Saturday, 13 September 2014

The wind beneath my Ebola virus.... [UPDATED]

Only a couple of weeks ago the report in Science presented 99 genomes representing some of the thousands of those circulating in Sierra Leone this year.[1] I say thousands because each infected person has a range of subtley different viral variants among the billions of viruses per millilitre of blood that all compete to be the champion. The words "mutant" and "ebolavirus" are now hard to avoid. And of course as soon as you talk mutations, you can only see one endgame - a virus that is easily transmissible and turns us all into zombies. spreads across the world in a pandemic and kills as many as 80% of those it infects. Yes, its seems the proportion of fatal cases (PFC) in West Africa may not be as simply calculated as most of us were thinking these past months. When we take into account that Ebola virus disease deaths occur in people that were part of a case tally days earlier (if they were counted of course) when the total case numbers were smaller, the PFC inflates. How much, we don't really know.

And so the story of mutants was brought full circle today thanks to Dr. Michael T. Osterholm. In a very nicely written piece for the New York Times,[2] Dr. Osterholm, ventured behind the scenes to crack the door into the world of whispered discussions, shadowy frappé meetings by chino and beige blazer-wearing figures, many of whom were men with with thinning hair. Yes, he found where the real virologists hang out and what were they discussing at length? Why they were talking about how soon it would be until Zaire ebolavirus was going to mutate and become an airborne killer virus identifiable only through watching big wall-mounted LCD screens as they are rendered in red because of the fusion of rapidly growing dots, spreading across a map of a world filling rapidly with infected hosts. Or red dots. Or something. Okay, some of that was from me.

Only problem is, I think he may have entered the tinfoil hat room next door to the (but very similarly attired) room full of virologists. Maybe not. Hard to tell sometimes. But seriously.

For sure, a virus changes over time. It will change randomly through mutations that happen because viruses, especially those with genes/a genome made of RNA, are always making errors in their gene/genome copying and sometimes those errors make the virus better at something. Viruses may hold on to those changes in response to all sorts of pressures on them. These genetic sequence changes sometimes results in change to the proteins that make their structures and enzymes. Sometimes the changes may revert back as pressures go away or new ones come to be. It's a constant micro-environment of change; evolution on fast forward.

We should also keep in mind ebolaviruses didn't come down in the last shower. They are viruses that are happy in their own envelopes...and natural host(s). But mutational changes can impact on how the viral "bits" assemble and release from the cell and perhaps on how the virus causes disease, where virus replicates in the body, how it interferes with the host immune system's attempts to interfere with it, how hardy it is, how well it replicates in response to temperature and so on. 

A virus doesn't "think" about any this of course. It doesn't plan to do the nastiest thing to us that we can imagine when it jumps into us from an animal (a zoonosis). Headlines might make you think otherwise. These changes happen because, in a new host species producing many subtley different viral variants all vying for supremacy, the virus with the mutation(s) that allow it to get out from under some sort of controlling pressure or to do something better than the earlier viral versions, wins the day. The winner thrives, makes more of itself or does it better, and passes to new hosts.

A virus may keep more of these mutational changes while it is "settling in" to a new animal host species if they help that process. It may be under more pressure to adapt to slightly different environments, different receptor structures, temperatures, immune responses - all sorts of things may created a different environment from the one the virus came from and so it may need to make use of more mutations in order to "find its footing". Or fail and not find a home in the new host.

There can be all sorts of new and negative pressures to try and avoid or adapt to for a virus. So ebolaviruses seem to naturally infect bats, not us, and in bats the infection does not seem to cause a whole lot of disease. Of course we don't know a whole lot about how bats spread virus among themselves. Perhaps they do it via an airborne route. The theory then goes that humans or other forest animals including chimpanzees, gorillas, porcupines and antelopes may eat the bats or bat/virus-contaminated fruit. We, and those animals, do get sick.

Another unsure thing, a sizable knowledge gap you might call it, is whether an ebolavirus would actually be under any pressure at all to keep the mutations that change its proteins, site of replication and disease course which result in it being:

  • More stable in dried droplets
  • Shed in higher concentrations from the upper respiratory tract
  • Able to trigger more coughing or sneezing.
Each and all of these major changes might be necessary to create the mythical airborne Ebola virus. The outcome? Creation and propulsion of more droplets from an infected human, that dry down and linger in the air (the airborne part) while still containing infectious ebolavirus, and enough of it to result in human infection and disease. Phew. That is an unbelievable series of huge changes, even for a "sloppy" replicating RNA virus. 

I think we all understand that a virus doesn't "know" that these changes would provide better spreading outcomes and we now know that Ebola virus already spreads very well between bats and in humans (see the West Africa outbreak numbers which have not at any time been linked to a different or unusual spread of virus compared to any earlier outbreak[11]). To date, airborne spread has never been found to happen naturally in the dissemination of Ebola virus disease in humans. That is some kind of significant considering it does not take a lot of virus to start an infection through direct contact and considering there have been non-human primate transmission chains in the forests for a long time.

Each of those changes to the virus and the host's disease might happen by a series of accumulating mutations over time. But is their pressure to keep each of them? And really to be airborne, these changes would need to co-occur and do so without any trade-offs that meant the 'new airborne virus' was negatively impacted in some other area of its attachment, cell entry, replication, interference with the immune response enzymatic efficiencies etc. 

We do already know that in the lab, under laboratory conditions, with lab animals, lab equipment, plenty of lab-grown virus and a closed space with a lot of aerosol (probably some of which is wet droplets, not just droplet nuclei, meaning not truly airborne conditions), an Ebola virus can be forced to infect non-human primates. I've written about that previously.[3] 

And yet even when it was sought, no sign of such airborne infection has been found to occur naturally among humans. Direct. Contact. 

So I think it was a stretch to expend so many words on the chances of an airborne virus emerging rather than one that causes more bleeding, or less diarrhoea, or more vomiting, or more shedding in sweat, or having lower viral loads, more rash, more hiccups etc. 

Many additional things could result from mutational changes. We know next to nothing about the mutations recorded from the 99 genomes in Sierra Leone.[1] So why all this focus on one specific yet really quite complex outcome of viral air travel instead of many/any others? I don't know. But hey, now we have indeed been able to talk about this aspect some more, so good one Dr O! 

Others have come out to comment too. 

  • Dr Anthony Fauci, director of the National Institute of Allergy and Infectious Diseases in the US noted that "it’s fundamentally unlikely"[9]
  • Dr Amesh Adalja, University Pittsburgh said "it may not be the best path for the virus to take"[10]
  • Dr Derek Gatherer of Lancaster University in the UK noted an airborne Ebola virus would need a "conjunction of coincidental, unlikely events" [10] 
  • Dr David Heymann, Chair of the Health Protection Agency in the UK stated "No one can predict what will happen with the mutation of the virus", reminding us that "The virus's epidemiology is consistent with transmission via bodily secretions and excretions, which is exactly the same as other past epidemics".[11]
  • Prof Vincent Racaniello, a virologist at the College of Physicians and Surgeons at Columbia University stated "We have been studying viruses for over 100 years, and we've never seen a human virus change the way it is transmitted."[12]
  • Story at Scientific American by Dina Fine Maron
    "Is it, for example, growing faster or at higher viral concentrations than previous strains? But the jury is still out on this and other questions"[13]

Dr Osterholm did hit some other nails flush with the timber though. West Africa needs fewer promises to defeat Ebola virus and more plans that include actual rapid mobilization and on the ground experienced leadership to make inroads into getting beds for sick people and tracing contacts. Two key items on a long list of things to do better (in my opinion).

Thankfully some promising signs are appearing. The scope of this outbreak has now been guesstimated - 20k-100k cases.[4,5,6,7] I list this range rather than extending it to much higher levels [8] because I do still have hope that things will improve and interventions will turn the exponential case growth curves away from the sky and back to the horizon, sooner rather than before entire nations are destroyed. Because that's what is coming without successful intervention.

Money is being freed up and arriving from all over and more resources are slowly moving in to the region. Resources needed just to keep the people safe who have come from all over the world, including the nations of Africa, to care for the overwhelming numbers of sick and sickening people. Not to mention the money needed to prevent more infections. More specific and insistent pleas for defined numbers of healthcare professionals are also being broadcast. Drugs and vaccines are closer than they have ever been to use in humans. They may be our only hope to stop this virus.

If the many thousands of people predicted to die from a virus that is killing 4 in 5 confirmed cases (see the Medicins Sans Frontieres tweet below) is not enough reason for stopping the spread of Ebola virus, then stopping this particular evolving variant before it does change into something worse or more ingrained to the communities all over Africa and beyond, really is. 

While this Ebola virus variant may never make the changes necessary for it to go airborne, it has shown signs of relatively rapid change and that was relatively early in what looks to be a very long chain of human-to-human-to-human-to-human... transmission. Each person allowing the virus to adapt further, if that's what it needs to do.

Such a long transmission chain, from 1 animal>human infection, has never been recorded before and so we are indeed in new territory when it comes to the ebolaviruses. For now at least, the Ebola virus in 5 countries in and around West Africa has the upper hand. This tiny self-assembling unthinking, randomly mutating thing is totally dependent on our cells to replicate itself - and we are not doing enough to starve it of those cells. 

It clearly doesn't "need" to be airborne to spread efficiently.