modified Man
4conjugate and D)Man
9-Qb bacteriophage conjugate. BSA: Bovine serum albumin; OMPC: Neisseria meningitidisserogroup B outer
membrane protein complex; p:D-proline. Adapted from [84-87].
(Figure omitted. See article PDF.)
Beyond their traditionally accepted roles as energy sources and structural polymers, glycans are associated
with cancer metastasis, protein stabilization, pathogen infection and the immune response [1,2]. Thus,
characterization and reconstruction of carbohydrate epitopes with authentic composition and presentation has
become one of the major goals in glycoscience. The attractive carbohydrate-based vaccine targets include
unique glycan structures on the surface of diverse pathogens and the aberrant glycosylation on malignant cells.
Francis and Tillett first reported carbohydrate-based vaccines in 1930 [3]. They found that injection of type-
specific polysaccharides could induce antibodies for heterologous types of pneumococci. In the mid-1940s,
Macleod et al.were the first to use polysaccharide as an immunogen against pneumococcal infection [4].
Bacterial pathogens possess a cell-surface capsular polysaccharide or a lipopolysaccharide shell. These
immense polysaccharides hide the cell-surface component of the bacteria from attack by the host immune
system and prevent antibody-triggered complement activation and phagocytosis. Therefore, antibodies that
specifically target to the bacterial surface polysaccharides may enhance elimination of the pathogens. In 1950,
Heidelberger et al.demonstrated that pneumococcal capsular polysaccharide vaccines could induce high titers
of type-specific antibodies that lasted for 5-8 months [5]. However, this discovery did not arouse much interest
until 1977, when PPV-14, a capsular polysaccharide vaccine derived from 14 pneumococcal serotypes, was
introduced. Later, the same company developed the Pneumovax 23 vaccine, which contains isolated
polysaccharides from 23 out of approximately 90 known serotypes [6,201]. Although a capsular polysaccharide
vaccine is effective in healthy adult populations, it arouses insufficient immunity in infants, young children and
the elderly; populations who are the most vulnerable to bacterial infections due to an immature or compromised
immune system.
Apart from the capsular polysaccharide vaccine, Avery and Goebel first presented the highly immunogenic
pneumococcal glycoconjugate vaccine by coupling carbohydrate to carrier protein [7]; the success of this
method has been widely accepted as a breakthrough in vaccine development. To date, four types of
glycoconjugate vaccines have been licensed that successfully prevent bacterial infections caused by
Haemophilus influenzaetype b, Neisseria meningitidis, Salmonella enterica Serovar Typhiand Streptococcus
pneumoniae[8]. Moreover, several vaccines are undergoing clinical evaluation in Phase II trials against
Staphylococcus aureus, Shigella sonnei, Shigella flexneriand many others.
After the success of antibacterial glycoconjugate vaccines, researchers shifted their attention to the
development of antiprotozoan, antiviral and anticancer vaccines. Advances in carbohydrate chemistry and an
explosion in glycomics have paved the way for vaccine design for a wide variety of diseases. Although manyexcellent reviews have already discussed the specific applications of carbohydrate-based vaccines, we intend
to provide a broader spectrum of recent discoveries in carbohydrate-based vaccination.
Antibacterial vaccinesDespite modern medical advances, bacterial infections remain a major cause of death for infants and children,
particularly in developing countries. Vaccine development could bring such life-threatening diseases to a
minimum. Among many types of antibacterial vaccine, Macleod et al.first successfully created a nonprotein
vaccine with isolated bacterial capsular polysaccharide (CPS) for preventing pneumonia [4]. Bacterial CPSs are
attractive vaccine targets because they are mostly virulence factors, while nonencapsulated bacteria have
reduced pathogenicity. Notable triumphs of polysaccharide vaccines have been made against several bacterial
infections, including S. pneumoniae, H. influenzaetype b, N. meningitidisand S. typhi. However, because
polysaccharides elicit insufficient immune responses, CPS vaccines remain ineffective for infants, the most
vulnerable population to infections.
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Polysaccharides have been considered as T-cell-independent type 2 (TI-2) antigens. In the absence of T-cell-
mediated activation, TI-2 antigens stimulate predominantly low-affinity, non-class-switching IgM antibody
production. Moreover, TI-2 antigens generally do not induce antibody affinity maturation and immunological
memory. To increase the immunogenicity, Avery and Goebel first conjugated oligosaccharides to an
immunogenic carrier protein [7]. The glycoconjugate can be digested by antigen-presenting cells and the
peptide fragments can be preented to the MHC-II complex. Recognition of the peptide-loaded MHC-II complex
and costimulatory signals can activate Th cells and induce Th-2 cytokine production. Th-2-bias cytokines can
further facilitate B-cell maturation into antibody-secreting plasma cells and immunological memory cells. In order
to enhance immunogenicity and efficacy in infants and the elderly, numerous glycoconjugate vaccines have
been investigated and have become widely used for many national immunization programs. In the following
section, we will describe current licensed glycoconjugate vaccines and some promising vaccine candidates that
are undergoing clinical evaluation (Table 1).
Neisseria me ningitidisNeisseria meningitidis, a Gram-negative diplococcal bacterium, causes sporadic bacterial meningitis in
industrialized countries and epidemics in Africa and Asia. The meningococcal disease mostly affects young
adults and children, especially those under 2 years of age. The epidemiology of meningococcal disease
worldwide is complicated by the presence of 12 different serotypes, which are classified according to the
antigenic structure of their polysaccharide capsules. The vast majority of diseases are caused by five
serogroups (A, B, C, Y and W-135) of the bacteria. Group A occurs predominantly in developing countries; while
groups B, C and Y are the major causes of meningitis in developed countries.
The first polysaccharide vaccine used capsular polysaccharides of group A and C N. meningitidisas the
immunogens. The bivalent vaccine was able to induce specific antibody in humans against the respective
serogroups and was subsequently licensed in the USA in 1976 [9]. The current use of a quadrivalent vaccine
(quadrivalent meningococcal polysaccharide vaccine [MPSV4]) against group A, C, W-135 and Y was approved
in 1981. However, the development of quadrivalent polysaccharide vaccines still encounters a variety of
limitations:
* Short protection period and poor immunogenicity in infants under 2 years of age [10];
* Ineffectiveness in attempts to overcome the poor immunogenic properties via repeat immunization [11];
* Deficient protection for group B meningitidis (still the major cause of meningococcal disease worldwide).
Therefore, the vaccine is more suitable for short-term protection, such as for travelers, rather than a national
vaccination campaign. In 2005, a quadrivalent (A, C, Y and W-135) diphtheria conjugate vaccine (MCV-4,
Menactra, Sanofi Pasteur Inc., PA, USA) was developed to improve immunogenicity in young children [12]. In
February 2010, an alternative vaccine (MenACWY-CRM, Menveo, Novartis Vaccines and Diagnostics, Inc.,
MA, USA) was licensed and recommended for individuals aged 11 to 55 years based on its statistically higherseroresponse and comparable safety profile to the older vaccine [13].
However, there is still no effective vaccine against group B meningitidis. The major difficulty in this type of
vaccine development is the structural similarity between normal human tissue and conserved antigenic
structure, (2[arrow right]8)-N-acetylneuraminic acid (polysialic acid [PSA]). Concerns about the high risk of an
autoimmune response limits the progression into of human clinical trials. A preclinical study using N-
propionylated PSA conjugate (NPrPSA-TT) showed elevated bactericidal IgG antibodies in mice without the
detection of autoantibody. A similar result was observed in NPrPSA-PorB (group B meningococcal porin
protein) conjugate vaccinated baboons and monkeys [14,15]. However, the vaccine development has been
suspended because the NPrPSA conjugate failed to induce bactericidal antibodies in adult male volunteers [16].
Although discouraging, this pioneering study ensured the feasibility of modified polysaccharides as an attractive
immunogen to induce functional antibodies. Overall, the capsular polysaccharide still remains an achievable
and challenging target for further investigation in human trials.
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Streptococcus pneumoniaeStreptococcus pneumoniae, a Gram-positive -hemolytic bacterium, has been recognized as a major
contributor to invasive pneumonia, bacteremia, meningitis and noninvasive otitis media. Children under 2 years
of age and adults over 65 years of age are most susceptible to infectious pneumococcal disease. There are
more than 90 types of pneumococci, which are classified by different capsular polysaccharide structures,
prevalence and the extent of drug resistance. The vast majority of diseases are caused by the following
serogroups, in descending order: 14, 6, 19, 18, 9, 23, 4, 1 and 15 in developed countries, but 6, 14, 8, 5, 1, 19,
9, 23, 18, 15 and 17 in developing countries [17,18].
The 14-valent polysaccharide vaccine was first described in 1977 and subsequently replaced by a more
effective 23-valent polysaccharide vaccine (PPV23 [Pneumovax, Merck, PA, USA]) in 1983. Pneumovax used
purified pneumoniae capsular polysaccharide from 23 serotypes, which accounted for 88% of bacteremic
pneumococcal diseases. However, this standard vaccine is ineffective for children under 2 years of age and the
high-risk elderly [19,20]. In 2000, a heptavalent vaccine (PCV7 [ Prevnar, Wyeth, PA, USA]), consisting of
conjugates of diphtheria toxin mutant, CRM197
, and 4, 6B, 9V, 14, 18C, 19F and 23F capsular polysaccharides,
was licensed for routine vaccination and prevention of invasive pneumococcal disease in the USA. The PCV7
vaccine was widely used in the developed world with theoretical coverage of 88.7% in North America, but only
43-67% in Asia and Africa, where nonvaccine serotypes 1 and 5 are highly prevalent [21]. As a result, several
other vaccines are undergoing clinical evaluation in order to increase protection from other prevalent serotypes
[22]. In February 2010, a 13-valent pneumococcal conjugate vaccine (PCV13) with additional serotypes
coverage (1, 3, 5, 6A, 7F and 19A) was approved by the US FDA and expected to offer more protective efficacy
for children aged from 2 to 59 months in most pandemic areas [23]. GlaxoSmithKline's Synflorix(TM),
GlaxoSmithKline Biologicals, Rixensart, Belgium (10-valent pneumococcal conjugate) was licensed in Europe in
2010.
Haemophilus influenzae type b)Haemophilus influenzae, a Gram-negative bacillus, can be recognized as six encapsulated groups (a-f), and
normally inhabits the nasopharyngeal region. However, when infection spreads to the cerebrospinal fluid or
bloodstream, H. influenzaeserotype b (Hib) is the main cause of the severe clinical symptoms of invasive
diseases, such as bacteremia, pneumonia and meningitis. Children under 5 years of age are most susceptible
to invasive disease and account for 80% of all cases. The first-generation vaccine, which was based on a
repeating linear poly-ribosyl ribitol phosphate (PRP), became available in 1985 [24]. However, like other
polysaccharide vaccines, the immune response is highly age-dependent. In infants under 2 years of age,
immunogenicity is uniformly poor and boosters do not elicit anamnestic responses [25].
Taking advantage of polysaccharide-protein coupling, second-generation Hib vaccines (HibTiter, PedvaxHIB
[Merck, PA, USA], ActHib
[Sanofi Pasteur Inc., PA, USA] and Vaxem-Hib
[Chiron, CA, USA]) composed ofdepolymerized PRP linked to various carriers were subsequently licensed in the 1990s (Figure 1) [26-30]. The
glycoconjugate vaccines sufficiently protected infections from Hib. and, thus, are recommended for vaccination
campaigns. However, the cost of available vaccine was among the major obstacles preventing it from becoming
part of the routine immunization program in developing countries [31]. To search for new production
alternatives, Verez-Bencomo et al.proposed a feasible methodology for large-scale manufacture of Hib
polysaccharide fragments. The resulting conjugate vaccine exhibited an excellent safety profile and
immunogenicity and was later approved in Cuba as part of the country's national immunization program in 2004
[30].
The successful large-scale synthesis of ribosylribitol oligomers utilized a key step in polycondensation reaction
with H-phosphonate chemistry. Ribosylribitol oligomers were conjugated to thiolated tetanus toxoid (TT) with an
average final formulation of eight repeating units and 1:2.6 synthetic PRP to TT ratio by weight (Figure 1) [30].
The resulting conjugate vaccine demonstrated a comparable bactericidal antibody response to the commercially
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available vaccine (Vaxem-Hib) in the Phase II trial, involving a total of 1141 infants. Subsequently, several
clinical trials also showed that the vaccine was effective in children with a 99.7% success rate and is now part of
Cuba's national immunization program. This successful study demonstrated a feasible alternative synthetic
strategy that obviates the complexity of vaccine production, including bacteria cultivation, purification and
modifications of CPS. In addition, homogenous compositions of a synthetic PRP minimize batch-to-batch
variation and permit higher quality control during the manufacturing process. Overall, the concept of synthetic
strategy provides a new platform for further development of conjugate vaccines against other infectious
diseases.
Antiparasitic vaccinesParasitic infections are among the most prevalent and severe diseases in human and other mammals. Half of
the world's population, especially those in developing countries, are at risk of the most notorious parasitic
diseases (i.e., malaria, leishmaniasis and trypanosomiasis). Although a wide variety of antiparasitic drugs are
available for treating malaria, reinfection and drug resistance have been major issues, notably in the case of
chloroquine. As a result, producing a widely available vaccine that provides high-level protection for a sustained
period is decisively the ultimate goal. However, to date, there is no commercial vaccine available for human
parasites, regardless of the notable success in several bacterial vaccines. Unlike bacterial vaccines, the major
obstacles for developing antiparasitic vaccines are:
* Complex morphological transitions during the parasites' life cycle, which constantly alters targeted antigens;
* The difficulty of large-scale cultivation, purification and characterization of parasitic surface oligosaccharides
(glycocalyx);
* The elicited antibody-mediated immunity does not sufficiently eradicate intracellular parasites.
MalariaWhile remarkable advances have been made in malaria research, this disease remains a major problem in
tropical areas. Half of the world's population still lives at risk of malarial transmission. Malaria infects more than
5% of the world's population and kills an estimated 1 million people, primarily young children, in Africa annually.
A variety of malaria vaccines are currently undergoing clinical trials. In 2007, the WHO reported that 15 vaccine
candidates against different stages of Plasmodium falciparumhad entered Phase I trials and another ten
vaccines were in Phase II trials [202]. However, the majority of vaccine candidates are peptide vaccines, which
are beyond the scope of this article. Here, we will briefly introduce the novel vaccine target based on
carbohydrate epitopes designed by Seeberger et al.[32].
The malaria parasite P. falciparumshowed particularly low levels of N- and O-linked glycosylation but up to 90%
highly conserved glycosylphosphatidylinositol (GPI) modifications on parasite proteins [33]. Parasite GPIs have
been identified as the prominent toxin that may contribute to malaria pathogenesis and cause symptoms
reminiscent of acute malaria in a mouse model. Therefore, the unique and abundant GPI modificationsrendered it a good target for vaccine development. Both Man
3and Man
4GPI have been observed on P.
falciparum, but their relative ratio varied continuously during maturation [34]. However, only the Man4GPI
anchor is displayed on parasite proteins while Man3GPI can exist as the free glycolipid form on the parasite cell
surface. Based on the nontoxic P. falciparumGPI sequence, Seeberger et al.used automated solid-phase
synthesis of the Man4GPI core structure, (Man1[arrow right]2)-(NH
2-CH
2-CH
2-PO
4)-6-Man(1[arrow right]2)-
Man(1[arrow right]6)-Man(1[arrow right]4)-GlcNH2(1[arrow right]6) myo-inositol- 1,2-cyclic-phosphate, and
conjugated it to maleimide-activated ovalbumin (OVA) and keyhole limpet hemocyanin (KLH) carrier proteins
(Figure 2) [32,35]. Mice immunized with P. falciparumGPI synthetic glycoconjugate vaccine were substantially
protected against Plasmodium berghei-induced cerebral malaria, and mortality was reduced. However, there
was no significant difference in parasitemia levels between vaccination and control groups, suggesting that the
prevention of mortality by anti-GPI antibody does not interfere with the parasite proliferation, but possibly
neutralizes the toxic GPIs.
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Although vaccination proved to be effective in the mouse model, the correlation between anti-GPI antibody
specificity and antitoxic immunity level remains unclear. Therefore, Seeberger et al.generated the synthetic GPI
array (seven GPI derivatives) to analyze anti-GPI antibody binding affinity from healthy subjects in an endemic
malaria region [36]. Their results suggested that the fourth mannose plays a key role in recognition of GPI-
reactive antibodies, but that the phosphate ethanolamine on the third mannose generally had no influence on
binding affinity. Overall, Seeberger's pioneering vaccine study and novel microarray platform using synthetic P.
falciparumGPIs proved the feasibility for preventing severe malaria and the possibility for high-throughput
malaria diagnosis. Further development of the glycoconjugate vaccine is currently undergoing clinical evaluation
by Ancora Pharmaceuticals (Cambridge, MA, USA).
LeishmaniasisLeishmaniasis is caused by intracellular protozoa that survive and replicate in intracellular vacuoles within
macrophages. The Leishmaniagenus has traditionally been differentiated into multiple species that cause
cutaneous, mucosal or visceral diseases [37]. Leishmaniasis is typically transmitted by Phlebotominesandflies
and occurs in 88 countries worldwide with an estimated 2 million cases every year. Cutaneous leishmaniasis
accounts for more than half of the Leishmania diseases and is mainly caused by L. major, L. tropicaand L.
mexicana, while L. donovanigives rise to the most severe visceral leishmaniasis. Although a variety of drugs
were developed for Leishmania treatment many decades ago, the most commonly used antimonials remain
expensive. Moreover, significant side effects and prevalent drug resistance make the development of a
prophylactic vaccine an urgent need. However, the vector-borne diseases are particularly difficult to tackle, as
protection must be effective against their arthropod vectors that enhance the transmission of parasites.
The cell surfaces of Leishmaniaspecies share similar lipophosphoglycan components such as the conserved -
6Galb1-4Man1-PO4- disaccharide repeating unit. The lipophosphoglycans are recognized as an important
virulence factor, crucial for the survival of the parasite in the insect vector, and pivotal for the entry of the
parasite into its mammalian host [38]. As a result, extensive studies were focused on synthesis of this definite
polysaccharide structure for vaccine development [39-41]. As reported by Rogers et al., phosphoglycans of
various structures from L. major, L. mexicanaand L. donovaniwere chemically prepared then conjugated to the
peptide of tetanus toxin (Figure 3A). Furthermore, to evaluate vaccine efficacy, groups of mice were immunized
with different glycoconjugates and then directly challenged by L. mexicana-infected sandfly bite. The majority of
glycoconjugates were unable to protect against fly bite challenge. However L. mexicanaglycoconjugate
conferred significant protection compared with tetanus toxin control. The study demonstrated a 50% reduction in
final lesion size and a 94% reduction in parasite burden [40]. The results revealed that the glycoconjugate
vaccine may induce specific antibody production in a highly species-dependent manner. Overall, the vaccine is
the first demonstration that a synthetic glycoconjugate vaccine can have a direct antiparasitic effect in
leishmaniasis rather than only neutralizing antitoxic effects as reported in malaria models [32].Recently, another glyoconjugate vaccine was developed based on the cap tetrasaccharide of L. donovani
(Figure 3B) [39]. The synthetic cap tetrasaccharide antigen was conjugated to succinimide-activated influenza
hemagglutinin (HA) and then formulated into the virosomal carrier, immunostimulating reconstituted influenza
virosomes. In addition, the virosomal formulations elicited both specific IgM and IgG antibodies in a mouse
model and reacted in vitrowith the natural L. donovani. These findings supported the assertion that the vaccine
candidate was highly immunogenic and had a great potential against leishmaniasis. Finally, with the advance of
more precise carbohydrate structure determination [42] and methods for large-scale synthesis, the development
of antileishmania and other parasitic vaccines has become more promising.
Anticancer vaccines immunotherapeutics)Cancer vaccines are vaccines that either prevent infection with cancer-causing viruses (prophylactic) or prevent
re-emergence or treat existing cancers (therapeutic). They are emerging as a possible treatment for human
malignancy, as prophylactic cancer vaccines against hepatitis B virus-associated liver cancer and human
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papilloma virus-associated cervical cancer were successfully developed and licensed. Besides the prophylactic
vaccines that target cancer-causing viruses, therapeutic cancer vaccines are also being developed (e.g.,
Provenge, Dendreon, WA, USA which has recently been approved to treat advanced prostate cancer
patients). The major development of cancer vaccines focuses mainly on specific protein or peptide antigens;
however, abundantly expressed tumor-associated carbohydrate antigens (TACAs) were also recognized as
specific molecular markers and highly correlated with the various stages of cancer progression [43,44].
Although relatively little is known about the role of surface glycans in malignant cells, evidence has shown that
passively administered or vaccine-induced antibodies against TACAs correlate with improved prognosis [45-47].
Therefore, TACAs have been targeted for cancer vaccine development.
The major challenge of targeting TACAs is their poor immunogenicity and TI feature. Without Th-cell
involvement, TI antigens generally induce low-affinity IgM antibodies. However, antibody-dependent cell-
mediated cytotoxicity (ADCC) is important for anticancer action, and IgM does not stimulate ADCC. Besides, the
antibody levels may constantly decline without arousing immunological memory; thus, repeated vaccinations
are required to maintain antibodies at a level suitable to provide protection. Recent advances have been made
in conjugating TACAs to a variety of carrier proteins (CRM197
, TT, outer membrane protein [OMP], bovine
serum albumin [BSA] and KLH) or peptides (mucin [MUC]1) in order to promote Th-cell activation. However,
despite glycoconjugate vaccines proving successful in treating antibacterial infections, hurdles remain for
cancer vaccine development: first, difficulties of large-scale isolation and purification of homogenous defined
TACAs impede vaccine manufacture; and second, TACAs could be recognized as 'self' antigens during specific
stage development and sporadically express in normal tissues; therefore, antibody production is limited.
Although several elegant reviews have discussed many aspects of cancer vaccines [48-51], we will discuss
recent efforts in cancer vaccine development in the following section. Table 2 lists the status of carbohydrate-
based anticancer vaccines.
Monovalent vaccineThe early generation of carbohydrate-based cancer vaccines was monomeric and consisted of a single antigen
(B-cell epitope) conjugated to an immunogenic carrier protein, in order to enhance the immunogenicity of the
carbohydrate epitope. Helling et al.linked the tumor-associated ganglioside to various carriers [52]. They first
extracted the ganglioside antigen GD3 from bovine brain tissue, and then selectively cleaved it with ozone at
the C4-C5 double bond in the ceramide backbone. After introducing an aldehyde group, the GD3 ganglioside
was coupled to the aminolysyl groups of proteins via reductive amination. Conjugates were constructed with a
great variety of carriers, including KLH, BSA, OMP, multiple antigenic peptide (MAP) and polylysine. Of the
proteins tested for conjugation, KLH showed the strongest ability to induce IgM and IgG antibodies in the
presence of immunological adjuvant, QS-21. In contrast to the GD3 conjugates, GD3 antigen alone induced a
weak IgM response and no IgG response. Their study demonstrated that KLH with QS-21 adjuvant was themost promising immunogenic carrier to enhance the antibody response. Consequently, several ganglioside-
based conjugate vaccines were constructed (e.g., GD2-KLH [53] and GM2-KLH [54]). Among the vaccines,
GM2-KLH showed great promise in clinical evaluation [55].
An alternative approach using synthetic chemistry can also be used to prepare highly complex TACAs.
Danishefsky and coworkers first reported synthesis of the complex Globo H antigen by convergent glycal
assembly strategy to KLH conjugate [56-58]. The Globo H-KLH conjugate was synthesized by reductive
amination after ozone cleavage of allyl glycoside. The Globo H epitope to carrier ratio was further improved
(from 150:1 to 720:1) via a MMCCH linker. In the Phase I trial [57], the conjugate vaccine treatment appeared to
be safe and was capable of inducing a high titer of IgM antibodies that participate in complement-mediated
tumor cell lysis. Overall, evidence of disease stability and the decrease of prostate-specific antigen slope in
treated patients suggested the feasibility of a glycoconjugate vaccine. In addition, a similar synthetic approach
was utilized to synthesize monomeric vaccines (e.g., Fucosyl-GM1-KLH [59] and Ley-KLH conjugate [60])
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against other cancer types.
Since TACAs are likely to be presented in clusters at the surface of cancer cells, single antigens on the
chemical clusters were expected to more closely mimic the architecture of the tumor cell surface. Accordingly,
Danishefsky also developed various KLH-conjugated cluster vaccines (Figure 4; e.g., 2-6-- N-
acetylgalactosamine [Tn](c), Thomsen-Friedenreich [TF](c) [61,62], Sialyl 2-6--N -acetylgalactosamine
[STn](c) [63], and Gb3(c) [64]). In the STn(c) vaccine trial, higher levels of IgM and IgG antibodies were induced
than when using the noncluster STn vaccine, suggesting the significance of clustered antigen presentation.
Polyvalent vaccineWhile the monovalent vaccines produced promising outcome in preclinical and clinical trials, Danishefsky and
Livingston's group has been targeting more TACAs with a particular cancer type in a single vaccine. They
established a hexavalent mixture vaccine consisting of six individual KLH conjugate vaccines: GM2, Globo H,
Ley, MUC1, Tn(c) and TF(c). The conjugate vaccine was co-administered with QS-21 to 30 high-risk prostate
cancer patients in a Phase II clinical trial [65]. The vaccine was well tolerated with no clinical adverse reaction
and all patients showed significant antibody production against at least two TACAs. However, compared with
the previous individual monovalent trials, the antibody titers against TACAs were lower. In addition, a similar
clinical trial was performed for patients with epithelial ovarian, fallopian tube or peritoneal cancer. The
heptavalent vaccine consisted of GM2, Globo H, Ley, Tn-MUC1, Tn(c), STn and TF(c), and was
coadministered with QS-21 [66]. Eight out of nine patients in the final evaluation showed elevated immune
response against at least three antigens and substantial complement-dependent cytotoxicity against MCF-7
breast cancer cells. However, except for anti-MUC1 IgG, the conjugate vaccine induced only IgM antibodies
against other TACAs in those patients.
Obviously, polyvalent antigen vaccines can be constructed by covalently linking different antigens into a single
backbone. Danishefsky's group were the first to synthesize the unimolecular pentavalent vaccine, which
contains five prostate cancer-associated carbohydrate antigens (Globo H, Ley, STn, TF and Tn) as superior
mimics of cell-surface antigens [67]. The antigen-containing amino acid monomers were assembled in a linear
sequential manner, from relatively small Tn to complex Globo H antigen. The glycopeptides were assembled
from fully protected glycosylamino acids with terminal fluorenylmethyl carbamate protecting groups by solution-
phase 9-fluorenylmethyloxycarbonyl-based peptide chemistry. The subsequent conjugation to the carrier protein
was achieved via derivatization of KLH with maleimide, and followed by Michael addition of the thiol handle to
obtain a pentavalent conjugate (ratio: 228:1). The evaluation of the immunogenicity of unimolecular pentavalent
vaccine showed higher immune response against Globo H, TF and STn antigens than the corresponding pooled
monovalent vaccines [68]. However, in both vaccines, no detectable response against Leywas observed,
probably owing to the immunotolerance of its high endogenous expression pattern. Moreover, the immune
reactivity analysis by fluorescence-activated cell sorting suggested that the vaccine-induced antibodies werecapable of recognizing three tumor cell lines. The biological results prompted the same group to develop a
second-generation pentavalent vaccine (Figure 5) [68-70]. In construct, first, the previously used Leyantigen
was replaced by tetrasaccharide GM2, because GM2 antibody levels were correlated with survival in the GM2-
alone vaccine human trial [45]. In particular, an improved conjugation protocol (via preservation of the intact
mercapto group to reduce unnecessary disulfide formation) was developed to obtain a higher epitope to carrier
ratio (505:1). Impressively, the second-generation pentavalent vaccine successfully induced antibodies against
all five TACAs and MCF-7 breast cancer cell lines. Furthermore, an additional immunogenic component, MUC1
random repeat, was introduced to trigger the desired T-cell-mediated immunity.
Overall, the synthesis of complex unimolecular polyvalent vaccine utilized a single bioconjugation reaction
rather than multistep low-yielding conjugations for each TACA; therefore, regulatory validation of each individual
component of vaccine mixture could be simplified. Moreover, compared with a mixture of monomeric vaccines,
the unimolecular polyvalent vaccine used less carrier protein, thus, the epitopic immune suppression was
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minimized.
Although TACA-protein conjugate vaccines are promising and undergoing clinical trials, some limitations
remain. First, the bioconjugation reaction is difficult to control, and the product may have undetermined
ambiguous compositions. The resulting batch-to-batch variations therefore influence the clinical evaluation and
vaccine efficacy. Second, the linkers for carbohydrate and protein conjugation may also be immunogenic,
leading to epitopic suppression [71]. Third, highly immunogenic carrier protein, such as KLH, ineluctably elicits a
strong immune response against the carrier itself. However, the undesired and irrelevant antibody production
may cause suppression of targeted epitopes and even interfere with the vaccine efficacy [72].
Fully synthetic multicomponent vaccineTo overcome these issues, fully synthetic homogeneous vaccines were designed. An early attempt was
described by Toyokuni et al.who covalently linked a dimeric Tn antigen to a Toll-like receptor (TLR) ligand,
tripalmitoyl-S-glyceryl-cysteinylserine (Pam3Cys) derived from Escherichia colilipoproteins (Figure 6A) [73].
Although low titers of specific IgG antibodies were induced, this study demonstrated that a small carbohydrate
antigen could elicit an immune response without the involvement of a carrier protein. Those devoid of IgG
antibody isotype indicated the importance of a Th-epitope in antibody affinity maturation. Later, Kunz et al.
developed a trimeric branched construct containing unglycosylated, Tn, and TF bearing MUC1 glycopeptide
with additional Th epitope, PADRE (Figure 6B) to promote antibody class switch and to target the
heterogeneous tumor surface epitopes. In their study, mouse antiserum were raised towards all three antigens
and also recognized human mammary adenocarcinoma cells [74]. In another attempt, Kaiser et al.efficiently
synthesized a modified MUC1 glycopeptide with Tn, TF or STF antigens and TLR-2 ligand Pam3CysSK4 by
fragment condensation (Figure 6C) [75]. The resulting glycoconjugate can selectively induce antisera when in
combination with complete Freund's adjuvant (CFA) and incomplete Freund's adjuvant (IFA).
Impressively, Boons et al.developed a three-component vaccine combining all required elements, a B-cell
epitope (Tn antigen), a built-in adjuvant (Pam3CysSK4) and a Th epitope (mouse MHC II-restricted peptide)
(Figure 6D) [76]. The lipid moiety of the vaccine coordinating with liposomal delivery assisted multivalent
antigen presentation and retention into liposomes; thus, the uptake by antigen-presenting cells was enhanced
and both T- and B-cell activation was triggered. Their study showed that the synthetic three-component vaccine
elicited exceptionally high titers of anti-MUC1 IgG antibodies and could further recognize MCF-7 human breast
cancer cells. When coadministered with QS-21, the vaccine did not elicit a significant increase in IgG1 class, but
a mixed Th1/Th2 response was observed. In addition, low titers of antibodies against Th epitopes indicated that
immune suppression was limited.
Later, Renaudet et al.reported a molecular defined four-component glycolipopeptide (GLP) vaccine PAM-OVA
257-264-PADRE-RAFT (-GalNAc)
4based on oxime/disulfide bond formation [77,78]. The GLP vaccine contained:
a cluster of TACA B-cell epitope; a CD4
+
Th epitope peptide (Pan-DR); a CD8
+
cytotoxic T lymphocyte epitopepeptide; and a palmitic acid built-in adjuvant. In their latest study, they took advantage of the synthetic versatility
of regioselectively addressable functionalized template (RAFT) platform to generate a Tn-clustered
glycolipopeptide vaccine (Figure 6E), which facilitated efficient antigen delivery. Furthermore, the built-in CD4+
and CD8+epitopes assisted in sustaining and priming both humoral and cellular immunity. Instead of using
Pam3CysSK4, which spontaneously forms stable aggregates, they exploited mono-palmitic acid, which has
higher solubility and much easier production and purification procedure under GMP conditions. In the animal
study, the self-adjuvanting GLP vaccine was well tolerated without local or adverse reactions. Moreover, the
vaccine showed promising prophylactic effects in a xenograft model. No tumor developed in any of the
vaccinated mice, and the survival rate was 100% when challenged with murine melanoma MO5 tumor cells
during the monitoring period of 90 days [78].
Overall, the new chemically well-defined synthetic vaccines have many advantages and can be made in a
reproducible manner. The incorporation of minimum relevant elements is required for a desired immune
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response and, hence, limits the immune suppression and any unnecessary immune response against other
antigenic epitopes. Moreover, the covalent incorporation of adjuvant-like TLR ligands may enhance the local
production of cytokines at the adjacent site and facilitate the maturation of relevant immune cells [76].
Furthermore, the CD8+epitope of the four-component vaccine is also crucial in cancer immunity in priming a
cytotoxic T-cell response. However, the mutually synergistic or antagonistic effects of humoral and cytotoxic
responses should be thoroughly considered to ensure vaccine efficacy. Despite the advances in vaccine
development, many obstacles remain: first, the single carbohydrate antigen induces antibody against solely
restricted tumor types or in a small portion of patients. Second, whether this synthetic strategy is applicable for
more complex glycans, such as ganglioside, or large-scale synthesis still needs to be verified. Third, the
therapeutic effect of vaccination in directly eradicating tumors is still limited. Fourth, it is difficult to select
appropriate models to elucidate the vaccine efficacy and bridge the gap between preclinical and practical
human cancer therapy.
Antiviral vaccinesVirus infections cause a great variety of diseases, ranging from the common cold, to influenza, to chronic
hepatitis and life-threatening AIDS. Recent studies have shown that the glycoproteins expressed on the
surfaces of various viruses are highly correlated with their virulence and immune evasion. In contrast to bacteria
or parasites, viruses can take advantage of host glycosylation machinery to construct their own outer-surface
glycans. The host-synthesized glycans are considered to be immune tolerated and, thus, enable viruses to
escape immune surveillance. Moreover, the rapidly mutating virus genome can alter glycosylation sites and
increase the structural diversity of viruses. Despite these challenges, recent advances have been made in
developing carbohydrate-based antiviral vaccines, such as HIV and influenza virus.
HIVHIV is a retrovirus that infects cells of the immune system and causes AIDS worldwide. As the WHO reported in
2009, the number of people living with HIV infection reached an estimated 33.4 million, and the number of
deaths caused by AIDS is approximately 2 million annually. Although important progress has been achieved in
preventing new HIV infections and lowering the mortality rate, the total number of infected is continuously
increasing, especially in Africa and East Asia. Therefore, the development of a prophylactic vaccine still remains
an urgent need.
It is well known that the heavily glycosylated gp120 on the surface of HIV can aggravate immune evasion by
shielding peptide epitopes from immune surveillance and promote infection by interaction with dendritic cells.
Moreover, the conserved dense cluster of oligomannose on gp120 has been recognized as the epitope for the
broadly neutralizing 2G12 antibody. As a result, this relatively unique oligomannose cluster has been targeted
for chemical synthesis in order to elicit 2G12-like antibodies. A combination of crystallographic, glycan array and
modeling studies have shown that Man 9(GlcNAc)2at positions 332, 392 and 339 contributes to the gp120-2G12 interaction with nanomolar affinity [79]. Wang et al.reported that using cholic acid and
D-galactose as
oligomannose cluster scaffolds can increase affinity to monoclonal antibody 2G12 in the range of 21-13 M
[80,81]. However, it remains beyond the affinity between gp120 and 2G12 which was found to be in the
nanomolar range. Recently, Wong's group developed synthetic multivalent Man4 and Man9 glycodendron (3-,
9- and 27-mer) via a copper(I)-catalyzed cycloaddition, and the synthetic glycodendron, especially (Man9)9-
dendron, exhibited promising inhibition ability of both gp120 mAb 2G12 and gp120 DC-SIGN in the nanomolar
range [82]. The results indicated the potential of synthetic glycodendrons to inhibit dendritic cell-mediated HIV
infection. In addition, Calarese et al.reported that Man4 of the D1 arm can inhibit 2G12 binding to gp120 as
efficiently as Man9
(GlcNAc)2
, indicating the potential use of Man4 as a minimum recognition immunogen [83].
Unfortunately, the significantly elicited IgG in rabbits induced by synthetic (Man9)9-dendron or Man4-BSA
conjugates can only bind to glycan structures presented by antigens, but does not cross-react with gp120 [84].
Through disappointing, limited progress, several synthetic strategies continuously performed to yield multivalent
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oligomannose mimetics by displaying on Neisseria meningitidisserogroup B outer membrane protein complex
[85], RAFT (cyclic-decapeptides) [86] and Qb bacteriophage (Figure 7) [87]. Overall, proper optimization of:
glycan spacing, flexibility and immunogenicity are required for synthetic oligomannose to adequately induce
2G12-like neutralizing antibody.
Influenza virusInfluenza virus causes acute viral disease of the respiratory tract and affects millions of people each year.
Among the three virus groups, influenza A is notorious for causing major epidemics and pandemics. The virus
serotypes are named according to two surface glycoproteins, HA and neuraminidase (NA). To date, 16 HA and
nine NA serotypes are described, but three major HAs (H1, H2 and H3) and two NAs (N1 and N2) account for
influenza pandemics in humans. In 1918, the Spanish H1N1 pandemic killed approximately 50 million people
worldwide, in 1957 the Asian influenza H2N2 outbreak killed approximately 2 million people and in 1968 the
Hong Kong influenza pandemic was caused by H3N2 [88]. Both HA and NA glycoproteins recognize host
sialylated receptors with diverse binding specificity. In addition, extensive studies showed that the
carbohydrates on HA and NA may assist in protein folding, virus entry, immune evasion and neurovirulence.
Presently available seasonal influenza vaccines are mainly comprised of purified HA/NA blends and are
effective for many people. However, the immunogenicity is reduced for high-risk populations. Thus, research
focusing on the extensively glycosylated HA of virulent strains is urgently needed. Recently, Wong et al.
discovered that systematic simplification of N-glycans on HA (from complex type HAfgto desialyated complex
type HAds
and from high mannose-type HAhm
to GlcNAc HAmg
) resulted in a successive increase in binding
affinity to 2,3-receptor sialosides [89]. Circular dichroism spectra of different HAs also implied that HA with a
single GlcNAc retained the intact secondary structure compared with the fully glycosylated HA. Moreover, HAmg
antiserum showed stronger neutralization and was much more protective than HAfgvaccination in a lethal-dose
of H5N1 challenge study. Overall, HAmg
is a promising vaccine candidate for influenza because it exposes the
conserved peptide epitopes that are much more immunogenic but were originally hidden by massive glycans. In
addition, the HA with a single GlcNAc showed relaxed specificity but enhanced affinity to 2,3-sialoside and can
be more easily prepared (e.g., via yeast). This strategy paves the way for vaccine design. Together with
successful experience, carbohydrate-based vaccines should facilitate the development of vaccines against viral
infections in the future.
Expert commentaryIn this article, we discuss early efforts and the current state of carbohydrate vaccine research for a variety of
human diseases. The prominent successes in bacterial vaccines provide insights into future vaccinology.
However, considerable issues and challenges remain to be addressed. For instance, identification of varying
parasitic epitopes during the parasite's life cycle and stimulation of both humoral and cell-mediated immunity
are major issues in developing parasitic vaccines. In HIV vaccination, the key challenges are: how to design andconstruct proper presentation of a dense cluster of glycans in order to induce functional neutralizing antibody as
well as to broadly neutralize highly mutated virus strains. Cancer vaccine development encounters similar
difficulties in the aforementioned fields; for example, how to overcome the immunotolerance of TACAs to
generate high levels of tumor-specific antibodies, which can eradicate tumor cells. In addition to humoral
immunity, cytotoxic T lymphocyte response is believed to play a major role in cancer immunotherapy. It is now
accepted that glycopeptides can mediate classical MHC-mediated immune responses. Therefore, cellular
immunity is expected to eliminate tumor cells and may provide an additional opportunity for synthetic
multicomponent vaccines. In recent decades, synthetic chemistry and advanced vaccinology have provided
solutions to common obstacles, such as heterogeneity and poor immunogenicity. Although significant
challenges remain, the rapid growth of glycomics and vaccinology will offer opportunities and accelerate the
development of carbohydrate-based vaccines.
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Although there have been great advances in complicated oligosaccharide synthesis by using programmable
one-pot or automatic solid-phase methods, no automatic machine is currently available in the market. To design
a dream machine for oligosaccharide synthesis is a long-term interest in this field. Carbohydrate-based vaccine
development will benefit from advances in carbohydrate synthesis, development in glycan structures analysis
methods and manipulation through the emerging fields of glycochemistry, glycobiology and immunology.
Carbohydrate recognition is a crucial event in many biological processes, including the development of diseases
such as AIDS, swine influenza and cancer. Thus, understanding and recreating authentic carbohydrate epitope
presentation and composition are important goals in glycoscience and have great value in drugs or vaccines
design. For example, carbohydrate epitopes resulting from virus or aberrant glycosylation of cancer cells
represent attractive targets in designing a carbohydrate-based vaccine. Exploring the carbohydrate epitope in
its natural environment enables us to more directly mimic the natural setting in the context of the vaccine. Now,
glycan array is commonly used as a tool for detecting pathogen-specific antibodies and human cancer for
serodiagonostics. Carbohydrate array technology has tremendous potential for accelerating carbohydrate-
based vaccine development. Employing mass spectrometry and other tools for quality control in carbohydrate-
based vaccines is equally important in this field.
Table 1.
Organism
Saccharidecomponents Carrier Development Licensed Ref.
Haemop
hilus
influenzae(type b)
Type b CPS-
derived 12 mers;
Type b CPS (size
reduced); Type b
CPS (high MW);
Type b CPS
(synthetic
oligosaccharides);
Type b CPS
CRM197
;
OMPs; TT;
TT; TT
Licensed;
Licensed;
Licensed;
Licensed(Cuba);
Licensed
HibTiter, Vaxem-
Hib1990;
PedvaxHIB1990;
ActHib1993;
QuimiHib2004;
Hiberix1998 (EU),
2009 (USA)
[26-30]
Neisseria
meningiti
disA, C,
W135
and Y
Group A, C, Y, W-
135 CPS; Group A,
C, Y, W-135 CPS;
Group A, C, Y, W-
135 CPS
None; DT;
CRM197
Licensed;
Licensed;
Licensed
ACWY Vax1981;
Menactra2005;
Menveo2010
[12,13]
N.
meningiti
dis
(group C)
Group C CPS-
derived oligos; De-
O-Ac CPS-derived
oligos
CRM197
; TTLicensed (UK);
Licensed (UK)
Meningitec,
Menjugate;
NeisVac C1999
[11,12]
Plasmodi
um
falciparu
m
Synthetic GPIsOvalbumin
and KLHPreclinical [32]
Salmon
ella
typhi
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Table 2.
Vi CPS;
Vi CPS;
Vi CPS;
O-acetyl
pectin (Vi
mimics)
None; TT; rEPA;
rEPA
Licensed;
Licensed
(India); Phase
III; Phase I
Typhim Vi
1994; Peda
Typh2001
; ; [90]; [91]
Staphyl
ococcu
s
aureus
Type 5
and 8
CPS;
Type 5
and 8
CPS
rEPA; HSAPhase III;
Phase I
StaphVAX
2004[92]; [93]
Strepto
coccus
pneum
oniae
Target antigen Spacer/other epitope Carrier Cancer type Ref.
Monomeric vaccine Globo H CH2CH
2
KLH, BSA Breast
[56] MMCCH KLH Prostate, breast [57,58]
p-nitrophenyl CRM197
, TTBrea
stFuc-GM1
Ceram
ide-
reducti
ve
aminat
ion
KLH Small-cell lung [59] GD2
Ceram
ide-
lacton
e
KLH Melanoma [53] GD3
Ceram
ide-
reducti
ve
aminat
ion
KLH Melanoma[52,9
6]GM2
Ceram
ide-
reducti
ve
aminat
ion
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KLH Melanoma[54,9
7]GM3
Proteo
liposo
mes
OMPC Melanoma [98] Ley CH2
CH2
KLH Ovarian [60] STnCrotyl
linker
KLH; KLHBreast; Breast, ovarian and
colorectal
[99,1
00];
[101,
102]
PSA, NP-PSA
Reduc
tive
aminat
ion
KLH Small-cell lung [103]Monomeric clustervaccine Tn(c)
MBS KLH, PAMProst
ate[61,62] TF(c)
MBS KLHProst
ate[61] STn(c)
STn(c) crotyl linker-MMCCH KLHBrea
st[63]
Gb3(c)
-
MUC5
Ac
Gb3-norleucine-MUC5Ac-
MBSKLH
Ovari
an[64]
Polyvalentvaccinepooledmonomericvaccines )
GD3, Ley, MUC1 and
MUC2
(GD3)-reductive amination;
(Ley)-CH
2CH
2; (MUC1,
MUC2)-MBS
KLHMelanoma;
Ovarian; Breast[104]
GM2, Globo H, Ley, Tn(c)
and TF(c) MUC1 (32mer)
(GM2 )-reductive amination;
(Ley, Globo H)-MMCCH;
(MUC1, Tn, TF)-MBS
KLH Prostate [65]
GM2, Globo H Ley, Tn(c),
TF(c), STn(c) and MUC1
(GM2)-reductive amination;
(Ley, Globo H)-MMCCH;
(MUC1, Tn, TF, STn)-MBS
KLH
Epithelial ovarian,;
fallopian tube or
peritoneal
[66]
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Unimolecular polyvalentvaccine consists ofmultiantigens onunimolecule)
Globo H, Tn, STn, TF, Ley
and (GM2)
Diami
nopro
pyl-
MBS
KLH
Breast
and
prostat
e
[67-69]Globo H, GM2, Tn, STn and
TF
Diami
nopropyl-
MUC
1-
alani
ne-
MBS
KLH Breast
[70] Multicompone nt vaccineFuco
syl
GM1
FucGM1-
norleucine-MHC II
binding peptide-
MBS
KLH
Small-cell lung [105]
Tn
(two
comp
onent
)
Pam3Cys-
aminobutyl-di-Tn[73]
Ley(two component Pam3Cys-peptide-(Le
y)
3
Ovari
an[106]
Tn, TF
or STF
Pam3CysSK4-ethylene
glycol-MUC1Breast [75]
Tn and TF (three-
component
branched)
Pan-
DR
epitop
e-Lys-
MUC1
-Tn-
Ala-
MUC1
-TF
Breast [74]
Tn(thre
e
comp
onent
)
TLR-2 ligand
(Pam3CysSK4)-
Th epitope-MUC1-
Tn
Breast
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Key issues
* Automatic and programmable one-pot glycan synthesis provides an accessible method to prepare large-scale
carbohydrates for vaccine development.
* Development of carbohydrate-based vaccines against bacterial polysaccharides has made significant
progress, leading to widespread clinical applications.
* Prevention of parasitic infection in tropical areas is particularly important. Despite many ongoing trials, no
effective vaccine is currently available.
* No carbohydrate-based anticancer vaccine is currently approved for clinical use; however, there are many
synthetic cancer vaccines based on tumor-associated carbohydrate antigens undergoing clinical trials, including
Phase III clinical trials.
* Development of a carbohydrate-based antivirus vaccine is more challenging. The similarity between human
and viral glycans can lead to immune responses against self structures.
* The majority of oligosaccharides belonging to T-cell-independent antigens mainly induce IgM antibody
production. Assisted by carrier proteins and adjuvants, high titers of IgG can be induced.
Financial &competing interests disclosure
This study was supported by the Academia Sinica, Taiwan and National Science Council, Taiwan. No. NSC 97-2113-M-001-009-MY2 to Chung-Yi Wu. The authors have no other relevant affiliations or financial involvement
with any organization or entity with a financial interest in or financial conflict with the subject matter or materials
discussed in the manuscript apart from those disclosed.
No writing assistance was utilized in the production of this manuscript.
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AuthorAffiliationYen-Lin Huang,
1
Genomics Research Center, Academia Sinica, 128 Academia Road, Section 2, Nankang,Taipei, 115, Taiwan. [email protected].
MeSH: Bacterial Vaccines -- chemistry, Cancer Vaccines -- chemistry, Humans, Protozoan Vaccines --chemistry, Viral Vaccines -- chemistry, Bacterial Vaccines -- immunology (major), Cancer Vaccines --
immunology (major), Carbohydrates -- immunology (major), Epitopes -- immunology (major), Protozoan
Vaccines -- immunology (major), Viral Vaccines -- immunology (major)
Substance: Bacterial Vaccines; Cancer Vaccines; Carbohydrates; Epitopes; Protozoan Vaccines; ViralVaccines;
Publication title: Expert Review of VaccinesVolume: 9
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Issue: 11
Pages: 1257-74
Publication year: 2010
Publication date: Nov 2010
Year: 2010Publisher: Informa Healthcare, Expert Reviews Ltd.
Place of publication: London
Country of publication: United Kingdom
Publication subject: Medical Sciences--Allergology And Immunology
ISSN: 1476-0584
Source type: Scholarly Journals
Language of publication: EnglishDocument type: Review, Journal Article
DOI: http://dx.doi.org/10.1586/erv.10.120
Accession number: 21087106
ProQuest document ID: 8