Evaluation of a yeast-based BVDV vaccine approach

Bovine Viral Diarrhoea Virus (BVDV) has been implicated as a major
economic disease risk for the cattle industry, resulting in a variety of
associated problems. Control of BVDV infection is economically
important to the cattle industry because the virus causes a variety
of clinical diseases and reproductive disorders, as well as potential
secondary infections such as mastitis that adversely affect
essentially all stages of the production cycle, and depending on the
country, various BVDV eradication programs are in place (Ridpath,
2013). Production losses primarily stem from reproductive failure
and from immunosuppression during acute BVDV infection, which
predisposes calves to respiratory or enteric diseases. Indeed, the
effects of a BVDV infection on the innate and acquired immune
system are unique and result in dramatic immune dysfunction.
Vaccination alone is not sufficient to protect against foetal infection
and losses due to BVDV. This is because no single BVDV vaccine has
been shown to give complete foetal protection. Despite increased
awareness regarding bio-security measurements and PI eradication
programs, vaccination is still the most important control strategy for
controlling BVDV infections in many countries (Ridpath, 2013).
Providing acquired immune protection against infection with BVDV
is challenging due to the heterogeneity that exists among BVDV
strains. Both modified live and killed vaccines have been shown to
be efficacious. Both humoral and cellular immune responses are
protective. Following natural infection or vaccination with a
modified live vaccine, the majority of the serum antibodies are
directed against the viral proteins E2 and NS2/3, with minor
responses against the Erns and E1 proteins. Current BVDV vaccines
require injection and a 'cold chain', and to date all commercially
available vaccines are produced in cell culture.
Here, new oral vaccines may provide a more convenient route of
administration, and thus being of great advantage, if shown to be as
protective as the current injectable ones. Saccharomyces cerevisiae
(S. cerevisiae), a non-invasive, non-pathogenic organism, is generally
considered to be a "generally regarded as safe" (GRAS) species and
for this reason, it is an attractive tool for delivering antigens and
therapeutic molecules (Chen et al., 2005; Garrait et al., 2007).
Indeed, as little as 5 recombinant yeast particles of S. cerevisiae
expressing ovalbumin have been shown to induce dendritic
cell-based T cell proliferation to the same degree as those primed
with saturating amounts of ovalbumin peptide. This was
accompanied by up-regulation of CD80, CD86, CD40, CD54 and MHC
II as well as an increase in IL-12 production by dendritic cells (Stubbs
et al., 2001). Similar to these data generated in mice, work by Lu et
al and by Franzusoff et al in humans has demonstrated that
immunisation with inactivated S. cerevisiae expressing tumour
antigens elicits a far stronger response compared to antigen alone,
and was equal to the anti-tumour response generated by
immunisation using their live counter-parts (Ardiani et al., 2010;
Franzusoff et al., 2005; Lu et al., 2004). Indeed, S. cerevisiae used as
a vaccine vehicle can effectively elicit mucosal and systemic
immunization by administration to mucosal sites, including the oral,
respiratory and genital tracts (Allnutt et al., 2007; Sasagawa et al.,
2005; Shin et al., 2005). In mammals in particular, S. cerevisiae has
been demonstrated to have superior safety and efficacy, where it
has been shown to elicit both innate and adaptative immune
responses due to the presence of TLR ligands in its cell wall (Ogra et
al., 2001) as well as its antigenic feature due to its size.
Thus, we propose to assess the value of using recombinant S.
cerevisiae yeast expressing BVDV E2 and/or NS2/3 proteins on its
surface in a non-secreted form as a vaccine candidate for oral
administration.