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Foot-and-Mouth Disease Vaccine Programme
Programme Leader: Dr Bryan Charleston
The Foot-and-Mouth Disease Programme is undertaken by researchers at the Pirbright Institute. The group has localised persisting virus in FMDV carriers to follicular dendritic cells within lymph node germinal centres. From studies of FMDV infection in calves, we showed antibody responses to capsid surface sites are T cell-independent, whereas those directed against nonstructural proteins are T cell-dependent. Furthermore, CD4(+) T-cell-independent antibody plays a major role in the resolution of disease. These results have shaped the course of our FMDV vaccinology programme to optimise the design of vaccine antigens.
Our substantial FMD vaccine development efforts focus on delivery of whole viral capsids by a variety of approaches and routes. Collaborating with Oxford structural biologists and baculovirus experts at Reading, we have developed an in vitro system to make empty capsids stabilised by targeted mutagenesis to survive heat and pH changes. These have potential as vaccines with safer production, better shelf life, and greater potency. Prime-boost using DNA vaccine combined with conventional antigen may broaden protection and capsid vaccines with deleted virion-surface loops have marker potential.
Transmission and disease spread modelling
We have recently conducted a large systematic study to quantify FMD virus (FMDV) transmission and our findings that cattle are infectious for less than 50 hours challenge previous assumptions on incubation and latent periods. In conjunction with work to quantify the degree of protection afforded by vaccines, this will improve the accuracy of disease spread models that were a highly controversial source of policy and culling advice during the UK 2001 epidemic.
Our conclusions will impact greatly on how the UK deals with future outbreaks. Identifying sources of FMD outbreaks is often confounded by incomplete epidemiological evidence and the many routes by which virus can spread. Our studies of UK outbreaks (2001 and 2007) have shown that whole genome sequence comparisons can track farm-to-farm spread, indicate the existence of undisclosed infected herds, and may contradict the conclusions of conventional epidemiological tracing. Greater resolution and profound evolutionary insights are in reach with next generation sequencing.
Detection and control
We have tracked new epidemics of FMD virus globally to predict threats and vaccine suitability and have established an international network of FMD Reference Laboratories to complement our own outputs. We have advised international agencies in establishing concepts for global control, regionalised efforts and trade incentives. Rapid detection of FMD is critical to containment. We have launched a fully validated FMD lateral flow device and developed/validated serological tests in support of vaccination to minimise culling requirements.
We elucidated the sequence and structural requirements for high affinity binding of FMD virus to its major integrin receptor, alphavbeta6, and identified a synergy site that helps to stabilise the virus/receptor complex. We showed that early-endosomes are the site of membrane penetration by the viral RNA. We have shown, for the first time, that FMD virus can cross the placenta and can infect foetal lambs, a finding to be taken into account in future FMD control strategies.
Charleston B, Bankowski BM, Gubbins S, Chase-Topping ME, Schley D, Howey R, Barnett PV, Gibson D, Juleff ND, Woolhouse ME. Relationship between clinical signs and transmission of an infectious disease and the implications for control. Science. 2011 332(6030):726-9.
Reid E, Juleff N, Gubbins S, Prentice H, Seago J, Charleston B. Bovine Plasmacytoid Dendritic Cells Are the Major Source of Type I Interferon in Response to Foot-and-Mouth Disease Virus In Vitro and In Vivo. J Virol. 2011 85(9):4297-308.
Robinson L, Windsor M, McLaughlin K, Hope J, Jackson T,
Charleston B. Foot-and-mouth disease virus exhibits an altered tropism in the presence of specific immunoglobulins, enabling productive infection and killing of dendritic cells. J Virol. 2011 85(5):2212-23.
Guzman E, Taylor G, Charleston B, Ellis SA. Induction of a cross-reactive CD8(+) T cell response following foot-and-mouth disease virus vaccination. J Virol. 2010 84(23):12375-84.
McLaughlin K, Seago J, Robinson L, Kelly C, Charleston B. Hsp70 enhances presentation of FMDV antigen to bovine CD4+ T cells in vitro. Vet Res. 2010 41(3):36.