Why can’t we cure the common cold?

It is the world’s most widespread infectious disease, responsible for 34 million sick days a year in Britain alone, and impossible to treat or prevent. But now, says Nicola Davison, scientists believe they might finally be able to vanquish the cold “We ca

The common cold has the twin distinction of being both the world’s most widespread infectious disease and one of the most elusive. The name is a problem, for starters. In almost every Indo-european language, one of the words for the disease relates to low temperature, yet experiments have shown that low temperature neither increases the likelihood of catching a cold, nor the severity of symptoms. Then there is the “common” part, which seems to imply that there is a single, indiscriminate pathogen at large. In reality, more than 200 viruses provoke cold-like illness, each one deploying its own peculiar chemical and genetic strategy to evade the body’s defences.

Adults suffer an average of between two and four colds each year, and children up to ten. “Winter remedy” sales in the UK reach £300m each year, yet most have not actually been proven to work. Taking vitamin C in regular doses does little to ward off disease. Hot toddies, medicated tissues and immune system “boosts” of echinacea or ginger are ineffective. Antibiotics do nothing for colds. Although modern science has changed the way medicine is practised in almost every field, it has so far failed to produce any radically new treatments for colds. The difficulty is that, while all colds feel much the same, the only common feature of the various viruses that cause them is that they have adapted to enter and damage the cells that line the respiratory tract. Otherwise, they belong to quite different categories of organisms, each with a distinct way of infecting our cells. Scientists today identify seven virus families that cause the majority of colds. Each has a branch of sub-viruses, known as serotypes, of which there are about 200. Rhinovirus, the smallest cold pathogen by size, is by far the most prevalent, causing up to three-quarters of colds in adults.

The first scientist to try and fail to make a rhinovirus vaccine was also the first to distinguish it from the jumble of other cold viruses. In 1953, an epidemiologist called Winston Price was working at Johns Hopkins University in Baltimore when a group of nurses in his department came down with a mild fever, a cough, sore throat and runny nose – symptoms that suggested the flu. Price took nasal washings from the nurses and grew their virus in a cell culture. What he found was too small to be influenza virus. In a 1957 paper, Price initially named it “JH virus”, after his employer. Price decided to try to develop a vaccine using a bit of dead rhinovirus. When the immune system

encounters an invading virus – even a dead or weakened virus – it sets out to expel it. One defence is the production of antibodies, small proteins that hang around in the blood system long after the virus is gone. If the virus is encountered a second time, the antibodies will swiftly recognise it and raise the alarm, giving the immune system the upper hand.

At first, Price was encouraged. In a trial that involved several hundred people, those vaccinated with JH virus had eight times fewer colds than the unvaccinated. Newspapers across the US wanted to know: had the common cold been cured? “The telephone by my bed kept ringing until 3 o’clock in the morning,” Price told The New York Times. But the celebration was shortlived. Though Price’s vaccine was effective against his particular “JH” rhinovirus strain, in subsequent experiments it did nothing. This indicated that more than one rhinovirus was out there.

By the late 1960s, dozens of rhinoviruses had been discovered. This level of variation in one species was unusual; there are just three or four influenza viruses circulating at any one time. Scientists at the University of Virginia tried combining ten different serotypes in one vaccine injection. But this, too, failed to shield participants from infection. As hope for a vaccine receded, scientists began investigating other ways to combat colds. From 1946 until it closed in 1990, most research into respiratory viruses in the UK was undertaken at the Common Cold Unit (CCU), a facility backed by the Medical Research Council that occupied a former wartime military hospital near Salisbury. In its four decades of operation, some 20,000 volunteers passed through the doors of the CCU, many to be willingly infected with cold virus in the name of scientific progress. An early experiment involved a group of volunteers being made to take a bath, then to stand dripping wet and shivering in a corridor for 30 minutes, and once they got dressed, to wear wet socks for several hours. But they did not get any more colds than a control group who had been kept cosy.

The CCU began focusing on cold treatments in the 1960s and 1970s, with research into interferons – proteins that are secreted by cells when they are attacked by a virus and act as messengers, alerting nearby cells to the invader. These cells in turn produce an antiviral protein that inhibits, or interferes with, the virus’s ability to spread, hence the name. In 1972, researchers at the CCU infected 32 volunteers with rhinovirus and then sprayed either interferon or placebo up their noses. Of the 16 given a

placebo, 13 came down with colds. But of the 16 given interferon, only three got ill. The findings made the front page of The New York Times. But, once again, the excitement was premature. A review by the CCU in the 1980s uncovered a fatal flaw: interferon only worked when it was given to the patient at the same time as the virus. In real life – that is, outside the lab – you don’t know you have caught a cold until the symptoms show up, eight to 48 hours later. In 1990, the CCU closed. It had advanced our understanding of the cold, yet it had also exposed the enormity of the task of defeating it. Sebastian Johnston is a professor of respiratory medicine at Imperial College, and an asthma specialist. As a PHD student in 1989, he was dispatched to the CCU, not long before it closed down, to study virus detection methods. For his PHD on asthma, Johnston developed a technique called polymerase chain reaction, which magnifies DNA so that viruses can be identified more precisely. To his amazement, Johnston discovered that viruses were behind 85% of asthma attacks in children; and about half of those were rhinoviruses. For a pathogen so spectacularly good at infecting our nasal passages – the “rhin” of the name is from the Greek for “nose” – rhinoviruses are astonishingly simple, being little more than strands of ribonucleic acid (RNA) surrounded by a protein shell. Under an electron microscope, they are spherical with a shaggy surface like the bobble on a knitted hat. Although all the rhinoviruses are much the same internally, a subtle alteration to the pattern of proteins on their outer shell means that, to the immune system, they all look different. It’s a cloak-and-dagger strategy.

In 2003, Johnston contacted Jeffrey Almond, a former professor of virology at Reading University who had been recently appointed as head of vaccine development at the pharmaceutical giant Sanofi. Perhaps the biggest barrier to curing the common cold is commercial. It falls to pharmaceutical companies to carry out the development of vaccines, a risky proposition. “You’re looking at ten-15 years’ work, minimum, with teams of people, and you’re going to spend $1bn (£760m) at least,” according to Almond. Successes have been rare, and there have been spectacular flops. Last year, shares in the US firm Novavax fell by 83% after its vaccine for RSV, one of the virus families responsible for colds, failed in a late-stage clinical trial. Even if a vaccine works, it can be hard to make money. Vaccines are usually administered on a single occasion, while drugs to treat illnesses can be taken for prolonged periods. And people don’t want to pay for vaccines. “Nobody wants to pay anything when they’re healthy,” said Almond. “It’s like car insurance, right? But when you’re sick, you will empty your wallet, whatever it takes.” Still, Almond thought there might be a commercial case for a rhinovirus vaccine. Last year, in the UK, coughs and colds accounted for almost a quarter of the total days lost to sickness, about 34 million. In the US, a survey carried out in 2002 calculated that the total cost of lost productivity caused by colds runs to almost $25bn (£19bn) each year. After talking to Johnston about teaming up, Almond convinced his bosses that, if it were possible to make one, a rhinovirus vaccination would be financially viable.

Almond and Johnston decided to investigate whether there was any tiny part of the structure of the rhinovirus that was identical, or “conserved”, across the entire species. They honed in on a particular protein on the virus shell that seemed to recur across many of the serotypes. They took a piece of the conserved shell from a single rhinovirus, and mixed it with an adjuvant – a stimulus that mimics the danger signals that trigger an immune response – and injected it into mice as a vaccine. The hope was that the immune system would be jolted into recognising the shell protein as an invasive pathogen, conferring immunity against the entire rhinovirus family. In petri dishes, the scientists mixed the immunised mouse blood with three other rhinovirus serotypes. The mice’s white blood cells responded vigorously against all three strains. But just as things were looking really promising, there was a change of management at Sanofi. The company decided its priorities were elsewhere and Imperial did not have the resources to develop the vaccine without outside investment. The project was shelved.

Across the Atlantic, Martin Moore, a paediatrician at Emory University in Atlanta, has spent three years working on a rival approach to the same problem. Moore, a specialist in children’s respiratory disease, first resolved to do something about the common cold in 2014, while on holiday with his family in Florida. Shortly after they had arrived, his son, then a toddler, came down with a cold. “He wanted me to hold him day and night,” Moore said. The pair hunkered down in the hotel room watching movies while the rest of the family went to the beach. “It was frustrating because, as a virologist, we can go into the lab and slice and dice these viruses. But what are we really doing about them?”

Moore reviewed the papers from the 1960s and 1970s that described the early attempts at a vaccine. Where the scientists of the past had been defeated by the sheer number of viruses, Moore saw promise. Why not simply create a vaccine made up of all the rhinoviruses? There was nothing to suggest that it would not work. The problem was not with the science, but with logistics. “I thought, the only thing stopping us is manufacturing and economics.” Moore developed a vaccine composed of 50 serotypes, reasoning that this would be enough to prove the principle. He tested it on a number of rhesus macaque monkeys. When their blood was later mixed with viruses in petri dishes, there was a strong antibody response to 49 of the 50 serotypes. “I never had a doubt that it would produce antibodies,” Moore told me. “Our paper was about showing it can be done.” There is still a long way to go before Moore’s dream becomes reality. Nevertheless, in May, his start-up, Meissa Vaccines, received a $225,000 (£170,000) grant for work on rhinovirus. He is taking leave from academia to work on the vaccines.

In August, Johnston told me that he had just received confirmation of new funding for his vaccine from Apollo Therapeutics, a start-up backed by Astrazeneca, GSK and Johnson & Johnson. This would allow his lab to test the vaccine on more strains of rhinovirus. If the vaccine were to make it through clinical trials, and was approved by regulators, it would first be rolled out to high-risk groups – those with asthma, say, and the elderly – and then to the rest of the population. In time, as the proportion of vaccinated individuals reaches a critical mass, the viruses would cease to circulate because the chain of infection will be broken – a phenomenon called herd immunity.

This scenario is still distant: about 80% of drugs that make it into clinical trials because they worked in mice do not go on to work in humans. Still, said Johnson, for the first time in decades “people are starting to believe it may be possible”.

A longer version of this article first appeared in The Guardian. © Guardian News and Media Ltd.