Ebola: Pandemic Virus Fail

I can’t help it; I find Ebola fascinating.  It pops out of nowhere.  It makes its victims bleed out of mucus membranes (is there really anything scarier than bleeding out of your mouth and eyeballs?).  It kills between 50-90% of those infected, depending on the strain.  But you know what?  If someone offered to let me go to the front lines to help collect samples during an Ebola outbreak, I’d jump at that opportunity.  Yeah, call me crazy, but to this virologist, seeing the effects of one of the scariest viruses is pretty much irresistible.  Okay, so no one is going to call me up and make such an offer, but I imagine even non-scientists have an interest (or at least a healthy fear) of Ebola, which is why I am taking the recent Ugandan Ebola outbreak as an opportunity to write another blog post.  After reading some of the comments on the cnn article (http://www.cnn.com/2012/08/02/health/uganda-ebola-virus/index.html?hpt=hp_t2), I thought it might be worthwhile to clear up some misconceptions about the actual threat of Ebola to the average person.

There are several strains of ebolavirus, and each strain has its own mortality rate.  For instance, Zaire ebolavirus kills 80-90% of those infected, while Reston ebolavirus is not pathogenic in humans (though it kills some non-human primate species).  The current Ugandan outbreak is Sudan ebolavirus, which typically kills 50-60% of those infected. Ebola is pretty cool in that most people think of virus shape as some type of geometric shape, but Ebola’s shape is essentially like a long, flexible rope.  It can be straight or twisted into various shapes as seen in this photo:

© Centre for Disease Control/AP

The thing that makes this particular outbreak interesting is that infected people don’t have the normal symptoms (like hemorrhaging) that Ebola victims typically exhibit.  As I write this, there are about 30 suspected cases, with 16 deaths, but I am pretty sure that number is going to increase based on the odd symptoms (people may think they have something less severe and not seek treatment), the fact that potentially-infected people fled the hospital (and may infect others), that infected people may not seek treatment out of fear (and thus infect those around them), and they are now reporting 5 prisoners are suspected of having the virus (close quarters, poor hygienic conditions increase the chances of transmission). Comments on popular news articles seem to suggest that many people are worried that Ebola could spread worldwide, but I am going to tell you why that is highly unlikely.

Although Ebola seems pretty scary, it is actually not a very “successful” virus in humans.  If you take into consideration that the whole point for a virus is to keep replicating (virus version of reproducing) and infecting new hosts, then the most deadly ebolaviruses pretty much fail.  Sure, they cause scary disease/death in a few humans before health officials realize that Ebola is afoot, but most ebolavirus outbreaks never make it past the immediate area they began.  Why? 

First, because ebolaviruses cause disease severe enough in a short amount of time that people recognize the need to contain the infection (separate sick from non-sick, identify people who might be infected). 

Second, transmission of ebolavirus is not as efficient as many other viruses.  This is because it is passed when infected bodily fluids like blood, vomit, and diarrhea contact mucus membranes or open wounds.  (This may just be me, but I try to make it a habit of NOT coming into contact with other peoples’ blood, vomit, and fecal matter—okay, the last is kind of lie since I study norovirus—but it holds true for pretty much everyone else) Note that Ebola is NOT passed via aerosols like many highly-contagious respiratory viruses.  By the time an infected person is highly contagious, it is usually obvious that they are sick (because they are either bleeding, vomiting, or having diarrhea), so oftentimes the only people infected are those caring for the patient without proper protective clothing (gloves, eye protection, mask, etc…).

Third, it cannot survive for long outside the body (unlike my beloved norovirus), so people don’t need to worry about touching an infected doorknob or something and picking it up.  (Well, unless you are caring for someone with Ebola who just used the threw up all over the floor and you decide to clean it up.)

Fourth, oftentimes, people die too quickly to infect others. 

Fifth, outbreaks start in remote areas. While we do not yet know for sure the reservoir animal (the animal that carries the virus around in between human infections), it is likely that it is either bats or non-human primates.  People in more remote areas come into contact with these animals, while those in populated areas tend not to.

Finally, most of these remote areas do not have adequate medical care, so many of the first people to handle Ebola patients do not use proper precautions when treating them and end up infected themselves.  Once trained medical staff arrive, outbreaks are usually contained relatively quickly.

Now how does this all relate to the relative non-risk of a worldwide Ebola pandemic?  Think about pandemic viruses:  influenza, HIV, norovirus, etc…All of these viruses have characteristics that allow them to quickly spread in a human population or evade immediate detection.  Influenza is air-borne, so it is very easy to transmit. HIV has a very long incubation period before symptoms start.  This means that you can infect someone (or many people) before you even know you’re sick.  Norovirus is extremely hardy and takes less than 10 virions to make you sick.  Ebola has none of these features.  It has a short incubation period, so you know you’re sick quickly, you know you’re sick by the time you really risk getting others sick, and the virus doesn’t stick around on surfaces waiting to be picked up by an unsuspecting victim.

 But let’s just run through a scenario:  One of the patients that ran away from the Ugandan hospital had Ebola—we’ll call them “Person A”.  For argument’s sake, let’s say that Person A actually made it onto a plane going to France (they must have been well enough to make it to a populated place from their remote village and rich enough to buy a plane ticket to a foreign country).  Let’s say they threw up on the person sitting next to them on the plane (that’s a better scenario than the other possible bodily fluids I’ve been talking about)—we’ll call this person “Person B”.  You can bet this will attract attention since everyone already knows there’s an Ebola outbreak in the country Person A is leaving, and they are displaying symptoms.  You can bet that there will be government health agencies at the airport by the time the plane lands.  But let’s say no one notices (well, except one pissed off Person B).  Person B lands in France, newly infected with Ebola.  Person A also lands in France, but ends up in the hospital within days.  They figure out Person A has Ebola.  They then try to figure out every person that Person A has been in contact with over the past several days.  You can bet they will be contacting every person on the plane.  They will quickly identify Person B as highly likely to be infected.  Those in contact with person B will also be examined, of course, and from here, it will probably be relatively easy to stop the virus from going too far.  Really, though, even the chance that Person A could make it onto a plane and then infect someone on the plane is very low. 

You might make the point that someone who does not know they are infected could leave the country before symptoms start and before anyone knows about the Ebola outbreak.  This is true, but unlikely.  If this did happen, chances are that the people on the plane would not be infected since this person is still well enough to go about their normal business.  This person may infect a few people around them in the country they go to, but the disease would quickly be identified as Ebola, and it would be contained.  The bottom line is that this is a virus that has burned itself out within a matter of weeks every time it has emerged.  It is too deadly too quickly in humans to keep up the transmission cycle long-term.  Make no mistake:  Ebola is no Herpes...or HIV…or influenza…or norovirus.  In my option, Ebola is a pandemic virus FAIL, but a REALLY cool one!

Eat Sh*t and Die (or at least get sick)

Okay, I will admit that I have been dying for someone in the norovirus field to use this as their research talk title.  Since I have yet to see it used, I figured I'd go ahead and do the honors for this blog post.  Since it's what I know best, norovirus is a natural topic to start off my blog.  As a side note, I have not cited my sources in this post, but if you are unsure about anything I have written, I am happy to provide my sources.  A friend from elementary school recently posted this article to my Facebook wall: http://vitals.msnbc.msn.com/_news/2012/02/21/10470608-norovirus-vaccine-showing-promise  The article discusses a recent norovirus vaccine that has been developed by university researchers (primarily at Baylor) and the pharmaceutical company, LigoCyte.  The actual research paper describing the results came out several months ago, which makes it kind of funny that it is just now getting press.  But there have been many norovirus cruise ship outbreaks in the news lately, so people may have heightened awareness and interest in the topic.  My lab is also working toward developing a norovirus vaccine, so I have a lot of interest in this and am also aware of some of the difficulties faced in developing a good norovirus vaccine.  Here is a link to the the Pubmed entry for the paper.  Most people won't be able to view it (unless you are at a university), but if you are really interested, I will e-mail you a PDF of the paper. http://www.ncbi.nlm.nih.gov/pubmed/22150036

Before I get into the vaccine and the article, I'd like to give a brief overview of what norovirus is and why it merits research.  Norovirus is a gastrointestinal virus (virus that infects the gut) that causes vomiting and diarrhea.  In severe cases, infected people (usually infants/toddlers or the elderly) can become dehydrated and sometimes die.  While norovirus only kills about 200 people per year in the United States, there are over 200,000 deaths per year worldwide in children under five alone.  In addition, over 21 million people in the U.S. become infected with norovirus (the article says 5.5 million, but this is not the correct CDC estimate--they may be citing confirmed sequenced cases or something); worldwide infection rates are around 267 million/year.  While Salmonella and E. coli traditionally get most of the press as food poisoning culprits, norovirus actually causes more food poisoning than either of these bacteria.

Norovirus is typically passed via the "fecal-oral" route, which means that the virus is found in feces and is passed when fecal particles get on a person's hands or on surfaces that people touch and then these people touch either food or put their hands/fingers in their mouths and become infected.  Norovirus outbreaks typically occur on cruise ships and in schools, nursing homes, universities, military barracks, restaurants, and other places where people are in close proximity.  An outbreak of norovirus is hard to control because this is a very hardy virus with a very low infectious dose.  It takes less than 10 particles to become infected!  Even if you do a good job of washing your hands, 10 particles can easily be left over and seed an infection.  In addition, alcohol-based hand sanitizers (like Purell) don't work well against norovirus, and their use has actually been linked to increased outbreaks in a hospital setting.  On top of this, people who are infected "shed" virus for several days (and sometimes weeks) after they recover from the illness and therefore may be contagious long after the diarrhea and vomiting is over.

There are several reasons that development of a vaccine for norovirus is warranted.  1) Norovirus outbreaks are extremely costly in terms of productivity and economics.  Schools shut down, hospital wards shut down, military operations shut down, cruises return to port, etc...  Studies have found that a single outbreak of norovirus in a hospital setting can cost hundreds of thousands of dollars.  2) This virus infects hundreds of millions of people every year and has a fairly high worldwide death toll.  3) Because of the low infectious dose and hardiness of norovirus, it is a potential bioterrorism agent.  4) NO ONE (well, I might be the exception) likes to get norovirus.  Who wants 2 days of explosive diarrhea and vomiting?  Wouldn't you rather get a nasal vaccination?

Now, getting on to the article.  This particular vaccine is made from virus-like particles (VLPs).  Norovirus VLPs have the outside (capsid) of the virus but do not contain any of the internal genetic information, so they cannot reproduce (replicate).  There is no danger of acquiring a norovirus infection from a VLP vaccine.  The reason that the VLPs protect a person from an actual norovirus infection is that they contain the part of the virus that immune cells recognize, so the body can produce antibodies against them.  To give you an idea of what norovirus (or at least the VLP) looks like, here's an electron microscopy picture of a norovirus VLP that I made in lab. 

This study is called a human challenge study.  The basic idea is that the study participants are given a vaccine and then infected with the pathogen to see if they are protected.  The researchers had 77 participants who completed the study.  Thirty-eight of these people were given the vaccine and 39 were given a placebo (they were given a nasal treatment that did not contain any VLPs).  The study participants do not know which group they are in.  The vaccine treatment contained VLP, an adjuvant (a substance that makes the immune response stronger), chitosan (a substance that makes the vaccine stick to the inside of your nose so it doesn't get washed away before it has a chance to work), and sucrose and mannitol (to stabilize the VLPs).  The placebo treatment only contained the sucrose and mannitol.  When conducting research on any drug, researchers need a placebo group because this allows researchers to determine if there are actually any good or bad effects from the drug or whether reported side effects and benefits are just psychological.  For instance, stuffy nose was one of the reported symptoms, but this occurred equally in both the vaccine and placebo groups.  This shows that this particular symptom is probably not related to the active part of the vaccine. (This case is most likely due to the nasal delivery of the vaccine.)

The study participants were given an initial dose of the vaccine or placebo, and then given a "boost" (a second dose) three weeks later.  The timing is important because it takes the body several weeks to develop "protective immunity".  Protective immunity means that your body has produced antibodies that are capable of fighting off a future infection.  The boost is given because it makes the immune system's protective response stronger.  Three weeks after the second dose of vaccine or placebo, the study participants were infected with the same strain of norovirus they were vaccinated against to see if they would get sick.  If the vaccine works, we expect that significantly more people in the placebo group will get sick than in the vaccinated group.  The study participants were monitored for at least 4 days for gastrointestinal illness.

The results showed that the vaccine gave some protection from norovirus infection.  Sixty-nine percent of the placebo group got sick (these are the ones who were not vaccinated), while 37% of the people who were vaccinated got sick.  Overall, this shows a relative reduction in gastrointestinal illness of 47% (about 50%) in vaccinated people.  The msnbc article is a little misleading in how they present the protection.  They indicate that the vaccine is about 60% effective.  I think they got to this number because only 37% of the vaccinated group got sick (leaving 63% that did not get sick).  This isn't quite correct because not all of the placebo group became ill, so not all of the protection was due to the vaccine.  The relative reduction that they give in the paper (47%) is a more accurate representation of the actual protection because it takes this into account.

Now I'd like to tell you why I'm not as impressed with these results as the headline "Norovirus Vaccine Shows Promise" would like me to be.  I would like to applaud the authors of this study because they do a good job of pointing out the drawbacks of their findings in the published paper.  However, the drawbacks are not conveyed in the news article communication to the general public, which I think is a problem.  1) This was done with one type of norovirus, a strain we call GI.1 noroviruses (or Norwalk virus).  This group of noroviruses is relatively stable--they don't mutate as much as the other group of noroviruses that infect humans.  We might expect that a protective response would be easiest to get from this strain since it doesn't change much.  However, GI.1 noroviruses only make up around 10% of infections.  Most human infections (about 70-80%) are caused by GII.4 noroviruses, which mutate a lot more.  It might be harder to get a long-term protective immune response from a GII.4 VLP vaccine.  2) They infected the participants with the exact same strain they gave them the vaccine against.  This is common practice for an initial study like this, which is fine.  But there may be several circulating strains within a year between the GI and GII noroviruses.  A vaccine with a mix of different strains is a must.  While they do address this in the article and in the paper, the study that was done was only done with one strain.  We do not yet know how having multiple strains will affect the immune response in humans.  It will likely still be protective, but I am anxious to see some results from a multiple-strain (multivalent) vaccine in humans.  3)  This is a big one.  They did their infection with virus only three weeks after the second vaccine dose.  All we can tell from this study is that a VLP vaccine protects for up to one month.  50% protection after one month is really not that great.  What we really need to see is results from an infection done 6 months or a year after vaccination.  I know they are working on this, but it is important to understand that these results are only "promising" if protection lasts for at least a year (or a disease season).  No one is going to get re-vaccinated every few months, and a pharmaceutical company would probably not waste money backing a vaccine that has to be administered more than once per year.  I think the bottom line is that when they say "If all goes well, a norovirus vaccine could come to market in the next four to five years," it is actually very unlikely that will happen based on these results.

I've been a little negative here, but I am not saying that developing a viable VLP norovirus vaccine is impossible (and of the different norovirus vaccine options, it is the most promising so far).  There are many options they could pursue in order to improve the vaccine, which I am sure they are already doing.  They could try different adjuvants to determine if there is one that can better stimulate the immune system.  They could try producing the VLPs in a different way.  They could try to increase the vaccine dosage.  It is especially challenging because human challenge studies are expensive and take years to get permission to do.  Because we have not yet found a way to grow human norovirus in lab-cultured cells or in mice, there is a lot we do not know about it.  Designing a norovirus vaccine is a tricky task, and while we may not be there yet, I am confident we will get there.

Welcome to Decipher the Science

Hello!  Welcome to my science blog.  The purpose of this blog is to break down science that makes it into the popular media (like msnbc, cnn, fox news, etc...) so that the average person more fully understands the research being presented.  Many times people who report on science do not have any science background and do not necessarily have the skills to fully explain the research they are reporting on.  This often leads to inaccuracies and misrepresentations of the work.  In addition, there is often key information that is important to the science is left out, leaving the average person without all the relevant information they need to fully understand the ethical considerations of the work as well as the potential benefits the research offers.  When I read the comments sections of health-related science articles, I see a lot of people with misconceptions about the work and about scientists in general.  I hope that I can bridge some of these gaps and better explain popular science articles to my readers.  I am also willing to answer questions you have about the articles/topics I cover or really anything (science-related) that a reader has a question about.

My main area of interest and expertise is virology, but I am well-versed in cell biology, genetics, evolutionary biology, microbiology, and (somewhat) immunology.  I also have a working knowledge in a broad range of other biology-related topics.  To give you a little bit of background about myself: I am currently a third-year Ph.D. student at UNC in the microbiology and immunology department, and my work focuses on evolution of GII.4 noroviruses (a gastrointestinal virus that strikes pretty much everyone at some point) and vaccine design for noroviruses.  I will probably write a post on norovirus soon since this is the time of the year that it hits cruise ships.  Before graduate school, I earned a B.A. in biology from New College of Florida and an M. Ed from Endicott College.  I spent 9 years as a middle school teacher (primarily in science and math) and really enjoyed it!   Someday I hope to get back to teaching students, ideally at a small liberal arts college.

Please enjoy reading my posts, ask questions, post comments, and definitely tell me if I've made a mistake!

Kari