SECTION TWO: Licensed vaccines

20

Measles vaccine
Peter M. Strebel*
Mark J. Papania
Amy Parker Fiebelkorn
Neal A. Halsey

The written history of measles is classically traced to the writings

of the Persian physician Rhazes, also known as Abu Becr, who
lived during the 10th century.13 However, the disease was apparently recognized as early as the 7th century by such ancients as
the Hebrew physician Al Yehudi.2 Rhazes referred to measles as
hasbah, which means eruption in Arabic.2 Rubeola and morbilli are descriptive Latin words first used in the Middle Ages.
The latter is a diminutive of morbus, meaning disease, which
was reserved to refer to the bubonic plague; morbilli referred to
a minor disease. Measles is probably derived from mesels, the
anglicized form of misellus, which in turn is a diminutive of the
Latin word miser, meaning miserable and referring to the sufferer of various eruptions or sores. The presence of nonspecific
leprous sores was incorrectly identified with the disease called
morbilli in Latin. Thus, mesels came to be equated with the disease and not the sufferer of ill-defined skin lesions.3
Rhazes appears to have been the first to make the distinction between measles and smallpox.2,3 He considered measles
to be a severe disease, more to be dreaded than smallpox.
Although Rhazes did distinguish between the two diseases, he
and others still probably considered them to be closely related.3
Furthermore, although he was aware of the seasonal nature of
measles, he did not think the disease was infectious.2
The distinction between measles and smallpox was becoming clearer by the beginning of the 17th century, when annual
bills of mortality in London in 1629 listed the two diseases separately.3 Thomas Sydenham clearly described the clinical characteristics of measles during this period and believed the disease
to be infectious.24 It was, however, Francis Home, a Scottish
physician who worked in Edinburgh in the mid-18th century,
who truly recognized the infectious nature of the illness in his
attempts to prevent it.5 Understanding of the epidemiology of
measles was greatly enhanced by the classic investigation of a
measles epidemic on the Faroe Islands in 1846 by the young
Danish physician Peter Panum.6 He not only confirmed that
measles was contagious but also defined the 14-day interval
between exposure and appearance of exanthem, recognized the
higher mortality at the extremes of age, and observed that infection provided lifelong immunity.
In 1911, using infected material from acute cases, Goldberger
and Anderson7 transmitted human measles infection to monkeys, clearly demonstrating the existence of an infectious agent
or substance responsible for measles. This finding antedated
the technology to isolate and culture the measles virus. In
1954, Enders and Peebles8 successfully isolated the measles
virus in human and monkey kidney tissue cultures. Adaptation
of the virus to chicken embryos9 and cultivation in chicken
embryo tissue culture10 paved the road to vaccine development
and licensure in 1963.1121

Widespread vaccination of children in the United States2227

and others2841 has had a dramatic effect on the incidence of
measles and its associated complications. Reductions in morbidity and mortality have been so great that global eradication
has been proposed4244 and judged feasible.4547 This would be a
fitting end to a disease once confused with smallpox, the first
infectious disease eradicated from the world.

Background
Clinical description
Usual clinical course
The first symptoms of measles occur after a 10- to 14-day incubation period that follows airborne or droplet exposure. A systematic review estimated the median incubation period to be
12.5 days (95% confidence interval [CI], 11.8-13.2) based on
55 observations from eight observational studies.48 If infection
occurs after parenteral exposure, the incubation period is shortened by 2 to 4 days.2,11,4951 Immunosuppressed persons may have
a prolonged incubation period because host immune responses,
which are responsible for the signs and symptoms of measles,
may be absent or delayed in persons with cellular immune
deficiencies.52,53 The prodromal stage is heralded by the onset
of fever, malaise, conjunctivitis, coryza, and tracheobronchitis
(manifesting as cough) and lasts 2 to 4 days. This symptom complex is similar to that seen with any upper respiratory infection.
The temperature rises during the ensuing 4 days and may reach
as high as 40.6 C (105 F). Koplik spots, the enanthema believed
to be pathognomonic of measles, appear on the buccal mucosa 1
to 2 days before the onset of a rash and may be noted for an additional 1 to 2 days after rash onset.54 The rash is an erythematous
maculopapular eruption that usually appears 14 days after exposure and spreads from the head (face, forehead, hairline, ears, and
upper neck) over the trunk to the extremities during a 3- to 4-day
period. The exanthem is usually most confluent on the face and
upper body and initially blanches on pressure. During the next
3 to 4 days, the rash fades in the order of its appearance and
assumes a nonblanching brownish appearance.
Virus can be isolated from both the nasopharynx and blood
during the latter part of the incubation period and during the
early stages of rash development.8,55 Although virus has been
*The author is a staff member of the World Health Organization.
The author alone is responsible for the views expressed in this
publication, and they do not necessarily represent the decisions,
policy, or views of the World Health Organization.

Measles vaccine

isolated from the urine as late as 4 to 7 days after rash onset,56

viremia generally clears 2 to 3 days after rash onset in parallel with the appearance of antibody.57 Persons with measles are
generally considered to be infectious 4 days before through 4
days after rash onset.
Measles virus infection causes simultaneous activation and
suppression of the immune system.5862 Measurement of cytokines released during measles suggests activation of CD8+ T
cells, which are important for viral clearance, and type 2 CD4+
T cells, which provide optimal antibody production. Measles
virus infection leads to a decrease of CD4+ lymphocyte counts
that begins before the onset of rash and lasts for up to 1 month.63
A study of measles patients in the Gambia found marked suppression of the production of interleukin-12, a known regulator
of cellular immunity, and suggests a mechanism for the immune
suppression associated with measles infection.62 Recovery from
infection is associated with the production of serum and secretory antibodies57,6472 as well as the establishment of cellular
immunity.60,61,7379 Although subclinical infection with boosting
of antibody may occur with subsequent exposure,65,67 immunity
after natural infection is believed to be lifelong.6,80

Complications
The complications associated with measles infection have been
the subject of much description and review.49,51,81102 In industrialized countries, the most commonly cited complications associated with measles infection are otitis media (7%-9%), pneumonia
(1%-6%), diarrhea (8%), postinfectious encephalitis (1 per 1,0002,000 cases of measles), subacute sclerosing panencephalitis
(SSPE) (1 per 100,000 cases), and death (1.0-3.0 per 1,000 cases).
Complications are likely to be present if the fever has not lysed
within 1 to 2 days of rash onset. The risk of serious complications and death is increased in children younger than 5 years
and adults older than 20 years.2,92,93,97,100 Pneumonia, which is
responsible for approximately 60% of deaths, is more common
in young patients, whereas acute encephalitis occurs more frequently in adults.92,100 Pneumonia may occur as a primary viral
pneumonia (Hecht pneumonia) or as a bacterial superinfection,
most commonly with staphylococcus, pneumococcus, or typable
(encapsulated) Haemophilus influenzae. Other described complications include thrombocytopenia, laryngotracheobronchitis,
stomatitis, hepatitis, appendicitis and ileocolitis, pericarditis and
myocarditis, glomerulonephritis, hypocalcemia, and StevensJohnson syndrome.49,51 Although it has long been assumed that
measles infection exacerbates or activates tuberculosis,103 it is no
longer certain that this is the case.104
Measles infection runs a devastating course in children in
developing countries, where the mortality rates can be as high
as 2% to 15%.2,49,51,105119 Pneumonia is the most common
severe complication from measles and is associated with the
greatest number of measles-associated deaths.120,121 The rash is
intense and often hemorrhagic (black measles), and it resolves
after marked desquamation. Inflammation of the mucosa leads
to stomatitis and diarrhea. Diarrhea is a frequent cause of death
because it may persist long after the acute insult and further
aggravate a preexisting malnourished state.101,122,123 Mediastinal
and subcutaneous emphysema, keratitis, corneal ulceration,
and gangrene of the extremities are not uncommon. The combination of vitamin A deficiency and keratitis results in a high
incidence of blindness.124126 Secondary bacterial infections,
often with staphylococci, produce pustules, furuncles, pneumonia, osteomyelitis, and other pyogenic complications.
SSPE is a rare degenerative central nervous system (CNS)
disease caused by a persistent infection with a defective measles virus.127131 The agent has been noted in affected brain
tissue by use of antigen detection assays, electron microscopy,
polymerase chain reaction (PCR), and in situ RNA hybridization
(and has been cultured by cocultivation techniques).132 Signs and

20

symptoms of mental and motor deterioration begin an average

of 7 years after measles infection, which frequently has occurred
before the age of 2 years. Patients have progressive personality
changes, develop myoclonic seizures and motor disability, lapse
into a coma, and die. The average age at onset is 9 years. Males
outnumber females 2:1 to 4:1.4,95,99,133 Patients with SSPE have
high titers of measles-specific antibodies in their sera and cerebrospinal fluid. Measles viruses that have been isolated from
affected brain tissue have mutations that prevent normal replication and budding from the host membrane; such mutations
can occur in M, H, or F genes of the virus.128,134 SSPE occurs as
a complication of measles infection, with a frequency of about
1 per 100,000 measles cases. A risk of 22 cases of SSPE per
100,000 reported cases of measles was found during the 1989 to
1991 resurgence of measles in the United States.130
A team of investigators in the United Kingdom has suggested that infection with measles virus or measles vaccine
virus results in a persistent infection of the gastrointestinal
tract, leading to Crohn's disease or ulcerative colitis later in
life.135138 They proceeded to study a subset of children with
developmental disorders and ileocolonic lymphonodular hyperplasia by using reverse transcriptasepolymerase chain reaction
(RT-PCR) techniques, and report finding evidence of measles
virus in biopsies from the terminal ileum of these children.139
The findings of this group of investigators have led to speculation that combined vaccination with measles-mumps-rubella
(MMR) vaccine may be responsible not only for some forms of
inflammatory bowel disease but also the increasing incidence
of childhood autism. Other researchers, however, have been
unable to replicate earlier laboratory findings by using similar
as well as more sensitive and specific methods.140,141 Subsequent
well-conducted epidemiologic studies have not found an association between measles vaccination and development of inflammatory bowel disease142144 or autism.144,145 In summary, the
available laboratory and epidemiologic evidence does not support hypotheses that measles or measles-containing vaccines
might contribute to or induce inflammatory bowel disease or
autism146 (see Adverse events). In 2010, the editors of The
Lancet retracted the original article that led to the controversy,147
and in January 2011, the British Medical Journal published an
investigative review that found the medical records had been
incorrectly abstracted to falsely implicate the vaccine.148
Measles has been proposed to be a causal factor for several
other diseases. Studies from different laboratories have revealed
conflicting evidence for persistence of measles virus in affected
tissues from patients with otosclerosis149 and Paget disease.150
Current evidence is inconclusive regarding a possible role of
measles infections in the pathogenesis of multiple sclerosis.151
Infection during pregnancy is associated with an increased
risk of miscarriage and prematurity,152,153 although there is no
convincing evidence that maternal infection with measles is
associated with congenital malformations.154,155 Clinical illness
in the newborn after intrauterine exposure follows a shortened
incubation period and may vary from mild to severe.155,156

Clinical variants
The typical course of measles described in the preceding section can be modified by the presence of antibody.2,49,51 This
situation usually arises in the infant with residual maternal
transplacental antibody or in a person given immune globulin (IG) after exposure, in an attempt to abort or attenuate
disease.67,157160 Although some persons have subclinical infection,161 most will have a mild abbreviated illness that confers
lasting immunity.160,162 A second clinical measles infection may
occur, however, if immunity is incomplete.51,163 Typical or modified measles illness also may rarely follow reinfection after either
natural infection164,165 or vaccination.165174 Schaffner and colleagues164 reported a case of typical, albeit mild, measles in a

353

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SECTION TWO Licensed vaccines

16-year-old girl who reportedly had measles 8 years earlier. She

had a hemagglutination-inhibition (HI) antibody titer of 1:200
on the second day of rash and titers of 1:1,600 and 1:320 at 23
days and 6 months, respectively, after rash onset. The rapidity of
antibody appearance, the high titer achieved, and the absence of
immunoglobulin M (IgM) antibody in all of the specimens suggested a secondary immune response. Although reports examining immunity after infection rely on antibody determination,
immunity relies heavily on T-lymphocyte memory and function.
Measles infection in the immunocompromised host (eg,
persons with malignancies or human immunodeficiency
virus [HIV] infection) can be prolonged, severe, and frequently
fatal.175180 Infection in these persons may occur in the absence
of rash.175,178181 The severity of illness is believed to be due primarily to impaired cell-mediated immunity.182185 Two especially severe complications are an acute progressive encephalitis
(measles inclusion body encephalitis)98,186,187 and a characteristic
giant cell pneumonia (Hecht pneumonia).175177,188 Measles has
been found to be more severe in persons with HIV infection. In
the United States, the case-fatality rate has been reported to be
as high as 50% in HIV-infected children.189
An atypical variant of measles occurred in some recipients of killed measles vaccine who were subsequently exposed
to wild-type virus.49,51,163,165,190202 Early studies found that
patients with atypical measles lacked antibody to the measles virus fusion (F) protein127,202,203 and had exaggerated cellular responses to measles antigen.75,204 Affected patients had
extremely high levels of measles-specific circulating antibody.51,75,76,191,202 Studies in monkeys have shown that this illness is caused by antigen-antibody immune complexes.205 The
formalin-inactivated vaccine induced complement-fixing antibodies that failed to undergo affinity maturation; after exposure to measles, an anamnestic production of nonprotective,
complement-fixing antibodies resulted in immune complex
deposition and atypical measles.206 After an incubation period
of 1 to 2 weeks, a prodrome consisting of high fever, headache, abdominal pain, myalgia and cough ensued. In the next
2 to 3 days, an unusual rash erupted on the extremities and
spread centripetally. Whereas the exanthem could be erythematous and maculopapular, it was frequently petechial or vesicular and accompanied by edema, and was occasionally pruritic.
Hepatocellular enzymes were sometimes strikingly elevated.
The illness was frequently mistaken for Rocky Mountain spotted fever and had to be differentiated from meningococcemia,
Henoch-Schnlein purpura, and drug eruptions.49,51 A nodular
pneumonitis with pleural effusion was common.199,207 Despite
the potential for serious illness, there was only one report of a
possible atypical measles-related fatality.208 This syndrome also
has been reported rarely after receipt of live measles vaccine
exclusively.209,210 Persons with atypical measles are believed to
be noncontagious.51,191,192 On the basis of humoral and cellular
immunity studies, they also are thought to be protected from
subsequent illness after exposure to measles.75,76,202 The syndrome probably can be prevented by appropriate immunization
with live vaccine.75,76,211,212

Virology
The measles virus is a pleomorphic, nonsegmented, singlestranded, negative-sense RNA virus with a diameter of 120 to
250 nm.127,203,213 It is a member of the genus Morbillivirus in
the family Paramyxoviridae and is closely related to the canine
distemper, rinderpest, peste-des-petits-ruminants viruses, and
a phocine distemper virus of seals.214,215 Recent phylogenetic
analysis suggests divergence of measles virus from its closest
relative, rinderpest virus, occurred around the 11th to 12th centuries.216 The only natural host for the measles virus is humans.
In susceptible populations, measles is one of the most transmissible viruses known. The viral structure is composed of eight

proteins encoded within a 16-kb genome, including replication

factors (polymerase [L] and phosphoprotein [P]), structural proteins (hemagglutinin [H], fusion [F], nucleoprotein [N] and
matrix [M]) and two accessory proteins of unknown function (C
and V).203 The F and H proteins are essential in viral pathogenesis. The F protein is involved in the viral/host cell membrane
fusion and viral entry into the host cell. The measles H protein
is involved in the attachment and entry of measles virus into
host cells via interaction with cell surface receptors. Signaling
lymphocyte activation molecule (SLAM, also called CD150) is
a membrane glycoprotein expressed on activated T and B lymphocytes and antigen-presenting cells that acts as the principal
cellular receptor for measles virus, accounting for its lymphotropism and immunosuppressive nature.217 Measles virus also
infects respiratory epithelial cells via a recently identified receptor molecule (CD147/EMMPRIN), thereby facilitating transmission via aerosol droplets.218 Vaccine and laboratory-adapted
strains of measles virus use ubiquitously expressed CD46 as an
alternate receptor. Other molecules have also been implicated in
measles virus infection, although their relevance remains to be
determined.
The entire 15,894-nucleotidelong genome of the prototype
Edmonston strain of measles and the genomes of the predominant measles vaccine strains219221 have been fully sequenced,
as well as an increasing number of wild-type strains, including
some identified from SSPE cases.222224 Although measles virus
is considered a monotypic virus, sequence analysis of the N, H,
P, and M genes has shown that there are multiple, distinct lineages of wild-type viruses.225232 This sequence variability has
made it possible to use molecular techniques to help monitor
the transmission pathways of measles virus.233 Molecular epidemiologic data, when analyzed in conjunction with standard
epidemiologic information, can confirm or suggest the source
of outbreaks and, over time, can provide a measurement of
the effectiveness of vaccination control programs and monitor elimination.231 For example, genetic analysis of wild-type
viruses isolated in the United States from 1988 to 2000 helped
to document the interruption of endemic transmission in the
United States.234 Comparison of genetic sequences from wildtype strains isolated in the United States with those isolated
elsewhere in the world has suggested international importations of measles virus as sources of outbreaks.233 To facilitate
the expansion of virologic surveillance activities, the World
Health Organization (WHO) has recommended a standard
nomenclature and analysis protocol.235 The WHO currently
recognizes 24 genotypes (Figure 20-1) of measles virus based on
phylogenetic analysis of the N gene and has established a set of
reference sequences.236 In 2000, the WHO established a global
measles and rubella laboratory network to provide standardized procedures for case confirmation and virus characterization.237 Although virologic surveillance is incomplete, increased
laboratory capability and improved surveillance in the past 2
years has seen a pattern for the global distribution of genotypes
(Figure 20-2).238 The biologic significance of differences in the
genetic sequence of wild-type strains is not known; the immune
response generated through vaccination protects against all
strains.
Measles virus can be cultured from clinical specimens and is
best isolated in the cell line, Vero/hSLAM.239 These are Vero cells
transfected with a plasmid encoding the gene for the human
SLAM molecule. The sensitivity of Vero/hSLAM cells for isolation of measles virus is equivalent to that of the previously
used B95a cells, which were coinfected with Epstein-Barr (EB)
virus. In addition, Vero/hSLAM cells are sensitive to laboratoryadapted measles strains, including vaccine viruses.240 Measles
virus can also be detected directly from clinical specimens, such
as oral fluid or throat swabs, through molecular techniques that
are being used to monitor measles transmission patterns without the need for virus culture.

Measles vaccine

20

Figure 20-1 Genetic variation in wild-type measles

viruses, 2012. The World Health Organization (WHO)
recognizes 24 genotypes of wild-type measles virus (A,
B1, B2, B3, C1, C2, D1, D2, D3, D4, D5, D6, D7, D8,
D9, D10, D11, E, F, G1, G2, G3, H1, and H2). The figure
shows a phylogenetic tree based on the sequences of the
nucleoprotein genes of the WHO reference strains for each
genotype. The horizontal scale is proportional to genetic
relatedness.

MVi/NEW YORK.USA/94 [B3]

MVi/BADAN.NIE/97 [B3]
MVi/YAOUNDE.CAE/83 [B1]
MVi/LIBREVILLE.GAB/84 [B2]
EDMONSTON (wild-type) [A]
MVs/MADRID.SPA/94 [F]
MVi/BRAXATOR.DEU/71 [E]
MVi/TOKYO.JPN/84-K [C1]
MVi/JM.USA/77 [C2]
MVi/WYF.DEU/90 [C2]
MVi/HUNAN.CHN/93 [H1]
MVi/BEIJING.CHN/94 [H2]
MVi/BERKELEY.USA/83 [G1]
MVi/AMSTERDAM.NET/97 [G2]
MVi/GRESIK.INO/02 [G3]
MVi/JOHANNESBURG.SOA/88 [D2]
MVi/UGANDA/01 [D10]
MVi/NEW JERSEY.USA/94 [D6]
MVi/MVP.UK/74 [D1]
MVi/MONTREAL.CAN/89 [D4]
MVi/PALAU.BLA/93 [D5]
MVi/VICTORIA.AUS/99 [D9]
MVi/CHICAGO.USA/89 [D3]
MVi/BANGKOK.THA/93 [D5]
MVi/MANCHESTER.UK/94 [D8]
MVi/YUNNAN.CHN/09 [D11]
MVi/VICTORIA.AUS/85 [D7]
MVi/ILLINOIS.USA/99 [D7]
5

Chart proportional to
number of genotypes
5
1

Distribution of measles genotypes, 2010

Genotypes:
Incidence:
(per 100,000)

B2
<0.1

B3

D11

0.1 <1

D4

D5

1 <5

D8
5

D9

G3

H1

No data reported

Figure 20-2 Worldwide distribution of measles virus genotypes, 2010.

Measles virus is inactivated rapidly in the presence of sunlight, heat, and extremes of pH.127 It can, however, be safely
stored for long periods at 70 C ( 94 F).
In cell cultures, the virus causes two distinct cytopathic effects.19,127,241,242 The first is formation of multinucleated syncytia

(giant cells) containing numerous nuclei of fused cells. This corresponds to the predominant pathologic process observed in infected
tissues, including skin and Koplik spots.243 When observed in lymphoid tissue, the giant cells are referred to as Warthin-Finkeldey
cells; otherwise they are known as epithelial giant cells.127 Whereas

355

SECTION TWO Licensed vaccines

this cytopathic effect is characteristic of wild-type virus isolates,

the cytopathic effects of passaged virus may additionally include
spindle cell transformation. This difference in cytopathic effects
as well as other factors, such as ability to grow in chick embryo
fibroblasts, plaque morphology, interferon production, and optimal
growth temperature, help differentiate wild-type virus from attenuated vaccine virus strains, as does sequencing.127,244246

Pathogenesis as it relates to prevention

The sequence of events between exposure to measles virus and
subsequent primary acute illness in the normal host has been
extensively studied, described, and reviewed;49,51,8183 it is based
on information from both monkeys and humans. In the standard model of measles virus pathogenesis, there is initial localized
infection of the respiratory epithelium of the nasopharynx, and
possibly of the conjunctivae,218,247 followed by spread to regional
lymphatics.246 Further events then occur in a manner similar to
those observed in the Fenner ectromelia-mouse experimental
model.248 Specifically, 2 to 3 days after exposure, there is a primary
viremia with further replication of virus at the site of inoculation
as well as in regional and distant reticuloendothelial tissue. Then,
5 to 7 days after exposure, there is an intense secondary viremia of
4 to 7 days duration that leads to infection of and further replication in the skin, conjunctivae, respiratory tract, and other distant
organs.249 The amount of virus in blood and infected tissues peaks
11 to 14 days after exposure and then falls rapidly during the next
2 to 3 days. Alternative models of measles virus pathogenesis
have been proposed. Lemon and colleagues,250 using a nonhuman
primate model, found that measles virus enters the host at the
alveolar level, followed by its appearance in regional lymphoid tissue and subsequent systemic dissemination by viremia.
The pathogenesis of measles infection indicates that prevention through immunization could be accomplished by inhibiting
replication at the initial site of infection or by inhibiting the viremia that occurs during the incubation period. The first approach
requires the presence of local secretory IgA antibody or transudated IgG;251 the second approach requires circulating antibody,
either actively or passively acquired, to neutralize the virus.
Although infection can be prevented solely after administration
of antibody,157160 induction of cellular immunity would also seem
to be desirable.2,246 Children with primary agammaglobulinemia
do not have more severe measles infections than do children with
normal immune systems, and both develop long-lasting immunity after infection.183,184 These observations indicate that the cellmediated immune system alone is capable of preventing measles.
On reexposure, it is uncertain whether prevention of the primary viremia is necessary or even feasible, but it is obvious
that the secondary viremia should be prevented. In fact, an initial limited replication and the circulation of a small amount of
viral antigen may be necessary to restimulate the immune system and to elicit an anamnestic antibody response.

Diagnosis
Measles should be suspected in children who present with an acute
erythematous rash and fever, preceded by a 2- to 4-day prodrome of
cough, coryza, conjunctivitis, and photophobia. Recent experience
suggests that clinical measles may be difficult to distinguish from
other causes of febrile rash illness, particularly in areas where the
incidence of measles has been low. Clinical features that support
the diagnosis of measles include the presence of Koplik spots, the
characteristic 2 to 4 days of intensifying prodromal symptoms, the
progression of the rash from the head to the trunk and out to the
extremities, and the lysis of fever shortly after the appearance of
the rash. Health care providers working in measles-endemic areas
may be more familiar with these clinical findings than are health
care providers working in areas with a low incidence of measles. A
clinical case definition for epidemiologic purposes is the presence

of rash lasting 3 or more days; a fever (temperature of 38.4 C (101

F)) or higher, if measured; and cough, conjunctivitis, or coryza.212
Its use for clinical diagnosis is limited, particularly because of the
criterion requiring at least 3 days of rash before the diagnosis is
made. In some parts of the world, a less specific clinical definition not requiring 3 days duration of rash is being used for epidemiologic purposes. Laboratory tests are necessary to confirm
the diagnosis, especially when measles is rare. Other illnesses,
such as rubella, dengue, parvovirus B19, human herpesvirus type
6, and measles vaccine reactions, can meet these clinical definitions.252254 In the United States, it is recommended that clinicians
obtain a blood or other suitable specimen for laboratory confirmation from all patients suspected of having measles.
Although virus isolation, direct cytologic examination of
clinical material, or demonstration of virus antigen can be used
to diagnose measles,55,56,255260 detection of measles-specific
IgM antibody from a single blood specimen is the most commonly used method. An increase in measles antibodies between
acute and convalescent serum specimens is also diagnostic but
requires the collection of two blood specimens. RT-PCR can be
used to identify measles virus RNA in urine, blood, oral fluid,
and nasopharyngeal mucus.261264 Because measles is an RNA
virus, RNA must be reverse transcribed to DNA before PCR
analysis, resulting in a much reduced sensitivity for diagnosing
measles compared with diagnosing DNA viruses.265
In primary acute infection, detectable antibodies generally
appear in the serum within the first few days of rash onset,
peak within about 4 weeks, and subsequently decline somewhat
but persist for life (Figure 20-3).49,51,6467,266268 Both IgG and IgM
antibodies are initially produced.269272 However, IgG antibodies
are detectable long after infection, whereas IgM antibodies are
rarely detected after 6 to 8 weeks. Serum and secretory IgA antibodies are also produced.7072,273,274 Reexposure usually induces a
characteristic anamnestic response with a rapid boosting of IgG
antibody; IgM may not be detected after reexposure with use
of some currently available serologic assays.67,171,270,271 If IgM is
detected after reexposure, it will be at a lower ratio to IgG than
the IgM-to-IgG ratio in a previously unexposed person.275
The tests for complement fixation (CF), HI, and neutralization (Nt) have been the assays historically employed to detect
fourfold rises in measles IgG antibody between acute and convalescent sera.127 However, the CF test has been shown to be less
sensitive,6567,80,276 and the HI and Nt tests have undergone technical modifications over time.277 The plaque reduction neutralization (PRN) test has remained the gold standard to which other
more rapid and simpler methods are compared, but, because it is
time and personnel intensive, it is generally limited to specialized

Virus

Nasopharynx
Blood

Rash

Relative antibody levels

356

EIA
HI
Nt
CF
IgM

14
Infection

0
Rash
onset

14 21 28 35
Days after onset

42 1 5 10
Years
after
illness

Figure 20-3 Schematic of the immune response in acute measles

infection. EIA, enzyme immunoassay; HI, hemagglutination; NT,
neutralization; CF, complement fixation; IgM, immunoglobulin M.

Measles vaccine

reference laboratories and research work.277 Fluorescence tests are

available,278 as are enzyme immunoassays (EIAs), also referred
to as enzyme-linked immunosorbent assays (ELISAs).279285
Currently EIA tests for measles IgG are the most widely used
because they are generally sensitive and convenient. Good correlation has been shown between HI and Nt antibody in many
studies,286 as well as between EIA and other serologic methods
for the diagnosis of acute measles.280,281,287 The EIA for measles
IgG is based on significant changes in optical density values and
cannot be translated directly to antibody concentrations or titers.
Currently, the recommended laboratory method for the confirmation of clinically diagnosed measles is a serum-based IgM EIA
collected at the time the patient is first seen for medical care.288
A single specimen is adequate to detect the presence of IgM antibody.274,284,285 A number of commercial kits using an indirect EIA
method (with removal of the patient's IgG antibody before testing
for IgM) or an antibody capture EIA technique (without removal
of IgG) are now available and have been shown to have similar
sensitivity (83%-92%) and specificity (87%-100%).289 However, if
measles prevalence is low (eg, 1%), a modest reduction in the
specificity of the assay from 99% to 95% will decrease the positive predictive value of the assay from 48% to 15% (ie, only 15%
of IgM-positive clinical cases will be true measles). Patients with
parvovirus B19 or rubella infections may have false-positive reactions (rate of about 4%) when tested with measles IgM EIAs.252,290
Correct interpretation of serologic data depends on proper
timing of specimens relative to rash onset. This is especially
important in interpreting negative IgM results. For example, in
one study, the sensitivity of an antibody capture IgM assay was
approximately 80% within the first 72 hours after rash onset and
rose to 100% between 3 and 14 days after rash onset.291 Sensitivity
of the assay within the first 3 days of rash onset is thought to be
similar for other commercially available kits. If the validity of the
initial measles IgM test is in doubt, a second convalescent specimen should be taken and tested for IgM and for a rise in IgG titer
compared with the initial specimen. In some cases, interpretation
may be difficult and requires precise information regarding dates
of rash onset, prior measles vaccination, and specimen collection.
Two approaches provide alternatives to venipuncture for collection of diagnostic specimens: oral fluid and blood spots on filter paper. In the United Kingdom, a commercial IgM EIA-based
assay has been developed and is routinely used to test oral fluid
specimens for measles, with a reported sensitivity of 94%, specificity of 91%, and positive predictive value of 99% compared with
serum.292,293 Use of oral fluid samples has appeal because the technique is noninvasive, can be used for rubella and mumps testing,
does not require processing in the field, can be shipped without
cold chain, and can be used to detect not only measles IgM and
IgG but also the measles virus genome for molecular characterization. Although still considered an invasive technique, fingerstick
as a method for sample collection may be more acceptable to parents than phlebotomy.265 Blood spots collected onto filter paper do
not require processing in the field, or a cold chain for transport to
the laboratory, and can be used to test for measles and rubella as
well as for molecular characterization of the measles virus genome.
In addition, the eluted serum can be tested by using commercially
available EIAs with minimal loss of sensitivity or specificity.294297

Treatment
A number of preparations, such as interferon,298,299 thymic
humoral factor,300 thymostimulin,301 levamisole,302 ribavirin303
and IG,157 have been used to treat measles. None of these is
commonly used to treat uncomplicated measles, although limited studies with ribavirin have shown reduced duration of illness.303 Ribavirin and interferon may be effective in treating
severe measles in immunocompromised persons.304
High doses of vitamin A have been shown to decrease mortality and morbidity in young children hospitalized with measles

20

in developing countries.305308 The WHO currently recommends

vitamin A for children with acute measles.309 Treatment with
vitamin A is once daily for 2 days at 200,000 IU for children
ages 12 months or older, 100,000 IU for infants 6 to 11 months
of age, and 50,000 IU for infants younger than 6 months. In the
United States as well as in developing countries, children with
measles have been found to have low levels of serum retinol,
and those with more severe illness have lower levels.310312 The
American Academy of Pediatrics (AAP) recommends using two
doses of vitamin A (200,000 IU) on consecutive days, which has
been shown to be associated with a reduction in the risk of mortality in children younger than two years (relative risk [RR], 0.18;
95% CI, 0.03-0.61) and the risk of pneumonia-specific mortality
(RR, 0.33; 95% CI, 0.08-0.92). There was no evidence that vitamin A in a single dose was associated with a reduced risk of mortality among children with measles.211,313 In addition, vitamin A
therapy should be administered to children with measles who
are immunosuppressed, who have clinical evidence of vitamin
A deficiency, or who have recently immigrated from areas with a
high mortality rate from measles.206 Antibiotics, in the absence
of pneumonia, sepsis, or other signs of a secondary bacterial
complication, are generally not recommended.314 However, a
recent clinical trial in Guinea-Bissau found that case-patients
who received prophylactic antibiotics (co-trimoxazole) had less
pneumonia and conjunctivitis and higher weight gain, suggesting a beneficial role of prophylactic antibiotics in the treatment
of measles in low-income countries.315
Various chemotherapeutic agents have also been used in patients
with SSPE in an attempt to treat or at least alter the clinical course
of the disease.130,316319 Of these, inosiplex (Isoprinosine) and interferon have been the most extensively studied;317321 despite anecdotal evidence of their effectiveness, controlled trials are lacking.

Epidemiology
General epidemiology
In the absence of an immunization program, measles is a ubiquitous, highly contagious, seasonal disease affecting nearly every
person in a given population by adolescence.2,322324 An important
exception is island populations, which can remain free of infection
for variable periods and then, after reintroduction of the virus, experience epidemic disease that involves all age groups not affected by
the last wave of infection.2,6,80,85,89,323 Thus, whereas peak transmission usually occurs among young children, outbreaks in isolated
communities involve many older persons. This is exemplified by
Panum's description of measles on the Faroe Islands,6 in which the
disease affected persons of all ages who were not affected by the
last epidemic that had occurred 65 years earlier.
Measles is transmitted primarily from person to person by large
respiratory droplets but also can be spread by the airborne route
as aerosolized droplet nuclei.2,325328 The period of maximal contagion occurs during the prodrome.7,49,51,90 Secondary attack rates
in susceptible household (and institutional) contacts are high and
can be on the order of 90% or greater.50,65,266,329331 Because virus is
excreted before and after the appearance of rash, the onset of exanthem in secondary household cases occurs an average of 14 to 15
days (range of 7-21 days) after that in the index case.330 Almost all
primary infections (except those modified by maternal antibody or
parenteral IG) are thought to be clinically overt.2 Asymptomatic
transmission from exposed immune persons has not been demonstrated.332,333 Although susceptible monkeys may become infected
with measles, there is no significant animal reservoir.2,49,127
Before the introduction of vaccines in most developed countries, school-age children had the highest risk of infection and
accounted for the largest proportion of cases.2,322 However,
in dense urban areas, transmission among preschoolers took
on greater importance.322 Although serious complications did

357

358

SECTION TWO Licensed vaccines

Table 20-1 Age Distribution and Mean Annual Incidence of Reported Measles Cases by Age Group
1981-1988

1960-1964*

1989-1991

1992-2000

2001-2010

Age (yr)

Total (%)

Cases/
100,000

Total (%)

Cases/
100,000

Total (%)

Cases/
100,000

Total (%)

Cases/
100,000

Total (%)

Cases/
100,000

0-4

37.2

766.0

31.9

4.9

43.6

43.7

39.9

1.08

33.1

0.12

5-9

52.8

1236.9

11.7

1.8

10.4

10.4

9.6

0.26

8.1

0.03

10-14

6.5

169.1

19.7

3.3

9.2

9.8

9.6

0.26

9.4

0.03

15

3.4

10.0

35.6

0.6

36.9

3.5

41.0

0.10

49.4

0.02

*Data represent prevaccine years and are from four reporting areas: New York City, District of Columbia, Illinois, and Massachusetts.

Data from the entire United States.

occur, they were relatively rare compared with the situation

in developing countries. In the United States before the introduction of vaccine in 1963, major epidemics occurred approximately every 2 to 3 years.2,334336 Each year, disease peaked in
late winter and early spring. The highest occurrence of disease
was in children 5 to 9 years of age, who accounted for more than
50% of reported cases (Table 20-1). More than 95% of cases had
occurred by age 15 years.2,322 The highest risk of death was in
children younger than 1 year and in adults. 92,93
The measles virus is so contagious that it can be expected to
circulate wherever a relatively large number of susceptible persons congregate, even in the face of a low population susceptibility
rate.2 This explains the outbreaks that were typical among military
recruits before the institution of routine measles vaccination.337
Outbreaks among high-school and college students, most of
whom have been vaccinated, demonstrate the virus's capability to
seek out the small number of remaining susceptible persons.337341
Before widespread vaccination, in many developing countries, the average age at infection was much lower than that
observed in developed countries.2,105111 In some areas of Africa,
more than 50% of 2-year-old and 100% of 4-year-old children
may be expected to have had measles. Poor nutrition and rapid
loss of maternal antibody may explain why a greater proportion
of these infants are susceptible at an earlier age than are those
in developed areas,286,342346 and infection, in turn, results from
the early age at which infants are exposed to the community at
large.105 Young age at infection contributes to the high risk of
serious complications and death. Also, malnutrition, especially
vitamin A deficiency, may be an important factor leading to the
marked severity of measles in the developing world because
of defects in cellular (and possibly humoral) immunity.112,347
However, there is some evidence that crowding, which leads
to a potential increased dose of transmitted virus, may be a
more significant determinant of the severity of infection than is
protein-calorie malnutrition.348350

Significance as a public health problem

Although remarkable control of measles has been achieved in
some areas of the world,39,351 in 2000, measles was still the leading
cause of vaccine-preventable deaths in children and the fifth leading cause of all deaths among children less than 5 years of age.352
Measles is also responsible for much diarrhea, respiratory disease,
and blindness in the developing world.116,121,122 Through mass vaccination campaigns and increased routine immunization coverage, the estimated number of measles deaths worldwide dropped
74% from 535,300 deaths in 2000 to 139,300 deaths in 2010.353
In the United States in the prevaccine era, approximately
500,000 cases of measles were reported each year, but, in reality, an entire birth cohort of approximately 4 million persons
was infected annually.354,354a Associated with these cases were
an estimated 500 deaths, 150,000 cases with respiratory complications, 100,000 cases of otitis media, 48,000 hospitalizations, 7,000 seizure episodes, and 4,000 cases of encephalitis,
which left up to one quarter of patients permanently brain dam-

aged or deaf.354a By using a 1992 dollar value, the annual estimated costs of measles in 1994 in the absence of vaccination
would have been $2.2 billion in direct costs and $1.6 billion in
indirect costs.355 An updated economic analysis of the two-dose
measles-mumps-rubella vaccination program in the United
States adjusted to 2001 dollars, found the direct and societal
benefit-to-cost ratios to be 14.2 and 26.0, respectively.356

Passive immunization
Passive immunity to measles can be acquired through physiologic transfer of maternal measles antibodies from mother to
child or by administration of measles antibodies from convalescent donors to persons at risk of measles.
Maternal antibodies provide time-limited protection against
measles during the first months of life when infection can be
most devastating.65 Women who have antibodies to measles,
from measles infection or vaccination, transfer antibodies to
their children during pregnancy via the placenta and after delivery by breastfeeding.357,358 Among newborns, the duration of
protection by transplacental measles antibody varies from some
being unprotected (ie, their mother lacked immunity) to others being protected for up to 15 months of age. The factors that
affect the duration of transplacental measles antibodies among
infants and the effect of these antibodies on response to measles
vaccination are presented in the section Maternal antibody
and age at vaccination. Measles-specific antibodies, including secretory IgA, are excreted in the breast milk of immune
mothers and have been shown to neutralize measles virus
in vitro.357,358 Many of the key factors related to breast milk antibodies against measles are not well determined. In two studies
in Africa in the 1980s, one showed a significant reduction in the
measles mortality rate of hospitalized children who were breastfed compared with those who had been weaned, while the other
study showed no protective effect of breastfeeding.359,360
Administration of measles antibodies as immune globulin
provides short-term protection from measles for susceptible
persons. Preexposure prophylaxis against measles and other
diseases is provided to persons with primary humoral immune
deficiency diseases (PIDD) via frequent administration of
immune globulin given intravenously (IGIV) or subcutaneously (IGSC). Postexposure prophylaxis with immune globulin given intramuscularly (IGIM) is recommended for persons
exposed to measles or at high risk of exposure for whom vaccine is either contraindicated or was not given within 3 days
of exposure (see Postexposure prophylaxis and Use of
immune globulin).
In 1926, Zingher361 summarized early efforts to prevent measles by injection of whole blood, serum, or plasma from donors
who had a previous measles infection. A significant reduction
in the measles attack rate among persons who received convalescent blood products after exposure to measles was shown,
and convalescent blood products were widely used as postexposure prophylaxis in the 1920s and 1930s. In the 1940s, Janeway

Measles vaccine

demonstrated that administration of IG within 6 days after intimate exposure prevented measles in about three of four persons, with mild measles occurring in the fourth.158
Immunoglobulin products are prepared from plasma pools
derived from thousands of donors. Measles disease results in
higher antibody titers than does vaccination. Therefore, donor
populations with predominantly vaccine-induced measles
immunity yield lower measles antibody titers in IG preparations. A study in Japan showed lower measles antibody titers in
IGIM may result in a reduced level of postexposure protection
from measles.362 Audet363 demonstrated a progressive decrease
in measles virus neutralizing antibodies in IGIV lots in recent
years in the United States, correlated with an increase in the
proportion of plasma donors who were born in the vaccine era.363
In the United States, the Food and Drug Administration (FDA)
requires that all IG preparations contain a measles-neutralizing
antibody level that demonstrates adequate potency when compared with the US standard.364 In 2007, the FDA Blood Products
Advisory Committee reduced the potency requirement from
0.60 to 0.48 of the standard lot titer for both IGIV and IGSC,
which are given in much higher volumes than IGIM. The new
potency requirement for IGIV and IGSC lots is calculated to provide a protective measles antibody titer given the recommended
minimum doses, and dose frequency.365 The potency requirement for IGIM remains 0.60 of the standard lot titer.

Active immunization
Vaccine strains
Origin and development
After the isolation and propagation of measles virus in tissue
culture by Enders and Peebles8 in 1954, vaccine development,
testing, and licensure quickly followed.1121 The Edmonston

20

strain, named after the youth from whom the virus was
isolated, was used for many of the vaccines developed worldwide (Figure 20-4).366383 To make the now-famous Edmonston
B vaccine, Enders and colleagues12,19,246 further passaged the
Edmonston strain at 35 C to 6 C (95 F-96.8 F) 24 times in
primary kidney cells and 28 times in primary human amnion
cells, adapted it to chicken embryos (6 passages), and then passaged it in chicken embryo cells. This attenuated Edmonston B
vaccine was licensed in the United States in March 1963 along
with another Edmonston B virus strain that had been adapted
to primary dog kidney cells.384386 Although the administration
of the Edmonston B vaccine was associated with a high rate
of fever (temperature of 39.4 C (103 F) or higher in 20% to
40% of vaccinees) and rash (approximately 50%), the recipients
remained remarkably well. However, simultaneous administration of a small dose of IG with the vaccine (eventually set at 0.02
mL/kg) reduced the occurrence of high fever and rash by approximately 50% (Figure 20-5).266,369,372,373,384,385,387392 Approximately
18.9 million doses of Edmonston B vaccine were administered
in the United States between 1963 and 1975 (Table 20-2 and
Figure 20-6).

Killed vaccine
A formalin-inactivated, alum-precipitated vaccine derived from
the Edmonston strain was also licensed in the United States in
1963 and used until 1967 (see Table 20-2 and Figure 20-6). This
vaccine was also used in some provinces in Canada. Usually,
three doses of killed vaccine or two doses of killed and one dose
of live vaccine were administered at monthly intervals with few
side effects.67,266,369,372,393400 Use of killed vaccine was eventually discontinued when it became apparent that this vaccine
produced short-lived immunity and placed many recipients at
risk for atypical measles infection.401 It has been estimated that
between 600,000 and 900,000 persons in the United States
received the 1.8 million doses of killed measles vaccine that
were administered (see Table 20-2 and Figure 20-6).402

Edmonston
HK
HA
CE
CEF
HA
SK
CEF

CEF
Edmonston A
CEF

AIK-C

CE
CEF
Edmonston B
CEF

Schwarz

Connaught

CEF
Moraten

CEF

WI-38
EdmonstonZagreb

Schwarz-f88

Leningrad

Shanghai

GPK
JQ

HK
HA
CEF

Leningrad-16

Shanghai-191

Tanabe
MK
HK
CE
CAM
CEF
CAM-70

HK
MK
GPK
CE
TD 97

Figure 20-4 Attenuation history of selected measles vaccine strains. Cell cultures in which strains were passed during attenuation: CAM, chick
chorioallantoic membrane; CE, chick embryo intra-amniotic cavity; CEF, chick embryo fibroblast; GPK, guinea pig kidney; HA, human amnion; HK,
human kidney; JQ, Japanese quail; MK, monkey kidney; SK, sheep kidney; WI-38, human diploid cell line.

359

SECTION TWO Licensed vaccines

100

96

100
Fever 39.4 C (103 F)

90

Rash

80
70
Percent

360

60
50

50
40
30

30
20

15

12

10

15
5

0
Natural
measles
(33)

Edmonston B Edmonston B
NO IG
+ IG
(175)
0.020.04 ml/kg
(854)

Further
attenuated
NO IG
(589)

Further
attenuated +
IG 0.2 ML
(452)

Figure 20-5 Incidence of fever and rash after natural measles infection and vaccination. The number of susceptibles is included in parentheses.
IG, immunoglobulin. (Adapted from Krugman S, Giles JP, Jacobs AM, et al. Studies with a further attenuated live measles-virus vaccine. Pediatrics 31:919-928, 1963.)

Table 20-2 History of Measles Vaccine Manufacture and Distribution in the United States, 1963 to 2010
Vaccine

Strain

Manufacturer

Brand

Years in use

Doses distributed

Inactivated

Lilly
Pfizer

Generic
Pfizer-Vax,
Measles-K

1963-1967

1.8 million

Live, attenuated

Edmonston B

Lederle
Lilly
Merck
Parke Davis
Pfizer

M-Vac
Generic
Rubeovax
Generic
Pfizer-Vax,
Measles-L
Generic

1963-1975

18.9 million

Live, further
attenuated

Schwarz

Lirugen

1965-1976

> 350 million

Attenuvax

1968 to 2010

Philips Roxane

Moraten

Pitman MooreDow
Merck

Modified from Hayden GF. Measles vaccine failure: a survey of causes and means of prevention. Clin Pediatr 18:155-167, 1979.

Further attenuated live vaccines

Many further attenuated vaccines have been developed and
are in active use worldwide (Table 20-3; see Figure 20-4). Most
were derived from the Edmonston strain. These further attenuated vaccines differ in the viral isolate of origin, the number
and temperature of cell culture passages, the type of cell culture
used for the passage and production, and whether plaquings
were performed during the passages.12,19,375,379,380,383,403 Although
differences in plaque size,375,404 subgenomic particles,405 temperature sensitivity,406 and pathogenicity in severe combined
immune-deficient mice containing human thymic tissue
implants407 have been described among the further attenuated
vaccine strains, their significance is uncertain.
Nucleotide sequence analysis of the F, H, N, and M genes
showed no more than 0.6% variability among vaccine strains
derived from the Edmonston strain.230 Complete genomic
sequence analysis of different measles vaccine strains have
been compared with the Edmonston wild-type virus. AIK-C,
Moraten, Rubeovax, Schwarz, and Zagreb were all found to be
of the Edmonston lineage, whereas CAM-70, Changchun-47,

Leningrad-4, and Shanghai-191 were derived from four different wild-type isolates.406,408 However, all the vaccine strains,
whether derived from Edmonston or from other wild-type
viruses, are members of the same genotype, genotype A.230,238
Studies have identified nucleotide sequence substitutions
in the H gene that appear to mediate some of the biologic characteristics of the Moraten strain of vaccine.409 Comparison of
the noncoding regions of a low-passage Edmonston wild-type
strain and five Edmonston vaccine viruses found 21 nucleotide positions at which the wild type and one or more of the
vaccine types differed. Five nucleotide substitutions were conserved in all of the vaccine strains. Comparison of proteinencoding nucleotide sequences of the N, P, M, F, H, and L genes
of these vaccine strains with Edmonston wild-type virus identified amino acid substitutions in each of the genes; however,
the overall level of heterogeneity did not exceed 0.3%.220,221
The role that these sequence differences in both the coding
and noncoding regions of the genome play in attenuation of
measles viruses is being characterized by using specialized
genetics systems.410

Measles vaccine

20

20
Live, further attenuated
Live, attenuated
Inactivated

18
16

Doses (in millions)

14
12
10
8
6
4
2
0
63 65 67 69 71 73 75 77 79 81 83 85 87 89 91 93 95 97 99 01 03 05 07 09
Year
Figure 20-6 Doses of measles virus vaccines distributed by vaccine type, United States, 1963 to 2010. Live attenuated is the Edmonston B strain;
live, further attenuated is the Schwarz and Moraten strains combined.

Table 20-3 Measles Vaccine Manufacturers and Vaccine Strains

Produced as of 2011
Manufacturer

Vaccine strain

Merck (United States)

Moraten

SanofiPasteur (France)

Schwarz

GlaxoSmithKline (Belgium)

Schwarz

Government Pharmaceutical
Organization (Thailand)

Schwarz

BioManguinhos (Brazil)

Schwarz

Takeda Chemical Industries, Ltd (Japan)

Schwarz F88

Berna Biotech (Switzerland)

Edmonston-Zagreb

Serum Institute of India

Edmonston-Zagreb

Institute of Immunology (Croatia)

Edmonston-Zagreb

Biken (Japan)

CAM-70

BioFarma (Indonesia)

CAM-70

The Kitasato Institute (Japan)

AIK-C

The Razi State Serum Institute (Iran)

AIK-HDC*/Schwarz

Moscow Plant of Biological

Preparations (Russia)

Leningrad-16

Beijing Tiantan Institute of Biological

Products (China)

Shanghai-191

Lanzhou Institute of Biological

Products (China)

Shanghai-191

Shanghai Institute of Biological

Products (China)

Shanghai 191

Wuhan Institute of Biological

Products (China)

Shanghai-191

Changchun Qijian Biological

Products (China)

Chang-47

*AIK-C vaccine produced in human diploid cells.

Two further attenuated live measles vaccines derived

from the Edmonston strain were licensed in the United
States, the Schwarz strain in 1965 and the Moraten strain in
1968 (see Table 20-2 and Figure 20-4). The Schwarz vaccine
was derived from Edmonston virus passaged an additional
85 times at 32 C (89.6 F) in chicken embryo cells.411414
The Moraten strain was also passaged at this lower temperature, but only an additional 40 times.415 Compared with
the Edmonston B vaccine, the frequency and severity of side
effects attributed to these and other further attenuated vaccines were significantly lower (see Figure 20-5).266,369,374,411416
A temperature of 39.4 C (103 F) or higher occurred in
only 5% to 15% and rash in only 3% to 5% of vaccinees.
Simultaneous administration of specially titered IG in a
low dose (0.02, 0.1, or 0.2 mL/kg) further reduced the incidence of high fever and rash to approximately 3% each (see
Figure 20-5).266 These doses of IG did not interfere with
seroconversion, but the peak geometric mean antibody titer
was lower than that observed without IG administration.
The further attenuated vaccines are used without IG.417
The Moraten vaccine (Attenuvax; Merck, Whitehouse
Station, NJ) is now the only measles vaccine used in the United
States; the Schwarz vaccine is the predominant product in many
other nations.378 Several different further attenuated measles
vaccines, including AIK-C, Schwarz F88, CAM-70, and TD97,
have been developed and are being used in Japan.379,380,383,403
The vaccine developed by Smorodintsev (Leningrad-16) was
introduced in Russia in 1967 and was the principal vaccine
virus strain in eastern Europe.376 The CAM-70 and TD97 vaccines were derived from the Tanabe strain.383,403 These vaccines, as well as those in use in China since 1965,381 are the
few not derived from the Edmonston virus.
Whereas most measles vaccines were attenuated and are
produced in chick embryo fibroblasts, a few currently used vaccines were attenuated in human diploid cells. The EdmonstonZagreb vaccine, used extensively in the former Yugoslavia since
1969, was derived from the Edmonston strain and underwent
additional passage in WI-38 cells.375 This vaccine is now produced by several other manufacturers and is the most widely
used vaccine in developing countries (see Table 20-3). Other
vaccine strains have been adapted to MRC-5 and R-17 human
diploid cells in Iran377,382 and in China.381

361

362

SECTION TWO Licensed vaccines

Dosage and route of administration

According to current regulations in the United States, measles vaccine must contain at least 1,000 median tissue culture
infective doses (TCID50) at the end of the expiration date of
the vaccine.418 The vaccine is administered in a 0.5-mL dose.
The minimum dose required to immunize a seronegative child
has been found to be as low as 20 TCID50 in some studies but
higher in others.419422 The dose in the commercial product is
designed to compensate for some of the virus deterioration that
may result either from improper storage or reconstitution or
from exposure to light or heat before injection.
The recommended route of administration is subcutaneous
injection. Although there are only limited data on the intramuscular route, it appears to be as effective as subcutaneous
vaccination.423 Studies with the Edmonston B and further attenuated vaccines have examined the effectiveness of other routes
of administration, such as intranasal and conjunctival inoculation.11,15,50,251,384,385,424426 Most of the results were not favorable.
In contrast, aerosol administration, which was evaluated during
the early 1960s and 1970s showed promising results.426 During
the 1980s, studies were undertaken to determine whether aerosol administration of measles vaccine could overcome maternal antibody and immunize younger infants.426431 Many of
these studies have found the Edmonston-Zagreb vaccine strain
to be more immunogenic than the Schwarz strain when it is
administered by aerosol.432 However, whereas some investigators reported high seroconversion rates after administration by
this route in young infants,427429,431 others found it inferior to
subcutaneous administration.430
Aerosol administration of measles vaccine in South Africa433
and of combined measles and rubella vaccines in Mexico434
resulted in boosting of antibody responses among schoolchildren. These studies have led to enthusiasm about the possible use of aerosol administration as a less invasive alternative
to needle-and-syringe administration during mass vaccination
campaigns, especially among schoolchildren. Subsequently,
aerosol administration of the Edmonston-Zagreb strain has
been shown to induce a primary immunization response at 9
months of age.435 However, the antibody and T-cell responses
were lower in the infants who received aerosolized vaccine
when compared with those vaccinated subcutaneously, possibly because of the lower dose contained in the aerosol preparation. The challenge remains to demonstrate immunization
safety with this new approach and license an aerosol device
together with an existing measles vaccine strain (see Future
vaccines).

Combination with rubella, mumps, and

varicella vaccines
In the United States, vaccination against measles is accomplished with combined live vaccines that also contain attenuated rubella and mumps vaccine viruses. Combined vaccines
were licensed in the United States in 1971. They contain
at least 1,000 TCID50 of the measles Moraten strain, at least
5,000 TCID50 of the mumps Jeryl Lynn strain, and at least
1,000 TCID50 of the RA27/3 strain of rubella vaccine virus.
The RA27/3 strain of rubella virus replaced the HPV-77:DE-5
strain as the rubella component in 1979. Currently, the only
licensed MMR vaccine is produced by Merck (M-M-R II). In
September 2005, a combined measles, mumps, rubella, and
varicella (MMRV) vaccine produced by Merck was licensed for
use in the United States.436 The measles, mumps, and rubella
vaccine viruses in this quadrivalent vaccine are identical and of
equal titer to those in MMR vaccine. The titer of Oka/Merck
varicella-zoster virus is higher in MMRV vaccine than in singleantigen varicella vaccine (see Chapter 37 on Varicella vaccine).

Combination products have been developed as other countries began vaccinating children against rubella or mumps
along with measles.3134,37,437 For example, GlaxoSmithKline
(Research Triangle Park, NC) produces a vaccine that contains
Schwarz measles vaccine, RIT 4,385 mumps vaccine strain
(derived from the Jeryl Lynn strain), and the RA27/3 strain
of rubella vaccine. Sanofi Pasteur (Swiftwater, PA) produces a
combined formulation with Schwarz measles vaccine, Urabe
mumps vaccine, and RA27/3 rubella vaccine. In Japan, several formulations of combined vaccines are available, including one containing the AIK-C measles virus, the Hoshino
mumps virus, and the Takahashi rubella virus strains.438 Two
other combined vaccines are also licensed: one containing the
CAM-70 measles strain and one containing the Schwarz F88
strain. The MMR vaccine containing the Urabe mumps strain
is no longer being produced in Japan. A triple vaccine with
the Edmonston-Zagreb strain of measles vaccine is being produced by the Institute of Immunology (Zagreb),439 Berna Biotec
(Berne; formerly the Swiss Serum Institute),440 and the Serum
Institute of India (Mumbai; Leningrad-Zagreb mumps strain
and RA27/3 rubella strain).
Safety and immunogenicity data indicate that combining
the measles antigen with rubella and mumps antigens437454 in
the MMR vaccine is both safe and efficacious. Initial results
also showed similar safety and efficacy for MMRV vaccine
compared with MMR given with varicella vaccine at the same
time but at different injection sites.455457 However, when
given as the first dose to young children, more recent studies have shown the risk of febrile seizures458,459 appears to be
higher after MMRV compared with MMR and varicella vaccine
administered simultaneously at separate sites.459 (see Adverse
effects). Based on the increased risk of febrile seizures when
MMRV is used as the first dose in young children, the Advisory
Committee on Immunization Practices (ACIP) has modified
its recommendations for use of MMRV (see General immunization guidelines ).

Production and constitution of vaccine

Preparation methods for the Merck vaccine provide generally
applicable information regarding the production and constitution of measles vaccines.460 Although there are minor differences in dose, antibiotic content, and other details among
manufacturers, there are no reports of significant differences in
side effects or vaccine effectiveness.
The vaccine virus is cultured in primary chick embryo cells.
After an initial cell growth phase, the cultures are inoculated
with the further attenuated Moraten strain of measles virus.
After several days incubation at 32 C (89.6 F), the cells are
washed to remove fetal bovine serum, and the medium is
replaced with one containing 50 g/mL of neomycin, sucrose,
buffered salts, amino acids, and human albumin. Fluids containing virus can be removed from the cultures for a period
of time as the cells are maintained at the same temperature.
These fluids are frozen until determinations of the virus titer
have been performed on retained aliquots. Harvested virus fluids having sufficient virus potency and satisfactorily passing
tests are thawed, pooled, sampled for safety testing, clarified,
dispensed, and refrozen.
When bulk vaccine has passed all quality control tests,
portions of the vaccine are thawed, dispensed into vials, and
lyophilized. At the time of use, the vaccine is reconstituted
with fluid (sterile distilled water) provided by the manufacturer.
A preservative-containing reconstitution fluid is not recommended for general use because it may inactivate the vaccine.
Each vaccine dose contains approximately 25 g of neomycin.
Sorbitol and hydrolyzed gelatin are added as stabilizers. When
reconstituted with the provided diluent, the vaccine is clear and
yellow in color.

Measles vaccine

In 1996, the existence of reverse transcriptase in several

vaccines that were grown in chick embryo fibroblast tissue
culture was reported, including measles vaccine,461 by use of
a new and highly sensitive technique to detect the reverse
transcriptase activity. With use of similar assays, other laboratories have confirmed the existence of the reverse transcriptase activity.462 Subsequent studies showed that this reverse
transcriptase activity is associated with the endogenous avian
retrovirus EAV-0463 and endogenous avian leukosis viruses
ALV-E.464 Extensive efforts to identify a transmissible virus
have failed to link the reverse transcriptase activity with a
transmissible virus. A study of 206 recipients of combined
MMR vaccine found no evidence of infection with either avian
leukosis virus or endogenous avian retrovirus.465 These findings and the fact that transmission of retroviruses across disparate species may be restricted466 indicate no apparent risk to
vaccine recipients.

Stability of vaccine
Measles vaccine is extremely stable between 70 C ( 94 F)
and 20 C ( 4 F).467 Although measles vaccine is affected
adversely by higher temperatures, the introduction of more
heat-stable vaccines in 1979 has led to increased stability under
normal working conditions, which is especially important in
the developing world.468 In the United States, manufacturers
must demonstrate that a minimum titer of 1,000 TCID50 is
maintained through to the labeled expiration date when the
vaccine is stored at 2 C to 8 C. The WHO has a requirement
that lyophilized measles vaccine, after exposure to 37 C for at
least 1 week, cannot lose more than 1 log10 and must maintain
a titer of at least 1,000 TCID50.469
For the currently available vaccine in the United States,
when it is stored at 2 C to 8 C (35.6 F-46.4 F), a minimum
titer of 1,000 TCID50 can be maintained in unreconstituted
vaccine for 2 years or more. This potency can be maintained
for 8 months at room temperature (20 C-25 C or 68 F-77 F)
and 4 weeks at 37 C (98.6 F). Reconstituted vaccine loses
50% of its potency in 1 hour at 20 C to 25 C (68 F-77 F)
and almost all its potency when it is held at 37 C (98.6 F) for
1 hour. Vaccine is also sensitive to sunlight; however, colored
glass vials further minimize loss of potency. Notwithstanding
its improved thermostability, the vaccine still needs to be
handled with care according to the recommendations of the
manufacturer.
As stated in the package insert, Merck recommends that
its product be shipped at a temperature of 10 C (50 F) or
less and stored, before reconstitution, at 2 C to 8 C (35.6
F-46.4 F) and protected from sunlight. Reconstituted measles vaccines (M, MR, and MMR) should be used immediately. If reconstituted vaccine is not used within 8 hours, it
must be discarded. MMRV vaccine must be stored frozen at
an average temperature of less than or equal to 5 F (15 C).
Unlike other measles-containing vaccines, MMRV vaccine
cannot be stored at refrigerator temperature, and once reconstituted, it should be used immediately to minimize loss
of potency and should be discarded if not used within 30
minutes.436

Results of vaccination
The immune response
The immune response after successful vaccination is similar
in most respects to that noted after natural infection. Although
the interval between vaccination and an immune response is
a few days shorter than that observed after natural infection,11

20

immunization induces both humoral21,67,70,72,266 and cellular7678

immunity and the production of interferon.470472
Laboratory evidence of immunity is most conveniently
documented by use of antibody assays because tests for cellmediated immunity are not standardized. However, even with
antibody assays, results of studies on vaccine-induced immunity may vary, depending on the sensitivity of the antibody
assay used.6567,80,276282,473481 Although the presence of antibodies detected by HI, ELISA, or CF correlates with immunity, Nt antibodies are probably most important in clinical
protection.2,65,80,286 After measles vaccination, IgG, IgM, and
IgA antibodies can be detected in both serum and nasal secretions.70,72,270,272,482 IgM antibody can be detected in the serum
between 2 and 6 weeks (peak at 3 weeks) after vaccination
and disappears soon thereafter.270,272,483 Although only small
amounts of IgA have been detected in serum, IgA is the predominant antibody found in nasal secretions.70,72 Although
detectable serum IgA and IgM antibodies are transient, IgG
antibodies generally persist for many years. The antibody
titers elicited by vaccination do decline over time (as do
those induced by natural infection) and may become undetectable.67,267,268,484490 A study done in 2007, found that measles antibody persisted in all vaccinees available for follow-up
10 years after a second dose of vaccine, with no seronegative
results detected. However, declining titers suggested the need
for vigilance in ensuring disease protection for the vaccinated
population.491
Vaccine-induced antibody titers are typically lower than
those induced by natural infection. Vaccine-induced immunity
is subject to boosting on challenge by either vaccine or wild-type
virus; likewise, similar boosting can be observed after natural
infection.65,67,267,268,413,482,486,487 Thus, as discussed in more detail
later, immunization usually provides immunity similar to that
induced by natural infection.
Although many investigators have described the initial antibody response elicited by live measles vaccination, the studies by Krugman and colleagues67,161,266268 serve as an excellent
example. Depending on the antibody assay used (CF, HI, or Nt),
antibodies first appear between 12 (HI and Nt) and 15 (CF) days
and peak 21 to 28 days after vaccination. Although antibodies
were detected in 95% or more of susceptible vaccinees, regardless of the vaccine strain, the CF geometric mean titer did vary
by strain of vaccine (Table 20-4). The geometric mean titers for
children 1 month after receipt of Edmonston B vaccine alone,
Edmonston B vaccine plus IG, Schwarz vaccine, and Schwarz
vaccine with IG were 1:208,161 1:96, 1:56, and 1:24 to 1:32,
respectively.266 The titer observed in 33 children 1 month after
natural infection was 1:128.266 Hilleman and colleagues415 also
noted a difference in the geometric mean titer by vaccine strain
when using the HI assay (Table 20-5). Although 98% or more of
vaccinees seroconverted, the HI geometric mean antibody titer
associated with the Edmonston B vaccine was 1:25, whereas
that noted after vaccination with either the Schwarz or Moraten
further attenuated strains was 1:16. Despite these differences
in geometric mean antibody titer, receipt of these vaccines was
associated with a markedly reduced risk of infection that did
not decrease over time.67,267,268
Studies of measles-specific cell-mediated immunity after
live attenuated vaccines are more challenging because of the
lack of a simple in vitro assay. With the importance that cellmediated immunity plays in natural infection,60,182185 it would
seem that successful vaccination would stimulate such immunity. Cell-mediated immune responses after live attenuated
vaccine appear to be similar to but less pronounced than those
after natural infection.182185,492 For example, Gallagher and colleagues78 reported that a positive lymphocyte stimulation index
was noted in 9 of 9 subjects with natural immunity and in
10 of 16 vaccinees. Pabst and colleagues493 found good correlation between antibody titers and lymphoproliferative responses

363

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SECTION TWO Licensed vaccines

Table 20-4 Antibody Response 21 to 28 Days after Measles

Vaccination with or without Immune Globulin*
Vaccination
regimen

Total
number

Seroconversion
(%)

GMT

171

96

27

1 : 208

185

99

1 : 96

Edmonston B vaccine
Alone

Immune globulin,
0.02 mL/kg

Further attenuated vaccine

Alone

121

99

1 : 56

Immune globulin,
0.1 mL total

89

95

1 : 32

Immune globulin,
0.2 mL total

452

98

1 : 32

Immune globulin,
0.02 mL/kg

193

95

1 : 24

*Neutralizing titer of 1:400/0.1 mL.

Complement fixation assay geometric mean antibody titer.

Schwarz strain.
Modified from Krugman S, Giles JP, Jacobs AM, et al. Studies with live
attenuated measles-virus vaccine. Am J Dis Child 103:353-363, 1962;
Krugman S, Giles JP, Jacobs AM, et al. Studies with a further attenuated live
measles-virus vaccine. Pediatrics 31:919-928, 1963.

Table 20-5 Antibody Response 28 Days After Attenuated and Further

Attenuated Measles Vaccine
Vaccine
Edmonston B

Total number

Seroconversion
(%)

GMT*

258

99

1 : 25

Schwarz

250

98

1 : 16

Moraten

273

98

1 : 16

*Hemagglutination-inhibition assay.

Attenuated vaccine.

Further attenuated vaccine.

GMT, Geometric mean antibody titer.
Modified from Hilleman MR, Buynak EB, Weibel RE, et al. Development and
evaluation of the Moraten measles virus vaccine. JAMA 206:587-590, 1968.

in 124 children receiving their first dose of MMR. However,

a study of the immune response to measles vaccination at 9
months of age among 55 Peruvian children found that 93%
developed a humoral response, and only 23% had lymphoproliferative responses.494 Gans and colleagues495 studied the ability
of infants ages 6, 9, or 12 months to respond to measles vaccine
and found that, unlike humoral responses, T-cell responses
can be established despite the presence of passive antibodies.
Outbreak investigations have documented vaccination before
the first birthday as a risk factor for vaccine failure,496499 suggesting that vaccine-induced cell-mediated immune responses
in young infants may not be protective. Ward and colleagues500
found good lymphoproliferative responses after revaccination,
even among those whose antibody titers dropped to low levels. It appears that both wild-type virus and vaccine infection
result in a biphasic immune response, beginning with transient production of interleukin-2 and interferon-, followed
by more sustained production of interleukin-4. First, CD8+
T cells are activated, which is important for viral clearance.
Later, beginning about the time of rash onset, CD4+ T cells
are activated and are involved in antibody production.60 These

responses by the cell-mediated immune system correspond to

an initial T-helper 1 (Th1)-type response with a shift to a Th2type response.
Vaccination suppresses cell-mediated immune function
(as does natural infection).103,492,501505 This manifests in vitro
as suppression of lymphocyte stimulation or in vivo as suppression of cutaneous delayed hypersensitivity to various
antigens. Fireman and colleagues502 noted suppressed cellular
immune function up to 4 weeks after administration of live
vaccine. Suppression did not occur after receipt of killed vaccine. A study of Bangladeshi infants found that delayed-type
hypersensitivity reactions to Candida antigen were significantly reduced at 6 weeks postvaccination.506 Data suggest that
this suppression is due to down-regulation of interleukin-12,
which is needed for cell-mediated immunity.507 Although there
was concern initially that this temporary suppression of cellular immunity might be harmful, for example, in patients
with unrecognized tuberculosis,104 no increased risk has been
documented.507,509
One would assume that the presence of a rash after parenteral injection of vaccine would be associated with viremia.
The generalized stimulation of T and B lymphocytes after
vaccination also suggests viremia. Few studies documented
viremia after vaccination. Early studies with the canine cell
vaccine isolated vaccine virus from blood,384386 and, more
recently, van Binnendijk and colleagues510 have isolated
Schwarz strain vaccine virus from monkeys 7 to 9 days after
vaccination. There are no reports of isolation of vaccine virus
from blood in normal humans.1113,18,50 Although Mitus and
associates175 did isolate vaccine virus from the throat and conjunctivae of a susceptible leukemic patient who died of giant
cell pneumonia after administration of Edmonston B vaccine,
they failed to isolate virus from the blood. The apparent difficulty of isolating vaccine virus may reflect the low level of
viremia after vaccination.
Because wild-type virus is so highly transmissible, both
virologic and clinical studies with susceptible contacts were
conducted in early vaccine investigations.11,1318,50,384,386 These
studies showed no evidence of virus excretion or transmission
by vaccinees. Measles vaccine virus was isolated from a throat
swab taken from a 3-year-old boy who presented with fever
only 12 days after vaccination with MMR vaccine.511 This case
report suggests that subcutaneous vaccination with live attenuated measles virus can result in respiratory excretion of the vaccine virus. Person-to-person transmission of vaccine virus has
never been documented.

Response to revaccination
The immune response after revaccination depends on the results
of the initial vaccination. Persons who have no response to
initial vaccination typically generate a primary immune response
to revaccination, with a significant rise in antibody titer and the
production of IgM antibody. After revaccination of a person with
some level of immunity, a fourfold or greater rise in antibody may
appear sooner than that seen after initial vaccination, but there
are usually no clinical signs of infection.67,267,268,270,272,480,481,488,512
IgG antibodies are first detected within 5 to 6 days and peak
around 12 days. IgM antibodies are not usually detected. As is
the case with immunity after natural infection, these are the
characteristics of an anamnestic immune response.269,271 Such
a boost is more likely to occur in the presence of a low or undetectable pre-existing antibody titer, whereas persons with a high
level of circulating antibody may not boost.67,267,268,474,486488,513
Krugman and colleagues67 reported that, after revaccination, a
significant increase in HI titer occurred in only 1 of 6 children
with HI titers of 1:16 or 1:32 but in 25 of 36 children with titers
of 1:8 or less. Similar findings were noted in vaccinees exposed
to wild-type virus.

Measles vaccine

Boosting of antibody titers appears to be transient, with several investigators finding decay of antibody levels to the prerevaccination level within months to years.495,514516 In one study,
antibody titers against measles in children with low levels of
antibody before revaccination decayed during a 6-month period
after revaccination; however, cellular immunity, measured in a
lymphocyte proliferation assay, appeared to persist.500
The booster phenomenon is not unique to vaccine-induced
immunity. It can also be observed after exposure to measles
or after vaccination in persons who have had measles, but it
occurs less frequently because antibody titers after natural
infection are usually higher than those after vaccination.65,67
Stokes and colleagues65 reported that, on reexposure to wildtype virus, 6 of 12 naturally immune persons with preexposure
Nt titers ranging from 1:2 to 1:8 experienced a boost in titer.
However, such boosts were not seen in any of 22 persons with
titers between 1:16 and 1:128. These data indicate that subclinical reinfection may occur after both natural infection and
successful vaccination.
Studies of the response to revaccination495,511,517519 have
shown that a high proportion of vaccinated persons who lack
detectable antibody to measles will respond to the second dose.
Among persons initially vaccinated after 12 months of age, at
least 95% will respond.

Effectiveness of protection
Measures of protection
A person's risk of measles is the product of his or her susceptibility to measles and risk of exposure to measles virus. Measles
vaccine provides both personal immunity to prevent disease
when exposed to measles virus and population immunity
through decreased intensity of transmission as the proportion
of immune persons in a population increases. The population
immunity effect decreases the risk of measles among immunized as well as unimmunized persons.
The most direct method of measuring the personal immunity effect of measles vaccine would be to challenge vaccinees
and controls with wild-type measles virus and document the
clinical outcome. Such studies are not done in humans because
of the harmful effects of exposure to measles virus. In studies in animals challenged with wild-type measles virus, vaccinated animals have significant decreases in clinical symptoms
and measles virus replication compared with unvaccinated animals.520 These studies are performed to evaluate the response
to new vaccines in terms of clinical protection, reduced viral
load, and development of serologic and cellular immunity.520522
Because tests of cell-mediated immunity to measles are less
widely available, antibody titers are most often used as evidence
of protection from measles (ie, as a correlate of protection).
Despite the fact that any detectable level of measles antibody
has been interpreted as evidence of protection after vaccination,
the development of more sensitive antibody tests277 has raised
concerns that low levels of antibody480 may not be protective.
A school blood drive before a measles outbreak permitted correlation of preexposure measles antibody titers by using the PRN
test with the level of clinical protection.523 Eight of nine students with low but detectable levels of measles antibody immediately before the outbreak (PRN titer 120) developed typical
measles compared with none of 71 with preexposure PRN titers
of greater than 120. Seven of 11 students with preexposure PRN
titers of 216 to 874 had a fourfold or greater rise in antibody
titer compared with none of 7 with a preexposure PRN titer of
1,052 or greater, indicating that high titers were associated with
protection against both infection and disease. Although many
persons with low antibody titers may not develop disease after
exposure, available data suggest that these low levels of antibody may not be fully protective.

20

Protection also can be evaluated by examining the immune

response of vaccinees challenged with vaccine virus through
revaccination.167,268,488,510,514,524,525 Such challenges most often
result in an anamnestic immune response (see Response to
revaccination).
The most commonly used method to quantify the protective effect of measles vaccine is to identify persons with similar
likelihood of exposure to measles virus and compare the attack
rate of disease in unvaccinated and vaccinated persons. The
decrease in attack rate among vaccinated compared with unvaccinated persons is called vaccine effectiveness or vaccine efficacy.526,527 (Refer to Chapter 67 for a more detailed discussion of
this topic, including formulas and methods for calculating vaccine effectiveness.) In outbreak settings in which a high proportion of the population is vaccinated, the proportion of cases that
are vaccinated will also be high, and it may appear erroneously
that the vaccine effectiveness is low.528,529 However, approximately 50% of cases can be expected to be vaccinated, with
vaccine effectiveness and vaccine coverage each 90%.526 This
proportion of cases will increase to 60% with a 95% coverage
rate. The majority of available data indicate vaccine effectiveness in the United States of 90% to 95% or greater,530 consistent
with seroconversion data.
Reduction in the occurrence of measles after the introduction
of vaccine is a common measure of vaccine-induced protection at
the population level. Both Krugman and colleagues266 and Baba
and colleagues531 noted virtual elimination of measles from a
population of institutionalized children after vaccination became
routine, despite high levels of infection in the surrounding community. Similarly, nationwide surveillance in many countries
with high levels of immunization has documented a significant
reduction in reported measles cases after vaccine licensure, and
many have eliminated endemic transmission of measles.2241
For more examples of the impact of measles vaccination on
measles incidence, see Experiences with measles control and
Elimination in various countries later in this chapter.
Monitoring the reproductive rate, or R value, is another
method of assessing the impact of vaccination on a population. The basic reproductive rate (R0) is the average number of
cases that would be expected to spread from a single case of
measles in a completely susceptible population. Measles is a
highly infectious disease, and R0 has been estimated as 12.5 to
18.532 The effective reproductive rate (R) incorporates the level
of immunity in a population with the factors that determine R0.
In a completely susceptible population, R = R0. In other populations, the difference between R and R0 is the effect of population immunity. When R is greater than 1, the number of cases
increases from one generation to the next and an epidemic
begins. As the spread of disease increases immunity in the population, R falls below 1, the number of cases decreases from one
generation to the next, and the epidemic ends. To achieve interruption of endemic transmission of measles, it is necessary to
achieve a level of population immunity that maintains R less
than 1 (see Chapter 71). In the United States, assessment of
the reproductive rates through surveillance data documented R
less than 1 for the period from 1992 to 1999.533 Analysis of vaccination programs in Western Europe found that four of eight
countries had vaccine coverage sufficiently high to eventually
eliminate measles.534
Population protection from measles can be evaluated without waiting for an outbreak to identify susceptible groups by
using tools such as population surveys of measles antibody
levels and by mathematical modeling of population immunity. Although antibody levels are a very useful measure of
measles immunity, a proportion of persons who do not have
detectable measles antibody may have a level of protection via
cellular immunity. In a national serosurvey conducted from
1988 to 1994, Hutchins535 reported that overall only 7% of persons greater than 6 years of age in the United States lacked

365

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SECTION TWO Licensed vaccines

serum IgG antibodies to measles. However, 19% of those born

between 1967 and 1976 were seronegative.535 This time frame
represents the early implementation phase of measles vaccination in the United States, when high coverage levels had not
been achieved, yet the incidence of measles was significantly
decreased; therefore, a proportion of children grew up without
getting measles or vaccination. This pocket of susceptibility
has not been a major focus of measles transmission; however,
it may have a significant impact on the amount of antibodies
mothers born in these years pass on to their infants.535 In a
follow-up survey conducted 1999 to 2004 in the United States,
the lowest levels of seropositivity were again found in persons
born in early vaccine implementation years of 1967 to 1976.536
Serosurveys in some other countries have demonstrated low
levels of seroposivity in persons born in the early vaccine implementation years.537,538 Serosurveys have also been used to plan
vaccine strategies or assess their impact.539541 More recently,
oral fluid surveys have assessed population IgG antibodies to
measure the impact of mass campaigns on population immunity and susceptibility in Kenya and Ethiopia.542544
Mathematical modeling can be used to compile and interpret
the factors related to measures of vaccine protection, including patterns of transmission, vaccination coverage estimates,
measles antibody surveys, and effects of primary and secondary
vaccine failure.544548

Correlates of immunity
Plaque reduction neutralization antibody titers at the time of
exposure to virus have been most closely correlated with immunity against measles. In one study, no one with a titer of greater
than or equal to 120 at the start of an outbreak developed measles.523 Further information on correlates of immunity is provided in the preceding section on Measures of protection.

Host factors affecting protection

The quality and durability of measles vaccine-induced immunity is dependent on a number of factors that relate both to the
vaccine and to the host.267,549 In considering factors affecting
protection, it is important to distinguish between primary vaccine failure, that is, a failure to seroconvert after vaccination,
and secondary vaccine failure, that is, loss of protection after
demonstrated seroconversion.

Maternal antibody and age at vaccination

A number of host factors may be responsible for primary vaccine failure. The most important and well described is maternal
antibody. Passively acquired measles antibodies may neutralize vaccine virus before a complete immune response develops.
The most common sources of these antibodies are maternal
transfer, IG, and other blood products. The presence of maternally derived transplacental antibody is particularly important
in evaluating the immunogenicity of live measles vaccine in
early childhood.286,550 The effect of maternal antibodies in breast
milk on response to measles vaccination is unknown.
As noted by Orenstein and colleagues,550 recommendations
for the age at vaccination must balance two factors: (1) the earliest age at which high rates of seroconversion can be obtained
and (2) the age group with the greatest risk of severe infection. A balance must be met that optimizes vaccine-induced
protection while minimizing the risk of morbidity and mortality that would occur by delaying vaccination.286,334 The age at
vaccination that achieves this balance is lower in developing
countries than in developed nations because of the increased
risk of measles exposure among infants and because of earlier
loss of maternally derived antibody. The reasons for the variation in duration of passive protection from maternal antibody
include differences in (1) levels of measles antibody in mothers,

(2) efficiency of transport of IgG across the placenta, and (3)

rate of loss of passively acquired antibody by the infant.286,551,552
Early in the clinical investigations of live measles virus
vaccine, it was recognized that maternal antibody interfered
with seroconversion by in vivo neutralization of vaccine virus
before adequate replication had occurred.549 On the basis of
data available at the time, it appeared that maternal antibody
rarely persisted beyond 7 months of age and that an adequate
immune response could be achieved if vaccination was limited to infants 9 months of age and older.65,67,476,478,553 Whereas
only 60% to 70% of infants younger than 9 months seroconverted, 95% or more of older infants produced antibodies.21,550
Accordingly, when vaccine was licensed in 1963 in the United
States, the recommended age for routine vaccination was 9
months.554
In the first few years after licensure, it became apparent,
however, that maternal antibodies actually persisted in many
infants until 11 months of age.67,475,476,479 On the basis of these
data, vaccination before 1 year would be expected to be associated with a high risk of primary vaccine failure and subsequent
infection in exposed vaccinees.163,167,478,555558 Thus, in 1965, the
recommended age for vaccination was raised to 12 months.417
The importance of this change is illustrated by Krugman's559
data showing that only 86% of 123 infants 9 months of age
seroconverted after administration of Edmonston B vaccine
and IG, compared with 97% of 899 children vaccinated at 12
months of age or older.
In 1965, it was also recommended that children vaccinated
before 1 year of age be revaccinated because a large proportion
of these children were susceptible and were expected to respond
well to revaccination. A number of studies confirmed these
findings,488,555,556,560 but there are also some data indicating that
early vaccination may alter the immune response after revaccination. Wilkins and Wehrle478 first raised concerns by reporting that 19 (51.4%) of 37 children who did not respond when
they were initially vaccinated at 6 to 10 months of age did not
have detectable HI antibodies 8 months after revaccination.
All 37 did, however, have detectable Nt antibody. Similarly,
Linnemann and colleagues561 reported that 29 (40.3%) of 72
children vaccinated before 10 months of age were HI negative
at a mean of 4.8 years after revaccination. In contrast, Lampe
and colleagues525 did not find any difference in seroconversion
rates in children vaccinated once at 15 months of age or later,
compared with children revaccinated after first being vaccinated before 1 year of age. By using an EIA assay, Murphy and
colleagues562 observed high seroprevalence rates at a mean of
6 months after vaccination in 302 children revaccinated after
early vaccination and in 300 vaccinated once at 15 months of
age or older (98% for both groups). However, they did observe
that the titers in the revaccinated group were lower than those
in the children vaccinated once. These findings were confirmed
by McGraw.423
One of the most complete descriptions of an altered
immune response is provided by Stetler and colleagues.481
These authors reported that children revaccinated after an initial vaccination before 1 year had no difficulty seroconverting;
postrevaccination HI antibody was detected in 116 (95.9%) of
121 children lacking HI antibody before revaccination. Eight
months later, HI antibodies were undetectable in 58 (47.9%)
children, but, after retesting with a cytopathic effect neutralization (CPEN) test, only 5 (4.2%) of 120 sera were negative.
Successful priming in some of the early vaccinees was also
suggested by the finding that IgM was detected in the sera of
only 22.2% of 63 revaccinated children lacking HI, EIA, and
CPEN antibody, compared with 74.0% of 50 random control
vaccinees. These findings were similar to those noted by Black
and colleagues.524
Although there may be some alteration of the immune
response, the most reliable indicator of the actual effectiveness

Measles vaccine

of revaccination of these children is the evaluation of their risk of

infection. Although revaccination may not provide 100% protection, available data indicate that revaccination is effective.556,560
Shasby and colleagues555 reported that, in an outbreak, the attack
rate in 73 children vaccinated once before 12 months of age was
35.6%, whereas the attack rate in 55 children revaccinated after
12 months of age was only 1.8%. Davis and colleagues560 noted
that none of 80 students revaccinated after their first vaccination before 12 months of age became infected during an outbreak. For comparison, the attack rate in children vaccinated
twice at 12 months of age or older was 1.4% (2 of 138), that in
children vaccinated once at 12 months of age or older was 1.8%
(21 of 1,191), and that in unvaccinated children was 57.1% (4
of 7). Hutchins and colleagues563 reported a vaccine effectiveness
of 99.5% for children vaccinated with a first dose at age 6 to 11
months and a second dose after age 12 months. Thus, the available data indicate that revaccination of children first vaccinated
before 1 year of age will result in good vaccine-induced protection, although it may be associated with an altered immune
response, manifested as a lower antibody titer. This conclusion
is especially important because vaccination of US children as
young as 6 months, with subsequent revaccination, is recommended in certain outbreak situations and for children traveling
internationally.211,212
The recommended age at vaccination was again changed in
1976 from 12 months to 15 months because newer data indicated that children vaccinated at 15 months of age and older
were even more likely to make and maintain antibodies and
were less likely to be infected in outbreak situations than those
children vaccinated earlier.550 Although some studies provide
contrary results, examination of data on seroconversion rates
and prevalence of antibodies after vaccination indicates that, in
general, 79% to 89% of children vaccinated at 12 months of age
have detectable antibodies, compared with 87% to 99% of those
vaccinated at 15 months or later.475477,479,550,555,564566 Similarly, a
number of studies measuring the risk of measles in vaccinated
and unvaccinated children indicated that measles occurred in
children vaccinated at 12 months of age approximately 1.5 to
5.0 times more frequently than in those vaccinated later than
12 months. 496499,550,555,556
Data on measles antibody titers in umbilical cord blood
and in infants suggested that infants whose mothers have vaccine-induced immunity may be receiving less maternal antibody than infants whose mothers had natural measles.493,566570
Many mothers born in the vaccine era have antibodies induced
by vaccination, which typically results in lower titers than does
measles disease. Also, an increased proportion of mothers born
since the introduction of measles vaccine may not have any
measles antibodies because they have not had measles or been
vaccinated. Serologic surveys have shown that up to 19% of
women of childbearing age in the United States, born between
1967 and 1976, are measles seronegative.535,536 Infants born to
seronegative mothers would lack maternal antibody from birth
onward. In 2009, greater than 99% of women giving birth in
the United States were born after 1963, the year measles vaccine was licensed.571
Infants whose mothers were born in the vaccine era are susceptible to disease at a younger age and are more likely to respond
to vaccination at an early age. In a 1992 cohort study in the
United States, Papania and colleagues572 documented a greater
than 2.5 relative risk of measles among infants whose mothers were born in the vaccine era compared with infants whose
mothers were born before 1963. Higher rates of seroconversion
at 12 months also have been found in children born to women
with vaccine-induced immunity.567569 Based on these findings,
in 1994, the recommended age of vaccination in the United
States was changed again to between 12 and 15 months.212
Factors that alter the efficiency of transport of IgG across
the placenta also can affect the amount of antibody infants

20

receive. Maternal measles antibody is transferred across the

placenta from mother to infant via an active transport system,
which results in a higher antibody titer in the infant than in the
mother. Because the majority of the maternal measles antibody
transfer occurs late in the third trimester, infants born prematurely often have low antibody titers.573 Several diseases that
affect the mother, most importantly HIV infection and possibly
malaria, have been shown to decrease the placental transfer of
maternal measles antibody and result in lower infant titers.574,575
Because infants in developing countries may lose maternal
measles antibody at an early age and may be exposed to measles
virus at an early age as a result of intense transmission, the
WHO recommendations indicate that 9 months is the most
appropriate age for delivery of the first dose of measles vaccine
in most developing countries576 (see Indications).
Studies of early measles vaccination regimens have found
that infants 6 months of age had lower seroconversion rates
and geometric mean titers than older infants or toddlers. This
effect was evident even among 6-month-old infants who lacked
maternal measles antibody, suggesting an age-related delay
in maturation of humoral immunity unrelated to passively
transferred maternal antibody.577 In contrast, markers of cellmediated immunity (eg, T-cell proliferation) were equivalent
after vaccination at 6, 9, or 12 months, regardless of the presence of passive antibodies. In addition, infants initially vaccinated at 6 or 9 months experienced increases in both humoral
and cell-mediated responses after administration of a second
dose. Although the cell-mediated immunity resulting from a
dose at 6 months alone may not be protective, early vaccination
may prime the humoral response to the second dose, thereby
providing clinical benefits.578

Intercurrent illness and malnutrition

There is a theoretic concern that interferon produced by an
intercurrent infection may interfere with successful vaccination.487,579 Studies addressing this question, which have been
conducted in developing and in developed countries, have produced discordant results. Two studies in developing countries
found no differences in seroconversion rates in ill and well children after receipt of measles vaccine.345,580 A small study in the
United States found that 80% of children with rhinorrhea seroconverted, compared with 98% of well children.581 Subsequent
studies conducted in the United States and Canada have found
equivalent seroconversion rates among children with upper
respiratory infections or mild illness and well children.582584 In
a study of 128 mildly ill and 258 well children given MMR,
seroconversion to measles was 97% in well children compared
with 99% in those with mild illnesses, mostly upper respiratory tract infection;584 no differences were observed in seroconversion to mumps or rubella. A study conducted in Wisconsin
found no association between vaccine failure and vaccination
during the high-risk season for respiratory infections.585 One
study conducted in Thailand found lower geometric mean antibody titers for children vaccinated at 9 months of age among
those who experienced an upper respiratory tract infection in
the 2 weeks after vaccination.586 However, the benefits of vaccinating mildly ill children outweigh any theoretic risk of lower
seroconversion rates.587 Several studies have found seroconversion rates in malnourished children similar to those in children
who are well nourished.344,345,588,589

Immunosuppression and HIV infection

Measles vaccination is not recommended for most immunocompromised patients, and as a result, few data are available on the immune response in such patients. However, the
increasing number of children with HIV infection, the high
risk of severe measles in these children, and the limited side

367

368

SECTION TWO Licensed vaccines

effects to measles vaccine found in HIV-infected children have

resulted in recommendations for vaccination. Studies in the
United States have found that HIV-infected children have
poor responses to vaccination, lose antibody more quickly
after vaccination, and respond poorly to revaccination.178,590592
Retrospective studies have found that only 12% of 24178 and 59%
of 37591 vaccinated children with HIV infection had detectable
measles antibody. Seroconversion rates in prospective studies
range from 33% of 39 children to 60% of 25 children.189,590 In
the Democratic Republic of Congo, seroconversion rates after
vaccination at 9 months were 77% in asymptomatic HIVinfected children and 36% in symptomatic HIV-infected children (36%).593 In two other studies in Africa, seroconversion
rates after vaccination at 6 months were greater than 75% in
HIV-infected children.594,595 A study in Thailand found that, by
age 9 months, 100% of 30 infants of HIV-infected mothers had
lost their maternally acquired antibodies and that, by 12 weeks
postvaccination, HIV-positive infants had lower seroconversion and median antibody levels when compared with HIVnegative infants.596 A recent study in Zambia found 88% of
HIV-infected infants vaccinated at 9 months of age developed
protective antibody levels; by 27 months after vaccination only
50% of children who survived had maintained protective antibody titers.587 HIV-infected children may respond better when
they are vaccinated at earlier ages, before they become severely
immunocompromised.598,599
Adults who were vaccinated in childhood before becoming
infected with HIV appear to retain protective levels of measles
antibody. High seroprevalence of measles antibody in HIVinfected adults in the United States has been documented,600
and antibody levels are maintained, even as immunosuppression progresses. In one study, measles seronegative HIV-infected
adults who were vaccinated while on highly active antiretroviral
therapy (HAART) responded to measles vaccine but lost antibody rapidly after vaccination.601

Vitamin A supplementation
Investigators in Indonesia found a lower rate of seroconversion among children vaccinated at 6 months of age who
received supplementary vitamin A compared with children
not receiving such a supplement.602 Subsequent studies conducted in Guinea-Bissau, India, and West Java found similar
rates of seroconversion among 9-month-old children receiving
and not receiving vitamin A supplements.603605 Among malnourished children in the Indian study, the postvaccination
geometric mean antibody titer was significantly higher in the
group receiving vitamin A compared with the placebo group.604
A large multicenter clinical trial confirmed the safety of vitamin A supplementation administered with routine immunizations at 6, 10, and 14 weeks of age and at 9 months with
measles immunization.606 The balance of evidence supports
the WHO recommendation that, in vitamin Adeficient countries, infants should receive a vitamin A supplement at the
time of measles immunization.607

Other host factors

Even after receipt of potent vaccine, approximately 2% to 5%
of vaccinees will fail to respond for unknown reasons.21,67,266 A
group of investigators at the Mayo Clinic has explored the role
of genetic factors and found associations with particular human
lymphocyte antigen (HLA) types and nonresponse or hyperresponse to measles vaccination.608 A study of monozygotic and
dizygotic twins found a high degree of heritability of measles
antibody level and subsequently showed associations between
homozygosity for class I and class II HLA alleles and poor
response to measles vaccination.609 Of importance, two doses
of MMR vaccine appear to induce sufficient antibody levels

and lymphoproliferative responses against measles regardless

of homozygosity status, suggesting genetically related nonresponse to the first dose is overcome by administration of a second dose.610
Although there may be some exceptions in the very
young,423,478,481,524 revaccination has been found in both epidemiologic and serologic studies to induce the same high rate of immune
response that follows initial vaccination.480,488,517519,555,556,572

Vaccine factors affecting protection

Vaccine antigen and strain
Although most further attenuated measles vaccines have been
found to be equally immunogenic in older children,415,427 differences in the ability of vaccine strains to immunize young
infants have been reported.428,430,611615 High measles morbidity
and mortality among infants younger than the recommended
age for vaccination (9 months) in developing countries616,617
has stimulated research on strategies for immunization of
younger infants. Sabin and associates,427,428 in the early 1980s,
investigated aerosol administration of two measles vaccines,
the Edmonston-Zagreb and Schwarz strains. Their finding
of higher seroconversion rates after Edmonston-Zagreb than
after Schwarz vaccine focused attention on this vaccine strain.
Several subsequent studies found that the Edmonston-Zagreb
strain was more immunogenic than the Schwarz vaccine in this
age group when given by injection (see paragraph on Vaccine
dose below). The AIK-C strain of measles vaccine also has
been found to be highly immunogenic in young infants and,
in some studies, more immunogenic than either Schwarz or
Edmonston-Zagreb vaccines.618620 The reasons for these differences are not known.

Vaccine dose
Small doses of vaccine can effectively immunize older infants
and children; however, the dose of vaccine administered has been
shown to be important in immunizing young infants.611,612,614
Increasing the Edmonston-Zagreb vaccine dose from 10,000
to 40,000 plaque-forming units (PFU) in the Gambia resulted
in an increase in response rate from 73% to 100% in 4- to
6-month-old infants.611 In Mexico, serologic response to vaccination of 6-month-old infants increased for both Schwarz
(66% to 91%) and Edmonston-Zagreb (92% to 98%) vaccines,
with a 100-fold increase in dose;612 the effect was greater for
Schwarz than for Edmonston-Zagreb vaccine. Because of these
data and interest in a vaccination strategy for children younger
than 1 year in developing countries, in 1990 the WHO recommended that a higher dose (initially defined as > 100,000 PFU
and later changed to > 50,000 PFU) Edmonston-Zagreb vaccine be administered at 6 months of age in areas where measles mortality in young infants was a major health problem.621
However, problems with vaccine availability resulted in little
use of the vaccine on a large scale. Questions were raised regarding the safety of high-dose measles vaccine in several developing
countries, with a higher mortality rate in girls who received
high-titer vaccines compared with those who received standardtiter vaccines.622624 Increased mortality rates after vaccination
with a high-titer vaccine were not observed in developed countries or in countries with an infant mortality rate less than 100
per 1,000 births.625 High-titer measles vaccines are not currently recommended.626

Vaccine handling
Primary vaccine failures with live vaccine have stemmed
from improper handling. Loss of potency of live vaccines can
result from poor shipping or storage practices.627,628 Although

Measles vaccine

administration of impotent vaccine had previously been implicated in outbreaks of measles in vaccinated persons, the likelihood of this occurring now has been greatly reduced by the
addition in 1979 of the new stabilizers discussed previously.421,467

Persistence of immunity

Natural
measles infection

512
256
128
64
32
16
8
4
2
<2

Live, further attenuated

measles vaccine

1 12

512
256
128
64
32
16
8
4
2
<2

Titer

Titer

The majority of data suggest that a dose of live vaccine properly

administered to an appropriate host that results in seroconversion will afford lifelong protection to nearly all vaccinees.629
The duration of vaccine-induced immunity has been documented by studying the persistence of measurable antibody,
the clinical characteristics and serologic response of measles
cases in vaccinated persons, the effects of vaccine challenge,
and the attack rate in vaccinees as a function of the time since
vaccination.
Although vaccine-induced antibody titers are lower than
those achieved after natural infection, this difference does not
appear to result in decreased personal protection from measles.
Serologic studies limited to children vaccinated at 12 months
of age or older indicate that, although antibody titers do decline
over time, detectable antibodies are present in most vaccinees.
Because titers can fall to levels undetectable with some assays,
the test used is important in the assessment of immune status. Furthermore, many persons lacking detectable antibody
manifest a secondary immune response on revaccination or
exposure to wild-type virus, indicating persistence of some
level of immunity.275
Krugman67,267,268 followed the serologic status of a population
of institutionalized children for 16 years. The HI geometric
mean antibody titer in 70 persons who received further attenuated vaccine was 1:333 at 1 month but, in the absence of exposure, had fallen to 1:6 after 16 years (Figure 20-7).268 Thirteen
percent had a HI titer of 1:4, 10% had a titer of 1:2, and 13%
had no detectable antibody. In contrast, whereas 47 naturally
infected children had a comparable 1-month HI geometric
mean antibody titer of 1:410, 16 years after disease, the geometric mean titer was 1:22 (see Figure 20-7). Only 4% had a HI
titer of 1:2, and none had undetectable antibodies. Sixteen sera
with HI titers ranging from less than 1:2 to 1:4, obtained from
persons vaccinated 6 to 15 years earlier, were retested with the
more sensitive PRN assay;277 the PRN titers ranged from 1:4 to
1:46.268 Typical booster responses after revaccination of some of
the HI-negative persons were also found.

1 2 3 4 5 6 7 8 10 11 12 13

Years after natural infection or immunization

Figure 20-7 Measles geometric mean hemagglutination-inhibition
antibody titers after natural infection and immunization with live, further
attenuated vaccine. (Courtesy of S. Krugman.)

See references 67,267,268,473,474,477,480,482,484486, 491,630.

20

Dine and associates631 followed up adults vaccinated in a

vaccine trial in the 1970s. The 56 participants, who were all
seropositive by HI tests after vaccination, all had detectable
measles antibody by PRN at least 26 years after vaccination.
PRN titers greater than 1:120 were found in 92% of the subjects, and the strongest predictor of lower titers was lower HI
titers in the original study. None of the subjects had been revaccinated in the interim period, or had had measles or known
exposure to measles. Fewer than five cases were reported annually from Cincinnati, the study setting, over the 12 years before
the follow-up study began. Therefore, boosting of antibody
titers from exposure to wild-type measles virus was unlikely to
play a major role in sustaining antibody titers in most of the
study subjects.
Seroprevalence studies also provide useful information
about duration of immunity, but, because information on seroconversion is lacking, one cannot be sure whether persons are
seronegative because of primary or secondary vaccine failure. In
addition, sensitivity of the assay procedure is important. These
variables account for some discrepancies in reported findings.
For example, Bass and colleagues474 reported that HI antibodies were detectable in 73% of 40 children more than 8 years
after vaccination; however, 98% had Nt antibody. Orenstein
and colleagues454 reported that the seroprevalence among 1,871
high-school students (10th, 11th, and 12th graders), 98.1% of
whom had been vaccinated at 14 months of age or older and
who had no history of measles, was 86.9% by an HI assay.
However, 98.8% were positive with both the HI assay and the
same PRN assay used in the Krugman study.277 Orenstein and
colleagues480 further documented the specificity of the PRN
assay by vaccinating HI-negative children. IgM was detected in
14 of 16 students with a PRN titer less than 1:4 but in only 1
of 68 who were PRN positive.
Although live-virus vaccine-induced immunity is accepted
as durable, there have been case reports of measles in persons
who had a previously documented seroconversion after vaccination, which indicates that secondary vaccine failure can
occur.170,172,632 Also, there have been reports of measles, or
modified measles, occurring in vaccinees who had laboratory
evidence of infection, although IgM was not detected, which
suggests a secondary immune response.165169,171 A secondary immune response indicates a preexisting level of immunity, although such reports are limited by the sensitivity of the
assays used to detect IgM antibody. These studies also suggest
that the clinical reinfection can be mild and may be more likely
to occur in persons vaccinated at younger than 12 months.
One study that provides data on the risk of clinical reinfection after vaccination was conducted in Canada; 5% (9 of 175)
of persons who initially seroconverted after receipt of measles
vaccine developed measles within 10 years of vaccination.170 In
this study, persons who developed measles had lower postvaccination titers than those who did not.
In epidemiologic studies of persons vaccinated with live
measles vaccine at 12 months of age or older, some studies
have shown that persons with increased time since vaccination have slight increases in attack rates compared with those
more recently vaccinated; however, none has yet documented
a significant increase (Table 20-6).497,555,556,558,570,633635 During
outbreaks, observed attack rates in persons vaccinated 15
years or more before infection have been on the order of 5%
or less, and calculated vaccine effectiveness has been 90% to
95% or greater. These results are consistent with the expected
frequency of primary vaccine failure that occurs in everyday
practice. Data from the United Kingdom, the United States,
and other countries340,629,630,636,637 have not found increases in
vaccine failures with time since vaccination. With overall incidence of measles in the United States at record low levels and
no evidence of increasing incidence among previously vaccinated persons, waning immunity does not appear to constitute

369

370

SECTION TWO Licensed vaccines

Table 20-6 Epidemiologic Studies of Duration of Measles Vaccine-Induced Immunity

Attack rate (%) by years since vaccination*
Study

0-4 yr

5-9 yr

> 10 yr

15 yr

Shasby et al555

9.4 (3/32)

6.9 (7/101)

5.4 (8/52)

Nkowane et al556

0 (0/18)

1.1 (1/21)

1.4 (10/158)

Davis et al560

1.1 (2/187)

1.7 (11/661)

2.6 (8/308)

0 (0/35)

4.0/1000

4.2/1000

5.4/1000

11.7/1000

0 (0/33)

0 (0/143)

2.2 (12/549)

3.1 (6/192)

Robertson et al

0 (0/2)

1.4 (1/74)

3.4 (10/292)

Guris et al625

11.8 (2/17)

0 (0/7)

Lynn et al624

0 (0/40)

0 (0/46)

558||

Marks et al

623

Hutchins et al

875

0 (0/3)
18.2 (2/11)

1.0 (18/1803)

0.3 (1/357)

*Single vaccination at 15 months of age or older except for Shasby, Nkowane, and Davis (12 months of age or older).

Years since vaccination: 5 to 8 and 9 or more.

Number ill/total number.

Projected from a 25% random sample.

||
Cases per 1000 person-weeks at 0 to 3 (2 of 499), 4 to 6 (6 of 1420), 7 to 9 (5 of 929), and 10 to 12 (4 of 343) years since vaccination.

Years since vaccination: grouped 0-4, 5-8, 9, > 15 years.

Modified from Markowitz LE, Preblud SR, Fine PE, et al. Duration of live measles vaccine-induced immunity. Pediatr Infect Dis J 9:101-109, 1990.

a problem. Although secondary vaccine failures have been documented, taken collectively, the serologic and epidemiologic
data during the past 35 years indicate that vaccine provides
long-term immunity.

Combined vaccines and simultaneous vaccination

Live measles vaccine has been administered successfully in
combination or in conjunction with a variety of immunizing agents, such as yellow fever vaccine, poliovirus vaccine,
diphtheria and tetanus toxoids and whole-cell pertussis vaccine (DTP), meningococcal vaccine, hepatitis B vaccine, and
smallpox vaccine.445,448,452,638647 There is one report of interference with the measles antibody response after simultaneous
administration of meningococcal A and C vaccine,643 although
a different team of investigators did not find interference with
simultaneous administration of measles vaccine and meningococcal A vaccine.642
In developed countries, measles vaccine is administered
today along with rubella and mumps vaccines as a combined
vaccine (MMR) as part of routine childhood immunization
programs.211,212 Use of MMR vaccine instead of single-antigen
measles vaccine increases the benefit-to-cost ratio of the measles vaccination program in the United States from 17.2:1 to
21.3:1.356 The varicella vaccine was included in the routine
childhood schedule in 1996, licensure of a combined MMRV
vaccine occurred in 2005, and the ACIP recommendation for a
routine second dose of varicella vaccine occurred in June 2006
(www.cdc.gov/mmwr/pdf/rr/rr5604.pdf). Thus, in the United
States, both recommended doses of measles vaccine could be
administered as MMRV. However, given the increased incidence
of febrile seizures with dose one of MMRV, most such doses are
likely to be MMR.458,459 MMR vaccine is also frequently administered to susceptible adults.
Studies consistently show that combinations of measles,
mumps, and rubella antigens, regardless of the virus strain,
elicit the same high rates of seroconversion seen with each
component individually and that there is no increased risk of
reactions in persons susceptible to all three antigens (Tables
20-7 and 20-8).437454 Furthermore, vaccination of persons
already immune to one or more of the antigens, from either
previous vaccination or infection, is not associated with any
increased risk of vaccine-associated adverse events.644,648652

Although there are reports of directly mixing measles vaccine

with DTP,652 this should not be done routinely. Rather, the vaccines should be administered in separate syringes and at separate sites.653
Immunization against varicella along with measles, rubella,
and mumps, either as two vaccines (varicella and MMR) or
as a quadrivalent vaccine (MMRV), has been studied.654,655
Seroconversion rates have been reported to be 95% or greater to
all antigens, although titers against varicella were lower among
persons receiving the quadrivalent vaccine. A second dose of
MMRV administered 6 to 8 weeks after the first dose resulted
in greater than or equal to 98% seropositivity for all four antigens.455 Concomitant administration of MMRV, Haemophilus
influenzae b/hepatitis B (Hib/HepB), and diphtheria-tetanusacellular pertusis (DTaP) vaccines was found to be immunogenic and well tolerated.456

Postexposure prophylaxis
Routine vaccination before exposure to measles provides the
best protection against measles. However, persons without
measles immunity who are exposed can receive some protection through measles vaccination or IG administration after
exposure.

Use of vaccine
Exposure to measles is not a contraindication to measles
immunization. Available data suggest that live virus measles vaccine, if given within 72 hours of measles exposure,
will prevent, or modify disease.397,509,656 Also, the vaccine
should induce protection against subsequent measles exposures should the initial exposure fail to result in measles and
protection. Therefore, vaccine is the intervention of choice
for persons older than 12 months of age who are exposed to
measles in most settings (eg, healthcare facilities, schools,
colleges, health care facilities), unless contraindicated (see
Precautions and contraindications). Infants 6 to 11 months
of age may receive measles vaccine instead of IG if the initial exposure is detected within 72 hours. Infants vaccinated
before age 12 months must be revaccinated on or after the
first birthday with two doses of MMR vaccine separated by at
least 28 days (see Indications).

20

Measles vaccine
Table 20-7 Antibody Response after Administration of Measles Vaccine Alone, in Combination with Mumps and Rubella Vaccines, and in
Combination with Mumps, Rubella, and Varicella Vaccines
Measles
Vaccine

Mumps

Rubella

Total number

GMT

GMT*

GMT

23

100

82

Measles, mumps, rubella (RA27/3)

91

96

89

90

31

100

301

Measles, mumps, rubella (HPV-77:DE-5)

85

99

77

89

15

99

144

Measles

Modified from Lerman SJ, Bollinger M, Brunken JM. Clinical and serologic evaluation of measles, mumps, and rubella (HPV-77:DE-5 and RA27/3) virus vaccines
singly and in combination. Pediatrics 68:18-22, 1981.

Measles
Vaccine
Measles,
mumps,
rubella,**
varicella

Mumps
||

||

Rubella

Varicella
||

Total number

GMT

GMT

GMT

GMT

2,331-2,532

97.1

2985.0

96.0

95.9

98.8

89.2

93.5

17.9

*Indirect immunofluorescent assay geometric mean antibody titer.

Hemagglutination-inhibition assay geometric mean antibody titer.

Moraten strain.

Jeryl Lynn strain.

||
Enzyme-linked immunosorbent assays (ELISA) measured 6 weeks after vaccination; mIU/mL for measles, ELISA antibody (Ab) units for mumps and ELISA Ab units
for rubella.

Glycoprotein antigen-based ELISA (gp ELISA) units/mL measured 6 weeks after vaccination.
**RA27/3 strain.

Oka/Merck strain.Postvaccination antibody titers 5 gp ELISA units measured 6 weeks after vaccination.
GMT, Geometric mean titer.
Modified from Liebermann JM, Williams WR, Miller JM, et al. Pediatr Infect Dis J 25:615-622, 2006.

Use of immune globulin

Current US recommendations are to give human immune
globulin, as an intramuscular injection (IGIM), to susceptible
persons exposed to measles and for whom vaccine either is contraindicated or was not given within 72 hours of initial exposure.
Measles is infectious during the prodrome and often is not diagnosed until the rash onset. Therefore, many exposed persons are
not identified until more than 72 hours after initial exposure,
which is too late for prophylaxis with measles vaccine. Human
IGIM provides measles antibodies to prevent or modify the disease when given up to 6 days after exposure.158160,361 However,
any immunity conferred is temporary (lasting approximately
3 to 4 weeks) unless modified or typical measles occurs.158,361
IGIM should not be used to control measles outbreaks.
Postexposure prophylaxis with IGIM is especially important
for exposed persons at increased risk for complications from measles (ie, infants less than 12 months of age, pregnant women, or/
and immunocompromised persons). The recommended dose of
IGIM is 0.25 mL/kg within 6 days of initial exposure. The dose
should be increased to 0.50 mL/kg for immunocompromised
persons. The maximum dose in all cases is 15 mL.211,212 Infants
younger than 5 to 6 months of age usually have partial or complete immunity to measles because of passive maternal antibody.
However, infants whose mothers develop measles are not protected by maternal antibody and should receive IGIM. Also, in
some countries up to 19% of women of childbearing age do not
have measurable measles antibody titers.548,657 Infants born to
these women would be susceptible to measles at birth. Persons
who receive IGIM and do not develop clinical measles should
receive measles vaccine 5 to 6 months later (depending on the
dose administered), as long as the patient is at least 12 months
of age and there are no contraindications to vaccination.212
Human IGIM is not indicated for exposed persons who have
received at least one dose of measles vaccine at 12 months of
age or older unless they are immunocompromised. All immu-

nocompromised persons (including anyone with HIV infection

and children of unknown infection status born to HIV-infected
women) who are exposed to wild-type measles should receive
IGIM postexposure prophylaxis (0.5 mL/kg, maximum dose
15 mL), regardless of their immunization status.658 An exception is the patient receiving IGIV at regular intervals, whose last
dose of at least 100 mg/kg was received within 3 weeks before
exposure.211,212 IGIV and IGSC are commonly used in immunocompromised patients with primary immunodeficiency, HIV
infection, or B-cell chronic lymphocytic leukemia. The FDArequired minimum standards for measles antibody titers are lower
for IGIV and IGSC than for IGIM preparations.364,365 However,
the IVIG doses commonly used (200-400 mg/kg) for immunocompromised patients should be sufficient to prevent measles
for 3 weeks. An additional dose of IGIV should be considered for
persons on maintenance IGIV therapy who are exposed to measles more than 3 weeks after receiving a standard dose of IGIV.659
Human IGSC is given in weekly doses that are calculated to provide similar mean immunoglobulin G levels as IGIV doses given
every 4 weeks. There are currently no published guidelines as to
whether persons on IGSC therapy should receive IGIM injection
if exposed to measles. Because current immune globulin preparations may contain lower levels of measles neutralizing antibodies
than in the past, there is active discussion as to whether recommended dosages should be modified. As of mid 2012, the ACIP
has not recommended any changes. Should there be any changes
to the recommended doses, they will be posted at HYPERLINK
http://www.cdc.gov/vaccines www.cdc.gov/vaccines under the
recommendations section.

Adverse effects
Adverse reactions after receipt of live, further attenuated measles
vaccines (alone and in combination) are generally mild. With
the exception of hypersensitivity reactions, adverse reactions are

371

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SECTION TWO Licensed vaccines

Table 20-8 Proportion of Children with Fever and Rash After

Administration of Measles Vaccine Alone, in Combination with Mumps
and Rubella Vaccines, and in Combination with Mumps, Rubella, and
Varicella Vaccines*

Vaccine

Total number

Fever
39.4 C
(%)

Measles

43

12

Measles, mumps,
rubella (RA27/3)

141

11

20

Measles, mumps,
rubella (HPV77:DE-5)

142

17

Placebo

42

Rash (%)

Modified from Lerman SJ, Bollinger M, Brunken JM. Clinical and serologic
evaluation of measles, mumps, and rubella (HPV-77:DE5 and RA27/3) virus
vaccines singly and in combination. Pediatrics 68:18-22, 1981.

Fever 38.9 C

Rash

Total
Number

Total
Number

Measles,
mumps, rubella,
and varicella||
given separately

982

33.1

1,000

4.5

Measles,
mumps, rubella,
varicella||

2,839

39.1

2,877

5.7

Vaccine

*During 6 weeks after vaccination.

Moraten strain.

Jeryl Lynn strain.

RA27/3 strain.
||
Oka/Merck strain.

P = .001. For fever measured 5-12 days after vaccination: 15.6% for
measles, mumps, rubella (MMR) and varicella vaccine recipients vs. 22.8%
for measles, mumps, rubella, and varicella combined vaccine recipients
(P < .001).
Modified from Liebermann JM, Williams WR, Miller JM, et al. Pediatr Infect
Dis J 25:615-622, 2006.

limited to susceptible vaccinees and occur primarily during the 6

to 12 days after vaccination when the peak in replication of the
live virus occurs.
Fever of 39.4 C or higher ( 103 F) occurs in approximately
5% to 15% of vaccinees between the 7th and 12th day after
vaccination and lasts approximately 1 to 2 days. In a study of
twins, when one twin received MMR vaccine while the other
received placebo, increased rates of fever occurred almost exclusively 9 or 10 days after vaccination.437,669
Rash occurs in approximately 5% of recipients, beginning 7 to
10 days after vaccination and lasting for 1 to 3 days. Determining
the etiology of a rash illness after measles vaccination can be difficult because other infections, such as human herpesvirus type
6 and human papillomavirus type 19, can often occur early in
life and can be confused with a vaccine reaction.253
When the vaccine is administered to a person already incubating natural disease, it is not usually possible to determine if
fever and rash are caused by the vaccine or if the child has a modified case of measles unless wild-type virus is isolated from urine
or the respiratory tract. Measles-like illnesses developing less
than 6 days after vaccination are usually the result of the wildtype virus or other concurrent illnesses because the measles-like

See references 266,369374,411414,437,438,441,444452,

644,653,660669.

rash associated with the vaccine is very unlikely to occur in this

period.437 The frequency of fever, rash, and other side effects
after second doses of measles-containing vaccines is lower than
after the first because most children are already immune from
the initial vaccination, thus preventing significant viral replication.661,662 One study found a slightly higher rate of adverse effects
after a second dose of MMR when that dose was given to 10- to
12-year-olds compared with 4- to 6-year-olds.668 This difference
was most likely the result of a higher rate of susceptibility among
10- to 12-year-olds and the recognized increased rate of arthralgia caused by rubella vaccine in older children.668 Adverse events
resulting in medical visits within 1 month after vaccination of
10- to 12-year-olds were still rare (attributable risk 1.7/1000) and
consisted mainly of rashes and joint pain.
A study conducted in the United States showed that during the
5 to 12 days after vaccination, children receiving the first dose of
MMRV vaccine had significantly higher rates of elevated temperatures than those who had been vaccinated with MMR and varicella
vaccine administered separately (27.7% vs. 18.7%, respectively).
Measles-like rash was also more common after the first dose of
MMRV than after MMR and varicella vaccine administered separately (5.9% versus 1.9%, respectively).456 A multicenter study
found rates of fever between days 5 and 12 postvaccination to be
higher in recipients of MMRV compared with recipients of MMR
and varicella vaccine administered separately (22.8% vs. 15.6%);
no statistical differences were observed for fever greater than or
equal to 40 C between the study groups.457 Another study conducted in Germany also showed a higher incidence of fever greater
than 37.5 C within 15 days after vaccination among children
vaccinated with MMRV when compared with children vaccinated
with MMR and varicella vaccine (67.7% vs. 48.8%). However, the
incidence of fever greater than 39 C was not statistically different
between the two groups.455,458,459 No increased fever or rash was
noted when these vaccines were administered as the second dose
of measles-containing vaccines.459,670673
Measles vaccine is associated with a mild decrease in platelet
counts within a few days after the vaccine is given, and rare cases
of idiopathic thrombocytopenic purpura (ITP) have been associated with measles-containing vaccines.674 A review of 12 studies revealed a median incidence of 2.6 cases of ITP per 100,000
children receiving the first dose of measles vaccine. In two studies in the United Kingdom, an increased risk of ITP was documented after measles vaccination, at a rate of 1 case in every
25,000 doses in the 6 weeks after immunization.675 The Vaccine
Safety Datalink Project found an attributable risk of 1 case of ITP
per 40,000 doses of MMR.676 The disease was generally mild and
resolved in 93% of children within 6 months. Recurrences were
uncommon. Therefore, although advisory committees recommend caution when administering measles-containing vaccines
to children with thrombocytopenia or a past history of ITP, data
from several small studies of children who had ITP did not reveal
recurrences after the administration of MMR.211,212,675,676
Immediate hypersensitivity reactions, including hives and
anaphylaxis, occur rarely.677 The rate of anaphylaxis is approximately 1 to 3.5 per million doses administered. The rate of
other immediate hypersensitivity reactions is estimated to be
about 10 per million doses.678 Measles vaccine is produced in
chick embryo tissue culture, and for many years, there were
concerns about administering these vaccines to children with
egg allergy. However, several studies using sensitive methods
have demonstrated that there is no evidence of egg protein
in measles vaccine. Although rare cases of anaphylaxis have
been reported in children with egg hypersensitivity, the allergen
in the vaccine responsible for these reactions is uncertain.679
The majority of children with immediate hypersensitivity reactions to measles-containing vaccines have evidence of allergy to
the gelatin stabilizer.680,681 Children with immediate hypersensitivity to eggs can be safely immunized with measles vaccines,
and no special precautions are necessary.680

Measles vaccine

Febrile seizures are the most commonly reported neurologic

adverse event after measles vaccination.246,663,666669 Fever from
any source lowers the threshold for seizures, and a febrile seizure is not a sign of central nervous system (CNS) infection or
disease. Febrile seizures occur primarily in the second and third
year of life and are not associated with long-term sequelae. The
risk of febrile seizures is increased approximately threefold in
the 8 to 14 days after receipt of MMR.669 The increased rate of
fever associated with MMRV results in an additional febrile seizure in about 1 in every 2,500 children compared with administering MMR and varicella vaccine separately.458,459 The rates of
fever and febrile seizures after administering measles vaccines
are much lower than the rates after measles disease. There has
been no increased risk of adverse neurologic events observed in
children who received measles vaccine combined with rubella
and mumps vaccines (MMR) compared with measles vaccine
administered alone.669
Postinfectious encephalitis is a recognized complication of
measles, but there is uncertainty as to whether or not encephalitis is caused by further attenuated measles vaccines in normal
hosts. In children who have died during the rash phase of measles, measles virus has been found in brain tissue, but measles
virus rarely has been found anywhere in the central nervous system (CNS) with postinfectious encephalitis, which is thought
to be the result of an altered immune response to myelin proteins.212 Encephalitis has been reported after measles immunization at a rate of approximately 1 case per 1 million vaccine
recipients.682 This rate is lower than the background rate of
encephalitis of unknown etiology in unvaccinated children in
the general population. There is temporal clustering of reports in
the 5 to 15 days after immunization when other adverse effects
from the vaccine occur.652 There has been one report of a vaccine isolate recovered from the cerebrospinal fluid of a normal
person who received Edmonston B strain vaccine.683 There have
been no cases of vaccine-strain virus identified as the cause of
encephalitis in persons with intact immune systems confirmed
by neuropathologic studies. Nine cases of encephalitis after
administering measles-containing vaccines were reported in the
United States during 1979 to 1986, when 22.7 million doses
of measles antigencontaining vaccine were distributed, for a
rate of 1 per 2.5 million doses (0.4 per 1 million doses).651 In
Albania, 2 cases of encephalitis were identified after 867,000
doses of MR were administered during a mass vaccination
campaign.684 This observed rate is lower than that noted for
severe neurologic disorders of unknown etiology in unimmunized children of the same age range, suggesting a possible chance
temporal association.685 In Finland and the United States, there
was no evidence of an increased risk of encephalitis after measles vaccines.686,687 In the United Kingdom, studies have found
an increased rate of serious neurologic disease in the 6 to 11 days
after vaccination.688,689 However, some of the increase was due
to complex febrile seizures, and other viruses known to cause
encephalitis (herpes simplex virus, HHV-6 and HHV-7) were
identified in some affected patients. The Institute of Medicine
concluded, in 1994, that there was inadequate evidence to
accept or reject a causal relation between measles vaccine and
encephalitis or encephalopathy.674 However, in a 1998 study,
done by Weibel and colleagues,689 the authors found a clustering of 17 cases of encephalopathy on days 8 and 9 after MMR
vaccination, but they stated that with the large denominator of
children vaccinated throughout 23 years, encephalopathy would
be an extremely rare complication (0.06 per 100,000 vaccinees).
If measles vaccines do cause acute encephalitis, the rate is at
least 1,000 times less than the rate after natural infection.
There are case reports but no evidence of increased risk or
causal associations of several other disorders after measles vaccines, including Reye syndrome, oculomotor palsy, optic neuritis,
retinopathy, hearing loss, cerebellar ataxia, arthralgia, arthritis,
and soft-tissue reactions.246,651,690699 There is no increased risk of

20

Guillain-Barr syndrome after measles vaccine.700,701 In a cohort

study of 167,240 children, no significant association between
timing of the receipt of measles vaccine and asthma was found.702
SSPE is caused by persistence of defective measles virus in
the CNS through as-yet undefined mechanisms. Analyses of
data from the United Kingdom and the United States have
shown the true incidence of SSPE to be approximately 4 to
11 cases of SSPE per 100 000 cases of measles, with higher
rates in children who had measles at an early age.703 No specific immune deficiency has been identified in children with
SSPE to explain the failure of the immune system to eliminate
the virus.704 There was an initial concern that measles vaccine
virus might cause a persistent CNS infection because some
patients with SSPE who have received vaccine had no history
of disease.94,99,133,704 However, when investigated carefully, most
of these persons have histories of measles-like illnesses and/
or known exposures to measles followed by administration of
passive IG.675,705 Genetic sequencing of viruses obtained from
the brains of patients with SSPE, including patients with no
history of having had measles, has revealed only viruses of
wild-type origin.130,706708 Case-control studies and the marked
decline of SSPE in parallel with the decline in measles after the
introduction and widespread use of measles vaccine demonstrate that the vaccine protects against SSPE (Figure 20-8).703
It is not known if measles virus persists in immunologically
normal persons who do not develop SSPE.704 Measles virus
genomic RNA was detected frequently in persons who had
been immunized or exposed to measles more than 2 months
before testing in one study, and one group of investigators
found evidence for persistence of measles virus nucleocapsid
in a variety of tissues many years after measles.709,710 An HIVinfected intravenous drug user developed progressive measles
retinitis and subsequent progressive CNS disease diagnosed
as SSPE at 30 years of age.711 His illness resembled measles
encephalitis in immunocompromised persons. He had a history of measles at 2 years of age, and HIV infection most likely
occurred in later life, secondary to intravenous drug abuse or
sexual contact.
Measles encephalitis in immunosuppressed children, including children with HIV infection or leukemia, is sometimes
referred to as subacute or inclusion body measles encephalitis
and is caused by progressive measles virus infection.712,713 Onset
is usually 5 weeks to 6 months after acute measles, and virus
has been identified in brain tissue and cerebrospinal fluid specimens. Virus isolated from brain tissue specimens from several
patients has been shown to be wild-type measles virus.708,712
One patient with an undefined immune disorder who developed this disorder at 21 months of age was found to have measles vaccine virus in brain tissue.714 The Institute of Medicine
concluded in 2011 that there was adequate evidence to accept a
causal relation between measles vaccine and measles inclusion
body encephalitis in persons with demonstrated immunodeficiencies (causation is attributed to the measles component of
the vaccine).705
In persons with severe immune suppression, there is an
increased risk of progressive measles vaccine virus replication
and severe complications, including fatal pneumonia.716,717
HIV infection has not been associated with increased risks of
adverse events in the few weeks after measles vaccination (see
Chapter 64 for additional information on immunization of HIVinfected persons).718,719 Only one well-documented instance of
a severe complication after measles vaccine in an HIV-infected
person has been reported. Measles vaccine virus was identified in the lung of a 20-year-old man who died of progressive
pneumonitis that was recognized about 9 months after receiving a second dose of measles vaccine.717,720 One HIV-infected
child who had received MMR vaccine at 15 months of age was
found to have characteristic inclusion bodies on brain biopsy
at 18 months of age, but no specific testing was performed to

373

SECTION TWO Licensed vaccines

60

600

500

50

400

40

300

30

200

20

100

10

Total reported SSPE onsets

SSPE (born USA)

Measles notifications
Measles notifications (in thousands)

99
19

96
19

93
19

90
19

87

84

19

19

81
19

78
19

75
19

72
19

69
19

66
19

63
19

60

19

374

Year
Figure 20-8 Subacute sclerosing panencephalitis (SSPE) cases and measles notifications in the United States, 1960 to 2000. (Adapted from Campbell
et al. Int J Epidemiol 36:1334-1348, 2007.)

determine the source or identity of the virus.712 Also, a 19-yearold HIV-infected man with hemophilia had paramyxovirus
nucleocapsids in intranuclear inclusion bodies, and there was
evidence of measles antigen on immunohistochemical staining, but the virus was not sequenced.713 He had received measles
vaccine at 10 years of age, and there was no history of measles
exposure in the year preceding the biopsy. The ages at which
he acquired HIV infection and possible subsequent exposures
to measles were not reported. The WHO recommends measles vaccine for asymptomatic HIV-infected children and those
with early signs of HIV-induced immunosuppression because
of the high risk of serious complications from measles in HIVinfected persons.566,719 In the United States, where the risk of
measles exposure is low, the ACIP recommends withholding
measles vaccine from persons with severe immunosuppression.
Severe immunosuppression is defined as (1) a CD4+ count of
less than 200 cells/mm3 for persons 6 years of age and older, a
CD4+ count of less than 500 cells/mm3 for children 1 to 5 years
old, and a CD4+ count of less than 750 cells/mm3 for children
younger than 12 months of age; or (2) CD4+ cells less than 15%
of total lymphocytes for children younger than 13 years.721,722
After bone marrow transplantations, advisory committees
recommend waiting 2 years to administer measles vaccine to
allow immune reconstitution.212 However, in a study of 51
patients, vaccination 1 year after transplantation was not associated with any increased rate of adverse reactions.723
The possibility that measles virus persists in selected tissues
after measles has been proposed by investigators who found
evidence for measles antigen or genomic material in human
tissues, including brain, lung, intestine, and bone, years after
measles disease.710 The investigators proposed that these viruses
contribute to or cause inflammatory diseases in these organs,
including Paget disease,150,724 otosclerosis,149 and inflammatory bowel disease.725 However, other investigators have found
no evidence for measles viruses or measles genomic material
in tissues from affected or normal patients.726,727 The hypothesis that measles vaccine given in combination with mumps
and rubella vaccines (MMR ) caused inflammatory bowel disease and autism was promoted by one particular investigator
who had unrevealed conflicts of interest. A later review of the

clinical records from the original 12 patients found evidence of

fraud in the data, and the article has been withdrawn.725,728731
Some of the other reports of persistent measles virus genomic
material in children with autism were based upon PCR methods that amplified host genomic material, not measles virus.727
In-depth reviews conducted by the Institute of Medicine146 concluded that the evidence favors rejection of the MMR-autism
hypothesis, and an expert review by the AAP726 concluded that
the evidence does not support either of these hypotheses. A systematic review of the literature by the Cochrane Collaboration
reached similar conclusions.732
Advisory committees in many countries recommend the use
of MMR to protect against these three diseases.211,212

Indications
General
The goal of measles vaccination programs is to protect persons
from the severe consequences of measles infection by providing
lifelong individual immunity to vaccinees and by reducing susceptibility to measles in the population to prevent transmission
of this disease. The major source of measles susceptibility in a
population is the birth of children, who will all lose their maternal antibody and become susceptible in the first or second year of
life. Maternal antibody interferes with the response to live measles vaccines. The most critical task of any vaccination program
is the timely delivery of the first dose of measles vaccine to young
children. The timing of the first dose must balance the proportion of infants who have lost maternal antibody and are able to
respond to vaccination at a given age against the risk of measles infection before that age.550 Therefore, recommendations for
measles vaccination vary by country.
The WHO recommends measles vaccine be administered
at 9 months of age in countries with ongoing transmission of
measles in which the risk of measles mortality among infants is
high.566,733 In countries with low rates of measles transmission
(ie, those near elimination) the WHO recommends the first dose
of measles vaccine be given at 12 months to take advantage of
higher seroconversion rates achieved at this age.566,733,734 In 2009,

Measles vaccine

the WHO recommended that a two-dose measles immunization

schedule should be the standard of care for all countries. The second dose may be offered either at a scheduled age through routine services or periodically through mass campaigns, depending
on which strategy achieves the higher coverage.566,733
Many developed and some developing countries now have
schedules for two routine doses of measles vaccine. In developed
countries, the first dose is usually recommended early in the
second year of life; the age for the second dose varies.3033,212,566
The following section provides detailed recommendations of
measles vaccination for the United States.

General immunization guidelines

In general, use of licensed combination vaccines, such as MMR,
is preferred over separate injections with equivalent component
vaccines, to minimize the number of injections and reduce
missed opportunities to protect through vaccination. ACIP,
AAP, and American Academy of Family Physicians (AAFP) recommend that combination vaccines may be used whenever
any components of the combination are indicated and its other
components are not contraindicated.659,735 Single antigen measles, mumps, or rubella vaccines are no longer available in the
United States.
MMR or MMRV vaccine may be administered simultaneously with other vaccines to persons at the recommended age
to receive these vaccines. Neither theoretic considerations nor
practical experience indicate that the simultaneous administration at separate anatomic sites of MMR or MMRV and other
live or inactivated vaccines will produce a diminished immune
response or increase the incidence of adverse events among vaccinated persons.212
The combined live attenuated measles, mumps, rubella, and
varicella (MMRV) vaccine was licensed in 2005 in the United
States and recommended in 2006 for use in children 12 months
to 12 years of age.736 In May 2010, ACIP updated its 2006
MMRV recommendations737 based on study results showing a
roughly twofold increased risk for febrile seizures after the first
dose of MMRV compared with the first dose of MMR and varicella vaccine administered separately at the same visit.458,459,738
The routinely recommended age for the first dose of measles,
mumps, rubella, and varicella vaccines is age 12 to 15 months;
children not vaccinated according to the routine schedule may
receive the first dose of MMRV vaccine up to age 12 years. For
the first dose of measles, mumps, rubella, and varicella vaccines
at age 12 to 47 months, either MMR vaccine and varicella vaccine or MMRV vaccine may be used. Providers who are considering administering MMRV vaccine should discuss the benefits
and risks of both vaccination options with the parents or caregivers. Unless the parent or caregiver expresses a preference for
MMRV vaccine, MMR vaccine and varicella vaccine should be
administered as separate vaccines for the first doses in this age
group. Use of MMR vaccine and varicella vaccine avoids the
increased risk for fever and febrile seizures after MMRV vaccine.
The 47-month cutoff was selected on the basis of the epidemiology of febrile seizures. Approximately 97% of febrile seizures
occur in children ages less than or equal to 47 months.458,459,738
Although the routinely recommended age for the second
dose of measles, mumps, rubella, and varicella vaccines is 4
to 6 years, the second dose may be administered before age
4 years, provided greater than or equal to 3 months have
elapsed since the first dose. MMRV vaccine is licensed for
use among children from age 12 months through age 12
years. For the second dose of measles, mumps, rubella, and
varicella vaccines at any age (15 months to 12 years) and
for the first dose at age greater than or equal to 48 months,
use of MMRV vaccine generally is preferred over separate
injections of its equivalent component vaccines (ie, MMR
vaccine and varicella vaccine). Catch-up vaccination is

20

recommended to ensure a second dose for all children, adolescents,

and adults who previously had received one dose.737
At least 1 month should elapse between doses of any live
virus vaccines. For children ages 12 months to 12 years at least
3 months should elapse between doses of varicella-containing
vaccines. Simultaneous administration of the most widely
used live and inactivated vaccines has produced seroconversion
rates and rates of adverse reactions similar to those observed
when the vaccines are administered separately.659,739 Therefore,
MMRV may be administered simultaneously with other vaccines recommended at ages 12 months and 12 years, although
data are absent or limited for the concomitant use of MMRV
vaccine with DTaP, inactivated polio, pneumococcal conjugate,
influenza, and hepatitis A vaccines.736 Additional information
regarding MMRV is provided in the chapters on Varicella vaccine (Chapter 37) and Combination vaccines (Chapter 40).
Specific criteria for documentation of measles immunity
have been established to identify the appropriate level of immunization for different groups. Persons can generally be presumed
immune to measles if they have documentation of adequate
vaccination, laboratory evidence of immunity to measles, or
documentation of physician-diagnosed measles or were born
before 1957 (few persons in the United States born before 1957
escaped natural infection). Physician-diagnosed measles is no
longer considered presumptive evidence of immunity for health
care personnel (see Health care personnel).740
In general, one dose of MMR is considered adequate vaccination for preschool children and adults who are not at high risk
of exposure to measles. Two doses of MMR are indicated for
schoolchildren, students at posthigh-school educational institutions, health care personnel, persons in measles outbreak settings, and international travelers because these groups are at
increased risk for exposure to measles. Criteria accepted as evidence of immunity for the purpose of meeting school or college
entry requirements or other government regulations may vary
among state and local jurisdictions.211,212
Proper documentation of immunization is critical to
ensuring that every person receives the appropriate vaccines.
Vaccination status and date of administration of all vaccinations should be documented in the patient's permanent medical
record. Only doses of vaccine for which written documentation
of the date of administration is presented should be considered
valid. Health care professionals should provide a vaccination
record for a patient only if they have administered the vaccine
or have seen a record that documents vaccination.211,212
Because of reduced efficacy of measles vaccine when it
is administered to young children, doses of measles vaccine
administered to children younger than 12 months are not considered valid doses in the United States. Children vaccinated at
ages younger than 12 months should be revaccinated at 12 to 15
months of age (provided at least 28 days have elapsed) to be considered to have received a single dose of measles vaccine.211,212

Routine vaccination schedule

Preschool children
All children should receive the first dose of MMR or MMRV at
12 to 15 months of age (Table 20-9). Children exposed to measles or at high risk of exposure (eg, during an outbreak or while
on international travel) may be vaccinated with MMR as early
as 6 months of age.
The second dose of MMRV or MMR vaccine is recommended when children are age 4 to 6 years (ie, before a child
enters kindergarten or first grade). This recommended timing
for the second dose has been adopted jointly by the Advisory
Committee on Immunization Practices (ACIP), the AAP, and the
AAFP.211,212 Evidence now indicates that (1) the major benefit of
administering the second dose for measles is a reduction in the
proportion of persons who remain susceptible because of primary

375

376

SECTION TWO Licensed vaccines

Table 20-9 Summary of Measles Vaccination Recommendations in the United States*

Preschool children
Routine childhood schedule
Special circumstances
Outbreak settings or before international travel

First dose: 12-15 mo

Second dose: 4-6 yr
First dose: may be given as early as 6 mo
Repeat first dose: 12 mo
Second dose: may be given as early as 13 mo

HIV infection

First dose: 12 mo
Second dose: may be given as early as 13 mo

School children and adolescents

All children in kindergarten through 12th grade should have documentation of two
doses of MMR unless they have other evidence of immunity

Adults

Adults without other evidence of immunity should have documentation of receipt of at

least one dose of MMR

Special circumstances

Students and staff in colleges and other posthigh-school educational institutions,

persons working in health care facilities, and international travelers should have
documentation of receipt of two doses of measles vaccine unless they have other
evidence of immunity

*All recommendations exclude persons for whom measles vaccination is contraindicated.

Wait at least 28 days after any dose before giving a subsequent dose.

Persons who were born before 1957 or have a history of physician-diagnosed measles disease or have laboratory evidence of immunity.

vaccine failure, (2) waning immunity is not a major cause of vaccine failure and has little influence on measles transmission, and
(3) revaccination of children who have low levels of measles antibody produces only a transient rise in antibody levels.170,515
For children greater than or equal to 12 months of age who are
exposed to measles or at high risk of exposure (eg, during an outbreak or for international travel), the second dose may be given
as early as 28 days after the first dose based on the principle that
live-virus vaccines not administered at the same time should be
separated by at least 1 month.211,212 For vaccines containing varicella antigens, a three-month interval between doses is required.

Schoolchildren
All children in school from kindergarten through 12th grade
should have documentation of two doses of measles vaccine,
unless vaccination is contraindicated. Children who do not have
documentation of adequate vaccination against measles or other
acceptable evidence of immunity should be admitted to school
only after administration of the first dose of MMR vaccine. If
required, the second MMR dose should be administered as soon
as possible, but no sooner than 28 days after the first dose. The
ACIP, AAP, and AAFP recommend the health maintenance visit
at age 11 to 12 years should serve as a special opportunity to
evaluate vaccination status and to administer MMR vaccine to
all persons who have not received two doses at the recommended
ages.211,212 As of the 2007 to 2008 school year, 49 states have state
immunization requirements for two doses of measles vaccine
that cover all grades, and all states require two doses for school
entry.741 The estimated national two-dose coverage rate in the
2009 to 2010 school year at kindergarten entry was 94.8%;741a
state estimates ranged from 84.5% to 100%.742 However, there
are limitations to the kindergarten survey data, because the
methodology for collection of the data differs among the states.

Vaccination of high-risk groups

Colleges and other posthigh-school educational
institutions
Risks for transmission of measles at posthigh-school educational institutions can be high because these institutions may
bring together large concentrations of persons who may be

susceptible to measles. College entry requirements for measles immunity substantially reduce the risk for measles outbreaks on college campuses where they are implemented and
enforced.743 Therefore, colleges, universities, technical and
vocational schools, and other institutions for posthigh-school
education should require that all undergraduate and graduate
students have received two doses of MMR vaccine or have other
acceptable evidence of immunity before enrollment. Students
without documentation of any measles immunization or
immunity should receive a dose on entry, followed by a second
dose 4 weeks later.211,212

Outbreak settings
During outbreaks in schools and other institutions, all students
and personnel born in 1957 or later, should have documentation
of two doses of measles-containing vaccine on or after the first
birthday.211,212 All persons who do not have such documentation
or other evidence of immunity should be vaccinated or excluded
from the school until 21 days after the onset of rash in the last
case of measles. Persons receiving their second dose and unimmunized persons receiving their first dose as part of the outbreak
control program may be readmitted immediately to school. In
outbreaks where there is increased risk of exposure for infants
younger than 1 year, vaccination with MMR vaccine is recommended for infants as young as 6 months. Children who are vaccinated before their first birthday should be revaccinated when
they are 12 months of age (provided at least 28 days have elapsed
since the first dose given before age 12 months) and again at
school entry. During outbreaks, IG should be administered to
immunocompromised persons, susceptible pregnant women,
and unvaccinated children younger than 12 months who are
exposed to measles. However, IG should not be used to attempt
to reduce measles transmission or control outbreaks. Likewise,
serologic screening before vaccination generally is not recommended during an outbreak because waiting for serology results
can impede the rapid vaccination needed to curb the outbreak.
Every suspected measles case should be reported immediately to the local health department, and every effort must be
made to rapidly verify that the illness is measles, especially if

Measles vaccine

this may be the first case in the community. Subsequent prevention of the spread of measles depends on prompt immunization of persons at risk of exposure or already exposed who
cannot readily provide documentation of measles immunity,
including the date of immunization.211,212
If an outbreak occurs in a health care setting, all employees who were born in 1957 or later who cannot provide documentation that they have received two doses of measles vaccine
on or after their first birthday or other presumptive evidence of
immunity to measles should be offered the first dose of MMR
vaccine immediately and receive the second MMR vaccination
at least 28 days later. Some health care personnel who were born
before 1957 have acquired measles while at work. Therefore,
during an outbreak of measles, health care facilities should recommend completion of two doses of MMR vaccine for unvaccinated or undervaccinated personnel born before 1957 who lack
laboratory evidence of measles IgG in their serum or laboratory confirmation of infection.740 Health care personnel without
evidence of immunity who are not vaccinated after exposure
should be removed from all patient contact and excluded from
the facility from day 5 after their first exposure through day 21
after the last exposure, even if they have received postexposure
intramuscular immune globulin of 0.25 mL/kg (40 mg IgG/kg).
Those with documentation of one vaccine dose may remain at
work and should receive the second dose.211,212

Health care personnel

Persons who work in health care facilities are at greater risk for
acquiring measles than the general population. During 1985 to
1989, physicians had an eightfold increased risk and nurses a
twofold increased risk of measles compared with nonhealth
care workers of the same age.744 In the 120 measles outbreaks
occurring during 1993 through 2001, health care facilities were the most commonly reported settings, with 24 outbreaks reported.745 In the postelimination years 2001 to 2008,
27 reported measles cases were transmitted in US health care
facilities, accounting for 5% of all reported US measles cases.746
Because persons working in medical settings have been infected
with measles and have transmitted the virus to patients and other
staff, the ACIP recommends that persons born in or after 1957
working in health care facilities be required to provide documented
receipt of two doses of measles-containing vaccine, laboratory
evidence of measles immunoglobulin (IgG) in serum (ie, a single specimen test for measles IgG), or laboratory confirmation of
acute prior measles infection (ie, positive serologic test for measles
immunoglobulin M [IgM] antibody or fourfold rise in measles IgG
antibody level or documentation of seroconversion by any standard serologic assay, detection of measles RNA in a clinical specimen, or isolation of measles virus from a clinical specimen).740,748
During 2001 to 2008, 12.5% (1 of 8) of measles cases reported
to the Centers for Disease Control and Prevention (CDC) among
health care personnel occurred in persons born before 1957.740
Thus, because measles has occurred in persons born before
1957, health care facilities should consider vaccinating personnel born before 1957 who lack documented receipt of two doses
of measles-containing vaccine, laboratory evidence of measles
IgG in their serum, or laboratory confirmation of infection,
with two doses of MMR vaccine at the appropriate interval.211,212
During an outbreak of measles, health care facilities should recommend two doses of MMR vaccine for unvaccinated personnel
born before 1957 who lack laboratory evidence of measles IgG in
their serum or laboratory confirmation of infection.740,748
Serologic screening need not be done before vaccinating for
measles and rubella unless the medical facility considers it cost
effective.748,749 For health care personnel who have two documented doses of MMR vaccine or other acceptable evidence
of immunity to measles, serologic testing for immunity is not
recommended.

20

International travelers
Measles is endemic in many countries including industrialized
countries in Europe and Asia. Of the 222 measles cases reported
in the United States in 2011, 200 (90%) were associated with
importations. Almost half of the imported cases occurred in people who acquired measles in Europe.740a Protection against measles is especially important for persons planning international
travel. Before their departure from the United States, children 12
months of age or older should have received two doses of MMR
vaccine separated by at least 28 days, with the first dose administered on or after the first birthday. Children ages 6 to 11 months
should receive a dose of MMR vaccine before departure. For
infants vaccinated before 12 months of age, revaccination should
be at 12 to 15 months of age (12 months of age for those remaining in areas of endemic or epidemic measles). The second dose
should be administered at least 28 days after the first dose.211,212
Because the risk of complications from measles is increased in
adults, it is also important to protect susceptible adults. Most persons born in the United States before 1957 are likely to be immune.
However, for persons born after 1956 who travel internationally,
two doses of measles vaccine should be administered separated by
at least 28 days, unless there is documentation of receipt of two
doses, other evidence of immunity, or a contraindication.211,212

Persons infected with human immunodeficiency virus

HIV-infected persons are at increased risk for severe complications if infected with measles.181,189 Among HIV-infected persons who did not have evidence of severe immunosuppression,
no increase in serious or unusual adverse events have been
reported after measles vaccination.189,750 Therefore, MMR vaccination is recommended for all asymptomatic HIV-infected
persons who do not have evidence of severe immunosuppression and for whom measles vaccination would otherwise be
indicated. MMR vaccination also should be considered for all
symptomatic HIV-infected persons who do not have evidence
of severe immunosuppression.751 Testing asymptomatic persons
for HIV infection is not necessary before administering MMR
or other measles-containing vaccines.211,212
Because the immunologic response to live and killed-antigen vaccines may decrease as HIV disease progresses, vaccination early in the course of HIV infection may be more likely to
induce an immune response.598 Therefore, HIV-infected infants
without severe immunosuppression (as defined in Adverse
effects) should routinely receive MMR vaccine as soon as possible on reaching the first birthday (ie, at age 12 months).751
Consideration should be given to administering the second dose
of MMR vaccine as soon as 28 days (ie, 1 month) after the first
dose rather than waiting until the child is ready to enter kindergarten or first grade. In addition, if at risk for exposure to
measles, (eg, in an outbreak setting or for international travel),
HIV-infected infants who are not severely immunocompromised should be administered MMR vaccine at age 6 to 11
months.211,212,566 These children should receive another dose as
soon as possible on reaching the first birthday, provided at least
1 month has elapsed since the administration of the previous
dose of measles-containing vaccine. An additional dose of MMR
vaccine can be administered as early as 28 days after the second
dose. Newly diagnosed HIV-infected adults and children ages 12
months or older without acceptable evidence of measles immunity should receive MMR vaccine as soon as possible after diagnosis, unless they have evidence of severe immunosuppression.

Close contacts of immunosuppressed patients

To minimize the risk of exposure to measles among patients
with immunosuppression, including HIV infection, all family
and other close contacts of these patients should be vaccinated

377

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SECTION TWO Licensed vaccines

with two doses of MMR vaccine, unless they are immunosuppressed, have other contraindications, or have other acceptable
evidence of measles immunity.211,212 No transmission of measles vaccine virus from a vaccinee to a contact has ever been
documented, which suggests that the risk of exposure to vaccine virus among immunosuppressed contacts is very low.
However, because of the extreme vulnerability of hematopoietic
cell transplantation (HCT) recipients, vaccine recipients who
develop a fever and/or rash postvaccination should be excluded
from visiting the HCT center while symptomatic and should
avoid close contact with HCT recipients in the home setting.752

Patients treated with chemotherapy, organ transplant,

or bone marrow transplant
When cancer chemotherapy or immunosuppressive treatment
is being considered, measles vaccination ideally should precede the initiation of chemotherapy or immunosuppression by
at least 2 weeks.751 Persons who were not immune to measles
when diagnosed with leukemia may receive measles-containing
vaccine during remission. Measles vaccination is contraindicated during the period of immunosuppression, and at least
3 months should elapse after termination of chemotherapy before
measles vaccination.212 Patients exposed to measles or at high risk
of exposure while immunosuppressed should be given IG regardless of previous immunization status (see Postexposure prophylaxis). Routine vaccination with MMR is recommended for all
children and seronegative adults who have received hematopoietic
stem cell transplants. The first dose should be given 24 months
after transplantation if the recipient is presumed to be immunocompetent, is not on immunosuppressive medications, and is
not affected by graft versus host disease. A second dose should be
given 6 to 12 months after the first dose.752-755 Regular testing of
long-term HCT survivors for maintenance of measles antibody
levels is recommended approximately every 4 to 5 years. The need
for revaccination has to be assessed on an individual basis.752

States. Furthermore, at least one study has suggested that there

is an increased rate of seronegativity when further attenuated
vaccine was administered with IG.555 Finally, and perhaps most
important, revaccination is indicated if there is any uncertainty
about the validity of doses in the vaccination record.499

Precautions and contraindications

In general, measles vaccination is contraindicated for patients
with acute severe illness, immunosuppression, pregnancy, or
a personal history of an anaphylactic reaction to measles-containing vaccines. For the rare patient with a personal history
of an anaphylactic reaction to gelatin or neomycin, measles
vaccine should be administered with extreme caution and
in consultation with an allergist. After administration of IG
(by IM, IV, or SC route) or other blood products, vaccination
should be delayed for the recommended interval, unless the
patient is exposed to measles or at high risk of exposure.212
Clinical judgment must be used in deciding whether to vaccinate a patient with a history of thrombocytopenia, but recent
studies suggest that the risk of stimulating a recurrance of
ITP is very low.676,757 Mild illness, personal or family history
of seizures, steroid therapy that is not immunosuppressive,
and allergic reactions to eggs, chicken, feathers, or penicillin are not contraindications to measles vaccination. Persons
with contraindications to measles vaccination should receive
IG if they are exposed to measles or at high risk of exposure.
Unfortunately, this only provides protection for a short time
(see Passive immunization). To reduce the risk of exposure
to measles in persons for whom the vaccine is contraindicated, their household contacts should be immune to measles
or be vaccinated (unless contraindicated). To prevent nosocomial exposure to measles in patients with contraindications,
all health care personnel should be immune to measles or be
vaccinated (unless contraindicated) (see Indications).

Severe illness

Revaccination of persons vaccinated according to

earlier recommendations
Anyone vaccinated at any age with inactivated (killed) measles vaccine alone or killed vaccine followed by live vaccine
within a 3-month period, and anyone vaccinated between 1963
and 1967 with a vaccine of unknown type, should be revaccinated with the current live vaccine to ensure protection and
to prevent atypical measles illness. Revaccinating persons who
received an unknown type of vaccine is recommended because
Edmonston B, inactivated, and further attenuated live vaccines
all were in use during this interval (see Figure 20-6). As noted
previously, vaccination of an immune person is not associated
with any increased risk of adverse events. However, revaccination of recipients of killed vaccine may be associated with local
reactions of pain, swelling, erythema, and regional lymphadenopathy lasting 1 to 2 days.75,76,191,192,664,665,756 These reactions
have been reported to occur in 4% to 55% of vaccinees. More
severe reactions have been noted, but only rarely.76 Whereas
revaccination has not been proved to totally eliminate the risk
for atypical measles,198 available data suggest that the risk is
reduced considerably.75,76,202 Thus, the risk of these reactions is
outweighed by the risk associated with atypical measles.212
A dose of further attenuated live vaccine with IG administered simultaneously should not be considered adequate
vaccination. This recommendation is based on the theoretic
consideration that passively derived antibody might interfere
with seroconversion. Whereas low doses of IG do not appear
to interfere with seroconversion,266 there is no information
available about the dose used in general practice shortly after
the introduction of further attenuated vaccines in the United

Measles-containing vaccines should not be administered to

patients with acute severe illnesses, including those with significant fever or evolving neurologic conditions. To avoid confusing the evolution of the illness with possible adverse events
resulting from measles vaccine, vaccination should be deferred
until the acute severe illness is resolved.
Withholding vaccination for false contraindications is a
major cause of late vaccination and low vaccine coverage.
Measles vaccination should not be deferred in the presence of
mild conditions, such as mild upper respiratory infections, otitis media, or diarrhea.550 Multiple large studies, in the United
States and in other countries, have documented that children
with mild illness have similar serologic responses to measles
vaccination compared with well children. These studies also
showed that the ill children had no increased risk of adverse
events after vaccination compared with well children.212,570,582,584

Tuberculosis
Because of a theoretic concern that measles vaccination might
exacerbate tuberculosis, patients with untreated active tuberculosis should begin antituberculosis therapy before measles vaccination. This theoretic concern is based on the reputed role
of measles disease as an aggravating factor in tuberculosis and
the similar suppression of delayed hypersensitivity for up to 4
to 6 weeks seen after both measles disease and measles vaccination.501,503 However, a 1976 review of studies examining the
effect of measles disease on tuberculosis patients concluded that
none of the studies provided conclusive evidence that measles
disease has a deleterious effect on tuberculosis.104 A review of the
incidence of tuberculosis after a measles outbreak in Korea did
not reveal an increased risk of tuberculosis.759 In several small

Measles vaccine

studies in the 1960s, measles vaccine did not exacerbate tuberculosis in children receiving antituberculosis therapy.508,509,760
However, there are no data available on the effect of measles
vaccine on patients with untreated tuberculosis.
Tuberculin skin testing is not a prerequisite for measles
immunization. In patients for whom tuberculin skin testing
is indicated, such testing can be undertaken at the same time
that vaccine is administered. If skin testing is not done at that
time, it is advisable to wait 4 to 6 weeks after vaccination before
administering a tuberculosis skin test.211,212

Immunosuppression
Live virus measles vaccine should not be administered to persons who are immunosuppressed because of medication (eg,
high-dose steroids, alkylating agents, and antimetabolites), other
therapy such as radiation, or underlying illness (eg, congenital
immunodeficiency, leukemia, lymphoma, generalized malignant disease) (see Indications). Although patients with severe
immunosuppression related to HIV infection should not receive
measles vaccine, HIV-infected persons who are not severely
immunosuppressed may be vaccinated. Immunosuppressed
patients who are exposed to measles or at risk of exposure
should receive IG regardless of their history of measles disease,
vaccination, or serology, because they are at high risk of complications and death from measles (see Passive immunization).
Replication of live vaccine virus may be augmented and prolonged in patients who are immunocompromised, and adverse
events after vaccination, including death, are more common in
immunosuppressed patients (see Adverse effects).712,714,720,761
Systemic corticosteroid treatment can result in immunosuppression. Because the minimum dose and duration of steroid
therapy necessary to induce immunosuppression are not well
defined, clinical judgment must be used to assess whether a
patient on steroid therapy is immunosuppressed. Most experts
would consider a steroid dose equivalent to or greater than a
prednisone dose of 2 mg/kg of body weight per day (or a total
of 20 mg/day) administered daily or on alternate days for 14
days or more to be sufficiently immunosuppressive to contraindicate measles vaccination.212 Patients receiving immunosuppressive doses of steroids should not receive measles vaccine
until 1 month after the end of steroid therapy. Vaccination is
not contraindicated in persons receiving topical, localized (eg,
intra-articular, bursal, or tendon injection); low- to moderatedose steroids; or physiologic steroid replacement. Patients who
receive high-dose steroids for less than 14 days generally can
be vaccinated immediately after cessation of steroid therapy.
Measles vaccine is contraindicated in any patient on any dose of
steroids with clinical or laboratory evidence of immunosuppression or an underlying disease that is immunosuppressive.212,751
MMR and other measles-containing vaccines are not recommended for HIV-infected persons with evidence of severe
immunosuppression (as defined above) because of the risk of
adverse events, the impaired immune response to MMR vaccination, and the current low risk of exposure to measles in
the United States.211,212,722 One case of fatal vaccine-associated
pneumonitis has been documented in a severely immunocompromised patient with HIV infection (see Adverse events).720
Available data suggest that persons with HIV infection who
are not severely immunosuppressed may be vaccinated
safely.189,594,595,722 Because measles has been documented to be
severe in HIV-infected persons in both the United States and
developing countries,762 measles vaccine is recommended routinely for asymptomatic HIV-infected children and adults without evidence of measles immunity and should be considered for
those with symptomatic HIV infections who are not severely
immunosuppressed. Asymptomatic patients at risk for HIV
infection do not need to be screened for HIV before vaccination
(see Indications).211,212,566,722

20

Pregnancy
On theoretic grounds, live-virus vaccines, including measles
vaccine, should not be administered to a pregnant woman.
However, in contrast to rubella and mumps vaccines, measles
vaccine virus has not been shown to cross the placenta and
infect the fetus. ACIP recommends that susceptible women
of childbearing age be asked if they are currently pregnant or
attempting to become pregnant before administering MMR
vaccine. Vaccination should be deferred for those who answer
yes. Those who answer no should be vaccinated and advised
to avoid pregnancy for 1 month after vaccination because of the
theoretic risks to the fetus.

Allergies
Severe immediate hypersensitivity reactions (urticaria, angioneurotic edema, wheezing, hypotension, and shock) are very
rare serious complications after measles vaccination. From
1991 to 2000, the US Vaccine Adverse Event Reporting System
received reports of events that were classified as probable or
possible anaphylaxis at an average of two reports per 1 million doses of MMR distributed.681 A detailed review of patients
enrolled in health maintenance organizations in the US Vaccine
Safety Datalink Project found three cases of anaphlyaxis among
848,945 persons who received MMR vaccine (two had also
received other vaccines at the same visit) for an estimated
risk of 3.5 episodes of anaphylaxis per million doses of MMR
administered.678,681 In China, the rate was 6.5 per million doses
administered.763 No anaphylaxis deaths have been reported in
association with measles vaccination in the United States, but
anaphylaxis can be life threatening. Persons with a history of
anaphylaxis or other serious allergic reactions after measlescontaining vaccines should be evaluated by using standardized
procedures to try to determine the offending allergen and the
need for and acceptability of administering additional doses of
vaccine.764 Most patients with anaphylactic reactions after measles vaccination do not have clinically evident risk factors for
anaphylaxis. Adequate treatment for hypersensitivity reactions,
including epinephrine injection, should be available for immediate use whenever measles vaccines are administered, along
with staff trained in treatment of anaphylactic reactions.211
Measles vaccines typically contain hydrolyzed gelatin as a
stabilizer. Allergic reaction to gelatin has been recognized as
a major cause of anaphylaxis after MMR vaccination.765768
Persons with previous systemic allergic reactions to gelatin should
be vaccinated with extreme caution and in consultation with an
allergist or immunologist.212 Vaccine skin testing may be useful
in these patients, but there is no protocol available. Patients with
severe immediate hypersensitivity reactions have been shown
to have high levels of antigelatin IgE and IgG and increased
gelatin-specific T-cell responses.765,766 In a study in Japan, 24 of
26 children who had allergic reactions to vaccines had antigelatin IgE. Only two of the children had allergic reactions to gelatin
(in food) before vaccination.768 In contrast, substantially fewer
children (6 of 22) with severe allergic reactions to MMR in the
United States had antigelatin IgE, and none had a reported history of allergic reactions to gelatin in food.681 Measles vaccines
contain trace amounts of the antibiotic neomycin. Allergic
reactions to topical or systemic neomycin are rare and typically
consist of delayed or cell-mediated immune responses, such
as contact dermatitis. The rare patients with systemic allergic
reactions to either topical or systemic administration of neomycin should be vaccinated with extreme caution and in consultation with an allergist or immunologist.211 Measles vaccines do
not contain other antibiotics, such as penicillin; therefore penicillin allergy is not a contraindication to vaccination.
Measles (and mumps) vaccines licensed in the United States
are grown in chick embryo fibroblast cultures. Fasano and colleagues770 measured 37 pg/dose of ovalbumin cross-reacting

379

380

SECTION TWO Licensed vaccines

protein in the MMR vaccine currently licensed in the United

States. Because some children with egg allergy have had anaphylactic reactions to measles vaccines,770 previous recommendations included an algorithm of vaccine skin testing and
desensitization for children who have had anaphylactic reactions after egg ingestion.771 However, more than 1,200 children
with severe allergic reactions to eggs have been vaccinated safely
in two studies.772,773 Vaccine skin testing and desensitization
are no longer recommended for persons with severe egg allergies.211 These persons may be vaccinated by using the same precautions (treatment for anaphylaxis immediately available) as
for persons without severe egg allergy. Also, persons with less
severe allergic reactions to eggs, or allergy to chicken or feathers, may be vaccinated as usual.211,212

Administration of immune globulin and other

blood products
Because passively derived antibody may interfere with vaccine
seroconversion, vaccination should be deferred for 3 to 11 months
after receipt of IG (by IM, IV, or SC route) and other blood products, depending on the dose of the blood product received.211,212,774
In addition, vaccination should precede receipt of IG by at least
2 weeks whenever possible. However, unvaccinated persons may
not be fully protected by the passive antibodies received during
the entire interval recommended prior to vaccination after receipt
of blood products. Therefore, additional doses of IG or measles
vaccination may be necessary if the patient is repeatedly exposed
to measles or at high risk of exposure to measles. If measles vaccination is given before the recommended interval has elapsed,
the dose should be repeated (at least 1 month after the measles
vaccination and after the recommended interval from the time of
blood product administration has elapsed).

Thrombocytopenia
Oski and Naiman775 reported significant depression of platelet counts without clinical symptoms after vaccination with
Edmonston B vaccine, including one infant who had thrombocytopenia repeatedly after three doses. Previous immunity to
measles did not prevent depression of the platelet count. ITP
has been associated with measles-containing vaccines currently
in use.674 The increased risk of ITP after MMR vaccination is
estimated at three to four cases for every 100,000 doses.776,777
There are no reports in which ITP solely associated with measles vaccines has resulted in death.
Two cases of recurrent MMR-associated ITP have been
reported in patients with ITP associated with a previous MMR
dose,778,779 and one case of MMR-associated exacerbation of
chronic ITP was reported in a 19-year-old female whose onset
of chronic ITP was associated with rubella vaccination in the
second year of life.781 In a study including 21 children with
ITP before their first dose of MMR, Miller and colleagues776
reported that none had a recurrence of ITP after vaccination.
A recent review identified 131 children with a history of ITP
who received MMR without a recurrence, including 26 children whose ITP followed a first dose of MMR.675 Advisory
committees recommend caution when administering measlescontaining vaccines to children with thrombocytopenia or a
past history of ITP, especially when the prior episode of ITP was
associated with measles vaccination.211,212 Serologic assessment
of immunity may be useful in assessing the risk and benefits of
immunization in such patients.

Family or personal history of seizures

Measles vaccination, like other causes of fever, may cause febrile
seizures in young children. The 5% to 7% of children who have
either a personal or family history of seizures may have an
increased risk of febrile seizures after measles vaccination.781

Febrile seizures after vaccination do not increase the risk of

epilepsy or other neurologic disorders. The benefits of administering measles vaccine to children with personal or family
history of seizures substantially outweigh the risks, and these
children should be vaccinated following the standard recommendations. Their parents should be advised of the benefits of
the vaccination and the minimal increased risk of febrile seizures. Because the fever induced by measles vaccine occurs
between 6 and 12 days after vaccination and seizures may occur
with the onset of fever, it is difficult to use antipyretics to prevent febrile seizures after measles vaccination. Patients taking
anticonvulsants should continue these medications after measles immunization.211,212

Future vaccines
Although measles vaccines are highly effective, the need to delay
immunization until passively acquired maternal antibodies
have declined has been an impediment to the global control and
eradication of measles.782 Research continues to develop new
vaccines that might effectively immunize children at younger
ages or be administered by routes that allow easy delivery during mass campaigns. Advances have been made in the development of subunit DNA and vectored measles vaccines that may
be immunogenic in young infants in the presence of maternal
antibody.783786 For example, a DNA vaccine expressing measles
virus hemagglutinin and fusion glycoproteins induced longlasting, high-avidity neutralizing antibodies in neonatal mice
born to measles-immune mothers despite the presence of high
levels of maternal antibodies.785 Studies in the monkey model
for atypical measles reveal that a DNA vaccine expressing hemagglutinin did not prime for atypical measles.206 However, some
vaccine constructs did induce antibodies of poor avidity.786
Oral vaccination using an enteric-coated live, attenuated
measles vaccine was not successful in monkeys.787 However,
oral administration of a measles peptide incorporated into a
vesicle induced a cell-mediated immune response to measles788
and orally administered adenovirus modified to express measles
nucleocapsid antigen induced both measles antibody and cytotoxic T-cell responses.789
Aerosol administration of live attenuated vaccines has been
studied for more than 30 years. In recent studies, aerosol administration was equally or more immunogenic than the same
vaccines administered by injection.432,790 Standardization of
administration techniques with practical devices have improved
as have the immune response rates.791 Aerosol administration
of the Edmonston-Zagreb strain as a second dose to older children and adults induces a booster response stronger than that
seen with vaccination by injection.792 The use of the Schwarz
strain via the aerosol route is no longer being pursued because
of low response rates. Aerosol administration could help simplify administration of vaccine to large numbers of children in
community-based campaigns similar to those used in the polio
eradication effort.451,790,793 The WHO, CDC, and the American
Red Cross have established a Measles Aerosol Project with
the goal of completing the necessary research and regulatory
requirements to license aerosol delivery of measles vaccine in
the developing world.794

Public health considerations

Epidemiologic results of vaccination
Measles is one of the most contagious diseases of humans
and is a classic communicable disease of childhood. The goal
of measles vaccination is to prevent illness and death caused

Measles vaccine

by measles directly among vaccinated persons and indirectly

among unvaccinated persons as a result of decreased transmission.796 In the absence of vaccination, measles occurs in
epidemic cycles. The magnitude and frequency of the epidemics depends on the population size, contact rates between persons, and the rate at which new susceptible persons are added
to the population through births or migration.797 In England
and Wales in the 1940s, epidemics occurred every second year,
starting in the large cities of London, Manchester, and Liverpool
and spreading outward to towns and rural villages.39,798 In the
large population centers, chains of transmission were sustained during the periods between epidemics, and these cities
were the reservoirs of measles. In towns and villages, transmission died out after an epidemic and had to be reintroduced for
each subsequent epidemic. Epidemic cycles of measles also can
be described in terms of the effective reproduction number, R,
defined as the average number of secondary cases produced by
a typical case in a population (see Chapter 71).532,799,800 When
R is less than 1, the average case gives rise to less than one
case, and the number of cases occurring subsequently begins
to decrease.
Introduction of measles vaccination leads to a reduction in
the size of epidemics and an increase in the interval between
measles epidemics.796 The widened interepidemic interval has
been referred to as the honeymoon period.801,802 Vaccination
of successive cohorts of young children results in a decrease in
incidence among vaccinated cohorts, an overall decline in measles incidence in all age groups (because of dampened transmission), and, when outbreaks occur, an increase in the proportion
of cases among older children.340,802,803 Susceptibility to measles
among older cohorts occurs most often because these persons
missed natural disease as young children and either missed getting vaccinated (program failure) or failed to respond to vaccination (primary vaccine failure). Waning of vaccine-induced
immunity (secondary vaccine failure) has been found to occur
in 0% to 5% of vaccinees but does not appear to play a major role
in reducing overall population immunity to measles.170,629,637
As vaccination coverage increases among successive birth
cohorts, measles transmission decreases, reducing the risk
of measles even among unvaccinated persons. At some vaccine-induced immunity level lower than 100%, measles virus
transmission is interrupted.804806 Mathematical models have
estimated the herd immunity threshold for measles in the
United States at 92% to 95%.807 If this level of population
immunity is maintained by a vaccination program, endemic
transmission of measles will die out and measles elimination
is achieved. Elimination does not result in zero measles cases
because importations of measles from endemic areas continue
to occur. However, spread from these importations is short lived
and will end without intervention. Documenting the elimination of measles is challenging. De Serres and associates808 have
proposed using the proportion of cases imported and the distribution of outbreak sizes to monitor elimination. These surveillance parameters can be used to estimate R, which must be
maintained at less than 1 to achieve elimination. Global eradication of measles will occur when the last chain of transmission
of measles virus is interrupted and can be defined as the simultaneous achievement of measles elimination in every country.
In industrialized countries, a single dose of measles vaccine
administered in the second year of life induces immunity in
about 95% of vaccinees.530 With a primary vaccine failure rate
of 5%, 100% of the population would have to be vaccinated
to reach a 95% immunity level with a single-dose strategy.
Approximately 95% of persons who fail to respond to the first
dose respond to a second dose,517 and with high vaccine coverage, the herd immunity target can be reached if two doses are
administered.
In developing countries, high morbidity and mortality resulting from measles among infants led to a recommendation to

20

vaccinate infants at 9 months of age, a time when maternal

antibody may interfere with seroconversion.808 Studies have
found the median seroconversion rate with vaccination at age
9 months to be 85% (range, 70% to 98%).809 This leaves three
times more infants susceptible (15% of vaccinees) than does
a rate of 95%. After a single dose with 90% coverage and 85%
seroconversion, 77% of the population would be immune. To
improve immunity, some have considered providing a second
dose, usually through routine health services at an older age,
when seroconversion is 95%. However, if only first-dose recipients were revaccinated through routine health services, given
90% coverage with both doses, immunity levels could rise to
only 90%, leaving 10% susceptible. Alternatively, if vaccination
activities were intensified both within and outside the routine
health services, such that many children never vaccinated could
receive a first dose while previously vaccinated children receive
a second dose, the resulting population immunity level would
be much higher. This is known as a second opportunity strategy. For example, if the second opportunity reached 90% coverage of prior first-dose recipients and previously unvaccinated
children, population immunity would increase to greater than
95%. In countries with poor access to preventive services, the
second opportunity for measles vaccination is most often provided through nationwide supplementary immunization activities or mass campaigns, because these are more effective at
reaching children who have never been vaccinated.
The impact of measles vaccination on overall childhood
mortality in developing countries was questioned by one study
that reported replacement mortality (ie, later death from other
causes).115 However, several subsequent studies have documented that measles vaccination increases overall child survival.810813 In Bangladesh, investigators found that the overall
mortality rate in measles-vaccinated children was 45% lower
than in unvaccinated children and that this difference persisted
for several years after vaccination.810 A similary large impact
of measles vaccination on overall child mortality was found in
rural India, where children who received measles vaccination in
infancy had 27% lower mortality.813 A comparison of the proportion of all-cause mortality resulting from measles, among children ages less than 5 years, found measles accounted for about
7% of all child deaths in 1990 and 1% in 2008, contributing
23% to the overall reduction in mortality in this age group.814

Experiences with measles control and elimination

in various countries
Industrialized countries
Experience in industrialized countries has shown that a single dose of measles vaccine, widely administered, can reduce
measles transmission, but a two-dose strategy is necessary
for elimination of indigenous transmission.815818 Many countries introduced measles vaccine as a single-dose schedule
and then added a second opportunity for vaccination because
of the persistence of outbreaks despite high single-dose coverage (Table 20-10). Industrialized countries have found that the
costs of patient care and outbreak control outweigh the cost
of a second opportunity for immunization.819 Some countries
(eg, Canada, United Kingdom, Australia, and New Zealand)
have adopted a two-dose schedule and have conducted a onetime, nationwide vaccination campaign to reduce susceptibility among school-age children. Other countries (eg, the United
States, Finland, and Sweden) have relied on a two-dose schedule alone.
In the United States, the distribution and use of more than
350 million doses of live measles vaccine between the year of
licensure (1963) and the end of 2010 (see Figure 20-6) has been
associated with a marked reduction in measles (Figure 20-9) and
its associated complications and estimated savings of billions

381

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SECTION TWO Licensed vaccines

Table 20-10 Evolution of Measles Vaccination Policy in Selected Countries and the Expanded Programme on Immunization (EPI), 1963 to 2010
First opportunity

Second opportunity

First dose in schedule

Country

Year

Recommended
age

United States

1963
1965
1976

9 mo
12 mo
15 mo

1994

12-15 mo

Canada

1963
1968

9 mo
12 mo

United Kingdom

1968
1988

12-23 mo
13-15 mo

Brazil

China

WHO EPI

1973
1976
1982

8 mo
7 mo
9 mo

1978

8 mo

1983
1989
1991

Supplementary
campaign

Second dose in schedule

Year

Recommended age

Year

Age range

1989

4-6 or 11-12 yr

1999

4-6 yr

1996

18 mo or 4-6 yr

1996

5-16 yr

1996

Before school entry

1994

5-16 yr

1992

12-15 mo

1992
1995
1997
2000
2009

9 mo-14 yr
1-3 yr
6 mo-4 yr
1-4 yr
19-29 yr

1986
2006

7 yr
18-24 mo
2010

8 mo-4 yr or
14 yr

9 mo
6 mo
9 mo
2001

2009

Either routine second dose or regular

supplementary campaigns
15-18 mo (or school entry) and/or
regular supplementary campaign

WHO, World Health Organization.

of dollars.26,356 Whereas approximately 4 million cases occurred

annually in prevaccine years, on average 400,000 to 500,000
cases were reported. In 2010, only 64 confirmed cases were
reported, with 87.5% of these cases linked to importations.
This represents a reduction of more than 99.9% compared
with the years preceding vaccine licensure. The reported occurrence of SSPE also has declined greatly (see Figure 20-8) and
was virtually eliminated in the late 1980s and early 1990s.
A small number of cases had been reported each year during
the late 1990s as a result of the resurgence of measles during
1989 to 1991.
The United States has embarked on three elimination
efforts (see Figure 20-9).22,23,805,820 The first, in 1966, was based
on a single-dose strategy with vaccination at 12 months of
age (see Table 20-10). The second, announced in 1978, had
three components: (1) a high level of population immunity
through vaccination with a single dose of measles vaccine, (2)
disease surveillance, and (3) prompt response to outbreaks.22,25
To reach high coverage, vaccination requirements for school
entry were enacted and enforced in every state. These requirements, which mandated not only measles vaccination but also

other childhood vaccinations, have become the major legacy of

this elimination initiative. Although sustained interruption of
transmission of measles was not achieved, measles was eliminated from most of the country; 54% of counties in the United
States were measles free for the entire decade from 1980 to
1989, and only 17 (0.5%) counties reported measles every year
during that period.821 During this interval, outbreaks continued to occur in schools among school-age persons with histories of vaccination and among unvaccinated preschool-age
children.338,499,556,560,633,822 In 1989, the United States introduced
a routine second dose of measles vaccine at 4 to 6 years or 11
to 12 years to address the problem of school outbreaks (see
Table 20-10).
After relatively low incidence during the 1980s, a 3-year epidemic of measles began in 1989 and resulted in over 55,000
cases and 123 deaths.823,824 The average annual incidence during 1989 to 1991 was 7.4 per 100,000 population compared
with an average incidence for 1981 to 1988 of 1.8 per 100,000.
Incidence was increased in all age groups; however, the greatest
increases were in children younger than 1 year and 1 to 4
years, resulting in almost half of all cases occurring in children

Measles vaccine

20

Reported cases (in thousands)

500

400

300

First elimination
goal announced

30
25
20
15
10
5
0

19
8
19 5
8
19 7
8
19 9
91
19
9
19 3
9
19 5
9
19 7
9
20 9
0
20 1
0
20 3
0
20 5
0
20 7
0
20 9
11

Vaccine
licensed

Reported cases (in thousands)

600

Year
200

100

Second elimination
goal announced

Third elimination
goal announced

19

6
19 0
6
19 2
6
19 4
6
19 6
6
19 8
7
19 0
7
19 2
7
19 4
7
19 6
7
19 8
8
19 0
8
19 2
8
19 4
8
19 6
8
19 8
90
19
9
19 2
9
19 4
9
19 6
9
20 8
0
20 0
0
20 2
0
20 4
0
20 6
0
20 8
10

Year
Figure 20-9 Reported measles cases, United States, 1960 to 2011.

younger than 5 years (see Table 20-1). This epidemic was due to
low measles vaccination levels among preschool-age children,
particularly in inner cities,825828 and was part of a hemispherewide measles epidemic.
In 1993, the third elimination initiative was launched. In
addition to the three components of the earlier strategy, this
initiative focused on increasing preschool immunization levels to greater than 90% and vaccination of all school children
with a second dose.740 To implement these vaccination strategies, between 10 and 16 million doses of measles vaccine were
distributed annually between 1994 and 2005 (see Figure 20-6).
In March 2000, the CDC convened a panel of experts to review
the pattern of measles transmission in the United States.
Evidence presented included an annual measles incidence of less
than 1 case per 1 million population since 1997,829 a maximum
outbreak size of 15 cases during 1999 to 2001,745 an increase in
the proportion of imported cases from 14% (1993 to 1996) to
35% (1997 to 2001),830 an overall population immunity against
measles of 93%,831 and the absence of an endemic measles virus
genotype since 1994.234 Based on this evidence, each participant concluded that measles was no longer an endemic disease
in the United States.26 The achievement of measles elimination in the United States is the result of three major factors:
(1) 90% or greater vaccination coverage with the first dose among
preschool-age children, (2) administration of a second dose to
more than 80% of all school-age children, and (3) reduction in
measles importations from Latin America because of aggressive
control measures recommended by the Pan American Health
Organization (PAHO).27 Focus on achieving measles elimination in the United States also played a central role in the overall development of the National Immunization Program during
the period from 1966 to 2000.832 Challenges to maintaining
elimination in the United States include frequent international
travel, large outbreaks of measles in highly traveled developed
countries, and clusters of US residents who remain unvaccinated because of personal belief exemptions.747,823a As evidence
of these ongoing challenges, a total of 222 measles cases were
reported in the United States during 2011, the highest number reported since 1996.740a There were 72 imported measles

cases, 20 in foreign visitors and 52 in US residents including

nine unvaccinated infants.740a The increase in importations
reflects recent increases in the incidence of measles in countries
with high levels of travel to and from the United States. The
source of almost half of the measles importations in 2011 was
the WHO European Region,740a which reported >30,000 cases
of measles, including eight measles-related deaths in 2011.823a
Of the 66 school-aged patients with measles in the United States,
50 (76%) had not been vaccinated because of a philosophic, religious, or personal objection.740a Despite these challenges, there
were only 22 reported US measles cases in 2011 for which an
association to importation could not be documented,740a which
indicates the continued absence of endemic transmission in the
United States.
Canada began a measles immunization program in 1963
(see Table 20-10). Despite achieving coverage in excess of 95%
with a single dose of measles vaccine throughout the 1980s,
measles outbreaks continued to occur.818 In 1995, 2,362 measles cases were reported in Canada (ie, more than one third
of the total in the Western Hemisphere). School outbreaks
among children who had received a single dose of measlescontaining vaccine accounted for most cases. Mathematical
modeling predicted a sizable measles epidemic, and cost-benefit
analyses showed that a national vaccination campaign to prevent the predicted epidemic would save $2.50 for every dollar
spent.819,823 On the basis of these analyses, 11 of the 12 provinces of Canada undertook mass vaccination campaigns targeting school-age children by using measles-rubella vaccine
in the spring of 1996. A coverage level of more than 90% was
achieved. In addition, a second dose was added to the routine
schedule at age 18 months or 4 to 6 years (see Table 20-10).
From 1998 through 2001, Canada interrupted endemic measles transmission as evidenced by the occurrence of only a few
small outbreaks, many linked to importation.753 In 2007, there
was an outbreak of 94 cases characterized by transmission lasting 25 weeks in unvaccinated persons belonging to unrelated
networks dispersed in the population.834 Genotyping of measles
virus in Canada supports epidemiologic information indicating
importation as the source of current measles cases.835

383

384

SECTION TWO Licensed vaccines

In 1968, the United Kingdom introduced measles vaccine

for children between the ages of 1 and 2 years, but throughout the 1970s and early 1980s coverage remained below 80%.
In 1988, combined MMR vaccine was introduced in place of
measles vaccine at age 13 to 15 months (see Table 20-10) and
coverage improved to over 90%. In November 1994, all children
ages 5 to 16 years in England and Wales were offered combined
measles-rubella vaccine, regardless of prior vaccination history, in an attempt to prevent a predicted epidemic of measles.
During the campaign, 6.2 million doses were administered for
a reported coverage of 92%.816 Between 1995 and 2000, among
594 confirmed measles cases, 212 (36%) were sporadic and
382 (64%) were associated with 51 clusters. Forty-eight sporadic cases (23%) and 18 of 51 clusters (35%) were associated
with an importation of infection from overseas. A wide variety
of measles virus genotypes were identified during this period.
The pattern of sporadic cases and small clusters associated with
importations is consistent with elimination of sustained indigenous measles transmission.816 However, unfounded concerns
about vaccine safety that began in 1998 (see Adverse events)
have contributed to a decline in MMR coverage that has resulted
in a number of large outbreaks.835 In 2007, measles endemicity
was reestablished with genotype D4 as the predominant genotype.837 Although coverage with MMR vaccine by 24 months in
England and Wales has increased from 84% in 2006 to 89% in
2010, outbreaks of measles continue.838
Excellent control of measles has been achieved in other industrialized countries. In 1982, Finland initiated a measles elimination program based on a two-dose vaccination strategy. Efforts
to improve vaccination coverage included mass media, a registry
system to track defaulters, and an intensive outreach program.
Measles elimination was achieved in Finland by 1996 and has
been maintained as a result of consistently high (above 95%)
two-dose vaccination coverage.34,839 Sweden has reported similar
success with a two-dose schedule.33 Australia and South Korea
have achieved elimination by using a two-dose routine schedule
supplemented by a one-time catch-up campaign.840,841 However,
in other industrialized countries (eg, Italy,842 Germany,843 France
and Switzerland845), measles remains endemic, with frequent
large outbreaks, in part because of the perception that vaccination may be more risky than the disease itself.846
The European Region of the WHO, which includes the
countries of the former Soviet Union, has updated its strategic plan for eliminating measles and rubella by 2015 and identified the accelerated actions needed to achieve the goal.846 In
addition to Finland and Sweden, a number of European countries are close to, or have already achieved, elimination (eg,
Hungary, Poland, the Netherlands, Slovenia, and the Russian
Federation847). Although successful catch-up vaccination campaigns using combined measles-rubella vaccine have been conducted,848 in a number of countries, outbreaks continue to occur
(eg, Ukraine,849 Bulgaria,850 and France852).

Less industrialized countries

Beginning in the late 1970s, the Expanded Programme on
Immunization (EPI) has played a major role in the development of
immunization programs in less industrialized countries. Measles
vaccination coverage in these countries rose from 18% in 1981
to 76% in 1990, and an estimated 1.7 million measles deaths
were prevented in 1995 alone.843 During the 1990s, donor support for the EPI decreased substantially, and measles vaccination
coverage levels plateaued or decreased, with the estimated annual
number of measles deaths stabilizing at about 1 million.351
Worldwide in 2000, measles was estimated to cause between
535,300 and 777,000 deaths (ie, 1.4% of 55.7 million total
deaths).352,353 Among children less than 5 years of age, measles
was the fifth leading cause of death, accounting for 5.4% of the
10.9 million total deaths in this age group. The vast majority of

measles deaths (> 95%) occur in less industrialized countries

because of lower measles vaccination coverage (ie, underdeveloped routine health services and lack of a second opportunity for
measles vaccination) and a higher case-fatality ratio in these countries. The higher risk of death from measles in less industrialized
countries compared with industrialized countries has been associated with a younger median age of cases, increased intensity of
exposure, increased likelihood of secondary infections, and malnutrition, especially vitamin A deficiency. Poverty, crowded living
conditions, and large family size are the underlying socioeconomic factors contributing to this epidemiologic pattern.808 Global
immunization programs have resulted in a decrease in worldwide
measles mortality to an estimated 139,300 deaths in 2010.353
During the late 1980s and early 1990s in less industrialized countries, two different approaches were developed to
address the problem of severe measles in children younger than
9 months, the age for vaccination recommended by the
WHO (see Table 20-10). First, high-titer measles vaccines
(eg, Edmonston-Zagreb measles vaccine) were developed to
overcome interference by maternal measles antibody when
administered at 4 to 6 months of age. For a short period from
1989 to 1991, the WHO recommended use of high-titer
Edmonston-Zagreb measles vaccines for 6-month-old infants
in countries where measles was a significant cause of death
for infants younger than 9 months.621 Although high-titer vaccines were more immunogenic than standard-titer vaccines,
they were unexpectedly associated with excess delayed mortality among females. For this reason, the WHO withdrew the recommendation for use of these vaccines in 1992.626 The second
approach, developed by PAHO,734 was based on the observation
that older siblings were often the source of measles infection for
infants. The concept of a one-time nationwide mass vaccination campaign for children ages 9 months to 14 years, regardless of prior disease or vaccination history, was pioneered in
Cuba in 1987.854 The objective of this so-called catch-up campaign was to interrupt measles virus transmission by rapidly
reducing susceptibility among older children and thereby prevent transmission to infants less than 9 months of age. This
approach proved highly effective and has been developed further
into the PAHO strategy for measles elimination.

The PAHO strategy

In 1994, ministers of health of countries of North and South
America established the goal of eliminating measles from the
Western Hemisphere by the end of 2000. To accomplish this
goal, PAHO developed a strategy with three essential vaccination components: (1) catch-upa one-time mass vaccination
covering all children ages 1 to 14 years, regardless of prior disease or vaccination status; (2) keep-upachievement of 90%
or greater immunization coverage in each successive birth
cohort; and (3) follow-upsubsequent mass campaigns conducted every 3 to 5 years, covering all children ages 1 to 5 years
irrespective of prior disease or vaccination history.734 After the
catch-up campaigns, most countries have increased the measles
vaccination age to 12 months to maximize vaccine effectiveness. In addition to the vaccination strategy, case-based surveillance with laboratory confirmation of suspected measles cases
has been established in all countries of the Americas.857
In Brazil, the National Immunization Program was created
in 1973, and routine measles vaccination was recommended
at 8 months of age.855 National measles control was intensified
in 1980 to 1981 with campaigns focused in areas of low coverage. The minimum recommended age for measles vaccination was changed to 7 months in 1976 and then to 9 months
in 1982. In 1992, with the adoption of a measles elimination
goal by 2000, a second dose was recommended at age 12 to 15
months (see Table 20-10). Based on the success of statewide
mass vaccination campaigns in Parana and Sa Paulo in 1987,

Measles vaccine

Brazil conducted a nationwide catch-up campaign in 1992 during which 48 million doses of measles vaccine were administered to children ages 9 months to 14 years. In 1995, the first
national follow-up campaign for children ages 1 to 3 years was
conducted; the state of Sa Paulo did not participate in this
campaign.
In 1997, after a 4-year period of good control, Brazil experienced a major resurgence of measles, with a total of 53,335
cases and 61 deaths.855 Transmission was concentrated in the
metropolitan area of Sa Paulo State but subsequently spread to
involve all states. The highest age-specific incidence rates were
among children younger than 1 year (1,577 per 100,000), young
adults ages 20 to 29 years (539 per 100,000), and children ages
1 to 4 years (205 per 100,000). This age distribution was similar throughout Brazil, with 55% of cases occurring among adults
ages 20 to 29 years, a cohort born between 1968 and 1977, when
the vaccination program was being initiated. Characterization of
measles viruses during the outbreak in 1997 identified the D6
genotype. This same genotype was identified in subsequent measles outbreaks in Argentina and Uruguay in 1998 and in Chile,
Bolivia, and the Dominican Republic during 1999 to 2001.856
The resurgence of measles in Brazil in 1997 led to a nationwide follow-up campaign in 1997 for children ages 6 months to
4 years. A third follow-up campaign was conducted in 2000 for
children ages 1 to 4 years. After two follow-up campaigns, measles transmission appears to have been interrupted in Brazil; of
8,358 suspected measles cases reported in 2000, only 36 cases
(0.4%) were confirmed. The last recorded measles outbreak,
with 15 cases, was in February 2000.855
Implementation of the PAHO strategy in the Western
Hemisphere has resulted in a greater than 99% decline in
reported measles cases from a high of almost 250,000 cases
in 1990 to 250 cases in 2010 (Figure 20-10).857 The pattern
of measles importations into the United States confirms the
success of the PAHO strategy.830 In 1990, at the height of
the regionwide resurgence in measles, 242 of 300 importations of measles were from Latin America; in contrast, of
27 importations in 2004, none was from Latin America.27
During 2001, measles outbreaks in Haiti and the Dominican
Republic were brought under control, ending known transmission of the D6 measles virus genotype in the Western
Hemisphere. Since November 2002, when transmission with
the D9 genotype was stopped in Venezuela and Colombia,
the Western Hemisphere has been free of endemic measles,

20

thereby achieving the goal of measles elimination.857 Measles

importations remain an ongoing threat to the Americas, as
evidenced by outbreaks in Mexico,858 Venezuela,859 and the
United States.860-862
The success of the PAHO strategy has led to expansion of its
use outside the Western Hemisphere. In Africa, the PAHO strategy has been adopted in an effort to reduce measles mortality.
Between 1996 and 1999, seven southern African countries (South
Africa, Namibia, Zimbabwe, Swaziland, Malawi, Botswana, and
Lesotho) conducted catch-up vaccination campaigns and introduced case-based measles surveillance.863 Reported measles
deaths in these countries decreased from 350 in 1996 to between
0 and 21 reported measles deaths in the years 1998 to 2008
(Figure 20-11). This period of low transmission was followed by
a widespread resurgence across all countries in southern Africa
that started in 2009 and peaked in 2010 with more than 140,000
reported measles cases and 764 measles deaths.864

Mortality reduction strategies

In February 2001, at a meeting hosted by the American Red Cross,
a new partnership was formed to advocate for reduction of measles
mortality in Africa.865 Worldwide, during 2000 to the end of 2008,
more than 650 million children received measles vaccine through
supplementary immunization activities, and global routine immunization coverage with one dose of measles vaccine increased from
71% to 83%. These accelerated control efforts have resulted in a
78% decrease in the estimated number of measles deaths worldwide by the end of 2008, thereby surpassing the 2005 global goal
of a 50% reduction.866 The current global goal set for 2015 is to
reduce measles deaths by 95% compared with 2000 levels.
Based on the success of implementing the PAHO strategy
in other regions of the world, a schedule that offers at least two
doses of measles vaccine delivered either through routine services or mass campaigns has become the standard of care in all
countries regardless of development status or routine vaccination coverage (see Table 20-10).566

Measles eradication
The feasibility of measles eradication has been debated for
many years.42,4446,867869 Hopkins and colleagues42 have proposed
global measles eradication and pointed out both the similarities
and differences between measles and smallpox. Measles will be

300000

Catch-up campaigns

100

Confirmed cases

250000

80
Cases
Coverage

200000

60

150000
Follow-up campaigns

100000

40
20

50000
0
19
8
19 0
8
19 1
8
19 2
83
19
8
19 4
8
19 5
8
19 6
8
19 7
8
19 8
8
19 9
9
19 0
9
19 1
9
19 2
9
19 3
9
19 4
9
19 5
9
19 6
9
19 7
9
19 8
9
20 9
0
20 0
0
20 1
0
20 2
03
20
0
20 4
0
20 5
0
20 6
0
20 7
0
20 8
0
20 9
1
20 0
11

Routine infant vaccination coverage (%)

Measles elimination*

Year
* Data as of 12 April 2012: 1310 confirmed cases in 2011; 2011 coverage data not yet available
Source: Country reports to FCH/IM
Figure 20-10 Reported measles cases, Latin America and the Caribbean, 1980 to 2011. (Data courtesy of the Immunization Unit, Family and Community
Health Area, Pan American Health Organization.)

385

SECTION TWO Licensed vaccines

Follow-up campaigns

Cases
Deaths

180

2,000
1,800

160

1,600

Catch-up campaigns

140

1,200

100

1,000
764

80

800

60

Deaths

1,400

120

600
400
90

10

08

200

20

20

06

0 12 5 11 12 21 4

20

98

96

19

19

92

90

88

86

94
19

19

19

19

19

82

84
19

19

19

80

00

04

20

02

20

20

350

20

40

20

Cases (in thousands)

386

Year
Figure 20-11 Reported measles cases and reported measles deaths, seven southern African countries, 1980 to 2010. (Data courtesy of the African
Regional Office of World Health Organization.)

substantially more difficult to eradicate than smallpox because

of its higher contagiousness, younger median age at infection,
and older age at which vaccine is effective.870
As of 2010, five of six WHO regions have established target
dates for measles elimination (the Americas by 2000, Europe
and the Eastern Mediterranean initially by 2010 and revised to
2015, the Western Pacific by 2012, and Africa by 2010). The
Southeast Asia Region has a measles mortality reduction goal
and, in 2009, passed a resolution urging member states to eliminate measles, with a target date to be established later. The
Region of the Americas stopped endemic measles transmission
in November 2002 and is the first region to be free of endemic
measles for over 8 years. At the global level, measles control targets have been set for 2015 to increase measles immunization
coverage to greater than or equal to 90% at the national level
and greater than or equal to 80% in every district, to decrease
the incidence of measles to less than five cases per million, and
to reduce measles deaths by 95% compared with 2000 levels.871
In July 2010, the WHO convened a global technical consultation to review the feasibility of measles eradication.47 There
was a comprehensive review of the biologic, programmatic, vaccine supply, economic, and health systems aspects of measles
eradication compared with mortality reduction targets. An epidemiologic and economic evaluation based on data collected in
Bangladesh, Brazil, Colombia, Ethiopia, Tajikistan, and Uganda
found that measles eradication by 2020 was the most costeffective measles control option both in the six countries and
globally, and it would cost an additional discounted $7.8 billion between 2010 and 2050.872 After reviewing all the available
information, the conclusion was that measles can and should
be eradicated and that global eradication by 2020 is feasible.
The report from the global technical consultation was reviewed
and discussed by the Strategic Advisory Group of Experts in
November 2010. They agreed that eradication of measles is
technically and biologically feasible and recommended measurable progress towards existing regional elimination targets
before establishing a target date for global eradication.873

Available evidence indicates measles meets the criteria for a

disease that can be eradicated: (1) there is no animal or environmental reservoir, and humans are critical to maintaining
transmission; (2) accurate diagnostic tests are available; (3)
measles vaccine and existing vaccination strategies are effective
and safe; and (4) measles transmission has been interrupted in
a large geographic area (eg, nationwide) for a prolonged period
of time.46 Major challenges to global measles eradication will
include (1) increasing urbanization and population density
that will require very high vaccination coverage, (2) war and
civil unrest, (3) the frequency of international travel and forced
migrations that facilitate importations of measles, and (4) the
HIV epidemic, which may reduce the effectiveness of measles
vaccination and increase the transmissibility of measles.762
Other potential impediments are lack of political will, risk of
unsafe injections, and the possibility of sustained transmission
among adults.
To address these challenges, research is ongoing to improve
diagnostic tests for measles by using filter paper blood spots295,286
and oral fluid293 and to develop alternative routes for administration of existing measles vaccines (eg, aerosol vaccination432435),
needle-free jet injectors to reduce the risk of unsafe injections,
and new candidate vaccines that could be administered in the
presence of maternal antibodies ('stealth vaccines').874 In addition, disease surveillance and program monitoring are being
strengthened to learn from recent field experience with measles
mortality reduction and regional elimination activities. These
efforts provide optimism that, in the future, the goal of global
measles eradication may be achieved.

Acknowledgment
Prior versions of this chapter were authored by Stephen
Preblud, Samuel Katz, Lauri Markowitz, and Stephen Redd.
Substantial sections of this chapter were taken from their previous work.

Measles vaccine

20

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