21-ICRAD Plants4NemaVax; Plant-based production of glyco-engineered nematode vaccines

Lead Research Organisation: Moredun Research Institute
Department Name: Vaccines and Diagnostics

Abstract

Parasitic nematodes are amongst the most common pathogens in grazing ruminants worldwide. The continuous exposure to these worms has a significant impact on the health status and productivity of the animals. Control of these infections currently relies almost completely on periodic mass administration of anthelmintic drugs. However, with the increasing incidence of anthelmintic resistance around the world, there is an urgent need for alternative control measures. Vaccination is often put forward as the most rational and cost-effective alternative to control infections with parasitic worms. In recent years it has been shown that it is possible to protect cattle and sheep against worm infections by vaccinating them with proteins ("antigens") isolated directly from the worms. Unfortunately, for most parasite species, this approach is unsustainable for large-scale application as it relies on infected host animals to produce the vaccines. The production of synthetic vaccines seems the most obvious solution. However, of all the synthetic vaccines that were evaluated in the past, none induced sufficient levels of protection to consider further commercial development. One of the bottlenecks explaining why many vaccination trials with nematode vaccines have been unsuccessful is that the synthetic antigens in these vaccines are not decorated with the sugar (or "glycan") molecules that they would usually be covered with. Recent research has shown that the natural glycans present on the antigens can be critical in the context of vaccination as removal of the glycans from the antigens impaired the protective immune responses elicited by the vaccines. The glycans on a given protein can shape immune responses by influencing which receptors and cells of the immune system are targeted. In addition, nematode antigens carry very diverse and sometimes unique glycan structures, which can be highly immunogenic and major targets of the host's antibody responses. Therefore, reconstructing these glycan structures on synthetic nematode proteins may be key for successful vaccine development. Towards a flexible and sustainable solution to this problem significant progress has been made in recent years on adapting the protein production machinery of tobacco plants, such as Nicotiana benthamiana, allowing the synthesis of nematode antigens with a defined and tailored glycan composition. The aim of this project is to use this versatile plant-based production platform to express a set of well-defined nematode vaccine antigens and deliver proof-of-concept that efficacious vaccines can be produced if glycans are taken into account properly.

Technical Summary

Parasitic nematodes are amongst the most common pathogens in grazing ruminants worldwide. Control currently relies on periodic mass administration of anthelmintic drugs. However, with the increasing incidence of anthelmintic resistance around the world, there is an urgent need for alternative control measures. Vaccination is often put forward as the most rational and cost-effective alternative to control infections with parasitic worms. However, of all the recombinantly produced subunit vaccines that were evaluated in the past, none induced sufficient levels of protection to consider further commercial development. This has been linked with the inability of the expression systems to reconstitute the antigens with their native post-translational glycan modifications. Helminth glycoproteins carry very diverse and sometimes unique glycan structures, which can be highly immunogenic. Therefore, reconstructing these sugar structures on recombinant nematode proteins may be key for successful vaccine development. Bacterial expression systems are not able to perform complex glycan modifications and the glycan decorations that occur in eukaryotic expression systems, like yeast and insect cells, show little resemblance to the glycans naturally found on nematode proteins. Towards a flexible and sustainable solution to this problem significant progress has been made in recent years on adapting the post-translational machinery of plants, such as Nicotiana benthamiana, allowing the synthesis of nematode- glycoproteins with a defined and tailored glycan composition. The aim of this project is to use this versatile plant-based production platform to express a set of well-defined nematode vaccine antigens and deliver proof-of-concept that efficacious vaccines can be produced if glycans are taken into account properly.

Publications

10 25 50
 
Description Vaccines to control complex organisms like parasitic worms have been difficult to successfully produce because the immune response against synthetic versions of the worm's proteins (antigens) often are too dissimilar to the natural versions of these antigens. One of the key diferences is that the synthetic antigens lack the sugars that commonly decorate the natural antigens. We have found that the natural antigens of the sheep parasitic worm, Teladorsagia circumcincta, are decorated with complex sugars which may be required for immune protection when used in a vaccine. We have worked with partners in the Netherlands to reproduce these antigens in a system with the potential to introduce such sugars onto the synthetic antigens.
Exploitation Route The obvious next step is to produce the vaccine antigens with appropriate sugar decoration to test the effectiveness in vivo. These findings are applicable to parasite vaccines in general.
Sectors Agriculture

Food and Drink

Manufacturing

including Industrial Biotechology

 
Description The findings of this study advance the potential for use of vaccines to control key endemic parasitic diseases of livestock. There is a growing awareness that novel solutions are needed in the livestock sector to address the biodiversity and climate change crises, to allow optimal and efficient livestock production to prodcue protein while addressing these twin crises. Novel, effective vacines are one way to achieve this and we have been discussing this approach beyond scientific audiences, with government policy experts in this area.
First Year Of Impact 2023
Sector Agriculture, Food and Drink,Environment
Impact Types Societal

Policy & public services

 
Description Giving evidence to the Scottish Affairs Committee (UK Govt) on Science in Scotland
Geographic Reach National 
Policy Influence Type Contribution to a national consultation/review
URL https://parliamentlive.tv/event/index/617a30ab-c663-45be-97c3-7464c58701d9
 
Description Presentation to Cabinet Secretary for Net Zero, Energy and Transport
Geographic Reach National 
Policy Influence Type Contribution to new or improved professional practice
URL https://twitter.com/MathesonMichael/status/1631015153641705488?s=20
 
Description Presentation to the Cabinet Secretary for Net Zero, Transport and Just Transition
Geographic Reach National 
Policy Influence Type Participation in a guidance/advisory committee
URL https://moredun.org.uk/news/foundation/visit-to-moredun-by-the-cabinet-secretary-for-transport-net-z...
 
Description Discussions and information about vaccines at the Royal Highland Show 2023 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact Attendance at the RHS to discuss livestock diseases and vaccines
Year(s) Of Engagement Activity 2023
URL https://www.royalhighlandshow.org/
 
Description Invited seminar at University of Glasgow Vet School 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Professional Practitioners
Results and Impact Delivered an invited talk entitled "Controlling parasitic nematodes with vaccines - prospects for the future" on October 12th 2022 to students, researchers, teaching staff and practitioners at University of Glasgow Vet School. The talk led to questions from a range of attendees and led to further discussions about joint research directions.
Year(s) Of Engagement Activity 2022
 
Description Invited talk, Microbiology Society, Development and optimisation of vaccines to control ruminant gastrointestinal nematode parasites using recombinant antigen approaches 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact The presentation (Abstract below) was delivered to the conference in Belfast, attended by >100 delegates. The presentation sparked questions from the audience, many of whom had not previously considered vaccination as an approach for helminths.

Abstract:
Gastro-intestinal nematode parasites are a significant cause of morbidity and mortality in grazing ruminants and represent a major constraint on efficient livestock production. Current control relies heavily on anthelmintic drugs; however, with increasing reports of drug resistant parasite, new methods of control are required. Cattle and sheep develop acquired immunity to these parasites following continuous exposure, indicating the potential for vaccine-based control. Over the last decade we have taken a recombinant protein vaccine approach in which candidate antigens are identified using a combination of immunoproteomics and reverse vaccinology. This has led to the development of a protective recombinant vaccine against Teladorsagia circumcincta, a highly pathogenic worm that resides in the abomasum (gastric stomach) of sheep. This vaccine shows evidence of cross-protection against a similar gastric parasite, Ostertagia ostertagi, of cattle; however, the efficacy of this vaccine shows considerable between-trial variation in both host species. Recent studies have shown that vaccine efficacy is influenced by both host genetic factors and age, and using temporal transcriptomic analysis of the abomasum during vaccination and infection, we have shown that protection is associated with an early local T-helper type 1 (Th1) response, which is less evident in young animals. Consequently, we are now evaluating Th1 promoting adjuvants in order to reduce variation in vaccine efficacy. To further optimize vaccines for T. circumcincta and O. ostertagi, we have developed ruminant gastric organoids to study early events in the infection process, with the aim of identifying novel vaccine targets for incorporation into next-generation vaccines.
Year(s) Of Engagement Activity 2022
URL https://microbiologysociety.org/event/annual-conference/annual-conference-2022.html#tab-1
 
Description Invited talk, University of Calgary 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact ~40 researchers attended a virtual invited seminar which contained some information arising from this grant award. Subsequent to the seminar, I was contacted by one of the audience to be a collaborator on one of her grant applications and to support a visit from one of her postgraduate students.
Year(s) Of Engagement Activity 2021
 
Description National Sheep Association webinar on sheep vaccines 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact A webinarorganised by the National Sheep Association and Moredun to inform NSA members about current vaccines for sheep and the development of novel vaccines.
Year(s) Of Engagement Activity 2023
URL https://www.nationalsheep.org.uk/events/forthcoming-events/243068/nsa-and-moredun-webinar-sheep-vacc...
 
Description Vaccine Highlight Event at Royal Highland Show 2022 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact The activity was attendance at the Royal Highland Show as apart of the Moredun Research Institute presence at this event. Specifically, for this project, the importance of livestock vaccines was highlighted through a Vaccines focus event along with Industry Silver Sponsors MSD. This introduced or reinforced the importance of vaccines in the industry to both the general public and stakeholders as a method for enhancing animal health, welfare and reducing the impact of livestock production on greenhouse gas emissions. Discussions were had with >100 individuals and the displays were visited by several hundred people over the course of the Show.
Year(s) Of Engagement Activity 2022
URL https://www.royalhighlandshow.org/