Infections at the maternal-fetal interface: an overview of pathogenesis and defence.

Infections are a major threat to human reproductive health, and infections in pregnancy can cause prematurity or stillbirth, or can be vertically transmitted to the fetus leading to congenital infection and severe disease. The acronym 'TORCH' (Toxoplasma gondii, other, rubella virus, cytomegalovirus, herpes simplex virus) refers to pathogens directly associated with the development of congenital disease and includes diverse bacteria, viruses and parasites. The placenta restricts vertical transmission during pregnancy and has evolved robust mechanisms of microbial defence. However, microorganisms that cause congenital disease have likely evolved diverse mechanisms to bypass these defences. In this Review, we discuss how TORCH pathogens access the intra-amniotic space and overcome the placental defences that protect against microbial vertical transmission.

Rubella transmissibility and reproduction number (Ro): A critical appraisal of the prospects for its control in Nigeria.

Rubella is a highly contagious disease of public health importance that is endemic in Nigeria. Rubella with its devastating sequel, congenital rubella syndrome, is a neglected disease with no surveillance system in place and no national incidence figure in Nigeria. This article, therefore, seeks to do reviews of rubella transmissibility, its reproduction number and the prospects for its control in Nigeria. This is a review of literatures with triangulation of findings along the objectives and the use of available secondary data to analyse the prospects of rubella control in Nigeria. Data were analysed and presented with appropriate tables and charts. A number of factors can fuel rubella transmission causing increase in reproduction number, Ro.The high birth rate, poor rubella surveillance and non-inclusion of rubella vaccines in the routine vaccination schedule among others are some of the factors working against a good outlook for rubella control in Nigeria. The Nigerian government should control the growing population, ensure a robust surveillance for rubella and incorporate rubella-containing vaccine in the immunisation schedule for infants with regular vaccination campaigns for older children and adults.

Accelerating measles and rubella elimination through research and innovation - Findings from the Measles & Rubella Initiative research prioritization process, 2016.

The Measles & Rubella Initiative (M&RI) identified five key strategies to achieve measles and rubella elimination, including research and innovation to support cost-effective operations and improve vaccination and diagnostic tools. In 2016, the M&RI Research and Innovation Working Group (R&IWG) completed a research prioritization process to identify key research questions and update the global research agenda. The R&IWG reviewed meeting reports and strategic planning documents and solicited programmatic inputs from vaccination experts at the program operational level through a web survey, to identify previous research priorities and new research questions. The R&IWG then convened a meeting of experts to prioritize the identified research questions in four strategic areas: (1) epidemiology and economics, (2) surveillance and laboratory, (3) immunization strategies, and (4) demand creation and communications. The experts identified 19 priority research questions in the four strategic areas to address key areas of work necessary to further progress toward elimination. Future commitments from partners will be needed to develop a platform for improved coordination with adequate and predictable resources for research implementation and innovation to address these identified priorities.

Reconstructing the transmission dynamics of rubella in Japan, 2012-2013.

BACKGROUND: Japan experienced a nationwide rubella epidemic from 2012 to 2013, mostly in urban prefectures with large population sizes. The present study aimed to capture the spatiotemporal patterns of rubella using a parsimonious metapopulation epidemic model and examine the potential usefulness of spatial vaccination. METHODOLOGY/PRINCIPAL FINDINGS: A metapopulation epidemic model in discrete time and space was devised and applied to rubella notification data from 2012 to 2013. Employing a piecewise constant model for the linear growth rate in six different time periods, and using the particle Markov chain Monte Carlo method, the effective reproduction numbers were estimated at 1.37 (95% CrI: 1.12, 1.77) and 1.37 (95% CrI: 1.24, 1.48) in Tokyo and Osaka groups, respectively, during the growing phase of the epidemic in 2013. The rubella epidemic in 2012 involved substantial uncertainties in its parameter estimates and forecasts. We examined multiple scenarios of spatial vaccination with coverages of 1%, 3% and 5% for all of Japan to be distributed in different combinations of prefectures. Scenarios indicated that vaccinating the top six populous urban prefectures (i.e., Tokyo, Kanagawa, Osaka, Aichi, Saitama and Chiba) could potentially be more effective than random allocation. However, greater uncertainty was introduced by stochasticity and initial conditions such as the number of infectious individuals and the fraction of susceptibles. CONCLUSIONS: While the forecast in 2012 was accompanied by broad uncertainties, a narrower uncertainty bound of parameters and reliable forecast were achieved during the greater rubella epidemic in 2013. By better capturing the underlying epidemic dynamics, spatial vaccination could substantially outperform the random vaccination.

Management and control of communicable diseases in schools and other child care settings: systematic review on the incubation period and period of infectiousness.

BACKGROUND: Information on the incubation period and period of infectiousness or shedding of infectious pathogens is critical for management and control of communicable diseases in schools and other childcare settings. METHODS: We performed a systematic literature review (Pubmed and Embase) to identify and critically appraise all relevant published articles using incubation, infectiousness or shedding, and exclusion period as parameters for the search. No language, time, geographical or study design restrictions were applied. RESULTS: A total of 112 articles met the eligibility criteria. A relatively large number were retrieved for gastrointestinal diseases and influenza or respiratory syncytial virus, but there were few or no studies for other diseases. Although a considerable number of publications reported the incubation and shedding periods, there was less evidence concerning the period of infectiousness. On average, five days of exclusion is considered for measles, mumps, rubella, varicella and pertussis. For other diseases, such as most cases of meningococcal disease, hepatitis A and influenza exclusion is considered as long as severe symptoms persist. However, these results are based on a diverse range of study characteristics, including age, treatment, vaccination, underlying diseases, diagnostic tools, viral load, study design and definitions, making statistical analysis difficult. CONCLUSIONS: Despite inconsistent definitions for key variables and the diversity of studies reviewed, published data provide sufficient quantitative estimates to inform decision making in schools and other childcare settings. The results can be used as a reference when deciding about the exclusion of a child with a communicable disease that both prevents exposure and avoids unnecessary absenteeism.

The pathogenesis of microcephaly resulting from congenital infections: why is my baby's head so small?

The emergence of Zika-virus-associated congenital microcephaly has engendered renewed interest in the pathogenesis of microcephaly induced by infectious agents. Three of the original "TORCH" agents are associated with an appreciable incidence of congenital microcephaly: cytomegalovirus, rubella virus, and Toxoplasma gondii. The pathology of congenital microcephaly is characterized by neurotropic infectious agents that involve the fetal nervous system, leading to brain destruction with calcifications, microcephaly, sensorineural hearing loss, and ophthalmologic abnormalities. The inflammatory reaction induced by these four agents has an important role in pathogenesis. The potential role of "strain differences" in pathogenesis of microcephaly by these four pathogens is examined. Specific epidemiologic factors, such as first and early second trimester maternal infection, and the manifestations of congenital infection in the infant, shed some light on the pathogenesis. Immune aspects of normal pregnancy and their role in congenital infections is examined. In this review, we integrate all these findings to create a unified hypothesis of the pathogenesis of congenital microcephaly induced by these infectious agents.

Two Imported Cases of Congenital Rubella Syndrome and Infection-Control Challenges in New York State, 2013-2015.

Rubella was declared eliminated in the United States in 2004. During 2013-2015, 2 infants with congenital rubella syndrome (CRS) were born in New York State. Both mothers were foreign born and traveled to Yemen during their pregnancy. Delayed consideration of CRS led to preventable exposures and a substantial public health response.

Pathogenesis of Non-Zika Congenital Viral Infections.

A widespread epidemic of Zika virus (ZIKV) infection was reported in 2015 from South and Central America and the Caribbean. Although the full spectrum of ZIKV infection of the newborn has yet to be determined, other maternal viral infections resulting in transmission to the fetus provide instructive lessons that can be applied to the prospective evaluation of individuals with ZIKV infection. This review focuses on those other congenital infections, including rubella, congenital cytomegalovirus, human immunodeficiency virus, hepatitis B virus, and neonatal herpes simplex virus, from which lessons for the evaluation of ZIKV in the newborn can be applied.

Molecular surveillance of measles and rubella in the WHO European Region: new challenges in the elimination phase.

BACKGROUND: The WHO European Region (EUR) has adopted the goal of eliminating measles and rubella but individual countries perform differently in achieving this goal. Measles virus spread across the EUR by mobile groups has recently led to large outbreaks in the insufficiently vaccinated resident population. As an instrument for monitoring the elimination process and verifying the interruption of endemic virus transmission, molecular surveillance has to provide valid and representative data. Irrespective of the country's specific situation, it is required to ensure the functionality of the laboratory surveillance that is supported by the WHO Global Measles and Rubella Laboratory Network. AIMS: To investigate whether the molecular surveillance in the EUR is adequate for the challenges in the elimination phase, we addressed the quality assurance of molecular data, the continuity and intensity of molecular monitoring, and the analysis of transmission chains. SOURCES: Published articles, the molecular External Quality Assessment Programme of the WHO, the Centralized Information System for Infectious Diseases of the WHO EUR and the WHO Measles and Rubella Nucleotide Surveillance databases served as information sources. CONTENT: Molecular proficiency testing conducted by the WHO in 2016 has shown that the expertise for measles and rubella virus genotyping exists in all parts of the EUR. The analysis of surveillance data reported nationally to the WHO in 2013-2016 has revealed some countries with outbreaks but not sufficiently representative molecular data. Long-lasting supranational MV transmission chains were identified. IMPLICATIONS: A more systematic molecular monitoring and recording of the transmission pattern for the whole EUR could help to create a meaningful picture of the elimination process.

Modeling the Transmission of Measles and Rubella to Support Global Management Policy Analyses and Eradication Investment Cases.

Policy makers responsible for managing measles and rubella immunization programs currently use a wide range of different vaccines formulations and immunization schedules. With endemic measles and rubella transmission interrupted in the region of the Americas, all five other regions of the World Health Organization (WHO) targeting the elimination of measles transmission by 2020, and increasing adoption of rubella vaccine globally, integrated dynamic disease, risk, decision, and economic models can help national, regional, and global health leaders manage measles and rubella population immunity. Despite hundreds of publications describing models for measles or rubella and decades of use of vaccines that contain both antigens (e.g., measles, mumps, and rubella vaccine or MMR), no transmission models for measles and rubella exist to support global policy analyses. We describe the development of a dynamic disease model for measles and rubella transmission, which we apply to 180 WHO member states and three other areas (Puerto Rico, Hong Kong, and Macao) representing >99.5% of the global population in 2013. The model accounts for seasonality, age-heterogeneous mixing, and the potential existence of preferentially mixing undervaccinated subpopulations, which create heterogeneity in immunization coverage that impacts transmission. Using our transmission model with the best available information about routine, supplemental, and outbreak response immunization, we characterize the complex transmission dynamics for measles and rubella historically to compare the results with available incidence and serological data. We show the results from several countries that represent diverse epidemiological situations to demonstrate the performance of the model. The model suggests relatively high measles and rubella control costs of approximately $3 billion annually for vaccination based on 2013 estimates, but still leads to approximately 17 million disability-adjusted life years lost with associated costs for treatment, home care, and productivity loss costs of approximately $4, $3, and $47 billion annually, respectively. Combined with vaccination and other financial cost estimates, our estimates imply that the eradication of measles and rubella could save at least $10 billion per year, even without considering the benefits of preventing lost productivity and potential savings from reductions in vaccination. The model should provide a useful tool for exploring the health and economic outcomes of prospective opportunities to manage measles and rubella. Improving the quality of data available to support decision making and modeling should represent a priority as countries work toward measles and rubella goals.

Rubella outbreak and outbreak management in a school setting, China, 2014.

BACKGROUND: An active response to a rubella outbreak may interrupt disease transmission, and outbreak response immunization (ORI) can increase immunity among persons who might otherwise not be protected. On March 17, 2014, a rubella outbreak was reported in a middle school in Guangzhou city, China. We conducted an investigation to assess impact of a policy of exclusion of cases from school and of ORI. METHODS: Active surveillance was used to find cases of rubella. Investigators interviewed teachers and reviewed the absentee records to determine implementation details of school exclusion. ORI was recommended on 2 occasions during the outbreak, one small-scale and one large-scale. Laboratory confirmation tests included serum IgM and IgG measurements to distinguish between acute infection and immunity. A serological survey in 4 classes was used to determine immunity status and identify symptomatic and asymptomatic cases. RESULTS: From February 17 to May 23, 2014, 162 rubella cases (24 laboratory-confirmed and 138 epidemiologically linked) were detected among 1,621 students. Cases ultimately occurred in 27 classes (72.97%) across 37 classes. In 11 classes in which exclusion from school was delayed by 1 or more days, the secondary attack rate was 12.30%, compared with 2.35% in 15 classes with immediate exclusion. ORI increased vaccine coverage from 25.83 % to 86.92%, and the final case of the epidemic was reported one month later. A serological survey of 91 students in 4 classes identified 15 cases, 6 of which were asymptomatic. CONCLUSIONS: The outbreak happened in school with low rubella-containing vaccination coverage. Exclusion from school upon rash/fever onset was associated with lowering the secondary attack rate, but school exclusion alone was not able to stop this outbreak - a large ORI was needed. Assuring complete vaccination upon entry to school is likely to be necessary to ensure coverage is above the herd immunity threshold and prevent outbreaks from happening.

Informing rubella vaccination strategies in East Java, Indonesia through transmission modelling.

An estimated 110,000 babies are born with congenital rubella syndrome (CRS) worldwide annually; a significant proportion of cases occur in Southeast Asia. Rubella vaccine programs have led to successful control of rubella and CRS, and even the elimination of disease in many countries. However, if vaccination is poorly implemented it might increase the number of women reaching childbearing age who remain susceptible to rubella and thereby paradoxically increase CRS. We used an age-structured transmission model to compare seven alternative vaccine strategies for their impact on reducing CRS disease burden in East Java, a setting which is yet to implement a rubella vaccine program. We also investigated the robustness of model predictions to variation in vaccine coverage and other key epidemiological factors. Without rubella vaccination, approximately 700 babies are estimated to be born with CRS in East Java every year at an incidence of 0.77 per 1000live births. This incidence could be reduced to 0.0045 per 1000 live births associated with 99.9% annual reduction in rubella infections after 20 years if the existing two doses of measles vaccine are substituted with two doses of measles plus rubella combination vaccine with the same coverage (87.8% of 9-month-old infants and 80% of 6-year-old children). By comparison a single dose of rubella vaccine will take longer to reduce the burden of rubella and CRS and will be less robust to lower vaccine coverage. While the findings of this study should be informative for settings similar to East Java, the conclusions are dependent on vaccine coverage which would need consideration before applying to all of Indonesia and elsewhere in Asia.

Evolution and Use of Dynamic Transmission Models for Measles and Rubella Risk and Policy Analysis.

The devastation caused by periodic measles outbreaks motivated efforts over more than a century to mathematically model measles disease and transmission. Following the identification of rubella, which similarly presents with fever and rash and causes congenital rubella syndrome (CRS) in infants born to women first infected with rubella early in pregnancy, modelers also began to characterize rubella disease and transmission. Despite the relatively large literature, no comprehensive review to date provides an overview of dynamic transmission models for measles and rubella developed to support risk and policy analysis. This systematic review of the literature identifies quantitative measles and/or rubella dynamic transmission models and characterizes key insights relevant for prospective modeling efforts. Overall, measles and rubella represent some of the relatively simplest viruses to model due to their ability to impact only humans and the apparent life-long immunity that follows survival of infection and/or protection by vaccination, although complexities arise due to maternal antibodies and heterogeneity in mixing and some models considered potential waning immunity and reinfection. This review finds significant underreporting of measles and rubella infections and widespread recognition of the importance of achieving and maintaining high population immunity to stop and prevent measles and rubella transmission. The significantly lower transmissibility of rubella compared to measles implies that all countries could eliminate rubella and CRS by using combination of measles- and rubella-containing vaccines (MRCVs) as they strive to meet regional measles elimination goals, which leads to the recommendation of changing the formulation of national measles-containing vaccines from measles only to MRCV as the standard of care.

[Verifying the Elimination of Measles and Rubella in the WHO European region: the Case of Spain].

Like some other countries in the Region, Spain has recently experienced multiple but small measles outbreaks resulting from several importations and in which health care professionals were also infected. The European Regional Verification Commission (RVC) for Measles and Rubella Elimination, an independent panel of experts, conducted an annual review of the reports submitted by the National Verification Committees (NVC) and a country visit to assess the status of interruption of endemic transmission of these diseases in Spain. Essential criteria supporting interruption included absence of endemic transmission in the presence of high-quality surveillance system and genotyping evidence. High vaccination coverage with the first dose of measles -and rubella-containing vaccine (MRCV1) has been maintained above 95% at national level. The figure is based on the number of doses administered to children aged 12-24 months. However, there are two autonomous regions, namely Cataluña and Castilla y Leon with low (<90%) vaccination coverage. In the autonomous regions of Murcia and Melilla, although the coverage with MRCV1 was above 95%, that of the second dose of measles -and rubella-containing vaccine was below 90. On the basis of the evidence provided, with only two imported cases of rubella in 2013, the RVC concluded that endemic transmission of rubella had been interrupted in Spain, but there is a risk of re-establishing transmission due to the sub-optimal population immunity in at least four regions as the coverage with two doses of measles- and rubella- containing vaccines was below the required minimum of 95%.

[Microbiological Surveillance of Measles and Rubella in Spain. Laboratory Network]. / Vigilancia microbiológica del sarampión y la rubéola en España. Red de laboratorios.

The Laboratory is a fundamental component on the surveillance of measles and rubella. Cases need to be properly confirmed to ensure an accurate estimation of the incidence. Strains should be genetically characterized to know the transmission pattern of these viruses and frequently, outbreaks and transmission chains can be totally discriminated only after that. Finally, the susceptibility of the population is estimated on the basis of sero-prevalence surveys. Detection of specific IgM response is the base of the laboratory diagnosis of these diseases. It should be completed with genomic detection by RT-PCR to reach an optimal efficiency, especially when sampling is performed early in the course of the disease. Genotyping is performed by genomic sequencing according to reference protocols of the WHO. Laboratory surveillance of measles and rubella in Spain is organized as a net of regional laboratories with different capabilities. The National Center of Microbiology as National Reference Laboratory (NRL), supports regional laboratories ensuring the availability of all required techniques in the whole country and watching for the quality of the results. The NRL is currently working in the implementation of new molecular techniques based on the analysis of genomic hypervariable regions for the strain characterization at sub-genotypic levels and use them in the surveillance.

Quantifying seasonal population fluxes driving rubella transmission dynamics using mobile phone data.

Changing patterns of human aggregation are thought to drive annual and multiannual outbreaks of infectious diseases, but the paucity of data about travel behavior and population flux over time has made this idea difficult to test quantitatively. Current measures of human mobility, especially in low-income settings, are often static, relying on approximate travel times, road networks, or cross-sectional surveys. Mobile phone data provide a unique source of information about human travel, but the power of these data to describe epidemiologically relevant changes in population density remains unclear. Here we quantify seasonal travel patterns using mobile phone data from nearly 15 million anonymous subscribers in Kenya. Using a rich data source of rubella incidence, we show that patterns of population travel (fluxes) inferred from mobile phone data are predictive of disease transmission and improve significantly on standard school term time and weather covariates. Further, combining seasonal and spatial data on travel from mobile phone data allows us to characterize seasonal fluctuations in risk across Kenya and produce dynamic importation risk maps for rubella. Mobile phone data therefore offer a valuable previously unidentified source of data for measuring key drivers of seasonal epidemics.