Extensive resources are being committed to improve global childhood vaccination coverage, but the response to standard vaccination is often diminished in children from developing nations. The ineffectiveness of vaccination programs in developing communities has been blamed on cold chain lapses and lack of supportable infrastructure, but chronic infections also play a significant role. Multiple maternal parasitic infections affect the unborn infant and are potentially important vaccine response modifiers, but have not been well studied. Increasing evidence suggests that chronic parasitic infections in pregnant women, such as schistosomiasis, filariasis, intestinal helminths, and malaria, can suppress fetal and infant immune responses to subsequent infections and vaccinations. The mechanisms of parasite effects on immune responses are not well understood, although the lack of appropriate vaccine response in infants of parasite-infected mothers appears to be due to dysregulation of maternal immunity, with resultant impaired fetal immunity. The central hypothesis to be tested is that treatment of maternal and infant parasitic infections will enhance infant responses to vaccination. We propose a prospective study of pregnant Kenyan woman and their offspring to evaluate the effects of parasitic infections and prompt anti-parasitic treatment on infant vaccine responses to Streptococcus ppneumonia, Haemophilus influenzae, and diphtheria. We propose the following specific aims: 1) To determine the individual and combined influence of maternal parasitic infections on infant vaccine responses, and 2) To measure the impact of maternal and infant anti-parasitic treatment on infant vaccine responses. The long term goals of this project are to determine the value of specific antenatal and postnatal parasitic treatments and to develop novel approaches to optimizing vaccine program effectiveness.
Outbreaks of arthropod-borne viruses, such as dengue (DENV) and chikungunya (CHIKV) viruses, demonstrate the substantial cost and health burden of these emerging/re-emerging health threats to the developing and developed world. In sub-Saharan Africa, routine passive surveillance for these diseases detects only a fraction of their impact, given the high probability of misdiagnosis and unknown levels of transmission across different landscapes and within different susceptible populations. Known and unknown entomologic, environmental, and behavioral factors differentially drive transmission in different habitats. We hypothesize that a significant burden of human disease due to DENV and CHIKV is undetected in the clinical setting, leading to missed opportunities for prevention and heightened risk for large-scale outbreaks. Preliminary data demonstrate that Kenyan children and adults are frequently exposed to DENV and CHIKV, both between and during known outbreaks, although acute arboviral infections are rarely diagnosed in this setting. Our objectives are to assess the true burden of human disease related to DENV strains 1-4 and for CHIKV across Kenya, and then to determine the drivers of viral circulation, estimate the thresholds for outbreak initiation, and provide improved outbreak risk assessment. We will investigate transmission of CHIKV and DENV1-4 in two regions of Kenya that represent heterogeneous degrees of urbanization with varied landscape, climate, and populations. Using several novel approaches, we address the following aims: 1) Quantify the incidence of human infection and disease due to CHIKV and DENV1-4 and determine their relative contribution to acute febrile illness; 2) Measure the level of CHIKV and DENV1-4 circulation in Aedes mosquito vectors and estimate the amount of human-vector contact in Kenya; and 3) Detect and predict spatial and temporal patterns of CHIKV and DENV transmission in rural and urban settings by integrating data on circulation in humans (Aim 1) and vectors (Aim 2) with environmental and weather/climate data collected both in situ and using satellite imagery. This research involves cohorts in and near Msambweni (coastal) and Kisumu (western), Kenya, where there is year-round transmission of arboviruses, and is based on 10 years of collaborative longitudinal studies. Methodologies include analyses of the relationship between well-defined entomologic, clinical, epidemiologic, and climatologic findings and immune biomarkers of virus and mosquito exposure. These studies will fill knowledge gaps about the persistence of CHIKV and DENV in local habitats and the factors that contribute to persistence during inter-epidemic periods and to regional variation during epidemic periods. The data will also answer fundamental questions about arboviral etiologies in severe fever syndromes among at-risk populations while providing better estimates of related disease burden and long-term sequelae.
The LaBeaud lab currently has an NIH R01 grant that studies acute dengue and chikungunya infection and disease in Kenyan children and measures circulation of these infections in vectors at all life stages (eggs, larvae, pupae, and adults). The planned study will capitalize on this data by allowing us to link child seroprevalence information with the control interventions to enable measurement of changes in disease incidence as a result of our planned child and community interventions. The ongoing vector sampling in our R01 study will allow us to easily perform the planned vector assessments (pupal and larval surveys) and maintain the highly trained human capital that will allow accurate measurement of our primary study outcome (pupal productivity). This study will transform years of successful field work into child and community focused benefits that will promote improved integrated vector management using sustainable grass-roots methods, results that will matter greatly to the study participants.Although the immediate benefits of this study will be for Kenyan children and their families, the methods employed will be generalizable to all children of the world, as children in Africa, Asia, and the Americas are all at risk for these infections. Although children are at greater risk for arboviral exposures than adults, previous surveys have rarely focused on this vulnerable population, yielding only imprecise estimates of disease burden among the pediatric (and general) population. CHIKV is now circulating in Florida and is likely to spread throughout the US. DENV has been circulating in Florida since 2009. The vectors for DENV and CHIKV have recently been identified locally in Hayward, Fresno and Menlo Park. Both mild and severe arboviral disease, including CHIKV, are known to cause chronic arthritic, neurologic and ocular sequelae in children. Cheap, sustainable methods of integrated vector management, as planned in this study, will be tested for their efficacy in preventing vector development and human virus exposure. Because there are no therapeutics or vaccines for these infections, vector control is the main strategy for prevention.This project is funded by The Bechtel Faculty Scholar Fund and Stanford Child Health Research Institute (CHRI).
CHIKV, an infectious cause of long-term chronic arthritis, is a communicable disease that evolves into a disabling non-communicable disease that can last for years; therefore, understanding how CHIKV-related arthritis is mediated and how it can be prevented will result in large savings of human health burden and costs. CHIKV introduction into Grenada in 2014 led to large outbreaks with substantial chronic disease burden. We hypothesize that specific measurable host and viral factors underpin these chronic sequelae. Preliminary data demonstrate that both host and viral factors are essential to determine CHIKV human disease outcome, but the most important drivers of disease have not been elucidated. Severe disease is also linked to host factors such as comorbidities and specific host immune responses. In the proposed research, through combined studies of humans and viral isolates, we will determine the influential drivers of chronic chikungunya disease in the island country of Grenada, linking disease phenotype and long-term health consequences to viral strain, demography, and host immune response.
Assays of cellular immunity are key to understanding the pathogenesis and mechanisms of control of viral and other infectious diseases. But such assays are difficult to perform as part of clinical studies because they are:Labile: They must either be performed on fresh blood, or on PBMC that are cryopreserved within a relatively short time after blood collection.Laborious: They require a lot of manual effort, as well as skills and equipment not commonly found at clinical sites.Sample-intensive: They tend to require large volumes of blood, particularly if performed on cryopreserved PBMCs.These challenges have limited the implementation of cellular immune function assays, particularly in children (where blood draw volumes are most limited) and in remote settings. Yet, children in remote settings are often the most affected by important infectious diseases, and stand the most to gain from advances in vaccines and other methods of control. Therefore, we propose to develop a sample-sparing and fully automated system for stimulation and stabilization of whole blood for functional cellular assays. This system will be based on the concepts pioneered by Smart Tube, Inc. in their existing whole blood stimulation system, but will use 80% less blood, and provide full automation, so that all pipetting steps are eliminated. It will withdraw blood directly from a collection tube, using as little as 2 cc, distribute the blood into multiple incubation chambers where it will be stimulated with lyophilized, pre-configured reagents (antigens, mitogens, etc.) to assay cellular function, then stabilized with a proteomic stabilizer for later analysis.The results of this study will not only validate the blood collection system’s performance, but will provide valuable biological data on the cellular response to these viruses in children. The blood collection system, in turn, will be useful for many different kinds of studies of cellular immunity, particularly in remote settings and situations where samples are limiting. The end result should be much more rapid advancement of our understanding of disease pathogenesis and of vaccine development for important infectious agents.
Disease outbreaks are not easily predicted because they occur only when multiple factors trigger the rapid spread of disease. Key factors can often be identified, e.g., excess rainfall leading to outbreaks of Rift Valley fever virus (RVFV)1,2, but the complex circumstances that lead to outbreaks remain elusive for several reasons. First, gathering varied datasets (climatic, genetics, demographic, historical, and behavioral) is time consuming and expensive. Second, the computing capabilities to mine and analyze such varied and complex datasets has not been available until recently. In this application using RVFV as a case study, we propose to model the interplay between vectors, livestock, wildlife, climate, and humans. Large historic and modern datasets are accessible to the key investigators and will be aggregated into a repository. In collaboration with an industry partner, we will then apply machine learning to construct models for inference and prediction of RVFV outbreaks. We achieve broad applicability by separating data gathering from deep learning and execution. As such, once data curation and conversion of a dataset has been completed, one can take advantage of deep learning in the absence of a computer expert. As deep learning makes few assumptions about the data, this approach is transferable to other outbreak scenarios and diseases. Rift Valley fever (RVF) is a deadly vector-borne disease that infects livestock and humans3–6. Transmitted via mosquitoes to livestock7, it can decimate entire herds and cause catastrophic economic hardship8. Humans are exposed via vector and animal transmission: animal husbandry, slaughter and butchery, and ingesting diseased meat, milk, and blood9,10. RVFV is endemic throughout much of Africa, but has recently caused outbreaks the Middle East11,12 and has significant potential to spread to the EU and USA, where all the necessary vectors and hosts to allow transmission are present13–15. Our proposal initiates a new collaboration between faculty who are uniquely suited to investigate RVF and use DL and diverse datasets to predict RVF outbreaks. Dr. LaBeaud brings clinical expertise in RVF transmission and epidemiology3–6,16,17. Dr. Seetah brings expertise in historical climate, meat processing as ‘social and economic’ practice, and is a trained butcher. We collaborate with Dr. Kumm, CEO of insightAI, to adapt their GPU-based deep-learning platform to “learn” what triggers RVF outbreaks. All three have worked in Kenya and have established in-country networks. In addition, the team is in discussion with IBM who has recently acquired weather.com, providing access to a massive database of past climate. This transformative, cross-disciplinary research project meets all CIGH priority areas: climate change and global health, new solutions to improve health care delivery, new interdisciplinary collaborations among faculty, and is a high-impact, high-risk project that lends itself to implementation among stakeholders in both endemic and at risk regions of the world.
Dengue, Zika, chikungunya, and other Aedes aegypti-transmitted viruses are a major concern throughout the tropics and sub-tropics, and better mosquito control could dramatically reduce disease burden. Mosquito control is currently inefficient and poorly targeted in part because of a general lack of mosquito surveillance data in most places. Understanding the links between climate, mosquito abundance, and dengue infections would promote a more effective allocation of costly and sometimes environmentally damaging mosquito control resources, such as insecticides. This project will develop improved models that use satellite imagery to predict the climate suitability for dengue transmission, and integrate the improved models into current decision-making procedures on vector control.
Kenya and Ecuador
Arthropod-borne viruses (arboviruses) comprise many of the most important emerging pathogens due to their geographic expansion and their increasing impact on vulnerable populations. In 2015, Zika virus (ZIKV) became the newest emerging public health threat to Latin America, with more than 14,000 cases in Salvador, Brazil, and accruing substantial evidence of resultant Guillain-Barré and microcephaly. After severe outbreaks of chikungunya virus (CHIKV) wherein some islands experienced more than 90% of residents infected, the Caribbean islands are now witnessing large- scale ZIKV exposure and infection. We propose to determine the true incidence of ZIKV compared to CHIKV and dengue virus (DENV) disease in Grenada, and identify the demographic and ecological drivers for ZIKV transmission and disease. Serum collected from participants will be tested by ELISA and PCR to document acute ZIKV infection and characterize the spectrum of disease, severity and impact of ZIKV in Grenada. Participants, especially pregnant women, will be followed to determine long-term consequences of ZIKV disease, including any microcephaly resulting from antenatal ZIKV infection. Clinical manifestations of disease in those with and without prior DENV infection will be compared to determine if previous DENV exposure alters resultant Zika disease. This information will provide crucial data to determine the full spectrum and medical sequelae from ZIKV in a naïve population.
Vector-borne diseases (VBD) pose a significant economic and public health threat throughout developingtropical regions worldwide, including the Caribbean. The introduction in December 2013 and rapid spread ofthe chikungunya virus (CHIKV) throughout all the Caribbean nations, and more recently the emergence of thezika virus in Suriname and Martinique highlights the need to develop regional capacity to investigate, predict,contain, and respond to VBD. For example, recent evidence from la Réunion suggests that CHIKV cannegatively impact neurodevelopment among infants born to mothers who were infected with the virus duringpregnancy. However, these results have not yet been replicated in other sites internationally – such as theCaribbean – nor have any longitudinal studies been carried out to follow children who have experiencedneurocognitive delay related to CHIKV infection. To address the paucity of data while building VBD researchcapacity in tropical LMICs where these diseases are endemic and the burden of impaired neurodevelopment isfelt most, researchers from St. George’s University (SGU) in Grenada will partner with researchers fromStanford University, Oxford University, and the Université de La Réunion to: (1) Determine the prevalence ofmother to child transmission of CHIKV in Grenadian pregnant mothers; (2) Measure the neurodevelopment ofchildren at 2 years of age exposed at different trimesters in utero to CHIKV and compare them with unexposedchildren; (3) Assess the burden of confounding factors to better understand the specific impact of VBD onneurodevelopment and inform public health priorities; (4) Build local capacity for arboviral andneurodevelopmental testing at SGU. To achieve Aim 1, 379 moms and their infants who were born during theCHIKV outbreak in Grenada, 473 moms and their infants who were born after the outbreak and may have beenexposed to the virus in utero, and 190 moms and their infants who were born at least nine months after theoutbreak (and thus, very unlikely to be exposed to the virus in utero) will complete a survey detailing the onsetand symptoms related to their CHIKV infection and will then be tested for exposure to CHIKV by ELISA. NonCHIKV-exposed infants and moms, CHIKV-exposed moms but not infants, CHIKV-exposed moms and infants,and time of exposure during pregnancy will be used to divide groups for neurocognitive comparison at 2-yearsof age. To achieve Aims 2 and 3, we will administer the intergrowth 21st Neurodevelopment Assessment – aholistic assessment of early child development developed at Oxford University – while controlling forconfounding neurodevelopmental factors. To achieve Aim 4, we will establish a Regional Center for ChildNeurodevelopment while addressing seven key areas of needed research support: (1) Financial (i.e., granting);(2) Expertise; (3) On-the-ground human resources; (4) Student trainees to build local capacity; (5) Equipment,IT, and facilities support; (6) On-the-ground university and research institute administrative support; and (7)Local and regional government, relevant NGO, and professional/academic institutional support.
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