A measles and rubella vaccine microneedle patch in The Gambia: a phase 1/2, double-blind, double-dummy, randomised, active-controlled, age de-escalation trial.

BACKGROUND: Microneedle patches (MNPs) have been ranked as the highest global priority innovation for overcoming immunisation barriers in low-income and middle-income countries. This trial aimed to provide the first data on the tolerability, safety, and immunogenicity of a measles and rubella vaccine (MRV)-MNP in children. METHODS: This single-centre, phase 1/2, double-blind, double-dummy, randomised, active-controlled, age de-escalation trial was conducted in The Gambia. To be eligible, all participants had to be healthy according to prespecified criteria, aged 18-40 years for the adult cohort, 15-18 months for toddlers, or 9-10 months for infants, and to be available for visits throughout the follow-up period. The three age cohorts were randomly assigned in a 2:1 ratio (adults) or 1:1 ratio (toddlers and infants) to receive either an MRV-MNP (Micron Biomedical, Atlanta, GA, USA) and a placebo (0·9% sodium chloride) subcutaneous injection, or a placebo-MNP and an MRV subcutaneous injection (MRV-SC; Serum Institute of India, Pune, India). Unmasked staff ransomly assigned the participants using an online application, and they prepared visually identical preparations of the MRV-MNP or placebo-MNP and MRV-SC or placebo-SC, but were not involved in collecting endpoint data. Staff administering the study interventions, participants, parents, and study staff assessing trial endpoints were masked to treatment allocation. The safety population consists of all vaccinated participants, and analysis was conducted according to route of MRV administration, irrespective of subsequent protocol deviations. The immunogenicity population consisted of all vaccinated participants who had a baseline and day 42 visit result available, and who had no protocol deviations considered to substantially affect the immunogenicity endpoints. Solicited local and systemic adverse events were collected for 14 days following vaccination. Unsolicited adverse events were collected to day 180. Age de-escalation between cohorts was based on the review of the safety data to day 14 by an independent data monitoring committee. Serum neutralising antibodies to measles and rubella were measured at baseline, day 42, and day 180. Analysis was descriptive and included safety events, seroprotection and seroconversion rates, and geometric mean antibody concentrations. The trial was registered with the Pan African Clinical Trials Registry PACTR202008836432905, and is complete. FINDINGS: Recruitment took place between May 18, 2021, and May 27, 2022. 45 adults, 120 toddlers, and 120 infants were randomly allocated and vaccinated. There were no safety concerns in the first 14 days following vaccination in either adults or toddlers, and age de-escalation proceeded accordingly. In infants, 93% (52/56; 95% CI 83·0-97·2) seroconverted to measles and 100% (58/58; 93·8-100) seroconverted to rubella following MRV-MNP administration, while 90% (52/58; 79·2-95·2) and 100% (59/59; 93·9-100) seroconverted to measles and rubella respectively, following MRV-SC. Induration at the MRV-MNP application site was the most frequent local reaction occurring in 46 (77%) of 60 toddlers and 39 (65%) of 60 infants. Related unsolicited adverse events, most commonly discolouration at the application site, were reported in 35 (58%) of 60 toddlers and 57 (95%) of 60 infants that had received the MRV-MNP. All local reactions were mild. There were no related severe or serious adverse events. INTERPRETATION: The safety and immunogenicity data support the accelerated development of the MRV-MNP. FUNDING: Bill & Melinda Gates Foundation.

Lessons learnt from the applying the Centers for Disease Control and Prevention (CDC) evaluation framework to the measles incident management system response, USA, 2020-2021.

The functionality and performance of public health programmes at all levels of government play a critical role in preventing, detecting, mitigating and responding to public health threats, including infectious disease outbreaks. Multiple and concurrent outbreaks in recent years, such as COVID-19, Ebola and Zika, have highlighted the importance of documenting lessons learnt from public health responses of national and global agencies. In February 2020, the US Centers for Disease Control and Prevention (CDC) Center for Global Health (CGH) activated the Measles Incident Management System (MIMS) to accelerate the ability to detect, mitigate and respond to measles outbreaks globally and advance progress towards regional measles elimination goals. The activation was triggered by a global resurgence in reported measles cases during 2018-2019 and supported emergency response activities conducted by partner organisations and countries. MIMS leadership decided early in the response to form an evaluation team to design and implement an evaluation approach for producing real-time data to document progress of response activities and inform timely decision-making. In this manuscript, we describe how establishing an evaluation unit within MIMS, and engaging MIMS leadership and subject matter experts in the evaluation activities, was critical to monitor progress and document lessons learnt to inform decision making. We also explain the CDC's Framework for Evaluation in Public Health Practice applied to evaluate the dynamic events throughout the MIMS response. Evaluators supporting emergency response should use a flexible framework that can be adaptable in dynamic contexts and document response activities in real-time.

Study protocol for a phase 1/2, single-centre, double-blind, double-dummy, randomized, active-controlled, age de-escalation trial to assess the safety, tolerability and immunogenicity of a measles and rubella vaccine delivered by a microneedle patch in healthy adults (18 to 40 years), measles and rubella vaccine-primed toddlers (15 to 18 months) and measles and rubella vaccine-naïve infants (9 to 10 months) in The Gambia [Measles and Rubella Vaccine Microneedle Patch Phase 1/2 Age De-escalation Trial].

BACKGROUND: New strategies to increase measles and rubella vaccine coverage, particularly in low- and middle-income countries, are needed if elimination goals are to be achieved. With this regard, measles and rubella vaccine microneedle patches (MRV-MNP), in which the vaccine is embedded in dissolving microneedles, offer several potential advantages over subcutaneous delivery. These include ease of administration, increased thermostability, an absence of sharps waste, reduced overall costs and pain-free administration. This trial will provide the first clinical trial data on MRV-MNP use and the first clinical vaccine trial of MNP technology in children and infants. METHODS: This is a phase 1/2, randomized, active-controlled, double-blind, double-dummy, age de-escalation trial. Based on the defined eligibility criteria for the trial, including screening laboratory investigations, 45 adults [18-40 years] followed by 120 toddlers [15-18 months] and 120 infants [9-10 months] will be enrolled in series. To allow double-blinding, participants will receive either the MRV-MNP and a placebo (0.9% sodium chloride) subcutaneous (SC) injection or a placebo MNP and the MRV by SC injection (MRV-SC). Local and systemic adverse event data will be collected for 14 days following study product administration. Safety laboratories will be repeated on day 7 and, in the adult cohort alone, on day 14. Unsolicited adverse events including serious adverse events will be collected until the final study visit for each participant on day 180. Measles and rubella serum neutralizing antibodies will be measured at baseline, on day 42 and on day 180. Cohort progression will be dependent on review of the unblinded safety data by an independent data monitoring committee. DISCUSSION: This trial will provide the first clinical data on the use of a MNP to deliver the MRV and the first data on the use of MNPs in a paediatric population. It will guide future product development decisions for what may be a key technology for future measles and rubella elimination. TRIAL REGISTRATION: Pan-African Clinical Trials Registry 202008836432905 . CLINICALTRIALS: gov NCT04394689.

Innovations in vaccine delivery: increasing access, coverage, and equity and lessons learnt from measles and rubella elimination.

Disease eradication and elimination programs drive innovations based on progress toward measurable objectives, evaluations of new strategies and methods, programmatic experiences, and lessons learned from the field. Following progress toward global measles elimination, reducing measles mortality, and increasing introductions of measles and rubella vaccines to national programs, the measles and rubella immunization program has faced setbacks in recent years. Currently available vaccine delivery methods have complicated logistics and drawbacks that create barriers to vaccination; innovations for easier, more efficient, and safer vaccine delivery are needed. Progress can be accelerated by new technologies like microarray patches (MAPs) that are now widely recognized as a potential new tool for enhancing global immunizations efforts. Clinical trials of measles-rubella vaccine MAPs have begun, and several other vaccine MAPs are in the pre-clinical development pathway. MAPs could significantly contribute to Immunization Agenda 2030 priorities, including reaching zero-dose children; increasing vaccine access, demand, coverage, and equity; and achieving measles and rubella elimination. With strong partnerships between public health agencies and biotechnology companies, translational novel vaccine delivery systems can be developed to help solve public health problems and achieve global health priorities.

Measles in the 21st Century: Progress Toward Achieving and Sustaining Elimination.

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 vaccination. 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.

Development of a Measles and Rubella Multiplex Bead Serological Assay for Assessing Population Immunity.

Serosurveys are important tools for estimating population immunity and providing immunization activity guidance. The measles and rubella multiplex bead assay (MBA) offers multiple advantages over standard serological assays and was validated by comparison with the enzyme-linked immunosorbent assay (ELISA) and the measles plaque reduction neutralization (PRN) assay. Results from a laboratory-produced purified measles virus whole-virus antigen MBA (MeV WVAL) correlated better with ELISA and PRN than results from the baculovirus-expressed measles nucleoprotein (N) MBA. Therefore, a commercially produced whole-virus antigen (MeV WVAC) was evaluated. Serum IgG antibody concentrations correlated significantly with a strong linear relationship between the MeV WVAC and MeV WVAL MBAs (R = 0.962 and R2 = 0.926). IgG concentrations from the MeV WVAC MBA showed strong correlation with PRN titers (R = 0.846), with a linear relationship comparable to values obtained with the MeV WVAL MBA and PRN assay (R2 = 0.716 and R2 = 0.768, respectively). Receiver operating characteristic (ROC) curve analysis of the MeV WVAC using PRN titer as the comparator resulted in a seroprotection cutoff of 153 mIU/ml, similar to the established correlate of protection of 120 mIU/ml, with a sensitivity of 98% and a specificity of 83%. IgG concentrations correlated strongly between the rubella WVA MBA and ELISA (R = 0.959 and R2 = 0.919). ROC analysis of the rubella MBA using ELISA as the comparator yielded a cutoff of 9.36 IU/ml, similar to the accepted cutoff of 10 IU/ml for seroprotection, with a sensitivity of 99% and a specificity of 100%. These results support use of the MBA for multiantigen serosurveys assessing measles and rubella population immunity.

Progress Toward Regional Measles Elimination - Worldwide, 2000-2019.

In 2010, the World Health Assembly (WHA) set the following three milestones for measles control to be achieved by 2015: 1) increase routine coverage with the first dose of 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 1 million population, and 3) reduce global measles mortality by 95% from the 2000 estimate* (1). In 2012, WHA endorsed the Global Vaccine Action Plan,† with the objective of eliminating measles§ in five of the six World Health Organization (WHO) regions by 2020. This report describes progress toward WHA milestones and regional measles elimination during 2000-2019 and updates a previous report (2). During 2000-2010, estimated MCV1 coverage increased globally from 72% to 84% but has since plateaued at 84%-85%. All countries conducted measles surveillance; however, approximately half did not achieve the sensitivity indicator target of two or more discarded measles and rubella cases per 100,000 population. Annual reported measles incidence decreased 88%, from 145 to 18 cases per 1 million population during 2000-2016; the lowest incidence occurred in 2016, but by 2019 incidence had risen to 120 cases per 1 million population. During 2000-2019, the annual number of estimated measles deaths decreased 62%, from 539,000 to 207,500; an estimated 25.5 million measles deaths were averted. To drive progress toward the regional measles elimination targets, additional strategies are needed to help countries reach all children with 2 doses of measles-containing vaccine, identify and close immunity gaps, and improve surveillance.

A microneedle patch for measles and rubella vaccination: a game changer for achieving elimination.

While morbidity and mortality associated with measles and rubella (MR) have dramatically decreased, there are still >100000 estimated deaths due to measles and an estimated 100000 infants born with congenital rubella syndrome annually. Given highly effective MR vaccines, the primary barrier to global elimination of these diseases is low vaccination coverage, especially among the most underserved populations in resource-limited settings. In contrast to conventional MR vaccination by hypodermic injection, microneedle patches are being developed to enable MR vaccination by minimally trained personnel. Simplified supply chain, reduced need for cold chain storage, elimination of vaccine reconstitution, no sharps waste, reduced vaccine wastage, and reduced total system cost of vaccination are advantages of this approach. Preclinical work to develop a MR vaccine patch has proceeded through successful immunization studies in rodents and non-human primates. On-going programs seek to make MR vaccine patches available to support MR elimination efforts around the world.

Recent setbacks in measles elimination: the importance of investing in innovations for immunizations.

The recent setbacks in efforts to achieve measles elimination goals are alarming. To reverse the current trends, it is imperative that the global health community urgently intensify efforts and make resource commitments to implement evidence-based elimination strategies fully, including supporting research and innovations. The Immunization Agenda 2030: A Global Strategy to Leave No One Behind (IA2030) is the new global guidance document that builds on lessons learned and progress made toward the GVAP goals, includes research and innovation as a core strategic priority, and identifies measles as a "tracer" for improving immunisation services and strengthening primary health care systems. To achieve vaccination coverage and equity targets that leave no one behind, and accelerate progress toward disease eradication and elimination goals, sustained and predictable investments are needed for the identified research and innovations priorities for the new decade.

Progress Toward Measles Elimination - Eastern Mediterranean Region, 2013-2019.

In 1997, during the 41st session of the Regional Committee for the Eastern Mediterranean, the 21 countries in the World Health Organization (WHO) Eastern Mediterranean Region* (EMR) passed a resolution to eliminate† measles (1). In 2015, this goal was included as a priority in the Eastern Mediterranean Vaccine Action Plan 2016-2020 (EMVAP) (2), endorsed at the 62nd session of the Regional Committee (3). To achieve this goal, the WHO Regional Office for the Eastern Mediterranean developed a four-pronged strategy: 1) achieve ≥95% vaccination coverage with the first dose of measles-containing vaccine (MCV1) among children in every district of each country through routine immunization services; 2) achieve ≥95% vaccination coverage with a second MCV dose (MCV2) in every district of each country either through implementation of a routine 2-dose vaccination schedule or through supplementary immunization activities§ (SIAs); 3) conduct high-quality, case-based surveillance in all countries; and 4) provide optimal measles clinical case management, including dietary supplementation with vitamin A (4). This report describes progress toward measles elimination in EMR during 2013-2019 and updates a previous report (5). Estimated MCV1 coverage increased from 79% in 2013 to 82% in 2018. MCV2 coverage increased from 59% in 2013 to 74% in 2018. In addition, during 2013-2019, approximately 326.4 million children received MCV during SIAs. Reported confirmed measles incidence increased from 33.5 per 1 million persons in 2013 to 91.2 in 2018, with large outbreaks occurring in Pakistan, Somalia, and Yemen; incidence decreased to 23.3 in 2019. In 2019, the rate of discarded nonmeasles cases¶ was 5.4 per 100,000 population. To achieve measles elimination in the EMR, increased visibility of efforts to achieve the measles elimination goal is critically needed, as are sustained and predictable investments to increase MCV1 and MCV2 coverage, conduct high-quality SIAs, and reach populations at risk for not accessing immunization services or living in areas with civil strife.

The potential role of using vaccine patches to induce immunity: platform and pathways to innovation and commercialization.

Introduction: In the last two decades, the evidence related to using vaccine patches with multiple short projections (≤1 mm) to deliver vaccines through the skin increased significantly and demonstrated their potential as an innovative delivery platform.Areas covered: We review the vaccine patch literature published in English as of 1 March 2019, as well as available information from key stakeholders related to vaccine patches as a platform. We identify key research topics related to basic and translational science on skin physical properties and immunobiology, patch development, and vaccine manufacturing.Expert opinion: Currently, vaccine patch developers continue to address some basic science and other platform issues in the context of developing a potential vaccine patch presentation for an existing or new vaccine. Additional clinical data and manufacturing experience could shift the balance toward incentivizing existing vaccine manufactures to further explore the use of vaccine patches to deliver their products. Incentives for innovation of vaccine patches differ for developed and developing countries, which will necessitate different strategies (e.g. public-private partnerships, push, or pull mechanisms) to support the basic and applied research needed to ensure a strong evidence base and to overcome translational barriers for vaccine patches as a delivery platform.

Progress Toward Regional Measles Elimination - Worldwide, 2000-2018.

In 2010, the World Health Assembly (WHA) set the following three milestones for measles control to be achieved by 2015: 1) increase routine coverage with the first dose of 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 less than five cases per 1 million population, and 3) reduce global measles mortality by 95% from the 2000 estimate* (1). In 2012, WHA endorsed the Global Vaccine Action Plan,† with the objective of eliminating measles§ in five of the six World Health Organization (WHO) regions by 2020. This report updates a previous report (2) and describes progress toward WHA milestones and regional measles elimination during 2000-2018. During 2000-2018, estimated MCV1 coverage increased globally from 72% to 86%; annual reported measles incidence decreased 66%, from 145 to 49 cases per 1 million population; and annual estimated measles deaths decreased 73%, from 535,600 to 142,300. During 2000-2018, measles vaccination averted an estimated 23.2 million deaths. However, the number of measles cases in 2018 increased 167% globally compared with 2016, and estimated global measles mortality has increased since 2017. To continue progress toward the regional measles elimination targets, resource commitments are needed to strengthen routine immunization systems, close historical immunity gaps, and improve surveillance. To achieve measles elimination, all communities and countries need coordinated efforts aiming to reach ≥95% coverage with 2 doses of measles vaccine (3).

Progress Toward Measles Elimination - China, January 2013-June 2019.

In 2005, the World Health Organization (WHO) Western Pacific Region countries, including China, resolved to eliminate measles by 2012 or as soon as feasible thereafter (1). As of 2018, nine* of the 37 Western Pacific Region countries or areas† had eliminated§ measles. China's Measles Elimination Action Plan 2006-2012 included strengthening routine immunization; conducting measles risk assessments, followed by supplementary immunization activities (SIAs) with measles-containing vaccine (MCV) at national and subnational levels; strengthening surveillance and laboratory capacity; and investigating and responding to measles outbreaks. Most recently, progress toward measles elimination in China was described in a 2014 report documenting measles elimination efforts in China during 2008-2012 and a resurgence in 2013 (2). This report describes progress toward measles elimination in China during January 2013-June 2019.¶ Measles incidence per million persons decreased from 20.4 in 2013 to 2.8 in 2018; reported measles-related deaths decreased from 32 in 2015 to one in 2018 and no deaths in 2019 through June. Measles elimination in China can be achieved through strengthening the immunization program's existing strategy by ensuring sufficient vaccine supply; continuing to improve laboratory-supported surveillance, outbreak investigation and response; strengthening school entry vaccination record checks; vaccinating students who do not have documentation of receipt of 2 doses of measles-rubella vaccine; and vaccinating health care professionals and other adults at risk for measles.

Preoptic Area Activation and Vasotocin Involvement in the Reproductive Behavior of a Weakly Pulse-Type Electric Fish, Brachyhypopomus gauderio.

Social behavior exhibits a wide diversity among vertebrates though it is controlled by a conserved neural network, the social behavior network (SBN). The activity of the SBN is shaped by hypothalamic nonapeptides of the vasopressin-oxytocin family. The weakly electric fish Brachyhypopomus gauderio emits social electrical signals during courtship. Three types of vasotocin (AVT) cells occur in the preoptic area (POA), one of the SBN nodes. In this study, we aimed to test if POA neurons of the nucleus preopticus ventricularis anterior (PPa) and posterior (PPp), and in particular AVT+ cells, were activated by social stimuli using a 2-day behavioral protocol. During the first night, male-female dyads were recorded to identify courting males. During the second night, these males were divided in two experimental conditions: isolated and social (male with a female). Both AVT cells and the cellular activation of the POA neurons (measured by FOS) were identified. We found that the PPa of social males showed more FOS+ cells than the PPa of isolated males, and that the PPa had more AVT+ cells in social males than in isolated males. The double-immunolabeling for AVT and FOS indicated the activation of AVT+ neurons. No significant differences in the activation of AVT+ cells were found between conditions, but a clear association was observed between the number of AVT+ cells and certain behavioral traits. In addition, a different activation of AVT+ cell-types was observed for social vs. isolated males. We conclude that the POA of B. gauderio exhibits changes induced by social stimuli in reproductive context, involving an increase in AVT production and a different profile activation among AVT+ cell populations.

Genetic Characterization of Measles and Rubella Viruses Detected Through Global Measles and Rubella Elimination Surveillance, 2016-2018.

All six World Health Organization (WHO) regions have established measles elimination goals, and three regions have a rubella elimination goal. Each region has established a regional verification commission to monitor progress toward measles elimination, rubella elimination, or both, and to provide verification of elimination* (1,2). To verify elimination, high-quality case-based surveillance is essential, including laboratory confirmation of suspected cases and genotyping of viruses from confirmed cases to track transmission pathways. In 2000, WHO established the Global Measles and Rubella Laboratory Network (GMRLN) to provide high-quality laboratory support for surveillance for measles, rubella, and congenital rubella syndrome (3). GMRLN is the largest globally coordinated laboratory network, with 704 laboratories supporting surveillance in 191 countries (4). This report updates a previous report and describes the genetic characterization of measles and rubella viruses during 2016-2018 (5). The genetic diversity of measles viruses (MeVs) and rubella viruses (RuVs) has decreased globally following implementation of measles and rubella elimination strategies. Among 10,857 MeV sequences reported to the global Measles Nucleotide Surveillance (MeaNS) database during 2016-2018, the number of MeV genotypes detected in ongoing transmission decreased from six in 2016 to four in 2018. Among the 1,296 RuV sequences submitted to the global Rubella Nucleotide Surveillance (RubeNS) database during the same period, the number of RuV genotypes detected decreased from five in 2016 to two in 2018. To strengthen laboratory surveillance for measles and rubella elimination, specimens should be collected from all confirmed cases for genotyping, and sequences from all wild-type measles and rubella viruses should be submitted to MeaNS and RubeNS in a timely manner.

Progress Toward Measles Elimination - Pakistan, 2000-2018.

In 1997, the 21 countries in the World Health Organization (WHO) Eastern Mediterranean Region* (EMR) passed a resolution during the 41st session of the Regional Committee for the Eastern Mediterranean to eliminate measles† (1). In 2015, this goal was included as a priority in the Eastern Mediterranean Vaccine Action Plan 2016-2020 (2), approved at the 62nd session of the Regional Committee (3). To achieve measles elimination, the WHO Regional Office for the Eastern Mediterranean developed the following four-pronged strategy: 1) achieve ≥95% vaccination coverage with the first dose of measles-containing vaccine (MCV) among children in every district of each country through routine immunization services; 2) achieve ≥95% vaccination coverage with a second MCV dose in every district of each country either through implementation of a routine 2-dose vaccination schedule or through supplementary immunization activities (SIAs)§; 3) conduct high-quality, case-based measles surveillance in all countries; and 4) provide optimal measles clinical case management, including dietary supplementation with vitamin A (4). Pakistan, an EMR country with a population of approximately 200 million, accounts for nearly one third of the overall EMR population. This report describes progress and challenges toward measles elimination in Pakistan during 2000-2018. During the study period, estimated coverage with the first MCV dose (MCV1) increased from 57% in 2000 to 76% in 2017. The second MCV dose (MCV2) was introduced nationwide in 2009, and MCV2 coverage increased from 30% in 2009 to 45% in 2017. During 2000-2018, approximately 232.5 million children received doses of MCV during SIAs. Reported confirmed measles incidence increased from an average of 24.6 per 1 million persons during 2000-2009 to an average of 80.4 during 2010-2018, with peaks in 2013 (230.3) and 2018 (153.6). In 2017 and 2018, the rates of suspected cases discarded as nonmeasles after investigation were 2.1 and 1.5 per 100,000 population, reflecting underreporting of cases. To achieve measles elimination, additional efforts are needed to increase MCV1 and MCV2 coverage, develop strategies to identify and reach communities not accessing immunization services, and increase sensitivity of case-based measles surveillance in all districts.

Progress Toward Measles Elimination - European Region, 2009-2018.

In 2010, all 53 countries* in the World Health Organization (WHO) European Region (EUR) reconfirmed their commitment to eliminating measles and rubella and congenital rubella syndrome (1); this goal was included as a priority in the European Vaccine Action Plan 2015-2020 (2). The WHO-recommended elimination strategies in EUR include 1) achieving and maintaining ≥95% coverage with 2 doses of measles-containing vaccine (MCV) through routine immunization services; 2) providing measles and rubella vaccination opportunities, including supplementary immunization activities (SIAs), to populations susceptible to measles or rubella; 3) strengthening surveillance by conducting case investigations and confirming suspected cases and outbreaks with laboratory results; and 4) improving the availability and use of evidence for the benefits and risks associated with vaccination (3). This report updates a previous report (4) and describes progress toward measles elimination in EUR during 2009-2018. During 2009-2017, estimated regional coverage with the first MCV dose (MCV1) was 93%-95%, and coverage with the second dose (MCV2) increased from 73% to 90%. In 2017, 30 (57%) countries achieved ≥95% MCV1 coverage, and 15 (28%) achieved ≥95% coverage with both doses. During 2009-2018, >16 million persons were vaccinated during SIAs in 13 (24%) countries. Measles incidence declined to 5.8 per 1 million population in 2016, but increased to 89.5 in 2018, because of large outbreaks in several EUR countries. To achieve measles elimination in EUR, measures are needed to strengthen immunization programs by ensuring ≥95% 2-dose MCV coverage in every district of each country, offering supplemental measles vaccination to susceptible adults, maintaining high-quality surveillance for rapid case detection and confirmation, and ensuring effective outbreak preparedness and response.

Evaluating vaccination policies to accelerate measles elimination in China: a meta-population modelling study.

BACKGROUND: Measles is among the most highly infectious human diseases. By virtue of increasingly effective childhood vaccination, together with targeted supplemental immunization activities (SIAs), health authorities in the People's Republic of China have reduced measles' reproduction number from about 18 to 2.3. Despite substantial residual susceptibility among young adults, more in some locales than others, sustained routine childhood immunization likely would eliminate measles eventually. To support global eradication efforts, as well as expedite morbidity and mortality reductions in China, we evaluated alternative SIAs via mechanistic mathematical modelling. METHODS: Our model Chinese population is stratified by immune status (susceptible to measles infection; infected, but not yet infectious; infectious; and recovered or immunized), age (0, 1-4, 5-9, …, 65+ years) and location (31 provinces). Contacts between sub-populations are either empirical or a mixture of preferential and proportionate with respect to age and decline exponentially with distance between locations at age-dependent rates. We estimated initial conditions and most parameters from recent cross-sectional serological surveys, disease surveillance and demographic observations. Then we calculated the reproduction numbers and gradient of the effective number with respect to age- and location-specific immunization rates. We corroborated these analytical results by simulating adolescent and young adult SIAs using a version of our model in which the age-specific contact rates vary seasonally. RESULTS: Whereas the gradient indicates that vaccinating young adults generally is the optimal strategy, simulations indicate that a catch-up campaign among susceptible adolescent schoolchildren would accelerate elimination, with timing dependent on uptake. CONCLUSIONS: These results are largely due to indirect effects (i.e. fewer infections than immunized people might otherwise cause), which meta-population models with realistic mixing are uniquely capable of reproducing accurately.

Increase in Infant Measles Deaths During a Nationwide Measles Outbreak-Mongolia, 2015-2016.

BACKGROUND: Surveillance data from a large measles outbreak in Mongolia suggested increased case fatality ratio (CFR) in the second of 2 waves. To confirm the increase in CFR and identify risk factors for measles death, we enhanced mortality ascertainment and conducted a case-control study among infants hospitalized for measles. METHODS: We linked national vital records with surveillance data of clinically or laboratory-confirmed infant (aged <12 months) measles cases with rash onset during March-September 2015 (wave 1) and October 2015-June 2016 (wave 2). We abstracted medical charts of 95 fatal cases and 273 nonfatal cases hospitalized for measles, matched by age and sex. We calculated adjusted matched odds ratios (amORs) and 95% confidence intervals (CIs) for risk factors. RESULTS: Infant measles deaths increased from 3 among 2224 cases (CFR: 0.13%) in wave 1 to 113 among 4884 cases (CFR: 2.31%) in wave 2 (P < .001). Inpatient admission, 7-21 days before measles rash onset, for pneumonia or influenza (amOR: 4.5; CI, 2.6-8.0), but not other diagnoses, was significantly associated with death. DISCUSSION: Measles infection among children hospitalized with respiratory infections likely increased deaths due to measles during wave 2. Preventing measles virus nosocomial transmission likely decreases measles mortality.