The war, the mouse, the protein and the lovers: the curious tale of the search for a common cold vaccine

 

“Would you like 10 days free holiday and travel expenses paid?”

The advertisements were enticing. They turned up regularly across England for decades. Posters. Newspaper ads. Leaflets. They offered time away in the countryside near Salisbury. Fresh air. Relaxation. Free meals. Not only that, you would be paid for your time. Sound lovely?

Married couples were welcome.  Singles were invited, too.  There was even the prospect of romance, provided that those interested in courting remain at least thirty feet apart at all times.  It wasn’t that the organisers were prudish, they just cared deeply about sneeze range.

Therein lay the catch, after all there’s no such thing as a free lunch, and certainly not ten free lunches in a row.  Every holiday maker had a one in three chance of catching a respiratory infection. The organisers would make sure of it. And still people came by the thousands. Their vacation, they were told, would help cure the common cold.

Video: British Pathé

By the end of World War II, while a number of advances were being made in other human viruses such as influenza and polio, still very little was known about the cold. There was strong evidence that it was viral, but that was it.

“In our artless 1946 way we talked about ‘the common cold virus’. We always knew there might be several of them,” explained Sir Christopher Andrewes in 1966.

But no one had isolated this elusive virus yet.  Thus the free holiday.  Andrewes and his colleagues at the Medical Research Council in the UK set up the Common Cold Unit in the countryside near Salisbury. One third of the volunteers were infected with a cold. The others were given a placebo.  The volunteers were monitored closely, every used tissue was examined and analysed. And then in 1953, some 2500 vacationers later, they discovered the rhinovirus. It was indeed a breakthrough, but it soon became clear that the original prediction of ‘several’ cold viruses was a vast underestimate. By 1967, 55 different rhinovirus ‘serotypes’ had been identified.  The numbers kept growing. A few other viruses were found to be culprits as well, but rhinoviruses made up the bulk. By the eighties there were more than 100 of them. The hope for a single, broadly protective vaccine began to fade.

At last count, more than 200 viruses cause the common cold, and the chief culprits remain the rhinoviruses. It’s now thought that there are at least 160 different serotypes.

B0006938 Common cold virus

Rhinovirus   photo credit:  Anna Tanczos, Wellcome Images CC BY-NC-ND 4.0

Rhinoviruses are so pervasive because their viral surfaces vary widely. The proteins that decorate the outside of the viral shell are inconsistent enough that the antibodies your immune system makes to identify and destroy one serotype simply won’t recognise the next one.  Immunologists call this a lack of cross-protective immunity.

The average adult will get 2-5 of these infections a year. Young children, those gorgeous little snot-machines, get even more — sometimes up to ten a year.  When you do the math, you can start to see why we get colds our whole lives.  But it’s not entirely random. Of the three major categories these viruses fall into — A, B, and C —  you’re most likely to end up with an A or a C ( A (47%); B (%12); C (39%)).

In addition to evading immune memory, the different surface proteins can tell us something about the history of the virus. Recently a group of scientists in Japan looked at the differences between the surface proteins on the C group of rhinoviruses, and used them to measure how much time has passed as the virus evolved.  The strains they analysed could be dated back to between 400 and 900 years.  For example, take the case of the surface protein called VP2.  When they looked across all the different rhinovirus serotypes in this group, there was quite a lot of diversity in the gene that makes this protein. They discovered that all the different versions of this gene had a common ancestor sometime around the year 1125.  So sometimes your sneezes can be a little bit medieval.

For most people, rhinoviruses are a nuisance, but for some the common cold can have serious consequences.  Rhinoviruses can cause acute exacerbations of conditions such as asthma, cystic fibrosis and COPD (chronic obstructive pulmonary disease), so there’s a very real need for a vaccine. Moreover, the economic cost of the common cold has been estimated at an eye-watering $40 billion a year in the US alone in terms of lost work and medical expenses.  Even back in World War II, the the common cold had become notorious for its negative impact on the war effort, prompting wary governments to fund post-war programs such as the Common Cold Unit.

The_Cost_Of_The_Common_Cold_&_Influenzaphoto credit: U.S. National Library of Medicine : History of Medicine via Wikipedia

Next year will mark 70 years since the first volunteers arrived in Salisbury for their viral holiday, so whatever happened to the common cold vaccine?  As it turns out, all those different serotypes weren’t the only problem. Moreover, they might not be as big a barrier as once thought.

Much of the time in the 40s and 50s was spent identifying cold viruses, so it wasn’t until the 60s that vaccine development began in earnest. Researchers were concerned about the increasing number of serotypes, but they had to start somewhere, so early clinical trials began by using a killed version of just one serotype of rhinovirus. The result was underwhelming. They then tried multiple different serotypes at once; still, not much luck.  The vaccines just didn’t trigger much of an immune response at all. It’s now thought that this was due in part to an unfortunate catch-22. The techniques used to kill a rhinovirus (so it could be used without causing an infection) were probably damaging many of the protein signatures on the viral surface, the very ones needed for an immune response.  It seems that the approach they used to make the rhinovirus vaccine harmless also made it useless.

There was also another technical issue that hampered vaccine development for decades: the majority of human rhinoviruses have an profoundly narrow host range. They are very specific for humans and a small number of other primates, but that’s it. This posed a problem for researchers who wanted to study cold viruses in smaller animals.  Such work was aiding progress in other diseases [polio (mice), influenza (ferrets, mice)]. Yet hamsters and mice all seem to impervious to infection with cold viruses. The researchers also looked at cats, vervet monkeys, weeper monkeys, hedgehogs, and for good measure, flying squirrels. Nothing.

Why do human rhinoviruses love humans best of all? It has to do with the cells lining your respiratory tract. In order to infect, a rhinovirus must first latch onto a protein called ICAM-1 that sits on the surface of those cells. Mice have ICAM-1, too, but there are enough small differences that human rhinoviruses tend to ignore them. It’s like trying to unlock a different house with the same key. Of course, ICAM-1 was never meant to be a viral access point, even in humans. It’s actually there to help the respiratory tract cells interact with the immune system. But evolution being evolution, human rhinoviruses found a way to use ICAM-1 to their advantage.

A number of researchers are now investigating ways to target ICAM-1 directly and block this viral entry, but it’s a fine line to walk. You want to prevent rhinovirus from latching on yet still allow those normal interactions with the immune system to take place. If you covered your door locks with steel plates, thieves wouldn’t be able to pick the locks, but then you couldn’t use them either.

Over in the vaccine development camp, things were moving slowly.  It wasn’t until the mid-1980s that they began making progress into the study of human rhinoviruses in mice. And it was really only a few years ago in 2008 that an effective mouse model was established.  These mice have ICAM-1 molecules that human rhinoviruses recognise.

And then just last year, another discovery was made. It seems that one animal had been overlooked all this time: the cotton rat. It catches human rhinoviruses and, importantly, its immune system then remembers the infection which means it can be immunized.  When female cotton rats were immunized for one serotype of human rhinovirus, not only were they protected against that particular virus, but their newborns were as well.

Curiously, the cotton rat is not new to the study of human viruses.  It’s known to be susceptible to a variety of them, including influenza, respiratory syncytial virus (RSV), measles and even polio.  But no one knew they also caught our colds.

 

鼻炎 子供 アレルギー

Sigmodon_hispidus1A cotton rat can catch a human rhinovirus  

photo credit: (top)  © NOBU / Dollar Photo Club; (bottom) CDC/ James Gathany via Wikimedia

“What had appeared to be a single disease capable of a single solution turns out to be something of unimagined complexity for which there is no straightforward answer”

~ David Tyrrell and Michael Fielder. Cold Wars: The Fight Against The Common Cold.

And so, this leaves us with the serotype problem. New research suggests that there may be a way around it and that a broadly protective vaccine may yet be possible.

As mentioned earlier, there’s quite a lot of difference between the individual surface proteins on each rhinovirus serotype. But it seems this isn’t actually the case for all of the surface proteins. In fact, the smallest of them, a protein called VP4, is quite similar across the board. In 2009, a group of US researchers made antibodies that target this particular protein on one serotype. They then found that the antibodies were also able to latch onto and neutralise other rhinovirus serotypes as well. The work suggested that VP4 may be the key to a vaccine, or at least part of it.

Then in 2014, another advance was made. It has to do with the fact that rhinoviruses, like all RNA viruses, travel light. They bring little in the way of biological luggage, opting instead to carry a small amount of genetic material. The virus invades the cell and then commandeers the cell’s normal mechanisms to help it make new viruses.  As part of this process, the genetic material (RNA) of the rhinovirus provides the instructions to make all the structural proteins it needs to make the viral shell.  Instead of these proteins being made one at a time, in the interest of efficiency, one giant protein is made which is then snipped up into individual proteins. This happens in every single serotype.

When a team of researchers in the UK and France examined how these proteins line up back to back in that big precursor protein, they noticed something interesting. Short regions of this big protein are highly similar in almost all of the viruses they examined. Importantly, some of these highly conserved regions are exposed on the viral surface, which means they should be visible to immune cells. One of them included not just VP4, but part of another protein as well — this gave the researchers more to work with than just VP4 alone. It suggested that maybe, just maybe, this snippet of that big protein might work as a vaccine against a wide range of rhinoviruses. So they tried it. They took this region of the protein from one serotype and tested whether it would protect against a different serotype.

It did.

The immunized mice did not get sick, they had no signs of illness at all.  There was a clear immune response taking place. The immunized mice produced antibodies to the rhinovirus infection much faster than normal, and they also cleared the virus from their system more rapidly.  In vaccinated mice, there was no longer any trace of rhinovirus 4 days after infection. In unvaccinated mice, the virus was still hanging around after 6 days. The findings were published in Plos Pathogens in September, 2014.

So far only a handful of serotypes have been tested and more work is needed to determine whether there is hope of developing a vaccine effective against the many other serotypes in circulation. Nevertheless, it’s a promising proof of concept.

The Common Cold Unit ran for decades. Thousands holiday volunteers came and went. Some sneezed. Some relaxed. There were flirtations. There are stories of serenades (performed safely out of sneeze range).  There were even a few honeymoons, with the experiments arranged so that the newlyweds could be together. Never let it be said that virologists are not romantics.

Then, in 1990, the Common Cold Unit closed. They had never found a cure, and a broadly protective vaccine seemed impossible. But it’s now clear that the story is far from over, and we can safely say that they laid the important groundwork for the progress being made today… and that’s nothing to sneeze at.

 

P34047

Image Credit:  Volunteers for the Common Cold Unit in 1946, courtesy Wiltshire Council

 

 

 

Sources:

Many thanks in particular to Gary McLean’s article ‘Developing a Vaccine for Human Rhinoviruses’. If you’re interested in reading more, visit McLean GR (2015) J Vaccines Immun Oct 1; 2(3): 15-20.

Andrewes C, et al (1953) Lancet Sep 12;265(6785):546-7.

Andrewes C (1966) Proc R Soc Med. Jul; 59(7): 635–637.

Kuroda M, et al (2015) Scientific Reports; 5: 8185.

Traub S, et al. (2013) PLoS Pathog 9(8): e1003520. doi: 10.1371/journal.ppat.1003520

Bartlett NW, et al (2008) Nature Medicine Feb; 14 (2): 199 – 204.

Blanco, JCG et al (2014) Trials in Vaccinology, 3: 52 – 60.

Katpally U, et al. (2009) Journal of Virology, Jul; 83(14): 7040–7048.

Glanville N, et al. (2013)  PLoS Pathog 9(9): e1003669. doi: 10.1371/journal.ppat.1003669

 

For more on the romantic side of the Common Cold Unit, visit Elena Carter’s blog “Love in a Cold Climate” at the Wellcome Library blog:  http://blog.wellcomelibrary.org/2015/02/love-in-a-cold-climate/

And for more on the history of the Common Cold Unit and its founders, see her other blog post here: http://blog.wellcomelibrary.org/2013/09/fighting-the-cold-war-david-tyrrell-and-the-common-cold/

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1901004/

 

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