Long-term Neutralizing Antibody Levels Against Measles and Rubella Viruses Among Adults With 3 Doses of Measles-Mumps-Rubella Vaccine.

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.

Mumps vaccine effectiveness of a 3rd dose of measles, mumps, rubella vaccine in school settings during a mumps outbreak -- Arkansas, 2016-2017.

Objectives: The largest mumps outbreak in the United States since 2006 occurred in Arkansas during the 2016-17 school year. An additional dose (third dose) of measles-mumps-rubella vaccine (MMR3) was offered to school children. We evaluated the vaccine effectiveness (VE) of MMR3 compared with two doses of MMR for preventing mumps among school-aged children during the outbreak. Study design: A generalized linear mixed effects model was used to estimate the incremental vaccine effectiveness (VE) of a third dose of MMR compared with two doses of MMR for preventing mumps. Methods: We obtained school enrollment, immunization status and mumps case status from school registries, Arkansas's immunization registry, and Arkansas's mumps surveillance system, respectively. We included students who previously received 2 doses of MMR in schools with ≥1 mumps case after the MMR3 clinic. We used a generalized linear mixed model to estimate VE of MMR3 compared with two doses of MMR. Results: Sixteen schools with 9272 students were included in the analysis. Incremental VE of MMR3 versus a two-dose MMR regimen was 52.7% (95% confidence interval [CI]: -3.6%‒78.4%) overall and in 8 schools with high mumps transmission it was 64.0% (95% CI: 1.2%‒86.9%). MMR3 VE was higher among middle compared with elementary school students (68.5% [95% CI: -30.2%‒92.4%] vs 37.6% [95% CI: -62.5%‒76.1%]); these differences were not statistically significant. Conclusion: Our findings suggest MMR3 provided additional protection from mumps compared with two MMR doses in elementary and middle school settings during a mumps outbreak.

Safety of measles, mumps, and rubella vaccine in adolescents and adults in the vaccine safety Datalink.

Background: Measles, mumps, and rubella vaccine (MMR) is routinely administered to children; however, adolescents and adults may receive MMR for various reasons. Safety studies in adolescents and adults are limited. We report on safety of MMR in this age group in the Vaccine Safety Datalink. Methods: We included adolescents (aged 9-17 years) and adults (aged ≥ 18 years) who received ≥ 1 dose of MMR from January 1, 2010-December 31, 2018. Pre-specified outcomes were identified by diagnosis codes. Clinically serious outcomes included anaphylaxis, encephalitis/myelitis, Guillain-Barré syndrome, immune thrombocytopenia, meningitis, and seizure. Non-serious outcomes were allergic reaction, arthropathy, fever, injection site reaction, lymphadenopathy, non-specific reaction, parotitis, rash, and syncope. All serious outcomes underwent medical record review. Outcome-specific incidence was calculated in pre-defined post-vaccination windows. A self-controlled risk interval design was used to determine the relative risk of each outcome in a risk window after vaccination compared to a more distal control window. Results: During the study period, 276,327 MMR doses were administered to adolescents and adults. Mean age of vaccinees was 34.8 years; 65.8 % were female; 53.2 % of doses were administered simultaneously with ≥ 1 other vaccine. Serious outcomes were rare, with incidence ≤ 6 per 100,000 doses for each outcome assessed, and none had a significant elevation in incidence during the risk window compared to the control window. Incidence of non-serious outcomes per 100,000 doses ranged from 3.4 for parotitis to 263.0 for arthropathy. Other common outcomes included injection site reaction and rash (157.0 and 112.9 per 100,000 doses, respectively). Significantly more outcomes were observed during the risk window compared to the control window for all non-serious outcomes except parotitis. Some variability was observed by sex and age group. Conclusion: Serious outcomes after MMR are rare in adolescents and adults, but vaccinees should be counseled regarding anticipated local and systemic non-serious adverse events.

Measles, Mumps, Rubella Vaccine (PRIORIX): Recommendations of the Advisory Committee on Immunization Practices - United States, 2022.

Vaccination is the main means for preventing measles, mumps, and rubella virus infections and their related complications (1,2). Achieving and maintaining high 2-dose measles, mumps, and rubella vaccination coverage in the United States has led to elimination of endemic measles in 2000, rubella and congenital rubella syndrome in 2004, and a sharp decrease in mumps cases. However, measles and rubella remain endemic in many countries, leading to importations of cases and occasional local transmission within the United States (3). Reported U.S. mumps cases declined >99% from the prevaccine period (4); however, mumps is endemic worldwide, and since 2006, the number of mumps cases and mumps outbreaks has increased in the United States, with wider geographic spread since 2016 (4). Given the risk for importation of measles and rubella and the resurgence of mumps, maintaining high measles, mumps, and rubella (MMR) vaccination coverage is important. Since 1978, only one MMR vaccine, M-M-R II (Merck and Co., Inc.), has been available in the United States. On June 6, 2022, the Food and Drug Administration approved a second MMR vaccine, PRIORIX (GlaxoSmithKline Biologicals), for the prevention of measles, mumps, and rubella in persons aged ≥12 months. The three live attenuated viruses contained in PRIORIX are genetically similar or identical to the corresponding components in M-M-R II (Table) (5-7). On June 23, 2022, the Advisory Committee on Immunization Practices (ACIP) unanimously recommended PRIORIX as an option to prevent measles, mumps, and rubella according to the existing recommended schedules and for off-label uses (i.e., indications not included in the package insert)* (1,2). ACIP considered PRIORIX to be safe, immunogenic, and noninferior to M-M-R II. Both PRIORIX and M-M-R II are fully interchangeable for all indications for which MMR vaccination is recommended. This report contains ACIP recommendations specific to PRIORIX and supplements the existing ACIP recommendations for MMR use (1,2).

The Effectiveness of Varicella Vaccine: 25 Years of Postlicensure Experience in the United States.

We summarize studies of varicella vaccine's effectiveness for prevention of varicella and lessons learned during the first 25 years of the varicella vaccination program in the United States. One dose of varicella vaccine provided moderate protection (82%-85%) against varicella of any severity and high protection (100%) against severe varicella, with some waning of protection over time. The 1-dose program (1995-2006) had a substantial impact on the incidence both of varicella and of severe outcomes (71%-90% decrease) although it did not prevent low-level community transmission and some outbreaks continued to occur in highly vaccinated populations. Two doses of varicella vaccine improved the vaccine's effectiveness by at least 10% against varicella of any severity, with further declines in the incidence both of varicella and of severe outcomes as well as in both number and size of outbreaks. There is no evidence for waning of the effectiveness of 2 doses of the vaccine.

Safety Surveillance of Varicella Vaccines in the Vaccine Adverse Event Reporting System, United States, 2006-2020.

BACKGROUND: . The Vaccine Adverse Event Reporting System (VAERS) is the United States national passive vaccine safety surveillance system. We updated the data on the safety of single-antigen varicella vaccine (VAR) and assessed the safety of combination measles, mumps, rubella, and varicella vaccine (MMRV) licensed in the United States using VAERS data. METHODS: US VAERS reports received after administration of VAR and MMRV during 2006-2020 were identified. Reports were analyzed by vaccine type, age, seriousness, most common adverse events (AEs), and concomitant vaccines. We reviewed medical records of selected reports of AEs of special interest and conducted empirical Bayesian data mining to identify disproportionally reported AEs. RESULTS: During 2006-2020, approximately 132.8 million VAR doses were distributed; 40 684 reports were received in VAERS (30.6/100 000 doses distributed), with 4.1% classified as serious (1.3/100 000 doses distributed). Approximately 35.5 million MMRV doses were distributed; 13 325 reports were received (37.6/100 000 doses distributed) with 3.3% classified as serious (1.3/100 000 doses distributed). The most common adverse health events after both VAR and MMRV were injection site reactions (31% and 27%), rash (28% and 20%), and fever (12% and 14%), respectively. Vaccination errors accounted for 23% of reports after VAR administration and 41% after MMRV administration, but ≥95% of them did not describe an adverse health event. AEs associated with evidence of vaccine strain varicella-zoster virus (vVZV) infection included meningitis, encephalitis, herpes zoster, and 6 deaths (all in immunocompromised persons with contraindications for vaccination). No new or unexpected AE was disproportionally reported. CONCLUSIONS: No new or unexpected safety findings were detected for VAR and MMRV given as recommended, reinforcing the favorable safety profiles of these vaccines. Providers should obtain specimens for viral testing and strain-typing for serious AEs if they consider vVZV as the possible causative agent.

Health and Economic Impact of the United States Varicella Vaccination Program, 1996-2020.

BACKGROUND: The aim of this study was to evaluate the health and economic impact of the varicella vaccination program on varicella disease in the United States (US), 1996-2020. METHODS: Analysis was conducted using the Centers for Disease Control and Prevention or published annual population-based varicella incidence, and varicella-associated hospitalization, outpatient visit, and mortality rates in the US population aged 0-49 years during 1996-2020 (range, 199.5-214.2 million persons) compared to before vaccination (1990-1994). Disease costs were estimated using the societal perspective. Vaccination program costs included costs of vaccine, administration, postvaccination adverse events, and travel and work time lost to obtain vaccination. All costs were adjusted to 2020 US dollars using a 3% annual discount rate. The main outcome measures were the number of varicella-associated cases, hospitalizations, hospitalization days, and premature deaths prevented; life-years saved; and net societal savings from the US varicella vaccination program. RESULTS: Among US persons aged 0-49 years, during 1996-2020, it is estimated that more than 91 million varicella cases, 238 000 hospitalizations, 1.1 million hospitalization days, and almost 2000 deaths were prevented and 118 000 life-years were saved by the varicella vaccination program, at net societal savings of $23.4 billion. CONCLUSIONS: Varicella vaccination has resulted in substantial disease prevention and societal savings for the US over 25 years of program implementation.

Celebrating 25 Years of Varicella Vaccination Coverage for Children and Adolescents in the United States: A Success Story.

Tracking vaccination coverage is a critical component of monitoring a vaccine program. Three different surveillance systems were used to examine trends in varicella vaccination coverage during the United States vaccination program: National Immunization Survey-Child, National Immunization Survey-Teen, and immunization information systems (IISs). The relationship of these trends to school requirements and disease decline was also examined. Among children aged 19-35 months, ≥1 dose of varicella vaccine increased from 16.0% in 1996 to 89.2% by the end of the 1-dose program in 2006, stabilizing around at least 90.0% thereafter. The uptake of the second dose was rapid after the 2007 recommendation. Two-dose coverage among children aged 7 years at 6 high-performing IIS sites increased from 2.6%-5.5% in 2006 to 86.0%-100.0% in 2020. Among adolescents aged 13-17 years, ≥2-dose coverage increased from 4.1% in 2006 to 91.9% in 2020. The proportion of adolescents with history of varicella disease declined from 69.9% in 2006 to 8.4% in 2020. In 2006, 92% of states and the District of Columbia (DC) had 1-dose daycare or school entry requirements; 88% of states and DC had 2-dose school entry requirements in the 2020-2021 school year. The successes in attaining and maintaining high vaccine coverage were paramount in the dramatic reduction of the varicella burden in the United States over the 25 years of the vaccination program, but opportunities remain to further increase coverage and decrease varicella morbidity and mortality.

Changing Epidemiology of Varicella Outbreaks in the United States During the Varicella Vaccination Program, 1995-2019.

We describe the changing epidemiology of varicella outbreaks informed by past and current active and passive surveillance in the United States by reviewing data published during 1995-2015 and analyzing new data from 2016 to 2019. Varicella outbreaks were defined as ≥5 varicella cases within 1 setting and ≥1 incubation period. During the 1-dose varicella vaccination program (1995‒2006), the number of varicella outbreaks declined by 80% (2003-2006 vs 1995-1998) in 1 active surveillance area where vaccination coverage reached 90.5% in 2006. During the 2-dose program, in 7 states with consistent reporting to the Centers for Disease Control and Prevention, the number of outbreaks declined by 82% (2016-2019 vs 2005-2006). Over the entire program (1995-2019), outbreak size and duration declined from a median of 15 cases/outbreak and 45 days duration to 7 cases and 30 days duration. The proportion of outbreaks with <10 cases increased from 28% to 73%. During 2016‒2019, most (79%) outbreak cases occurred among unvaccinated or partially vaccinated persons eligible for second-dose vaccination, highlighting the potential for further varicella control.

Diagnostic and Immunologic Testing for Varicella in the Era of High-Impact Varicella Vaccination: An Evolving Problem.

The clinical presentation of varicella in unvaccinated persons, with skin vesicles and scabs, has facilitated the use of rapid diagnostic methods for confirming disease. Polymerase chain reaction (PCR) assays are the diagnostic method of choice. The sharp decline in unmodified cases of varicella due to the US varicella vaccination program has led to fewer healthcare providers being familiar with varicella presentation and an increased reliance on laboratory diagnosis to confirm suspected cases. The mild, atypical presentation of the disease in vaccinated persons (fewer skin lesions, mostly maculopapular) has made it more challenging for providers to recognize and also to collect samples to detect the virus. Nonetheless, PCR is highly sensitive and specific in confirming modified disease if adequate samples are provided. While a positive PCR result is confirmatory, interpreting a negative result can prove to be more challenging in determining whether suspected varicella is falsely negative or attributable to other causes. Enhanced education of healthcare providers is critical for adequate specimen collection from modified varicella cases. In addition, more sensitive commercial serologic assays are needed in the United States for varicella immunity testing in the vaccine era.

Decline in Severe Varicella Disease During the United States Varicella Vaccination Program: Hospitalizations and Deaths, 1990-2019.

To describe the impact of the US varicella vaccination program on severe varicella outcomes, we analyzed varicella hospitalizations using the National Inpatient Sample 1993-2019 and varicella deaths using the National Center for Health Statistics data 1990-2019. Over 25 years of vaccination program (1995-2019), varicella hospitalizations, and deaths declined 94% and 97%, respectively, among persons aged <50 years. Most of the decline (∼90%) occurred during the 1-dose period (through 2006/2007) by attaining and maintaining high vaccination coverage; additional declines occurred during the 2-dose period, especially in the age groups covered by the 2-dose recommendation. The greatest decline for both hospitalizations and deaths (97% and >99%, respectively) was among persons aged <20 years, born during the varicella vaccination program. In the <20 age group, varicella hospitalization has become a rare event, and varicella deaths have been practically eliminated in the United States. A total of >10 500 varicella hospitalizations and 100 varicella deaths are now prevented annually in the United States as a direct result of vaccination and reduction in varicella-zoster virus circulation.

Merck/Centers for Disease Control and Prevention Varicella Vaccine Pregnancy Registry: 19-Year Summary of Data From Inception Through Closure, 1995-2013.

BACKGROUND: The VARIVAX® Pregnancy Registry was established in 1995 to monitor pregnancy outcomes of women who received varicella vaccine (ie, VARIVAX) inadvertently while pregnant. METHODS: Health care providers and consumers sent voluntary reports about women who received VARIVAX 3 months before or during pregnancy. Follow-up occurred to evaluate pregnancy outcomes for birth defects. Outcomes from prospectively reported pregnancy exposures (ie, reports received before the outcome of the pregnancy was known) among varicella-zoster virus (VZV)-seronegative women were used to calculate rates and 95% confidence intervals (CIs). RESULTS: From 17 March 1995 through 16 October 2013, 1601 women were enrolled-966 prospectively-among whom there were 819 live births. Among 164 infants born to women who were VZV seronegative at the time of vaccination, no cases of congenital varicella syndrome (CVS) were identified (rate, 0 per 100, 95% CI, 0.0-2.2) and the birth prevalence of major birth defects was 4.3 per 100 liveborn infants (95% CI 1.7-8.6) with no pattern suggestive of CVS. No defects consistent with CVS were identified in any registry reports. CONCLUSIONS: Data collected through the VARIVAX pregnancy registry do not support a relationship between the occurrence of CVS or major birth defects and varicella vaccine exposure during pregnancy, although the small numbers of exposures cannot rule out a low risk. VARIVAX remains contraindicated during pregnancy.

Monitoring Varicella Vaccine Impact on Varicella Incidence in the United States: Surveillance Challenges and Changing Epidemiology, 1995-2019.

Surveillance is critical for monitoring vaccine impact. Varicella surveillance challenges predated varicella vaccine US licensure in 1995. Several interim steps were needed before case-based surveillance could be established in most states, and both active and passive surveillance was needed to document the vaccination program's impact on varicella incidence. By the end of the 1-dose program in 2005, incidence had declined 90% in the active surveillance areas, with significant declines occurring in all age groups within 5 years of program implementation. Additional declines occurred during the 2-dose program leading to >97% decline in incidence over the 25 years of program implementation through 2019, based on data from 4 states with continuous passive reporting. Surveillance showed that declines were highest among children and adolescents covered by the routine vaccination recommendations but occurred in all age groups. Although surveillance systems changed and were adapted to reflect evolving epidemiology, data consistently demonstrated decreasing varicella incidence following the vaccination program implementation. The vaccination program dramatically decreased virus circulation and increased community protection. Continued and improved varicella surveillance is needed to accurately monitor disease epidemiology and further guide prevention efforts.

Clinical Manifestations of Varicella: Disease Is Largely Forgotten, but It's Not Gone.

After 25 years of varicella vaccination in the United States, classic varicella and its complications have become an uncommon occurrence. The clinical manifestation of varicella among vaccinated persons is usually modified, with fewer skin lesions, mostly maculopapular, and milder presentation. However, the potential for severe manifestations from varicella still exists among both vaccinated and unvaccinated persons, and thus healthcare providers should keep varicella in the differential diagnosis of a maculopapular or vesicular rash. The prompt recognition and diagnosis of varicella is important because when confirmed, clinical and public health measures need to be taken swiftly.

The Impact of Universal Varicella Vaccination on Herpes Zoster Incidence in the United States: Comparison of Birth Cohorts Preceding and Following Varicella Vaccination Program Launch.

When the US varicella vaccination program was introduced in 1995, its impacts on the epidemiology of herpes zoster (HZ) were not precisely known. We used a large claims database to examine HZ incidence in the US during 1998-2019 among persons aged ≥30 years (the prevaccine cohort, born before 1990), and aged 1-29 years (includes the postvaccine cohort, born since 1990). We defined incident HZ as the first instance of an outpatient or emergency department (ED) claim with an HZ diagnostic code. Additionally, we examined the proportion of HZ visits among all ED visits as a complementary method to assess for healthcare-seeking artifacts in the findings. In persons aged ≥30 years (prevaccine cohort), we observed age-specific increases in HZ incidence during the earlier study years, with decelerations in later years, starting in 2007 with oldest age groups. Similar patterns were seen when we examined HZ visits as a proportion of all ED visits. For persons aged 1-29 years, age-specific HZ incidence increased early in the study period for the oldest age groups who were born prevaccine, but later declined in a stepwise pattern once each age group was comprised of persons born in the postvaccine period. Our results, corroborated with previously published studies, do not support prior modeling predictions that the varicella vaccination program would increase HZ incidence among adult cohorts who previously experienced varicella. Our findings also suggest that continued declines in age-specific HZ incidence as varicella-vaccinated cohorts age are likely.

Public Health Actions to Control Measles Among Afghan Evacuees During Operation Allies Welcome - United States, September-November 2021.

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).

Mumps in Vaccinated Children and Adolescents: 2007-2019.

BACKGROUND: Despite a >99% reduction in US mumps cases after the introduction of mumps vaccine in 1967, outbreaks have occurred in schools and other settings involving vaccinated children and adolescents since 2006. METHODS: We analyzed mumps cases reported by US health departments to the National Notifiable Diseases Surveillance System. We present the incidence and vaccination status of pediatric cases (age <18 years) during 2007-2019 and describe demographic, clinical, and vaccination characteristics of pediatric cases reported during the most recent resurgence in 2015-2019. RESULTS: During 2007-2019, 9172 pediatric cases were reported, accounting for a median of 32% of all cases reported each year (range: 13%-59%). A median of 87% (range: 81%-94%) of pediatric patients each year had previously received ≥1 measles, mumps, and rubella (MMR) vaccine dose. During 2015-2019, of 5461 pediatric cases reported, only 2% of those with known import status (74%) were associated with international travel. One percent of patients had complications and 2% were hospitalized. Among patients aged ≥1 year with known vaccination status (72%), 74% of 1- to 4-year-olds had received ≥1 MMR dose and 86% of 5- to 17-year-olds had received ≥2 MMR doses. Since 2016, pediatric mumps cases have been reported in most US states each year (range: 38-45 states). CONCLUSIONS: Since 2007, one-third of US reported mumps cases occurred in children and adolescents, the majority of whom were vaccinated. Clinicians should suspect mumps in patients with parotitis or mumps complications, regardless of age, travel history, and vaccination status.