Veterinary vaccines against epsilon toxin
Objective
OHV is seeking a commercial partner either to:
- licence a novel, proprietary animal vaccine against epsilon toxin with worldwide opportunities; or
- enter into a joint venture agreement to commercially exploit the vaccine.
Enterotoxaemia and epsilon toxin
Epsilon toxin is a protein produced by the bacterium Clostridium perfringens. This toxin is very important in veterinary medicine because it plays a major role in enterotoxaemia of sheep and goats (and occasionally other livestock animals). The toxin is produced in the gut, often following the ingestion of feeds rich in carbohydrates, and then crosses the gut wall entering the blood stream.
C. perfringens targets the central nervous system resulting in neurological symptoms and in most animals the disease is rapidly fatal. Consequently, the disease is of global economic significance and is controlled by vaccination.
Enterotoxaemia and epsilon toxin
Epsilon toxin is a protein produced by the bacterium C. perfringens (strains B and D). This toxin is important in veterinary medicine because it plays a major role in enterotoxaemia of sheep and goats (and occasionally other livestock animals). The toxin is produced in the gut, often following the ingestion of feeds rich in carbohydrates, and then crosses the gut wall entering the blood stream. Recent evidence has identified myelin and lymphocyte protein (MAL) is the receptor for the toxin. The toxin targets the central nervous system resulting in neurological symptoms and in most animals the disease is rapidly fatal. Consequently, the disease is of global economic significance and is controlled by vaccination.
The Worldwide Market for a Vaccine against ETX in Sheep and Goats
The worldwide, veterinary vaccine market for a vaccine against ETX is large and well-established.
Currently the global sheep population stands at more than 1 billion head with 19 per cent found in Asia and Africa. In 2013, the five countries with the largest number of heads of sheep were mainland China (175 million), Australia (75.5 million), India (53.8 million), the former Sudan (52.5 million), and Iran (50.2 million).
The global goat population stands at approximately 450 million goats. Of the 450 million goats in the world, it is estimated that approximately 6%to 8 % of them are in North America. The majority of the world goat population can be found in the Middle East and Asia.
The Market in India
The veterinary vaccine market in India is forecast to grow to over $170M by 2020. The vaccines serving this market will be supplied by a mixture of Indian companies and the Indian arms of global vaccine manufacturing companies, mainly from the USA and Europe.
We have not been able to locate information on the size of the market for an enterotoxaemia vaccine in India. However, the annual production of enterotoxaemia vaccine in near East countries ranges from 500,000 doses in Egypt, to 6.25 million doses in Pakistan and 15 million doses in Morocco (1). An enterotoxaemia vaccine would be used primarily in sheep and goats in India. According to the Indian National Dairy Development Board the goat and sheep populations were approximately 135 and 65 million animals respectively in 2012 (https://www.nddb.coop/information/stats/pop), and continue to grow year on year. Considering that the combined goat and sheep populations in Pakistan and Morocco are approximately 73 and 23 million animals respectively, it is reasonable to estimate that the market size in India is between 17 and 130 million doses per year.
Existing vaccines
A range of enterotoxaemia vaccines are produced by global veterinary vaccine companies. These contain epsilon toxin which has been treated with a chemical such as formaldehyde to detoxify it. Some vaccines incorporate the detoxified epsilon toxin into a multi-component vaccine which protect against enterotoxaemia and other diseases.
Current-vaccinesThese vaccines are primarily for use in sheep and goats and, typically, kids or lambs are immunised with two doses of the vaccine several weeks apart, followed by annual boosters. The limitations of these vaccines are well recognised, including by Indian researchers (Rai et al., 2013); batch to batch variation, poor immunogenicity in goats and inflammatory responses following vaccination resulting in reduced feed consumption.
Vaccines against enterotoxaemia (ET-VACCINE and Raksha-ET) are produced by at least 2 companies in India (Brilliant Bio Pharma Private Limited, Hyderabad – 500004 Telangana, India and Indian Immunologicals Ltd, Hyderabad – 500033, Telangana, India).
The Vaccine
One Health Ventures, in association with Professor Rick Titball and Exeter University in the UK, has developed a “genetic toxoid” (2) of epsilon toxin (Y30A-Y196A-A168F).
This means that the protein does not require any processing to render it safe to use a vaccine. Y30A-Y196A-A168F is safe when tested towards different cultured cells, and when tested in mice, rabbits and in sheep.
The immunisation of sheep with Y30A-Y196A-A168F and Montanide ISA 61VG adjuvant results in very high levels of neutralising antibodies which persist for at least one year (2). Immunisation with a single dose of vaccine was sufficient to generate high levels of neutralising antibodies. Alternatively, it may be possible to use whole bacteria expressing the genetic toxoid as a bacterin vaccine, negating the need for protein isolation and adjuvanting. The vaccine OHV is offering provides an opportunity to develop a cutting-edge product with a number of advantages over the existing vaccines;
- There is no requirement to detoxify the product – a process that often results in batch to batch variability.
- The vaccine can be produced at higher yields, requiring smaller fermenter volumes
- The vaccine can be produced safely, without growing the pathogen Clostridium perfringens
- The technologically advanced toxoid and adjuvant promotes a potent response which may not require annual boosting, making the product more attractive to farmers
- The technologically advanced toxoid and adjuvant should resolve the problem of poor protective responses in goats immunised with the conventional vaccines
- It would be possible to use a whole bacterin vaccine derived from E. coli expressing Y30A-Y196A-A168F. This would much simplify processing and reduce production costs
- The Y30A-Y196A-A168F toxoid can be included in combination vaccines
- Y30A-Y196A-A168F can be used as a carrier for polysaccharides to generate glycoconjugates
- The advanced formulation and dosing schedule would also provide a competitive advantage in overseas markets
Intellectual Property
One Health Ventures’ vaccine is covered by two patents and both patents are owned by OHV.
Titball, R.W., BokoriBrown,M., Naylor, C. Epsilon toxin epitopes from Clostridium perfringens with reduced toxicity. WO2013144636 (A1). Priority date 29/03/2013 (19)
and
Titball,R.W. Lewis,N., Bokori-Brown,M., Morcrette,H. Polypeptide and vaccine. Application number 1803401.7. (P3260GB00) Priority date 2/03/18. (https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2019166830&_cid=P20-K0QUC1-54536-1) (49).
Who would be interested in this vaccine?
Veterinary vaccine producers who are keen to invest in developing next generation vaccines and wish to develop a product that would have clear advantages over competitor products.
(1) Preliminary Data on Veterinary Vaccine Production / Needs In Some Countries Of The Near East (2002). Food and Agriculture Organization of The United Nations Regional Office for The Near East (RNE).
(2) Morcrette M, Bokori-Brown M, Ong S, Bennett L, Wren BW, Lewis N, Titball RW. (2019) Clostridium perfringens epsilon toxin vaccine candidate lacking toxicity to cells expressing myelin and lymphocyte protein. NPJ Vaccines, 4:32.