BACKGROUND: In the United States, 2 doses of measles-mumps-rubella (MMR)-containing vaccines are recommended routinely during childhood; a third dose may be given under certain circumstances. We present observed seroprotection rates and estimate long-term dynamics of measles, mumps, and rubella neutralizing antibody (nAb) levels among 2- and 3-dose MMR (MMR2 and MMR3, respectively) vaccinees. METHODS: Persons who received MMR2 at age 4-12 years or MMR3 at age 18-31 years were enrolled in 1994-1995 and 2009-2010, respectively. Per cohort, sera were collected before vaccination (baseline) and at various intervals ranging from 1 month to 10 years postvaccination to assess nAb levels. Annual changes in nAb levels per virus and cohort were estimated through 10 years postvaccination using generalized estimating equations. Models were stratified by baseline nAb levels. RESULTS: Among MMR2 participants (n = 621), 93.7%, 73.4%, and 83.9% had protective nAb levels against measles, mumps, and rubella, respectively, at the 10-year visit; among MMR3 participants (n = 665), 90.5%, 69.1%, and 100% had protective nAb levels, respectively, at the 9-11-year visit. Estimated nAb levels declined annually across both cohorts, all viruses, and baseline nAb strata, though patterns and magnitude varied. More than one-quarter of participants had mumps nAb levels below the presumed seroprotection threshold at the terminal visits. CONCLUSIONS: These findings indicate that even when MMR antibodies wane, protection against disease is largely retained. Waning of mumps antibodies was greater than for measles and rubella in both 2- and 3-dose vaccinees, likely because a greater proportion failed to mount a robust initial response.

BACKGROUND: The first dose of measles-rubella (MR) vaccine is routinely administered to infants aged 9 months as part of a standard two-dose schedule. However, during large measles outbreaks and in other settings of increased circulation or increased risk, WHO recommends administering a supplementary dose at age 6 months to protect young infants. We aimed to assess the immunogenicity and safety of a first dose of MR vaccine administered to infants aged 6 months and its effect on the immune response to the routine MR vaccine at age 9 months. METHODS: This open-label, randomised trial enrolled healthy infants aged 6 months in Matlab, Bangladesh, who had never received an MR vaccine dose and had no history of measles or rubella. Using a computer-generated block randomisation scheme, infants were randomly assigned (1:1) to receive either two doses of the MR vaccine, one at age 6 months and the second at age 9 months (two-dose group), or one dose at age 9 months (one-dose group). Baseline characteristics were recorded for all enrolled participants at age 6 months. Blood samples were drawn for antibody assays before each vaccination and at final follow up when infants were aged 11 months. The primary outcome was immunogenicity of a first MR vaccine in infants aged 6 months or 9 months and the immunogenicity of a second MR vaccine in infants aged 9 months who received their first MR vaccine at 6 months. Immunogenicity was measured as the proportion of infants who seroconverted in the 12 weeks after vaccination at age 6 months or the 8 weeks after vaccination at age 9 months. Seroconversion was defined as a 4-times increase in IgG concentrations relative to the pre-vaccination concentrations or achieving seroprotective antibody concentrations between study timepoints. The modified intention-to-treat analysis included all infants who received MR vaccines per group assignment and had antibody results at baseline, 9 months, and 11 months. All enrolled infants were included in the safety analysis of the immediate reactions (observed by study staff at the fixed-site clinic in the first 30 min after vaccination), adverse events within 48 h of vaccination among infants in the two-dose group receiving their first MR vaccine at age 6 months, and adverse events observed by study staff or parents at any time during the study. The trial is registered on ClinicalTrials.gov, NCT03071575, and is closed to enrolment. FINDINGS: Between March 9, 2017, and March 18, 2018, 620 infants were enrolled and randomly assigned to the two study groups (312 in the two-dose group and 308 in the one-dose group). Of the 301 infants vaccinated at 6 months, 282 seroconverted for measles (94%, 95% CI 90-96), and 283 seroconverted for rubella (94%, 91-96). By 11 months, after receiving a second dose at age 9 months, 297 (cumulative 99%, 95% CI 97-100) infants seroconverted for measles and 297 infants seroconverted for rubella (cumulative 99%, 96-100). Of the 292 infants vaccinated at 9 months only, 291 seroconverted for both antigens by age 11 months (100%, 95% CI 98-100). 123 adverse events were observed; 72 in the two-dose group and 51 in the one-dose group, with no differences in severity (p=0·78) or outcomes (p=0·71) by study group. 12 (17%) events in the two-dose group and seven (14%) in the one-dose group were severe; most events were mild, resolved without sequelae, and were unrelated to the MR vaccine. One death occurred in the one-dose group before the infant received the 9-month dose of the vaccine, and therefore was deemed to be unrelated to the MR vaccine. INTERPRETATION: The data presented support use of MR vaccine at 6 months to protect young infants during measles outbreaks and in settings with increased risk or high transmission. We recommend additional studies to evaluate longer-term immunity based on age at vaccination. FUNDING: US Centers for Disease Control and Prevention. TRANSLATIONS: For the French and Spanish translations of the abstract see Supplementary Materials section.

BACKGROUND: Despite high vaccine effectiveness, wild-type measles can occur in previously vaccinated persons. We compared the clinical presentation and disease severity of measles by vaccination status and age in the postelimination era in the United States. METHODS: We included U.S. measles cases reported from 2001 to 2022. Breakthrough measles was defined as cases with ≥1 documented dose of measles-containing vaccine, classic measles as the presence of rash, fever, and ≥1 symptoms (cough, coryza, or conjunctivitis), and severe disease as the presence of pneumonia, encephalitis, hospitalization, or death. Vaccinated cases with low- and high-avidity immunoglobulin G were classified as primary (PVF) and secondary (SVF) vaccine failures, respectively. RESULTS: Among 4056 confirmed measles cases, 2799 (69%) were unvaccinated, 475 (12%) were breakthrough infections, and 782 (19%) had unknown vaccination; 1526 (38%), 1174 (29%), and 1355 (33%) were aged <5, 5-19, and ≥20 years, respectively. We observed a general decline in classic presentation and severe disease with an increase in the number of doses and fewer complications among children aged 5-19 years compared to other age groups. Among 93 breakthrough cases with avidity results, 11 (12%) and 76 (82%) were classified as PVF and SVF, respectively, with a higher proportion of PVFs having a classic measles presentation and severe disease than SVFs. DISCUSSION: Breakthrough measles cases tended to have milder disease with less complications. A small proportion of breakthrough infections were due to PVF than SVF. It is critical to maintain high measles-mumps-rubella vaccination coverage in the United States to prevent serious measles illnesses.

On April 24, 2023, the American Samoa Department of Health (ASDoH) declared a public health emergency amid concern about a possible measles outbreak given low 2-dose vaccination coverage at the time. ASDoH had received two positive measles immunoglobulin (Ig) M test results after Flag Day festivities 1 week earlier from vaccinated children. ASDoH performed active case finding, took actions to mitigate transmission, and requested technical assistance from CDC. ASDoH implemented a vaccination campaign to improve suboptimal coverage. Confirmatory molecular testing of specimens from these initial persons under investigation (PUIs) was not possible, but subsequent testing of specimens from additional PUIs by Hawaii State Laboratories Division and CDC ruled out measles. In settings with low measles prevalence, measles antibody testing results have low positive predictive value and can lead to difficulties with interpreting results. Testing for additional pathogens revealed a variety of viruses known to cause common childhood viral exanthems. Both molecular and serologic testing should be performed for all suspected measles cases. To decrease the probability of false-positive IgM results, testing should be reserved for cases that meet the Council of State and Territorial Epidemiologists measles case definition, especially those in persons with no evidence of immunity and with a history of recent international travel. In addition, maintaining high measles vaccination coverage can prevent future outbreaks.

Mumps virus (MuV) is a highly contagious paramyxovirus that is endemic in most regions of the world and continues to cause outbreaks even in highly immunized populations. Outbreaks of mumps in countries with high measles, mumps, and rubella vaccination coverage have been attributed to waning immunity and antigenic differences between the Jeryl Lynn vaccine strain (genotype A) and circulating wild-type viruses. To obtain a subunit vaccine, we used structure-based design to engineer the mumps fusion (F) glycoprotein stabilized in its prefusion conformation (Pre-F) as well as a chimeric immunogen comprising Pre-F linked to mumps hemagglutinin neuraminidase (HN); in mice, both Pre-F antigen and the chimeric antigen elicited potent cross-reactive plaque reducing neutralizing titers to genotypes A, G, and H mumps. A crystal structure of mumps Pre-F at 2.16 Å resolution validated the stabilization strategy, while a post-fusion form of F was engineered as a comparator. Monoclonal antibodies to mumps Pre-F and HN were isolated from immunized mice; 7 of 14 Pre-F-specific antibodies and 9 of 15 HN-specific antibodies were capable of neutralizing genotype G MuV with a range of potencies. Additionally, 7 of 14 Pre-F-specific antibodies neutralized genotype A mumps. Structural and binding analyses of Pre-F-specific antibodies revealed binding to four discrete neutralizing antigenic sites and binding analyses of HN-specific antibodies revealed binding to five discrete neutralizing antigenic sites. Overall, the PreF and the chimeric Pre-F/HN immunogens are promising candidates to boost MMR-elicited immunity to mumps or as a next-generation vaccine.

With 762 laboratories, the Global Measles and Rubella Laboratory Network (GMRLN) is the largest laboratory network coordinated by the World Health Organization (WHO). Like the Global Polio Laboratory Network, the GMRLN has multiple tiers, including global specialized laboratories, regional reference laboratories, national laboratories, and, in some countries, subnational laboratories. Regional networks are supervised by regional laboratory coordinators reporting to a global coordinator at WHO headquarters. Laboratories in the GMRLN have strong links to national disease control and vaccination programs. The GMRLN's goal is to support member states in obtaining timely, complete, and reliable laboratory-based surveillance data for measles and rubella as part of the strategy for achieving measles and rubella elimination. Surveillance data are reported to the national program and are included in annual reports on the status of measles and rubella elimination to national verification committees for review by regional verification commissions. Quality within the GMRLN is ensured by monitoring performance through external quality assurance programs, confirmatory and quality control testing, accreditation, and coordination of corrective action and training where needed. The overall performance of the laboratories has remained high over the years despite many challenges, particularly the COVID-19 pandemic. The GMRLN is well-positioned to support high-quality laboratory-based surveillance for measles and rubella and to transition to supporting laboratory testing for other pathogens, including vaccine-preventable diseases.

Measles and rubella remain global health threats, despite the availability of safe and effective vaccines. Estimates of population immunity are crucial for achieving elimination goals and assessing the impact of vaccination programs, yet conducting well-designed serosurveys can be challenging, especially in resource-limited settings. In this review, we provide a comprehensive assessment of 130 measles and rubella studies published from January 2014 to January 2024. Methodologies and design aspects of serosurveys varied greatly, including sample size, assay type, and population demographics. Most studies utilized enzyme immunoassays for IgG detection. Sample sizes showed diverse sampling methods but favored convenience sampling despite its limitations. Studies spanned 59 countries, predominantly including adults, and revealed disparities in seroprevalence across demographics, regions, and notably among migrants and women. Age-related declines in antibodies were observed, particularly among infants, and correlations between vaccination status and seropositivity varied. We conclude with an outlook on measles and rubella serosurveillance, emphasizing the need for proper survey design and the advantages of standardized, multiplex serology assays.

Measles and rubella are vaccine-preventable viral diseases and can be prevented by safe, highly effective vaccination with measles- and rubella-containing vaccines. Given the myriad causes of febrile exanthems, laboratory surveillance for both measles and rubella is important to document the incidence of these diseases and to track the progress and maintenance of elimination in near- and post-elimination settings. Diagnostic challenges can hinder effective surveillance and classification challenges can hinder efforts to demonstrate achievement or maintenance of elimination. In this report, we review diagnostic and classification challenges for measles and rubella in near- and post-elimination settings.

Mongolia experienced a nationwide measles outbreak during 1 March 2015-31 December 2016, with 49,077 cases reported to the WHO; many were among vaccinated young adults, suggesting a possible role of vaccine failure. Advanced laboratory methods, coupled with detailed epidemiological investigations, can help classify cases as vaccine failure, failure to vaccinate, or both. In this report, we conducted a study of cases to identify risk factors for breakthrough infection for a subset of laboratory-confirmed measles cases. Of the 193 cases analyzed, only 19 (9.8%) reported measles vaccination history, and 170 (88%) were uncertain. Measles-specific IgG avidity testing classified 120 (62%) cases as low IgG avidity, indicating no prior exposure to measles. Ten of these cases with low IgG avidity had a history of measles vaccination, indicating primary vaccine failure. Overall, sixty cases (31%) had high IgG avidity, indicating breakthrough infection after prior exposure to measles antigen through vaccination or natural infection, but the IgG avidity results were highly age-dependent. This study found that among young children aged 9 months-5 years, breakthrough infection was rare (4/82, 5%); however, among young adults aged 15-25 years, breakthrough infection due to secondary vaccine failure (SVF) occurred on a large scale during this outbreak, accounting for the majority of cases (42/69 cases, 61%). The study found that large-scale secondary vaccine failure occurred in Mongolia, which highlights the potential for sustained outbreaks in post-elimination settings due to "hidden" cohorts of young adults who may have experienced waning immunity. This phenomenon may have implications for the sustainability of measles elimination in countries that remain vulnerable to the importation of the virus from areas where it is still endemic. Until global measles elimination is achieved, enhanced surveillance and preparedness for future outbreaks in post- or peri-elimination countries may be required.

Measles is a highly infectious febrile rash illness and was declared eliminated in the United States in 2000. However, measles importations continue to occur, and U.S. measles elimination status was threatened in 2019 as the result of two prolonged outbreaks among undervaccinated communities in New York and New York City. To assess U.S. measles elimination status after the 2019 outbreaks and to provide context to understand more recent increases in measles cases, CDC analyzed epidemiologic and laboratory surveillance data and the performance of the U.S. measles surveillance system after these outbreaks. During January 1, 2020-March 28, 2024, CDC was notified of 338 confirmed measles cases; 97 (29%) of these cases occurred during the first quarter of 2024, representing a more than seventeenfold increase over the mean number of cases reported during the first quarter of 2020-2023. Among the 338 reported cases, the median patient age was 3 years (range = 0-64 years); 309 (91%) patients were unvaccinated or had unknown vaccination status, and 336 case investigations included information on ≥80% of critical surveillance indicators. During 2020-2023, the longest transmission chain lasted 63 days. As of the end of 2023, because of the absence of sustained measles virus transmission for 12 consecutive months in the presence of a well-performing surveillance system, U.S. measles elimination status was maintained. Risk for widespread U.S. measles transmission remains low because of high population immunity. However, because of the increase in cases during the first quarter of 2024, additional activities are needed to increase U.S. routine measles, mumps, and rubella vaccination coverage, especially among close-knit and undervaccinated communities. These activities include encouraging vaccination before international travel and rapidly investigating suspected measles cases.

BACKGROUND: A third dose of measles-mumps-rubella vaccine (MMR) may be administered for various reasons, but data on long-term immunity are limited. We assessed neutralizing antibody levels against measles and rubella among adults up to 11 years after receipt of a third MMR dose. METHODS: In this longitudinal study, healthy adults who received a third MMR dose as young adults (ages 18-28 years) were recalled around 5 years and 9-11 years after the third dose. Measles and rubella antibody levels were assessed by plaque-reduction and immunocolorimetric neutralization assays, respectively. Antibody concentrations <120 mIU/mL and <10 U/mL were considered potentially susceptible to measles and rubella, respectively. Geometric mean concentrations (GMCs) and 95% confidence intervals (CIs) over time were estimated from generalized estimating equation models. RESULTS: Approximately 5 and 9-11 years after receipt of the third dose, 405 and 304 adults were assessed, respectively. Measles GMC was 428 mIU/mL (95% CI, 392-468 mIU/mL) 5 years postvaccination, declining to 381 mIU/mL (95% CI, 339-428 mIU/mL) 11 years postvaccination. At the last follow-up visit (9-11 years postvaccination), 10% of participants were potentially susceptible to measles infection. Rubella GMCs were stable throughout the follow-up period (63 U/mL to 65 U/mL); none of the participants was susceptible to rubella at the last follow-up visit. CONCLUSIONS: Eleven years after receiving a third MMR dose, measles and rubella neutralizing antibody levels remained high in adults. However, on the basis of waning antibody levels, some adults may become susceptible to measles infection over time despite receipt of 3 vaccine doses.

On November 5, 2022, Columbus Public Health, Ohio and the Ohio Department of Health were notified of two children aged 2 years who were admitted to a central Ohio hospital with rash, fever, cough, and congestion, suggestive of measles. Both children were undergoing medical evaluation and treatment for other etiologies before measles was considered in the differential diagnosis. Neither child had received measles, mumps, and rubella (MMR) vaccine, and neither had known contact with a person with measles. Each patient subsequently received a positive measles real-time reverse transcription–polymerase chain reaction (RT-PCR) test result. Neither child had traveled internationally, but during June 12–October 8, 2022, four internationally imported measles cases had been confirmed among unvaccinated Franklin County, Ohio residents who had traveled to areas in East Africa where measles outbreaks were ongoing (1). Investigation of the U.S.-acquired measles cases identified additional measles cases, and local and state health departments confirmed a community outbreak on November 9, 2022. During this community measles outbreak in central Ohio, 85 locally acquired measles cases were confirmed with rash onsets during October 22–December 24, 2022; however, no definitive link to the previous international importations was established. The outbreak was declared over on February 4, 2023, 42 days (two measles incubation periods) after the last reported case.

Laboratory confirmation of infection is an essential component of measles surveillance. Detection of measles specific IgM in serum by enzyme linked immunosorbent assay (ELISA) is the most used method for confirming measles infection. ELISA formats vary as does the sensitivity and specificity of each assay. Specimens collected within 3 days of rash onset can yield a false negative result, which can delay confirmation of measles cases. Interfering substances can yield a false positive result, leading to unnecessary public health interventions. The IgM capture assay developed at the Centers for Disease Control (CDC) was compared against 5 commercially available ELISA kits for the ability to detect measles virus-specific IgM in a panel of 90 well-characterized specimens. Serum samples were tested in triplicate using each commercial kit as recommended by the manufacturer. Using the CDC measles IgM capture assay as the reference test; sensitivity and specificity for the commercial kits ranged from 50 to 83% and 86.9 to 98%, respectively. Discrepant results were observed for samples tested with all five commercial kits and ranged from 13.8 to 28.8% of the specimens tested. False positive results occurred in 2.0 to 13.1% of sera while negative results were observed in 16.7 to 50% of sera that were positive by the CDC measles IgM capture assay. Evaluation and interpretation of measles IgM serologic results can be complex, particularly in measles elimination settings. The performance characteristics of a measles IgM assay should be carefully considered when selecting an assay to achieve high quality measles surveillance. Copyright The copyright holder for this preprint is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. This article is a US Government work. It is not subject to copyright under 17 USC 105 and is also made available for use under a CC0 license.

Laboratory confirmation of infection is an essential component of measles surveillance. Detection of measles-specific IgM in serum by enzyme-linked immunosorbent assay (ELISA) is the most common method used to confirm measles infection. ELISA formats vary, as does the sensitivity and specificity of each assay. Specimens collected within 3 days of rash onset can yield a false-negative result, which can delay confirmation of measles cases. Interfering substances can yield a false-positive result, leading to unnecessary public health interventions. The IgM capture assay developed at the Centers for Disease Control (CDC) was compared against five commercially available ELISA kits for the ability to detect measles virus-specific IgM in a panel of 90 well-characterized specimens. Serum samples were tested in triplicate using each commercial kit as recommended by the manufacturer. Using the CDC measles IgM capture assay as the reference test; the sensitivity and specificity for each commercial kit ranged from 50 to 83% and 86.9 to 98%, respectively. Discrepant results were observed for samples tested with all five commercial kits and ranged from 13.8 to 28.8% of the specimens tested. False-positive results occurred in 2.0 to 13.1% of sera, while negative results were observed in 16.7 to 50% of sera that were positive by the CDC measles IgM capture assay. Evaluation and interpretation of measles IgM serologic results can be complex, particularly in measles elimination settings. The performance characteristics of a measles IgM assay should be carefully considered when selecting an assay to achieve high-quality measles surveillance.

On August 29, 2021, the United States government oversaw the emergent establishment of Operation Allies Welcome (OAW), led by the U.S. Department of Homeland Security (DHS) and implemented by the U.S. Department of Defense (DoD) and U.S. Department of State (DoS), to safely resettle U.S. citizens and Afghan nationals from Afghanistan to the United States. Evacuees were temporarily housed at several overseas locations in Europe and Asia* before being transported via military and charter flights through two U.S. international airports, and onward to eight U.S. military bases,(†) with hotel A used for isolation and quarantine of persons with or exposed to certain infectious diseases.(§) On August 30, CDC issued an Epi-X notice encouraging public health officials to maintain vigilance for measles among Afghan evacuees because of an ongoing measles outbreak in Afghanistan (25,988 clinical cases reported nationwide during January-November 2021) (1) and low routine measles vaccination coverage (66% and 43% for the first and second doses, respectively, in 2020) (2).

BACKGROUND: While administration of the measles-mumps-rubella (MMR-II®) vaccine has been effective at preventing rubella infection in the United States, the durability of humoral immunity to the rubella component of MMR vaccine has not been widely studied among older adolescents and adults. METHODS: In this longitudinal study, we sought to assess the durability of rubella virus (RV)-specific humoral immunity in a healthy population (n = 98) of adolescents and young adults at two timepoints: ~7 and ~17 years after two doses of MMR-II® vaccination. Levels of circulating antibodies specific to RV were measured by ELISA and an immune-colorimetric neutralization assay. RV-specific memory B cell responses were also measured by ELISpot. RESULTS: Rubella-specific IgG antibody titers, neutralizing antibody titers, and memory B cell responses declined with increasing time since vaccination; however, these decreases were relatively moderate. Memory B cell responses exhibited a greater decline in men compared to women. CONCLUSIONS: Collectively, rubella-specific humoral immunity declines following vaccination, although subjects' antibody titers remain well above the currently recognized threshold for protective immunity. Clinical correlates of protection based on neutralizing antibody titer and memory B cell ELISpot response should be defined.