Bunyavirus Immunity Consortium: Delineating the immune response against CCHFV and other Nairoviruses to aid effective vaccine design

Viral haemorrhagic fevers (VHF) are characterised by very high temperatures and bleeding, and are associated with high levels of morbidity and mortality. A number of viruses can cause VHF, including Crimean-Congo haemorrhagic fever virus (CCHFV), which is the most widespread, tick-borne viral disease affecting humans. The disease is endemic in many regions, such as Africa, Asia, Eastern and Southern Europe, and Central Asia. CCHFV-associated deaths are estimated to be as high as 30% during outbreak settings.

The study of VHFs that affect humans is limited by the need to work in high containment laboratories and by the relative absence of easily-accessible and appropriate models of disease. Nairobi sheep disease virus (NSDV) is an important veterinary-specific and naturally occurring VHF of sheep and goats. NSDV infection of small ruminants is associated with high mortality of up to 90% but is of low risk to humans. NSDV is very closely related to CCHFV, and investigation of NSDV will positively inform CCHFV work and vice versa, whilst simultaneously increasing our knowledge of VHFs and helping inform vaccine development.

The immune response that protects post-exposure to CCHFV and NSDV remains unknown. However, there are no reports of patients being re-infected with CCHFV and disease outbreaks of NSDV only occur when naive animals are moved to an enzootic area; suggesting that prior exposure can result in protective immunity. Delineating the immune response following CCHFV/ NSDV infection is the main objective of this project.

Detailed studies of the immune response in recovery post VHF will be achieved through the assessment of antibody functionality, antigenic profiling and B-cell cohort evaluation. The functionality, population cohorts and type of recall response for T-cell immune responses against CCHF and NSDV, in exposed humans and animals, will also be measured. This will help define the breadth and repertoire of immunity needed to develop protective immunity and in this manner identify the protein(s) of choice for vaccine inclusion.

We will therefore assess the immune responses post exposure to nairoviuses (e.g. CCHFV and/ or NSDV) foreseeing that this immune profiling will identify antigenic targets to become vaccine components in elimination campaigns which will directly and positively impact the economy, health and welfare of endemic countries. This is the principle and direct aim of this research proposal.

Viral haemorrhagic fevers (VHF) are associated with high levels of morbidity and mortality. A number of viruses within the Bunyavirales order can cause VHF with significant impact on human and animal health. Crimean-Congo haemorrhagic fever virus (CCHFV), is a single-stranded, negative sense RNA virus within the nairovirus family of the Bunyavirales order. CCHFV is the most widespread, tick-borne viral disease affecting humans with CCHFV-associated deaths estimated to be as high as 30% during outbreak settings. The study of VHFs that affect humans is limited by the need to work in high containment laboratories. Nairobi sheep disease virus (NSDV) is a veterinary-specific VHF of sheep and goats with fatality rates as high as 90%. NSDV is very closely related to CCHFV, and research on NSDV will positively inform CCHFV work and vice versa.

The correlates of protection post-exposure to nairoviruses remain unknown. There are no reports of patients being re-infected with CCHFV and disease outbreaks of NSDV occur when naive animals are transited to an enzootic area; thus evidence suggests that convalescence results in protective immunity. Detailed studies of the immune response in recovery post VHF will help elucidate correlates of protection and define the breadth and repertoire of immunity needed to develop effective vaccines.

This will be achieved through systems serology including the assessment of antibody functionality, antigenic profiling and B-cell cohort evaluation. The functionality, population cohorts and type of recall response for T cell immune responses against CCHF and NSDV, in exposed humans and animals, will also be measured.

This systematic profiling of the immune responses to nairoviuses will escalate antigenic targets to become vaccine components in elimination campaigns directly impacting the economy, health and welfare of OECD DAC listed countries. This is the principle and direct aim of this research proposal.

CCHFV is one of the WHO priority pathogens for which a vaccine is urgently needed. Vaccines for both livestock and humans are required, to protect human health both directly and indirectly. In order to generate vaccines that can achieve protective efficacy, the breadth, repertoire and antigenic targets of the acute and memory immune responses must be assessed following infection with CCHFV or other related nairoviruses (e.g. Nairobi sheep disease virus, NSDV).

We will therefore utilise immune profiling methods which will identify antigenic targets for use in elimination campaigns which will directly and positively impact people living in endemic areas. These include people living in enzootic areas who are associated with livestock and ticks e.g. foresters and farm labourers (herders, milkers, shearing staff and slaughtering staff) and additionally, health care workers that have direct contact with CCHF patients. Since CCHFV was first discovered (1944), the known geographic distribution has expanded from the Crimea to cover a vast area, from western China across southern Asia to the Middle East, Bulgaria and the Balkans, and throughout most of Africa, encompassing a number of low and/or middle income countries on the Organisation for Economic Co-operation and Development (OECD) /Development Assistance Committee (DAC) List. While reported CCHF cases have risen significantly between 2000-2009, it is widely accepted that cases are under-reported due to limited resources, poor diagnosis and stretched healthcare systems in many endemic countries.

As CCHFV occurs in humans, new strategies to control the spread of the CCHFV such as quarantine or mass culling of infected livestock could have huge economic impact for farmers in enzootic countries. However to date, there are no unified approaches to prevent transmission and infection - governmental agencies are considering containment and curtailment measures. In addition to CCHFV, there are a number of significant, veterinary-specific nairovirus of sheep and goats, (e.g. NSDV), that negatively impact economic stability in OECD DAC listed countries. NSDV is of low risk to researchers but the VHF that ensues when naïve livestock (sheep & goats) are moved into enzootic areas is regarded as one of the most pathogenic in small ruminants, with mortality rates as high as 90%. NSD was first identified as a disease affecting sheep and goats in parts of Kenya, but has been mapped to large parts of East Africa, most of the Indian sub-continent and China. The disease tends to have an impact upon the introduction of naïve livestock into an enzootic area, e.g. for the purposes of improving local breeds by crossing. The impact of NSDV will increase as the need for breed improvement and maximising land-use to facilitate the increasing global demands for food continues. The knowledge amassed from studying NSDV mediated disease will positively inform the understanding of NSD and other VHFs, which in turn may facilitate the development of therapeutics for nairovirus mediated disease.

Our studies of the immune response following nairovirus infection will help elucidate correlates of protection and identify antigenic targets needed to develop effective vaccines. These antigenic targets will be taken forward either feeding into the CCHFVaccine program or through externally-sourced adjunct-funding to use with our pre-developed viral-vectored vaccine platforms to develop vaccines for the prevention of nairovirus-mediated disease.

By the end of this work, we aim to facilitate the translation of the programme's results into socio-economic benefits through the generation of relevant immunogenicity profiling that can be easily and rapidly escalated to generate tenable therapeutics which will in turn be appealing to both commercial investors and philanthropic entities, ensuring an adequate route to market and availability to populations in need.