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2 Antifungal Glycoconjugate Vaccines

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Carbohydrate-Based Antiviral Vaccines

Adrián Plata1 and Alberto Fernández-Tejada

CIC bioGUNE, Basque Research and Technology Alliance (BRTA), Chemical Immunology Lab, Biscay Science and

Technology Park, Building 801A, Derio, Biscay 48160, Spain

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 (COVID19) pandemic due to the severe acute respiratory syndrome coronavirus2 (SARSCoV2) 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 longlasting 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 liveattenuated 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 hostcell “self”

3 Carbohydrate-Based Antiviral Vaccines

glycans, particularly Nglycans [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 carbohydratebased vaccines against representative viral diseases (e.g. HIV, influenza, hepatitis, Ebola, and COVID19), while also providing some examples of glycanbased immunoadjuvants and therapeutic agents.

3.2 Human Immunodeficiency Virus

Human immunodeficiency virus type 1 (HIV1) is the causative agent of AIDS, a pandemic that has affected more than 76 million people since its onset in 1981, with over 33 million deaths (680 000 of them in 2020) because of AIDSrelated diseases[2]. As such, the development of an effective and safe prophylactic vaccine against HIV1 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 HIV1. The most successful results correspond to the RV144 efficacy trial, which used a replicationdefective canarypox vector (ALVAC) together with the recombinant AIDSVAX B/E HIV1 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 HIV1 vaccine still poses a significant scientific challenge, whereby induction of both neutralizing antibodies and Tcell responses should be ideal for optimal vaccine efficacy[12].

The HIV1 virus surface is covered by a dense sugar coat, with the envelope glycoprotein (Env) spike being extensively glycosylated with hostsynthesized 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 HIV1 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 Nlinked 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 HIV1infected individuals have circulating bnAbs,

3.2 Human Immunodeficiency Virus

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which are characterized by special, uncommon features (e.g. extensive somatic hypermutation, long heavychain third complementaritydetermining 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 sofar target specific, conserved regions of vulnerability of the HIV1 Env, particularly within established glycan/peptide domains corresponding to the gp120 variable loops 1/2 (V1V2) and 3 (V3), the CD4binding site (CD4bs) on gp120, the bridging region between gp120 and gp41, and the gp41 membraneproximal external region (MPER)[17]. Therefore, these bnAb epitopes represent promising targets for HIV1 vaccine design, with the main goal of inducing such type of bnAb with the ability to neutralize multiple, diverse HIV1 strains.

Given the key role of the HIV1 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 HIV1 vaccines[13, 18]. In this context, the development of carbohydratebased 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 glycanbased epitope mimics as promising targets for the development of bnAbeliciting HIV1 vaccine candidates[19, 20]. We summarize recent advances on carbohydratebased minimal immunogen design for the induction of glycanrecognizing bnAbs that target three key domains on gp120: the outer domain highmannose glycan cluster around N332 and the conserved glycopeptidedependent epitopes in the V1V2 and V3loops, respectively.

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 2G12was the first bnAb identified to bind the HIV1 glycan shield. It was isolated from an HIV1positive patient and has been found to neutralize an array of HIV1 virions[21] as well as to protect against simianhuman immunodeficiency virus (SHIV) via passive immunization in macaques[22, 23]. As shown by epitope mapping studies, 2G12 recognizes a conserved highmannose carbohydrate cluster on the gp120 surface that includes primarily Nglycans 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

domainswapped dimer, yielding an extended multivalent

binding surface for the glycan cluster[26].

Additional binding analysis using welldefined 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-

GlcNAc[27]

sented the highest binding affinities with this bnAb [29–31], emphasizing the

3 Carbohydrate-Based Antiviral Vaccines

(a)

(c)

(e)

importance of the terminal Manα1→2Man moiety for 2G12 recognition and in agreement with previous crystallographic studies[26]. Based on these observations, several groups have focused on the development of different synthetic structures that can mimic the 2G12 epitope and have assessed their binding affinity in vitro (antigenicity) as well as their ability to elicit bnAbs invivo (immunogenicity).

3.2.1.2 Synthesis and Immunological Evaluation of 2G12 Epitope Mimics

In 2004, Wang and Li synthesized several oligomannoside clusters by conjugating highmannose glycans with cholic acid[32] and galactoside moieties[27] through a maleimide–thiol coupling reaction (Scheme3.1a). Multivalent Man

GlcNAc2 struc-

tures (Figure 3.1a,b) presented relatively high binding affinity to 2G12, but they were not comparable to that of native gp120. In a subsequent study, the tetravalent galactosidescaffolded moiety was conjugated through a maleimidebased linker to keyhole limpet hemocyanin (KLH, a carrier protein that promotes Thelper responses and multivalent antigen presentation) (Figure3.1b) in order to evaluate its capacity to induce bnAbs in rabbits[33]. Unfortunately, most of the antibodies were raised against the maleimide linker, and only modest titers of carbohydratespecific antibodies were elicited, which showed weak crossreactivity against gp120 and no HIVneutralizing activity.

Meanwhile, the Danishefsky laboratory performed the total synthesis of hybrid

type and Man

GlcNAc2 glycan structures and incorporated them into a gp120 pep-

tide fragment via Lansbury aspartylation (Scheme3.1b), obtaining fully synthetic N322glycosylated gp120 (A316R355) fragments [34, 35]. Although surface plasmon resonance (SPR) experiments showed weak binding of the compounds with 2G12 bnAb, subsequent dimerization of the structures through a disulfide bond (C331) resulted in enhanced antigenicity[36].

Collectively, the studies by the groups of Wang and Danishefsky suggested a crucial effect of glycan multivalency in binding the 2G12 bnAb. Therefore, later efforts have been focused on the design and synthesis of carbohydrate clusters by

(b)

(d)

Scheme 3.1 Conjugation reactions and linker chemistry applied in the synthesis of 2G12 epitope mimics. (a) Thiol–maleimide coupling/thioether linkage, (b) Lansbury aspartylation/ amide linkage, (c) Copper(I)-catalyzed alkyne–azide cycloaddition (CuAAC)/triazole linkage, (d)Amide linkage (via NHS ester), (e)Thiourea linkage.

3.2 Human Immunodeficiency Virus

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Table3.1 Significant examples ofsynthetic 2G12 epitope mimics.

Coupling reaction/

Year(s) Author(s)

linkage Template/scaffold

Reference(s)

2004–2006 Wang Maleimide–thiol/

2004 Danishefsky Lansbury

2007 Wang CuAAC/triazole Cyclopeptide (c) [37] 2007–2008 Danishefsky Lansbury

2008 Wong CuAAC/triazole Glycodendrimer (e) [40] 2010 Costantino NHSbased/amide Glycodendrimer (f) [41] 2008 Burton Thiourea BSA protein (g) [42] 2019 Kosma Thiourea BSA protein (h) [43] 2010 Finn, Burton CuAAC/triazole Qβ viruslike particle

2010 Wilson,

Davis

2011–2021 Krauss CuAAC/triazole DNA, peptide (k),

a) Corresponding author(s). b) Structures indicated in Figure3.1.

thioether

aspartylation/amide

CuAAC/triazole Qβ viruslike particle

Cholic acid (a) and galactoside (b)

Gp120 peptide [34–36]

Cyclopeptide (d) [38, 39]

(i)

(

and RNA

[27, 32, 33]

[44]

[45]

[46–52]

incorporating glycan moieties into different scaffolds using several conjugation strategies (Scheme3.1). Table3.1 and Figure3.1 illustrate significant examples of synthetic 2G12 epitope mimics developed over the last 15 years.

The synthetic Man

(D1 arm of Man9GlcNAc2) tetravalent constructs (Figure3.1c)

synthesized by the Wang group using CuAAC (Scheme3.1c) afforded relatively high 2G12 affinities, albeit decreased binding was observed for the fluorinated derivative[37]. In parallel, Danishefsky and coworkers prepared a range of Man

GlcNAc2

Nglycan clusters on a modular cyclic peptide (Figure3.1d) via Lansbury aspartylation (Scheme3.1b), with the divalent and trivalent structures showing significantly higher affinities compared to monovalent ones, which confirmed the importance of multivalent presentation. Subsequently, they attached the bivalent compound to the outer membrane protein complex (OMPC, an immunostimulatory carrier protein) via thiol–maleimide coupling (Scheme 3.1a) (~2000 glycopeptide monomers per conjugate) (Figure3.1d)[38], in order to perform immunogenicity studies in guinea pigs and rhesus macaques. Although high levels of carbohydratespecific antibodies were elicited in both species, they were not able to recognize a recombinant HIV gp120 precursor, thus failing to elicit a 2G12like bnAb response[39]. These results show that despite their antigenicity, the synthetic highmannose structures do not mimic the 2G12 antibody epitope realistically, and lack the ability to induce bnAbs, presumably due to a suboptimal oligosaccharide conformation/presentation necessary for efficient immune recognition.

3 Carbohydrate-Based Antiviral Vaccines

(a)

(d)

(g)

(j) (k)

Other multivalent structures, such as Wong’s Man9 glycodendron (Figure3.1e) obtained via CuAAC (Scheme3.1c)[40] or Costantino’s Man

 and Man9containing

glycodendrimers (Figure3.1f) synthesized using amide coupling (Scheme3.1d)[41], both exhibited significant binding affinities with 2G12. The latter were linked to the CRM

carrier protein via amide linkage (Scheme3.1d) for subsequent immuniza-

197

tion studies invivo[41]. Analogously, Astronomo etal. synthesized a (Man (bovine serum albumin) conjugate via a thiourea linkage (Scheme3.1e) using BSA as a carrier protein for multimeric presentation (Figure 3.1g) and evaluated its immunogenicity in rabbits [42]. In both cases, carbohydratespecific antibodies were generated, but the antisera were not crossreactive to HIV1 gp120[41, 42]. Notably, Clark etal. showed that a bacterial lipooligosaccharide (LOS) derived from Rhizobium radiobacter Rv3 that included a Man4 D1like arm was bound with

4)14

–BSA

(b) (c)

(e) (f)

(h)

Figure3.1 Synthetic 2G12 bnAb epitope mimics.

(i)

3.2 Human Immunodeficiency Virus

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reasonable affinity by 2G12. Mouse immunization with heatkilled Rv3 bacteria elicited glycanspecific antibodies that recognized monomeric gp120 but could not neutralize HIV1 virions[53]. Based on these findings and on the crystallographic structure of the 2G12/LOS complex[54], Kosma and coworkers conjugated several LOSderived, penta or heptamannose structures to BSA and assessed their antigenicity, with a thiourealinked (Scheme3.1e), βanomeric Man

glycan (Figure3.1h)

showing the highest 2G12affinity[43].

In other studies, Finn and collaborators investigated the use of viruslike particles (namely, bacteriophage Qβ), as scaffolds to facilitate a multivalent, ordered presentation of highmannose glycans via triazole linkers (Scheme3.1c) with the purpose of mimicking the oligomannose clustering on gp120. The highest 2G12 affinities were obtained with Qβ–Man

constructs (Figure 3.1i). The first two conjugate types (Qβ–Man4 and Qβ–

Man

) induced mannosespecific antibodies in rabbits that recognized the respec-

Man

, Qβ–Man9, and especially with a mixture of Qβ–Man8/

tive glycans, but they did not crossreact with native gp120 or show HIV1neutralizing activity[44].

In a rationally designed strategy to enhance the immunogenicity of synthetic 2G12 epitope sugar mimics, Davis and coworkers synthesized a number of unnatural mannosederived monosaccharides and their respective D1arm tetrasaccharides for antigenicity and immunogenicity studies [45]. Interestingly, the nonself Man

glycan incorporating a terminal C6methylated mannose (see

Scheme3.2 for synthesis) showed the highest binding to 2G12, and its corresponding triazolelinked (Scheme3.1c) Qβ conjugate (Figure3.1j) was evaluated in rabbits. Although considerably increased titers of mannosespecific antibodies were induced, they were not crossreactive with native gp120 and failed to neutralize HIV1.

In the last decade, Krauss and coworkers have applied a directed evolutionbased approach to the development of multivalent carbohydrate clusters as effective 2G12 epitope mimics. Following their early work with DNAscaffolded Man

and Man9

Scheme 3.2 Synthesis of unnatural C6-methylated mannose and assembly of a nonself

tetrasaccharide D1-arm mimic.

3 Carbohydrate-Based Antiviral Vaccines

glycoclusters[46, 47, 55], they developed a method to select Man9bearing multivalent glycopeptides as glycocluster scaffolds by combining mRNA presentation, incorporation of alkynecontaining unnatural amino acids, and subsequent glycan coupling via CuAAC (Scheme3.1c)[48]. This strategy led to invitro selected glycopeptides incorporating 3–5 oligosaccharides that showed binding affinities comparable with natural 2G12–gp120interactions (in the picomolar to low nanomolar range), which represents the most antigenic 2G12 glycopeptide epitope mimic reported to date. The best Man functionalized CRM

(Scheme 3.1a) (Figure 3.1k) [49] for immunological

197

bearing peptides were conjugated to maleimide

evaluation in rabbits[50]. While glycopeptidereactive antibodies targeting the carbohydrate part were generated, low binding to the nativelike soluble trimeric HIV Env protein (SOSIP) was observed (only in two cases), with negligible HIV1 neutralizing activity. Moreover, the induced antibodies were found to bind mainly to the core mannoses rather than the Manα1→2Man termini recognized by 2G12, which might result from serum mannosidase trimming invivo before immunogen presentation to Bcell receptors[50]. In a subsequent study to assess the effect of the vaccination regimen with a view to promote Manα1→2Manspecific antibodies, an evolved Man

glycopeptide immunogen was coadministered with the QS21 adju-

vant in liposomes using standard bolus dosing, an exponential series of mini doses, or continuous infusion[51]. The two latter regimens led to higher overall IgG titers to the glycopeptide, whereas bolusimmunized mice showed the strongest HIV Env binding antibody response. Nonetheless, Manα1→2Manbinding antibodies were not induced in either case, suggesting that mannosidase activity might be saturated under the bolus immunization protocol, resulting in an increased presentation of intact Man

to B cells, albeit still insufficient to elicit antibodies to the Manα1→2Man

motif. These findings highlight the need for an improved understanding of these biological processes in order to rationally develop optimal bnAbeliciting HIV1 vaccines. Recently, the Krauss group has also developed a novel directed evolution platform for the selection of stable2′fluoromodified RNAsupported Man

glycoclusters

that bind to 2G12with low nanomolar affinities[52].

Taken together, while the synthetic glycoconjugates developed so far could induce oligomannosespecific antibodies with high 2G12binding affinities (as described above), they have not proven to be effective HIV immunogens, failing to elicit 2G12 like antibodies that are crossreactive with the native Env protein to lead to an HIV1neutralizing response. The lack of immunogenicity of these 2G12 epitope mimics can be attributed to several reasons. First and foremost, the conformation of the glycan and its presentation as part of the synthetic immunogen may be different from that of the natural gp120 protein, making it, therefore, unable to recapitulate the native spatial orientation in the Env spike. This may be due to their distinct, inherent physicochemical properties as well as the subsequent glycan processing invivo. For instance, the inner GlcNAc

core that is missing in most of the con-

structs developed may have an important effect in defining the optimal carbohydrate orientation, which together with the high flexibility of the synthetic glycans may lead to unproductive immune recognition of irrelevant oligosaccharide conformations. This notion is supported by observations from Doms and coworkers, who

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