Progress Toward Regional Measles Elimination - Worldwide, 2000-2021.

All six World Health Organization (WHO) regions have committed to eliminating measles.* The Immunization Agenda 2021-2030 (IA2030)† aims to achieve the regional targets as a core indicator of impact and positions measles as the tracer of a health system's ability to deliver essential childhood vaccines. IA2030 highlights the importance of ensuring rigorous measles surveillance systems to document immunity gaps and achieve 95% coverage with 2 timely doses of measles-containing vaccine (MCV) among children. This report describes progress toward measles elimination during 2000-2021 and updates a previous report (1). During 2000-2021, estimated global coverage with a first MCV dose (MCV1) increased from 72% to a peak of 86% in 2019, but decreased during the COVID-19 pandemic to 83% in 2020 and to 81% in 2021, the lowest MCV1 coverage recorded since 2008. All countries conducted measles surveillance, but only 47 (35%) of 135 countries reporting discarded cases§ achieved the sensitivity indicator target of two or more discarded cases per 100,000 population in 2021, indicating surveillance system underperformance in certain countries. Annual reported measles incidence decreased 88% during 2000-2016, from 145 to 18 cases per 1 million population, then rebounded to 120 in 2019 during a global resurgence (2), before declining to 21 in 2020 and to 17 in 2021. Large and disruptive outbreaks were reported in 22 countries. During 2000-2021, the annual number of estimated measles deaths decreased 83%, from 761,000 to 128,000; an estimated 56 million measles deaths were averted by vaccination. To regain progress and achieve regional measles elimination targets during and after the COVID-19 pandemic, accelerating targeted efforts is necessary to reach all children with 2 MCV doses while implementing robust surveillance and identifying and closing immunity gaps to prevent cases and outbreaks.

Topology of the U12-U6atac snRNA Complex of the Minor Spliceosome and Binding by NTC-Related Protein RBM22.

Splicing of precursor messenger RNA is catalyzed by the spliceosome, a dynamic ribonucleoprotein assembly including five small nuclear (sn)RNAs and >100 proteins. RNA components catalyze the two transesterification reactions, but proteins perform critical roles in assembly and rearrangement. The catalytic core comprises a paired complex of U2 and U6 snRNAs for the major form of the spliceosome and U12 and U6atac snRNAs for the minor variant (∼0.3% of all spliceosomes in higher eukaryotes); the latter shares key catalytic sequence elements and performs identical chemistry. Here we use solution NMR techniques to show that the U12-U6atac snRNA complex of both human and Arabidopsis maintain base-pairing patterns similar to those in the three-helix model of the U2-U6 snRNA complex that position key elements to form the spliceosome's active site. However, in place of the stacked base pairs at the base of the U6 snRNA intramolecular stem loop and the central junction of the U2-U6 snRNA complex, we see altered geometry in the single-stranded hinge region opposing termini of the snRNAs to enable interaction between the key elements. We then use electrophoretic mobility shift assays and fluorescence assays to show that the protein RBM22, implicated in remodeling the human U2-U6 snRNA complex prior to catalysis, also binds the U12-U6atac snRNA complexes specifically and with similar affinity as to U2-U6 snRNA (a mean K d for the two methods = 3.4 and 8.0 µM for U2-U6 and U12-U6atac snRNA complexes, respectively), suggesting that RBM22 performs the same role in both spliceosomes.

Label-free horizontal EMSA for analysis of protein-RNA interactions.

We describe a method to analyze the affinity and specificity of interactions between proteins and RNA using horizontal PAGE under non-denaturing conditions. The method permits tracking of migration of anionic and cationic biomolecules and complexes toward anode and cathode, respectively, therefore enabling quantification of bound and free biomolecules of different charges and affinity of their intermolecular interactions. The gel is stained with a fluorescent intercalating dye (SYBR®Gold or ethidium bromide) for visualization of nucleic acids followed by Coomassie® Brilliant Blue R-250 for visualizations of proteins; the dissociation constant is determined separately from the intensity of unshifted and shifted bands visualized by each dye. The method permits calculation of bound and unbound anionic nucleic acid and cationic protein components in the same gel, regardless of charge, under identical conditions, and avoids the need for radioisotope or fluorescent labeling of either component.

Role of the central junction in folding topology of the protein-free human U2-U6 snRNA complex.

U2 and U6 small nuclear (sn)RNAs are the only snRNAs directly implicated in catalyzing the splicing of pre-mRNA, but assembly and rearrangement steps prior to catalysis require numerous proteins. Previous studies have shown that the protein-free U2-U6 snRNA complex adopts two conformations in equilibrium, characterized by four and three helices surrounding a central junction. The four-helix conformer is strongly favored in the in vitro protein-free state, but the three-helix conformer predominates in spliceosomes. To analyze the role of the central junction in positioning elements forming the active site, we derived three-dimensional models of the two conformations from distances measured between fluorophores at selected locations in constructs representing the protein-free human U2-U6 snRNA complex by time-resolved fluorescence resonance energy transfer. Data describing four angles in the four-helix conformer suggest tetrahedral geometry; addition of Mg2+ results in shortening of the distances between neighboring helices, indicating compaction of the complex around the junction. In contrast, the three-helix conformer shows a closer approach between helices bearing critical elements, but the addition of Mg2+ widens the distance between them; thus in neither conformer are the critical helices positioned to favor the proposed triplex interaction. The presence of Mg2+ also enhances the fraction of the three-helix conformer, as does incubation with the Prp19-related protein RBM22, which has been implicated in the remodeling of the U2-U6 snRNA complex to render it catalytically active. These data suggest that although the central junction assumes a significant role in orienting helices, spliceosomal proteins and Mg2+ facilitate formation of the catalytically active conformer.

Meningococcal Meningitis Outbreaks in the African Meningitis Belt After Meningococcal Serogroup A Conjugate Vaccine Introduction, 2011-2017.

BACKGROUND: In 2010-2017, meningococcal serogroup A conjugate vaccine (MACV) was introduced in 21 African meningitis belt countries. Neisseria meningitidis A epidemics have been eliminated here; however, non-A serogroup epidemics continue. METHODS: We reviewed epidemiological and laboratory World Health Organization data after MACV introduction in 20 countries. Information from the International Coordinating Group documented reactive vaccination. RESULTS: In 2011-2017, 17 outbreaks were reported (31 786 suspected cases from 8 countries, 1-6 outbreaks/year). Outbreaks were of 18-14 542 cases in 113 districts (median 3 districts/outbreak). The most affected countries were Nigeria (17 375 cases) and Niger (9343 cases). Cumulative average attack rates per outbreak were 37-203 cases/100 000 population (median 112). Serogroup C accounted for 11 outbreaks and W for 6. The median proportion of laboratory confirmed cases was 20%. Reactive vaccination was conducted during 14 outbreaks (5.7 million people vaccinated, median response time 36 days). CONCLUSION: Outbreaks due to non-A serogroup meningococci continue to be a significant burden in this region. Until an affordable multivalent conjugate vaccine becomes available, the need for timely reactive vaccination and an emergency vaccine stockpile remains high. Countries must continue to strengthen detection, confirmation, and timeliness of outbreak control measures.

Assessment of a health facility based active case finding system for Ebola virus disease in Mbandaka, Democratic Republic of the Congo, June-July 2018.

BACKGROUND: The ninth outbreak of Ebola Virus Disease (EVD) in the Democratic Republic of the Congo occurred in Équateur Province from 8 May-24 July 2018. A system of health facility (HF)-based active case finding (ACF) was implemented in Mbandaka, a regional capital with four confirmed EVD cases, following completion of contact tracing. The goal of this HF-based ACF system was to look for undetected EVD cases among patients that visited HFs beginning one week prior to the system's implementation. METHODS: From 23 June - 24 July 2018, ACF teams visited HFs in Mbandaka and reviewed all medical records as far back as 17 June for any consultations meeting the suspected EVD case definition. The teams then assessed whether to validate these as suspected EVD cases based on factors such as recovery, epidemiological links, and their clinical judgement. ACF teams also assessed HFs' awareness of EVD symptoms and the process for alerting suspected cases. We calculated descriptive statistics regarding the characteristics of reviewed consultations, alert cases, and visited HFs. We also used univariate and multivariate random effects logistic regression models to evaluate the impact of repeated ACF visits to the same HF on the staff's awareness of EVD. RESULTS: ACF teams reviewed 37,746 consultations, of which 690 met the definition of a suspected case of EVD. Two were validated as suspected EVD cases and transferred to the Ebola Treatment Unit for testing; both tested negative. Repeated ACF visits to the same HF were significantly associated with improved EVD awareness (p < 0.001) in univariate and multivariate analyses. CONCLUSION: HF-based ACF during EVD outbreaks may improve EVD awareness and reveal many individuals meeting the suspected case definition. However, many who meet this definition may not have EVD, depending on the population size covered by ACF and amount of ongoing EVD transmission. Given the burdensome procedure of testing suspected EVD cases, future HF-based ACF systems would benefit from improved clarity on which patients require further testing.

The seasonal influence of climate and environment on yellow fever transmission across Africa.

BACKGROUND: Yellow fever virus (YFV) is a vector-borne flavivirus endemic to Africa and Latin America. Ninety per cent of the global burden occurs in Africa where it is primarily transmitted by Aedes spp, with Aedes aegypti the main vector for urban yellow fever (YF). Mosquito life cycle and viral replication in the mosquito are heavily dependent on climate, particularly temperature and rainfall. We aimed to assess whether seasonal variations in climatic factors are associated with the seasonality of YF reports. METHODOLOGY/PRINCIPAL FINDINGS: We constructed a temperature suitability index for YFV transmission, capturing the temperature dependence of mosquito behaviour and viral replication within the mosquito. We then fitted a series of multilevel logistic regression models to a dataset of YF reports across Africa, considering location and seasonality of occurrence for seasonal models, against the temperature suitability index, rainfall and the Enhanced Vegetation Index (EVI) as covariates alongside further demographic indicators. Model fit was assessed by the Area Under the Curve (AUC), and models were ranked by Akaike's Information Criterion which was used to weight model outputs to create combined model predictions. The seasonal model accurately captured both the geographic and temporal heterogeneities in YF transmission (AUC = 0.81), and did not perform significantly worse than the annual model which only captured the geographic distribution. The interaction between temperature suitability and rainfall accounted for much of the occurrence of YF, which offers a statistical explanation for the spatio-temporal variability in transmission. CONCLUSIONS/SIGNIFICANCE: The description of seasonality offers an explanation for heterogeneities in the West-East YF burden across Africa. Annual climatic variables may indicate a transmission suitability not always reflected in seasonal interactions. This finding, in conjunction with forecasted data, could highlight areas of increased transmission and provide insights into the occurrence of large outbreaks, such as those seen in Angola, the Democratic Republic of the Congo and Brazil.

Mapping the burden of cholera in sub-Saharan Africa and implications for control: an analysis of data across geographical scales.

BACKGROUND: Cholera remains a persistent health problem in sub-Saharan Africa and worldwide. Cholera can be controlled through appropriate water and sanitation, or by oral cholera vaccination, which provides transient (∼3 years) protection, although vaccine supplies remain scarce. We aimed to map cholera burden in sub-Saharan Africa and assess how geographical targeting could lead to more efficient interventions. METHODS: We combined information on cholera incidence in sub-Saharan Africa (excluding Djibouti and Eritrea) from 2010 to 2016 from datasets from WHO, Médecins Sans Frontières, ProMED, ReliefWeb, ministries of health, and the scientific literature. We divided the study region into 20 km × 20 km grid cells and modelled annual cholera incidence in each grid cell assuming a Poisson process adjusted for covariates and spatially correlated random effects. We combined these findings with data on population distribution to estimate the number of people living in areas of high cholera incidence (>1 case per 1000 people per year). We further estimated the reduction in cholera incidence that could be achieved by targeting cholera prevention and control interventions at areas of high cholera incidence. FINDINGS: We included 279 datasets covering 2283 locations in our analyses. In sub-Saharan Africa (excluding Djibouti and Eritrea), a mean of 141 918 cholera cases (95% credible interval [CrI] 141 538-146 505) were reported per year. 4·0% (95% CrI 1·7-16·8) of districts, home to 87·2 million people (95% CrI 60·3 million to 118·9 million), have high cholera incidence. By focusing on the highest incidence districts first, effective targeted interventions could eliminate 50% of the region's cholera by covering 35·3 million people (95% CrI 26·3 million to 62·0 million), which is less than 4% of the total population. INTERPRETATION: Although cholera occurs throughout sub-Saharan Africa, its highest incidence is concentrated in a small proportion of the continent. Prioritising high-risk areas could substantially increase the efficiency of cholera control programmes. FUNDING: The Bill & Melinda Gates Foundation.

Facile synthesis of chlorin bioconjugates by a series of click reactions.

A multifunctional chlorin platform appended with four short polyethylene glycols and a carboxylate-linker allows rapid conjugation to biotargeting motifs such as proteins and oligonucleotides. The stability and photophysical properties of the chlorin enable development of diagnostics, imaging, molecular tracking, and theranostics.

Achievements and challenges for the use of killed oral cholera vaccines in the global stockpile era.

Cholera remains an important but neglected public health threat, affecting the health of the poorest populations and imposing substantial costs on public health systems. Cholera can be eliminated where access to clean water, sanitation, and satisfactory hygiene practices are sustained, but major improvements in infrastructure continue to be a distant goal. New developments and trends of cholera disease burden, the creation of affordable oral cholera vaccines (OCVs) for use in developing countries, as well as recent evidence of vaccination impact has created an increased demand for cholera vaccines. The global OCV stockpile was established in 2013 and with support from Gavi, has assisted in achieving rapid access to vaccine in emergencies. Recent WHO prequalification of a second affordable OCV supports the stockpile goals of increased availability and distribution to affected populations. It serves as an essential step toward an integrated cholera control and prevention strategy in emergency and endemic settings.

Exposure Patterns Driving Ebola Transmission in West Africa: A Retrospective Observational Study.

BACKGROUND: The ongoing West African Ebola epidemic began in December 2013 in Guinea, probably from a single zoonotic introduction. As a result of ineffective initial control efforts, an Ebola outbreak of unprecedented scale emerged. As of 4 May 2015, it had resulted in more than 19,000 probable and confirmed Ebola cases, mainly in Guinea (3,529), Liberia (5,343), and Sierra Leone (10,746). Here, we present analyses of data collected during the outbreak identifying drivers of transmission and highlighting areas where control could be improved. METHODS AND FINDINGS: Over 19,000 confirmed and probable Ebola cases were reported in West Africa by 4 May 2015. Individuals with confirmed or probable Ebola ("cases") were asked if they had exposure to other potential Ebola cases ("potential source contacts") in a funeral or non-funeral context prior to becoming ill. We performed retrospective analyses of a case line-list, collated from national databases of case investigation forms that have been reported to WHO. These analyses were initially performed to assist WHO's response during the epidemic, and have been updated for publication. We analysed data from 3,529 cases in Guinea, 5,343 in Liberia, and 10,746 in Sierra Leone; exposures were reported by 33% of cases. The proportion of cases reporting a funeral exposure decreased over time. We found a positive correlation (r = 0.35, p < 0.001) between this proportion in a given district for a given month and the within-district transmission intensity, quantified by the estimated reproduction number (R). We also found a negative correlation (r = -0.37, p < 0.001) between R and the district proportion of hospitalised cases admitted within ≤4 days of symptom onset. These two proportions were not correlated, suggesting that reduced funeral attendance and faster hospitalisation independently influenced local transmission intensity. We were able to identify 14% of potential source contacts as cases in the case line-list. Linking cases to the contacts who potentially infected them provided information on the transmission network. This revealed a high degree of heterogeneity in inferred transmissions, with only 20% of cases accounting for at least 73% of new infections, a phenomenon often called super-spreading. Multivariable regression models allowed us to identify predictors of being named as a potential source contact. These were similar for funeral and non-funeral contacts: severe symptoms, death, non-hospitalisation, older age, and travelling prior to symptom onset. Non-funeral exposures were strongly peaked around the death of the contact. There was evidence that hospitalisation reduced but did not eliminate onward exposures. We found that Ebola treatment units were better than other health care facilities at preventing exposure from hospitalised and deceased individuals. The principal limitation of our analysis is limited data quality, with cases not being entered into the database, cases not reporting exposures, or data being entered incorrectly (especially dates, and possible misclassifications). CONCLUSIONS: Achieving elimination of Ebola is challenging, partly because of super-spreading. Safe funeral practices and fast hospitalisation contributed to the containment of this Ebola epidemic. Continued real-time data capture, reporting, and analysis are vital to track transmission patterns, inform resource deployment, and thus hasten and maintain elimination of the virus from the human population.

Perceptions of oral cholera vaccine and reasons for full, partial and non-acceptance during a humanitarian crisis in South Sudan.

Oral cholera vaccination (OCV) campaigns were conducted from February to April 2014 among internally displaced persons (IDPs) in the midst of a humanitarian crisis in Juba, South Sudan. IDPs were predominantly members of the Nuer ethnic group who had taken refuge in United Nations bases following the eruption of violence in December 2013. The OCV campaigns, which were conducted by United Nations and non-governmental organizations (NGOs) at the request of the Ministry of Health, reached an estimated 85-96% of the target population. As no previous studies on OCV acceptance have been conducted in the context of an on-going humanitarian crisis, semi-structured interviews were completed with 49 IDPs in the months after the campaigns to better understand perceptions of cholera and reasons for full, partial or non-acceptance of the OCV. Heightened fears of disease and political danger contributed to camp residents' perception of cholera as a serious illness and increased trust in United Nations and NGOs providing the vaccine to IDPs. Reasons for partial and non-acceptance of the vaccination included lack of time and fear of side effects, similar to reasons found in OCV campaigns in non-crisis settings. In addition, distrust in national institutions in a context of fears of ethnic persecution was an important reason for hesitancy and refusal. Other reasons included fear of taking the vaccine alongside other medication or with alcohol. The findings highlight the importance of considering the target populations' perceptions of institutions in the delivery of OCV interventions in humanitarian contexts. They also suggest a need for better communication about the vaccine, its side effects and interactions with other substances.

Population-Level Effect of Cholera Vaccine on Displaced Populations, South Sudan, 2014.

Following mass population displacements in South Sudan, preventive cholera vaccination campaigns were conducted in displaced persons camps before a 2014 cholera outbreak. We compare cholera transmission in vaccinated and unvaccinated areas and show vaccination likely halted transmission within vaccinated areas, illustrating the potential for oral cholera vaccine to stop cholera transmission in vulnerable populations.

Interaction between the Spliceosomal Pre-mRNA Branch Site and U2 snRNP Protein p14.

We have probed the molecular basis of recognition between human spliceosomal U2 snRNP protein p14 and RNA targets representing the intron branch site region. Interaction of an RNA duplex representing the branch site helix perturbed at least 10 nuclear magnetic resonance cross-peaks of (15)N-labeled p14. However, similar chemical shift changes were observed upon interaction with a duplex without the bulged branch site residue, suggesting that binding of p14 to RNA is nonspecific and does not recognize the branch site. We propose that the p14-RNA interaction screens charges on the backbone of the branch site during spliceosome assembly.

Meningococcal Meningitis Surveillance in the African Meningitis Belt, 2004-2013.

BACKGROUND: An enhanced meningitis surveillance network was established across the meningitis belt of sub-Saharan Africa in 2003 to rapidly collect, disseminate, and use district weekly data on meningitis incidence. Following 10 years' experience with enhanced surveillance that included the introduction of a group A meningococcal conjugate vaccine, PsA-TT (MenAfriVac), in 2010, we analyzed the data on meningitis incidence and case fatality from countries reporting to the network. METHODS: After de-duplication and reconciliation, data were extracted from the surveillance bulletins and the central database held by the World Health Organization Inter-country Support Team in Burkina Faso for countries reporting consistently from 2004 through 2013 (Benin, Burkina Faso, Chad, Democratic Republic of Congo, Ghana, Côte d'Ivoire, Mali, Niger, Nigeria, Togo). RESULTS: The 10 study countries reported 341 562 suspected and confirmed cases over the 10-year study period, with a marked peak in 2009 due to a large epidemic of group A Neisseria meningitidis (NmA) meningitis. Case fatality was lowest (5.9%) during this year. A mean of 71 and 67 districts annually crossed the alert and epidemic thresholds, respectively. The incidence rate of NmA meningitis fell >10-fold, from 0.27 per 100,000 in 2004-2010 to 0.02 per 100,000 in 2011-2013 (P < .0001). CONCLUSIONS: In addition to supporting timely outbreak response, the enhanced meningitis surveillance system provides a global overview of the epidemiology of meningitis in the region, despite limitations in data quality and completeness. This study confirms a dramatic fall in NmA incidence after the introduction of PsA-TT.

Introduction and Rollout of a New Group A Meningococcal Conjugate Vaccine (PsA-TT) in African Meningitis Belt Countries, 2010-2014.

BACKGROUND: A group A meningococcal conjugate vaccine (PsA-TT) was developed specifically for the African "meningitis belt" and was prequalified by the World Health Organization (WHO) in June 2010. The vaccine was first used widely in Burkina Faso, Mali, and Niger in December 2010 with great success. The remaining 23 meningitis belt countries wished to use this new vaccine. METHODS: With the help of African countries, WHO developed a prioritization scheme and used or adapted existing immunization guidelines to mount PsA-TT vaccination campaigns. Vaccine requirements were harmonized with the Serum Institute of India, Ltd. RESULTS: Burkina Faso was the first country to fully immunize its 1- to 29-year-old population in December 2010. Over the next 4 years, vaccine coverage was extended to 217 million Africans living in 15 meningitis belt countries. CONCLUSIONS: The new group A meningococcal conjugate vaccine was well received, with country coverage rates ranging from 85% to 95%. The rollout proceeded smoothly because countries at highest risk were immunized first while attention was paid to geographic contiguity to maximize herd protection. Community participation was exemplary.