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not markedly affected by circulating antibodies in chickens, but rice (Wu et al., 2007), and Nicotiana benthamiana (Richetta et al.,
the T-cell-mediated immune response to the inactivated IBDV is 2017). Immunization of chickens with recombinant VP2 con-
scarcely elicited unless cross-presentation is induced by a special ferred protection for chickens with some success (Pitcovski et al.,
adjuvant such as ISCOM, liposome or saponin that can directly 1996, 2003; Omar et al., 2006), but the adjuvant for VP2 subunit
help antigen enter the cytosol of host cells. Inactivated IBDV vac- vaccine seems very important to enhance the immunogenicity
cines are most efficiently used in a prime-boost regimen, using of VP2. In addition to conventional adjuvant, some cytokines
attenuated live IBDV as priming vaccine (Müller et al., 2012), and such as IL-2 (Liu et al., 2005; Wang et al., 2010), IL-6 (Sun et al.,
immunization of adult chickens with inactivated IBDV vaccines 2005), IL-7 (Cui et al., 2018), IL-12 (Su et al., 2011), and IL-18
is intended to mount a strong humoral immune response for the (Li et al., 2013) that were either expressed alone or together
protection of the progeny against IBDV infection. with VP2 as fusion recombinant proteins, were used as adjuvant
for enhancing immune response to VP2 with some success, and
IBDV immune complex vaccines might be commercialized as adjuvant for VP2 subunit vaccines
The original idea of using immune complex vaccines (Icx) to in the future. A variety of VP2-expressing viral vectors have been
immunize animals could be traced back to 120 years ago, when constructed and examined for the protection against IBDV infec-
Theobald Smith suggested in 1907 that toxin–antitoxin mixtures tion. These viral vectors, derived from live viral vaccine strains for
might be used to immunize man against diphtheria (Behring other avian diseases, are constructed by inserting IBDV vp2 gene
1967). However, it was Emil von Behring, the founder of humoral into their genome via molecular biological methods to express
immunity theory and the first Nobel Prize laureate for Physiology recombinant VP2 during viral replication, and the resultant
or Medicine, who really put this idea into practice. Behring made VP2-expressing viral vectors can be used as vaccines to protect
a mixture of toxin of diphtheria with antitoxin (antibodies against chickens against two diseases (IBD and viral vector-related dis-
toxin) for vaccinating human against diphtheria and achieved a ease) at the same time. A couple of VP2-expressing viral vectors
great success in control of diphtheria. In contrast to live IBDV have been reported to confer protection in chickens against IBDV
vaccines, IBDV immune complex vaccines are favourably taken successfully, including fowlpox virus (Bayliss et al., 1991; Heine
up by macrophages and dendritic cells via Fc receptor-mediated and Boyle, 1993; Butter et al., 2003), canarypox virus (Zanetti
phagocytosis. In such a case, IBDV-induced apoptosis and deple- et al., 2014), herpesvirus of turkey (HVT) (Darteil et al., 1995;
tion of B cells from bursa follicles could be avoided as much as Roh et al., 2016), fowl adenovirus (Sheppard et al., 1998; Fran-
possible. Experimental evidence showed that the depletion of cois et al., 2004), Marek’s disease virus (MDV)-CVI-988 strain
bursal and splenic B lymphocytes was markedly diminished in (Tsukamoto et al., 1999), MDV type 1 (MDV1) vaccine strain
chickens vaccinated with IBDV Icx as compared with the chick- (Li et al., 2016), NDV-LaSota strain (Huang et al., 2004), and
ens immunized with the native live IBDV vaccine (uncomplexed) NDV-F strain (Dey et al., 2017). Currently some VP2-expressing
(Jeurissen et al., 1998). Furthermore, in ovo inoculation with the viral vector is commercially available such as HVT-VP2 vaccine
IBDV Icx vaccine induced more germinal centres in the spleen and used clinically to control MD and IBD. Development of VP2-
and larger amounts of IBDV were localized on both splenic and expressing viral or bacterial vectors is necessary and promising
bursal follicular dendritic cells. It might be worth trying to use and would provide an alternative to control two avian diseases
IBDV Icx containing intermediate virulent IBDV strain in control with one shot.
of IBD in epizootic areas since IBDV Icx could reduce BF damage
and maintain its immunogenicity.
Future perspective
VP2-related vaccines (subunit and viral Although IBD first appeared as ‘Gumboro disease’ over 55 years
vector-based vaccines) ago, it continues to threaten the poultry industry worldwide.
VP2, a structural protein of IBDV, serves as a viral ligand bind- IBDV, as a dsRNA virus with a high resistance to disinfectants, is
ing to the receptor on host cell membrane for virus attachment, inclined to mutate in the genome, especially under the immune
a crucial step of IBDV infection. The titre of IBDV VP2-specific pressure, resulting in the emergence of new virulent strains in vac-
antibody is directly correlated to the protection of chickens from cinated flocks. IBDV is the only known avian pathogen that infects
challenge with virulent IBDV (Nakamura et al., 1994), indicating and destroys B lymphocyte in BF, a central component of adaptive
that VP2 carries neutralizing epitopes. Thus, VP2, like a glit- immunity. Among different types of IBDV vaccines, live IBDV
tering star, attracts much attention as a promising immunogen vaccines are widely used to control IBDV infection especially in
in vaccine development for the prevention and control of IBD. IBD epizootic areas. However, currently used live vaccines, which
Many efforts have been made to express recombinant VP2 as an were traditionally developed via serial passages in tissue cell
immunogen for protecting chickens from IBDV infection using cultures or embryonated eggs, cause more or less damage to BF,
different expression systems ranging from bacteria to plants, such leading to immunosuppression, followed by increased suscepti-
as yeast (Macreadie et al., 1990; Pitcovski et al., 2003; Arnold et bility to other microbial diseases and the failure of vaccinations
al., 2012), baculovirus (Vakharia et al., 1994b; Pitcovski et al., against commonly seen diseases such as avian influenza (AI),
1996; Yehuda et al., 2000; Ge et al., 2015), E. coli (Omar et al., Newcastle disease (ND), infectious bronchitis (IB), etc. There-
2006; Jiang et al., 2016), lactic acid bacteria (Liu et al., 2018), fore, it is highly desirable to have live IBDV vaccines without
silkworm (Xu et al., 2014), Arabidopsis thaliana (Wu et al., 2004), immunosuppressive consequences. Recent research progresses