This is part II of “Measles Week”; see Part I for an explanation of what this is about, and an outline of what’s to come.

Measles is a fairly young disease. Just how young is it?

One of the most characteristic features of measles is its epidemic nature. For example, look at the huge difference between the peaks and valleys here:

Weekly measles cases, England and Wales, 1950-1965 (click for a larger version)

There are usually a couple of years (one to five years is typical) in between each epidemic. There are a couple of things that drive this pattern:

1. Measles is incredibly contagious. R₀ for measles — the number of new cases that can arise from a single case, in the absence of immunity — is around 15, more than ten times higher than that of the swine-origin H1N1 we recently have been seeing.
2. Measles is very immunogenic and infection confers pretty much life-long immunity.  As a corollary to this: Measles infection is short-lived. The immune system eliminates the virus fairly quickly — there’s no carrier stage.

That means that when measles has enough susceptible hosts, it can explode and spread across a country almost overnight. But it leaves behind it a firebreak of people who are immune, who are no longer potential hosts. After the epidemic, just about everyone is immune; the virus smolders at some very low level, in the handful of people who are not yet immune. After a couple of years, there are enough new births that there’s a new population of susceptible hosts who can sustain a new epidemic, and so on.

If you think about it, those two factors mean that measles virus needs a pretty good-sized population to keep going. With no carrier stage, the virus has to meet up with a susceptible host in the brief period during which it sheds. In between epidemics, there aren’t many of those. If you’re talking about family groups or tribes or villages with a few hundred people, there aren’t enough newborns to keep the virus going in the epidemic valleys.

Given the observed facts on epidemic timing, spread, and so on, you can calculate out how many people you need to keep measles from going extinct: It’s somewhere around 250,000 to 500,000 people in contact with each other.¹

In other words, measles needs cities. It’s a disease of urbanization, and it couldn’t have existed in its present form before good-sized city-states were around.

Even in our highly connected modern world, measles is still an urban disease. Epidemiologically, measles epidemics look like standing waves emanating from cities:

In the pre-vaccination era, conspicuous hierarchical waves of infection moved regionally from large cities to small towns; the introduction of measles vaccination restricted but did not eliminate this hierarchical contagion. A mechanistic stochastic model suggests a dynamical explanation for the waves-spread via infective ’sparks’ from large ‘core’ cities to smaller ’satellite’ towns.²

Gozu Tenno, a Shinto god, punishes two gods of measles and offers advise on what to eat while suffering from measles. (1862)

Populations of that size arose around 2000-3000 BC, in the Middle Eastern river valleys; so measles really can’t be older than 4000-5000 years. It’s an emerging disease that emerged some time in recorded history. (Also, it probably arose from the closely-related cattle disease rinderpeste, or some common ancestor; so again, it has to post-date domestication of cattle.)

I personally don’t read Confucian-era Chinese or medieval Arabic, but there are people who do, who say that measles may be described in various old writings. But apparently these earliest descriptions aren’t very clear, and are most likely referring to some other disease. The earliest description that is clearly of measles is around the 9th century, by the great Persian physician Abu Becr Mohammed Ibn Zacariya Ar-Razi (Rhazes) (Wikipedia link).

Rhazes’ description may well have been of a brand-new disease, because it turns out to fit pretty well with a recent analysis, ³ tracking back measles mutation rates to see when it arose, that found a likely origin of measles from Rinderpeste somewhere around 1000 AD — somewhere in the range of 500 – 1600 AD. Also:

Linguistic evidence suggests that the disease was recognized before the Germanic migrations but after the fragmentation of the Roman Empire, i.e., between 5th and 7th centuries … Epidemics identified as measles were recorded in the 11th and 12th centuries³

So, based on genomic information, written documentation, and linguistic evidence, measles isn’t an ancient disease; it’s a disease that jumped into humans some time in the first millennium A.D.

Tomorrow in Measles week: Some explanations for the drastic drop in measles deaths that are plausible, but probably not correct.

1. Bartlet MS (1957) Measles periodicity and community size. Journal of the Royal Statistical Society 120:48–70.
2. Grenfell, B., Bjørnstad, O., & Kappey, J. (2001). Travelling waves and spatial hierarchies in measles epidemics Nature, 414 (6865), 716-723 DOI: 10.1038/414716a
3. Furuse, Y., Suzuki, A., & Oshitani, H. (2010). Origin of measles virus: divergence from rinderpest virus between the 11th and 12th centuries Virology Journal, 7 (1) DOI: 10.1186/1743-422X-7-52

I’ve talked before about measles incidence and the effect of vaccination.  Now I’m going to spend this whole week talking about measles deaths, because I ended up with more than I could cover in one or two posts.  So this is Part I of a five-parter.

A group of diseases which … even now are considered to be unavoidable are scarlet fever, measles, and whooping cough. … According to the statistics collected in the census of 1900, these three diseases were responsible for upward of thirty thousand deaths in the course of a year.”

–”The Conservation of the Child”, by Earl Mayo.  in The Outlook. A Weekly Newspaper. Volume XCVII.  January-April, 1911 (pp. 893-903)

That was the situation in 1911 and in the early 20th century generally, and for centuries before that.  Almost every child caught measles, and a lot of them died.  Measles wasn’t quite as lethal as smallpox, but it wasn’t too far behind:

Measles should no longer be considered a “minor” infection. It is a major illness causing a considerable mortality and a much greater morbidity among young children affected by it. ¹

(By the way, as well as citing my direct quotes in footnotes as usual, I’ve collected the 40-odd references I read while trying to figure this story out and put them up here.)

But, starting somewhere around 1915, that began to change.  Very gradually (so gradually that it almost escaped attention) measles stopped being a fatal disease.  In 1945, William Butler said:

In three-score years or so, during which the population of England and Wales has nearly doubled, the gross annual contribution of deaths from measles has fallen to about one-twelfth of the mean figure at which during several quinquennia it stood in the eighties and nineties of the last century.  Nor is there reason to believe–on the contrary–that measles is now less prevalent than it was. It is still true that nearly everyone at one time or another has measles. ²

And the trend didn’t stop there.  In 1945, about 163 out of every 100,000 measles cases died.  In 1955, just 25 of 100,000 died, and it’s hovered around there since.

In other words, a person who caught measles in 1900 was between 40 and 150 times more likely to die than someone who caught the virus in 1955.  You can play with the numbers in various ways, but no matter what you do there has been an absolutely, spectacularly, incredible drop in measles case-fatality rates.

Below are a couple of charts to illustrate this.  The UK (number of measles deaths in England and Wales) is on the left, the US (measles deaths per 100,000 population) on the right (click for larger versions).  The dashed blue lines are the actual numbers.  Because measles is a very, very epidemic disease, the numbers change hugely every year, so I’ve applied a crude smoothing to the raw numbers (the green solid lines) to make the trends easier to see.  My US numbers only go up to 1940, but here’s a chart through the 1960s, if you like – there’s no surprises in it, it’s pretty much like the UK.

Measles deaths in the UK, 1900 – 1965	Measles deaths in the US, 1900 – 1940

Important note: In England, measles was not a notifiable disease between 1919 and 1939 (and I believe the rules for notification changed for a few years before 1919³ as well), and the effect of this is easily seen — the abrupt drop in reported deaths just before 1920, and the flatter line for a few years afterward, is almost certainly not real (I’ve boxed that non-notifiable period off in red.)  But the overall trend is still easy to see even so.

This had nothing to do with the measles vaccine, because this survival increase happened entirely before the vaccine was available in 1963.  There was essentially no change in the number of measles cases over this period (adjusted for population, of course), it’s just that once you caught measles you weren’t as likely to die.  And case-fatality rates didn’t change significantly after the vaccine was introduced.  The death rate per case in 1955 (pre-vaccine) is pretty much what we see today in first-world measles outbreaks.

The vaccine did spectacularly reduce the number of cases, of course, and therefore did reduce the total number of deaths.  Also, equally obviously, vaccines aren’t only given to prevent deaths.  Even if measles doesn’t actually kill your child, she’ll still, quite possibly, be pretty sick; there’s a pretty good chance she’ll be hospitalized; and a significant number of survivors have some form of medium- or long-term complications.

Was measles unusual? Overall mortality, and especially childhood mortality due to disease, did drop over this period, and quite dramatically so:

The infant mortality rate has shown an exponential decline during the 20th century.  … For children older than 1 year of age, the overall decline in mortality during the 20th century has been spectacular. … Between 1900 and 1998, the percentage of child deaths attributable to infectious diseases declined from 61.6% to 2%.  ⁴

Here’s the famous chart of 20th-century mortality.⁵  (Note the brief, huge spike in 1918, due to the 1918 pandemic influenza!)

Mortality rates in the US through the 20th century

So yeah, in general mortality rates did improve greatly since 1900, flattening out in the 1950s, just the same pattern as with measles deaths.  But check the scale, and compare to the UK (especially) chart above: Measles outpaced this overall improvement, and by a huge amount.  Overall, during this period childhood mortality rates improved perhaps 8-10-fold — clearly a tremendous improvement, but still, at best a quarter of the improvement in measles survival. (And measles was a late starter, too — overall mortality had been dropping for at least 15 years before measles case-fatalities started to go down.)

So what happened between 1915 or so, when measles death rates began their decades-long drop, and 1955, when the drop stopped?  That’s the subject of this entire week’s worth of posts, but to give you a peek at the answer I came up with: It beats the hell out of me. There really isn’t a single, simple explanation for this, as far as I can find.

(I’m not a historian, a medical doctor, or a measles researcher, and I’m more than happy to be corrected.  Anyone who has actual information on this, please let me know.  If you have an opinion, no offense, but I’m not interested unless you have data to back it up.)

The problem is that the usual answers are either too vague to be useful (what exactly does “quality of living” mean, medically?) or inadequate (improved nutrition is certainly important, but as far as I can see probably only improves survival maybe 5-fold, not 100-fold).  Specific advances (antibiotics, etc) undoubtedly helped, but you don’t see abrupt short-term drops in mortality, as you’d expect if any single advance was a major factor; rather, you see a constant, gradual, improvement.

I’m left with the unsatisfying conclusion  that either a conglomeration of many factors may have acted together (the most likely situation, and that’s what the real world is often like — no simple answers), or that there’s some specific factor that I haven’t found out about.  I’ll talk about specific causes later this week.

Here’s my plan for Measles Week:

1. Monday: Explanation of the question, and evidence for it being a real question. Done!
2. Tuesday: History of measles virus
   • Origins and impact
3. Wednesday: Answers that are (probably) wrong
   • Changes in surveillance or notification
   • Sanitation
   • Change in the virus
   • Antiserum treatment
4. Thursday: Answers that (might be) right
   • Nutrition
   • Vitamin A
   • Less overcrowding
   • Antibiotics and other treatments
   • Demographic changes
5. Friday: What would measles be like today, without the vaccine?
   • Mortality and complication rates in modern 1st-world epidemics

Put on your party hats, blow up a balloon, pull up a chair, and stick around.

1. Prevention of Measles in a Children’s Hospital. W. E. Crosbie. Br Med J 1938;1:1003-1004
2. The Fatality Rate of Measles: A Study of its Trend in Time William Butler Journal of the Royal Statistical Society, Vol. 108, No. 3/4 (1945), pp. 259-285
3. Butler W (1945) The Fatality Rate of Measles: A Study of its Trend in Time. Journal of the Royal Statistical Society 108:259–285.
4. Guyer B, Freedman MA, Strobino DM, Sondik EJ (2000) Annual summary of vital statistics: trends in the health of Americans during the 20th century. Pediatrics 106:1307–1317.
5. Armstrong, G. (1999). Trends in Infectious Disease Mortality in the United States During the 20th Century JAMA: The Journal of the American Medical Association, 281 (1), 61-66 DOI: 10.1001/jama.281.1.61

Investigators face a daunting black box with emerging viruses: the challenge of developing a universal therapeutic agent to combat a genetically proficient virus that quite likely has many more options for emergence than we have yet considered.

–Graham, R., & Baric, R. (2009). Recombination, Reservoirs, and the Modular Spike: Mechanisms of Coronavirus Cross-Species Transmission. Journal of Virology, 84 (7), 3134-3146 DOI: 10.1128/JVI.01394-09

By analyzing hepatitis C virus genome sequences, you can trace the virus’s history through its spread by the slave trade, and linked 19th-century health models in different countries to viral spread and transmission. Similarly, by looking at leprosy DNA, you can track its spread along the Silk Road and along slave routes.

Yellow Fever was one of the most dreaded plagues of the 18th and 19th centuries, waning only after it was understood to be mosquito-borne, so that mosquito control pushed the virus back. It’s still prevalent in Africa and in some parts of South America, though. Yellow Fever virus, too, originated in Africa and was spread to the New World through the slave trade:

The most commonly cited hypothesis of the origin of YFV in the Americas is that the virus was introduced from Africa, along with A. aegypti,¹ in the bilges of sailing vessels during the slave trade. … We estimate that the currently circulating strains of YFV arose in Africa within the last 1,500 years and emerged in the Americas following the slave trade approximately 300–400 years ago. These viruses then spread westwards across the continent and persist there to this day in the jungles of South America.²

Mosquitoes aren’t merely passive carriers of the Yellow Fever virus. The virus actively infects the mosquitoes as well as their mammalian host, entering the insect gut, replicating and multiplying in various organs until it reaches the saliva, from which it can re-infect mammals³ when the mosquito bites and injects its anticoagulant saliva.

“Latest from the front — our friends the mosquitoes preparing and off for the summer campaign” (Harper’s Weekly, 1873)

Another pattern is possible: The virus could also be spread vertically, from the mosquito to its egg, infecting the newborn mosquito before it hatches. However, although this was shown to happen as long ago as 1905,⁴ just after mosquitoes were proven to be carriers, it hasn’t been very clear if this is a significant part of the natural viral cycle or if it’s more of a lab curiosity:

Although transovarial transmission of YFV has been demonstrated, the relative importance of this in maintaining the transmission cycle is unknown. ⁵

Now, genome sequence analysis suggests that in fact transovarial spread of Yellow Fever virus may well be common and important in the viral life cycle.⁶

This was based on comparisons of Yellow Fever virus genome sequences over time, with those of a close relative, Dengue virus. Dengue and YFV probably arose about the same time, in the same area, and were both spread along the slave trade. But Dengue seems to have diversified much more than YFV:

… it is intriguing that the overall age of YFV (emergence within the last 2,500 years) is broadly similar to the time of origin of the four DEN viruses. Hence, YFV and DENV seem to have radiated at approximately the same time. However, since this time, DENV has differentiated into four antigenically distinct viruses while YFV is still classified as a single serotype.⁶

(This is actually clinically very significant, because the most severe form of Dengue disease is caused by sequential infection with two different Dengue serotypes.) In fact, in general YFV shows a much slower rate of evolution over time than Dengue — about 5-fold slower per year. The authors consider a reject a number of explanations for this — it’s not that they have different mutation rates, because their raw mutation rates are probably quite similar; it’s not that they infect different hosts, because they have very similar insect and mammalian hosts; and so on — and finally suggest that the difference may be because YFV spends a significant part of each year lying more or less dormant in mosquito eggs:

In particular, it is possible that a mechanism of vertical transmission, such as transovarial transmission where the virus may remain quiescent in mosquito eggs for many months, plays a more important role in YFV than in DENV⁶

As a result of this quiescent period, YFV would simply have fewer replication cycles per year than does Dengue, and so it appears to evolve more slowly. For this to be detectable at this level, transovarian transmission would have to be a fairly common event, not just a once-in-a-while half-accidental option.

1. A. aegypti is the mosquito that is most involved in spreading the virus
2. Bryant, J., Holmes, E., & Barrett, A. (2007). Out of Africa: A Molecular Perspective on the Introduction of Yellow Fever Virus into the Americas PLoS Pathogens, 3 (5) DOI: 10.1371/journal.ppat.0030075
3. Mainly primates, for functional transmission
4. Marchous E, Simond PL. 1905. La transmission hereditaire du virus de la fievre jaune chez la Stegomyia fasciata. C. R. Soc. Biol. 59:259
5. Barrett, A., & Higgs, S. (2007). Yellow Fever: A Disease that Has Yet to be Conquered Annual Review of Entomology, 52 (1), 209-229 DOI: 10.1146/annurev.ento.52.110405.091454
6. Sall, A., Faye, O., Diallo, M., Firth, C., Kitchen, A., & Holmes, E. (2009). Yellow Fever Virus Exhibits Slower Evolutionary Dynamics than Dengue Virus Journal of Virology, 84 (2), 765-772 DOI: 10.1128/JVI.01738-09

Vaccinia virus is a widespread virus whose natural host remains unknown.  It turns out to be pretty good at jumping across species.

Vaccinia, of course, is the vaccine against smallpox.  Even though smallpox is eliminated in the wild,¹ vaccinia is still very widely used in research and even, to some extent, in the clinic, because the broad and deep experience with the virus gained from its importance in vaccination has carried over into other fields.

When Jenner developed his vaccine against smallpox, he used the cowpox virus.  But — in spite of a widespread misconception — vaccinia is not cowpox.  They’re quite distinct viruses, though they are related.  At some point along the centuries of vaccine use cowpox was replaced by vaccinia. (It’s also worth pointing out that the disease Jenner called cowpox, may not have been cowpox as we know it today. ²  It may have been a distinct strain of virus, or it may have been a different virus altogether.)

Remember that for a couple of hundred years, there was no tissue culture to grow the virus in, and it was basically propagated by continually re-infecting animals and collecting virus from their scabs.  At some point, presumably a cow that was being used as a vaccine incubator was infected with vaccinia instead of cowpox, and the vaccinia proved more effective, or perhaps safer or more convenient, as a vaccine, crowding out the vaccine cowpox.

“Cowpox inoculation sites” Douzhen dinglun (Definitive Treatise on Pox Diseases) by Zhu Chunxia, 1888

(By the way, it’s interesting to note that cowpox has an MHC class I immune evasion function,³ whereas vaccinia virus does not.  Obviously this immune evasion doesn’t prevent cowpox from acting as a strong immunogen, because it was an effective  vaccine for decades if not centuries, but perhaps it’s one reason vaccinia was a more popular vaccine.)

Where vaccinia virus came from — what animal it was infecting before it jumped into cattle  — no one knows.  Although vaccinia must have (or have had) a natural host at one point, the true host for the virus is now cultured cells in the lab incubator.

Does that mean vaccinia isn’t found in the wild? Not at all.  Vaccinia virus does infect a bunch of animals, in many parts of the world.  But what’s happened is that the virus has gone feral: It’s jumped from vaccinated humans into other species — usually cattle — and then spread among that population.  In Brazil, this feral vaccinia virus has become a significant emerging disease in cattle, from which it jumps back again into humans:

Starting in 1999 several VACV strains were shown to be responsible for zoonotic disease affecting more than 1100 dairy cattle and up to 80% of their handlers in rural tropical rainforest and woodland savanna areas in southeast Brazil ⁴

The origin of this Brazilian bovine vaccinia is unknown.  Almost certainly it’s derived from the vaccine — the alternative explanation, that it’s derived from the original, natural host of vaccinia, seems really unlikely, especially since the disease has only been detected in the past ten to twenty years. But genetically, it doesn’t look much like any of the known vaccine strains.⁵  (However, I remember reading a paper that I can’t turn up right now, that talked about vaccinia-based vaccines in the early 20th century. It made the point that there wasn’t particularly careful oversight or recording of precise strains or provenance of smallpox vaccines, and emphasized that there were several different strains of vaccinia used in South America, not all of which were well characterized.)   Grant McFaddden’s interpretation of the feral virus’s relationships is that there were probably recombinations between different strains of the virus, which makes it hard to reconstruct the genetic history of the virus; complicated by a long period of adaptation to its new host(s):

On the other hand, the Brazilian isolates appear to have escaped in a single event or in multiple events and probably adapted to a new host, until they re-emerged in man or cattle at least 25 years later. ²

Cowpox on a cow’s udder Trattato di vaccinazione con osservazioni sul giavardo e vajuolo pecorino by Luigi Sacco, 1809

There’s another puzzling aspect to the Brazilian vaccinia epidemics: How are they spreading? Although most of the epidemics can be traced back to infected humans, there are some exceptions:

… some VACV outbreaks are temporally and spatially distant from previously notified BV areas. … Rats, mice, opossums, foxes, wild dogs and small felids are frequently observed around farming properties. In theory, some of these species, especially rodents, could be VACV reservoirs. ⁶

Indeed, the virus was recently isolated from a wild mouse,⁶ suggesting that rodents might be spreading the virus between farms.

The implication is that over the past hundred years or so, vaccinia virus has sequentially jumped from its original, unknown host, into cattle, into humans, then back into cattle, into rodents, back into cattle, and then back into humans, not counting its long side-trip into the laboratory incubator.  It’s the Michael Jordan of jumping viruses.

1. Hopefully! But see this post for more
2. Moussatché N, Damaso CR, & McFadden G (2008). When good vaccines go wild: Feral Orthopoxvirus in developing countries and beyond. Journal of infection in developing countries, 2 (3), 156-73 PMID: 19738346
3. Alzhanova, D., Edwards, D., Hammarlund, E., Scholz, I., Horst, D., Wagner, M., Upton, C., Wiertz, E., Slifka, M., & Früh, K. (2009). Cowpox Virus Inhibits the Transporter Associated with Antigen Processing to Evade T Cell Recognition Cell Host & Microbe, 6 (5), 433-445 DOI: 10.1016/j.chom.2009.09.013
4. Essbauer, S., Pfeffer, M., & Meyer, H. (2010). Zoonotic poxviruses? Veterinary Microbiology, 140 (3-4), 229-236 DOI: 10.1016/j.vetmic.2009.08.026
5. DRUMOND, B., LEITE, J., DAFONSECA, F., BONJARDIM, C., FERREIRA, P., & KROON, E. (2008). Brazilian Vaccinia virus strains are genetically divergent and differ from the Lister vaccine strain Microbes and Infection, 10 (2), 185-197 DOI: 10.1016/j.micinf.2007.11.005
6. Abrahão, J., Guedes, M., Trindade, G., Fonseca, F., Campos, R., Mota, B., Lobato, Z., Silva-Fernandes, A., Rodrigues, G., Lima, L., Ferreira, P., Bonjardim, C., & Kroon, E. (2009). One More Piece in the VACV Ecological Puzzle: Could Peridomestic Rodents Be the Link between Wildlife and Bovine Vaccinia Outbreaks in Brazil? PLoS ONE, 4 (10) DOI: 10.1371/journal.pone.0007428

There’s a constant viral assault on us humans, as there is on just about all other species. We as a species have to contend not only with the vast pool of human pathogens, those viruses that constantly circulate among humanity; but also with the continual probes on our defenses from other viruses, viruses that normally infect other species.  All of us are exposed to these on a regular basis: Dog and cat viruses, mouse viruses, crow and pigeon viruses, bat viruses, not to mention the ocean of insect and fungus and amoeba and plant viruses.

Almost all of these assaults don’t even scratch our defenses.  The viruses can’t even enter our bodies, and if they do then they can’t enter our cells, and if they do they can’t replicate in our cells, and if they do then they can’t  …

Most viruses, in other words, can’t effectively jump species.  Even when they do, they’re usually not well adapted to the new species, and they can’t establish a productive chain of infections. Even if they cause a disease, they burn themselves out, infecting fewer and fewer individuals each round of infection, until they disappear.

But every so often, in a tiny minority of cases, the virus does get a foothold.  This is one of the ways that “emerging infections” get started.  It covers things like HIV, SARS, parvovirus of dogs, Ebola, and of course the new H1N1 swine-origin influenza virus (SOIV), among many others.

Why did these guys take off, when so many other viruses failed? Why did SOIV infect people last year, while decades of exposure to pigs and swine H1N1 influenza viruses didn’t lead to earlier pandemics?  Basically, we don’t know, and we’d really, really like to know, so we have a chance of predicting the next SOIV or HIV before it’s a pandemic.

OK, so that explains why I’ve written a fair number of posts here on species-jumping in viruses (here, here, here, here, and here), and partly explains why I want to mention a new paper from Bertram Jacobs‘ lab¹.  (The rest of the reason is, as always, that I just think it’s  cool.)  I’m not sure why Jacobs has done this particular project, because he’s more of an interferon guy, but he’s looked at the origins of ranaviruses and finds evidence for lots of species shifts in their history.

“The Smooth Terrapin (Emys terrapin)”, by James Dekay (Zoology of New York; or, The New York fauna, 1843)

Ranaviruses are probably best known as frog viruses, but they infect a bunch of cold-blooded animals — fish, frogs, salamanders, turtles, and so on — and several of them are causes of emerging infectious disease (as I discussed last time I talked about ranaviruses, here).  Jacobs’ group looked at about a dozen of them whose genomes are completely sequenced², and tried to put together their evolutionary history, which turns out to involve all kinds of cross-species jumps:

…we hypothesize that the most recent common ancestor of the ALRVs was an ancestral fish virus …  Both of these hypotheses suggest that for the majority of evolutionary time vertebrate iridoviruses were confined to fish, and much more recently, there appear to have been at least three species jumps, from fish to frogs, from fish to salamanders, and from frogs to reptiles, and perhaps as many as four species jumps, including a jump from tetrapod amphibians back to fish. It is tempting to speculate that activities associated with human harvesting of aquatic organisms during the past 40,000 years led to the more common recent jumping of ranaviruses among aquatic organisms.¹

(My emphasis) They don’t offer any specific reasons why the ranaviruses should be able to leap from species to species like the chamois of the Alps, but they do make the general point that these viruses tend to be rather promiscuous to start with.  Not only are closely-related viruses able to infect different hosts, but even the same viruses often are able to infect a wide range of species; the fish virus they sequenced in this paper, epizootic hematopoietic necrosis virus, can infect a half-dozen different species of fish.  They raise an interesting comparison:

In addition, the ability of this group of viruses to infect such a wide variety of host species suggests that more host shifts are likely. Therefore, it is important that we understand more of the evolutionary traits of this unique group of viruses, as there is no other closely related group of viruses that infect such a broad group of hosts, with the possible exception of the orthomyxoviruses.¹

Orthomyxoviruses, of course, include influenza viruses, which notoriously infect humans, pigs, ducks, chickens, wild waterfowl, horses, and dogs; and you’ll recall all the reports during the epidemic phase of SOIV of the virus infecting all kinds of other pets and domestic animals.  Influenza viruses are apparently evolving at an even faster pace than the ranaviruses, and experimenting with even more species; but there may be lessons for us (as influenza hosts) in the ranaviruses.

1. Jancovich, J., Bremont, M., Touchman, J., & Jacobs, B. (2009). Evidence for Multiple Recent Host Species Shifts among the Ranaviruses (Family Iridoviridae) Journal of Virology, 84 (6), 2636-2647 DOI: 10.1128/JVI.01991-09
2. Including epizootic hematopoietic necrosis virus, whose genome they sequenced themselves

But this indifference is new. Until the beginning of the 20th century, yellow fever ran rampant, and was one of the most dreaded of all diseases. Epidemics of yellow fever in New York, Philadelphia, Memphis, and New Orleans killed tens of thousands. There’s a WHO manuscript [pdf link] on yellow fever that lists these and many more outbreaks – page after page of fine-print dates and deaths.

Those who have not lived between Cancer and Capricorn can well fail to conceive readily the sensation of numb, chill dreariness which steals on all hearts, when the news spreads, from mouth to mouth, that Yellow Jack has once more come. … at last it is admitted on the housetops, as well as whispered in the closet, that the deadliest, most awe-inspiring of the plagues of the equatorial regions has obtained admittance within our borders.

–”Yellow Jack“, in Cornhill Magazine, 1892¹

As I noted earlier, Carlos Finlay made the original suggestion that yellow fever was a mosquito-borne disease in 1881;² in English, in 1886. ³ Walter Reed and his team confirmed this in 1900, and the discovery was seized on at once.

“Shows the Distribution of the Principal Mosquitoes of New Orleans”. Dark squares represent Stegomyia fasciata, the major carrier of yellow fever 4	Yellow fever cases in New Orleans, 1905. “The infected blocks are most numerous in the old, Italian, quarter of the city.”

(This post was mainly an excuse to post those maps.⁵  Click for larger versions.)

New outbreaks were checked with enthusiastic mosquito control.

In a few days with very little opposition, sixty to seventy thousand cisterns had been screened in order to prevent the breeding of the Stegomyia fasciata. Mosquito nets became more than ever the rule …

–Yellow Fever Prophylaxis in New Orleans, 1905⁵

The virus itself was was isolated in 1927 and the vaccine, made in 1937 by Max Theiler, turned out to be extremely effective; but even before that,  the understanding that mosquitoes were the carriers allowed great strides in reducing the disease.  Not just in the USA, but throughout the Americas:

Havana and Cuba freed from fever by Gorgas, who organized anti-mosquito measures, 1901-1902; example followed in Rio de Janeiro and Vera Cruz, 1903-1909; Panama Canal Zone successfully protected by same methods, 1904-1906 …  intensive campaign, 1918-1919, under Connor eliminated disease from Guayaquil, the chief endemic centre …

–”Yellow Fever in Retreat“, 1922⁶

1. Cornhill Magazine
   New Series, Vol. XIX, July to December 1892
   Smith, Elder, & Co.
   15 Waterloo Place, London
2. C. Finlay (1881). El mosquito hipoteticamente considerado como agente de trasmislon de la flebre amarllla An. de la Real Academia de ciencias med. de la Habana, 18, 147-169
3. C. Finlay (1886). Yellow Fever, its transmission by means of the Culex mosquito Am. Journ. Med. Sci., 92, 395-409
4. If I follow this right — I’m neither an entymologist nor an entomologist — Stegomyia fasciata was subsequently renamed Stegomyia aegypti, then Aedes agyptyi, and now (since 2005) is properly is officially called Stegomyia aegypti once again but usually, if not always, with “Aedes” in brackets to clarify. There was also, maybe, a point at which it was Stegomyia calopus, unless that was something else.
5. Yellow Fever Prophylaxis in New Orleans, 1905
   Rubert Boyce
   April, 1906
   Published for the Committee of the Liverpool School of Tropical Medicine
   by Williams & Norgate
   14 Henrietta Street, Covent Garden, London
6. Current History
   A Monthly Magazine of the New York Times
   Volume XVI, April-September, 1922

Everyone knows about rabbits in Australia. Introduced in the mid-1800s, they multiplied ridiculously and ate their way across the country, leaving barren devastation behind them.

Myxomavirus, a poxvirus that originated in South America, was introduced in the early 1950s and temporarily controlled the rabbit population, cutting their numbers by 85% (to a mere hundred million rabbits); but the rabbits evolved some resistance, and the virus evolved somewhat reduced virulence, and after about 15 years the rabbit population started to build up again. (I’ve talked about myxomatosis and rabbit control here and here.)

Myxomavirus isn’t a natural pathogen of European rabbits; its natural hosts are American rabbits, in which it causes a much more mild disease. It’s a virus that jumped into a new species, was very virulent in that new species, and then became less so over 15 years or so of transmission in the new species.

Myxomavirus is often used as an example of a virus that evolves toward avirulence, with the message usually being that this is the usual path of evolution. For example, you’ll see comments like, “Typically, viruses that rapidly kill their host have a very short history, as they rapidly run out of places to reproduce.” As I’ve tried to point out several times (see the myxomavirus links above), this isn’t true; pathogens in general evolve toward improved transmission, not reduced virulence. In many cases, reducing virulence does enhance transmission, but it’s not the only path. And myxomavirus doesn’t even support the claim all that well, given that even the “low-virulence” strain that’s out there now still has a mortality rate about the same as Ebolavirus, or smallpox.

OK, hold that thought.

Extermination of rabbits in California (From “The Picture Magazine,” 1894)

Myxomavirus worked well to control rabbits for a while, then became less effective. In 1995, a new virus was introduced into Australia and New Zealand,¹ a calicivirus that causes Rabbit Hemorrhagic Disease, called (with stunning originality) Rabbit Hemorrhagic Disease Virus (RHDV). Where did RHDV come from?

Basically RHDV is the opposite of myxomavirus. The parent of RHDV is a natural virus of European rabbits, but it causes little or no disease. RHDV is a natural mutation of this virus, and it has very high virulence – the opposite of the viruses-evolve-to-low-virulence claim. Even with the help of Australian farmers, RHDV is highly successful. It spread around the world in the mid-1980s after first appearing in Chinese rabbits in 1984.

One of the most intriguing aspects of RHDV evolution is that this virus appears to have maintained its very high virulence during the 25 years since it emerged. At face value this suggests that virulence is adaptive for transmission. ²

Rabbit’s eye (Max Brödel, 1932)

In fact, it’s been believed that the virulent RHDV is such a successful mutation that it arose several times, independently, from the mild parent virus. (Compare to the feline infectious peritonitis story, where the prevalent explanation for the appearance of a virulent FIP infection is that innocuous gastrointestinal coronaviruses, that are widespread in cats, mutates to form the virulent form; and this mutation is independent for each cat, rather than arising once and then spreading.)

At least, that’s been the established explanation, but a recent paper² shows that a couple aspects of that aren’t correct. The authors looked at genome sequences of many rabbit caliciviruses (the mild parent calicivirus as well as the virulent RHDV) to track its origins and spread. RHDV is indeed a recent mutation from a mild parent virus; that much is correct. But RHDV probably only arose once, not multiple times, and the origin of RHDV was well before 1984) when it was identified as a disease.

The independent-mutation hypothesis was based mainly on finding RHDV-related viruses circulating in Europe in the 1950s:

Prior phylogenetic work led to suggestions that RHDV with sequences closely related to those that emerged from China in 1984 were circulating harmlessly in the United Kingdom and other European localities during the 1950s; hence, it was suggested that virulence emerged at least twice during the late 20th century: once in Europe and once in China. ²

But Kerr et al looked more closely at these early isolates, and don’t think they’re real:

… we show here that the sequences from the 1950s and 1970s from the United Kingdom appear to be modern contaminants: given the rate of RHDV evolution documented here and that of RNA viruses more generally, these early RHDV sequences are expected to be far more divergent from their modern counterparts. ²

(Compare to the influenza database, where there also seems to be a significant level of mis-identified virus.)

So RHDV probably only originated once, which is a little more reassuring than the notion that this high virulence is so easy to achieve that it can appear many times over a short period. Did the original mutation appear around 1984, when the disease was noted? The authors identified 4 distinct strains of RHDV and noted:

A common feature of all of these groups is that many lineages likely originated during the 1970s, suggesting that there was a period of viral radiation at this time…. Crucially, this also means that there were already multiple separate lineages of RHDV before the documented emergence of RHD in China in 1984.  … This implies either that high virulence evolved multiple times in multiple viral lineages close to 1984 or (more plausibly) that virulence emerged earlier in the 20th century but the disease was not documented until 1984 when the trade in rabbits provided the opportunity for RHDV to spread from an established, but apparently cryptic, transmission cycle. … Therefore, we propose that the most likely scenario is that virulent RHDV strains evolved once, early in the 20th century, but were not detected until 1984. ²

(My emphasis) This seems, at first glance, surprising. RHDV kills almost all of the rabbits it infects. Wouldn’t you notice it if all your rabbits suddenly fell over dead? How could RHDV circulate for years or decades without being detected? Kerr et al make some points about the nature of the disease (it can infect very young kits without killing them, for example), but also comment:

Given the difficult sociopolitical conditions in China and neighboring countries in the first half of the 20th century, it is plausible that a virulent disease in rabbits was able to evolve in this region without leaving a clear record. ²

The pandemic swine-origin H1N1 probably has been circulating in swine for quite a while (years? decades?) without being picked up, and probably circulated in humans in Mexico for months before it was detected there. It’s pretty easy to believe that rabbits in China during the Cultural Revolution didn’t get as much attention as pigs in the US in the 2000s.

So, an interesting story in its own right, especially thinking about evolution of virulence in pathogens; and also, a story that probably reflects some important lessons for human health.

1. It wasn’t supposed to be introduced then; it was penciled in for few years later, after more study, but somehow it jumped from the island where it was being studied to the mainland. The usual explanation is “via insects”, but of course one has to wonder if some Australian farmers didn’t help the insects along some. As I recall from the news reports at the time, the “accidentally introduced” virus spread throughout Australia very fast, almost as if dead rabbits were being carted around by car or something.
2. Kerr, P., Kitchen, A., & Holmes, E. (2009). Origin and Phylodynamics of Rabbit Hemorrhagic Disease Virus Journal of Virology, 83 (23), 12129-12138 DOI: 10.1128/JVI.01523-09

Despite the fact that the recent pandemic was the best studied and recorded to date, the knowledge gained will probably have little predictive value for the next pandemic, either in qualitative or quantitative terms.

–Communicable Diseases and Epidemics
Martin M. Kaplan
Bulletin of the Atomic Scientists, June 1960

Kaplan  was referring to the 1957-58 influenza pandemic, but the sentence could have been taken from many places in 2009. In any case, Kaplan was pretty much correct; the next three pandemics after that were quite different from the 1957-58 pattern, and quite different from each other.

I’ve been expecting a resurgence of swine-origin influenza virus (SOIV) in North America for a while now, and it hasn’t happened. The virus is still out there, still infecting a few thousand people per week, but there hasn’t been a third large-scale wave of virus transmission. That’s different from the 1918 and 1957 pandemics (see here for details). What’s different this year?

Of course there are tons of things that are different this year, but I recently got around to doing something I should have done a while ago: Trying to estimate what proportion of Americans are now immune to SOIV. I’ve seen estimates that around 40% of the population should now be immune. I get roughly the same number (slightly higher, closer to 50%, because those estimates didn’t take into account pre-existing immunity to SOIV), but I think there’s an important point that might be missed in this: Most of the immunity might be clustered in the two most susceptible populations (children and the elderly), with two-thirds to three-quarters of them being immune.

There are three ways someone could be immune to SOIV. They could have been exposed to a related virus, some time in the past, and have developed a long-term immunity. They could have been infected with SOIV, somewhere in the first or second wave. Or, of course, they could have been vaccinated.

Numbers for each of those are available. They’re more or less approximate; not all the sources break down age groups in exactly the same way, for one thing, and I don’t have precise numbers for everything.¹ I’ll try to flag places where I’m especially guessing, and it’s entirely possible that this I’ve made some obvious, basic mistakes in here, since this has been written in the interstices of cleaning our house for Chinese New Year (a Herculean task) and hosing down the kids to get them ready for the party at YongHui’s this evening.  If so, let me know and I’ll try to correct them.

We need to break immunity down by age, because pre-existing immunity to SOIV was strongly age-dependent. (That’s presumably why the virus was strongly biased to infecting younger people this year.) For the demographics of the US I’m using the 2008 census data. All this is summarized in the table below, and my explanations follow.

1. Pre-existing immunity. A paper in New England Journal of Medicine last year² found that 4% of children, 6% of young adults, and 34% of older adults (born before 1950; I’m going with 65 years old as the dividing line just to make it easier to compare to other data) were already immune to H1N1. That’s more or less consistent with other studies I’ve seen, so let’s go with that.

2. Infection. The CDC estimates that somewhere over 55 million people in the US were infected in the first and second wave of SOIV, and gives approximate age distribution here. I’ve used the mid-point of their range estimates, so it’s possible that significantly more people were infected.  This works out to a quarter of US children being infected with SOIV,  which is broadly consistent with measures elsewhere — for example, a recent Lancet paper³ that estimated that about a third of children in the UK were infected.

3. Vaccination. The CDC’s Anne Schuchat’s Feb 5 press conference was very useful for this. The CDC has estimated that somewhere over 70 million people in the US have been vaccinated. Schuchat gave two further figures: Some 37% of children, and about 21% of adults have been vaccinated. These figures come from two different sources — a CDC survey and a Harvard survey respectively — so they may not be directly comparable, and I don’t know the breakdown in adults (young adults vs. elderly) but these figures do work out to about the right total, around 80 million people. Probably a little high, but not by much.

Another source of fuzziness is how much overlap there is between infected people and vaccinated people. It’s probably safe to say that most vaccinated people were not subsequently infected, but it’s quite possible that people were infected (perhaps with no symptoms, which we know happened quite frequently) and were subsequently vaccinated. ⁴ I’ve tried to adjust for this by assuming that half of infected people didn’t know it, and went on to get vaccinated, ⁵ as well as subtracting the proportion of people who were already immune (who presumably had no way of knowing that).  That’s the “Vaccinated uninfected” column.  Or, I’ve assumed  no overlap (just plain “Vaccinated”), to get an approximate range of immunity out there.

Including “Vaccinated uninfected” gives the “Number immune (low)”; assuming that all vaccinated were not infected gives the “Number immune (high)”.

And my conclusions are that:

• Over half the US population as a whole is now immune to the new SOIV.
• As many as three-quarters of the elderly and two-thirds of the children — the most important populations as far as flu is concerned — may be immune.
• Between a third and about half of this immunity was due to vaccination.

That level of immunity is probably enough to impact virus transmission drastically. In the early waves, if a child was infected then virtually every child she contacted in school or on the playground would be susceptible. Now only one in three of them are potentially infectable. I’ll have to spend some time looking at the models of influenza spread but I think that considering that the SOIV was not spectacularly infectious anyway, this level of population immunity is easily enough to prevent the third winter wave of disease I was expecting to see.

(I am particularly curious about modeling the impact of vaccination. Without vaccination would there have been a third wave? My guess is that there would have been, but that’s just a guess.  Update for clarification: Vaccination rates were highest in children. Without vaccination only about 25% of children would be immune — vaccination therefore doubled or tripled the amount of immunity in this critical population, and I think SOIV would have resurged in schools in winter without this intervention.)

What’s more, this level of immunity, especially in the apparent absence of the usual seasonal flu strains, has important implications about influenza over the next few years, but this post is already too long, so maybe I’ll talk about that some other time.

1. Probably quite accurate numbers are available, but not to me. Or, at least, not without a lot more work.
2. Hancock, K., Veguilla, V., Lu, X., Zhong, W., Butler, E., Sun, H., Liu, F., Dong, L., DeVos, J., Gargiullo, P., Brammer, T., Cox, N., Tumpey, T., & Katz, J. (2009). Cross-Reactive Antibody Responses to the 2009 Pandemic H1N1 Influenza Virus New England Journal of Medicine, 361 (20), 1945-1952 DOI: 10.1056/NEJMoa0906453
3. Miller, E., Hoschler, K., Hardelid, P., Stanford, E., Andrews, N., & Zambon, M. (2010). Incidence of 2009 pandemic influenza A H1N1 infection in England: a cross-sectional serological study The Lancet DOI: 10.1016/S0140-6736(09)62126-7
4. This is another significant potential source of error, I think.
5. That is, I’ve subtracted that proportion of people from the vaccinated totals.