Special Report - Emerging Viruses

One move ahead?

Chikungunya virus Chikungunya virus
©Institut Pasteur
Dengue virus Dengue virus
©Institut Pasteur
Checking poultry samples for avian flu viruses at the Disease Investigation Centre in Jakarta (Indonesia). © M.Depardieu Checking poultry samples for avian flu viruses at the Disease Investigation Centre in Jakarta (Indonesia). © M.Depardieu

SARS, avian flu, chikungunya – these and other new viruses present a real threat in the absence of effective drugs to treat them. Vizier, the wideranging European genome project, is gathering data for designing new antiviral drugs – ready for when these new viruses strike again.

It is summer 2015. Two cases of atypical haemorrhagic fever are reported simultaneously in Sardinia and Provence. Before public health authorities wake up to the risk of an epidemic, hospitals across Southern Europe are inundated with patients with the same symptoms. Mortality soars, especially among the elderly. Faced with a new disease they can’t even name, doctors are at a loss. The only certainty is that it’s viral. No drug works. Panic reigns. With people afraid to leave their homes, economic activity grinds to a halt. In autumn, the epidemic vanishes, leaving thousands of dead in its wake.

This is not science-fiction. It is a scenario extrapolated from real-life facts. All experts agree that, with global warming, Southern Europe is at risk from epidemics previously limited to the tropics. The Aedes albopticus and Aedes aegypti mosquitoes, vectors of the chikungunya and dengue viruses, have already been spotted in several Mediterranean regions. The WHO warns that Rift Valley fever, which affects both cattle and humans, was reported for the first time outside Africa in 2000 and could hit Europe. Health authorities’ lack of preparedness for our catastrophe scenario is not a figment of the imagination. In 1998, faced with three encephalopathy cases in the New York region, the CDC in Atlanta (Centers for Disease Control and Prevention) took too long to arrive at the right diagnosis. The culprit, the West-Nile virus (named after the Ugandan district where the virus was first isolated in 1937) simply was not included in the battery of tests conducted by its diagnostic laboratories, considered among the best in the world.

An anticipatory strategy

“Confronted with the threat of such a catastrophe, the solution – as in chess – is always to be one move ahead,” says Vizier (1) pro gramme coordinator Bruno Canard from the AFMP, a structural biology laboratory in Marseille (FR) belonging to the French National Centre for Scientific Research (CNRS). One move ahead? To be prepared for such epidemics, we must set to work right away on gathering the background knowledge we need in order to be able to develop new drugs very fast once the need arises.

To counter the threat of avian flu, stocks of Tamiflu ® have been built across Europe. Moreover, the mechanisms of the viral cycle which the drug is supposed to disrupt were outlined some fifteen years ago. It would be disastrous to have to wait so long with an epidemic on the doorstep.

Vizier, a consortium of 23 European laboratories, is determined to be one move ahead. This project, unprecedented in its size, has set out to sequence the genomes of hundreds of viruses, define the proteins essential to their replication, and identify the crucial sites on these proteins that can be blocked by drug action. In short, to have a whole range of pre-drugs adapted to each viral family, from which scientists can rapidly develop antivirals the day the virus strikes.

The project’s size stems from the fact that antiviral research, like research into antibiotics in general, was somewhat neglected by the pharmaceuticals industry in the eighties and nineties. Only the AIDS virus and, to a lesser extent, hepatitis were intensively researched. It was widely believed that the fight against infectious diseases had been won with advances in vaccination and hygiene. Such optimism proved premature in an era of globalisation, in which pathogens participate. Viruses evolve, mutate, recombine or adapt to new hosts. Their vectors, often insects, invade new territories. “The 2003 SARS (severe acute respiratory syndrome) crisis led to the birth of Vizier,” explains Bruno Canard. “This event brought into the open what scientists had long been fearing – the possibility of a virus from a family thought to be harmless to human beings having an unknown neighbour which suddenly appears and becomes a formidable pathogen. SARS is not a mutant but a completely new virus.”

Epidemics’ mysteries

The reason for this relative neglect of antiviral research which Vizier intends to remedy is not only due to pharmaceutical companies’ unwillingness to engage in unpredictable and often financially unattractive markets. Real scientific obstacles have to be overcome, beginning with simple disease identification. Rémi Charrel from the UVE virology laboratory in Marseille (FR), one of Vizier’s partners, has investigated different haemorrhagic fever epidemics that have hit mainly tropical countries in the last few years. “In 79 % of all cases we don’t know when the epidemic started,” he says. “In 38 %, the travel patterns of infected persons remain unrecorded, preventing any tracing of its progress. And in 27 % we have no clinical data on the disease.”

Put plainly, the information available is very patchy. At the other end of the chain, from a disease’s epidemiological identification to the invention of a drug to treat it, there are other difficulties to be overcome. Viral infections are often swift, violent and short – an Ebola patient can be dead within a week. In such conditions, what time do you have to organise a clinical trial?

The problem is not restricted to countries from the southern hemisphere with their often frail public health systems. Pilar Najarro from the British company Arrow Therapeutics knows this from working on a promising compound to combat the respiratory syncytial virus that causes the infant bronchiolitis epidemics that fill up the paediatric wards of European hospitals each winter. “It was very difficult to be ready to organise tests at the drop of a hat, as we never knew when the epidemic would hit.”

Imagining tomorrow’s viruses

The final obstacle in antiviral research is knowing how to invent drugs today for viruses not yet in existence. “Applied virology has a history of the unexpected,” says Ernie Gould from the Centre for Ecology and Hydrology in Oxford, another Vizier partner. To overcome this obstacle, researchers sieved through his team’s virus collections and selected 300 viruses representing different known families and particularly feared pathologies. The project has opted to focus initially on RNA viruses (whose genetic material is made up of ribonucleic acid (RNA) and not the DNA typical of all living beings), which are the cause of most emerging diseases. These are also often the most formidable pathogens known to man and working with them requires formidable safety measures. Laboratories must have P4(2) certification to carry out any such work. Vizier’s scientists use bioinformatics to sequence and compare their genomes to identify the proteins that are vital to viral replication. The three-dimensional molecular structures of these proteins are then studied in one of the nine European crystallography centres taking part in the project to try and identify the sites that play a key role in their activity. Finally, these data are analysed by drug design specialists like Erik De Clercq’s team from the Katholieke Universiteit Leuven (BE), to whose team we owe some of the biggest advances in HIV drugs. Their task is to validate the relevance of these target sites and to define families of chemical compounds which can hit these surfaces and disrupt viral replication. It is like throwing sand into the virus’s finely tuned molecular machine.

The European Union has provided €13 million of funding to the project. After two years, how far has it got? At Vizier’s first industrial and scientific conference held on 27 April in Marseille, the project’s partners reported just how far they had progressed. 180 genomes have been sequenced, almost 250 proteins vital for their replication have been purified and analysed and four new protein structures are being defined each month, several months ahead of schedule.

“What makes Vizier unique is the integration of different disciplines into a common project culture. Epidemiology, molecular genomics, virology and crystallography hardly spoke with each other before the project started,” says Bruno Canard. “It is no accident that such a project was born in Europe, in a framework of mutual cooperation and for the benefit of everyone. In the USA the fierce competition between laboratories has long blocked the launch of such cooperation, which started there only in 2006. Here too, we are one move ahead.”

Mikhaïl Stein

  1. Comparative structural genomics on VIral enZymes nvolvEd in Replication.
  2. Class 4 pathogen (P4) severe hazard laboratories are permitted to store highly pathogenic microorganisms. Designed to be totally hermetic (decontamination areas, airtight doors), they provide maximum protection to those working in them.

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Diversified commercial exploitation

Even if there are only two private companies among the 23 Vizier partners – BioXtal from Strasbourg (France) and British Global Phasing from Cambridge (UK), the question of industrial exploitation of the antiviral research results is taken very seriously by the project leaders. An industrial evaluation unit has been set up to coordinate management of the intellectual property rights to the consortium’s work, on behalf of all participating academic laboratories. Diagnostic tests, potential drug targets and families of potential antiviral compounds are methodically patented, even if this means postponing the publication of results in scientific journals. “We have chosen not to link up with any one big pharma company,” explains evaluation unit head Jean-Louis Romette, “but to choose case by case the best industrial partner for producing the drug created from our research.”

Two agreements have already been signed. Sanofi Aventis will test a promising drug against the chikungunya epidemic at present raging in the Indian Ocean. Novartis’s Institute for Tropical Diseases in Singapore is organising trials of a new antiviral against dengue (see p. 12). Finally Vizier is working closely with the International Consortium on Antivirals (ICAV), a non-profit organisation created in 2004, which networks academic and private players in antiviral research. “We are working downstream of Vizier,” explains ICAV’s Canadian president, Jeremy Carver. ”By pooling our resources and skills, we are aiming to bring new drugs to the market within three to four years from now at 75% below current market prices, targeting influenza, AIDS, dengue, hepatitis and haemorrhagic fevers like Ebola.”



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