HUMAN VACCINES & IMMUNOTHERAPEUTICS
https://doi.org/10.1080/21645515.2021.1880210

COMMENTARY

β-glucans: wide-spectrum immune-balancing food-supplement-based enteric (β-WIFE)
vaccine adjuvant approach to COVID-19
Nobunao Ikewakia,b, Masaru Iwasakic, Gene Kurosawad, Kosagi-Sharaf Raoe, Johant Lakey-Beitiae, Senthilkumar Preethyf,
and Samuel JK Abraham f,g,h,i,jaDepartment of Medical Life Science, Kyushu University of Health and Welfare, Nobeoka, Japan; bInstitute of Immunology, Junsei Educational
Institute, Nobeoka, Miyazaki, Japan; cCentre for Advancing Clinical Research (CACR), University of Yamanashi - School of Medicine, Chuo, Japan;dDepartment of Academic Research Support Promotion Facility, Center for Research Promotion and Support, Fujita Health University, Aichi, Japan;eInstituto de Investigaciones Científicas y Servicios de Alta Tecnología (INDICASAT AIP), City of Knowledge, Panama City, Panama; fThe Fujio-Eiji
Academic Terrain (FEAT), Nichi-In Centre for Regenerative Medicine (NCRM), Chennai, India; gEdogawa Evolutionary Laboratory of Science (EELS),
Edogawa Hospital, Tokyo, Japan; hThe Mary-Yoshio Translational Hexagon (MYTH), Nichi-In Centre for Regenerative Medicine (NCRM), Chennai, India;i
Biomaterials and Cell Biology Division, JBM Inc, Tokyo, Japan; jImmune Systems R & D Division, GN Corporation Co. Ltd, Kofu, Japan
ABSTRACTARTICLE HISTORY

Conventional vaccines to combat COVID-19 through different approaches are at various stages ofdevelopment. The complexity of COVID-19 such as the potential mutations of the virus leading toantigenic drift and the uncertainty on the duration of the immunity induced by the vaccine have
hampered the efforts to control the COVID-19 pandemic. Thus, we suggest an alternative interim
treatment strategy based on biological response modifier glucans such as the Aureobasidium pullulans
AFO-202-derived β-glucan, which has been reported to induce trained immunity, akin to that induced by
the Bacille Calmette-Guérin vaccine, by epigenetic modifications at the central level in the bone marrow.
These β-glucans act as pathogen-associated molecular patterns, activating mucosal immunity by binding
with specific pathogen recognition receptors such as dectin-1 and inducing both the adaptive and innate
immunity by reaching distant lymphoid organs. β-Glucans have also been used as immune adjuvants for
vaccines such as the influenza vaccine. Therefore, until a conventional vaccine is widely available, an orally
consumable vaccine adjuvant that acts like biosimilars, termed as the wide-spectrum immune-balancing
food-supplement-based enteric (β-WIFE) vaccine adjuvant approach, with well-reported safety is worth indepth investigation and can be considered for a clinical trial.

Received 23 November 2020
Revised 23 December 2020
Accepted 14 January 2021

Background
The COVID-19 pandemic is wreaking havoc on the lives ofbillions of people worldwide, with unprecedented conse­
quences and implications. COVID-19 biology and pathology
are very complex, posing a big challenge in clinical and drug
management. Hence, researchers across the globe are creating
strategies for developing drugs, antibodies, vaccines, and othertherapies to fight the causative virus, SARS-CoV-2.1 According
to the World Health Organization (WHO) [last accessed
December 19, 2020], there are 202 companies and universities
worldwide working on a SARS-CoV-2 vaccine.2 The vaccines
mRNA-1273 (Moderna), Ad5-nCoV (CanSino Biologicals),
INO-4800 (Inovio, Inc.), LV-SMENP-DC, Pathogen-specificaAPC (ShinzenGeno-Immune Medical Institute), andChAdOx1 (University of Oxford) have entered the phase I/II
clinical trials.2,3 Authorisation/approval has been obtained insome countries such as China, United Arab Emirates, andRussia for six vaccines: CoronaVac by Sinova in China;
Inactivated vaccine by Wuhan Institute of Biological Products
in China and National Pharmaceutical Group (Sinopharm) in
China, BBIBP-CorV by Sinopharm in China, United ArabEmirates, and Bahrain; Sputnik V, Non-replicating viral vector
CONTACT Samuel JK Abraham
400-0866, Japan.

drsam@nichimail.jp; drspp@nichimail.jp

KEYWORDS

Covid-19; vaccine adjuvant;AFO-202 Beta glucan; trained
Immunity; immune
enhancement

by Gamaleya Research Institute, Acellena Contract Drug
Research and Development in Russia; EpiVacCorona, Peptide
vaccine by Federal Budgetary Research Institution State
Research Center of Virology and Biotechnology in Russia;
and BNT162b2, mRNA-based vaccine by Pfizer, BioNTech,and Fosun Pharma in UK, Bahrain, Canada, Mexico, USA,
Singapore, Oman, Saudi Arabia, and Kuwait.4 As of
July 2020, there were over 158 vaccine candidates, 135 ofwhich were in the preclinical or exploratory stage ofdevelopment,5 virtually all concentrating on inducing neutra­
lizing antibodies (nAbs) against the spike (S) protein on thevirus surface.1,6
Vaccine approaches conventionally use live attenuatedviruses, inactivated virus proteins, polysaccharide-conjugatedsubunits, virus-like particles, nucleic acid (DNA and RNA),
viral vectors, and recombinant proteins. The vaccine’s ability to
induce cellular immunity (other than B-cell-produced antibo­dies) has been indicated as necessary for a rational vaccine
design, because nAb responses wane rapidly.1 Furthermore,
the coronavirus genome is highly prone to mutations thatcan lead to genetic drift and escape immune recognition. In
fact, several variants that can cause drifts have already been

University of Yamanashi - School of Medicine, 3-8, Wakamatsu, Chuo, Kofu, Yamanashi© 2021 The Author(s). Published with license by Taylor & Francis Group, LLC.
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use,
distribution, and reproduction in any medium, provided the original work is properly cited.

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N. IKEWAKI ET AL.

identified.7 Undesired immunopotentiation in the form ofeosinophilic infiltration or increased infectivity has limited
the exploration of some of the COVID-19 vaccine candidates
and is currently a challenge in vaccine biology.7
An ideal vaccine should meet all or most of the following
criteria:(i) It should offer wide-spectrum protection across various
substrains and novel variants that are emerging or may
emerge later(ii) It should possess characteristics such as minimal unde­sired immunopotentiation(iii) It should be suitable for stockpiling for adult healthcare
workers and for adults > 60 years old or for whom has
underlying diabetes or hypertension8(iv) It should induce long-lasting effective immunity in all
vaccinated subjects across ages(v) It should be safe, stable, and easily available andadministrable
Given the above criteria, we evaluated the suitability of βglucans as they have been reported to exert several beneficial
effects on human and animal health.9

β-glucans and immunity
Trained immunity (TRIM) induction is a promising defense
strategy against COVID-19.10 The widely known BacilleCalmette-Guérin (BCG) vaccine induces TRIM, protects against
severe forms of tuberculosis (TB) caused by Mycobacterium
tuberculosis, with limited effect against pulmonary tuberculosis,
and confers nonspecific protective properties against unrelated
infections and mortality.10 BCG’s nonspecific protection is
T-cell and B-cell independent and is mediated by the functionaland epigenetic reprogramming of innate immune cells such as
monocytes, macrophages, and natural killer (NK) cells. This
protection is called TRIM. TRIM has been reported to be
induced by stimulants like β-glucans, LPS, or the BCG
vaccine.11 We focused on how β-glucans could serve as inducersof TRIM in the context of a wide-spectrum vaccine adjuvant
approach to COVID-19.

β-glucans and TRIM
β-Glucans are a heterogeneous group of polysaccharides abun­dant in the cell walls of yeasts, bacteria, and fungi that reportedly
induce TRIM. β-Glucans induce epigenetic reprogramming in
innate immune cells, leading to cellular activation, augmented
cytokine production, and changes in metabolic function thatshift cellular metabolism from oxidative phosphorylation to
glucose fermentation mediated by the Akt/mammalian targetof rapamycin (mTOR)/hypoxia-inducible factor 1α (HIF1α)pathway,12 thus effectively inducing TRIM. Epigenetic altera­tions such as histone methylation and acetylation lead to thepositive regulation of gene expression. When such epigenetically“trained” cells have contact with heterologous secondary stimuli,
they are programmed to produce a more robust immune
response.10,11 The cells are reportedly not peripherally trained,but β-glucans can impact the bone marrow (BM) and lead toa lasting TRIM phenotype.

Arms of the immunity stimulated by β-glucans andimplications in COVID-19
Administering intraperitoneal β-glucans specifically expand
Lin−Sca1+ cKit+ (LSKs) and multipotent myeloid progenitor
3 (MPP3)-expressing hematopoietic stem cells (HSC) in theBM, and such trained HSCs generate a “central” memory.12,13
Epigenetic modifications driven by β-glucans are rapidly acti­
vated by secondary infections or stimuli such as viruses andmay serve as a potent strategy for vaccines against COVID-19.8
β-Glucans act as pathogen-associated molecular patterns(PAMPs), because they are present in the cell wall of several
pathogenic yeasts and bacteria and are involved in microor­ganism recognition and clearance by the human immune sys­tem. Upon reaching the intestine, β-glucans are internalized byintestinal epithelial and/or M cells and presented to immune
cells within the Peyer’s patches. β-Glucan particles can alsoreach distant lymphoid organs via the blood or lymph. In thePeyer’s patches, β-glucan particles are recognized by the liga­
tion of specific pathogen recognition receptors (PRRs) such as
toll-like (TLR) and C-type lectin-like receptors. Among C-type
lectin-like receptors, dectin-1 is the most-studied receptor thatbinds β-glucan from various sources. Dectin-1 is expressed on
the surface of monocytes, macrophages, neutrophils, dendritic
cells, and T lymphocytes, which are all activated by β-glucan
binding. This binding leads to a number of cellular responses
via the modulation of inflammasome and transcription factor
activation, which results in the production of cytokines, che­mokines, and reactive oxygen species. β-Glucans stimulate NK
cell cytotoxic activity as part of the innate immune response bybinding directly to the NKp30 activating receptor.13,14 βGlucan innate immunity targets are monocytes, macrophages,
dendritic cells, and NK cells. β-Glucans induce the antimicro­bial activity of mononuclear cells and neutrophils as well.13
Regarding T cells, β-glucans help in CD4 + T-cell immunomo­
dulation, allowing them to infiltrate tumors and thereby inhibit
tumor growth.15 Orally administered β-glucans can reachthe spleen and lymph nodes and significantly reducetumor burdens by activating DCs, expanding and activating
antigen-specific CD4 and CD8 T cells, and inducing IFN-γ
production.16 β-Glucans also induce B lymphocytes to produce
antibodies. Short-term supplementation with β-glucans
improves the levels of salivary immunoglobulins (sIgM, sIgG,
and sIgA).16 Orally administered β-glucans significantly stabi­lize IgG1 levels, maintaining anti-infectious immunity. Thus,
all aspects of the immune system are activated and modulatedby β-glucans, making them worth considering as an ideal
vaccine that produces long-lasting effective immunity, isbroadly protective, is effective in all vaccinated subjects acrossages, and is stable and easily administrable.17,18

β-glucan supplementation for COVID-19
Long-lasting immunity is currently a big challenge in COVID19-affected patients.17 β-Glucans can produce long-lasting TRIM
against a wide range of pathogens.18 Furthermore, β-glucans are

HUMAN VACCINES & IMMUNOTHERAPEUTICS

safe for consumption at all ages, and they fall under the FDA’s
generally recognized as safe category.19 β-Glucans are stable andcan be consumed continuously as a food supplement.9 Many
types of β-glucans exist, but yeast- and mushroom-derived βglucans exert stronger immunomodulatory effects than do othertypes of β-glucans.20 Oral β-glucans have been thoroughly
described as prophylactic supplements to boost immune
responses and to abrogate COVID-19 symptoms via their
TRIM actions.10 Though SARS-CoV-2 is predominantly consid­
ered a virus that affects the respiratory system, the viral host
receptor ACE2 appears in the cytoplasm of gastrointestinal
epithelial cells, with the viral nucleocapsid protein appearing in
the cytoplasm of rectal, duodenal, and gastric epithelial cells,suggesting that the intestine may be relevant in the pathogenesis
of COVID-19 and maybe a possible route of infection.21 βGlucans with immune effects on the intestine may therefore bean advantageous supplementation strategy for COVID-19 ther­apy. Gut-dysbiosis is also a key element in determining infectionrelated diseases. β-Glucans can also modulate the gut bacteria,
improving immune response.22 β-Glucan supplements decrease
the incidence of upper respiratory tract infections in randomized
control trials.23–27 A β-glucan extract from the edible shiitake
mushroom Lentinus edodes has recently been reported toshow differential in vitro immunomodulatory and pulmonary
cytoprotective effects and may be indicated for COVID-19
immunotherapy.27 The study compared two types of Lentinan
extracts that differentially reduced cytokine-induced NF-κB acti­
vation in human alveolar epithelial A549 cells and attenuatedpro-inflammatory cytokine production (TNF-α, IL-8, IL-2, IL-6,
and IL-26), as well as TGF-β and IL-10 secretion. The study
suggested that β-glucans delivered as a tailored cocktail might
fit future nutraceutical-based intervention for COVID-19. The
study also mentioned a major drawback: maintaining functional
bioactivity and increasing the β-glucan yield required less harm­
ful extraction processes without enzyme and harsh chemical
usage.27 This extraction process is crucial for using β-glucans
against COVID-19.28

AFO-202 β-glucan
We herein describe the β-glucan derived from the black yeast
Aureobasidium pullulans AFO-202 strain that is uniquely
secreted as an exopolysaccharide. Therefore, it does not need
any kind of extraction-to-purification procedure, resulting inhighly pure β-glucan with significant bio-functional activity.28
The AFO-202 β-glucan can induce various positive immune
responses relevant to COVID-19. It decreased levels of IL-6,
which is commonly the most elevated cytokine in a COVID-19
cytokine storm, the main mechanism leading to organ damage
and mortality. It enhances IFN-γ and sFAS levels. It is asso­
ciated with increased production of IL8, which causes theactivation, migration, and chemotaxis of cytotoxic neutrophils.
It decreases CCL2 and CXCL10 levels, inhibiting the chemoat­
traction of monocytes/macrophages, T cells, NK cells, anddendritic cells. The prevention of chemoattraction modulates
immune responses. It also increased IL-7 production, leading
to mature T-cell survival and development. Activating CD8+(cytotoxic T cells), CD4+ (mainly Th1 cells), and Treg cells
helps balance the regulatory immune response. Activation of3

B cells by AFO-202 β-glucan results in the production of virusspecific antibodies.28,29 AFO-202 β-glucan enhances NK cell
activity against Leishmania amazonensis infection.30 AFO-202
β-glucan is also present in the inner wall of Candida albicans,making it a strong PAMP candidate with a significant chanceof recognition by PRRs. AFO-202 β-glucan has been consumed
since 1996, when the Japanese Regulatory Authority approved
it as a food additive. It has been established as safe and effica­
cious in elderly patients.31 AFO-202 β-glucan also helps tomaintain blood glucose and lipid levels,32,33 addressing thehigh risk of comorbidities like diabetes and cardiac diseases
in the pathogenesis of COVID-19. As fasting plasma glucose
has been indicated as an independent predictor of the outcome
at the time of admission in COVID-19 patients, the metabolic
effects of AFO-202 β-glucan may have prophylactic potential in
COVID-19.34 In addition, AFO-202 β-glucan has been sug­gested to be beneficial in decreasing the risk of coagulopathy
due to the presence of a dysregulated inflammatory system in
COVID-19 patients, especially in vulnerable individuals basedon race (Caucasians, African Americans and Hispanics), peo­
ple with comorbidities, including diabetes, hypertension, andcardiovascular diseases, pregnant women.35

AFO 202 β-glucan as a wide-spectrum immune
effector
Oral vaccines generate immunity in gut-associated lymphoidtissue (GALT) that consists of lymph nodes, Peyer’s patches(containing 75% of B cells and 20% of T cells), and isolated
lymphoid follicles in the gastrointestinal tract (GIT).36 M cells
transport the antigen in the vaccine across the mucosal barrier
into Peyer’s patches, and the antigen is presented to T cells by
antigen-presenting cells. CD4 + T cells are activated, support­
ing the germinal center development, B-cell affinity matura­tion, and class-switching to IgA, along with CD40/CD40 ligand
interactions and cytokine secretion. The antigen-primed B cells
migrate to distant effector regions, where they differentiate into
plasma cells that secrete dimeric or polymeric IgA molecules.
These molecules are transported into the intestinal lumen as
secretory IgA (sIgA) that can prevent attachment and pathogen
invasion, neutralize enterotoxins, and induce serum IgG via thevaccine, acting against mucosally and systemically invasive
pathogens. Vaccines also activate cell-mediated immune
responses against intracellular bacteria and viruses, alongwith antibody-dependent cellular cytotoxicity responses.37,38
Following intra-dermal vaccination, immune cells such as
DCs, T lymphocytes, NK cells, macrophages, and mast cells
present in the skin epithelium trigger the skin’s inflammationcascade, mainly via Langerhans cells (a specific DC subset that
migrates into the lymph nodes following antigen capture andinitiates the adaptive immune response). These cells are stimu­
lated by PAMPs via an array of germline-encoded PRRs,
including TLR and langerin (CD207). The skin’s resident
mast cells induce the innate immune response in the skin byreleasing granules containing inflammatory mediators.39
The immune system triggers pathways of oral and intrader­
mal vaccination depend on components of the reticuloen­
dothelial system or the mononuclear phagocyte system39
employed to access the immune system. Oral vaccines start

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N. IKEWAKI ET AL.

with mucosal-associated lymphoid tissue and GALT, while
intra-dermal vaccines start with peripheral lymphoid tissues.

AFO-202 β-glucan as a vaccine adjuvant
β-Glucans have been suggested to be promising anti-infective
vaccine adjuvants, as they alone can stimulate various immune
reactions, including antibody production without any adverse
reactions. β-Glucans have been employed as adjuvants to vac­cines against Yersinia ruckeri.39 β-Glucans as adjuvants havebeen found to enhance immunogenicity of hepatitis B vaccine,
influenza vaccine, and vaccines against systemic aspergillosis
and coccidioidomycosis. The AFO-202 β-glucan has been pro­ven to be a potential immune adjuvant, because when it wasadministered with an avian influenza H5 subtype vaccine, itelicited strong immune responses with high hemagglutination
inhibition titers and 10–20% ELISA seroconversion.40
Figure 1 illustrates the mechanisms and pathways that differ
between oral and intra-dermal vaccines, and how β-glucans
interact with components involved in both the types of vaccines.
Table 1 provides the details on the various immune effector
mechanisms and pathways through which β-glucans may beable to serve as vaccine adjuvants for COVID-19 therapy.

β-glucans as wide-spectrum immune-balancing foodsupplement-based enteric (β-WIFE) vaccine adjuvant
approach to COVID-19
β-Glucans induce TRIM with epigenetic reprogramming in
innate immune cells at the BM level, leading to a long-lasting
central and peripheral TRIM.9–11 Since β-glucans are recog­
nized as PAMPs, they are recognized by the ligation of specific
PRRs, such as TLR and C-type lectin-like receptors, which
stimulate both innate immunity by targeting cells, including
macrophages and NK cells, as well as adaptive immunity by
expanding and activating antigen-specific CD4 and CD8 T cells
and enabling B lymphocytes to produce antibodies.15,16,28 βGlucans also enhance mucosal immunity, employing the
majority of the components of the reticuloendothelial system
by inducing gut mucosal immunity, traveling to distant effector
sites such as the spleen and lymph nodes.39,41 β-Glucans acti­
vate all aspects of the immune system,9–13 resulting ina continuous, lasting immune response against various patho­
gens that can elicit specific antiviral immunity.28 Above all, this
β-glucan-based immune response is obtained through a simple
oral food supplement administration, with a proven trackrecord of safe consumption at all ages,28 besides having been
employed as vaccine adjuvants.37,38,40 Thus, for COVID-19, weFigure 1. Schematic illustration describing (i) stepwise, the mechanisms of orally administered vaccines starting from Peyer’s patches of the gut to induce mucosal
immunity and parenteral vaccines starting from immune cells of the skin to induce systemic immunity, (ii) ability of β-glucans to activate all aspects of the immune
system including the central trained immunity (TRIM) of bone marrow and (iii) the strategic key advantages of β-glucans at five different stages and actions to play a roleas vaccine adjuvant.

HUMAN VACCINES & IMMUNOTHERAPEUTICS

Table 1. Various immune effector mechanisms and pathways through which βglucans may be able to serve as vaccine adjuvants for COVID-19 therapy.

ORCID

Immune mechanisms of β-glucans as vaccine adjuvants
S. No
for COVID-19 therapy
Reference(s)1Trained immunity (TRIM); both central and peripheral
10–12
2
Epigenetic reprogramming in innate immune cells
113
Activation of pathogen recognition receptors (PRRs) such
12,13
as toll-like (TLR) and C-type lectin-like receptors,
including dectin-1
4
Stimulation of monocytes, macrophages, dendritic cells,
13,14
and NK cells
5Enhancing antimicrobial activity of mononuclear cells and13,14
neutrophils
6
Expanding and activating antigen-specific CD4 and CD8
15,16
T cells7
Antiviral response by stimulating production of IFN-γ
15
8
Induction of B lymphocytes to produce antibodies
169Increasing of salivary immunoglobulins (sIgM, sIgG, and
16sIgA) for saliva-based mucosal immunity
10
Induction of mucosal immunity including that of the gut 8,13,39,41
by acting on reticuloendothelial system
11
Immune balance against cytokine storm by decreasing
28,35,36levels of IL-6, CCL2, and CXCL10 levels and increasinglevels of IL-7, IL-8, IFN-γ, and sFAS

Samuel JK Abraham

have termed this approach as a β-WIFE vaccine adjuvant
approach.
Our group has recently initiated a pilot study in healthy
volunteers (men aged between 40 and 60) on evaluation of
biomarkers relevant to thrombogenicity, apart from immune
enhancement and immune modulation with AFO-202 βglucan and the interim results are encouraging. Based onthese encouraging preliminary results, we plan to undertakea controlled study in COVID-19 patients whose general healthconditions permit oral consumption.

Conclusion
Without definitive therapeutics for COVID-19, and althoughsome vaccine candidates have been authorised/approved, sig­
nificant hurdles still exist in identifying an ideal vaccine witha wide-spectrum activity and no side effects. Orally consumed
β-glucans such as the AFO-202 β-glucan might be able to serve
as a β-WIFE vaccine adjuvant approach to COVID-19.
However, this approach needs extensive validation by multicentric randomized clinical trials.

Acknowledgments
The authors thank Prof. Gary Levy, (University of Toronto Transplant
Institute, Multi Organ Transplant Program, University Health Network,
Toronto, Canada) for his valuable guidance with the drafting of thismanuscript. Mr. Takashi Onaka, (Sophy Inc, Kochi, Japan), for necessary
technical clarifications. KR & JL are thankful to the National Science
System (SNI) of National Secretariat for Science, Technology, andInnovation of Panama (SENACYT) for support.

Disclosure of potential conflicts of interest
Author Samuel JK Abraham is a shareholder in GN Corporation, Japan
which in turn is a shareholder in the manufacturing company of the AFO
202 Beta Glucan & also an inventor in several patents of relevance to the
AFO 202 Beta Glucan.

5

http://orcid.org/0000-0003-2646-2687

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