Measles virus

This is the first of a short series of posts in which I give some basic information on viruses that cause serious disease in humans.  It's motivated by the current pandemic with SARS-CoV-2.

The focus is on viruses that are human-specific but may have "jumped" species, the development of live attenuated virus vaccines, and the general nature of host restriction.

In this post, we'll talk about measles.  Measles is commonly known as rubeola (not to be confused with rubella), but also red measles and "English measles".

Morphology

Measles virus is a single-stranded negative-sense, enveloped RNA virus.  The measles virus is a member of the Paramyxoviridae, family Morbillovirus.  Below on the left is measles virus, its relative mumps virus (also a Paramyxovirus) is on the right.

Pathogenesis

Typically the first symptoms of measles include high fever of about 4 days duration, a characteristic rash, and what are called the "three C's":  cough, coryza (runny nose) and conjunctivitis.

Here are two pictures showing the characteristic rash.



The rash is called "flat" because

A maculopapular rash is a type of rash characterized by a flat, red area on the skin that is covered with small confluent bumps. It may only appear red in lighter-skinned people. The term "maculopapular" is a compound: macules are small, flat discolored spots on the surface of the skin; and papules are small, raised bumps. It is also described as erythematous, or red.

There is a special pathognomonic sign called Koplik's spots, seen inside the mouth on the cheek next to the molars.  Pathognomonic means it is characteristic enough to make a diagnosis by itself.  However, the spots are transitory and frequently missed.

Epidemiology

Measles is a highly contagious infectious disease.  Nine out of ten people who are not immune and share living space with an infected person will be infected. People are infectious to others from four days before to four days after the start of the rash.

Not only are presymptomatic individuals infectious, but the virus spreads by aerosol, meaning that it can survive in an infectious state even in the very small droplets that waft around and don't fall to the ground within a few minutes.  The particles can stay airborne for hours.  This ability is unusual, and indicates the virus resists inactivation due to drying out.

The CFR (case fatality rate) ranges from 1-3/1000 for a well-nourished, healthy individual, to as much as 10% or more, for other populations.  Vitamin A-deficiency is very problematic, and supplementation is recommended.

According to wikipedia, measles killed 20 percent of Hawaii's population in the 1850s. In 1875, measles killed over 40,000 Fijians, approximately one-third of the population.

Typically the first tissue infected is the lining of the airways, but the virus eventually travels through lymph nodes, infects cells of the immune system, and then moves into the blood causing widespread viremia.

Bacterial pneumonia is one of the common sequelae, and that's what most people die from.  Other problems include ear infections, blindness, severe diarrhea, encephalitis (1/1000) and problems in pregnancy.  In very rare cases (1/1M), measles can reactivate years later to cause SSPE (subacute sclerosing pan-encephalitis).

Host restriction

Measles virus infection is presumed to be sustained through an unbroken chain of human-to-human transmission, and no animal or environmental reservoir is known to exist. However, nonhuman primates can be infected with measles virus and can develop an illness similar to measles in humans with rash, coryza, and conjunctivitis. Many primate species are susceptible to measles virus infection, including Macaca mulatta ... Much of the evidence for the susceptibility of these nonhuman primates comes from laboratory colonies and the use of nonhuman primates as animal models for the study of measles virus pathogenesis.

One of the most interesting aspects of measles epidemiology is that the virus is so infectious, it runs out of hosts if the population is too small.  With a larger population, it comes back every few years as a new crop of susceptible hosts develops.

To provide a sufficient number of new susceptibles through births to maintain measles virus transmission in humans, a population size of several hundred thousand persons with ∼5000–10,000 births per year is required

Surveys of wild populations have sometimes revealed non-human primates with antibodies to measles virus.  It is believed that the virus was spread from humans to one of these animals, followed by limited spread and then die-out.

ref

Vaccine

The first laboratory to grow the virus was that of John Enders and colleagues.  They also were first to culture poliovirus, which lead to work on the vaccines by Salk and Sabin.  Enders et al received the Nobel Prize in 1954 for this work.

The vaccine strain is named for the boy from whom that virus was cultured, Edmonston.

The virus was weakened by successive culture in
- human kidneys
- human placenta
- hen's eggs
- chick embryos

Although significantly weakened by this serial culture,  it still caused rash and fever, sometimes high enough so that children had seizures.

The first thing Hilleman did was give the vaccine together with gamma globulin from people who had recovered from measles.  He then passed Enders' measles vaccine strain through
chick embryo cells more than 40 times.

Vaccinated is a biography of Hilleman.  It tells the story of Hilleman obtaining specially-bred chickens that were free of chicken leukemia virus.

The vaccine is highly effective.

Despite significant diversity of virus isolates, Measles virus remains a monotypic virus for which protective immunity is induced by vaccine strains first isolated in the 1950’s.

Origin

The genus Morbillivirus includes similar viruses that infect dogs, cats, whales, seals and cattle.  The disease of cattle is referred to by a Boer term:  Rinderpest.  Of the relatives, the rinderpest virus is the closest to measles.

At NCBI I searched for measles and found 363 genome nucleotide sequences, most of which appear complete.  I just chose one at random, NC_001498, and then got the sequence of its nucleocapsid gene, NP_056918.  A BLAST search gave a large number of hits with other Measles virus isolates down to 97% identity.

Restricting the search to Rinderpest (taxid: 11241), I got numerous hits as well, in the range of 75-80% identity.  But if you look at the alignments, there is a C-terminal region that diverges.  The N-terminal 400 aa (of 524) matches very well.  Restricting the search to 1-400 the matches were more like 88% identical, like this one:

Here is a phylogenetic tree of Morbilliviruses from this review:

One can often recognize present-day diseases in descriptions from ancient times, but measles is missing from those accounts.  The first systematic description of measles, and its distinction from smallpox and chickenpox, is credited to the Persian physician Rhazes (860–932), who published The Book of Smallpox and Measles.

By analyzing the diversity of the sequences of viral isolates, it is believed that the last common ancestor of Measles virus and Rinderpest occurred about 1000 AD plus or minus.  It is also thought that the virus "jumped" from cattle to humans, due to domestication of livestock and growth of the human population to a level that could support the virus.

Links

Enders Nobel prize and lecture
Enders biography
Hilleman biography
Hilleman obit