Monthly Archives: March 2015

The Origin and Natural History of Measles Virus

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.

References:

(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.

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Norman McAlister Gregg and the Discovery of Congenital Rubella Syndrome

Our last posting (1) reviewed key facts about mumps and rubella; the other two viruses targeted by the trivalent MMR vaccine. The current posting tells how, in 1941, Australian ophthalmologist, Norman McAlister Gregg (1892-1966), discovered a link between rubella infection of a woman during pregnancy and her baby suffering from severe birth defects. Gregg’s finding was astonishing at the time because rubella, which is characterized by a rash and swollen glands, was regarded as nothing more than a mild childhood illness; a mere nuisance.

Norman Mcalister Gregg
Norman McAlister Gregg

Rubella is also known as German measles, since it was initially recognized in Germany (in 1814), and since it was at first thought to be a variant of measles. It was suspected of having a viral etiology as early as 1914, but rubella virus per se was not isolated until 1961. Norman Gregg’s story and his remarkable 1941 discovery are as follows.

Gregg received his medical degree in Australia in 1915. World War I was underway at the time, and Gregg immediately joined the British Expeditionary Force, which was then fighting in France. While Gregg was serving in France, as a captain in the Royal Army Medical Corps, he was wounded and was awarded the British Military Cross for gallantry in the field.

Gregg’s Military Cross citation read: “For conspicuous gallantry and devotion to duty during a raid. He untiringly attended to the wounded under heavy enemy fire until the last man was cleared, and showed great coolness and devotion to duty. He worked persistently throughout the raid in the open, and searched for any wounded that might have been overlooked. He behaved splendidly.” [See Aside 1]

[Aside 1: For more on the wartime experiences and heroism of several other important individuals in the history of virology see references 2, 3, and 4.]

Incidentally, Gregg was an outstanding athlete, who excelled at several sports. And, if it were not for the occurrence of World War I, he likely would have played on the Australian Davis Cup team. Note that Australian tennis players dominated international tennis tournaments until the 1960s.

When World War I ended, Gregg returned to Australia, where he served as a resident at the Royal Prince Alfred Hospital in Sydney. He then went to England in 1922 for further training in ophthalmology, and returned to Australia the following year to practice ophthalmic surgery. By 1941, Gregg established himself as senior ophthalmic surgeon at both the Royal Prince Alfred Hospital and the Royal Alexandra Hospital for Children. That very same year he published his landmark paper linking rubella infection during pregnancy to congenital birth defects.

The story of Gregg’s discovery began in 1940, during the Second World War. Australia was then in the midst of a severe rubella epidemic that began in 1939 under the crowded conditions in Australia’s wartime army camps. The illness was spread to the general population by infected soldiers, and it is very likely that some of these young soldiers transmitted the virus to their young wives; some of whom were likely pregnant. There had not been a rubella epidemic in Australia for many years prior to the 1939 outbreak.

In 1940, Gregg, in his role as an ophthalmologist in Sydney, noticed an unusually high incidence of infants born with cataracts. Gregg’s concern over the frequency of these infant cataract cases led him to write to other doctors in Australia to inquire into whether they might likewise have noticed an unusually high incidence of newborns with cataracts. After Gregg’s colleagues reported back, he knew of a total of 78 infant cataract cases, 44 of whom also had heart defects.

Several aspects of these of fetal cataract cases led the perceptive Gregg to suspect that they might be caused by an infectious agent, rather than by a solely developmental or genetic abnormality. First, from his perspective as an ophthalmologist, Gregg noted that the cataracts were atypical in that only the innermost layers of the lens, which form early in development, were affected. Second, many of the children also had heart defects and stunted development, suggesting to Gregg that a more systemic factor caused the syndrome . And, third, there was the uncommonly high frequency and widespread distribution of cases.

To determine whether these cases of congenital birth defects indeed might have a common thread, Gregg carried out a retrospective study (also called a case-control study), in which one tries to identify possibly relevant factors or conditions that existed before the outbreak of the disease. Gregg interviewed the mothers of the 78 affected infants. Remarkably, from these interrogations he learned that 68 of these mothers had contracted rubella early in their pregnancies. [Note that rubella can be so mild that some mothers, who did not report having been infected, may unknowingly have been infected.]

To inquire further into whether there might be a causal relationship between maternal rubella infection and congenital fetal deformities, Gregg next carried out a prospective study (also called a cohort study), in which one tracks a sample of the population that was exposed to the putative etiologic agent before the onset of disease. Thus, Gregg identified a cohort of pregnant women, who had experienced a rash-like illness during their current pregnancies, and then monitored those women to see if their babies displayed congenital defects. A comparison of this group of babies, with those born of mothers who had not experienced a rash-like illness, corroborated the relationship between congenital defects and maternal exposure to rubella virus.

Gregg was bold to assert that rubella during pregnancy could cause congenital malformations. First, the prevailing view at the time was that the placenta provides an impenetrable barrier to infections in utero. Second, the established belief among medical doctors was that all congenital abnormalities are inherited. Third, doctors found it difficult to accept that rubella, which was thought of as a mild disease of childhood, could be connected to severe birth defects. Fourth, there was not yet a laboratory test for rubella. Thus, Gregg’s proposition was based entirely on clinical assessments. For these reasons, Gregg’s work was initially met with skepticism by the medical community.

Nonetheless, Gregg’s findings aroused enough interest that the Australian National Health and Research Council sponsored a follow-up study by medical researcher, Charles Swan, which, when published in 1943, completely substantiated Gregg’s findings. Incidentally, it was Swan who added deafness to the symptoms of congenital rubella syndrome. Mental retardation was noted later by others.

Despite Swan’s corroborating findings, several more years would pass before Gregg’s determinations were widely accepted. [Curiously, the British medical journal The Lancet, which later published Andrew Wakefield’s discredited paper claiming a link between autism and the measles vaccine (5), stated in 1944 that Gregg had failed to prove his case.] The key that led to Gregg’s findings being finally accepted was the analysis by Oliver Lancaster, a statistician and epidemiologist at the University of Sydney, who concluded that Gregg’s data, which related severe birth defects to rubella infection during pregnancy, was statistically significant. Once accepted, Gregg’s pioneering study would greatly stimulate further research into birth defects and their causes. See Aside 2.

[Aside 2: The history of science contains many examples of correct hypotheses that were initially viewed as too radical to be accepted by the scientific community. Howard Temin’s provirus hypothesis is a particularly apt case in point (6).]

Gregg received numerous prestigious awards for his discovery from the governments and scientific societies of Australia, Canada, Great Britain, and New South Wales. But despite his many honors, Gregg is said to have remained an exceptionally humble, friendly, and caring man, who was “held in great respect and affection by all.” When he was notified that there was interest in nominating him for the 1958 Nobel Prize in physiology or medicine, he modestly stated: “I must confess that it comes as a great surprise and rather a shock that my name should even be considered . . . I feel it only fair to you to inform you that I have really no serious publications except those on Rubella as I have found very little time or inclination for writing during a very busy life.”

As noted above, rubella virus was isolated in 1961, and a live attenuated rubella vaccine was developed by 1969. The vaccine, usually given as a component of the trivalent MMR (measles, mumps, and rubella) vaccine, has vastly decreased the incidence of congenital rubella syndrome in regions where it has been used (1).

References:

(1) Andrew Wakefield and the MMR Vaccine Controversy: What about Mumps and Rubella?, Posted on the blog February 18, 2015.

(2) Max Delbruck, Lisa Meitner, Niels Bohr, and the Nazis, Posted on the blog October 30, 2014.

(3) Renato Dulbecco and the Beginnings of Quantitative Animal Virology, Posted on the blog November 19, 2014.

(4) Genealogies and a Selective History of Lysogeny: Featuring Friedrich Loeffler, Emile Roux, Andre Lwoff, Elie Wollman, and Francois Jacob, Posted on the blog January 28, 2015.

(5) Andrew Wakefield and the Measles Vaccine Controversy, Posted on the blog February 9, 2015.

(6) Howard Temin: “In from the Cold”, Posted on the blog November 25, 2014.