- Avian and Swine Flu
- Bovine Tuberculosis
- Foot and Mouth Disease
- Genetic Susceptibility to Infection
- Grand Challenge Project
- Hepatitis C
- Human Influenza
- Human Tuberculosis
- Other Livestock Diseases
- Oxford Martin Programme
- Staphylococcus Aureus
- Vaccine Delivery Technology
- Vector Engineering
Other Livestock Diseases
Rift Valley Fever (RVF)
Programme Leader: Dr George Warimwe
This Programme aims to:
1. Develop a safe and effective Rift Valley fever vaccine for use in sheep.
2. Develop a safe and effective Rift Valley fever vaccine for use in future human clinical trials.
Rift Valley fever (RVF) is a viral zoonosis caused by the RVF virus (RVFV), an RNA virus of the Bunyaviridae family that was first isolated from livestock on a Kenyan farm in 1930.
It is primarily a disease of ruminants such as sheep, goats and cattle but human infections occur following close contact with infected animal tissue and body fluids. The effects of RVF are most pronounced in newborn lambs and pregnant ewes where mortality and abortion rates approach 100%, respectively. In humans, the clinical spectrum varies from a mild febrile illness to the more severe manifestations of encephalitis and haemorrhagic diathesis that are frequently fatal.
RVFV is mainly transmitted by Aedes spp. mosquitoes, with a wide range of other mosquito species playing a role in virus dissemination during epizootics. The global distribution of the mosquito vectors has contributed, in part, to the spread of RVFV to much of Africa and parts of the Middle East and there are growing concerns of RVFV spread to other parts of the world. This, together with its potential use as a biological weapon, underlies the strict animal import controls and the inclusion of RVFV on the lists of notifiable diseases in many countries where the disease has not yet occurred.
To date, Kenya has had the highest frequency of RVF epizootics and the causative virus is now enzootic in six of the eight provinces in the country. Because RVF epizootics tend to be worst in areas where the virus is enzootic, Kenya and other countries with previous RVFV incursions will continue to bear the brunt of RVF for years to come unless effective control measures, including vector control and vaccination of susceptible hosts, are put in place. Two vaccines, one live-attenuated and the other formalin-inactivated, are available for livestock use. However, the formalin-inactivated vaccine requires repeat immunizations to achieve protective efficacy and, though the live-attenuated vaccine (termed Smithburn vaccine) confers long-lasting immunity, it is not safe for use in pregnant animals. No licensed vaccine is available for use in humans.
Recent approaches to a RVF vaccine
Recent approaches to RVF vaccine development have focused on two viral glycoproteins, Gn and Gc, encoded by the M segment of the RVFV genome. Mounting evidence shows that recombinant vaccines based on these glycoproteins induce neutralizing antibodies that confer protection from experimental challenge in mice and sheep. However, these studies are geared more towards livestock vaccines and the vectors used for the vaccine constructs have not been tested for safety in humans as part of any other licensed or experimental product and are very unlikely to be licensed for safety reasons. Using vaccine types with a known safety profile in humans obviates the need for extensive safety studies of new attenuated or inactivated viruses in human trials should a promising vaccine construct and schedule be identified.
This Programme’s approach
In this Programme, Dr Warimwe proposes to develop a safe and effective human vaccine based on Gn and Gc RVFV glycoproteins encoded by two viral vectors: modified vaccinia virus Ankara (MVA) and a simian Adenovirus, ChAdOx1.
The choice of these vectors is informed by the following observations from human clinical trials using MVA and ChAd63 (a group E simian adenovirus similar to ChAdOx1)-vectored malaria antigens: 1) both are safe, 2) highly immunogenic, 3) their optimal doses and routes of administration have already been established and, 4) neither is prone to significant anti-vector immunity and thereby subsequent attenuation of responses to vaccine constructs.
Thus, ChAdOx1-GnGc and MVA-GnGc vaccine constructs will be prepared and their immunogenicity and protective efficacy will be evaluated.
African Swine Fever
African Swine Fever is a highly contagious fatal acute haemorrhagic viral disease of pigs which causes major economic losses. ASFV is currently endemic in many sub-Saharan African countries and in Madagascar and Sardinia. There is no vaccine available and disease control relies on implementing movement restrictions and slaughter policies which are difficult to achieve in countries lacking a good infrastructure. To date, the use of empirical methods have failed to produce an effective vaccine, partly due to the complexity of the virus, the acute fatal nature of the disease and a poor understanding of the what types of immune response protect against infection.
ASFV has a large DNA genome, which replicates in the cytoplasm and encodes 150 to 165 proteins. These include a large number of proteins that help the virus to evade host defence systems. We are investigating the role of these viral proteins in evasion of host defences and this knowledge is being applied to the development of candidate vaccine strains by sequential deletion of ASFV genes that encode proteins involved in virus virulence and evasion of host defences. In addition, since recent studies have highlighted an important role for CD8+ T cells in immunity, we are characterizing the role of various CD8+ T cell subsets in protection; identifying the ASFV proteins recognized by these cells; and investigating vaccine strategies that induce protective ASFV-specific CD8+ T-cell responses in the pig.
Blue Tongue Virus (BTV)
Vector-borne diseases are transmitted between hosts by other animals such as midges, mosquitoes and ticks. Most vector species are small, cold-blooded, and fast-breeding, meaning that they can respond quickly to changes in their environment such as flooding or a warm summer. Climate change and the globalisation of trade mean that some vector-borne diseases are currently spreading into previously unaffected areas. For example, bluetongue virus (BTV) has been emerging in southern Europe for the last ten years, and arrived in northern Europe for the first time ever in 2006.
The arrival of the ruminant disease bluetongue (BT) for the first time ever in the UK in 2007 dramatically demonstrated the reality of the threat that is posed to UK livestock by arboviruses – viruses that are transmitted to mammalian hosts by arthropods e.g. midges and ticks. Biting midges transmit BT virus and related viruses of ruminants and horses that are endemic in most of Africa, and are already present in countries on the edges of Europe.
Blue Tongue Virus exists as 24 serotypes. The practical significance of this is that infection/vaccination of an animal with one serotype does not confer immunity to any of the other serotypes. It is virus protein 2 (VP2), located at the surface of the virus, that is the major inducer of protective immune responses and, indeed, determines the serotype. Vaccines exist for just a few of the 24 serotypes. Knowing the serotype of BTV associated with a given outbreak is important in relation to the possibility that an appropriate BT vaccine might be available, and in working out from where the virus came from, which also gives clues as to by what mechanism and route the virus had spread. Prof Mertens’ group have sequenced the gene that encodes VP2 of all 24 serotypes, and have developed polymerase chain reaction tests to identify them. These tests are much more rapid (results within a day) than conventional virus neutralisation tests (approx. three weeks).
These efforts, in partnership with many others, including farmers, veterinarians, vaccine producers, Defra and overseas authorities resulted in the nipping in the bud of the 2007 bluetongue (BT) outbreak in the UK. In contrast, continental northern Europe, in which the virus arrived one year earlier, when no vaccine was available, had scores of thousands of cases in cattle, sheep and goats.
Bovine Respiratory Syncytial Virus (BRSV)
Jenner Investigator: Dr Geraldine Taylor
Bovine respiratory syncytial virus (a pneumovirus) is endemic in the UK, causing pneumonia in calves. We also study it because it serves as a model for the closely related human respiratory syncytial virus which causes particularly serious pneumonia in young children.
Respiratory disease in young calves is a major animal welfare problem, affecting approximately 1.9 million calves in the UK each year, at a cost of £54 million. BRSV is the most important primary viral cause of respiratory disease in young calves in the UK. This virus is structurally and antigenically related to human (H)RSV, which is the single most important cause of bronchiolitis and pneumonia in infants. The high degree of similarity between HRSV and BRSV indicates that comparative studies of the immunobiology of these viruses will yield important insights that should benefit both man and cattle.
The development of safe and effective RSV vaccines has been hampered by the need to induce protective immunity within the first month of life, at a time when maternal antibodies can pose a major obstacle to successful vaccination; and the observation that vaccination can exacerbate RSV disease. Because vaccine-augmented disease is associated with inactivated virus, it has been proposed that a live, attenuated virus administered intranasally would make a safer and more effective vaccine. The lack of disease potentiation following natural RSV infection is a critical safety advantage of the live vaccine strategy. The mucosal route of vaccination would directly stimulate local immunity, prime CD8+ T cells, which are important in virus clearance, and overcome the immunosuppressive effects of maternally-derived antibodies. Recent advances in the molecular biology of negative-sense RNA viruses have provided a means to manipulate the genome of BRSV and opened the way for producing genetically stable, attenuated BRSV vaccine candidates.
We are currently comparing a number of live, attenuated mutant BRSV vaccine candidates for their ability prime bovine T cells, induce local and humoral antibody responses and protect against challenge with virulent virus. In addition, we have developed recombinant vaccinia virus vaccines and DNA vaccines which induce a protective immune response against experimental BRSV challenge in calves or against HRSV in a mouse model and we are currently exploring other vaccine vectors for greater efficacy against RS viruses.
Peste des petits ruminants virus (PPRV)
Peste des petits ruminants virus (PPRV, a morbillivirus), which causes disease in sheep and goats in Africa and Asia, is a close relative of rinderpest which has recently been eradicated globally. Our research is aimed at producing better vaccines and diagnostics for the control of PPR, with the possibility of eradicating it.
PPRV is spreading rapidly through most of Africa, Asia and the Middle East, and is the focus of a great deal of international effort. The first meeting of the Global PPRV Research Alliance was held recently in London, organised by The Pirbright Institute.
Dr Michael Baron’s group at the Pirbright Institute has the following aims:
1. Development of a DIVA vaccine against PPRV and improved diagnostic tools for field use
2. Investigate the mechanisms by which viral proteins of RPV and PPRV block specific host defence mechanisms (primarily the induction and actions of interferons)
3. Analyse the roles of specific viral and host proteins in viral genome and mRNA synthesis