Emerging Infectious Diseases
Crimean-Congo haemorrhagic fever (CCHF) and Rift Valley fever (RVF) are caused by bunyaviruses, and are transmitted to humans via insect vectors (ticks of the genus Hyalomma and Aedes/Culex mosquitoes respectively), as well as zoonotic transmission from infected animal tissues. Reservoir hosts of the CCHF virus include a range of animals – such as cattle, sheep, goats and hares – which become infected by the bite of infected ticks but do not manifest the disease.
Human-to-human transmission of CCHF can occur upon direct contact with virus-infected bodily fluids. In contrast, RVF can cause disease in livestock, with transmission to humans upon contact with virus-infected blood or organs. Human infection from bites of virus-infected mosquitoes is less common. There is no documented evidence of human-to-human transmission of RVF.
CCHF and RVF have similar symptoms to other viral haemorrhagic fevers, making early clinical diagnosis challenging, including fever, sensitivity to light, fatigue and dizziness, sometimes progressing to haemorrhage, organ failure and shock. Less than one in ten RVF cases progress to severe disease, manifesting as ocular, meningoencephalitis, and/or haemorrhagic fever.
CCHF is endemic everywhere its tick vector is located, including sub-Saharan Africa, South and Central Europe, the Middle East and Central Asia. In contrast, RVF is mainly limited to sub-Saharan Africa, and, since 2000, the Middle East. CCHF cases occur sporadically, primarily in rural areas, with a case fatality ratio of up to 40%. There have been more than a dozen RVF outbreaks since 2000, with an average case fatality ratio of 1%, although this can vary widely depending on the outbreak – reaching up to 50%. Given the central role of livestock in contributing to human disease, CCHF and RVF are both exemplars of the need for a One Health approach to developing new countermeasures.
CCHF and RVF have similar symptoms to other viral haemorrhagic fevers, making early clinical diagnosis challenging. Initial symptoms of both may include fever, fatigue, dizziness, and muscle aches with progression to severe disease with bruising, haemorrhage, organ failure and shock. Whereas most cases of RVF are asymptomatic or mild with only one in ten progressing to severe disease and haemorrhagic fever occurring in less than 1% of all cases, the case fatality rate from CCHF can range from 10% up to 40%.
CCHF is endemic in regions where the tick vector is located, including in sub-Saharan Africa, South and Central Europe, the Middle East and Central Asia. The geographic distribution of RVF is mainly limited to sub-Saharan Africa, however, since 2000 it has also spread to the Middle East. There have been more than a dozen RVF outbreaks since 2000, with 4,830 cases and 967 deaths recorded as of June 2018.
Standardised models of non-human primates susceptible to CCHFV infection are needed for a better understanding of disease pathogenesis and immunology while offering insights for developing therapeutics and vaccines.
In the absence of approved drugs, CCHF case management relies on supportive care. Off-label use of Ribavirin, a broad-spectrum antiviral, lacks sufficient supporting evidence. There are no CCHF therapeutic candidates in clinical development. Broadly neutralising and non-neutralising mAbs, along with favipiravir, a small molecule drug, have shown potential in pre-clinical studies. Randomised controlled trials of favipiravir and ribavirin, and further development of novel biologics are urgently needed.
An inactivated, mouse brain-derived CCHF vaccine has been used in Bulgaria since 1974; but safety concerns, instability and a lack of efficacy trials make it unsuitable for global use. KIRIM-KONGO-VAX, an inactivated vaccine, is the only candidate currently in clinical development. Effective CCHF vaccines targeting humans and animal reservoirs are urgently needed.
CCHF detection currently involves direct isolation or molecular tests, each requiring sophisticated facilities. The WHO highlights three urgent R&D needs: clinically validated and quality assured RT-PCR, ELISA Assay for reference laboratories, and RDTs for near-patient settings.
As with CCHF, supportive therapy is the only option for managing patients with severe RVF. While no RVF drug candidates have reached clinical development, a chemotherapeutic agent, mitoxantrone, and two broad-spectrum antivirals – a non-nucleoside inhibitor (favipiravir) and a nucleoside analogue (BCX4430) – are in pre-clinical development. As RVF can cause encephalitis and miscarriages, an ideal therapeutic candidate should cross the blood-brain barrier and be usable in pregnant women.
The WHO’s draft RVF Target Product Profile calls for three RVF vaccines: one for reactive/emergency use, one for long term protection for high-risk populations, and an animal vaccine for prevention of transmission. There are several veterinary vaccines in routine use, albeit with concerns about their safety, effectiveness and the potential for reassortment with wild strains. To date, only two RVF vaccine candidates, one inactivated (TSI GSD 200) and one live-attenuated (MP12), both developed by the US DOD, have undergone human testing. Candidates based on novel approaches such as DNA and viral vectors remain in the pre-clinical stage.
There are no validated point-of-care molecular tests in late-stage of development, and no validated commercial serology assays for use in humans.
A team of researchers at CIRAD Réunion have developed the first specific rapid detection test for RVF virus. This first-line lateral flow immunochromatographic strip test is able to identify all strains of the RVF virus and has demonstrated high specificity and sensitivity during validation, offering a promising first-line, on-site diagnostic assay for use in resource-limited settings.