One Health and accelerating Vaccines for Ebola and Lassa (OVEL)

The One Health and accelerating Vaccines for Ebola and Lassa (OVEL) is a focused comparative One Health vaccine project based on the need to understand future threats of zoonotic virus spill-overs from their natural animal reservoirs to humans. This information is important to develop the most effective protective vaccines to prevent future human outbreaks.
A disproportionally high number of emerging and re-emerging diseases are caused by RNA viruses and many are carried naturally by animals (Heeney, J Internal Med, 2006). Their genomes are notoriously variable due to the high mutation rate that occurs during replication. These accumulate over time and results in evolvolution of the viruses as they circulate in their natural animal reservoir populations. Thus, these variant viruses carried by animals are a risk to human health and may spill-over to people who share the same environment. If some viral variants arise and are able to adapt to use human cell receptors and if they are able to escape immune defences, they may become highly infectious and cause large disease outbreaks.
Vaccines are only as good as the immune targets (the viral protein (antigen) presented by vaccines) of the pathogen that they are designed for. If the antigen changes, vaccines fail to protect. In most cases current vaccine candidates against RNA viruses are from past human outbreaks with little or no information of future risks from viral variants carried in animal reservoirs, especially those with the potential for animal to human (zoonotic) transmission.
We propose to establish an extended viral sequence database derived from animal reservoirs for two virus families which cause viral haemorrhagic diseases in geographically overlapping regions of West Africa. By gaining new molecular/genomic and antibody data from animal hosts, we will acquire an understanding of the infection dynamics and viral persistence in their natural reservoirs, while providing essential viral diversity data in reservoirs to discover new vaccine antigens and accelerate truly protective vaccine design.
We will acquire Lassa/Arenavirus sequence diversity data from a comprehensive survey of the natural rodent hosts (Mastomys natalensis and other rodent reservoir species) in Nigeria where documented Lassa outbreaks occur in states with cases caused by diverse isoaltes of Lassa fever virus. A second reservoir viral sequence database is likely to arise from a complementary study funded by the UK GCRF award to Prof J Wood based from sampled bat colonies in Ghana which Ebolavirus antibody and antigen positive animals have been found.
Equipped with this information on the sequence diversity of viruses in animal reservoirs which threaten to spill-over to humans, we will be able to design better vaccine antigens for more effective and broadly protective vaccines. We will achieve this using a new accelerated vaccine development platform using cutting edge technologies to achieve dramatic improvements in vaccine efficacy and the speed of vaccine development.
We will use the new EVAC (Emerging viral Vaccine Antigen Construct) platform vaccine technology we previously developed with Innovate-UK funding. The EVAC platform, which significantly accelerates vaccine development, merges (i) sequences of outbreak pathogens and their reservoirs in West Africa, (ii) broadly anti-viral neutralising monoclonal antibodies derived from viral haemorrhagic fever survivors, (iii) computational modelling methodologies, (iv) synthetic gene technology, and (v) in vivo immune selection and vaccine efficacy readouts. The end products are novel vaccine antigens to trigger the broadest spectrum of protective immune responses using Digitally Designed, Immune Optimised and Selected (DIOS) vaccine antigens against re-emerging RNA viruses Lassa Fever and Ebola viruses.

This One Health vaccine project specifically aims to develop new vaccine antigens informed from animal reservoir viruses that have the potential to spill-over to humans.
With proven new platform technology that uses pathogen sequence databases to computationally design highly conserved B and T-cell antigens. We are able to generate antigen genes and to express these as virus-like particles in antigen libraries that are screened in high throughput assays based on an understanding of the immune correlates of protection. Monoclonal antibodies from human Lassa and Ebola survivors have demonstrated protection from pathogenic challenge, and highly conserved antigens have been identified. Called "Digitally Immune Optimised and Selected" (DIOS) vaccine antigens, animals are immunised to insure that vaccine sera is broadly neutralising. However, what is missing is knowledge on the circulating viral diversity in the animal reservoirs that carry these two geographically overlapping Viral Haemorrhagic Fever (VHF) viruses that constantly threaten to spill-over to humans living in West Africa.
This "OVEL" project aims to fill this important One Health knowledge gap and to first compile and then feed full genome viral sequence data from viral diversity surveys of known positive animal reservoirs into the DIOS vaccine pipeline. One viral diversity reservoir study will come from a survey and deep sequencing of Old World Arenaviruses in rodent reservoirs in Nigeria where there is most diversity (lineages) and large numbers of human cases annually. The second data-set will come from an independently GCRF funded project to define the Ebola/Filovirus reservoir in positive well studied bat colonies in Ghana. Importantly sera from DIOS antigens derived from reservoir virus immunised animals will be screened for neutralisation against our diverse virus-like particles panel and vice versa. This data will inform a new generation of improved, broadly protective VHF vaccines.

Ebola (EBOV) and Lassa (LASV) viruses, which cause haemorrhagic fever, are highly feared human diseases in Africa. Outbreaks, when they occur, can cause devastating local epidemics in the human population, not to mention the widespread devastation they can cause to wildlife, including non-human primates. The recent Ebola crisis in West Africa devastated the infrastructure and economy of 3 war torn countries for 2 years.
This was complicated and superimposed on Lassa Fever which is endemic with annual spill-overs from Lassa virus carrying rodents. The sequence diversity with Lassa is greatest in Nigeria which is where there is a complex geographic mix of 4 different lineages circulating in wild rodents. While much attention has rightly been paid to mitigating the impact of haemorrhagic fever viruses once they have spread to the human population, very little is known about the future threats and the viral diversity within reservoir species and what facilitates the transmission to humans.
Currently, pathogen sequence data from viral haemorrhagic disease cases are almost exclusively from human cases occurring in past outbreaks. This leaves a huge void of information on the threat of emerging viral variants circulating in animal reservoirs, especially the potential for spill-over of unanticipated new variants of LASV, Arenaviruses and of EBOV-related Filoviruses. Prophylactic vaccines for endemic pathogens with seasonal re-emergence such as LASV would be best designed based on advanced knowledge of the spectrum of potential variants in animal reservoirs. Therefore, this project aims to expand the knowledge of genomic diversity of the two geographically overlapping zoonotic haemorrhagic fever viruses (LASV and EBOV) and use such knowledge to inform vaccine design.

Who will benefit from the research?
The direct beneficiaries of this research will be the people living in the high-risk areas of Africa where Viral Haemorrhagic Fevers occur. Health care workers, hospital staff, international Aid workers and tourists to the country will be direct beneficiaries.

How will they benefit from the research?
Prevention of these very serious disease threats will assist in the economic recovery and stability in threatened countries. Furthermore, this new DIOS technology, once proven for these VHFs will be immediately applicable for other vaccines that are needed. This technology has the potential to dramatically reduce the time of development of vaccines and change the way and accelerate the speed at which the industry makes vaccines, thus having an enormous positive impact on Global Public Health.
The assays and expertise that will be developed will be transferred to centres in Guinea, Ghana and Nigeria, to expand our efforts to continue in-country capacity building.

What will be done to ensure that they benefit from this research?
The U of Cambridge through Cambridge Enterprise and Centre for Science and Policy has an established track record in knowledge transfer to the private sector, policy bodies and consumers. A website will be established that will initially face science peers and collaborations. We will publicise relevant findings of our research and discuss with the public the implications and relevance of these developments to society. Cambridge, has a strong track record in disseminating the outcomes of research to the community and engaging in dialogue with lay audiences. In addition to his advisory experience in the World Health Organisation, the PI will explore public outreach opportunities and, along with fellow co-investigators, also has experience on BBC TV and radio engaging public media about research and public benefit. The team will communicate results worldwide through high profile peer reviewed publications as well as with the lay press whenever timely.