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Production problems, the risk of live virus release, poor inactivation, antigen
instability and the lack of cross-serotype protection of inactivated whole virus
vaccines have led to the pursuit of a more stable heterotypic bioengineered vaccine,
based on the inclusion of immunogenic peptides derived from FMDV genome sequences.
Such vaccines have the potential to act as markers with companion differential diagnostic
tests for use during eradication programmes. However, for developing countries, the
technology required for recombinant virus production may be as prohibitive as the
maintenance of high-containment facilities for the manipulation of live FMDV.
In the last 20 years there has been considerable effort directed towards
the production of synthetic or sub-unit FMDV vaccines based on the major
immunogenic sites of the virus. However, no commercial bio-engineered
vaccine against FMD has been forthcoming, despite encouraging early work
with VP1 produced by recombinant DNA technology and expression as a fusion
protein (Kleid et al., 1981).
Synthetic peptides based upon the antigenic sites of VP1 were shown to
induce neutralising antibody and protection in laboratory animals when
conjugated with carrier proteins (Bittle
et al., 1982), polymerised (Pfaff
et al., 1982) or used as high payload free peptide in Freund's adjuvant
(Doel et al., 1990). Modified-live
viral (Kitson et al., 1991)
and bacterial (Ruppert et al.,
1994) vectors able to express the immunogenic sites of FMDV have also
been developed with some success, and enhanced immunogenicity has also
been shown with FMDV peptides as fusion products in hepatitis B core particles
(Clarke et al., 1987).
In most instances the induction of protection by synthetic peptide FMDV
vaccines in natural host species has been disappointing (DiMarchi
et al., 1986) compared with the earlier results from guinea pig studies.
It has been shown that the humoral response in cattle immunised with free
FMDV peptide vaccines was of relatively low avidity (Steward
et al., 1991) and high IgG2 titre (Mulcahy
et al., 1990) compared with the response in conventionally vaccinated
cattle. There is evidence to suggest that even in an outbred group of
cattle MHC polymorphism may have a significant influence upon the efficiency
of T cell epitope presentation (van
Lierop et al., 1995). However, larger, more complex antigens with
multiple B and T cell epitopes may represent a better option. Recent results
have shown that processed FMDV capsid precursor protein P1 (Grubman
et al., 1993) can be expressed in vitro and can induce protection
in pigs. Work currently underway at the Institute for Animal Health, Pirbright,
has identified epitopes on the structural and non-structural proteins
which are important in generating both B and T cell responses. Complex
constructs incorporating both types of epitope are being evaluated for
their ability to protect against challenge. This approach of understanding
more precisely which determinants of the virus are immunogenic and which
are protective offers the best chance of developing an effective sub-unit
vaccine.
In recent years our understanding of the molecular basis of many of the
functions and properties of FMD virus has much improved. Using attenuated
FMD viruses as vaccines became discredited in the past due to reversion
to virulence in the field. The genetic determinants of virulence are now
understood for many picornaviruses at the molecular level. For FMD, several
regions of the genome are associated with virulence, particularly the
viral non-structural proteins (Giraudo
et al., 1990; Almeida et al.,
1998). A better understanding of how virulence can be altered by direct
manipulation of the genome offers the prospect of developing vaccine strains
with multiple, specific mutations which are much less likely to revert
to virulence on passage in animals. Early results are promising (Almeida
et al., 1998) but it will be several years before it is known whether
or not this approach offers a realistic prospect of developing useable
vaccines.
A second aspect of the biology of FMD virus that is now better understood
is the molecular basis of the cellular receptors to which the virus binds
and the corresponding receptor-binding sites on the virus. An important
receptor has long been known to be the 'RGD' sequence which is conserved
across all strains of FMD virus on the major immunogenic GH loop of VP1
(Fox et al., 1989). Using
recombinant techniques, viruses have been produced which lack this receptor
and which consequently cannot replicate in vivo or in vitro. Animals vaccinated
with the receptor-deleted viruses were protected against challenge (McKenna
et al., 1996). If a way can be found to produce receptor-deleted viruses
in bulk, they would represent a safer option than current vaccines as
there would be no risk of the vaccine causing the disease it is intended
to protect against. However, FMD virus possesses at least two receptors,
the second being a heparan sulphate receptor which is apparently of particular
importance in strains adapted to tissue-culture (Jackson
et al., 1996). The relevance of this to the potential use of RGD-deleted
viruses as vaccines is not yet clear. A better understanding of the interaction
between virus and host offers the prospect not only of designing vaccine
viruses which are incapable of causing disease but also of developing
therapeutic antiviral agents that are capable of preventing or eliminating
infection completely.
Advances in molecular biology make it likely that better and safer vaccines and/or antiviral
agents against FMD will be developed in the future. For the present, control of FMD can be
achieved by the effective use of currently available vaccines provided they are combined
with the other zoosanitary measures described in this module.
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