IMPH Research in Infectious Disease

Caribbean, Central and South America Network for HIV Epidemiology (CCASNET) 
Determinants of Early Childhood Asthma and Atopy Following Infant RSV Infection 
Effectiveness of the Influenza Vaccine in the Aging Population 
Examination of Odorant Receptors in Vector Mosquitoes 
Expanded Testing, Linkage, and Treatment for HIV Prevention Among MSM in China 
Genetic & Structural Basis for Viral Neutralization: Vaccinia and Influenza Virus 
Helicobacter Pylori Blood Biomarker for Gastric Cancer Risk in East Asia 
Human Neutralizing Monoclonal Antibodies for Rift Valley Fever Virus 
Immune Response to H. Pylori Infection 
The Incidence and Etiology of Influenza-Associated Community-Acquired Pneumonia I 
LEDEA Networks Coordinating Center at Vanderbilt 
Long-Term Follow-Up of Cohorts Previously Treated for H. Pylori Infection 
Midcareer Investigator Patient-Oriented Research Award in Bronchiolitis & Asthma 
Molecular Determinants of Cross-Reactive Antibody Response to Influenza in Humans 
Multi-Component HIV Intervention Packages for Chinese MSM 
Optimizing Integrated PMTCT Services in Rural North-Central Nigeria 
Primary Prevention of Strokes in Nigerian Children with Sickle Cell Disease 
Rates of Rhinovirus Species in Adults and Children with Acute Respiratory Illness 
Rational Design of a Respiratory Syncytial Virus Vaccine to Prevent Asthma 
Studies on Emergent Diarrheagenic E. Coli Pathogens 
Tools to Reduce Infant RSV Morbidity and Asthma: Use, Adherence and Effectiveness

Caribbean, Central and South America Network for HIV Epidemiology (CCASNET)

The Caribbean, Central and South America network for HIV epidemiology (CCASAnet) is an established and productive network that is responsive to scientific opportunities arising in the region and across International Epidemiologic Databases to Evaluate AIDS (leDEA) regions worldwide. This successful collaboration, created during the first leDEA funding cycle, has resulted in the productive enrichment and merging of human and technological resources from HIV clinical care and research sites in Port-au-Prince, Mexico City, Tegucigalpa, Lima, Rio de Janeiro, Buenos Aires, and Santiago, and the Vanderbilt Data Coordinating Center (DCC). The Vanderbilt DCC will continue to effectively harmonize and analyze complex databases and manage the CCASAnet 2.0 consortium. The project will conduct and facilitate research using the shared data repository to answer questions that cannot be answered by any single source. The clinical outcomes and complications related to HIV infection and antiretroviral therapy in the region will be evaluated. Studies are proposed to determine the impact of infections other than HIV, particularly tuberculosis, hepatitis, and human papillomavirus. Factors uniquely related to adolescents and young adults with HIV will be addressed across the region. Innovative biostatistical and informatics methods will be developed and applied. Biologic specimen repositories will be established that will facilitate future translational research. Programs for mentoring and education to enhance clinical research and data management capabilities at CCASAnet sites, promote junior researchers, and catalyze ongoing growth of scientific leadership in the region will be implemented. By these activities, CCASAnet 2.0 will help advance both the science of HIV epidemiology, and the information science that underpins international research collaboration. RELEVANCE: The project seeks to articulate contemporary research questions that are important to the dynamics of the global HIV epidemic and other infectious diseases within CCASAnet consortium countries. The proposed research will increase the understanding of similarities and differences in patterns of HIV care and disease outcomes in the Caribbean and Latin America, and will address issues that are also compelling in other regional settings. Read more.

Funding Source: NIH/NIAID
PI: Catherine McGowan

Determinants of Early Childhood Asthma and Atopy Following Infant RSV Infection

RSV bronchiolitis and early childhood asthma are the most common, serious, acute, and chronic conditions of infancy and childhood, respectively, and diseases that disproportionately burden vulnerable populations. Opportunity and Impact. This project draws together three important elements in understanding the role of RSV on recurrent wheezing and asthma inception - RSV infection severity, host response and susceptibility. In studying the association of RSV with asthma inception, studies have overwhelmingly focused on the 3-5% of RSV-infected infants requiring hospitalization, while the vast majority of RSV infections are mild. Whether mild infection confers intermediate risk or has a protective effect is an important question. The answer will influence proposals for primary asthma prevention strategies. The proposed series of investigations will aid in our understanding of the role and mechanisms through which RSV may both lead to chronic lung disease, and may protect from chronic lung disease. Approach. Utilizing the ReSPIRA cohort, established for this investigation and described in Core B, we will investigate the relationship between infant RSV infection, host response to infection, and genetic determinants of recurrent wheezing, asthma and allergic disease development following RSV infection. Our specific aims are to: (1) Establish the association between RSV LRTI, RSV URI/exposure, and no RSV infection in the first 6 months of life on the risk of recurrent wheezing and asthma, (2) Define whether host immune response and/or airway injury biomarkers assessed during infant RSV infection are associated with recurrent wheezing, atopic disease or early childhood asthma, and (3) Identify the genetic determinants of the phenotype of recurrent wheezing, early childhood asthma and atopy following infant RSV infection. Utilizing the ReSPIRA cohort which includes 2000 infants followed from early infancy through early childhood, and established through this U19 grant, this project will answer the following questions: (1) how does RSV cause asthma, (2) does mild RSV infection during infancy increase or decrease the risk of asthma, and (3) what host factors are important in the progression from infant RSV infection to early childhood asthma. Answering these questions will allow us to develop preventive interventions for chronic lung disease in children, and ultimately improve the health of infants and children with bronchiolitis and asthma in the U.S. and worldwide. Read more.

Funding Source: NIH/NIAID
PI: Tina Hartert

Effectiveness of the Influenza Vaccine in the Aging Population

This study application is a secondary analysis of an existing database in response to the Program Announcement, PA-09-265: Secondary Analyses of Existing Data Sets and Stored BioSpecimens to Address Clinical Aging Research Questions (R01) to determine influenza vaccine effectiveness in older adults. Recent work has shown that more is needed to be known about influenza vaccine effectiveness in older adults and the methodology used to determine that vaccine effectiveness. This database is an accumulation of three studies that prospectively tested older adults for influenza. This data will be used to determine if the current methodology of test-negative controls will actually control for the bias of frailty, will determine vaccine effectiveness in the very old, and will explore if vaccne manufacturing process impacts effectiveness. Read more.

Funding Source: NIH/NIA
PI: H. Keipp Talbot

Examination of Odorant Receptors in Vector Mosquitoes

Chemosensory responses are critical components in the control of several essential behaviors of insects that are vectors for pathogens responsible for many important human diseases. In particular, olfaction plays a major role in host seeking and oviposition selection behaviors of blood-feeding female mosquitoes and, as such, constitutes a critical component of the mosquito's ability to transmit diseases such as malaria, dengue, yellow fever and West Nile virus encephalitis. Within this context, and together with our colleagues, we have undertaken a molecular and cellular examination of several elements of the olfactory signal transduction cascade in the principal African malaria vector mosquito Anopheles gambiae sensu stricto and the arbovirus vector Aedes aegypti. An increased understanding of olfactory mechanisms and their underlying chemical cues in these systems may provide insight into the processes of insect behavioral responses in general and disease transmission by vectors in particular and would likely be instrumental in the development of novel mosquito control strategies. We have made significant progress in the characterization of several aspects of olfactory process in both mosquito systems leading to, among other things, the identification and initial characterizations of a family of odorant receptor proteins in An. gambiae (AgORs) and Ae. aegypti (AaORs) that lie at the heart of the olfactory signaling pathway. Building on those advances, this proposal for competitive renewal focuses on extending several elements of our ongoing program including characterization of: (1) structure/function relationships between AgORs and AaORs, (2) the role of AgORs and cognate odorant binding proteins (AgOBPs) in the context of larval olfaction and odor coding in vivo and (3) the molecular events underlying oviposition site selection by gravid adult females. Read more.

Funding Source: NIH/NIAID
Pi: Laurence Zwiebel

Expanded Testing, Linkage, and Treatment for HIV Prevention Among MSM in China

The success of global HIV control efforts for men who have sex with men (MSM) will depend on how effective and sustainable the interventions are, but also how efficiently the intervention programs are implemented. A testable hypothesis is that a package of prevention interventions may have a substantial impact even if single approaches are less impressive. We further hypothesize that combination interventions will be even more sustainable than isolated interventions, due to improved community support of a popular package of services. One package of HIV-specific interventions has been termed "test-and-linkage-to-care" (TLC). The theory behind TLC is that the increase in the proportion of HIV-infected persons who know their status, are bridged to HIV combination antiretroviral therapy (cART)-based care, and who adhere to cART will reduce the amount of virus circulating in a community. TLC integrated with risk reduction intervention and formulated at the individual-level can facilitate one's engagement and commitment in care, reducing infectiousness to others at the same time that personal health is enhanced and restored. TLC seeks to reduce "community viral load," reducing the risk to uninfected persons by reducing the infectiousness of HIV-infected individuals. Our goal in this one-year clinical trial planning (R34) grant is to prepare for a community-level randomized clinical trial (RCT) to test the efficacy of our multicomponent TLC intervention package to reduce HIV incidence among MSM in China. By collaborating with Chinese CDC networks and local MSM community based organizations, we will develop all documents required for initiation of an RCT, complete all local, federal, and international human subjects and regulatory approvals necessary for implementation of the trial, and identify clinical trial sites and establish community advisory boards for a clinical trial. At the end of the study, we will have a RCT protocol ready for testing two research hypotheses: (1) MSM in communities receiving 24 months of TLC intervention will achieve a reduction in HIV incidence relative to MSM in standard prevention communities; and (2) TLC intervention will improve secondary and intermediary indicators of treatment success and risk reduction, compared to the standard prevention approaches. PUBLIC HEALTH RELEVANCE: Our study proposal represents an innovative adaptation of an integration of biomedical and behavioral methods of HIV prevention whose promise is supported by epidemiological data, but has never been tested in a clinical trial design in China. This grant will prepare a clinical trial in which men who have sex with men (MSM) in China who are unaware of their status will be tested and those HIV-infected MSM will benefit from prolonged life by available cART. The patient-centered prevention will be able to target the unrecognized individuals with HIV infections or at high risk of contracting HIV such that the further transmission can be prevented effectively. Read more.

Funding Source: NIH/NIAID
PI: Sten Vermund

Genetic & Structural Basis for Viral Neutralization: Vaccinia and Influenza Virus

The goal of the B Cell Epitope Discovery and Mechanisms of Antibody Production program is to identify novel B cell epitopes and elucidate novel mechanisms of antibody-mediated protection or pathogenesis that are important in humoral immunity in humans to emerging and re-emerging infectious diseases and potential agents of bioterrorism and their toxins. Results from this B cell epitope discovery program will advance our understanding of antibody functions and greatly facilitate the design and development of improved immunotherapeutics, diagnostics, and vaccines. In addition, an expansion of the list of known B cell epitopes and antibody functions will facilitate the development of more robust algorithms and mathematical models to predict B cell epitopes and antibody-mediated immune responses to pathogens and toxins in vivo. This specific contract will identify epitopes of influenza virus and vaccinia virus. Read more.

Funding Source: NIH/NIAID
PI: James Crowe

Helicobacter Pylori Blood Biomarker for Gastric Cancer Risk in East Asia

Infection with Helicobacter pylori is the leading risk factor for gastric cancer, the second-most deadly and fourth-most common cancer in the world, yet only a fraction of those infected will develop the disease. Utilizing novel H. pylori multiplex serology in a nested case-control study in China, we have recently found a novel biomarker panel that could identify individuals with a 10-20% absolute risk of gastric cancer, and are now seeking to determine if we can replicate and validate this finding in other prospective cohorts in East Asia most likely to be infected with similar bacterial strains. As H. pylori eradication therapy can effectively reduce gastric cancer incidence and mortality, a validated risk prediction model in high-incidence populations will create the opportunity to substantially decrease the burden of gastric cancer through targeted prevention strategies among H. pylori-infected individuals at highest risk, while reducing unnecessary antibiotic use among those at low risk. Read more.

Funding Source: NIH/NCI 
PI: Meira Epplein

Human Neutralizing Monoclonal Antibodies for Rift Valley Fever Virus

Rift Valley fever (RVF) is a viral zoonosis that most commonly causes disease in animals, but also can cause severe human disease. The virus is a member of the family Bunyaviridae, genus Phlebovirus and has been designated a Category A agent. The virus is most common in the Rift Valley of East Africa, especially Kenya, Somalia and Tanzania, but also has now spread outside the African continent to Saudi Arabia and Yemen. Experts have raised concerns that this infection threatens to spread further geographically. Very little is understood about human immunity to RVF. Vaccine candidates are being tested. One is an inactivated vaccine principally developed by the U.S. Army. The Army has developed and tested an improved version of inactivated RVF vaccine, designated TSI-GSD-200. At-risk workers at the US Army Medical Research Institute of Infectious Diseases (USAMRIID) were vaccinated as part of an occupational safety and health program. The second involves intramuscular (IM) injection of live-attenuated, mutagenized RVF 12th mutagenesis passage (MP-12) vaccine, which has progressed to Phase II trials, also being studied by USAMRIID. The central hypothesis of this study is that survivors of Rift Valley fever (RVF) virus infections likely possess circulating B cells encoding naturally-occurring human antibodies (Abs) that neutralize virus and protect against disease. The key requirements for successful treatment of RVF infections with monoclonal antibodies (mAbs) may include (A) use of high-affinity mAbs, and (B) administration of a cocktail of mAbs binding to the diverse viral epitopes, rather than an individual mAb. This possibility will be tested by generation of comprehensive reagents for study of RVF recognition by human Abs that will be used to define the determinants of neutralization of RVF. This proposal incorporates experts in molecular immunology and RVF virology and viral pathogenesis with access to CDC/USDA approved BSL-3 enhanced (BSL3+) facilities. We have access to blood of survivors of RVF from East Africa. In addition, we have access to blood from research subjects who were previously inoculated with inactivated or MP-12 vaccine. The proposed research is significant because it will result in generation of large panels of human mAbs that neutralize RVF, and can be used as therapeutic Abs, and the molecular, genetic, and structural basis for development of neutralizing mAbs made by survivors or vaccinees. Understanding the principles underlying molecular recognition of RVF will have a broad impact on the rational design of therapeutic Abs and development and testing of vaccines against RVF and other emerging and biothreat viruses. Read more.

Funding Source: NIH/NIAID
PI: James Crowe

Immune Response to H. Pylori Infection

The host immune response plays a critical role in determining disease manifestations of chronic infections. Inadequate immune response may fail to control infection, although in other cases the specific immune response may be the cause of tissue damage and disease. The majority of patients with chronic infections are likely to be infected by more than one organism; however, the interaction between multiple active infections is not known, nor is the impact on disease outcome clear. Chronic infections such as Helicobacter pylori are the cause of considerable morbidity and mortality, worldwide. Unlike acute infections, where the "one microbe- one disease" concept can be applied, disease caused by chronic infectious organisms more likely represents interactions between the infecting organism(s) and a multitude of hosts and environmental factors including interaction with other infectious agents [1]. We and others have demonstrated the high incidence of helminthiasis in select Colombian populations, particularly children (2,3]. Our preliminary studies [2] suggest that the immune response to H. pylori infection in the low-risk coastal population is predominantly type Th2 and that it may be related to intestinal helminthiasis. This observation is consistent with our report that intestinal helminthiasis reduced gastric atrophy, a premalignant lesion, in the C57BL/6 mouse model of Helicobacter gastritis [4]. Our recent studies in gerbils demonstrating an H. pylori-associated attenuation of premalignant lesions in gerbils coinfected with Brugia sp. also support this hypothesis. In these proposed studies, we will test the hypothesis that progression to gastric cancer is influenced not only by the genotype of H. pylori (i.e., the ability of H. pylori strains from patients in regions of high gastric cancer risk areas to cause more nitrosative and oxidative damage vs. H. pylori strains in low gastric cancer risk areas) [5], but also by concun-ent infection with parasites which can modulate systemic immune responses and the Th1/Th2 gastric cytokine profile. RELEVANCE (See Instructions): The host immune response is important in determining how an individual responds to the chronic infection in the stomach caused by Helicobacter pylori. These immune responses play a critical role in predicting why certain patients with H. pylori infection develop gastric cancer. Read more.

Funding Source: NIH/NCI 
PI: James Fox

The Incidence and Etiology of Influenza-Associated Community-Acquired Pneumonia I

Pneumonia remains the leading infectious cause of morbidity and mortality in the United States. In spite of its substantial public health burden, recent measurements of pneumonia incidence in the United States are surprisingly scarce and differences in research methodologies make the comparison of available estimates problematic. Moreover, our current knowledge of the distribution of etiologic organisms for community-acquired pneumonia (CAP) is limited and largely based on case series or studies performed decades ago or abroad. The availability of novel molecular techniques provides opportunities to reassess this knowledge systematically. Without current large-scale population-based studies to inform clinicians about the most likely etiologies of pneumonia and the identification of resistant organisms, clinicians would continue to assess and treat patients with pneumonia as they have for the past several decades. Since January 2010 we have conducted active population-based surveillance for pneumonia in subjects of all ages through the CDC-funded study, "The incidence and etiology of influenza-associated pneumonia in hospitalized persons." The procedures for enrolling and testing eligible pneumonia patients have been well established; data collection forms have been developed and tested; CDC-endorsed laboratory procedures have been established; extensive data are now being collected and systematically entered into the master project databases; and radiographs from each pneumonia case are being evaluated by study radiologists. With these well established study methodologies and experience, we are well positioned to continue the CDC-funded pneumonia project for two additional years. We propose to use our existing infrastructure, skilled personnel, network capabilities, and previous experience to perform a multicenter, population-based, prospective cohort study to determine the incidence and etiologies of pneumonia leading to hospitalization for both children and adults. Our project encompasses the following specific aims: 1)To determine the incidence of hospitalization for community- acquired pneumonia in children and adults living in Middle Tennessee; 2) To determine the relative contributions of the different respiratory pathogens to the etiology of community-acquired pneumonia in children and adults hospitalized in Middle Tennessee; and, 3)To establish the burden of influenza associated with community-acquired pneumonia in children and adults hospitalized in Middle Tennessee. Read more.

Funding Source: NIH/NCIRD 
PI: Kathryn Edwards

LEDEA Networks Coordinating Center at Vanderbilt

Vanderbilt University has been integrally involved in the leDEA network via its activities as an active CCASAnet (Caribbean, Central America, South America region) data center. With its proven track record as a coordinating center for the Fogarty International Clinical Research Scholars and Fellows Program and the Vanderbilt-CIDRZ AIDS International Training and Research Program, as well as its established expertise in communications, graphics design/web development, HIV/AIDS clinical care and guidelines development, as well as international HIV/AIDS research, Vanderbilt University proposes a multi-tiered and innovative approach in its role as coordinating center for the leDEA network. Our primary aims include: 1. To support the coordination and implementation of leDEA-specific meetings and develop and enhance communications including investigator and specialty conference calls; 2. To transform the leDEA website into an online Community of Practice, with both password-protected internal, and open external sections for public access; and 3. To provide the requisite technical assistance and scientific leadership for the harmonization of data, standardization of clinical definitions, and dissemination of quality assurance practices across the network in order to advance the leDEA scientific agenda and foster multi-regional research projects within the leDEA consortium. Vanderbilt proposes significant enhancements and innovations to the leDEA website, including a web-based content management system to facilitate true networking and collaboration, and enhanced data coordination for multi-regional leDEA projects, site assessment surveys using a Research Electronic Data Capture system, and assistance to increase the quality of data collection. In summary, through the leDEA Network Coordinating Center at Vanderbilt, the leDEA network should expect far more than meeting, conference call, and web support (all of which we will do very well), but also vital technical assistance, support, and expertise while providing a novel approach to data management and analysis capacity. Read more.

Funding Source: NIH/NIAID
PI: Mary Lou Lindegren

Long-Term Follow-Up of Cohorts Previously Treated for H. Pylori Infection

While Helicobacter pylori is now established as a pivotal factor in gastric carcinogenesis, its mechanisms of action and timing in the premalignant process are the subject of research. This project builds upon a recently completed 12-year randomized chemoprevention trial in a high-risk region of Colombia. A significantly greater regression of premalignant lesions was observed in study participants who were treated and were cleared of H. pylori infection. Upon completion of the trial, participants who had not been in the ant\-H.pylori treatment arm were offered standard triple therapy. Quarterly contact has been maintained with trial participants, and this project now proposes to evaluate the long-term effectiveness of anti-H.py/or/treatment in an adult population in which the community prevalence of infection is greater than 90%. A cohort of children has been followed-up for 6 years, String tests to culture H. pylori and stool samples to extract DNA are obtained periodically. The specific aims of the study are to: 1. Conduct endoscopy survey, gastric biopsies, and cultures at 18 and 20 years after intervention 2. Test biomarkers of progression of the precancerous process, mainly methylation of CpG islands 3. Genotype Helicobacter pylori at different ages and different stages in the precancerous process RELEVANCE (See instructions): This project provides information of the long term effects of treating patients with antibiotics to cure their infection with the bacterium Helicobacter pylori. The original treatment took place in 1992-1993. How effective the treatment was in preventing cancer development will be investigated. Read more.

Funding Source: NIH/NCI
PI: Pelayo Correa

Midcareer Investigator Patient-Oriented Research Award in Bronchiolitis & Asthma

Asthma is the result of host and environment interactions. Lower respiratory tract infections (LRTI), caused by viruses such as respiratory syncytial virus (RSV) and rhinovirus (RV), are a leading cause of bronchiolitis in infants. Infants hospitalized with bronchiolitis not only experience significant morbidity, but are also at significantly increased risk for both recurrent wheezing and childhood asthma. We have established that respiratory syncytial viral infections appear to directly contribute to asthma causation, not just simply identify persons at risk for subsequent wheezing. Viral infections outside the infant period are also important, as they are modifiable environmental factors that have been established to be the most common cause of asthma exacerbations in both children and adults. This proposal uses a combined, parallel clinical and experimental approach to evaluate the contribution of, causality, and mechanisms through which respiratory syncytial virus, and human rhinovirus, contribute to asthma development and disease natural history. These studies all relate to the central hypothesis that viruses, as one significant environmental factor, alter the risk for developing asthma, as well as the natural history of prevalent disease. Specific testable questions related to this hypothesis include: 1) to determine the host factors among those with RSV and HRV infection that contribute to asthma development, 2) to determine the timing of infection during infancy and how that impacts the risk of developing childhood asthma; 3) to determine the mechanisms through which RSV and HRV contribute to asthma development, specifically focusing on lung injury and differential immune response to infection; 4) to determine if there are allelic variations in host genes involved with severity of respiratory viral infection that correlate with a predisposition or resistance to both infant bronchiolitis and childhood asthma; 5) to determine if there are allelic variation in RSV genes that are associated with both infant LRTI severity, and subsequent risk of asthma development. PROJECT NARRATIVE The aims of this mid-career investigator award will be met by allowing the candidate to translate her experimental expertise to both mentor trainees and to direct patient-oriented studies of the progression and functional outcome of childhood viral illness in asthma development, moving from risk factor determination to intervention studies, and ultimately to disease prevention. Read more.

Funding Source: NIH/NIAID
PI: Tina Hartert

Molecular Determinants of Cross-Reactive Antibody Response to Influenza in Humans

Work in Project 2 will explore exciting recent developments in the study of cross-reactive immunity to influenza viruses.The goal of this project is to determine the molecular and structural basis for broadly erbss-reactive human mAb responses to influenza HAs; As the epitope sequences and structures reccjgnized by broadly cross-reactive Abs are defined, we will be better able to rationally design broadly protective immuriogens. The work seeks to investigate the repertoire of human Abs recognizing three principal Gonserved regions of the HA molecule; a canonical stalk domain epitope, the long alpha-helix stalkdomain, and the globular head domain. The hypothesis is that, unexpectedly, there are at least three immunogenic domains in influenza HA that retain highly conserved structural features and that most adult healthy subjects do possess circulating cross-reactive B cell clones to these conserved sites on HA. These domains are complex, however, and relatively inaccessible-for conventional Ab structures, w e have developed robust technologies for isolating human mAbs that reveal the relatively frequent nature of eross-reactive B ceils, and the genetic'arid structural basis for broad cross-reactivity of the secreted Abs for influenza viruses of diverse subtypes. We hypothesize that such cross-reactivity is driven by unusual features in the Ab repertoire^ especially an exceptionally high levefof somatic point mutations and somatic insertions. This highly interactive project will engage in collaborative work with Project 1 to determine mAb-HA co-crystal structures. Project 4 to study the biology of viral escape mutant viruses,; Project 5 to examine the effect of mutants on DCs, and will use the Glycan Array core to study glycosyiation in escape sites and the Animal Core to determine in vivQ potency of antibodies. Studies of such Abs and the sites recognized by them will inform the rational design of universalinfluenza vaccines based on the underlying principles of heterosubtypjc immunity; The stalk domain is of interest because highly eross-reactive Ab have been identified that recognized a conserved region in this area. However, the rare Abs identified to date do not possess both group 1 and 2 specificities, , In preliminary datBi we show that it is possible to isolate such Abs. Using these unusual reagents, we will define the basis for the group determinants or conserved elelmentS: by mapping the interaction of large panels of new Abs to the: stalk;region. We also will seek to isolate novel human Abs from human subjects that recognize the stalks of both major HA antigenic groijps. The head domain is better studied, however there are only rare Abs:that exhibit cross-reactiyity for ahtigenically distinct HAs. By large-scale sci-efening of B cells from subjectis immunized with seasonal and experimental vaccines, we have identified cross-reactive Abs that i-ecdgnize the head domain of HAs of multiple subtypes of influenza. By epitope mapping using biochemical arid biologic studies, coupled with studies to determine co-crystal stuctures, we will determine the structural basis for cross reactivity. Read more.

Funding Source: NIH/NIAID
PI: James Crowe

Multi-Component HIV Intervention Packages for Chinese MSM

There is no proven effective prevention intervention specifically for men who have sex with men (MSM) population. Bundling partial measures and optimize combinations of interventions may have a substantial impact on HIV seroincidence. The goal of this study is to develop and pilot test a package of Test and Link-to-Care (TLC)-based interventions for preparation of future community-level randomized clinical trial. The specific aims are: (1) To conduct a systematic review of the literature and mathematical modeling to guide the selection of HIV prevention interventions for MSM in China; (2) To conduct a pilot study to evaluate the feasibility, acceptability and initial efficacy of a multi-component TLC intervention packages among MSM in China; and (3) To refine and finalize menu-driven HIV prevention packages and design a multi-site randomized clinical trial in 12 Chinese cities to evaluate its impact on HIV seroincidence among Chinese MSM. As a team of an expert network of American and Chinese researchers and community members with rich knowledge in the subject domains and substantial experience in China, we will develop a culturally competent and potentially effective intervention packages for Chinese MSM at the end of this project. The rapid rise of HIV epidemic among Chinese MSM and the comprehensive disease prevention networks in China provide unique environment for conducting a large scale community-based clinical trial. PUBLIC HEALTH RELEVANCE: These sustainable intervention packages, if proven feasible and effective, will be adopted in future research and public health programs for preventing new HIV infections and improving the lives of HIV-infected MSM. This MP3 grant is to develop and pilot test a multi-components prevention intervention package of Test and Link-to-Care (TLC) strategy to reduce HIV transmission by engaging expanded HIV testing with prompt initiation of risk reduction intervention and optimal antiretroviral treatment among a HIV high risk but largely ignored population-men who have sex with men (MSM) in China. These sustainable intervention packages, if proven feasible and effective, will be adopted in future research and public health programs for preventing new HIV infections and improving the lives of HIV-infected MSM in China and other parts of the world. Read more.

Funding Source: NIH/NIAID
PI: Sten Vermund

Optimizing Integrated PMTCT Services in Rural North-Central Nigeria

In resource-limited settings progress in scaling up services for prevention of mother-to-child transmission of HIV (PMTCT) continues to lag behind the rest of the world. Nigeria has one of the highest burdens of mother-to-child transmission of HIV in the world. The elimination of mother-to-child transmission of HIV in Nigeria will require innovative methods of PMTCT service delivery at the lowest level of the health care system, consistent with appropriate, feasible and effective care. The goal of this study is to implement and evaluate the impact of a family- focused integrated PMTCT package comprising task shifting, point-of-care CD4 testing, and a prominent role for influential family members (particularly male partners) in rural primary health centers in Nigeria. The specific aims of this study are: (1) To evaluate whether implementation of the integrated PMTCT package in primary level antenatal clinics increases the proportion of eligible pregnant women who initiate antiretroviral medications for the purposes of PMTCT; (2) To determine whether implementation of the PMTCT package improves postpartum retention of mother-infant pairs at 6 weeks; and (3) Conduct a cost-effectiveness analysis of the impact of this novel PMTCT intervention compared to the existing standard-of-care referral model. We have assembled a strong team of Nigerian and American scientists with expertise in PMTCT cluster randomized trials, adherence and retention in care, HIV risk behavior, cART outcomes, and cost-effectiveness analysis of HIV programs. We include a rigorous study design and triangulation of data collection methods (quantitative outcomes, cost effectiveness analysis, qualitative surveys) that will yield valuable complimentary data. We will build on existing in- country PEPFAR infrastructure, established partnerships, and strong local presence, thereby increasing the likelihood of successful study implementation. Read more.

Funding Source: NIH/NICHD
PI: Muktar Aliyu

Primary Prevention of Strokes in Nigerian Children with Sickle Cell Disease

Sickle cell disease (SCD) is the most common genetic disease in the world. Approximately 150,000 Nigerian children are born each year with SCD, making it the country with the largest burden of sickle cell disease in the world. SCD is the most common cause of stroke in children and results in considerable morbidity in affected children. The current primary prevention approach of regular monthly blood transfusion therapy of children at high risk of stroke (identified by elevated transcranial Doppler measurements) is not feasible in a low income country such as Nigeria due to scarcity of supply, cost, and high rate of blood borne infections. In the United States, hydroxyurea (HU) is standard therapy for adults with SCD and may be a reasonable prevention alternative to regular blood transfusion for treatment of primary stroke in high-risk children. Given large absolute numbers of individuals with SCD in Nigeria, HU therapy for all individuals with SCD may not be initially feasible; however, a targeted strategy of HU use for primary prevention of strokes is an alternative to the standard therapy (observation) for high-risk individuals. We therefore propose a feasibility study to determine the acceptability of randomization to HU vs. placebo for primary prevention of strokes in Nigerian children with sickle cell anemia (SCA) in preparation for a NIH sponsored multicenter, phase III Trial. We will establish a safety protocol for using HU in a clinical trial setting and complete the necessary preparations for a definitive phase III trial. To accomplish these aims we have assembled a strong multidisciplinary team representing Vanderbilt University and two premier in-country institutions: Aminu Kano Teaching Hospital, Nigeria, and Friends in Global Health-Nigeria. Completion of a definitive trial will not only benefit children wth SCA in sub-Saharan Africa, where the majority of children with SCA live in the world, but could provide reasonable evidence for an alternative to blood transfusion therapy for the primary prevention of strokes in the US. To our knowledge this would be the first stroke prevention trial in Nigeria and could establish a precedent to expand to secondary stroke prevention for children and adults with SCA, as regrettably, no therapy is available to prevent recurrent stroke in these high-risk patients in resource-poor nations. Read more.

Funding Source: NIH/NINDS
PI: Michael Debaun et al.

Rates of Rhinovirus Species in Adults and Children with Acute Respiratory Illness

Human rhinoviruses (HRV) are the leading cause of the common cold and more recently have been implicated in lower respiratory illness, in infants and children. While many respiratory viruses have been associated with asthma exacerbations, HRV are the most common trigger of asthma exacerbations and chronic obstructive pulmonary disease (COPD) in children and adults. The rates of HRV-associated acute respiratory illness medical visits in US adults are not known. Recently, a new group of HRV designated HRVC was identified that may associate with asthma and COPD exacerbations. The impact of the novel HRVC on US adults has not been established, and the association of HRVC with obstructive wheezing diseases such as asthma and COPD is unclear. We propose to define the role of HRV and the novel HRVC group in adults and children seen as outpatients or hospitalized with ARI/fever, including those with asthma or COPD exacerbation. The central hypotheses of our proposal are that HRV are commonly associated with ARI/fever in adults and children and that HRVC associate with wheezing and more severe respiratory disease. The results of the proposed research will help guide vaccine development and elucidate mechanisms of virus-induced asthma. The findings of this work may lead to new approaches to treat and prevent asthma. We propose three Specific Aims: 1) to determine the rates of HRV in adults and children who seek medical care for acute respiratory illness (ARI) or fever, 2) to determine the rates of HRV species A, B, and C that are associated with ARI/fever in adults and children seen in different clinical settings, and 3) to determine rates of HRV and HRV species associated with obstructive wheezing illness such as asthma and chronic obstructive pulmonary disease (COPD) among adults and children. This research allows us to understand the burden of HRV and HRVC in US adults and children, as well as which HRV genotypes affect certain age groups, and elucidates the relationship between severity and type of respiratory disease and viral species. This may ultimately allow for a more targeted vaccine to be developed against HRV and may shed light on certain groups, such as those with asthma or COPD, at risk for more severe HRV-associated disease. Read more.

Funding Source: NIH/NIAID
PI: Eva Kathryn Miller

Rational Design of a Respiratory Syncytial Virus Vaccine to Prevent Asthma

Respiratory syncytial virus (RSV) severe lower respiratory tract infections (LRTIs) in infants and young children associate with 25-80% greater subsequent rates of recurrent wheezing, airways hyperreactivity (AHR) and asthma compared to same age children not experiencing severe RSV LRTIs. Some of these severe RSV LRTIs may identify those infants genetically predisposed to develop asthma at older age, but epidemiological studies and animal models suggest that severe RSV LRTIs may also specifically contribute to asthma inception. In fact, enough evidence exists today to consider a potential role for protective RSV vaccines in decreasing pediatric asthma rates by preventing severe RSV LRTI. Interestingly, and in line with the overwhelming evidence supporting the Hygiene Hypothesis, upper respiratory tract infections (URTIs) during infancy have been shown to decrease the rates of pediatric asthma and AHR. Moreover, epidemiological data, studies in animal models, and preliminary data from our laboratory support the hypothesis that a rationally designed live attenuated intranasal (IN) RSV vaccine (mimicking an RSV URTI) may contribute to modulate the development of immunity in the host and prevent asthma inception. Data from others and our laboratory show that RSV and its main protective antigen, the fusion (F) protein, can elicit a long-lived natural T regulatory (nTreg) lymphocyte response, presumably through Myd88-dependent activation, negatively modulating asthma inception. In addition, animal and human data from our laboratory demonstrate that RSV can downregulate TLR4 expression in the respiratory tract. TLR4 expression in the respiratory epithelium is critical for the inception f asthma in the classic house dust mite (HDM) model of disease. Therefore, if all these observations - which we propose to study- are confirmed, rationale design of an RSV vaccine considering the aforementioned effects, may change the landscape of pediatric asthma by: I) protecting against the pro-asthmatic effects of RSV LRTI, and 2) "maturing" host immunity. Understanding the protective effects of RSV vaccines and the virus glycoproteins against the inception of asthma, and their mechanisms of risk modulation, can lead to the rationale design of a pediatric vaccine working simultaneously against two critical pediatric diseases. Our Specific Aims are: Aim 1. Determine whether intranasal immunization using RSV surface glycoproteins F and G modulates the inception of asthma. Aim 2. Determine whether RSV F vaccines decrease inception of asthma by expanding nTregs through Tlr2 activation and downregulation of Tlr4 expression in respiratory epithelium. Aim 3. Determine whether IN immunization with cptsRSV248-404 prevents the inception of asthma. Read more.

Funding Source: NIH/NIAID
PI: Fernando Polack

Studies on Emergent Diarrheagenic E. Coli Pathogens

Childhood diarrhea leads to 2 million deaths every year among children less than 5 years of age mainly in underserved countries. E. coli pathogens are believed to be the second most common cause of death after Rotavirus. Six categories of diarrheagenic E. coli have been known to cause diarrhea, yet, recent studies by our group have identified a new diarrheagenic category designated localized adherent E. coli (LAEC) that is significantly associated with childhood diarrhea in Colombia, South America. The long term goal of this study is to understand the epidemiology and the molecular mechanisms of pathogenesis of this new LAEC emergent pathogen. The first specific aim proposes to evaluate the frequency and association of LAEC with childhood diarrhea by conducting two international multicenter case-control studies. We hypothesize that LAEC is associated with childhood diarrhea in children less than 5 years of age living in developing countries. The second specific aim will explain how LAEC virulence factors are essential to cause disease in a piglet model of human infection. We hypothesize that the type IV bundle-forming pilus and a novel type III secretion system directing bacterial-cell invasion are directly associated with the pathogenesis of LAEC diarrhea. The last specific aim will conduct genome DNA sequencing analysis of LAEC strains to identify the genetic elements that resulted in the emergence of LAEC as a pathogen. We hypothesize that LAEC shares in common well defined virulence genes that were acquired by horizontal gene transfer. This project if significant because it will bring fundamental knowledge on the epidemiology, genetics, and pathogenesis of LAEC and will generate molecular biology tools to facilitate future studies on LAEC diarrhea epidemiology, prevention measures and vaccine. Read more.

Funding Source: NIH/NIAID
PI: Oscar Gomez

Tools to Reduce Infant RSV Morbidity and Asthma: Use, Adherence and Effectiveness

One ubiquitous and modifiable environmental factor associated with both significant infant morbidity, as well as asthma development, is infant respiratory syncytial virus (RSV) infection. While most children who experience RSV infection have mild symptoms, a significant minority experience more severe disease, often requiring hospitalization and sometimes intensive care. We, and others, have shown that, among children with RSV infection severe enough to require medical attention, the severity of the infection has a strong association with subsequent development and severity of asthma. In addition, we have shown a causal relationship between RSV-attributable infant illness and childhood asthma inception. Because an RSV vaccine is not currently available, RSV immunoprophylaxis is the only currently available alternative approach, licensed for use in preventing RSV-attributable morbidity in high-risk infant groups. RSV immunoprophylaxis been evaluated in children who experience excessive RSV morbidity. While there have been a number of randomized clinical trials that have enrolled selective populations investing significant resources to ensure adherence that have established "efficacy" (can it work?), the "effectiveness" (does it work?) data are limited and conflicting. No investigations have assessed patterns of use, adherence, and effectiveness in US Medicaid and insured "real world" populations. Neither are there any investigations of the impact of reducing RSV infant morbidity on long-term outcomes such as asthma. These are critically important questions to answer in informing policy for the most costly preventive therapy in pediatrics, and in assessing effectiveness of our only currently available "tool" for decreasing infant RSV morbidity. Lastly, neither are there investigations of the more long-term impact of reducing RSV infant morbidity on the development of asthma, a lifelong chronic disease known to be more common among most groups of children considered high-risk for RSV. In three specific aims utilizing two denominator-based study populations of children enrolled in Tennessee Medicaid and six Kaiser Permanente-Northern California integrated medical care practices, we will study infants born between 1995 and 2008 and followed longitudinally to: (1) Determine RSV immunoprophylaxis utilization patterns and adherence; (2) Determine the effectiveness of RSV immunoprophylaxis on RSV hospitalizations and outpatient visits as well as comparative effectiveness with birth timing; and (3) assess the impact of RSV immunoprophylaxis on asthma inception, estimate the effect size, and compare the impact of RSV immunoprophylaxis on asthma inception with the effect we have shown of timing of birth on reducing childhood asthma. Read more.

Funding Source: AHRQ
PI: Tina Hartert