Highly contagious viral diseases of livestock are endemic in the Middle East, Asia, Africa and Southern/ Central America where they affect circa 900 million people who depend on livestock for their livelihoods. Outside of their endemic range they can also cause economically devastating events; the Foot and mouth disease outbreak in the UK (2001) cost the public sector over £3 billion and the private sector over £5 billion[i].

Vaccination is an efficient tool for control of endemic foot and mouth disease virus (FMDV)[ii] classical swine fever virus (CSFV)[iii] and peste des petits ruminants virus (PPRV)[iv]; in the UK vaccines are also advocated to control spread of CSFV[v] should outbreaks occur. However, with the traditional (first generation) live or inactivated strain-based veterinary vaccines currently available, there is a risk of environmental contamination and also residual virulence and reversion to pathogenic wild type viruses. Second generation vaccines based on sub-units of virus are safer but require careful formulation in carriers/ delivery systems that preserve antigen integrity while simultaneously providing powerful stimulation of the innate immune system.

In ground-breaking research, scientists at the Quadram Institute  have developed bacterial Outer Membrane Vesicles (OMVs) as innovative oral/ nasal vaccine delivery systems. By sharing their cutting-edge expertise with colleagues in China they have enabled the translation of this technology to be expanded to include control of livestock viruses of global concern.

Description of project

Dr Yang Yang

From August 2018 to July 2019, Dr Yang Yang, an early-stage career scientist from Lanzhou Veterinary Research Institute (LVRI), visited the laboratories of Professor Simon Carding and Dr Regis Stentz at Quadram Institute Bioscience (QIB) where he became proficient in the techniques needed to develop OMV delivery systems. He used these techniques to produce and evaluate the potential of OMVs to deliver vaccines against CSFV, FMDV and PPRV.

The project was made possible by a collaboration between QIB, the University of East Anglia (UEA), LVRI and the Institute of Infection and Global Health at Liverpool University that was funded by a BBSRC China Partnering Award and LVRI. It also progressed work on a previous China Partnering Award grant (2016-2019) for exchange of vaccine technology and establishment of productive relationships with international partners; this was led by Professor Tom Wileman at QIB, and held between UEA, QIB and the John Innes Centre, working with Prof. Zhidong Zhan of LVRI and the Institute Pasteur of the Shanghai Chinese Academy of Sciences (IPS).

Results and impact

Dr Yang sub-cloned reading frames for antigens against CSFV, FMDV and PPRV, into plasmid vectors for expression and secretion in bacterial OMVs. He then prepared and characterized the OMV-carrying vaccine candidates in preparation for field evaluation trials at LVRI, on his return to China.  The rapid production of new vaccine candidates by Dr Yang demonstrates the wider commercial potential of OMVs as a novel drug delivery platform for which the ground-breaking proof of principle study has only recently been published (2019). The proof of principle was a collaboration between QIB, the University of Liverpool and the University of Zurich; it demonstrated, in mice, that OMVs administered intranasally provided targeted delivery of protective antigens of the influenza A virus directly to the upper and lower respiratory tract where they prevented infection, and inflammation and contained viral replication following challenge with a 10-fold lethal dose of the virus. This new collaboration with Dr Yang has brought the research closer to generating impact by applying the fundamental science to address a real world ‘need’. This research has also supported a successful patent (click here) for QIB concerning OMV’s as a delivery mechanism to the respiratory tract which could feasibly generate economic impact for the inventors.

The paper concerning OMVs as mucosal biologics and in the delivery of biologically active proteins, such as vaccine antigens and therapeutic proteins, to the respiratory and gastrointestinal tracts, respectively, was published in the Journal of Extracellular Vesicles DOI: 10.1080/20013078.2019.1632100. At the time of drafting this article the paper has been read 3,278 times and cited in other research five times (involved in understanding mechanisms of action, probiotic development, IBD research and cancer therapeutics).

OMV technology is highly adaptable and compared to conventional vaccine production, easy to manufacture but is not yet readily available in China. Therefore, Dr Yang’s collaboration with QIB has opened up a significant commercial opportunity to effectively compete with or replace first-generation vaccines currently used in China (and potentially other countries worldwide). The most successful vaccine candidates will be manufactured and marketed by China Agricultural Vet Biology and Technology Co., LTD. The market for novel veterinary vaccines is large. Globally, the animal medicines market was worth nearly $38 billion in 2019[vi] 23% of that market is attributable to veterinary vaccines[vii] and is expected to be the fastest-growing segment going forward at a Compound Annual Growth Rate of 13.7%[viii].

For farmers the development of mucosal OMV-based veterinary vaccines that can be administered in a single dose for key diseases will provide substantial economic benefits and cost savings compared with first-generation vaccinations; oral vaccines are less stressful to livestock and healthier animals are better able to achieve economically-viable weight-gain ratios. For example, outbreaks of peste des petits ruminants currently costs between $1.4-2.1 billion per year globally[ix]; worldwide eradication through an estimated fifteen-year programme would represent a combined saving of $74.2 billion[x]. Cost savings achieved by effective vaccination programmes on small scale, impoverished pastoral farms also frequently alleviate short-term poverty and allow funds to be diverted to improve education and diet of livestock-dependant families. Therefore, not only could effective new vaccines improve animal health globally, they could also have long-term positive societal impacts.

Apart from improving animal health and productivity, veterinary vaccines also significantly impact human public health; by reducing veterinary pharmaceutical use, residues are significantly reduced in the human food chain. This will be of significant importance with the ever-increasing regulatory requirements of government agencies and consumer groups, particularly in the major markets of Europe and the United States[xi].

Dr Yang will also be training his colleagues on the methods learnt at QIB which will expand the reach achieved by this collaboration. As a result, OMVs could be utilised in numerous follow-on and translational applications. OMVs as delivery systems could also perceivably lead to significant health and welfare impact in human medicine as well as in livestock.

Summary

This work illustrates the value of relationship progression, innovation and international collaboration. Bringing together diverse expertise from several partners generates impact at an international scale by translating exceptional blue-sky research into effective solutions for globally-relevant problems. Although it may take several years, commercially viable outputs could feasibly go on to generate significant economic and animal welfare benefits alongside the significant translation achieved through knowledge exchange and training.

“It takes many people, all with different areas of expertise to get an innovation out of the laboratory and into the real world. This collaboration is a fantastic example of how we can work with other organisations, both nationally and internationally to solve problems and make a difference.” Dr Regis Stentz, Quadram Institute Bioscience.

References

[i] The 2001 outbreak of Foot and mouth disease. National Audit Office report to UK Parliament. https://www.nao.org.uk/press-release/the-2001-outbreak-of-foot-and-mouth-disease-2/#:~:text=A%20National%20Audit%20Office%20report%20to%20Parliament%20today,and%20the%20private%20sector%20more%20than%20%C2%A35%20billion.

[ii] Developing vaccines against foot and mouth disease and some other exotic viral diseases of livestock https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3146785/

[iii] Classical Swine fever. World organisation for animal health fact sheet. https://www.oie.int/en/animal-health-in-the-world/animal-diseases/classical-swine-fever/

[iv] Peste des petits ruminants. OIE technical disease card. https://www.oie.int/fileadmin/home/eng/animal_health_in_the_world/docs/pdf/disease_cards/peste_des_petits_ruminants.pdf

[v] Disease control strategy for African and classical swine fever in the UK. DEFRA. https://assets.publishing.service.gov.uk/government/uploads/system/uploads/attachment_data/file/877081/disease-control-strategy-csf-2020a.pdf

[vi] Global animal medicine industry report 2019-2023. https://www.prnewswire.com/news-releases/global-animal-medicine-industry-report-2019-2023—market-to-grow-from-38-billion-in-2019-to-61-billion-by-2023-300985798.html

[vii] Current status of veterinary vaccines. Clinical Microbiology review. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1932753/

[viii] https://www.ptcommunity.com/wire/global-animal-medicine-industry-report-2019-2023-market-grow-38-billion-2019-61-billion-2023

[ix] Pirbright tackle peste des petits ruminants from all fronts. The Pirbright Institute. https://www.pirbright.ac.uk/news/2019/03/pirbright-tackle-peste-des-petits-ruminants-all-fronts

[x] The economic impact of eradicating peste des petits ruminants: a benefit cost analysis. PLOS1. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4764769/

[xi] The future of anti-infective products in animal health. Nature reviews microbiology. https://pubmed.ncbi.nlm.nih.gov/15100695/