SPOTLIGHT ON IMMUNOLOGY

Stopping a pandemic in its tracks

When a pandemic looks likely to break out, scientists across multiple disciplines must cooperate to limit its spread.

SINCE APRIL 2012, seventeen people around the world have been infected with a virus that has baffled scientists, public health officials and governments. Initial cases in the Middle-East were reported to the World Health Organisation's Global Outbreak Alert and Response Network, set up to detect epidemics and other public health emergencies. The type of virus is known, a novel coronavirus, a species of the virus behind the common cold, but its origins are still a mystery. This new virus is currently moving slowly, but it was a coronavirus that caused the 2003 Severe Acute Respiratory Syndrome (SARS) pandemic which killed 774 people, so scientists who work on controlling the spread of new infections are on full alert.

The discovery of a universal flu vaccine could be on the cards. Credit: DESIGN PICS/THINKSTOCK

One of them is Eric Snijder, Professor of Molecular Virology at Leiden University Medical Center, in the Netherlands, who has been studying coronaviruses for more than 25 years. In October 2012, his team identified the genome properties of this emerging strain. It is now collaborating with an international group of labs in the hope of identifying compounds that may inhibit the virus's replication. The collaboration is part of the European project SILVER, a drug design program to tackle emerging diseases caused by RNA viruses such as the new coronavirus.

Outbreak alert

Snijder's work represents the initial action taken when a new infection emerges. Be it a new subtype of influenza, such as H1N1 (‘swine flu’), or a new coronavirus, understanding the biology of the virus and estimating the threat it poses is crucial. But the first step is to find the virus, using global monitoring and surveillance systems.

Every day we see patients, and we see families that lose people. This is not about my career, this is about the patient. Helen Sabzevari, Senior Vice President of Immuno-Oncology, EMD-Serono

The WHO response network consists of 140 laboratories in 110 UN member states recognized as National Influenza Centres. John McCauley is Director of the WHO Influenza Centre at the National Institute for Medical Research in London, one of six that regularly analyses significant flu viruses seen in the population as well as other emerging viruses which may be cause for concern. If the prevalence of new influenza strains increases, “it might indicate that the world is at increased risk of an influenza epidemic,” says McCauley. Global and domestic surveillance in the US is carried out by scientists at the Centers for Disease Control and Prevention (CDC), whose labs in Atlanta are part of the WHO network. Constant communication is needed between centers to identify whether viruses recorded in different countries share characteristics.

Once a threat has been identified, potential treatments must be trialed quickly and a pandemic preparedness plan put into action. This is part of the remit of Anthony Fauci, Director of the National Institute of Allergy and Infectious Disease (NIAID) in Bethesda, Maryland. “We need to understand the pathogenesis of the virus and how it may mutate and become highly transmissible to cause a pandemic,” says Fauci. His lab then starts testing drugs and vaccines to stop the virus in its tracks. “We collaborate [with industry] and run clinical trials for new vaccines to determine the right dose, if it's safe, if it's effective, especially in vulnerable members of the population,” he says.

“In 2009, as soon as H1N1 became clear, we immediately went into action to develop a vaccine and tested the virus for sensitivity to drugs we already have such as Tamiflu – fortunately, it was [sensitive],” he says. Identifying effective drugs helps ‘buy time’ from a public health perspective, as developing a vaccine currently takes about six months.

When a pandemic threatens, scientists play a vital role in influencing protection policies. Credit: ISTOCKPHOTO/THINKSTOCK

During this waiting game, another field – infectious disease modeling – comes into play, to predict and mitigate the extent to which a virus will spread.

Predicting possibilities

John Edmunds is dean of the Faculty of Epidemiology and Population Health at the London School of Hygiene and Tropical Medicine, and in his former role running the modeling and economics unit at the UK Health Protection Agency (HPA) was among those responsible for modeling outcomes for the 2009 H1N1 pandemic. “We run through different control scenarios, such as the use of vaccines or anti-virals, and see what may happen to the epidemic,” says Edmunds. The aim is to gauge the trajectory of an infection and the effect of any actions, including economical and political control measures such as travel restrictions and school closures.

Models use characteristics like pathogenicity of the virus (how likely it is to cause an infection) to predict its spread, but these days can also use current information on cases and timings to model epidemics in real-time, a technique known as ‘nowcasting’.

“We use many different data sources and patch them together to get a glimpse of how many cases there really have been,” Edmunds says. For those wanting to get into modeling, it helps to have a diverse skill set. “You need a range of people and skills to handle this. You need to understand biology, statistics, computer programming, economics and bioinformatics.”

Manufacturing the FluMist influenza vaccine at MedImmune. Credit: MEDIMMUNE

An ability to work effectively with others is also vital, says Edmunds, who sits on the Scientific Pandemic Influenza (SPI) committee alongside other modelers, virologists, and experts in risk management, behavioural sciences and diagnostics. Together, they feed information to the government to guide policy and mobilize resources.

Policy pressures

Influencing policy decisions is not a role which always sits well with scientists, especially under the time pressures of dealing with the spread of dangerous viruses. “Anyone that can provide clear information and communicate the risk has the power to lead a response,” says David Heymann, Head of the Centre for Global Health Security at Chatham House and Chair of the UK Health Protection Agency.

A particularly contentious problem is prioritising who should receive medicines first, including chemoprophylaxis – where drugs are used before infection to avoid people getting the disease. “During H1N1, the UK Department of Health and the HPA made the decision to treat contacts of patients prophylactically to slow down the spread of the virus,” says Heymann.

Despite the time needed for their development, the most desirable response to every pandemic is a vaccine. This involves collaboration between government-run organizations and industry. Kanta Subbarao, who leads the emerging respiratory viruses section at the NIH's Laboratory of Infectious Diseases, in Bethesda, collaborates with biotech company MedImmune to develop vaccines against influenza strains that show pandemic potential. “We share our data in presentations and publications – this becomes part of the body of information that informs further decision making in the government and pharma,” Subbarao says. Pharmaceutical companies instigate their own pandemic preparedness plans and played an integral role during the H1N1 pandemic. For instance, Glaxosmithkline set aside two million eggs for vaccine production, as hen eggs are traditionally used to incubate the virus.

Dangerous encounters

Working with highly contagious pathogens comes with risk. “We have to work in a way that minimizes the risk of infection, by using high containment conditions such as safety cabinets with gloved ports, negative pressure and use of filters to trap viruses,” McCauley says.

This type of research is also extremely controversial, and the potential for viruses to become transmissible from animals to humans in the future – the study of which is seen as an important part of pandemic preparedness – notoriously led to a year-long moratorium on this type of research from January 2012. These issues are among those considered by the newly-established Centre for Global Health Policy at the University of Sussex, UK. “Safeguards should be in place to minimize the risk of accidental or deliberate misuse of research on deadly strains of influenza viruses,” says center director Stefan Elbe.

Universal ambitions

For many immunologists working to reduce pandemics, the ultimate goal is a universal flu vaccine. “We want to make a vaccine that produces a response to a section of the influenza virus that doesn't change from pandemic to pandemic,” says Fauci. Such a vaccine, if administered every 5 to 8 years throughout the population, could prevent a pandemic altogether. Of course, it won't tackle the problem of emerging infections such as SARS and the current coronavirus, but it's a step in the right direction to fight influenza which has seen the biggest pandemics to date. “It's going to take several years to get there,” says Fauci, “but we're starting to see the first glimmers of success.”

Vaccines for cancer

Dr Helen Sabzevari has been in the field of immunotherapy since its infancy, working to harness the body's own immune system to treat cancer. As she was doing her first postdoc, at Scripps Research Institute, in San Diego, Sabzevari realised that there was a disconnect between scientists working in her own field of cancer immunotherapy, and those working on auto-immunity diseases. “Normally, these two diseases are opposite sides of the coin,” she says. “Autoimmunity is over-activity of the function of immune cells but with cancer there is a quiescence of the immune system. In my opinion it was really important to understand both sides.”

Sabzevari ignored the advice of mentors, who had already seen her career progress in immunotherapy, and decided on a senior postdoc in the field of autoimmunity. In doing so, she hoped she might find a way to use the mechanisms that cause the immune system to over-react in autoimmune diseases to kick-start the same cells, which don't respond to cancer.

The decision paid off. Sabzevari spent almost 10 years researching cancer vaccines at the National Institutes of Health, before moving to pharma company EMD-Serono where she leads their immuno-oncolgy research. Using the body's own defences to attack cancer cells should lead to less toxic treatments for patients, says Sabzevari. “With some of the advances that have been made, the patient can remain on the treatment for much longer periods of time with a better lifestyle.”

Sabzevari is also keen to build bridges between academia and industry to hasten the availability of possible treatments. To this end she has set up a programme at EMD-Serono which allows postdocs to spend two or three years in industry before returning to academia if they wish.

Ultimately, for Sabzevari and her colleagues, the aim is to see their findings get to the clinic as quickly as possible. “Every day we see patients, and we see families that lose people,” she says. “This is not about me, this is not about my career, this is about the patient.”