Publications

To deal with the incompleteness of observations and disentangle the complexities of transmission much use has been made of mathematical modelling when investigating the epidemiology of sheep transmissible spongiform encephalopathies (TSE) and, in particular, scrapie. Importantly, these modelling approaches allow the incidence of clinical disease to be related to the underlying prevalence of infection, thereby overcoming one of the major difficulties when studying these diseases. Models have been used to investigate the epidemiology of scrapie within individual flocks and at a regional level; to assess the efficacy of different control strategies, especially selective breeding programmes based on prion protein (PrP) genotype; to interpret the results of scrapie surveillance; and to inform the design of surveillance programmes. Furthermore, mathematical modelling has played an important role when assessing the risk to human health posed by the possible presence of bovine spongiform encephalopathy in sheep. Here, we review the various approaches that have been taken when developing and analysing mathematical models for the epidemiology and control of sheep TSE and assess their impact on our understanding of these diseases. We also identify areas that require further work, discuss future challenges and identify data gaps.

Foot-and-mouth disease virus (FMDV) causes a highly contagious infection in cloven-hoofed animals. Current inactivated FMDV vaccines generate short-term, serotype-specific protection, mainly through neutralizing antibody. An improved understanding of the mechanisms of protective immunity would aid design of more effective vaccines. We have previously reported the presence of virus-specific CD8(+) T cells in FMDV-vaccinated and -infected cattle. In the current study, we aimed to identify CD8(+) T cell epitopes in FMDV recognized by cattle vaccinated with inactivated FMDV serotype O. Analysis of gamma interferon (IFN-gamma)producing CD8(+) T cells responding to stimulation with FMDV-derived peptides revealed one putative CD8(+) T cell epitope present within the structural protein P1D, comprising residues 795 to 803 of FMDV serotype O UKG/2001. The restricting major histocompatibility complex (MHC) class I allele was N*02201, expressed by the A31 haplotype. This epitope induced IFN-gamma release, proliferation, and target cell killing by alpha beta CD8(+) T cells, but not CD4(+) T cells. A protein alignment of representative samples from each of the 7 FMDV serotypes showed that the putative epitope is highly conserved. CD8(+) T cells from FMDV serotype O-vaccinated A31(+) cattle recognized antigen-presenting cells (APCs) loaded with peptides derived from all 7 FMDV serotypes, suggesting that CD8(+) T cells recognizing the defined epitope are cross-reactive to equivalent peptides derived from all of the other FMDV serotypes.

In a recent article, Oscherwitz et al. endeavor to enhance the immunogenicity of a multiple antigenic peptide (MAP) vaccine that targets a loop-neutralizing determinant (LND) of Bacillus anthracis protective antigen (PA) (1). They showed in a previous study (2) that this MAP, consisting of four copies of amino acids 305 to 319 of PA (PA 305-319) extending from a lysine core, can elicit humoral immunity in rabbits that is specific and strongly neutralizing for the 2?2-2?3 loop in domain 2 of PA. However, LND-specific antibodies were not detected in rabbits immunized with whole PA, and it was concluded that PA 305-319 may be a cryptic epitope. T cell assays in PA 305-319-immunized mice showed that this peptide appeared to lack activity as a T helper cell epitope. We have good evidence that humans exposed to PA, either following cutaneous anthrax infection or through vaccination, generate long-term, T cell memory to both whole PA and PA 305-319. In a study including samples from naturally exposed patients recovered from cutaneous anthrax, from vaccine-hyperimmunized AVP (anthrax vaccine precipitated) donors, and from recombinant PA-vaccinated donors, positive T cell gamma interferon (IFN-?) enzyme-linked immunospot (ELISPOT) assay responses were detected across all groups on restimulation of peripheral blood mononuclear cells (PBMC) with both whole PA and PA 305-319 (Table 1; unpublished data). This shows that humans exposed to B. anthracis and whole PA recognize and generate memory to PA 305-319, suggesting that it is immunodominant rather than cryptic. Donors expressed a range of HLA haplotypes, with a majority being HLA-DR4 positive. While many important discoveries on the immunology of infection are made in experimental models, the human T cell response to PA in this respect differs from that of both rabbits and mice. In this light, the epitope used by Oscherwitz and colleagues may indeed be more relevant to eliciting appropriate human immunity than previously envisaged.