News and Views: Measles — the Virus, the Disease, the Vaccine

Did you know that in some parts of Africa, people don’t name their children until the threat of measles has passed? In the United States, and many other parts of the world, this might seem odd, particularly as some parents have come to fear the MMR vaccine more than the three diseases it prevents. In light of the ongoing measles outbreaks caused in part by the decisions of some to forgo vaccination, we thought it might be useful to review information about measles.

Read on to find answers to the following questions:

• How does measles virus infect the brain and cause acute or chronic disease?
• Why might tuberculosis flare and juvenile arthritis go into remission during a measles infection?
• What percent of patients have identifiable Koplik’s spots?
• How is atypical measles different from regular measles?
• Where are outbreaks more likely to start — in cities or rural areas?
• Why do measles vaccine age recommendations differ in other countries?
• Why might some adults born in the early- to mid-1960s require vaccination against measles?

Measles — the virus

Measles is an RNA virus of about 100 to 300 nm in size. In the scheme of viral size, measles is on the larger side. Related most closely to rinderpest virus (cow measles), measles is believed to have evolved in an environment in which cattle and people were in close proximity. The eradication of rinderpest, the only virus other than smallpox to be eradicated, increases hope that someday measles can be eradicated as well. Although we hear more about polio eradication, measles virus is a good candidate because it meets three important criteria. First, it only infects humans. Second, it is genetically stable. Third, a safe and effective vaccine is available.

Measles virus can infect several different kinds of cells, including epithelial, endothelial, and immune system cells. Immune cells infected by measles virus include immature lymphocytes, T and B cells, activated monocytes, macrophages, and mature dendritic cells. Because measles virus buds from, rather than lyses, infected cells, it typically spreads through the body inside of infected cells. After infecting the lower respiratory tract and local lymph nodes, viral-infected cells travel through the blood to the spleen and lymph nodes, lungs, thymus, liver, skin, conjunctivae, kidneys, gastrointestinal tract, and genital mucosa. It is rare for cells of the central nervous system to be infected, so the mechanism for complications that include involvement of the central nervous system has been studied. Working theories include altered presentation of myelin antigens, molecular mimicry, genetic susceptibility, or dysregulation of the immune response. This latter theory currently seems to be the most likely.

Cells infected with measles can be identified microscopically by their large size, altered shape, which may include spindles, multi-nucleated appearance, and the presence of inclusion bodies in the cytoplasm or nuclei of the cells. Infected cells will start to appear in the blood around 4 to 7 days after the infection begins. The immune response is characterized by a CD8+ T cell response; however, CD4+ T cells also respond. Individuals who experience the most severe disease have been found to have low levels of CD4+ T cells.

Measles was the first infection to be recognized as an immune suppressive agent. In addition to decreased levels of CD4+ cells, a decreased CD4/CD8 ratio can be found during the acute phase of infection, and lymphocytopenia is also evident, albeit the latter is more often seen in infected females and malnourished individuals. The immune suppression lasts for weeks after measles infection and can cause reactivation of chronic infections that were previously controlled, such as tuberculosis, or result in a period of remission from immune-mediated conditions, such as juvenile rheumatoid arthritis, nephrotic syndrome, or idiopathic thrombocytopenic purpura.

Measles — the disease

Classic measles

The time from infection to start of symptoms is about 10 to 14 days. The earliest symptoms, lasting about two to four days, include:

• Rising fever
• Watery, pink eyes
• Cough
• Koplik spots in the mouth — Koplik spots can be found on the inside of the cheeks in about 70 percent of patients and tend to appear one to two days before the body rash and last for one to two days after the body rash begins.

The body rash typically begins on the head and then spreads to the trunk before reaching the limbs. And while the body rash is a tell-tale sign of infection, clinically it offers information that may not be as quickly recognized. Specifically, the appearance of the body rash means:

• The adaptive immune response, characterized by B and T cell activation and antibody production, is underway
• Viral clearance has begun
• The fever will begin to diminish

Early on, the body rash will blanch with pressure. It will begin to fade in the order it appeared — typically about three to four days later, and its color will change from red to brown, The disappearance of the rash may be accompanied by flaking or sloughing of skin, particularly in malnourished individuals.

Clinical notes:

• Fever or rash or both may not occur in very young infants, immune compromised persons, malnourished children, and individuals who were previously immunized.
• Clinical serology, preferably with acute and convalescent samples, is the standard. IgM will be detectable at the time of the rash and for up to four weeks after; whereas, IgG will be measurable beginning around two weeks after rash appearance. Over time, IgG antibodies will increase in their avidity.
• The World Health Organization (WHO) recommends two doses of vitamin A for every child with measles:
  • One dose per day for two days
  • Recommended dose:
    • 200,000 IU for those 12 months and older
    • 100,000 IU for those 6 to 12 months of age
    • 50,000 IU for those younger than 6 months
• The AAP recommends following the WHO recommendation in the U.S. for children younger than 2 years of age who also have one of the following:
  • Immune suppression
  • Clinical evidence of IgA deficiency
  • Recently immigrated from an area with increased measles mortality
• Antivirals do not work, but some newer ones show promise. Medications are not typically used for treatment of uncomplicated cases, but some immune-based preparations may offer clinical support.

Atypical measles

Atypical measles presents with:

• Higher and longer-lasting fever
• Severe pneumonitis
• Abdominal pain
• Liver malfunction
• Headache
• Eosinophilia
• Pleural effusion and edema
• Unusual rash. The rash tends to begin on the extremities and then spread to the trunk. It sometimes includes hemorrhaging and formation of vesicles.

This version of the disease is most often associated with a group of individuals who received an inactivated version of the measles vaccine available in the 1960s (see “Measles — The vaccine” section of story for more information).

Complications of measles

Complications can occur based on which body systems are involved, whether the infection persists, or as a result of secondary infections taking advantage of the coincident immune suppression caused by infection. While most deaths that occur from measles are the result of other infections, the importance of preventing measles as a means of preventing the coincident immune suppression cannot be understated. In industrialized settings, about 60 percent of deaths are due to pneumonia, but the causal agents can be viral or bacterial in nature. The bacteria that most likely are associated with pneumonia include staph, pneumococcus, or Haemophilus influenzae type b.

The likelihood for, and type of, complications is dependent on economic and individual factors, such as immune status. For example,

• In industrialized settings, more common complications include ear infection (7-9 percent), pneumonia (1-6 percent), and diarrhea (about 8 percent). Other conditions can include thrombocytopenia, bronchitis, stomatitis, hepatitis, appendicitis and ileocolitis, pericarditis and myocarditis, kidney-related conditions, hypocalcemia, and Stevens-Johnson syndrome.
• In developing countries, measles results in death in about 2 to 15 percent of patients. A hemorrhagic form, called “black measles,” has also been identified. Pneumonia is the most common cause of death.
• Pregnant women are at greater risk of miscarriage and maternal death when infected with measles. At issue is the greater fluid volume, increasing susceptibility to infections of the respiratory tract. The result is that pregnant women are more likely than non-pregnant women to be hospitalized and die from pneumonia.
• While measles infection does not cause congenital malformations, unborn babies are at greater risk of preterm birth and low birthweight.
• Immune-compromised individuals, particularly those with cancer and HIV, may experience prolonged and more severe infections. They are less likely to develop the telltale rash, and they are at higher risk for fatality. Some evidence suggests that HIV-infected children could have a 50 percent fatality rate.

Neurologic involvement can result in a series of severe conditions:

• Autoimmune demyelinating disease (ADEM) — Occurs in the first two weeks to one month after a primary measles infection; mostly observed in children older than 5 years of age.

• Measles inclusion body encephalitis — Occurs one to 9 months after primary measles infection.
• Subacute sclerosing panencephalitis (SSPE) — Occurs seven to 10 years after primary infection, but could occur a couple of decades later. SSPE most often:
  • Occurs after measles infection before 2 years of age
  • Affects boys from rural areas
  • Is seen more frequently in children whose mothers are HIV positive
  • Occurs in about 1 in 10,000 cases
  • Involves progressive neurologic degeneration and is uniformly fatal; the deterioration can occur over months to years

Although only about 500,000 cases of measles were reported in the U.S. annually before a vaccine became available, it was likely that the entire birth cohort was infected (about 4 million cases). Each year, measles infections caused:

• 150,000 respiratory complications
• 100,000 ear infections
• 48,000 hospitalizations
• 7,000 seizures
• 4,000 cases of encephalitis (about 1,000 of which resulted in permanent brain damage or deafness)
• 500 deaths

Transmission

Measles virus is spread by respiratory droplets — directly by coughing and sneezing and indirectly by small-particle aerosols that remain in the air after an infected person has left the area. The coughing and sneezing that results from infection is due to the sloughing of infected epithelial cells lining the upper respiratory tract. Because it takes time for the rash to appear, people are contagious for about four days before the rash develops, and remain infectious for about another four days after its appearance.

One of the most infectious diseases known, measles has an R0 of about 12 to 18, meaning that every infected individual is likely to infect 12 to 18 more susceptible people a day. In a home with more than one susceptible individual, the susceptible individuals have a 76 to 90 percent likelihood of being infected.

In temperate climates, measles tends to be a disease of the winter and early spring. Further, because the virus requires a supply of susceptible people and spreads easily in close quarters, it has been shown to spread most often from cities to suburbs to rural areas.

Measles — the vaccine

The earliest attempts to protect against measles infection occurred in 1749 when passing measles from one infected person to another was tried, such as was done for smallpox. The process, called morbillization, did not work.

Between 1920 and 1940, attempts to create inactivated or attenuated vaccines in chick embryos met with only limited success.

The breakthrough that paved the way for modern measles vaccine success was tissue culture. By 1963, the first measles vaccine in the U.S., derived using tissue culture, was licensed. Unfortunately, it had a troublesome side effect portfolio, often causing fever and rash. If immunoglobulin was given simultaneously, side effect rates improved, but scientists realized that the strain, called the Edmonston strain, needed further attenuation to improve its safety. In 1965, a further weakened version became available, but the strain used in today’s measles vaccine, Moraten which stands for “more attenuated,” was not introduced until 1968. While most other countries also use strains developed from the Edmonston strain, they do not necessarily use Moraten. A few notable exceptions use vaccines developed from strains that did not derive from Edmonston, including Russia, Japan and China, among others.

In addition to different versions of measles vaccine throughout the world, vaccination schedules also vary. Public health officials from different regions of the world work to balance the average age of exposure with the disappearance of maternal antibodies, which interfere with vaccine effectiveness. In areas where the likelihood for exposure in infancy is greater, the vaccine tends to be recommended around 9 months of age; whereas in areas, such as the U.S., where early exposure is (typically) of less concern, the first dose is delayed until 12 to 15 months of age. The trade-off for the three to six month window is an increase in effectiveness from about 85 percent to more than 95 percent. In the U.S., the second dose, recommended between 4 and 6 years of age, is primarily meant to increase the number of protected individuals to closer to 100 percent.

Clinical notes:

• Antibodies take about 12 to 15 days following vaccination to develop, and they peak around 21 to 28 days; therefore, patients are not likely to be protected until a couple of weeks after vaccination.
• Like natural measles virus, the live, weakened vaccine causes immune suppression. Studies have shown the effects last for about four weeks; vaccine recipients do not appear to be at increased risk of infection resulting from the immune suppression caused by vaccination (in contrast to that caused by infection).
• Although throat swabs have detected evidence of virus following vaccination, no clinical evidence of viral transmission has been found. However, precautions and contraindications consider the possibility.
• Because the measles vaccine contains live, weakened virus, effectiveness relies on proper storage and handling. The vaccine is both temperature and light sensitive:
  • 50 percent potency is lost if the vaccine remains at 20 to 25 degrees Celsius for one hour.
  • At 37 degrees Celsius, virtually all potency is lost after one hour.
  • Once MMR vaccine is reconstituted, it must be used within eight hours.
  • MMRV must be used immediately and discarded if not used within 30 minutes. It cannot be stored in the refrigerator.
  • The vaccine should be protected from light.
• Between 1963 and 1967, an inactivated version of measles vaccine was administered to between 600,000 and 900,000 children. The vaccine was found to generate only short-term protection and led to atypical measles (described in “Measles — The Disease” section of story) upon subsequent exposure. Children who received this version of the vaccine were recommended to be revaccinated. The current recommendations address this concern as shown here:
  
  

  “Adults born in 1957 or later should receive at least one dose of MMR vaccine unless they have other acceptable evidence of immunity to these three diseases (Table 3). However, persons who received measles vaccine of unknown type, inactivated measles vaccine, or further attenuated measles vaccine accompanied by IG or high-titer measles immune globulin (no longer available in the United States) should be considered unvaccinated and should be revaccinated with one or two doses of MMR vaccine.” (Refer to section of recommendations, “Recommendations for Vaccination for Measles, Rubella, and Mumps, Vaccination of Adults (Aged >18 Years)”).

Resources

• Use these animations from the Vaccine Makers Project to illustrate how viruses enter and replicate in a cell as well as how viruses are attenuated to make live viral vaccines:
  • How a virus attacks a cell
  • How do viruses replicate?
  • Attenuation: How scientists make live vaccines
• Read two personal stories about losing children to subacute sclerosing panencephalitis (SSPE), as well as a public health perspective related to a measles outbreak on the Parents PACK website.
• Visit the CDC's website for complete recommendations related to MMR vaccine.

References

World Health Organization. Let every child have a name: The road to a world without measles. 26 Sept. 2012. Accessed: https://www.who.int/immunization/newsroom/let_every_child_have_a_name/en/

Griffin DE. “Measles Virus” in Fields Virology, Sixth Edition. Knipe DM and Howley PM, eds. 2013. Wolters Kluwer, Philadelphia, PA, pp.1042-1069.

Strebel PM, Papania MJ, Gastañaduy PA, and Goodson JL. “Measles Vaccines” in Plotkin’s Vaccines, Seventh Edition. Plotkin SA, Orenstein WA, Offit PA, and Edwards KM, eds. 2018. Elsevier, Philadelphia, PA, pp.579-618.