̽��ֱ�� of Cambridge - Lassa fever

Ebola and Lassa fever targeted by new vaccine trial and improved surveillance

cjb250 — Tue, 25 Sep 2018 09:08:41 +0000

Researchers from the ̽��ֱ�� of Cambridge will shortly begin clinical trials of a new vaccine that builds on almost two decades of research to protect against diseases caused by RNA viruses. At the same time, they will begin studying the natural animal reservoirs of the viruses in an attempt to try and predict which strains are likely to cause future outbreaks, information that will be essential for creating effective vaccines.

Ebola, Lassa and Marburg viruses cause haemorrhagic fever, leading to severe disease, often with high mortality rates. Outbreaks can cause devastating local epidemics in the human population and to wildlife, including non-human primates. ̽��ֱ��recent Ebola epidemic in West Africa (2013–2016) killed over 11,000 people and devastated the infrastructure and economies of Liberia, Sierra Leone and Guinea.

A new approach to vaccine development

Professor Jonathan Heeney and colleagues at the Laboratory of Viral Zoonotics, ̽��ֱ�� of Cambridge, have developed and successfully tested a trivalent vaccine in guinea pigs that protects against Ebola, Lassa and Marburg viruses. As a result, Professor Heeney has been awarded a further £2 million by Innovate UK and the Department of Health and Social Care to take the vaccine to clinical trials in humans.

̽��ֱ��research takes a new approach pioneered by Professor Heeney and builds on Cambridge’s strengths in genomics, monoclonal antibody research and computational biology. It has led to the formation of DIOSynVax, a spin-out company of Cambridge Enterprise.

A virus’s genetic code is written into its ribonucleic acid (RNA), just as ours is written into our DNA, which leads to the generation of proteins. When we are infected by a virus, our immune system responds to these proteins, known as ‘antigens’, producing antibodies that can identify and try to eliminate the invading pathogen.

̽��ֱ��approach developed by Professor Heeney involves understanding how the immune system correctly identifies the virus from its proteins, and using this information to create ‘viruses’ that can generate an immune response. Using monoclonal antibodies – copies of antibodies taken from survivors of the target diseases – they can then test whether the body can effectively eliminate these fake viruses, leading to protection.

“We’ve taken fundamental science that stretches back almost two decades and developed a new approach to vaccine development,” says Professor Heeney. “This has the potential to dramatically reduce the time needed to produce new vaccines and change the way in which the industry makes them.”

With the new funding, the team hopes to scale up production while ensuring that the quality of the vaccine is maintained. They will then carry out toxicity tests in animals and human blood samples to test for potential adverse effects; if successful, they will then trial the vaccine in healthy human volunteers.

̽��ֱ��funding is part of a £5m commitment from the Department of Health and Social Care to fund five projects to develop new vaccines with a ‘One Health’ focus, considering how the environment, the health of animals and the health of humans interact. This sits within the government’s £120m UK aid commitment to develop vaccines to help tackle diseases with epidemic potential.

Predicting the next outbreak

In recent Ebola outbreaks, the approach used successfully by the World Health Organization is known as ‘ring vaccination’, focused on vaccinating and monitoring a ring of people around each infected individual. However, this approach can only be used in response to an outbreak. In order for a vaccine to be used proactively – to prevent an outbreak in the first place – it is necessary to predict which strain or strains of a virus are most likely to cause future epidemics.

“A disproportionally high number of emerging and re-emerging diseases – from Ebola and Lassa through to rabies and influenza – are caused by RNA viruses carried naturally by animals,” says Professor Heeney. “We know very little about the viral diversity within these reservoir species and what enables them to spread to humans – and hence where the likely future threats lie.”

Viral genomes are notoriously variable due to the high mutation rates that occur during replication. These accumulate over time and result in evolution of the viruses as they circulate in their natural animal reservoir populations. If some viral variants arise and are able to adapt to use human cell receptors and are then able to escape immune defences, they may become highly infectious and cause large disease outbreaks.

“Vaccines are only as good as the antigen immune targets of the virus that they are designed for,” adds Professor Heeney. “If the antigen changes, the vaccine will no longer be effective. 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 transmission.”

Professor Heeney has also received £1.4 million from the Biotechnology and Biological Sciences Research Council (BBSRC) to lead a project that aims to predict where future outbreaks may arise from and the likely strains, and to then use this knowledge to inform vaccine design. This One Health project enlists veterinarians, clinicians, ecologists and medical and public health workers in West Africa to understand how people catch Lassa fever from rat populations. Their work will include trapping rat species that carry these viruses and placing GPS tags to monitor their movements, as well as obtaining molecular, genomic and antibody data from the animals and viral sequences from infected rats.

Professor Melanie Welham, Executive Chair of BBSRC, says: “This important research from the team at the ̽��ֱ�� of Cambridge is about providing effective treatments for some potentially deadly diseases spread by rats and bats: Lassa and Ebola respectively. Novel strategies to combat dangerous infections like these are essential and often underpin the development of much-needed next generation vaccines.

“Professor Heeney and team have already made a significant difference in this area, researching cross species transmissions of these viruses, with a view to developing vaccines for Ebola and Lassa that would be effective against multiple strains.”

In addition, the team is collaborating with Professor James Wood, Head of the Department of Veterinary Medicine at Cambridge, who is conducting a complementary study funded by the Global Challenges Research Fund to sample bat colonies in Ghana, believed to be a natural reservoir for the Ebola virus.

“Equipped with this information, we should be able to design better vaccine antigens for more effective and broadly-protective vaccines,” says Professor Heeney. “Combined with our accelerated vaccine development platform, this has the potential to have an enormous positive impact on global public health.”

Scientists hope that a new approach to vaccine development, combined with improved surveillance of potential future threats of outbreak, could help to massively reduce the impact of deadly diseases such as Ebola, Marburg and Lassa fever.

"This has the potential to have an enormous positive impact on global public health"

Jonathan Heeney

NIAID

Ebola Vaccine Study in West Africa

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New model could help improve prediction of outbreaks of Ebola and Lassa fever

cjb250 — Fri, 02 Sep 2016 18:00:41 +0000

Many of the major new outbreaks of disease, particularly in Africa, are so-called zoonotic infections, diseases that are transmitted to humans from animals. ̽��ֱ��Ebola virus, for example, which recently killed over 11,000 people across Africa, was most likely transmitted to humans from fruit bats.

Modelling how outbreaks arise and whether they will take hold or quickly die out has proved challenging, with two factors in particular being difficult to quantify. ̽��ֱ��first is ‘spillover’, where the pathogen – a virus or parasite, for example – passes from an animal to a person. This can be through direct transmission, for example by being bitten or by eating ‘bush meat’ (wild animals such as fruit bats or monkeys that are caught and consumed), or indirectly, such as through contact with faeces or disease-carrying mosquitoes.

In many cases, a spillover will go no further. When a human is bitten by a rabid dog, they may become infected, but as the disease cannot transmit from human-to-human, the disease hits a dead end.

However, in some cases the infected person goes on to infect other humans. This is the case for diseases such as Ebola, Lassa fever (spread from rodents) and Crimean Congo haemorrhagic fever (spread from ticks). But in many cases, unless there are additional spillover events, the disease eventually fades out. This is referred to as a ‘stuttering chain’, and even though the disease is transmitted from human-to-human, they are still considered to be zoonotic infections.

Diseases such as HIV, however, which almost certainly began as a spillover from chimpanzees, are no longer considered to be zoonotic as the chain of transmission from humans to other humans is continuous and no longer relies on spillover to sustain transmission.

“Modelling spillovers is a real challenge,” says Dr Gianni Lo Iacono from the Department of Veterinary Medicine at the ̽��ֱ�� of Cambridge. “We don’t have particularly good data on wildlife numbers, such as fruit bats in Sierra Leone, and only a crude idea of their geographic distribution and how many are infected. Even in the UK, we don't really know how many deer we have, which would be really useful to estimate the risk of Lyme disease.”

In addition, measuring the likelihood of contact with the infected animals is also extremely difficult as it involves understanding human and animal behaviour.

Stuttering transmission, too, can be difficult to model, says Dr Lo Iacono. “In the case of Lassa fever, people who catch the disease from animals show the same symptoms as those who get it from humans. So is this case a spillover or part of a human-to-human chain of transmission? And if members of the same family get the disease, have they caught it from a family member or from the same pot of contaminated rice?

“Sometimes you can be lucky and work this out, as we did in a previous study, but this was possible because information of outbreaks that were known to be pure human-to-human chains was, unusually, available. But we need more general methods.”

Dr Lo Iacono and colleagues have developed the most coherent and potentially most accurate mathematical model to date for zoonotic diseases, which incorporates spillover and stuttering transmission.

“ ̽��ֱ��pathogen does not care if it jumped from an animal or from another human; the only difference is that in a stuttering transmission an infected person can trigger other chains of human infections. A general, realistic model should capture this mechanism,” adds Dr Lo Iacono.

Details of the model, including a demonstration applying the framework to Lassa fever, are published today in the open access journal PLOS Neglected Tropical Diseases.

“By modelling potential outbreaks more accurately, we can help inform public health messages,” explains Professor James Wood, Head of the Department of Veterinary Medicine, and senior author. “If you know that most cases of an outbreak of Lassa fever come from spillovers, then the message might be ‘kill the rats’, but if it is now mainly spreading between humans, the messages will be around washing your hands or avoiding contact with bodily fluids.”

̽��ֱ��beauty of the model, say the researchers, is that it is simple to implement, so public health officials and non-mathematicians could easily use it. It also allows for the incorporation of data from different disciplines, factoring in socioeconomic, ecological and environmental factors, for example.

“It’s important to understand if and how these other important factors can increase the impact of stuttering chains,” says Professor Wood. “Ebola has always been a very severe disease but previously confined to small, remote regions. Then suddenly, in the last two years it exploded in West Africa. Why? Was it because social patterns changed? Our model could be used to address such questions better.”

̽��ֱ��research informing the paper was carried out as part of the Dynamic Drivers of Disease in Africa Consortium, which was funded by Ecosystem Services for Poverty Alleviation (ESPA).

Reference
Lo Iacono, G et al. A unified framework for the infection dynamics of zoonotic spillover and spread. PLOS NTD; 2 Sept 2016; DOI: 10.1371/journal.pntd.0004957

Potential outbreaks of diseases such as Ebola and Lassa fever may be more accurately predicted thanks to a new mathematical model developed by researchers at the ̽��ֱ�� of Cambridge. This could in turn help inform public health messages to prevent outbreaks spreading more widely.

If you know that most cases of an outbreak of Lassa fever come from spillovers, then the message might be ‘kill the rats’, but if it is now mainly spreading between humans, the messages will be around washing your hands or avoiding contact with bodily fluids

James Wood

Global Panorama

Ebola in West Africa

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Lassa fever controls need to consider human to human transmission and the role of ‘super spreaders’, say researchers

Anonymous — Thu, 15 Jan 2015 00:00:00 +0000

Lassa fever is an acute viral haemorrhagic illness caused by Lassa virus. First identified in the village of Lassa, Nigeria, in 1969, the disease is thought to be transmitted to humans from contact with food or household items contaminated with rat urine or faeces. There have also been recorded cases of human-to-human transmission within hospital settings, but until now the risk – or mode – of transmission has not been clear. Understanding the different modes of transmission and how they are affected by factors such as people’s interaction with their environment is crucial for understanding the link between Lassa and changes in the ecosystem, and has important implications for public health strategies.

“Given the many competing health priorities in West Africa – exacerbated by the current Ebola epidemic – it is essential that we know the relative risk of human-to-human transmission of other potentially deadly diseases, such as Lassa fever,” says first author Dr Gianni Lo Iacono from the Department of Veterinary Medicine at the ̽��ֱ�� of Cambridge. “That way, public health officials can decide where to focus their public health campaigns and how to prevent or respond to potential outbreaks.”

̽��ֱ��researchers, part of the Dynamic Drivers of Disease in Africa Consortium, used mathematical modelling to analyse data from outbreaks known to be due to human-to-human chains of transmission, and calculated the ‘effective reproductive number’. This number represents the number of secondary infections from a typical infected individual – for an outbreak to take hold, this number needs to be greater than one. They compared data from hundreds of Lassa infected patients from Kenema Government Hospital, in Sierra Leone, who could have been infected either by rodents or humans, with the data from human-to-human chains. By considering the effective reproductive numbers, they inferred the proportion of patients infected by humans rather than rodents.

̽��ֱ��researchers estimated that around one in five cases (20%) of infection is caused by human-to-human transmission. However, the study also highlighted the disproportionate number of infections that could be traced back to a small number of people, whom the researchers describe as ‘super-spreaders’ – rather than passing their infection on to just one other person (if at all), these individuals infected multiple others. It is not clear what makes them a super-spreader – their physiology, the environment in which they live, their social interactions or probably a combination of these factors.

Dr Donald Grant, chief physician at the Lassa ward in Kenema Government Hospital and co-author of the research, said: "Simple messages to the local people could change their perceptions of risk and hopefully make the difference. For example, making people aware that the virus can remain in urine for several weeks during the recovery period, could promote improved hygienic practices.

“What’s more, measures to target human-to-human spread of Lassa virus can be bundled in with prevention interventions for diseases with similar transmission routes, such as Ebola and even Hepatitis B.”

Professor James Wood, Head of the Department of Veterinary Medicine and senior author on the study, says: “ ̽��ֱ��idea of super-spreaders in infectious diseases is not new. We’ve known about them since the notorious case of ‘Typhoid Mary’ in the early twentieth century and they’ve been documented for other diseases including TB, measles and SARS.

“Although we don’t understand what makes someone a ‘super-spreader’, it highlights the importance of strict hygiene measures in preventing infection. In the case of Lassa fever, we now know that whilst the chance of transmission between humans is much lower than it is from rodents, it is still a very real risk.”

Further progress has been hampered by the Ebola outbreak, which has resulted in the death of key collaborators in Kenema Government Hospital, which was used to nurse Ebola patients, in particular Dr Sheik Humarr Khan, who played such a key role in establishing and furthering the Lassa fever research programme.

̽��ֱ��Dynamic Drivers of Disease in Africa Consortium, a multidisciplinary research project considering the linkages between zoonoses, ecosystems, health and wellbeing, is supported the UK Government through the Ecosystem for Poverty Alleviation (ESPA) research programme.

Reference
G. Lo Iacono, A. A. Cunningham, E. Fichet-Calvet, R. F. Garry, D. S. Grant, S. H. Khan, M. Leach, L. M. Moses, J. S. Schieffelin, J. G. Shaffer, C. T. Webb, J. L. N. Wood. Using modelling to disentangle the relative contributions of zoonotic and anthroponotic transmission: the case of Lassa fever. PLOS NTD; January 2015.

One in five cases of Lassa fever – a disease that kills around 5,000 people a year in West Africa – could be due to human-to-human transmission, with a large proportion of these cases caused by ‘super-spreaders’, according to research published today in the journal PLOS Neglected Tropical Diseases.

Given the many competing health priorities in West Africa – exacerbated by the current Ebola epidemic – it is essential that we know the relative risk of human-to-human transmission of other potentially deadly diseases, such as Lassa fever.

Dr Gianni Lo Iacono

Catherine Grant

Housing in Kenema, Sierra Leone

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