The Journal of Infectious Diseases

SUPPLEMENT ARTICLE

Measles in the 21st Century: Progress Toward Achieving

and Sustaining Elimination
Paul A. Gastañaduy,1 James L. Goodson,2 Lakshmi Panagiotakopoulos,3 Paul A. Rota,1 Walt A. Orenstein,4 and Manisha Patel1
1
Division of Viral Diseases, National Center for Immunization and Respiratory Diseases, Centers for Disease Control and Prevention, Atlanta, Georgia, USA, 2Global Immunization Division, Center
for Global Health, Centers for Disease Control and Prevention, Atlanta, Georgia, USA, 3Immunization Safety Office, National Center for Emerging and Zoonotic Infectious Diseases, Centers for
Disease Control and Prevention, Atlanta, Georgia, USA, and 4Emory University and the Emory Vaccine Center, Atlanta, Georgia, USA

The global measles vaccination program has been extraordinarily successful in reducing measles-related disease and deaths worldwide.
Eradication of measles is feasible because of several key attributes, including humans as the only reservoir for the virus, broad access
to diagnostic tools that can rapidly detect measles-infectious persons, and availability of highly safe and effective measles-containing
vaccines (MCVs). All 6 World Health Organization (WHO) regions have established measles elimination goals. Globally, during 2000–
2018, measles incidence decreased by 66% (from 145 to 49 cases per million population) and deaths decreased by 73% (from 535 600
to 142 300), drastically reducing global disease burden. Routine immunization with MCV has been the cornerstone for the control and
prevention of measles. Two doses of MCV are 97% effective in preventing measles, qualifying MCV as one of the most effective vaccines
ever developed. Mild adverse events occur in <20% of recipients and serious adverse events are extremely rare. The economic benefits
of measles vaccination are highlighted by an overall return on investment of 58 times the cost of the vaccine, supply chains, and vacci-
nation. Because measles is one of the most contagious human diseases, maintenance of high (≥95%) 2-dose MCV coverage is crucial
for controlling the spread of measles and successfully reaching measles elimination; however, the plateauing of global MCV coverage
for nearly a decade and the global measles resurgence during 2018–2019 demonstrate that much work remains. Global commitments
to increase community access to and demand for immunizations, strengthen national and regional partnerships for building public
health infrastructure, and implement innovations that can overcome access barriers and enhance vaccine confidence, are essential to
achieve a world free of measles.
Keywords. measles; measles; mumps; rubella vaccine; MMR; elimination; eradication.

Measles is a febrile rash illness that can lead to serious compli- profiles, global trends in vaccination coverage, the economic
cations and death and one of the world’s most contagious viral benefits of investing in measles vaccination, the various setbacks
diseases. The basic reproduction number (or average number of encountered in measles control in recent years, and key challenges
secondary cases generated by an infectious person in a fully sus- that must be overcome to achieve a world free of measles.
ceptible population) for measles is estimated to be 12–18, higher
than that of many other common childhood illness (eg, influenza, MEASLES DISEASE BURDEN AND IMPACT OF
MEASLES VACCINATION
pertussis). Under the assumption of a homogenously mixing
population, such high transmissibility means that significantly Before the introduction of measles vaccination, measles caused
high population immunity levels of >92%–94% are needed to substantial human disease and death worldwide, infecting
impede sustained measles virus transmission. Measles vaccines nearly everyone by 15 years of age. Measles was common in all
have been enormously successful in controlling measles globally, parts of the world and caused an estimated 135 million cases
demonstrating the feasibility of reaching a measles eradication and more than 6 million deaths globally each year [1]. In the
goal (ie, reduction of measles cases globally to zero). In the cur- United States alone, an estimated 3–4 million people acquired
rent article, we review the significant impact measles vaccination measles every year (roughly equivalent to a birth cohort), of
uptake has had on reducing measles disease burden worldwide, which approximately 500 000 cases and nearly 500 deaths were
the origin of measles vaccines and their safety and effectiveness reported annually [2].
Although most persons fully recover from measles
without sequelae, the disease entails significant morbidity
Correspondence: Paul A. Gastañaduy, Centers for Disease Control and Prevention, 1600 and mortality risks. Common complications of measles in-
Clifton Rd NE, MS H24-5, Atlanta, GA 30333 ([email protected]).
clude otitis media and diarrhea, but more serious complica-
The Journal of Infectious Diseases®  2021;224(S4):S420–8
© The Author(s) 2021. Published by Oxford University Press for the Infectious Diseases Society tions can also occur and include pneumonia, encephalitis,
of America. This is an Open Access article distributed under the terms of the Creative Commons and subacute sclerosing panencephalitis, a slowly progres-
Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted
reuse, distribution, and reproduction in any medium, provided the original work is properly cited.
sive neurologic sequela of measles that is universally fatal
DOI: 10.1093/infdis/jiaa793 (estimated risk, 1 subacute sclerosing panencephalitis case

S420 • jid 2021:224 (Suppl 4) • Gastañaduy et al

per 5000 measles cases) [3]. Secondary bacterial infections After more widespread use of measles vaccines globally in
related to measles-induced immunosuppression (inhibition the 1980s, measles incidence and mortality rates decreased to
of lymphocyte proliferation and decrease in specific preex- low levels in all regions of the world [11]. During 2000–2018,
isting antibodies) can further complicate disease progres- the worldwide annual reported measles incidence per million
sion and recovery [4–8]. Measles case fatality ratios (CFRs) population decreased by 66%, from 145 to 49 cases, the an-
vary widely, depending on access to quality healthcare and nual number of reported measles cases decreased by 59%, from
the underlying nutritional and health status of those in- 853 479 to 353 236 (Figure 1), and annual estimated measles
fected [9]. Measles CFRs in high-income countries such as deaths decreased by 73%, from 535 600 to 142 300 [11]. In the
the United States can be as low as 0.1% (or lower), but are United States, where measles elimination (ie, absence of contin-
much higher in other settings; CFRs have been estimated to uous endemic measles virus transmission for more than a year)
be 4%–5% in Africa, and as high as 30% among vulnerable was achieved in 2000, new measles cases originate through
children during humanitarian crises [10]. measles introductions from abroad, mainly from unvaccinated

A
1989 - 1991
600 000 30 000 Resurgence
1963
Vaccine licensed 25 000

500 000 20 000 1993

Vaccines for
15 000
Children
400 000 10 000 program
Cases, No.

5000

300 000 0
1985 1990 1995 2000 2005 2010 2015

200 000

1989 2000
100 000 2nd Dose Elimination declared
recommended

0
1960 1963 1966 1969 1972 1975 1978 1981 1984 1987 1990 1993 1996 1999 2002 2005 2008 2011 2014 2017
B 4 500 000

4 000 000

3 500 000

3 000 000
Cases, No.

2 500 000

2 000 000

1 500 000

1 000 000

500 000

0
1980 1982 1984 1986 1988 1990 1992 1994 1996 1998 2000 2002 2004 2006 2008 2010 2012 2014 2016 2018

Figure 1. Number of reported measles cases in the United States from 1962 to 2019 (A) and worldwide from 1980 to 2019 (B). Data from US Centers for Disease Control and
Prevention Morbidity and Mortality Weekly Report; global data available at http://apps.who.int/immunization_monitoring/globalsummary/timeseries/tsincidencemeasles.
html.

Progress Toward Measles Elimination • jid 2021:224 (Suppl 4) • S421

US travelers becoming infected and returning home with mea- Most of the measles vaccine strains currently in use were de-
sles. During 2001–2018, a median of 79 total cases (range, rived from the prototype Edmonston strain (Edmonston wild-
37–667), including a median of 28 internationally imported type) which was isolated by Enders and Peebles in 1954 [19].
cases (range, 18–82 importations), were reported annually in In addition to the live attenuated vaccine strains, a formalin-
the United States, with 3 confirmed measles-related deaths re- inactivated Edmonston vaccine was in use during 1963–1967;
ported during that 18-year period [12, 13]. This low burden of however, use of this vaccine was discontinued because vaccin-
measles equates to more than a 99% decline in the reported ated individuals were at risk for developing atypical measles after
number of cases and deaths due to measles when comparing wild-type measles virus infection. Atypical measles is caused by
US prevaccine and postelimination periods (Figure 1) [14]. antigen–antibody immune complex deposition and character-
As of 2019, a total of 83 countries have verified measles elim- ized by high fever, abdominal pain, myalgias, pneumonitis, and
ination, paving a path forward for global eradication. Several a petechial or vesicular and edematous rash. The syndrome is
key attributes position measles as a prime candidate for eradi- preventable by vaccination with a live-attenuated vaccine [20].
cation: (1) absence of a nonhuman reservoir (ie, unimmunized To develop live-attenuated vaccines, the Edmonston strain
humans are essential for the life cycle of the measles virus), (2) was passaged in human amnion and human kidney cells be-
availability of practical and sensitive diagnostic tools, such as fore being adapted to chicken embryo fibroblasts to generate
immunoglobulin (Ig) M serologic assays and molecular tests the commonly used Moraten and Schwarz strains. Several vac-
to identify persons with acute measles, and, most importantly, cine strains were derived from other wild-type measles virus
(3) highly effective measles vaccines. Measles eradication is fea- isolates, including the Leningrad-16 strain used in Russia, the
sible [15]; however, global commitment is essential to sustain Shanghai-191 strain used in China, and the CAM-70 strain
longstanding progress to reduce measles morbidity and mor- used in multiple countries. All measles vaccines are produced
tality rates and to achieve regional elimination goals. in chicken embryo fibroblasts, except the Edmonston-Zagreb
strain (from the Serum Institute of India), which was derived by
GENOTYPIC VARIATION AND PATHOGENESIS OF further passage in human diploid cells, MRC-5 [20].
MEASLES VIRUS
Comparison of the genomic sequences of nine measles vac-
Measles virus is a negative sense, single-stranded RNA virus cine strains with the sequence of the Edmonston wild-type
with a genome size of 15 894 nucleotides [16]. Measles virus is virus has shown a relatively small amount of genetic heteroge-
considered monotypic (ie, a genus with only a single species); neity. Although nucleotide substitutions were found in the non-
however, multiple genetically distinct lineages of wild-type coding and protein coding regions of the genomes, the overall
measles virus have been described [17]; the WHO currently genetic organization of the vaccine strains was conserved [21],
recognizes 24 genotypes [18]. and there are no clear genetic markers for attenuation. The bi-
Measles is characterized by a generalized maculopapular ologic basis for attenuation may be the result of use of different
skin rash, fever above 38.3°C (101°F), and cough, coryza, and/ cellular receptors by vaccine and wild-type viruses. Vaccines
or conjunctivitis. During the incubation period, the virus rep- strains can use both CD46 and human signaling lymphocyte
licates in alveolar macrophages and dendritic cells before marker for entry, while wild-type viruses recognize only human
establishing a systemic infection in which infected lympho- signaling lymphocyte marker. Vaccine and wild type viruses
cytes disseminate the virus to major organ systems, peripheral use nectin 4 to infect epithelial cells before viral shedding [16,
tissues, including the skin, the respiratory tract and epithelial 22]. Importantly, the high attenuation of measles vaccine vir-
cells. In uncomplicated measles cases, clinical signs start to sub- uses impedes human-to-human transmission of these viruses; a
side a few days after rash onset, and patients develop a robust systematic review of 773 articles including genotyping of virus
immune response that mediates recovery and provides lifelong strains in close contacts of vaccinated individuals found that all
immunity [16]. cases of measles in close contacts were due to wild-type virus
[23].
MEASLES VACCINE HISTORY AND DEVELOPMENT
The only wild-type measles viruses currently detected in
Measles vaccines are attenuated (or weakened) measles vir- circulation are members of genotypes D8, D4, B3, and H1.
uses, so that infection through vaccination of immunocom- Although some antigenic variation between wild-type and vac-
petent persons leads to replication and immunity, but not cine strains has been described [24], the necessity for conserva-
disease. Data suggest that genotype A was widely distributed in tion of the receptor-binding domains on the viral hemagglutinin
the prevaccine era when the progenitors of the vaccine strains (H) protein, the surface glycoprotein that is the target of neu-
were first isolated; however, only a few measles viruses from the tralizing antibodies, constrains antigenic drift (ie, accumulation
1950s and 1960s have been available for sequencing. All live at- of mutations in virus-surface proteins). This conservation of the
tenuated vaccine strains used in measles vaccines are members H protein allows measles vaccines to be highly effective against
of genotype A. all wild-type viruses, directly contributing to overall success of

S422 • jid 2021:224 (Suppl 4) • Gastañaduy et al

the global measles vaccination program, and likely cessation of vaccine, and to administer MMRV as the first dose only if the
transmission of 20 of the 24 known genotypes [25]. parent or caregiver expresses a preference for MMRV vaccine
Vaccination elicits long-lived humoral and cellular immune [28].
responses. Serologic correlates for protection from measles Thrombocytopenia can occur after natural measles infec-
virus have been established and a titer >120 mUI/mL is con- tion, and a causal relationship between MMR vaccine and
sidered protective [26]. Most vaccination studies rely on meas- thrombocytopenia has been established based on observational
urement of the concentration of neutralizing antibodies in studies, case reports, and biologic plausibility [34]. A large US
serum samples as a surrogate for the immune response [27]. study evaluating the risk of immune thrombocytopenic pur-
pura (ITP) in children aged 12–23 months in the 6 weeks after
MEASLES VACCINE SAFETY MMR vaccination [38] found that 76% of ITP cases in children
The safety of MCVs, including measles-only, measles-rubella in this age-group were attributable to the MMR vaccine, and
(MR), measles-mumps-rubella (MMR), and MMR-varicella estimated a rate of 1 case of ITP per 40 000 vaccine doses given.
(MMRV) vaccines is well-established. MCVs have similar safety Thrombocytopenia associated with vaccination was generally
profiles and are well tolerated, and common reactions after mild and resolved within 7 days, on average. In addition, the
vaccination are mild [20, 28]. Common adverse events after risk for thrombocytopenia after MMR vaccination is several-
MMR vaccination depend on components of the vaccine and fold lower than after wild-type rubella (estimated as 1 case per
include fever (5%–15%), rashes (5%), and lymphadenopathy 3000 infections) [39]. Persons with a history of thrombocyto-
(5%–20%), as well as parotitis and transient arthralgias/arthritis penia or thrombocytopenic purpura might be at increased risk
[29–32]. These adverse events occur approximately 6–12 days for clinically significant thrombocytopenia after MMR vaccina-
after vaccination, the time period of peak vaccine virus repli- tion; thus, a history of these conditions is a precaution for MMR
cation. Compared with the first dose of vaccine, adverse events vaccination.
are less common after the second dose of vaccine, because most Anaphylaxis and other immediate hypersensitivity reactions
children are immune at the time they receive the second vacci- can occur after MMR vaccination, and are likely related to al-
nation, and therefore, less viral replication occurs [33]. lergies to the gelatin or neomycin components of the vaccine
MMR vaccination is only rarely associated with serious ad- [40–42]. In a large population-based study, the risk of anaphy-
verse events, and both precautions and contraindications to laxis following MMR vaccine was estimated to be 5.14 per mil-
MMR vaccination have been carefully delineated to minimize lion vaccine doses (95% confidence interval, 1.06–15.01) [43].
serious reactions. A review by the Institute of Medicine assessed History of severe allergic reaction to any component of the vac-
whether there was both epidemiologic and mechanistic evi- cine is a contraindication to MMR vaccination [28].
dence of serious adverse events associated with MMR vaccine Immunocompromised patients should also not receive the
[34]. This review concluded that there is an increased risk of MMR vaccine. Potential fatal adverse events in immunocom-
febrile seizures following MMR vaccine, and that the evidence promised hosts include measles pneumonia, MIBE, and dis-
supported a causal relationship between MMR vaccine and fe- seminated measles infection [44–47]. This recommendation
brile seizures. The review also concluded a causal relationship is inclusive of persons with human immunodeficiency virus
between MMR vaccine and anaphylaxis, and MMR vaccine and (HIV) infection who are severely immunocompromised.
MIBE in individuals with demonstrated immunodeficiencies. However, a systematic review of 28 safety studies of MMR vacci-
The attributable risk of febrile seizures after MMR vaccine nation among HIV-infected children found that adverse events
has been evaluated in multiple large population-based studies to and deaths after measles vaccines were uncommon in this pop-
be approximately 25–34 additional febrile seizures per 100 000 ulation [48]; thus, persons with HIV infection should receive
children vaccinated, and occurs most commonly 7–14 days MMR vaccine if they are not severely immunosuppressed (eg,
after vaccination [35]. The risk is approximately twice as high T-lymphocyte percentage >15% at any age or CD4 cell count
for children aged 12–23 months who receive the MMRV com- >200/µL for those >5 years of age) [28].
bination vaccine compared with those who receive MMR and MMR vaccine is contraindicated in pregnancy owing to the-
varicella vaccines separately [36]. These studies found that there oretical concerns of fetal harm including congenital rubella
was 1 additional febrile seizure per every 2300–2600 MMRV syndrome [28]. Nevertheless, a systematic review of vaccines
vaccine doses given, compared with MMR and varicella vac- given to pregnant women found that among 4918 pregnant
cines given separately. There was no increased risk in individ- women who inadvertently received MMR vaccine while preg-
uals receiving a second dose of MMRV compared to MMR and nant, no cases of congenital rubella syndrome were reported
varicella separately at the recommended 4–6-year-old age range [49]. Similarly, a safety review of 131 reports to the Vaccine
[37]. Based on these findings, providers are recommended to Adverse Event Reporting System of MMR vaccine adminis-
discuss the benefits and risks of vaccination with MMRV versus tered to pregnant women found that most vaccines were given
MMR and varicella separately for the first dose of measles to women early in pregnancy (when they were unaware of their

Progress Toward Measles Elimination • jid 2021:224 (Suppl 4) • S423

pregnancy), and in the majority of reports, no adverse events Although infants are at risk of severe disease and serious compli-
were reported [50]. The highly favorable safety profile of MCV cations, studies have suggested that vaccination at <12 months
has been an essential component of the global measles eradica- of age can lead to suboptimal immune responses that continue
tion strategy. to be low despite additional doses [52, 53, 54]. In the United
States, where exposure to measles is rare, the first dose is re-
MEASLES VACCINE USE AND EFFECTIVENESS commended at 12–15 months of age and the second dose at
All 194 countries have added MCV into their routine child- 4–6 years, in order to effectively protect young children and
hood immunization programs, a critical step toward global to ensure they are fully vaccinated before school entry. Other
measles eradication. MCV is usually delivered as a combined countries that have achieved measles elimination recommend
multiantigen vaccine, either MR or MMR vaccine. Combination different schedules (eg, both Canada and Australia recom-
vaccines are cost-effective, in that the addition of other antigens mend the first dose of MMR at 12 months and the second at
increases cost by much smaller margins compared with the sub- 18 months of age), highlighting that even in countries with sim-
stantial costs incurred by administration, delivery, and wastage ilar measles epidemiology, country-specific healthcare delivery
of multiple vaccines. Currently, 122 countries have intro- systems play a critical role in establishing the optimal timing for
duced MMR into their routine immunization schedules, with vaccination [39].
MMR being used solely in most countries in the European and
MEASLES VACCINATION COVERAGE
Americas regions [51].
The effectiveness of the measles component of the MMR vac- During 2000–2019, estimated coverage with the routine first-
cine is high, 93% after 1 dose and 97% after 2 doses in persons dose MCV (MCV1) increased globally from 72% to 85%
aged ≥12 months. Duration of immunity is likely lifelong after (Figure 2), and the number of countries with ≥90% MCV1
2 doses [28]. Although the incremental vaccine effectiveness coverage increased from 86 (45%) to 122 (63%) [55]. Among
between 1 and 2 doses may seem small, the measles herd im- countries with ≥90% MCV1 coverage nationally, those that
munity threshold is high (>92%), necessitating implementation also had ≥80% MCV1 coverage in all districts increased from
of a second dose for optimal measles control and elimination 1% in 2003 to 22% in 2019. From 2000 to 2019, the number of
to be successfully achieved. As a result of numerous measles countries providing a second dose of MCV (MCV2) nation-
outbreaks occurring in vaccinated school-aged children in the ally through routine immunization services increased from 95
United States during the 1980s, a second dose of MMR was re- (50%) to 177 (91%), and estimated global MCV2 coverage in-
commended for school-aged and college students in 1989. The creased from 18% to 71%. However, as of 2019, 17 countries
assimilation of a 2-dose recommendation into the US child- had yet to introduce MCV2 nationally, and MCV1 coverage
hood immunization schedule, in addition to school-entry im- has remained at 84%–85% globally since 2010. Therefore,
munization requirements, the introduction of the Vaccines for mass vaccination campaigns remain a necessary strategy for
Children program in 1993 to improve vaccine access, and con- eliminating measles in many countries. In 2019, approximately
certed efforts in the 1990s by other countries in the Americas 204 million persons received MCV during supplementary
region to reduce measles cases and outbreaks (which limited the immunization activities in 55 countries, and an additional
number of introductions of measles from these countries), ul- 9 million received MCV during measles outbreak response
timately led to the elimination of measles in the United States activities.
by 2000. Countries that have achieved measles elimination have in-
Timing and delivery strategies for MCV vaccination vary vested heavily in routine immunization programs to ensure
by country and are contingent on multiple factors, including consistently high vaccination coverage against measles and
the infrastructure to implement routine immunizations and other vaccine-preventable diseases. In the United States, after
mass vaccination campaigns, the capacity and preparedness for the first licensure of measles vaccine in 1963 and MMR in 1971,
rapid outbreak response, and the local epidemiology of mea- MCV coverage steadily increased, with almost 20 million doses
sles based on surveillance data. Overall disease burden and distributed in 1989 alone [20]. National vaccination coverage
age at highest risk of disease is often a primary consideration surveys including MMR were implemented beginning in 1994
when establishing an immunization schedule. Currently, 41% of for young children and 2006 for adolescents; estimates have
countries with measles vaccination programs begin vaccinating remained steady at ≥90% for both 1 and 2 doses since 2010
infants before 1 year of age (usually at 9 months), owing to the (Figure 2). In 2017, MMR vaccination coverage was reported
high disease burden in infants. to be 91.5% for children aged 19–35 months vaccinated with ≥1
The chance of exposure to measles for infants and young dose and 94.3% for children in kindergarten with ≥2 doses [56,
children in each country must be carefully weighed against 57]. Similarly, in Canada and Australia, the estimated MCV1
the age-specific immunogenicity of each dose of measles vac- coverage among 2-year-olds in 2017 was 90% and 90.5%, re-
cine in order to define the optimal age for routine vaccination. spectively [58, 59].

S424 • jid 2021:224 (Suppl 4) • Gastañaduy et al

 A
MMR 1+ (19–35 mo) MMR 2+ (13–17 y)
100

Coverage, %

90

80

95 97 99 01 03 05 07 09 11 13 15 17 19
19 19 19 20 20 20 20 20 20 20 20 20 20

B MCV1 MCV2
100
Coverage, %

50

0
80 82 84 86 88 990 992 94 96 98 00 02 04 06 08 010 012 014 016 18
19 19 19 19 19 1 1 19 19 19 20 20 20 20 20 2 2 2 2 20

Figure 2. A, Estimated measles-mumps-rubella (MMR) vaccination coverage among children aged 19–35 months or 13–17 years. (Data from National Immunization
Surveys, United States, 1995–2019; available at https://www.cdc.gov/vaccines/imz-managers/coverage/childvaxview/data-reports/mmr/trend/index.html and https://
www.cdc.gov/vaccines/imz-managers/coverage/teenvaxview/data-reports/mmr/trend/index.html). B, Estimated measles-containing-vaccine (MCV) first dose (MCV1) and
MCV second dose (MCV2) coverage (worldwide data from World Health Organization, 1980–2019; available at http://www.who.int/immunization/monitoring_surveillance/
data/en). A, B, Horizontal dashed lines represent 90% vaccination coverage.

ECONOMIC BENEFITS OF MEASLES VACCINATION economic benefits, the overall societal return on investment for
The economic benefits of investing in vaccines, particularly 10 vaccines is 44 (range, 27–67) times the cost of the vaccines,
measles vaccines, are well established [60–64]. Even in coun- supply chains, and vaccine delivery [60]; the measles vaccine
tries with low disease incidence, periodic measles outbreaks has the highest return on investment, 58 (28–105) times the
continue to occur, causing costly disruptions to society and cost [60]. In the United States, it has been estimated that routine
requiring resource-intensive outbreak response activities [65]. measles vaccination of the 2009 birth cohort prevented 3.8 mil-
A review of cost estimates of 11 measles outbreaks during the lion measles illnesses and >3000 measles-related deaths, a net
postelimination era in the United States, found that measles savings of more than >$3 billion in direct costs and $8 billion
costs public health and healthcare institutions a median of ap- in societal costs [67]. Achieving an eventual measles eradica-
proximately $33 000 (US dollars) per case, and $4000 per day tion goal would have massive economic implications and could
of investigation [66]. Furthermore, after accounting for broad save current ongoing annual costs of >$2 billion in measles

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treatment and >15 million disability-adjusted life-years, valued clinic locations and hours), and combating dissemination of
at >$63 billion globally each year [68]. misinformation eroding trust and confidence in vaccines [11,
76, 77]. A midterm review of the Measles and Rubella Strategic
BARRIERS TO ACHIEVING AND MAINTAINING Plan concluded that measles could be eradicated and offered a
MEASLES ELIMINATION AND FUTURE
number of recommendations to try to support eradication [78].
CONSIDERATIONS
Notably, vaccine hesitancy was listed by WHO in 2019 as among
Despite significant progress in decreasing measles incidence the top 10 challenges to global health [79]. Both the Centers
and mortality rates globally since 2000, measles elimination for Disease Control and Prevention and WHO have established
efforts have encountered setbacks in recent years. Estimated comprehensive initiatives to address vaccine hesitancy [80, 81].
MCV1 coverage worldwide has plateaued at 84%–85% for Intensified efforts and resource commitments by global part-
nearly a decade and reported global measles cases increased ners and countries are needed to get back on track toward mea-
from a historic low of 132 490 in 2016 to 869 770 in 2019 (556% sles elimination. A new immunizations guidance document, the
increase) [55]. Among persons with confirmed measles cases Immunization Agenda 2030 (IA2030) [82], cocreated by WHO
reported to WHO during 2013–2018, 45% were reported to and partners and to be endorsed by the World Health Assembly,
have never received MCV, and 30% had an unknown vaccina- builds on lessons learned and progress made toward the Global
tion history [69]. Vaccine Action Plan goals. The IA2030 aims to use measles, a
Several countries lost their elimination status in 2019. In the proven effective surrogate or marker for the performance of
Americas, the first region of the WHO to have been declared Expanded Programmes on Immunization [83], to drive efforts
free of measles in 2016, recent reestablishment of endemic virus to strengthen immunizations and primary healthcare systems
transmission in Venezuela and Brazil led to a loss of regional [82].
elimination. The United States has similarly experienced sev- Focusing on measles elimination strategies can enhance de-
eral sizeable outbreaks following measles importations, mostly livery of routine immunization for other vaccine-preventable
in settings with low vaccination coverage, including communi- diseases, help identify unvaccinated or undervaccinated com-
ties in Ohio [70], Minnesota [71], and Washington [72]. During munities and close immunity gaps, lead to improvements in
2018 and 2019, prolonged outbreaks of almost 1-year duration surveillance and expansion of cold-chain capacity, create op-
in undervaccinated communities in New York threatened the portunities to provide refresher training on vaccination to
measles elimination status of the United States. The 1282 mea- healthcare workers, and advance the adoption of strategies used
sles cases reported in the United States in 2019 was the highest for measles elimination to ensure high coverage for vaccines
annual number of reported cases since 1992 [73, 74]. Since against other diseases (eg, school-entry requirements) [84]. The
2001, 88% of US residents with confirmed measles cases are ei- IA2030 thus provides an opportunity to strengthen vaccination
ther unvaccinated or have an unknown vaccination status [12]. programs, build on public health partnerships, and leverage
The Measles & Rubella Initiative (M&RI), a global partner- data-driven approaches that use disease surveillance to increase
ship formed in 2001, coordinates efforts to achieve a world vaccination coverage and equity in all communities [65, 85].
without measles and rubella. The M&RI is led by the American
Red Cross, the United Nations Foundation, WHO, United KEY INNOVATIONS FOR MEASLES CONTROL IN
Nations Children’s Fund (UNICEF), and the US Centers for RESOURCE-LIMITED COUNTRIES
Disease Control and Prevention. Since 2001, it has invested Innovative approaches for measles diagnostics and vaccination
>$1.2 billion for measles and rubella elimination efforts. In methods, principally to address challenges in resource-limited
2012, a Measles and Rubella Strategic Plan was released cov- settings lacking strong healthcare infrastructures, could facili-
ering the period 2012–2020 and was endorsed by the M&RI tate the control of measles and help overcome critical barriers
[75]. Among its goals were reaching measles elimination in ≥5 to achieving measles elimination.
of the 6 WHO regions, establishing a target date for measles
eradication, and achieving a ≥95% coverage with MCV in all New Rapid Diagnostic Test
districts of all countries no later than 2020. While considerable Because many of the typical clinical signs of measles can also be
progress in measles control has been made, none of those tar- caused by other infectious agents, including rubella virus, labora-
gets have been met. tory confirmation of measles is a critical component of the measles
There are multiple challenges to achieving and maintaining control strategy but may not always be feasible in resource-limited
the measles herd immunity threshold needed for measles erad- settings. Detection of measles-specific IgM antibodies by enzyme
ication, estimated generally to be >92%–94%. Achieving such immunoassay is the most common method used for case confir-
immunity levels requires substantial political will, elimination mation, though detection of viral RNA by reverse-transcription
of financial and physical access barriers to measles vaccination, polymerase chain reaction is increasing in many countries. While
strengthening of public health infrastructure (eg, inconvenient most of the IgM tests are performed with serum samples, the use of

S426 • jid 2021:224 (Suppl 4) • Gastañaduy et al

alternative samples, such as dried blood spots and oral fluid sam- Supplementary Data
ples, has helped to expand laboratory surveillance. The recent de- Supplementary materials are available at The Journal of Infectious
velopment of a rapid diagnostic test that can provide results in <20 Diseases online. Consisting of data provided by the authors to
minutes to detect measles IgM in field settings, will facilitate rapid benefit the reader, the posted materials are not copyedited and are
detection of cases and response activities in resource-limited set- the sole responsibility of the authors, so questions or comments
tings where the logistics of sample transport and storage are often should be addressed to the corresponding author.
challenging [86, 87]. The complete references are available as online Supplemental
Material.
Alternative Vaccine Delivery Approaches
Alternative vaccine delivery methods that eliminate the need Notes
for cold-chain transportation and hypodermic needle and sy- Disclaimer: The findings and conclusions in this report are
ringe subcutaneous injection could improve vaccine delivery those of the authors and do not necessarily represent the official
in resource-limited settings and increase vaccination coverage position of the Centers for Disease Control and Prevention, US
and equity. Several routes of administration have been evalu- Department of Health and Human Services.
ated. A measles vaccine delivered by the respiratory route as Supplement sponsorship. This supplement is sponsored by
an aerosol was immunogenic but the seroconversion rate was the Bill and Melinda Gates Foundation.
inferior to the rate observed after subcutaneous injection [88]. Potential conflicts of interest. All authors: No reported
A dry powder was immunogenic in nonhuman primates, but conflicts. All authors have submitted the ICMJE Form for
work was discontinued after a phase I clinical trial [89, 90]. Disclosure of Potential Conflicts of Interest. Conflicts that the
Measles vaccination via the intradermal route produced lower editors consider relevant to the content of the manuscript have
seroresponses because efficient and reliable delivery methods been disclosed.
were not available [91]. However, the recent success in devel-
opment and testing of dissolving microneedle patches for the References
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