Introduction
The 2019 novel coronavirus (COVID-19) has faced global pandemic. This is
different from the past Severe Acute Respiratory Syndrome(SARS-CoV) and
Middle East Respiratory Syndrome coronavirus (MERS-CoV), and may suggest
that the COVID-19 situation may not be easily terminated through the
second and third wave. Various strategies have been applied to control
the rapidly expanding COVID-19 (Kannan,
Shaik Syed Ali, Sheeza, & Hemalatha, 2020;
Singhal, 2020). There is a need for the
development of vaccines that allow the formation of antibodies capable
of controlling COVID-19, which is why global pharmaceutical companies
are in the process of clinical research on vaccines
(L. Yang, Tian, & Liu, 2020). Vaccine
development requires three technologies, an antigen, a vaccine adjuvant,
and delivery technology. Antigen-related technologies relate to antigen
design and production techniques that induce protective immune
responses. Vaccine adjuvants are designed to maintain high protective
immune responses to the antigen over long periods of time. Finally, the
vaccine delivery technology determines the vaccination route{Ahmed,
2011 #1}. Presently, vaccine development has mainly focused on antigen
development (Calzas & Chevalier, 2019;
Martinon, Cisneros, & Villicana, 2019;
Mohan, Zhu, Wang, & Wang, 2018).
However, the importance of immunity-enhancing vaccine adjuvants has been
emphasized to develop new preventive vaccines against infectious
diseases or to improve the efficacy of present vaccines
(Roy et al., 2014;
Rydell & Sjoholm, 2004). The use of
adjuvants may increase the long-term immunogenicity of the vaccine and
thus, reduce or eliminate the need for additional inoculations
(Ahmed, Plotkin, Black, & Coffman, 2011).
Moreover, since immunity-enhancers tends to increase the
cross-reactivity of the vaccine, it can also increase the protective
effect against serotype strains not included in the vaccine. If a
vaccine, such as an influenza vaccine, is temporarily needed due to a
global pandemic, it is also possible to increase the vaccine supply by
lowering the antigen dose(Ahmed et al.,
2011; Cribbs et al., 2003).
Immune cells generate a specific immune response to each pathogenic
bacterium or virus at the time of infection but they also have receptors
called pattern recognition receptors (PRRs) that respond to
commonly-encountered molecules, such as bacterial cell walls, LPS,
proteins or viral RNA and DNA
(Jahanban-Esfahlan, Seidi, & Majidinia,
2019; Joshi, Shaw, & Quagliarello,
2009). The Toll-like receptor (TLR) is a typical PRR and 11 species are
known in humans. TLR agonists are highly active against immune cells and
are being developed as vaccine adjuvants
(Medvedev, 2013).
Polysaccharides derived from natural products have potential as
immunomodulators because they are large molecules that affect the immune
system and they have been widely used in clinical applications. Most
polysaccharides present in natural products are non-toxic and do not
cause the serious side effects associated with other bacterial
polysaccharides or synthetic substances that are capable of
immunomodulation. They also maintain homeostasis in the body
(Harandi, 2018). Recent studies have
shown that polysaccharides present in natural products exert
immunosuppressive effects on antigens and vaccines in both cellular and
humoral immunity, making them alternatives to conventional aluminum
salts as vaccine adjuvants for vaccines
(Liu et al., 2019;
Tian & Liang, 2019). Specifically, plant
polysaccharides can safely induce humoral immunity, as well as cellular
immunity, as vaccine adjuvants. Their advantages are availability at
relatively low cost and application to a wide range of vaccines against
cancer and infectious diseases (Gu et al.,
2019; Munoz, Porsch, & St Geme, 2019;
Tian & Liang, 2019).
Morus alba L . is enriched in polysaccharides, anthocyanins,
alkaloids, and flavonoids. Pharmacological functions attributed toM. alba L. include anti-oxidative, anti-inflammatory,
anti-diabetic, as well as cardiovascular, hepatoprotective, and
neuroprotective activities (Hwang & Kim,
2004; H. G. Kim et al., 2010). M.
alba L. has been found to be immunostimulatory in vitroand in vivo . We also found that when M. alba L. was
used in combination with anticancer drugs, such as fluorouracil (5FU),
it decreased the side effects of the anticancer drug and increased
immune function. We recently found that M. alba L. can
activate Toll-like receptor 4 (TLR4) on antigen-presenting cells (APCs)
(Chang, Kim, Lee, Park, & Kim, 2015;
S. B. Kim et al., 2013;
X. Y. Yang et al., 2009). However, the
oral administration of M. alba L. to improve immunogenicity as a
vaccine adjuvant has been rarely reported. If effective, the ingestion
of the M. alba L. would be more a more readily accepted and
convenient application than intramuscular or nasal administration.
In this study, we conducted studies in a mouse model to investigate the
effects of orally administered M. alba L. on modulating the
efficacy of ovalbumin and PR8 influenza vaccine immunizations.