Our last three postings focused on measles, mumps, and rubella, and the trivalent measles, mumps, and rubella (MMR) vaccine. The first of these postings considered the controversy surrounding the MMR vaccine, provoked by a discredited paper which alleged a link between the vaccine and autism (1). The second of these postings highlighted mumps and rubella, the “other” two diseases targeted by the MMR vaccine (2). The third posting told how Australian ophthalmologist, Norman McAlister Gregg, discovered the link between fetal birth defects and rubella infection of the mother during pregnancy (3). The current posting considers the origin and natural history of measles virus.
We begin by asking why measles virus, unlike Ebola virus, is one of the most contagious viruses known. Measles is a member of the paramyxovirus family of RNA viruses, which also includes mumps virus, respiratory syncytial virus, and the parainfluenza viruses. Each of these viruses is similarly highly contagious, mainly because each is efficiently transmitted via the respiratory route. That is, these viruses can be transmitted between individuals through the air via a cough or a sneeze. In contrast to measles virus, the inefficiently transmitted Ebola virus (a member of the filovirus family of RNA viruses that also includes the Marburg virus) is spread only by direct contact with the blood or body fluids (e.g., urine, diarrhea, and vomit) from a person who is expressing Ebola symptoms (4, 5).
Measles is hardly unusual in being transmitted by the respiratory route. Indeed, that route is the most common means of viral transmission between humans. A majority of viruses evolved to use the respiratory route because of several key features of the respiratory mucosa (the epithelium that lines the respiratory tract). Most importantly, the respiratory mucosa encompasses a very large surface area of about 140 square meters. For comparison, the entire surface area of the skin is a mere 2 square meters. Also, the respiratory mucosa is delicate and in intimate contact with the vasculature. Another factor which contributes to the communicability of measles is that an infected individual can unknowingly transmit the virus for several days before showing signs of illness.
The rhinoviruses and coronaviruses, which give rise to mild common colds, are likewise transmitted by the respiratory route. Why then do measles infections have the potential to be severe, even fatal? The answer, in part, is that the mild rhinoviruses and coronaviruses remain in the respiratory tract during infection, whereas measles virus is able to disseminate widely throughout the body. One reason it can do so is that it can bind to several different receptors, including one called CD46, which is present on most cells of the body. Because measles virus can disseminate widely, serious complications from measles can occur in almost every organ system.
Nonetheless, most measles fatalities actually result from secondary bacterial and viral infections of the respiratory and digestive tracts. These secondary infections are facilitated by a prolonged immunosuppressed state brought on by the primary measles infection. Paradoxically, the specific immune response against the measles infection is accompanied by a not-yet-understood suppressed immune response to other new antigens.
Our next (and perhaps most interesting) issue concerns the origin of measles virus and its establishment in the human population. We begin this topic by first defining the contagiousness of measles virus in quantitative terms.
The contagiousness of any virus is quantitatively defined by its reproduction number (R0), which is the average number of new individuals who are infected by each previously infected individual in a completely susceptible population. The R0 of measles virus is important to our analysis since, as we will see, measles virus was once an emerging virus in humans, and an emerging virus can successfully establish itself in a new host only when its R0 in that host is greater than 1. If the R0 is less than 1, then outbreaks in the new host will be self-limiting, even if the virus emerges in the host on multiple independent occasions. [Although Ebola virus is extremely virulent in humans, it has not established itself in humans, since its R0 in humans is less than 1.]
What then is the R0 of measles virus in humans? The answer is 15! On the one hand, this implies that if the contemporary measles virus were to emerge in an isolated and completely susceptible human population, it would readily spread into that population. On the other hand, consider the following. Since measles virus is so highly transmissible in humans, nearly every individual in that wholly susceptible population would be infected. Moreover, each of those infected individuals would either succumb to measles and die, or survive and develop lifelong immunity to the virus. This creates a dilemma for measles virus. How would it be able to continually find new susceptible individuals in order to sustain itself in the population?
The answer to the above dilemma is that measles virus, as it now exists, can survive only in populations that are large enough to continually generate a sufficient number of new susceptible individuals. Mathematical modeling by epidemiologists has led to the estimate that a community of at least 500,000 persons is necessary to sustain measles virus. This leads to the somewhat astonishing conclusion that measles virus, as we know it, has existed in the human population for no longer than the last several millennia, since communities large enough to sustain measles virus did not exist before then, and the much smaller communities that did exist had only occasional contact with other human groups. [By the same reasoning, measles virus is not present in other primates, since their population sizes are not nearly large enough to sustain this highly contagious virus.]
The above line of argument also explains why, in the pre-vaccine era, measles outbreaks or epidemics occurred every several years, with many fewer cases occurring between epidemics. Moreover, it leads to the notion that epidemic diseases in humans are a relatively recent development. To these points, consider the following. Measles virus shares the following three essential features with other epidemic viruses (e.g., poliovirus). First, each of these viruses is highly contagious, such that each spreads quickly through the susceptible individuals in the population. Second, epidemic viruses give rise to acute infections. [In contrast, non-epidemic viruses, like the herpesviruses, give rise to life-long persistent infections.] Individuals who recover from an acute infection are immune to re-infection by that agent. Third, epidemic human viruses have no animal reservoir to sustain them.
At the end of an epidemic, the virus persists in the human population, but only at a low incidence, and only if the population is large enough. Then, as a sufficient number of new susceptible individuals are born into the population, the epidemic threshold is reached, and the cycle repeats. The above argument also explains why very young children are the targets of epidemic viruses; they are the only non-immune individuals in the population.
Since measles virus, as it now exists, only recently became established in the human population, and since measles virus has no known animal reservoir, where did it come from? Viruses do not emerge from out of nowhere, nor do they leave fossils that might provide insights into their natural history. Nevertheless, the origin of measles virus can be inferred with a fair degree of certainty. First, there is the general principal that animals are the source of the emerging viruses that become established in humans. Second, nucleotide sequence analysis can identify the closest relative of measles virus among zootic viruses. That virus turns out to be rinderpest virus, which infects cattle, sheep, and goats.
Most studies estimate that rinderpest virus emerged in humans about 8,000 to 9,000 years ago, around the time that some human groups began to domesticate large herd animals. Clearly, the development of animal husbandry meant that these human groups would live in close proximity to herd animals. Moreover, and extremely important, the development of animal husbandry (as well as the emergence of agriculture) enabled human populations to grow enormously in size, since population size was no longer constrained by the limited availability of food which, previously, was either gathered, or killed on the hunt. Thus, the development of animal husbandry created the conditions for the emergence of rinderpest virus in humans, and for its subsequent evolution into measles virus.
The emergence of rinderpest virus in humans is generally believed to have occurred in the Fertile Crescent of the Middle East; one of the first areas where humans developed animal husbandry. A probable sequence of events was as follows. At first, rinderpest virus was transmitted to humans only from the animal host. Then, as the virus adapted to humans, it eventually evolved to the point where it could be transmitted from human-to-human, but only inefficiently. At this stage in the evolution of measles virus, outbreaks in humans would have been self-limiting and brief. In time, measles virus evolved to sustain longer outbreaks in humans. It then became so well adapted to humans that it was no longer able to infect its original animal hosts. As measles virus was evolving from its rinderpest precursor, it spread from the Middle East throughout Europe and Asia. See Asides 1 and 2.
[Aside 1: The developments of animal husbandry and agriculture made it possible, even necessary for some humans to settle in one place. This in turn made it possible for civilization to thrive and produce art, science, technology, the development of cities, etc., which could not happen under the earlier conditions of a nomadic existence.]
[Aside 2: Domestication of large herd animals developed in the Old World, rather than elsewhere, simply because that is where these animals were available. Old World populations eventually developed widespread resistance to many of these “new” human pathogens (e.g., smallpox, influenza, and measles). Then, when Europeans first came into contact with native groups in the Americas and Oceana, which had no previous exposure to Old World pathogens, the consequences were devastating to the native populations. Indeed, the germs carried by these European newcomers played a far greater role in their conquests of native populations than any advantages the Europeans had in weapons or technology (6).]
In the past, rinderpest virus caused severe disease in domestic cattle, with death rates during outbreaks actually approaching 100%. Indeed, the term rinderpest is adapted from German, meaning cattle-plague. Such cattle plagues were common, with documented outbreaks dating back to the time of the Roman Empire.
Rinderpest does not readily infect people. Nonetheless, rinderpest outbreaks in animals had enormous consequence for humans. For instance, when the virus spread to Africa from India in the late 19th century, it killed an estimated 90% of domestic cattle. This, in turn, led to the deaths from starvation of one third of the people of Ethiopia and two thirds of the Maasai people. The virus also spread to wild ungulates in sub-Saharan Africa and was considered a greater threat to the survival of these animals than human encroachment on their habitats.
Thanks to a rinderpest vaccine developed by Walter Plowright (at the Animal Virus Research Institute in Pirbright Laboratory in Surrey, England), and a world-wide eradication program, the last confirmed case of rinderpest was reported in Kenya in 2001. In June of 2011, the United Nations Food and Agriculture Organization declared that the disease had been eradicated, making rinderpest only the second disease in history, after smallpox, to be eradicated.
The stamping out of rinderpest might well be the greatest achievement in the history of veterinary medicine. Compare the rinderpest case to the situation that prevails in the case of measles (1)! But, as stated by English rinderperst virologist, Michael Baron: “When it came to vaccination, the cows never had a choice.”
Some final points: First, just as measles virus requires a large human population to sustain itself, its rinderpest progenitor likewise needed large herds to sustain itself. However, cattle population size was not as severe a hindrance to rinderpest virus as human population size is to measles virus. That was so, at least in part, because of the more rapid turnover rate of cattle, which led to the more rapid emergence of new susceptibles.
Second, more than half of all human infectious diseases, including influenza (from wild birds), and HIV/AIDS (from chimpanzees and gorillas), originated in animals; domestic and wild. And, pathogens may jump the other way as well, since humans have in fact transmitted measles virus to mountain gorillas, and poliovirus to chimpanzees.
Third, RNA viruses (e.g., Ebola, HIV, SARS, H5N1 influenza) are disproportionately represented among emerging viruses. This is explained in part by the facts that RNA viruses must use their own RNA polymerases to copy their RNA genomes, and that RNA polymerases do not have the proofreading activity of DNA polymerases. Consequently, RNA virus genomic replication is vastly more error-prone than DNA virus genomic replication. Indeed, RNA virus genomic replication may result in as many as one mutation per every thousand nucleotides. The higher mutation rate of RNA viruses is a key reason why they are much more likely than DNA viruses to adapt to a new host. In addition, an RNA virus may only need to recognize a new cell surface receptor to adapt to its new host, while a DNA virus may also need to adapt to the DNA replication “machinery” of a new host.
(1) Andrew Wakefield and the Measles Vaccine Controversy, Posted on the blog February 9, 2015.
(2) Andrew Wakefield and the MMR Vaccine Controversy: What about Mumps and Rubella?, Posted on the blog February 18, 2015.
(3) Norman McAlister Gregg and the Discovery of Congenital Rubella Syndrome, Posted on the blog March 4, 2015.
(4) The American Public’s Response to the 2014 West African Ebola Outbreak, posted on the blog August 10, 2014.
(5) The American Public’s Response to the 2014 West African Ebola Outbreak: Update, Posted on the blog October 7, 2014.
(6) Smallpox in the New World: Vignettes featuring Hernan Cortes, Francisco Pizarro, and Lord Jeffrey Amherst, Posted on the blog February 25, 2014.