Development of a vaccination strategy for the control of malignant catarrhal fever

This proposal aims to further develop and refine our recent breakthrough of an immunisation strategy for the control of malignant catarrhal fever (MCF) by increasing the magnitude and duration of immunity through improved adjuvancy (compounds given along with virus antigens that help direct the type of immune response to an infectious agent and improve its magnitude and duration - all important for a good vaccine) and testing the potential vaccine in field trials in Tanzania where MCF is a problem. Malignant catarrhal fever (MCF) is a fatal disease of cattle, deer, bison and pigs, caused by a group of viruses (herpesviruses) including ovine herpesvirus-2 and alcelaphine herpesvirus-1. These viruses infect their natural hosts efficiently (sheep for OvHV-2 and wildebeest for AlHV-1), causing no apparent disease, but in the disease-susceptible animals, MCF is usually fatal and consequently has a profound affect on animal welfare and production. The virus is transmitted by aerosol or by contact and most lambs or wildebeest calves are infected shortly after birth and are capable of then infecting susceptible cattle. There is no vaccine currently available for MCF, but we have recently developed a potential vaccine that works well in experimental studies. The effect of AlHV-1 MCF on pastoralist communities in sub-Saharan Africa is profound, with social, economic and welfare impact. In two studies of MCF in Tanzania and Kenya, incidence in studied areas was found to be 6% and 10% respectively. The high rate of cattle death meant that MCF was rated as the most important disease risk in areas with wildebeest contact. Field trials in Tanzania are essential to determine the efficacy of the alcelaphine herpesvirus-1 (AlHV-1) MCF vaccine and will inform further refinement of the vaccine as necessary. It is important to determine the contribution of the different components of an immune response that will protect affected cattle. Although there is a strong correlation between virus-neutralising antibody and protection, we need to determine whether cell-mediated immunity (CMI) including cytotoxic T cell activity (CTL) is involved or not in protection. Furthermore, we need to identify virus component antigens that stimulate protective immune responses in cattle. This will allow vaccine development for ovine herpesvirus-2 (OvHV-2, a highly genetically-related virus to AlHV-1) MCF, which is a problem not only in Africa but worldwide where natural carrier animals and disease-susceptible animals mix. This dual approach is important as there is more likely to be a commercial uptake of an AlHV-1 and OvHV-2 MCF vaccine than either one singly. This study will use defined new generation adjuvant compounds to improve the current AlHV-1 MCF vaccine and test this in field trials in Tanzania. For very little extra effort, we can identify the protective virus component antigens of AlHV-1 and use the equivalent OvHV-2 ones to attempt a vaccine to OvHV-2 MCF. This increases the chances of commercial uptake of an MCF vaccine. The expected principal outcome of this work wil be implementation of a vaccine disease control strategy to have an impact on animal mortality due to MCF and improvement of quality of life of pastoralists and farmers within 5 years of the conclusion of this project.

This proposal aims to further develop and refine our recent breakthrough of an immunisation strategy for the control of malignant catarrhal fever (MCF) by increasing the magnitude and duration of immunity through improved adjuvancy and testing the potential vaccine in field trials in Tanzania where MCF is a problem. MCF is a major contributor to cattle mortality in Eastern and Southern Africa wherever wildebeest are found (natural disease-free carriers of the alcelaphine herpesvirus-1 MCF virus). This in turn adversely affects the income and quality of life of pastoralists and poor farmers. There is no vaccine currently available for MCF. However we have recently developed a potential vaccine for AlHV-1 MCF that stimulates a mucosal barrier of virus-neutralising antibody. We aim to improve this vaccine by the strategic use of toll-like receptor (TLR)agonists as adjuvants to stimulate the appropriate protective immunity in cattle and test the improved vaccine in field trials in Tanzania. TLR agonists are proving very useful as adjuvants to direct the quality and magnitude of immune responses for improved vaccine design. We know that high virus neutralising antibody titres correlate with protection, but the role of cell-mediated immunity will be studied for its contribution (if any). Furthermore, for minimum effort and added value, protective antigens of AlHV-1 will be identified to clone the equivalent antigen genes from ovine herpesvirus-2 (OvHV-2) into an attenuated AlHV-1 bacterial artificial chromosome (BAC) that we have developed as a viral vector. AlHV-1 and OvHV-2 are genetically very similar. We predict that the outcomes will include: An improved immunisation strategy leading to a vaccine for AlHV-1 MCF; Proof of concept for an OvHV-2 MCF vaccine based on OvHV-2 antigens in an AlHV-1 BAC; Field trial confirmation of the efficacy of an AlHV-1 MCF vaccine. This will have an impact on pastoralist quality of life within 5 years of project completion.

Field trials with the existing potential AlHV-1 vaccine will determine its efficacy and could give a quick result in respect of MCF control (within 2 years) that would benefit the pastoralists, the consortium and be a public relations coup for the initiative. The Maasai and others have long wanted to see an effort in reducing the negative impact of MCF on their cattle and consequently their livelihoods. We predict that the vaccine will need to be improved (see objectives) and that implementation of an improved vaccine would give a measurable reduction of MCF in target areas within 2-5 years of the completion of this study. The development of an OvHV-2 vaccine strategy is envisaged within 5-6 years and an impact of this (as a consequence of future-funded work) in 6-8 years. We will know within 3-5 years of the completion of this project the degree of welfare and economic improvement of pastoralist cattle and the knock-on effect of improved wealth for the communities. The impact of the study goes beyond its immediate goal to implement a vaccine for MCF. By targeting MCF, the pastoralists will avoid upland areas where they currently take their cattle to avoid the disease. By doing this they will minimise exposure of their cattle to trypanosomosis and East Coast Fever, two serious diseases that also affect cattle production and pastoralist livelihoods. In fact the local Tanzanian scientific community position on this is that there is no doubt that control of MCF would result in an increase in survival of adult animals, with a direct improvement in herd productivity. It is also likely that, by permitting wet-season grazing on the short-grass plains, a vaccine against MCF would also reduce mortality and morbidity from tick-borne diseases and directly-transmitted diseases, as well as enhance survival and fertility through access to high-quality grazing at a critical time of year. Adverse environmental impacts associated with concentration of people and cattle in the highlands, which include overgrazing, erosion and tree-felling, might also be mitigated. One concern expressed by conservationists has been that the reduction in MCF-related mortality may lead to a rise in cattle numbers, which might further increase land-use pressure. Despite the importance of cattle as a measure of status and wealth in pastoralist society, current trends suggest that Maasai are now more likely to sell 'excess' animals that are produced or survive as a result of MCF control. For most herds, the growing demand for cash income to pay for grain, medicines, and school fees is likely to necessitate sustained commercial offtake. There is also a growing realisation of the need to improve the quality of livestock, not merely the quantity. Thus, although cattle numbers may increase slightly, a cattle population explosion is unlikely to occur in pastoralist communities, even if MCF is controlled. Another important impact of this work is that the development of a mucosal immune barrier to prevent MCF may translate to the vaccine control of other herpesvirus infections in other species, including humans. There is currently no herpesvirus vaccine that prevents infection and the establishment of latency. The strategy within this application will address this and the outcome should be of value to a much wider community.