Novel vaccines to combat significant endemic diseases of livestock in Scotland: Vaccines for reproductive diseases
Project Lead
Challenges
Reproductive pathogens in sheep
Chlamydia abortus, the bacterial pathogen is responsible for the death of lambs and the cause of a disease known as enzootic abortion of ewes. This is the most common infectious casue of lamb death in Scotland, that is also zoonotic (i.e., can result in infections of humans) and can result in spontaneous abortion and stillbirths in humans, and death of the pregnant mother. Over the last 60 years, several inactivated vaccines have come and gone due to high production costs, manufacturing difficulties, low efficacy, and disease outbreaks.
Our previous work has shown that live vaccines can cause disease in some animals, while recent evidence shows the live vaccine strain is not attenuated. There is a clear need to produce a better vaccine, which will provide increased stability, reduce shedding of infectious organisms at parturition and be more economical to manufacture. Additional research has revealed the main targets for developing a recombinant subunit vaccine, as well as for the delivery of antigens using viral vectors.
Reproductive pathogens in Cattle
Neospora caninum is a parasite that can result in abortions in cows, sheep and goats and is the most diagnosed infectious cause of abortion in cattle in Scotland while it also been confirmed as a cause of abortions in sheep and neonatal mortality in lambs in the UK and worldwide. There are no vaccines that prevent abortions caused by Neospora or that prevent transmission from dam to foetus in uterus.
Questions
- What economically and biologically viable novel vaccines could be developed to combat significant endemic diseases in Scotland?
Solutions
This project is developing vaccines to control reproductive diseases in sheep and cattle, caused by the microbes Chlamydia abortus and Neospora caninum, respectively.
Chlamydia abortus
We are providing a rapid and lower-cost screening method for determining vaccine efficacy. Additionally, we are also contributing to the development of a new subunit vaccine for future evaluation in the natural host animal. This project builds on our previous work which revealed the main targets for developing a recombinant subunit vaccine, as well as for delivery of antigens using viral vectors. Using these approaches, two antigens have been identified that have good humoral and cellular responses. Antigen-specific humoral and IFN-gamma recall responses to one of these viral-vectored antigens has also been demonstrated in two studies in sheep. We are currently extending these studies and evaluating other candidate antigens.
Neospora caninum
CRISPR-Cas9 technology can be used to inactivate genes from the Neospora caninum genome which are essential to the fast-replicating stage of the parasite, that is key for the parasite’s persistence. We are evaluating the efficacy of these attenuated strains in an in vitro stage conversion assay and following this with persistence studies. Isolates that fail to cause a persistent infection will be tested in vaccine trials.
Project Partners
Progress
Vaccine delivery systems for controlling reproductive chlamydial infections in livestock
We have identified the proteins that are on the surface of the bacterium and which are all a target for the immune system. These could therefore be used to provide protection from infection and so represent potential candidate proteins for testing in new vaccine formulations. Thus far we have produced eight synthetic versions of one of the predominant proteins on the bacterial surface and tested its reactivity to sheep antibodies from diseased animals to determine their suitability for vaccine production. The proteins were not found to be optimal however, and therefore we are currently producing newer versions for future testing as well as evaluating other surface proteins.
Development of a vaccine for Neosporosis in cattle
We have conducted a literature review and in silico analysis to identify Neospora genes that are essential for the formation of bradyzoites/tissue cysts, which are the lifecycle stages responsible for persistent infections in cattle. We have identified four main genes, which will be targeted for silencing using CRISP-Cas9 gene editing technology. The resulting parasites generated would not be able to cause a persistent infection which would make them good candidates for vaccine strains. We have also started on the methodology to be able to select transfected parasites by incorporating genes essential for CRISPR-Cas9 editing as well as genes used in antibiotic selection and fluorescent markers into a transfection plasmid. This plasmid has successfully been used to transiently transfect Neospora tachyzoites, making these parasites fluorescent and resistant to Bleomycin for a short time.
Knowledge exchange and Impact
We have discussed the development of vaccines for reproductive diseases at the Royal Highland Show, the 6th International Meeting of Apicomplexan Parasites in Farm Animals (ApiCOWplexa 2022), the British Society for Immunology Congress and Moredun Press Day. Five publications focusing on livestock abortion, the development of a new Chlamydia vaccine and effect of adjuvants on vaccine efficacy has been published in open access journals, while we have also presented at the European Chlamydia meeting and at an EU Consortium meeting, following the successful acqusition of Horizon Europe funding. We have set up a new collaboration with the University of Dundee to improve the CRISPR-Cas9 editing of Neospora to assist vaccine development.
We have had discussions with a company regarding vaccine delivery and proof-of-concept antigen testing in their proprietary vaccine delivery system. We have identified research gaps and priorities for the control of chlamydial infections in animals as part of the EU Discontools project and signed a licensing agreement with an industrial partner to commercialise a new Chlamydia vaccine for use in sheep. New reproductive vaccines for ruminants were also discussed when speaking with farmers and/or veterinarians, at the Royal Highland Show, other farming events, or by phone and also during two webinars given to international audiences of over 100 veterinarians and pharma representatives.
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