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Emerging threats: the evolving immunological response

“The recent Ebola outbreak was a shocking reminder of the threat we all face from a disease outbreak,” said David Cameron on the eve of a G7 summit in June 2015. “We will face an outbreak like Ebola again and that virus could be more aggressive and difficult to contain. It is time to wake up to that threat.”

The Prime Minister’s words came as the Ebola epidemic that cost more than 11,300 lives in West Africa was coming to an end. Two months earlier, the Cabinet Office’s National Risk Register of Civil Emergencies identified emerging infectious diseases as among the most serious threats facing the UK. Mr Cameron went on to outline plans for a new UK Vaccines Research and Development Network to coordinate national research efforts on some of the most threatening emerging risks including Ebola, Lassa fever, Marburg virus disease and Crimean-Congo fever.

UK’s scientific strength

The recent political lead the UK has taken is pre-dated by a long history of world class science in this field. An AllParty Parliamentary Group on Health report published last year ranked UK research on infection and immunology as of the highest quality among G7 nations between 2010-14, as measured by impact, or the frequency of referencing of scientific papers in peer-reviewed journals.

This scientific strength came to the fore during the Ebola epidemic as UK immunologists made vital contributions to the race for a vaccine, yet sadly their efforts came too late to prevent the large-scale loss of life. In a report published in January, the House of Commons Science and Technology Select Committee argued the government response was too slow, emergency research was inadequately coordinated and a lack of domestic vaccine manufacturing capabilities makes the UK vulnerable. More positively, however, the response to the disease and ongoing advances in the field generally offer hope that we can improve our resilience to future emerging infectious diseases outbreaks.

Anatomy of the outbreak

The West Africa Ebola outbreak is believed to have started with the death of a young boy in Guinea at the end of 2013. New cases emerged among his family members, their contacts and healthcare workers. By the end of March 2014, the disease was identified as the deadly Zaire species of the 

Ebola virus, and the infection had spread to nearby Liberia and Sierra Leone. The World Health Organization (WHO) announced the outbreak to be a public health emergency of international concern in August 2014, and set about fasttracking clinical trials of two candidate Ebola vaccines.

Vaccine trials begin

Professor Adrian Hill, Director of the University of Oxford’s Jenner Institute, agreed to lead a human trial of a  chimpanzee adenovirus Ebola vaccine called ChAd3 EBOZ, previously developed by GSK and the US National Institutes  of Health. Funding and regulatory approval were rapidly  agreed, and the first healthy volunteers were vaccinated on  17 September 2014. “We started just over a month after being first contacted, which was unprecedented,” says Hill.

The trial results, showing the vaccine generated an immune response and had an acceptable safety profile, were published  in January 2015. During that year, further trials of both ChAd3 and other vaccines were launched. In July, the results of a  large trial of the other existing vaccine, rVSV-ZEBOV, were published. Based on vesicular stomatitis Indiana virus, it was shown to offer at least short-term effective protection. By  the time it was used, the numbers of new Ebola cases were rapidly decreasing. It is however believed that use of  rVSV-ZEBOV hastened the end of the Ebola outbreak in Guinea.

Hill, who believes ChAd3 EBOZ is likely to offer more effective long-term protection, says that the hard truth is that there was no vaccine ready to use against Ebola at the start of the outbreak because it was not a commercial priority for the pharmaceutical industry. “We need to get on and put vaccines through clinical tests as well as making them,” he says. “The wider lesson people are grappling with now is that there are probably another dozen outbreak pathogens for which it’s relatively feasible to develop vaccines; however there just isn’t a business case for doing so.”

Had the Ebola outbreak occurred a decade earlier, it is unlikely that vaccines would have played a major role in the response. Vaccines based on adenovirus and VSV were not yet available, and vaccine manufacturing processes have also come a long way since then. Another technology that was central to the fight against Ebola, and which has developed rapidly in the last 10 years, is genetic sequencing.

Know your enemy

The ability to quickly and accurately sequence pathogen samples has had major impacts on how we respond to emerging threats more generally. It can firstly identify pathogens, helping to reveal whether an outbreak has been caused by something previously known or entirely new. It can play a role in determining the sensitivity and specificity of diagnostic tests. When it comes to looking for treatments, genetic tests can reveal whether a virus or bacteria is related to other known threats, and therefore offer clues to drug susceptibility or resistance.

A key variable for epidemiologists dealing with an emerging threat is its ‘basic reproductive number’. Also called R0, this is the average number of infections one existing case generates. It can be calculated simply by counting the number of existing and new cases; however this is prone to error, and genetics can provide an alternative means of calculating R0.

"An All-Party Parliamentary Group on Health report published last year ranked UK research on infection and immunology as of the highest quality among G7 nations between 2010-14"

Once the virus’s rate of mutation and the length of time that cases are symptomatic and infectious are known, genetic testing can reveal useful details of transmission chains that can help shape infection control methods. US researchers who sequenced 99 samples of the Ebola virus were able to determine that it was spread from Guinea to Sierra Leone by 12 people who attended the same funeral. Genetic testing also demonstrated camel-to-human transmission of MERS coronavirus.

Speed is of the essence

“We shouldn’t give the impression that genetics is a panacea,” says Paul Kellam, Professor of Virus Genomics at Imperial College London. “Nevertheless it is an important tool because it can speed up the understanding of patterns of transmission, and the quicker you can target public health measures or deploy interventions effectively the better.”

Professor Peter Openshaw, of Imperial College and the President of the British Society for Immunology, agrees. “Speed is absolutely of the essence in infection control. If sequencing can allow you to intervene two weeks earlier, you could prevent an exponential growth in cases, which might prevent hundreds of thousands of people being infected or needing to be put in quarantine.”

Genetic testing’s potential value has in the past been held back by the need to transport samples from sometimes remote locations to laboratories equipped with large, expensive sequencers. During the Ebola outbreak, however, a DNA sequencer smaller than a mobile phone was used to reveal the unique genetic fingerprints of Ebola virus samples taken from patients in Guinea within 24 hours. The MinION, developed by Oxford Nanopore Technologies, works by passing DNA strands through proteins with holes at their cores. As the four chemical building blocks of DNA (known as bases) pass through the hole, they impede an electric current passing through it in a characteristic way, allowing them to be identified and therefore the molecule to be sequenced.

Data on DNA mutations in samples from Guinea was sent to microbiologist Dr Nick Loman and colleagues at the University of Birmingham for analysis, providing insights into the sources of cases. It helped confirm, for example, fears that the flow of people across the border with Sierra Leone was prolonging the outbreak, and facilitated the more effective targeting of resources to fight the epidemic. Loman now has Medical Research Council funding for the mobile collection of 750 Zika virus genomes in Brazil.

Know your own weaknesses

Just as it is possible to sequence pathogen samples from different people, genetics can also be used to identify immune system variations of individuals. B cells play a vital defensive role in flagging up the presence of invading pathogens to stimulate other immune cells to attack them. In recent years, researchers have developed immune repertoire sequencing to profile B cells present in healthy individuals, as well as those with infections and malignancies.

Dr Rachael Bashford-Rogers, of the University of Cambridge, has used the technique to profile changes in B cell populations as a result of treatment for chronic and acute lymphocytic leukaemia. She was able to detect the small numbers of leukaemia cells that remain in patients following treatment to a high degree of accuracy. This is important as it is a strong predictor of relapse. Dr Dominic Kelly, at the University of Oxford, is using the technique to study B cell responses to hepatitis B and influenza infections. It has also been used in a similar way to study dengue fever. The hope is that the technique will lead to the development of improved vaccines, diagnostics and treatments for emerging infections and other conditions.

Individual variations

Another application of genomics is in providing greater insight into the role of human genetic variability on disease severity. Within a given human population infected with a pathogen, some may become severely ill and die, while others experience only mild symptoms or may even not know they have the infection. Researchers have shown that in many cases variation in human genetics is more significant in determining disease severity than pathogen genetic variability.

In 2012, Paul Kellam’s group at the Virus Genomics lab at the Wellcome Trust Sanger Institute discovered that different variants of the human gene IFITM3 , which encodes a protein that can make it harder for viruses to penetrate cells and replicate, are a key determinant of disease severity in influenza A (H1N1) patients. Research has also shown that variants of a gene that encodes the protein CCR5 can protect against HIV-1 by making it harder for the virus to penetrate target cells – Pfizer’s HIV drug Maraviroc is based on this work.

“This offers us a new paradigm for the future of genetics,” says Kellam. “If you can find a genetic variation in the human host that protects from a pathogen and does not cause any negative effects, this suggests a target for drugs to prevent infection.”

Effective use of data

While researchers are now better able to collect information during emergency outbreak situations, what really counts is how that data is used. “The best patterns emerge when you cross compare everybody’s data,” says Kellam, “and that means being willing to share it openly and rapidly.”

The WHO and Wellcome Trust have emphasised the importance of finding ways to encourage the sharing of data, while respecting patient confidentiality. Researchers leading the way in this endeavour include Dr Richard Neher of the Max Planck Institute for Developmental Biology in Germany, and Dr Trevor Bedford of the Fred Hutchinson Cancer Research Center in the USA who have developed websites that generate real-time visualisations of seasonal influenza and Ebola virus evolution. Professor Andrew Rambaut of the University of Edinburgh collates outbreak data and blogs about it.

Preventing future outbreaks

Hill believes that beyond developing and testing vaccines for the most dangerous emerging infectious diseases, two strategies offer hope for preventing outbreaks. First, small quantities of vaccines should be stockpiled in the locations in which infections are most likely to occur. Secondly, healthcare workers and first responders should be protected with routine vaccinations. “It would protect them of course, but it could also stop outbreaks from getting going because doctors and nurses often play key roles in spreading infectious pathogens,” says Hill.

"Speed is absolutely of the essence in infection control. If sequencing can allow you to intervene two weeks earlier, you could prevent hundreds of thousands of people being infected or being put in quarantine"

Those who highlight the tragedy of the loss of thousands of lives as a result of the failure to carry out clinical trials of candidate vaccines that existed before the West Africa Ebola outbreak are right to do so. Yet if the right lessons can be learnt, and real progress be made in key areas like rapid mobile genetic sequencing, immune repertoire sequencing, understanding the role of genetic variability in human hosts and in data sharing, we can at least improve humanity’s odds in the inevitable battles with emerging infectious pathogens that tomorrow will bring.
 


This article was written by Nic Fleming as part of the BSI's report '60 years of immunology: past, present and future'. This article is licensed under Creative Commons Attribution-NoDerivative Licence (CC BY-ND 4.0). Additional permissions may need to be sort from image licence owners.