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1 Antibacterial Carbohydrate Vaccines
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249 ClinicalTrials.gov. A Single Ascending Dose Study in Adults (Stage 1) and Single
Ascending DoseFinding Study (Stage 2) in Elderly Subjects With ASP3772, A
Pneumococcal Vaccine 2021. https://clinicaltrials.gov/ct2/show/NCT03803202.
250 Affinivax. https://affinivax.com/pipeline/overview/.
251 Matrivax. https://www.matrivax.com/
252 Thanawastien, A., Cartee Robert, T., Griffin Thomas, J. etal. (2015). Conjugate
like immunogens produced as protein capsular matrix vaccines. Proceedings of the
National Academy of Sciences. 112 (10): E1143–E1151.
253 Cartee, R.T., Thanawastien, A., Griffin Iv, T.J. etal. (2020). A phase 1 randomized
safety, reactogenicity, and immunogenicity study of Typhax: a novel protein
capsular matrix vaccine candidate for the prevention of typhoid fever. PLoS
Neglected Tropical Diseases. 14 (1): e0007912.
254 ClinicalTrials.gov. Safety and Immunogenicity of Typhax, a Typhoid Vaccine 2019.
https://clinicaltrials.gov/ct2/show/NCT03926455.
2
Antifungal Glycoconjugate Vaccines
Linda Del Bino, Maria R. Romano, and Roberto Adamo
GSK, Via Fiorentina 1, Siena, 53100, Italy
2.1 Human Fungal Infections
Fungi are heterotrophic eukaryotes morphologically classified into yeast and filamentous forms. Most fungi are ubiquitous in the environment, and humans are
exposed by inhaling spores or small yeast cells. Fungi are very proficient at responding to surrounding signals that promote their survival in several environments. As a
result, they can interact with plants, animals, or humans in multiple ways, establishing symbiotic, commensal, latent, or pathogenic relationships. Out of hundreds of
thousands of known fungal species in the world, only about 300 are human pathogens[1], with Candida, Aspergillus, Cryptococcus, and Pneumocystis spp. responsible for more than 90% of reported deaths due to fungal disease[2]. The manifestation
of fungal infections can be mucocutaneous, mucosal, or tissue‐invasive. The majority of fungal infections are opportunistic, since healthy people can mount an efficient immune response against them, and cause mainly mucosal or superficial
infections. Advances in medicine and surgery over the past century have led to
increased life expectancy, and many diseases previously considered to have a very
poor prognosis can now be controlled in such a way that patients can live with them.
This is the case for individuals with immunodeficiency due to chemotherapy, AIDS,
diabetes, or organ transplant[3]. In this population, the number of high‐risk groups
exposed to invasive fungal infections (IFIs) has increased. Hospital‐acquired fungal
infections are less frequent than bacterial ones, but they account for higher
mortality rates, longer hospitalization times, and increased healthcare costs. To
date, concerns over IFIs are rising since they kill 1.5 million individuals annually
with an unacceptable mortality rate, which for Candida has been estimated to be
27–55% [4]. On the other hand, mucosal fungi infections are common in non‐
immunocompromised subjects. They are generally not life‐threatening; however,
they are associated with high morbidity, socioeconomic impact, and low quality of
life. The most common mucosal infection sites are the oral cavity and the
genitourinary tract in apparently healthy people. Approximately two‐thirds of all
57
Carbohydrate-Based Therapeutics, First Edition. Edited by Roberto Adamo and Luigi Lay.
© 2024 WILEY-VCH GmbH. Published 2024 by WILEY-VCH GmbH.
2 Antifungal Glycoconjugate Vaccines
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women will experience an acute episode of candidal vaginitis at least once in their
lives, and nearly 7% will develop recurrent vulvovaginal candidiasis (RVVC), which
often needs chronic medical treatment[5]. The main therapeutic options for IFIs
consist of a limited number of systemic drugs, whose antifungal activity comes
together with severe adverse effects. Furthermore, new antimicrobial‐resistant
strains are emerging, enhancing the need to develop alternative treatments, especially for Candida auris and Candida spp.[6]. Particular concern is raised by the
emergence of C. auris in health care settings due to its high resistance to drugs and
capacity to spread from person to person, which increases the need of efficacious
therapeutic measures[7] (Singh 2019 #728).
Immunoprophylaxis with antifungal vaccines represents an appealing therapeutic option, and, despite the fact that no licensed vaccines are currently on the market, a lot of work has been done on potential vaccine targets as well as on passive
immunization with monoclonal antibodies (mAbs) against systemic mycosis.
In Table2.1, the advantages of each approach and the corresponding drawbacks
are reported:
Table2.1 Main advantages and disadvantages ofpotential treatments forsystemic mycosis.
Antifungal drugs
Advantages ● Only treatment currently
available on the market
● Low production cost
● Easier to store
and administer
● Use in patients with
underlying medical
condi tions causing
immuno deficiency
Disadvantages
● Few obsolete drugs are
available
● Severe adverse effects
● Possible selection of
resistant strains
Glycoconjugate
antifungal vaccines
● Potential to provide long‐
term immunity to
systemic mycosis
● Less expensive
production compared to
mAbs
● Some fungal antigens
could be used to produce
a pan‐fungal vaccine
against multiple mycosis
● Use to treat recurrent
mucosal infections in
immunocompetent
patients
● No selection of resistant
strains
● Only immunocompetent
patients can mount an
efficient response to
fungal antigens
● Proof of concept of
their safety and
immunogenicity in
humans still missing
● Weeks to months are
needed to confer
protection
mAbs targeting
fungal glycans
● Reduced toxicity risk
● Immediate immunity is
provided against
systemic mycosis
● Potentially efficient also
in immunocompromised
patients
● Highly specific, so avoid
selection of resistant
strains
● A Phase I clinical study
has been completed
● Highly specific,
therefore, a precise
diagnosis is required
● Higher production cost
compared to traditional
drugs
● More difficult to store
and administer
compared to traditional
drugs
Source: Del Bino and Romano[8]/with permission of Elsevier.
2.2 Immunity Against Fungal Pathogens
Fungal cell wall (CW) is the outer component responsible for the initial recognition by the host immune system. Most fungal CWs are mainly composed of different
polysaccharides, which are not present in humans and thus can be considered
excellent targets for antifungal immunotherapy.
2.2 Immunity Against Fungal Pathogens
The interaction between fungal pathogens and the host immune system is a very
complex mechanism involving both innate and adaptive immunity. Skin and epithelial surfaces are the first barrier against fungi, and, indeed, many fungal infections occur in patients in whom the integrity of the natural barriers is disrupted.
Once the skin’s physical barrier is passed, neutrophils, monocytes, macrophages,
natural killer (NK) cells, and dendritic cells (DCs) sense the fungal pathogens, and
innate and adaptive immune responses are both activated. The constitutive elements of innate immunity reside in the skin and the mucosal epithelial surfaces,
where pattern recognition receptors (PRRs) of innate immune cells such as neutrophils and macrophages detect fungal pathogen‐associated molecular patterns
(PAMPs). The fungal CW is the main source of PAMPs recognized by PPRs in
mammalian cells. This detection promotes the engulfment of fungal cells and their
subsequent degradation within phagosomal compartments [9, 10]. At the same
time, adaptive immunity is activated; for example, antigen‐presenting cells like
DCs prime T cells by presenting sampled antigens in association with Major
Histocompatibility Complex Class II or Class I molecules, leading to the differentiation of CD4
fungal antigens and activate adaptive T‐cell immune responses makes them logical
cellular targets for the development of fungal vaccination strategies [12]. T‐cell
immune responses, in particular Th1/IL12, are considered key for protective immunity to fungi, and a dominant Th1 cell response correlates with protective immunity
against fungi and effective fungal vaccines[9]. Therefore, to achieve activation of
adaptative immune responses, it is necessary to activate pathogen‐detection mechanism of the innate immune system. Th17 cytokines have been shown to act as
effector molecules during the immune response to fungal infections at the mucosal
inflammation and seem to play a critical component of the protective host response
to fungal infections. However, need to elicit Th17‐driven response appears not to be
crucial for developing an antifungal therapeutic. While antibody‐mediated immunity has been considered for a long period of time less important in host defense
against fungi, the advances in mAb technology have made it possible to elucidate
their protective role, consisting of supporting infection clearance via opsonization
or direct antifungal activity[13, 14]. Protective mAbs target protein as well as carbohydrate epitopes of fungi CW[15–17].
In addition, there is growing evidence that an efficacious antifungal therapy can
be achieved by targeting CW components that exert critical functions in fungal CW
structure and adherence to host cells[18].
+
or CD8+ T cells, respectively[11]. The ability of DCs to recognize
59
2 Antifungal Glycoconjugate Vaccines
Chitin/glucan
Aspergillus fumigatus
Aspergillus fumigatus
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2.3 Carbohydrate Antigens inFungal Cell Wall
Carbohydrates dominate the CW of fungi, and, in the case of Candida and
Cryptococcus neoformans, surface polysaccharides have been identified as involved
in PAMP–pathogen recognition receptor (PRR) interactions initiating downstream
immune responses[17].
Since polysaccharide vaccines act as T‐cell‐independent antigens, they do not
generate a protective immune response in children under two years of age and do
not induce immunological memory and high‐affinity antibodies. The development
of glycoconjugate vaccines, in which the polysaccharide antigen is covalently linked
to a carrier protein, has made it possible to overcome this limit, creating T‐cell‐
dependent antigens capable of inducing a potent and specific immune response and
arousing protective immunological memory from infancy[19, 20]. Accordingly, to
study their immunogenicity at preclinical level, several fungal carbohydrate antigens have been conjugated to selected protein carriers. Differently from bacterial
glycans, which usually have a core repeating unit composed of one or a few monosaccharides, fungal polysaccharides show a higher level of complexity. Indeed, fungal CWs present a complex multilayered architecture where the inner skeleton is
relatively conserved and composed mainly of chitin, chitosan, and glucan polysaccharides, while the outer layer presents highly variable specific polysaccharides and
glycoproteins, often organized in an irregular structure[21] (Figure2.1).
Outer layer
matrix
Cell membrane
Candida albicans
Membrane proteins
Chitin
Galactoxylomannan
(GalXM)
Cryptococcus neoformans
Glycoprotein
Glucans
Mannans
coniudium
Galactomannan
(GM)
Melanin
Glucuronoxylomannan
hyphae
Rodlet
(GXM)
Galactosaminoglycans
(GAG)
Figure2.1 Schematic representation of carbohydrates in fungal cell walls. Source: Gow
etal.[8]/with permission of Elsevier.
While bacterial vaccines have been successfully developed by conjugation of
extracted polysaccharides to carrier proteins, this approach proves challenging for
fungal sugars due to their complex organization and variable structure.
Given the challenge associated with fungal carbohydrate production, synthesis of
oligosaccharide structures has appeared as an attractive alternative. Several synthetic glycoconjugate vaccines have been prepared and studied for the fungal pathogens causing most invasive infections in humans (Candida, C. neoformans). For
Aspergillus fumigatus and C. neoformans, many efforts have been directed toward
the synthesis of oligosaccharide components of the CW for structural studies aiming to identify the chemical features responsible for immunogenicity. Recent findings based on the use of synthetic oligosaccharides are summarized in this chapter.
2.4 Glycoconjugate Vaccines Against Candida albicans/
Candida auris
The outer core of Candida albicans CW is essentially composed of mannans, forming
a network that functions as a scaffold for highly glycosylated proteins. This mannan
polysaccharide is characterized by a set of different structural motifs, namely antigenic factors, distinguished by size, type of the glycoside bond, presence of phosphodiester linkages, branching points, etc., and its composition varies depending on
species and strain of Candida microorganism. β‐(1,3)‐glucans, β‐(1,6)‐glucans, and
chitin are instead present in the inner core of Candida CW. These polysaccharides
are the main PAMPs that are recognized by PRRs.
Laminarin from the brown alga Laminaria digitata is composed of branched
β‐(1→3)‐(1→6)‐glucans and, due to its structural similarity with fungal sugars, has
been considered a source of carbohydrates to develop vaccines against Candida
infections[17, 22–29]. Other sources of β‐glucans, such as the fully linear β‐(1,3)
glucan Curdlan (from Alcaligenes faecalis bacteria) or the β‐(1,6) glucan Pustulan
from Umbilicaria papullosa, have been exploited to determine the structural features needed for optimal immunogenicity. These studies indicated that the antibodies raised against β‐(1,3) glucans were protective in a mouse model of systemic
candidiasis, while structures containing β‐(1,6) glucan side chains might induce
non-protective antibodies[22, 23].
β‐(1,3) glucan binds to the C‐type lectin‐like receptor Dectin‐1, which is expressed
on immune cells such as macrophages, neutrophils, and DCs[30, 31]. The binding
residues have been identified in Trp221 and His223 [32]. The polysaccharide is
structurally well organized[33], and its long form appears to assume a triple helical
conformation, as it has been demonstrated by conformational nuclear magnetic
resonance (NMR) studies[34] and also by combined static light scattering, dynamic
light scattering, and atomic force microscopy[35]. However, a structurally disordered hexamer seems sufficient to bind to Dectin‐1[34].
The protective role of β‐(1,3) glucans was thoroughly investigated by employing
synthetic oligosaccharides conjugated with different conjugation chemistries to the
carrier proteins in order to elucidate the optimal structure of the protective epitope
612.4 Glycoconjugate Vaccines Against Candida albicans/Candida auris
2 Antifungal Glycoconjugate Vaccines
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and of the resulting glycoconjugate (saccharide/protein ratio, type of carrier, and
conjugation site). By comparing a linear 15‐mer with a branched 17‐mer (1), it was
observed that β‐(1→6) branches need to be separated by at least six β‐(1→3) residues
for efficient antibody production[22].
Following this, a CRM
‐conjugate of a synthetic linear β‐(1,3) glucan hexamer
197
(2) was tested invivo and showed to elicit in mice anti‐β‐glucan IgGs in a comparable manner to Lam‐CRM
[23]. This result well correlates with the findings that
197
mAb 2G8, which is protective in mice challenged with C. albicans, mostly targets
linear β‐(1,3) glucan sequences. Subsequently, the impact of the conjugation site on
CRM
was further investigated by preparation of the linear β‐(1,3) glucan hexamer
197
conjugates through site‐selective conjugation to tyrosines [24] via a newly developed 4‐phenyl‐1,2,4‐triazoline‐3,5‐dione linker or controlled conjugation at the surface‐exposed lysines [25] via active ester chemistry [36] (4). The resulting
glycoconjugates were compared to those obtained through traditional random conjugation chemistry for CRM
lysines[25]. All the constructs elicited a comparable
197
level of IgGs[26, 37], and sera from immunized mice were able to inhibit the adhesion of C. albicans to human epithelial cells[25]. Therefore, it was concluded that
four conjugation sites are sufficient to elicit a robust immune response in the animal
model. The potential as an antigen of β‐glucans was further confirmed by other
investigators who conjugated a synthetic linear octasaccharide to the protein carrier
Keyhole limpet hemocyanin (KLH) (3)[26]. The same team then investigated the
immunogenicity of synthetic nonasaccharides of β‐(1,3) glucans bearing β‐(1,6) or
β‐(1,3) branches. Both conjugates showed similar immunological properties to the
previously tested octasaccharide, and in addition to this, competitive ELISA experiments suggested that the majority of the induced antibodies were directed against
the linear β‐(1,3) backbone[37]. Overall, these studies suggested that β‐(1,3) glucan
oligomers could be promising candidates for antifungal vaccines and contributed to
the development of a well‐established synthetic route giving access to libraries of
β‐(1,3) glucan structures.
Due to its irregular structure, Candida mannan’s immunogenic properties are difficult to reproduce, which makes its use problematic for the vaccine design. Therefore,
the synthetic approach has been helpful in identifying the protective epitope to
ensure the immunogenicity of the corresponding glycoconjugate vaccines. Short oligomers ranging from di‐ to hexasaccharide were synthesized in order to investigate
the structure and size of the protective epitope based on the interaction with two
protective mAbs generated by hybridoma techniques from mice immunized with a
natural mannan–liposome preparation[16, 38]. Their findings indicated that a trisaccharide was recognized by both mAbs and, therefore, was a promising antigen for
further vaccine development[39]. The synthetic β‐(1,2)‐mannan trisaccharide conju-
gated to TT (5) showed a robust secondary antibody response in rabbits but poor
immunogenicity in mice [40, 41]. In order to improve the immunogenicity of the
mannan trisaccharide, a synthetic conjugate was constructed using the 14‐mer peptide Fba (6), deriving from a C. albicans CW protein and prepared through solid‐
phase peptide synthesis. After being tested in mice, the conjugate elicited a strong
antibody response and offered protection against a lethal challenge of C. albicans
[42, 43]. β‐glucans act as immune potentiator molecules through Dectin‐1 activation,
and a hexamer has been shown to be sufficient to enhance the antibody response
against protein antigens[44]. This feature has been harnessed to generate a tricomponent β‐glucan and β‐mannan conjugate, where the sugars were both conjugated to
TT as carriers. This type of approach resulted in an enhanced antibody response to
the β‐mannan epitope of the conjugate while exploiting the proven targeting and
antifungal response of the β‐glucan conjugates[29]. Recently, a fully synthetic conjugate vaccine was constructed from a β‐(1,2)‐linked mannose trisaccharide conjugated
to a T‐cell peptide. This combined B‐ and T‐cell epitope was synthesized and subsequently conjugated by click chemistry to an asymmetric dendrimer component bearing four copies of a β‐(1,3)‐linked hexaglucan DC epitope, obtaining a conjugate
vaccine (7) that induced antibodies to all three epitopes of the fully synthetic construct. Unfortunately, the preparation of a synthetic dendrimer‐based immunogen
proved very challenging, discouraging the authors from continuing with further
work on fully synthetic vaccines[45].
Other researchers focused their attention on the α‐mannosides and studied the
immunological properties of a series of synthetic oligo α‐mannosides with and
without branches conjugated to bovine serum albumin (BSA) via squarate chemistry. According to reported results, the presence of branches does not correlate with
the induction of protective antibodies as measured by in vitro opsonophagocytic
assay, while the length does not seem to play a major role, suggesting that oligomannoside structure more than their length might influence the quality of the antibody
response and that the use of linear oligomannosides for vaccine design might be
preferable[46].
Recent research demonstrated the immunobiological activity of synthetically prepared biotinylated α‐mannooligosaccharides mimicking Candida antigenic factors.
Macrophage exposure to a set of eight structurally different mannooligosaccharide
conjugates induced the release of Th1, Th2, Th17, and Treg cytokine signature patterns, making these conjugates potential invitro immunomodulative agents suitable
for in vitro Candida diagnostics or prospectively for subcellular anti‐Candida
vaccine design[47] (Figure2.2).
632.4 Glycoconjugate Vaccines Against Candida albicans/Candida auris
2 Antifungal Glycoconjugate Vaccines
HO
Fully synthetic three-component vaccine 7
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64
O
HO
HO
HO
HO
H
O
O
OH
HO
HO
O
H
HO
HO
O
H
HO
HO
HO
O
Robust immune response in mice model
HO
HO
HO
HO
O
HO
O
O
OH
3
OH
HO
O
HO
O
OH
minimal linear epitope of Laminarin
HO
HO
O
O
OH
O
OH
Hexa-CRM
O
O
4
OH
O
3
197
Octa-KLH 3
OH
O
O
HO
O
HO
HO
O
HO
O
HO
HO
O
β-(1,2)-mannan trisaccharide-TT 5
Robust antibody response in rabbit,
poorly immunogenic in mice
HO
O
HO
S
3
2
O
O
OH
H
N
4
2
O O
O
O
N
H
H
N
S
3
4
2
O O
O
HO
O
OH
H
N
CRM
KLH
H
N
HO
OH
HO
O
HO
protective in a Candida mice model
TT
O
OH
17-mer-Glucan-CRM
197
O
HO
O
O
2
OH
1
197
4 copies of the glycan sufficient for robust Ab production
HO
HO
HO
Candida peptide
Protection against a lethal challenge of C. albicans
OH
HO
O
HO
HO
HO
HO
HO
O
O
HO
O
HO
HO
OH
O
HO
OH
O
HO
O
HO
HO
OH
O
O
OH
O
HO
O
O
OH
H
O
N
S
3
2
O
OH
OH
O
OH
OH
HO
O
OH
HO
HO
∗
CRM
197
site-selective conjugation at tirosine or lysines
OH
O
HO
HO
HO
HO
Fully synthetic vaccine 6
Strong antibody response
TT
NH
N
N
N
NH
O
HO
O
O
OH
OH
O
N
HN
N
O
HO
HO
O
H
Hexa-CRM
O
O
O
HO
O
HO
HN
O
2
n
2-3
H
N
O
2
OH
O
O
O
HO
HO
O
O
OH
4
197
H
O
N
S
3
2
O
S
O
O O
N
N
O
OH
4
H
N
4
CRM
197
N
O
3
O
Figure2.2 Vaccine candidates against Candida infections.
2.5 Glycoconjugate Vaccines Against Cryptococcus
neoformans
The first fungal glycoconjugate vaccine was designed against C. neoformans, whose
capsular polysaccharide is an important virulence factor and is composed mostly of
glucuronoxylomannan (GXM), while galactoxylomannan (GalXM) and mannoproteins (MPs) are present to a lesser extent.
GXM has a very complex structure: it is a heteropolymer, not consisting of repeating
units as bacterial polysaccharides but rather of six different chemotypes, occurring in
various ratios depending on both strain and batch of the microbe and distributed
among four serotypes: A, B, C, and D[48]. NMR experiments aiming to elucidate the
structure of GXM concluded that this polysaccharide consisted of a linear α‐(1,3)
mannan trisaccharide backbone containing β‐1,2 and β‐1,4 xylose branches and a
β‐1,2 glucuronic acid branch attached at different mannoses of the repeating unit.
Additional structural complexity and heterogeneity are introduced by O‐acetylation,
whose variability makes the identification of protective epitopes difficult.
GalXM represents about 7% of the capsular mass, and it is made of a α‐1,6galactan
backbone with potentially four short oligosaccharide branch structures. Other carbohydrates present in the CW of C. neoformans are α‐(1‐3) glucans, which anchor
the polysaccharide capsule to the CW, and β‐(1‐3) glucans.
Early attempts to make an anti‐Cryptococcal glycoconjugate vaccine have been
focused on GXM and resulted in a poorly characterized product, which showed
immunogenicity in mice but did not give a protective antibody immune response[49].
The first evidence that GXM can be regarded as a target for immunotherapy was
obtained using a natural polysaccharide conjugated with tetanus toxoid (GXM‐TT
conjugate 8), which resulted in immunogenicity and protection in mice[50, 51]. The
results of both active and passive protection experiments suggested that the presence
of GXM‐TT‐elicited antibodies during the first — four to six weeks of infection was
critical for the clearance of cryptococci from various organs, for limiting serum GXM
titers from reaching immunosuppressive levels, and ultimately for survival[51, 52].
Thanks to the availability of anti‐GXM mAbs isolated from mice infected with C. neo-
formans and mice immunized with GXM‐TT, the presence of protective as well as
nonprotective epitopes within GXM structure was demonstrated[53, 54].
Thus, further studies were directed toward determination of the protective epitope
structure using synthetic oligosaccharides to be used in the conjugated vaccine. First,
the synthetic heptasaccharide IX, representing the dominant putative epitope of
C. neoformans serotype A GXM, was synthesized with different O‐acetylation patterns and tested for binding against a library of seven mAbs. Both O‐acetylated and
nonacetylated forms of the heptasaccharide were strongly recognized by two mAbs
(13F1 and 7B13). The mono‐O‐acetylated synthetic serotype A heptasaccharide was
conjugated to human serum albumin (HSA) (9) and tested for immunogenicity in
mice with or without Freund adjuvant. Only the conjugate administered with adjuvant was able to elicit anti‐GXM antibodies, which unexpectedly recognized primarily and in an irregular manner the surface of serotype D and B strains in
immunofluorescence experiments[55]. In a subsequent study, the ability of the antibodies elicited by the above conjugate to protect mice against challenge with serotype
D C. neoformans was investigated, but unfortunately, no protection was observed[56].
To elucidate the oligosaccharide structure, which could be regarded as an efficient
ligand for vaccine development, a synthetic glycan array containing immobilized oligosaccharides related to GXM fragments, ranging from di‐ to octadecasaccharides, was
developed and the interactions of such oligosaccharides with available protective and
nonprotective mAbs were investigated. The screening revealed that a serotype A decasaccharide was recognized by several neutralizing mAbs, making this structure a promising candidate for anti‐C. neoformans conjugate vaccine development[57].
Another cell‐wall polysaccharide that has been considered as vaccine antigen is
GalXM, which was conjugated to BSA and to a protective antigen from Bacillus
anthracis as protein carriers (10), demonstrating its effectiveness to induce robust
652.5 Glycoconjugate Vaccines Against Cryptococcus neoformans
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