Viral haemorrhagic fevers are a poorly understood group of diseases, but they have entered the public consciousness in unprecedented fashion due to the Ebola outbreak in West Africa. The viruses that cause these diseases are transmitted by a range of vectors that can include primates, rodents and insects. They rely on these animals to survive and don’t always pose a risk to them; however, the viruses cause disease when they infect humans. A team of researchers at Public Health England’s Porton Down laboratories have now studied the Crimean-Congo Haemorrhagic Fever virus (CCHF) and developed a new vaccine against the disease, which infects up to 1,500 people each year and kills between 10-40% of them. We spoke to lead author Dr Karen Buttigieg to find out how they did it.
CCHF: a brief introduction
Like many viruses, Crimean-Congo Haemorrhagic Fever, or CCHF, is named after the place – or, in this case, places – it was first discovered. The virus was first identified by Soviet scientists in 1944 and provisionally named Crimea virus, although they could not isolate the virus to formally describe it until June 1967. However, four months earlier, a virus called Congo virus had been officially described in the East African Medical Journal – and the two turned out to be identical. Because the Congo virus discovery was published first, the International Committee on Taxonomy of Viruses proposed the name Congo-Crimean Haemorrhagic Fever virus. However, Soviet authorities insisted on the Crimean-Congo nomenclature and as a result of the extreme tensions of the cold war at the time, this variant of the name was adopted. This remains one of only a handful of virus name changes as a result of political pressure.
The CCHF virus is transmitted to humans predominantly through bites from ticks of the Hyalomma and Haemaphysalis genera, which also bite animals such as cattle and ostriches. The blood and bodily fluids of infected people are also infectious, so transmission of the virus in hospitals is possible.
Like most viral haemorrhagic fevers – including Ebola – CCHF’s early symptoms are not particularly dramatic or specific and include a fever, vomiting, rashes and aching joints. However, these symptoms escalate to generalised haemorrhaging quite quickly, usually within just five days of the first observation of symptoms. Within a day or two of the onset of bleeding, patients will generally either start to get better or succumb to the virus. On average, between 10-40% of patients die of the disease, a lower figure than for Ebola.
Why do we need a vaccine?
CCHF is endemic in parts of Africa, Asia and the Middle East, but particularly in parts of Eastern Europe. Its range is mostly limited by the habitats of the ticks that spread the disease, but these habitats are likely to expand into the rest of Europe as a result of future climatic change. For now, the presence of the virus in areas frequently visited by tourists could be a cause of concern; for example, 1,300 CCHF cases and 62 fatalities were recorded in Turkey in 2009, and the first case in Greece was recorded in 2008. From these areas, the disease could be imported to the UK on flights.
Indeed, a CCHF case was imported to the UK just two years ago. A man took ill while flying to Glasgow from Kabul in Afghanistan and was eventually transferred to the Royal Free Hospital in London, where he succumbed to the disease in the hospital’s isolation ward.
Dr Buttigieg notes that war zones are areas particularly at risk of increased transmission and spread of CCHF. Livestock and pets can be rare in such areas, meaning that a higher proportion of mammals are likely to be humans. Under these circumstances, the ticks carrying the CCHF virus are more likely to bite humans and transmit the virus to them.
Developing a vaccine
An experimental vaccine against CCHF was developed in 1974 in Bulgaria, where the disease remains endemic. This vaccine consists of live CCHF viruses inactivated with chloroform and injected into mouse brains. The brains are subsequently crushed using a mortar and pestle, and the resulting solution is absorbed into aluminium hydroxide before being administered to patients. While this vaccine shows some efficacy and is still used in Bulgaria for at-risk population groups, a lack of clinical studies and its crude production process mean that it has never received regulatory approval in the EU or the USA.
Dr Buttigieg and her colleagues used a more elegant approach to produce a vaccine. Initially, the team considered using the Hazara virus, the virus most closely related to CCHF virus, to produce a vaccine. The Hazara virus causes a disease similar to CCHF in mice, but it is not known to be harmful to humans. This means that the stringent precautions required for working with CCHF – known as Biosafety Level 4 (BSL-4) – are not needed. However, we simply do not know whether Hazara virus-based vaccine might mutate or undergo changes in the presence of CCHF that could make it dangerous to humans. This means that the Hazara virus is unsuitable for vaccine development.
While the Hazara virus cannot be used for vaccines itself, it has nevertheless proven useful because it has allowed laboratories with lower biosafety levels to investigate potential avenues for CCHF vaccine development. This has left the BSL-4 facilities free to prioritise the most promising projects and trial them with the actual CCHF virus – and also to respond to emergencies such as the current West African Ebola outbreak.
Dr Buttigieg and her team at Porton Down used a smallpox vaccine known as MVA to create their CCHF vaccine. Since smallpox was eradicated worldwide in the 1980s, the substance itself has become obsolete. MVA is based on a live virus that is a distant relative of smallpox, but it cannot cause disease because most of its genetic material is lost in the process of vaccine production. The researchers adapted MVA to deliver proteins found on the surface of the CCHF virus into the body. These proteins are harmless on their own and allow the immune system to learn to defend the body against the CCHF virus without being exposed to the virus itself.
The human immune system produces two different types of immunity called antibodies and immune cells, respectively, which Dr Buttigieg describes as “separate but complementary arms of the immune system”. While the new vaccine protected 100% of the animals that received it from the CCHF virus, she says that her team are not yet sure whether it encourages the production of antibodies or immune cells.
This is a crucial question to answer before the vaccine can move on to the human clinical trial stage. The mice the vaccine was tested could simply be infected with CCHF to see whether the vaccine worked – clearly this is not an option in human trials. In humans, scientists will have to investigate whether the immune system has produced appropriate immunity to protect the body from CCHF – and to do so, they will have to know what immune response to look for.
The new Crimean-Congo Haemorrhagic Fever vaccine developed at Porton Down has shown great promise in preventing a disease that has the potential of spreading and infecting growing numbers of people. Until it is approved for human use, however, it is important for people in areas where CCHF is endemic to protect themselves in the old-fashioned way. Avoiding getting bitten by ticks by wearing long clothing and ankle protection is the simplest way to do so, although high-power insect repellents using DEET also help.
Dr Buttigieg and her colleagues also verified that MVA, the smallpox vaccine that forms the basis of the new CCHF vaccine, could also be adapted to provide protection against a range of other diseases. A previously obsolete vaccine may therefore yet be put to good use in humanity’s ongoing fight against dangerous diseases worldwide.
Buttigieg, K., Dowall, S., Findlay-Wilson, S., Miloszewska, A., Rayner, E., Hewson, R., & Carroll, M. (2014). A Novel Vaccine against Crimean-Congo Haemorrhagic Fever Protects 100% of Animals against Lethal Challenge in a Mouse Model PLoS ONE, 9 (3) DOI: 10.1371/journal.pone.0091516