Norovirus: The perfect human pathogen

ORIGINAL: New Scientist

by Dan Jones

25 March 2013 

Magazine issue 2909

Norovirus. Source: Chemex UK

The audacious norovirus has a range of amazing abilites that allow it to spread like wildfire.Yet its inner workings still elude us

IT HAS almost certainly happened to you. You suddenly start feeling very ill and rush to the bathroom. Soon you don't know which way to turn as you alternate between projectile vomiting and diarrhoea. And if that were not enough, your head throbs, your muscles ache and your stomach hurts.

We tend not to take norovirus too seriously because the misery doesn't last long. The vast majority of people recover after a day or two. But outbreaks can affect so many people at once – particularly in confined environments like childcare centres, barracks, hospitals and cruise ships – that they cause a lot of disruption. It is common for wards to have to be closed and even schools shut.

What's more, a huge number of people fall sick each year. Norovirus hit the headlines in the UK this winter when a million people caught it in just a couple of months. Yet such numbers are not unusual. In the US, norovirus infects 20 million people a year, at an estimated annual cost of $8 billion in lost productivity and healthcare bills.

For the very young and very old, or people with weakened immune systems, the disease can cause more than misery. It hospitalises 70,000 people each year in the US and kills about 800. At least 200,000 people die of it in poorer countries, mostly children under 5.

Yet there are no treatments or vaccines for norovirus. So do we just have to put up with this nauseating infection, or is there something we can do?

There are reasons why norovirus runs rampant; it is a pretty amazing virus. It may be the perfect human pathogen, says Aaron Hall, an epidemiologist at the Centers for Disease Control and Prevention in Atlanta, Georgia. For starters, it is highly infectious. Exposure to as few as 18 virus particles can lead to infection, compared with upwards of 1000 for flu (Journal of Medical Virology, vol 80, p 1468). Infected people produce billions of viruses, which are shed in vomit and faeces.

As a result, even with strict hygiene it is difficult to stop the virus spreading. It can strike at any time, but outbreaks are most common in the winter months as people spend more time with each other in enclosed spaces. Most infections are thought to be from person to person, either as a result of direct contact or by touching contaminated surfaces. Such contamination is hard to get rid of as the virus is very tough: it can withstand many chemical detergents, heat up to 60 °C, freezing, and it survives on surfaces like doorknobs and tablecloths for as long as two weeks. In pooled groundwater, it may survive for months or even years.

Another major source of infection is food. A single sick food-handler at a restaurant or factory can infect hundreds of people, while shellfish such as mussels become infectious if grown in waters contaminated with sewage. The danger is greatest with uncooked foods, such as salads and oysters.

The virus can even spread aerially: when vomit splashes on a hard surface, billions of viruses fly into the surrounding air and can be inhaled or swallowed. In theory, one batch of vomit could contain enough viruses to infect 3 million people.

A 2009 study of an outbreak at a scouting jamboree in the Netherlands estimated that each person who fell sick infected 14 others on average. If this is typical, it would make norovirus one of the most contagious diseases on the planet.

Another extraordinary thing about norovirus infections is that people vary immensely in their susceptibility. With most viruses, such as measles or chickenpox, people develop lifelong immunity after catching the disease or being vaccinated. Some viruses, like colds and flus, mutate so fast that people can catch the diseases again every few years despite still being immune to the older strains.

Yet about a fifth of people almost never get infected by noroviruses. They are thought to get into our cells by binding to carbohydrates called histo-blood group antigens. These coat the surface of mucosal cells, such as those lining our airways and intestines. Different strains target different HBGAs, but a particular sugar group seems to be important. People without a working copy of the FUT2 gene do not produce this sugar, and a 2003 study led by Ralph Baric, a virologist at the University of North Carolina at Chapel Hill, showed that they are not infected by common norovirus strains even if exposed to high doses (Nature Medicine, vol 9, p 548). Later work has shown that these people are vulnerable to a few strains, however.

Another tenth of the population lack this genetic protection but can usually fight off the virus before it takes hold, says Baric. "These people have most likely developed long-term immune protection after a previous infection." In other words, they respond in the way you would expect. But even then, having long-term protection against one strain of norovirus does not necessarily protect against other strains, and there are plenty of them.

So far about 40 strains have been identified. The viruses that infect humans usually belong to one of two main groups, called genogroups GI and GII. Within each genogroup there are lots of variants, or genotypes, designated GI.1, GI.2 and so on.

Not only are there lots of different strains, in the majority of people the immunity gained by fighting off an infection does not seem to last long. Small studies in which people were deliberately exposed to the virus suggest that most people can be reinfected by the same strain after as little as six months. Why this is so remains a mystery.

Immune hijacker

Amazingly, we do not even know exactly which gut cells the virus infects. Studies of tissue taken from the intestines of infected people have failed to reveal its presence, and so far all attempts to infect human cells growing in culture have failed. This makes studying norovirus extremely difficult because it cannot be grown in the lab.

In fact, much of what we think we know actually comes from studying related viruses. In 2004, researchers managed to grow a mouse strain of norovirus in cells in culture. They found that it infected two kinds of immune cells, including dendritic cells. Found in the lining of the gut, these cells usually act as immune sentinels, alerting the rest of the immune system to whatever's in the gut. But norovirus seem to be able to hijack them.

Another thing that is not clear is whether norovirus is becoming more common. Some researchers think it might be, due to factors such as our rising consumption of prepared foods and an increase in norovirus breeding grounds in the form of care homes and cruise ships. But we do not have any reliable long-term records. Most people who fall ill never go to the doctor, let alone have any samples taken for testing, so researchers can only guess at the true number of cases. A study out last year found that even in hospitals, half of all cases may go undiagnosed, because not everyone has the full set of symptoms.

It does seem likely that there was a sudden jump in norovirus outbreaks in the 1990s, because this is when pandemic variants of the GII.4 strain emerged. This strain had been around since at least 1967, but in 1996 a variant emerged that rapidly spread around the world infecting unprecedented numbers of people. This soon became a pattern: it happened again in 2002, 2004, 2006, 2009 and 2012.

Studies led by Peter White at the University of New South Wales in Sydney, Australia, suggest that GII.4 has become the dominant form of the virus because it evolves more rapidly than other strains. Like all RNA viruses, noroviruses mutate fast, but GII.4 viruses have an especially high mutation rate because the enzyme that copies their RNA is particularly error-prone. "It makes about one mistake every time the genome is copied," says White (PLoS Pathogens, vol 6, p e1000831).

Unsurprisingly, the protruding parts of the virus – those our immune system learns to recognise – are evolving fastest. It appears that every few years, a new GII.4 emerges that is different enough to previous strains to evade what immunity still remains in the population, and this strain can then rampage around the world. So in some ways norovirus has become like flu, with new strains emerging regularly and sweeping across the world.

Yet there are key differences, too. One seems to be that while old flu strainstend to disappear, old strains of norovirus keep circulating at low levels. "From outbreak surveillance, we have seen that the seasonal winter peak really is mostly explained by outbreaks of the most common genotype, GII.4," says Marion Koopmans of the National Institute of Public Health in the Netherlands. "But if you take those outbreaks away, a much greater diversity of strains is seen."

The latest pandemic virus to emerge, called GII.4 Sydney, was first detected in Australia in March 2012. It has gone on to become the dominant pandemic strain of the 2012/13 norovirus season, making headlines around the world. White's work suggests it formed when two GII.4 strains that had been circulating for a few years swapped parts of their genomes. "Someone got infected with those two viruses, which recombined to create GII.4 Sydney," he says.

In the UK last year, the seasonal uptick in norovirus cases typically seen in November began a month earlier. "We began seeing Sydney 2012 early in this year's outbreaks, and as the season has gone on more and more cases are attributable to this variant, although other GII.4 strains are also circulating," says David Allen, a virologist at the UK's Health Protection Agency (HPA). By mid-December, it was estimated that there had been more than a million cases.

By January, the virus was running wild in the US and Canada, too. Back in the UK, though, the number of cases was falling much earlier than usual (see graph). If this continues, the 2012/2013 norovirus season could yet prove unexceptional, in the UK at least, despite the alarming early numbers. But it could also go the other way. "One thing that we've learned is that norovirus is unpredictable," says John Harris, an epidemiologist at the HPA. "We could easily see peaks in March and April."

The capacity of norovirus to continually reinvent itself means that we will be living with pandemics for some time to come – unless, of course, a vaccine becomes available. Two are already in the works. One is being developed by Ligocyte Pharmaceuticals in Bozeman, Montana. It consists of the main proteins that makes up the outer shell of the virus, which self-assemble into empty shells called virus-like particles that looks like the real deal to the immune system but cannot replicate themselves.

Vaccine hope

For its initial version, Ligocyte used GI shell proteins. The vaccine was sprayed into the noses of volunteers, who were later exposed to the GI.1 virus. Only 37 per cent developed gastroenteritis, compared with 69 per cent of those given a placebo (NEJM, vol 365, p 2178).

"Although these results were promising, it left a lot of room for improvement," says Robert Atmar, an immunologist at Baylor College of Medicine in Houston, Texas, who led the trials. Ligocyte is now working on an injected version – which should boost effectiveness but will deter some people – with both GI and GII proteins.

The other vaccine, being developed by Charles Arntzen and colleagues at Arizona State University in Tempe, also combines GI and GII proteins, but these proteins are produced in plants. The plan is to create a dry powder for nasal delivery. "We're using a formulation that can be stored at room temperature for many months, which could make it easy to use in the developing world," Arntzen says.

An early version of the vaccine showed promise in a clinical trial. Arntzen is now working with NanoTherapeutics of Alachua, Florida, and Kentucky BioProcessing in Owensboro to develop a new formulation, as yet only tested in animals, that he hopes will offer improved protection.

It remains to be seen whether either effort will lead to a commercially viable vaccine. Even if a vaccine can be produced that provides strong protection against the strains included in it, it's far from clear how long the protection will last and whether it will work against different strains. New versions would have to be produced every few years to ensure it remains effective against the latest GII.4 strains, says Atmar.

Then again, a vaccine does not have to be 100 per cent effective. In theory at least, even a partially effective one could reduce the severity of people's symptoms, slow the virus's spread and reduce the overall number of cases. But at around £30 per dose, will individuals and healthcare providers regard it as a worthwhile investment?

It will be a few years before we find out. In the meantime, make like Lady Macbeth if you want to dodge this disgusting disease.

How to dodge noro

What can be done to avoid two days hunched over, or sat on, a toilet? The first and most obvious thing, says John Harris of the UK's Health Protection Agency, is to keep your hands clean by washing with old-fashioned soap and running water. The evaporating alcohol gels found in hospital dispensers do a good job of killing bacteria, but they are not as effective against norovirus. After the gel has evaporated, many live viruses will be still left on your hands, he says.

If you do come down with norovirus, stay at home for three days after your symptoms have subsided, especially if you handle food or work in healthcare. Don't try to please your boss by rushing back to the office as soon as you go a day without vomiting or diarrhoea: you will still be shedding billions of virus particles, and are likely to infect legions of colleagues, friends and commuters. They will not thank you.

Dan Jones is a freelance writer based in Brighton, UK