Estimating the future global dose demand for measles-rubella microarray patches.

Background: Progress toward measles and rubella (MR) elimination has stagnated as countries are unable to reach the required 95% vaccine coverage. Microarray patches (MAPs) are anticipated to offer significant programmatic advantages to needle and syringe (N/S) presentation and increase MR vaccination coverage. A demand forecast analysis of the programmatic doses required (PDR) could accelerate MR-MAP development by informing the size and return of the investment required to manufacture MAPs. Methods: Unconstrained global MR-MAP demand for 2030-2040 was estimated for three scenarios, for groups of countries with similar characteristics (archetypes), and four types of uses of MR-MAPs (use cases). The base scenario 1 assumed that MR-MAPs would replace a share of MR doses delivered by N/S, and that MAPs can reach a proportion of previously unimmunised populations. Scenario 2 assumed that MR-MAPs would be piloted in selected countries in each region of the World Health Organization (WHO); and scenario 3 explored introduction of MR-MAPs earlier in countries with the lowest measles vaccine coverage and highest MR disease burden. We conducted sensitivity analyses to measure the impact of data uncertainty. Results: For the base scenario (1), the estimated global PDR for MR-MAPs was forecasted at 30 million doses in 2030 and increased to 220 million doses by 2040. Compared to scenario 1, scenario 2 resulted in an overall decrease in PDR of 18%, and scenario 3 resulted in a 21% increase in PDR between 2030 and 2040. Sensitivity analyses revealed that assumptions around the anticipated reach or coverage of MR-MAPs, particularly in the hard-to-reach and MOV populations, and the market penetration of MR-MAPs significantly impacted the estimated PDR. Conclusions: Significant demand is expected for MR-MAPs between 2030 and 2040, however, efforts are required to address remaining data quality, uncertainties and gaps that underpin the assumptions in this analysis.

Progress Toward Regional Measles Elimination - Worldwide, 2000-2016.

The fourth United Nations Millennium Development Goal, adopted in 2000, set a target to reduce child mortality by two thirds by 2015. One indicator of progress toward this target was measles vaccination coverage (1). In 2010, the World Health Assembly (WHA) set three milestones for measles control by 2015: 1) increase routine coverage with the first dose of a measles-containing vaccine (MCV1) among children aged 1 year to ≥90% at the national level and to ≥80% in every district; 2) reduce global annual measles incidence to <5 cases per million population; and 3) reduce global measles mortality by 95% from the 2000 estimate (2).* In 2012, WHA endorsed the Global Vaccine Action Plan,† with the objective of eliminating measles in four World Health Organization (WHO) regions by 2015 and in five regions by 2020. Countries in all six WHO regions have adopted goals for measles elimination by or before 2020. Measles elimination is defined as the absence of endemic measles virus transmission in a region or other defined geographic area for ≥12 months, in the presence of a high quality surveillance system that meets targets of key performance indicators. This report updates a previous report (3) and describes progress toward global measles control milestones and regional measles elimination goals during 2000-2016. During this period, annual reported measles incidence decreased 87%, from 145 to 19 cases per million persons, and annual estimated measles deaths decreased 84%, from 550,100 to 89,780; measles vaccination prevented an estimated 20.4 million deaths. However, the 2015 milestones have not yet been met; only one WHO region has been verified as having eliminated measles. Improved implementation of elimination strategies by countries and their partners is needed, with focus on increasing vaccination coverage through substantial and sustained additional investments in health systems, strengthening surveillance systems, using surveillance data to drive programmatic actions, securing political commitment, and raising the visibility of measles elimination goals.

Measles Outbreak Associated With Low Vaccine Effectiveness Among Adults in Pohnpei State, Federated States of Micronesia, 2014.

Background. A measles outbreak in Pohnpei State, Federated States of Micronesia in 2014 affected many persons who had received ≥1 dose of measles-containing vaccine (MCV). A mass vaccination campaign targeted persons aged 6 months to 49 years, regardless of prior vaccination. Methods. We evaluated vaccine effectiveness (VE) of MCV by comparing secondary attack rates among vaccinated and unvaccinated contacts after household exposure to measles. Results. Among 318 contacts, VE for precampaign MCV was 23.1% (95% confidence interval [CI], -425 to 87.3) for 1 dose, 63.4% (95% CI, -103 to 90.6) for 2 doses, and 95.9% (95% CI, 45.0 to 100) for 3 doses. Vaccine effectiveness was 78.7% (95% CI, 10.1 to 97.7) for campaign doses received ≥5 days before rash onset in the primary case and 50.4% (95% CI, -52.1 to 87.9) for doses received 4 days before to 3 days after rash onset in the primary case. Vaccine effectiveness for most recent doses received before 2010 ranged from 51% to 57%, but it increased to 84% for second doses received in 2010 or later. Conclusions. Low VE was a major source of measles susceptibility in this outbreak; potential reasons include historical cold chain inadequacies or waning of immunity. Vaccine effectiveness of campaign doses supports rapid implementation of vaccination campaigns in outbreak settings.

Elimination of endemic measles, rubella, and congenital rubella syndrome from the Western hemisphere: the US experience.

IMPORTANCE: To verify the elimination of endemic measles, rubella, and congenital rubella syndrome (CRS) from the Western hemisphere, the Pan American Health Organization requested each member country to compile a national elimination report. The United States documented the elimination of endemic measles in 2000 and of endemic rubella and CRS in 2004. In December 2011, the Centers for Disease Control and Prevention convened an external expert panel to review the evidence and determine whether elimination of endemic measles, rubella, and CRS had been sustained. OBJECTIVE: To review the evidence for sustained elimination of endemic measles, rubella, and CRS from the United States through 2011. DESIGN, SETTING, AND PARTICIPANTS: Review of data for measles from 2001 to 2011 and for rubella and CRS from 2004 to 2011 covering the US resident population and international visitors, including disease epidemiology, importation status of cases, molecular epidemiology, adequacy of surveillance, and population immunity as estimated by national vaccination coverage and serologic surveys. MAIN OUTCOMES AND MEASURES: Annual numbers of measles, rubella, and CRS cases, by importation status, outbreak size, and distribution; proportions of US population seropositive for measles and rubella; and measles-mumps-rubella vaccination coverage levels. RESULTS: Since 2001, US reported measles incidence has remained below 1 case per 1,000,000 population. Since 2004, rubella incidence has been below 1 case per 10,000,000 population, and CRS incidence has been below 1 case per 5,000,000 births. Eighty-eight percent of measles cases and 54% of rubella cases were internationally imported or epidemiologically or virologically linked to importation. The few cases not linked to importation were insufficient to represent endemic transmission. Molecular epidemiology indicated no endemic genotypes. The US surveillance system is adequate to detect endemic measles or rubella. Seroprevalence and vaccination coverage data indicate high levels of population immunity to measles and rubella. CONCLUSIONS AND RELEVANCE: The external expert panel concluded that the elimination of endemic measles, rubella, and CRS from the United States was sustained through 2011. However, international importation continues, and health care providers should suspect measles or rubella in patients with febrile rash illness, especially when associated with international travel or international visitors, and should report suspected cases to the local health department.

Laboratory confirmation of measles in elimination settings: experience from the Republic of the Marshall Islands, 2003.

OBJECTIVE: To highlight the complications involved in interpreting laboratory tests of measles immunoglobulin M (IgM) for confirmation of infection during a measles outbreak in a highly vaccinated population after conducting a mass immunization campaign as a control measure. METHODS: This case study was undertaken in the Republic of the Marshall Islands during a measles outbreak in 2003, when response immunization was conducted. A measles case was defined as fever and rash and one or more of cough, coryza or conjunctivitis. Between 13 July and 7 November 2003, serum samples were obtained from suspected measles cases for serologic testing and nasopharyngeal swabs were taken for viral isolation by reverse transcriptase polymerase chain reaction (RT-PCR). FINDINGS: Specimens were collected from 201 suspected measles cases (19% of total): of the ones that satisfied the clinical case definition, 45% were IgM positive (IgM+) and, of these, 24% had received measles vaccination within the previous 45 days (up to 45 days after vaccination an IgM+ result could be due to either vaccination or wild-type measles infection). The proportion of IgM+ results varied with clinical presentation, the timing of specimen collection and vaccination status. Positive results on RT-PCR occurred in specimens from eight IgM-negative and four IgM+ individuals who had recently been vaccinated. CONCLUSION: During measles outbreaks, limiting IgM testing to individuals who meet the clinical case definition and have not been recently vaccinated allows for measles to be confirmed while conserving resources.

Aerosol measles vaccination in macaques: preclinical studies of immune responses and safety.

The comparative efficacy and safety of measles vaccination via the aerosol route versus subcutaneous injection has not been fully resolved. We vaccinated cynomolgus monkeys (Macaca fascicularis) with the live-attenuated Edmonston-Zagreb measles virus (MV) vaccine and compared different routes of administration in the immunocompetent and the immunocompromised host. Immunogenicity and protective efficacy of aerosol vaccination using devices similar to those previously used in humans were comparable to those in animals vaccinated by injection. No evidence for a safety hazard associated with the route of vaccination was detected. The results of this study support further clinical evaluation of aerosol vaccination for measles.

Measles transmission and vaccine effectiveness during a large outbreak on a densely populated island: implications for vaccination policy.

BACKGROUND: The Republic of the Marshall Islands (RMI) is a South Pacific nation freely associated with the United States. In 2003, the RMI experienced the largest measles outbreak within the United States or its associated areas for more than a decade, although the reported coverage of 1-dose measles-mumps-rubella (MMR) vaccine was 80%-93%. The outbreak ended only after vaccination of >35,000 persons among a population of 51,000. Of outbreak cases, 41% were reported to have been previously vaccinated. We studied measles attack rates in RMI households to assess vaccine effectiveness and patterns of disease transmission. METHODS: For the household secondary attack rate study, households were selected by convenience sampling of outbreak measles cases. The primary case was defined as the first person with measles in a household. Secondary cases were household members with measles onset 7-18 days after the primary case's rash onset. Vaccine effectiveness analysis was limited to children aged 6 months to 14 years, with vaccination status verified against written records. RESULTS: Seventy-two households were included in the study. The median household size was 11 persons, and the median number of persons per room was 5.5. Secondary cases were more likely than primary cases to be infants (46% vs. 13%; P=.03). MMR vaccine effectiveness was 92% (95% confidence interval [CI], 67%-98%) for 1 dose and 95% (95% CI, 82%-98%) for 2 doses. CONCLUSIONS: Measles vaccine effectiveness was high; thus, diminished effectiveness was not the main cause of the outbreak. In communities with high population density and household crowding, very high population immunity is needed to prevent measles outbreaks and to protect infants below the age of vaccination. This may require excellent implementation of a routine 2-dose measles vaccination strategy.

Measles outbreak in the Republic of the Marshall Islands, 2003.

BACKGROUND: Measles is a highly contagious viral infection. Measles transmission can be prevented through high population immunity (>or=95%) achieved by measles vaccination. In the Republic of the Marshall Islands (RMI), no measles cases were reported during 1989-2002; however, a large measles outbreak occurred in 2003. Reported 1-dose measles vaccine coverage among children aged 12-23 months varied widely (52-94%) between 1990 and 2000. METHODS: RMI is a Pacific island nation (1999 population: 50,840). A measles case was defined as fever, rash, and cough, or coryza, or conjunctivitis, in an RMI resident between July 13 and November 7, 2003. A vaccination campaign was used for outbreak control. RESULTS: Of the 826 reported measles cases, 766 (92%) occurred in the capital (Majuro). There were 186 (23%) cases in infants aged <1 year and 309 (37%) of cases in persons aged >or=15 years. The attack rate was highest among infants (Majuro atoll: 213 cases/1,000 infants). Among cases aged 1-14 years, 281 (59%) reported no measles vaccination before July 2003. There were 100 hospitalizations and 3 deaths. The measles H1 genotype was identified. The vaccination campaign resulted in 93% coverage among persons aged 6 months to 40 years. Interpretation Populations without endemic measles transmission can accumulate substantial susceptibility and be at risk for large outbreaks when measles virus is imported. 'Islands' of measles susceptibility may develop in infants, adults, and any groups with low vaccine coverage. To prevent outbreaks, high population immunity must be sustained by maintaining and documenting high vaccine coverage.

A limited measles outbreak in a highly vaccinated US boarding school.

OBJECTIVES: We investigated a measles outbreak that began in March 2003 in a Pennsylvania boarding school with >600 students to identify all cases, including the source; implement outbreak control measures; and evaluate vaccine effectiveness. METHODS: Measles was suspected in any person at the school with a generalized rash and fever during March 21 to May 28, 2003 and investigated with serologic testing. We reviewed vaccination history from school records and conducted a survey to determine country of measles vaccination. Vaccine effectiveness was calculated using the cohort method. RESULTS: We identified 9 laboratory-confirmed cases at the school: 8 students and 1 staff member. Among them, 2 had never received any doses of measles-containing vaccine (MCV), 1 received 1 dose of MCV, and 6 received 2 doses of MCV. Three of the 6 who received 2 doses of MCV received both doses outside the United States. The source case had been infected in Lebanon. Two laboratory-confirmed spread cases were identified in New York City. Measles virus of genotype D4 was isolated in cases from the school and New York City. Of the 663 students in the school, 8 (1.2%) had never received any doses of MCV, 26 (3.9%) had received 1 dose, and 629 (94.9%) had received 2 doses before the outbreak. Vaccine effectiveness among students who had received 2 doses of MCV was 98.6%. However, students who received both doses outside the United States had a higher attack rate (3 of 75) than those who received both doses in the United States (3 of 509; rate ratio: 6.8; 95% confidence interval: 1.4-33.0). CONCLUSIONS: This is the largest measles outbreak to occur in a school in the United States since 1998, but it was limited to only 9 cases in a boarding school with >600 students. The limited extent of this outbreak highlights the high level of population immunity achieved in the United States through widespread implementation of a 2-dose measles-mumps-rubella vaccination strategy in school-aged children. States and schools should continue to enforce strictly the 2-dose measles-mumps-rubella vaccination requirement and, in an outbreak setting, consider revaccinating students who received measles vaccine outside of the United States. Continued vigilance by health care providers is needed to recognize measles cases.

Evolution of measles elimination strategies in the United States.

There have been 3 efforts to eliminate measles from the United States since the introduction of measles vaccine in 1963. To date, 10 major lessons have been learned from elimination efforts. First, elimination requires very high vaccination-coverage levels by age 2 years. Second, school immunization requirements ensure high coverage rates among schoolchildren. Third, a second dose of measles vaccine is needed to achieve satisfactory levels of immunity. Fourth, school immunization requirements can also ensure delivery of a second dose. Fifth, coverage assessment is crucial. Sixth, measles surveillance is critical for developing, evaluating, and refining elimination strategies. Seventh, surveillance requires laboratory backup to confirm a diagnosis. Eighth, tracking measles virus genotypes is critical to determining if an endemic strain is circulating. Ninth, once endemic transmission has been interrupted, internationally imported measles cases will continue and will cause small outbreaks. Tenth, collaborative efforts with other countries are essential to reduce imported measles cases.

Defining and assessing measles elimination goals.

Although 3 of 6 World Health Organization regions have established measles elimination targets, measles elimination goals are not well defined. In general, disease elimination has been defined as the reduction of incidence in a population to zero. However, measles is so contagious that zero incidence is difficult to achieve and sustain because the risk of imported measles remains while measles is endemic in any country. Also, imported cases will occasionally result in short chains of indigenous transmission unless a country achieves 100% immunity. Therefore, the United States currently uses the absence of endemic measles (i.e., no indigenous chains of transmission persisting for >or=1 year) as the programmatic goal for measles elimination. To document the absence of endemic measles in the United States, we compiled information on the epidemiology of measles, genotype distribution, population immunity, and adequacy of measles surveillance. A panel of experts, convened in March 2000 to review the data, concluded that measles is no longer endemic in the United States.

Assessment of the status of measles elimination from reported outbreaks: United States, 1997-1999.

The status of measles elimination is best summarized by evaluation of the effective reproduction number R; maintaining R<1 is necessary and sufficient to achieve elimination. Previously described methods for estimating R from the sizes and durations of chains of measles transmission and the proportion of cases imported were applied to the measles data reported for the United States in 1997-1999. These comprised 338 cases, forming 165 chains of transmission, of which 43 had >1 case. One hundred seven cases were classified as importations. All 3 methods suggested that R was in the range 0.6-0.7. Results were not sensitive to the minimum size and duration of outbreak considered (so long as single-case chains were excluded) or to exclusion of chains without a known imported source. These results demonstrate that susceptibility to measles was beneath the epidemic threshold and that endemic transmission was eliminated.

Measles outbreak epidemiology in the United States, 1993-2001.

To evaluate the extent of measles virus circulation and populations at risk in the United States, we reviewed measles outbreaks during 1993-2001. A total of 120 measles outbreaks, constituting 1804 outbreak-related cases, were reported during this period. The maximum outbreak size decreased from 233 cases in 1993-1995 to 119 cases in 1996-1998 and 15 cases in 1999-2001. The maximum outbreak duration decreased from 127 days in 1993-1995 to 65 days in 1999-2001. The majority of outbreaks resulted from documented spread from an internationally imported case (42%) or had a strain of measles virus not endemic in the United States (12%). Outbreaks in which adults were the predominant age group affected accounted for 35% of all outbreaks, compared with 29% of outbreaks predominantly affecting preschool children, 30% predominantly affecting school-aged children and adolescents, and 6% with no predominant age group. The extremely limited size and duration of measles outbreaks indicates very high population immunity to measles and suggests that measles is no longer endemic in the United States.

International importation of measles virus--United States, 1993-2001.

To determine trends in international importations of measles, data from the National Notifiable Diseases Surveillance System were analyzed. Of the 2632 measles cases reported between 1993 and 2001, 449 cases (17%) were internationally imported. An additional 186 cases (7%) resulted from spread of measles virus from these imported cases, and 388 cases (15%) had virological evidence of importation. The number of imported cases averaged 50 per year (range, 26-79 cases). The proportion of cases imported increased from an average of 14% in 1993-1996 to an average of 35% in 1997-2001. Imported measles cases were acquired in 63 countries, with 6 countries (Japan, Germany, China, the Philippines, Italy, and the United Kingdom) accounting for 44% of all imported cases. Further reduction of measles in the United States requires international cooperation and improved global surveillance and control of measles.

Epidemiology of measles in the United States, 1997-2001.

Of the 540 measles cases (annual incidence, less than 1/million population) reported during 1997-2001 in the United States, 362 (67%) were associated with international importation: 196 imported cases, 138 cases epidemiologically linked to imported cases, and 28 cases associated with an imported measles virus genotype. The remaining 178 (33%) "unknown-source" cases were analyzed as potential evidence of endemic measles transmission. A total of 83 counties (2.6% of the 3140 US counties) in 27 states reported unknown-source cases; 49 counties reported only 1 unknown-source case, and the maximum reported by any county was 10. Nationally, unknown-source cases were reported in 103 of the 260 weeks. The largest unknown-source outbreak included 13 cases and lasted 5 weeks. The rarity of unknown-source cases, wide gaps in geographic and temporal distribution, and the short duration of the longest unknown-source outbreak indicate that endemic transmission of measles was not sustained in the United States during this period.

Acute measles mortality in the United States, 1987-2002.

We used capture-recapture methodology to estimate total deaths and efficiency of reporting for 2 systems. During 1987-1992, there were 165 measles-associated deaths in the multiple-cause mortality database at the National Center for Health Statistics (NCHS) and 184 reported to the measles surveillance system at the National Immunization Program (NIP). We estimated that 259 measles deaths actually occurred; the reporting efficiencies were 64% for the NCHS and 71% for the NIP. Overall the death-to-case ratio was 2.54 and 2.83 deaths/1000 reported cases, using the NCHS and NIP data, respectively. Pneumonia was a complication among 67% of measles-related deaths in the NCHS data and 86% of deaths in the NIP data. Encephalitis was reported in 11% of deaths in both databases. Preexisting conditions related to immune deficiency were reported for 16% of deaths in the NCHS system and 14% in the NIP; the most common was human immunodeficiency virus infection. Overall, 90% of deaths reported to the NIP occurred in persons who had not been vaccinated against measles. During 1993-1999, only 1 acute measles-related death was reported to the NCHS and no deaths were reported to the NIP. This is consistent with the extremely low reported incidence of measles in the United States during these years.

Progress toward implementation of a second-dose measles immunization requirement for all schoolchildren in the United States.

In 1998, the Advisory Committee on Immunization Practices and the American Academy of Pediatrics recommended that states ensure that all children in grades kindergarten through 12 receive 2 doses of measles-mumps-rubella (MMR) vaccine by 2001. In 2000, the National Immunization Program surveyed states, the District of Columbia, and United States territories, commonwealths, and protectorates to assess progress toward this goal. Almost all respondents (53 [98%] of 54) reported a second-dose requirement for entry to elementary school, middle school, or both. By fall of 2001, most (82%) school-aged children in the United States were in grades requiring a second dose of measles vaccine. For 29 responding programs, the requirement did not yet affect all grades. By 2009, 52 of 54 responding programs will require a second dose for all grades. Although not all states have achieved coverage of all schoolchildren with 2 doses of MMR vaccine, most states are well on their way toward this goal.

An economic analysis of the current universal 2-dose measles-mumps-rubella vaccination program in the United States.

To evaluate the economic impact of the current 2-dose measles-mumps-rubella (MMR) vaccination program in the United States, a decision tree-based analysis was conducted with population-based vaccination coverage and disease incidence data. All costs were estimated for a hypothetical US birth cohort of 3803295 infants born in 2001. The 2-dose MMR vaccination program was cost-saving from both the direct cost and societal perspectives compared with the absence of MMR vaccination, with net savings (net present value) from the direct cost and societal perspectives of US dollars 3.5 billion and US dollars 7.6 billion, respectively. The direct and societal benefit-cost ratios for the MMR vaccination program were 14.2 and 26.0. Analysis of the incremental benefit-cost of the second dose showed that direct and societal benefit-cost ratios were 0.31 and 0.49, respectively. Varying the proportion of vaccines purchased and administered in the public versus the private sector had little effect on the results. From both perspectives under even the most conservative assumptions, the national 2-dose MMR vaccination program is highly cost-beneficial and results in substantial cost savings.