COBRE

Grants

NIH / NIAID / 1R01AI149502-01, 05 June 2020 - 31 May 2024
Multiplex Serodiagnostic Assays for Pathogenic Arboviruses in Brazil: A critical need exists for highly sensitive and specific serodiagnostic tests to discriminate infections by pathogenic arboviruses in geographic regions, such as Brazil, where multiple flaviviruses including Zika virus (ZIKV), four serotypes of dengue virus (DENV1-4), West Nile virus (WNV), and yellow fever (YFV), as well as chikungunya virus (CHIKV), Mayaro virus (MAYV) (both alphaviruses) and Oropouche virus (OROV) (a bunyavirus), are endemic. However, cross-reactivity of antibodies against different flaviviruses present major challenges, such that even neutralization tests cannot confirm a specific flavivirus infection among individuals who have experienced previous flavivirus infections. The objective of the proposed research is to develop highly sensitive and specific serodiagnostic tests to discriminate infections by pathogenic arboviruses. The central hypothesis is that a combination of fusion loop (FL)-mutated VLPs and nonstructural protein 1 (NS1) proteins of different flaviviruses and recombinant proteins and VLPs of CHIKV, MAYV and OROV in multiplex formats can distinguish different arbovirus infections. The first Aim is to develop and validate multiplex IgG and IgM microsphere immunoassays (MIAs) based on recombinant proteins to distinguish arbovirus infections. We will employ recombinant NS1 proteins of 7 flaviviruses, envelope (E) 2 protein and nucleocapsid (N) protein of CHIKV, MAYV and OROV for multiplex IgG and IgM MIAs using Luminex 200 and test with 15 panels of convalescent-phase serum/plasma from individuals with confirmed arbovirus infections. The second Aim is to develop and validate multiplex IgG and IgM MIAs based on VLPs to distinguish arbovirus infections. We will use purified and FL-mutated VLPs of 7 flaviviruses and VLPs of CHIKV, MAYV and OROV, and test with 15 panels of serum/plasma as in Aim 1. The third Aim is to compare the multiplex IgM MIAs and IgG MIAs with currently available serodiagnostic assays to determine arbovirus seroprevalence in Bahia, a northeastern state with multiple arbovirus transmissions in Brazil. For serodiagnosis, we will test serum samples from patients with acute febrile illness and their follow-up at outpatient clinics of 4 study sites (Salvador, Feira de Santana, Itabuna and Campo Formoso) in Bahia. For seroprevalence study, we will enroll and test household members at communities of the 4 study sites. The proposed study is innovative as it employs two promising antigens (NS1 protein and FL-mutated VLPs) to overcome flavivirus cross-reactivity for seven flaviviruses, as opposed to traditional E protein-based tests, plus CHIKV, MAYV and OROV in two multiplex formats to discriminate arbovirus infections in Brazil. It would contribute to a detailed understanding of the epidemiology of 10 arbovirus infections in Bahia. The successful employment of the multiplex platforms can serve as a new paradigm for serodiagnosis and serosurveillance in countries where multiple arboviruses co-circulate. Most importantly, this research will facilitate the implementation of arbovirus vaccines, in particular ZIKV, DENV and CHIKV vaccines in endemic regions.
Centers for Disease Control / 1 U01GH002256-01, 30 September 2019 - 29 September 2024
Epidemiology and Immunity to Ebola Virus and Other Emerging Viral Infections in Liberia: Liberia, a resource rich but economically poor country, continues to struggle with growth and recovery following a 14-year civil war that destroyed its infrastructure. The 2014-16 Ebola Virus Disease (EVD) epidemic had a devastating impact in West Africa resulting in 10,678 suspected, probable and confirmed cases and 4,810 deaths in Liberia. As not all individuals infected with Ebola virus (EBOV) sought medical attention or received laboratory confirmation of EVD, the full magnitude of the outbreak is still unknown. While the West African outbreak permitted advancement of scientific inquiry into the natural history, sociobehaviorial context, and effectiveness of countermeasures for EVD, significant gaps in knowledge remain about post-Ebola sequelae, immune responses to Ebola virus infection and disease, and durability of immunity over time. Another subject of concern is the persistence of EBOV in immunologically protected sites of EVD survivors (and potentially undiagnosed Ebola virus infections). Persistent infection has resulted in sexual transmission of the virus and subsequent clusters of disease following the end of widespread transmission. This viral persistence combined with minimal available seroepidemiological surveillance data for Ebola and other viruses with epidemic potential in West Africa poses a continued risk for resurgence of Ebola virus infection or disease cases and the possibility of new clusters or large-scale outbreaks originating from previously reported or unrecognized infections. In line with the mission of CDC, this project is aimed at establishing a serological baseline for a future surveillance platform, allowing the study of underlying etiologies, characteristics, and response to emerging infections. This will advance our combined knowledge on priority epidemic-prone viral diseases in Liberia, allowing development of strategies to prevent future outbreaks through a combination of conventional, targeted serosurveillance and disease and intervention modeling. We propose to address the overall research goals with the following four Specific Aims: (1) Develop and optimize virus-specific antibody-detection assays. Multiplex immunoassays for detection of antibody responses to relevant viral antigens will be further refined. (2) Establish assays to document cell-mediated immune responses in humans against emerging viral pathogens. Cell-mediated immunity in survivors of Ebola and Lassa virus infections will be documented using flow cytometry and transcriptome analysis to develop an immunological signature for these infections. (3) Determine a serological baseline of evidence of Ebola virus and other emerging viral infections throughout Liberia. Samples from all health districts in Liberia will be collected and analyzed for evidence of prior viral infections. (4) Conduct temporal assessment of the immune status and associated health outcomes in Ebola and Lassa virus symptomatic and asymptomatic survivors in comparison to the seronegative population. Following cohorts of persons previously infected with EBOV or Lassa virus will allow establishment of a time course for waning immunity to these priority pathogens.
NIH/FIC / 1D71TW010434-01A1, 08 September 2017 - 31 August 2019
Sustainable Research Training and Capacity Building in Liberia for Emerging Viral Epidemics : Liberia, a resource rich but economically poor country, continues to struggle with growth and recovery following its 14-year civil war that destroyed its infrastructure. During the recent Ebola virus (EBOV) epidemic, Liberia had fewer than 100 physicians and needed help from the international community for its control. The assistance Liberia received largely improved physical resources (e.g., laboratory equipment and containment facilities), but did not significantly increase human resources. Today, the healthcare workforce has only ~25% of the nurses, midwives, and pharmacists, and 9% of the physicians the country needs. For Liberia to develop sustainable research capacity for early identification and control of emerging viral diseases with the potential for regional and global pandemics, Liberia needs a mechanism to garner students' interest, and a continuous supply of university-educated students graduating with current knowledge on viruses, epidemiology and how to conduct research. The University of Liberia (UL) is the largest government supported institution in Liberia, and its College of Science and Technology awards Bachelor of Science degrees to students who wish to enter the health professions. Also, UL's College of Medicine and Tubman Institute of Medicinal Arts train physicians and nurses, respectively. In 2015, UL conducted a needs assessment and developed a strategic academic plan. In response to this plan, faculty in the Department of Tropical Medicine, Medical Microbiology and Pharmacology, University of Hawaii (UH), and the University of Yaounde 1 (UY) propose to partner with faculty at UL to establish a creative training program with the goal of garnering interest and improving teaching and student learning experience in biomedical sciences at UL, and providing training in the conduct of research on emerging viral epidemics. The planning process has 12 steps: 1) devise a career development plan for faculty; 2) determine how to strengthen the curriculum in virology, emerging epidemic diseases, and research; 3) assess feasibility of long-distance learning between UL and UH; 4) evaluate the possibility of introducing a laboratory-based course entitled "Research on Emerging Epidemic Viruses" into the curriculum; 5) identify opportunities for students to participate in in-country mentored research projects; 6) investigate other activities for inclusion in a training grant; 7) explore training of Liberian students in Hawaii; 8) establish south-south academic and research collaboration; 9) identify a method for selecting students for training; 10) assess needs for specific skilled personnel in the Liberian healthcare workforce; 11) identify individuals with multi-disciplinary backgrounds to serve on a Training Advisory Group; and 12) write a D43 application. The ten-person planning committee consists of UL, UH and UY faculty who are teacher-scholars, and their D71 planning efforts are supported by a larger group of faculty with experience in virology, epidemiology and global health research. Strengthening the research capacity at the UL is the only way to guarantee a sustainable cadre of health professionals with research expertise to identify and control future emerging viral epidemics in Liberia.
NIH/OD / R21OD024896, 01 September 2017 - 31 August 2019
A Guinea Pig Model of Zika Virus Disease: Zika virus (ZIKV) has recently emerged as a new public health threat. ZIKV infection has been linked to the development of severe fetal abnormalities that include spontaneous abortion, stillbirth, hydranencephaly, and microcephaly. No effective therapies currently exist for treating patients infected with ZIKV. Very little information is available on the natural history of ZIKV infection in pregnant women and its outcomes. Development of animal models that reflect true clinical disease is a significant barrier to advancing our understanding of ZIKV disease and its long-term pathophysiological effects. Recently, we demonstrated that guinea pigs are susceptible to infection by a contemporary American strain of ZIKV. We also demonstrated that after subcutaneous inoculation, ZIKV is neurotropic in guinea pigs. The principal objective of the proposed exploratory research is to characterize and utilize the guinea pig model to study in utero ZIKV infection, sexual transmission and ZIKV neurological disease. With this model in place, we will examine the relationship between clinical disease and the derangements observed in the immune system, the nervous system and viral load. In aim 1, we will develop ZIKV in utero infection model in guinea pigs. In Aim 2, we will develop ZIKV sexual transmission model in guinea pigs. In Aim 3, we will develop ZIKV neurological disease model in guinea pigs. The proposed research is highly innovative as it will be the first study to employ the guinea pig model to characterize in utero transmission and pathogenesis of ZIKV. The findings from this study will have a significant impact on understanding mechanisms associated with ZIKV transmission to the fetus, pregnancy outcomes, pathogenesis of sexual transmission, short-term neurological sequelae in infants, and other ZIKV manifestations in infants including developmental delays and physical disorders. This study will help understand pathogenic mechanisms underlying the development of ZIKV associated neurological disease. Also, this model system will form the basis to understand the basic biology of ZIKV infection and disease, and to develop strategies to prevent transmission of ZIKV to the fetus, and for evaluating vaccines and therapeutics.
NIH/FIC / 2D43TW009345-06, 01 July 2017 - 30 June 2022
Northern/Pacific Universities Global Health Research Training Consortium : Our D43 proposal, entitled Ã¢??Northern Pacific Global Health Research Fellows Training ConsortiumÃ¢?? is a consortium of four U.S. universities (the Universities of Hawaii, Michigan, Minnesota and Washington) with research training partnerships in seven countries (Kenya, Uganda, Ghana, Cameroon, Peru, Thailand and India). The Consortium will continue to be housed within the Department of Global Health at the University of Washington. Our Consortium will offer 12-month research training fellowships with (1) an expedited global research project trajectory, progressing from development of a research protocol to implementation, analysis of data and publication; (2) an enhanced mentoring program including a manual of required, specific commitments and guidelines for mentors and mentees, bimonthly Internet-based research-in-progress sessions involving all Global Health Fellows with joint participation of U.S. and international mentors, and institutionalization of mentorship training at participating institutions; and (3) an Ã¢??alumni warrantyÃ¢?? for trainees, with a potential second year of fellowship funding for the most promising trainees, short-term return to country to advance research, assistance launching independent careers through mock interviews, ongoing mentoring of alumni on applications for new global health grants, an alumni and mentor network providing posting of new publications, funding and job opportunities, and participation in cross-consortium Global Health trainee reunions at global health conferences. The four U.S. universities have each committed matching funds totaling $575,000 to support additional fellows and a second year of fellowship for the most productive fellows. This proposal would provide funding for 18 trainees each year, for a total of 90 trainees.
NIH/NIAID / R01AI132323, 20 June 2017 - 31 May 2022
Preclinical Development of a Thermostable Trivalent Filovirus Vaccine : The overall goal of this project is to develop a thermostable, trivalent, recombinant subunit filovirus vaccine that can protect at risk populations against infection by all pathogenic strains of EBOV (Zaire Ebolavirus), SUDV (Sudan Ebolavirus), and MARV. Thermostability will be achieved by lyophilization of the recombinant antigens allowing reconstitution at the time of use. The highly purified recombinant filovirus subunit proteins are expressed from stably transformed insect cells. A key advantage of this production system is the ability to consistently produce large quantities of pure, stable, and properly folded viral proteins. Immunoaffinity chromatography is key for the highly efficient production and is being facilitated by the use of plant-expressed monoclonal antibodies. Unlike other vaccine technologies, the recombinant subunit approach permits inclusion of antigens from diverse pathogens to achieve truly broad spectrum efficacy. Fine tuning of antigen dosing, immunization schedule, and adjuvant selection allow the rapid inclusion of new or modified targets into a core vaccine formulation. This core formulation will be further defined during the proposed work. The unique advantages of our platform are initially targeted at demonstrating feasibility in a candidate with protection against three filoviruses, having a safety profile only achievable with the use of highly purified subunit proteins.
NIH/NIDDK / 2R25DK078386-11, 01 March 2017 - 28 February 2022
Pacific High Schools STEP-UP to Biomedical Research: The University of Hawaii at Manoa proposes to continue to develop the Pacific STEP-UP Program to provide research training and mentoring to underrepresented minority and disadvantaged high school students in the State of Hawaii, and the US Territories in the Pacific: American Samoa, Guam, the Commonwealth of the Northern Mariana Islands, the Federated States of Micronesia, the Republic of the Marshall Islands, and the Republic of Palau. For the past 5 years, Pacific STEP-UP has enrolled and trained 145 student interns in the NIDDK STEP-UP summer program, and exposed another 414 students to laboratory sciences during the school years. We built the capacity for laboratory research in the Pacific colleges (including personnel training) where there were none before us. We tracked over 270 STEP-UP alumni from as early as 2005 to find that a great majority pursued college education with a science emphasis, and many also sought post-graduate training and terminal degrees. To date, Pacific STEP-UP remains the only formalized research training program for high school students in the US Pacific, amid the urgent need to build and foster a pipeline of underrepresented individuals seeking health research careers in order to combat health disparity in this region of the world. With confidence that Pacific STEP-UP has established roots in the region, we will continue to develop and expand our STEP-UP research training and mentoring program. Moreover, new strategies and approach in training and mentoring, as well as in capacity building will be used to further STEP-UPÃ¢??s reach into the Pacific communities. The goal is that in the process of providing the NIDDK mandated research training/mentoring, our Program will raise community awareness of relevant health issues and of the future values in the Ã¢??home-grownÃ¢?? healthcare researchers; thereby drawing support for health-related research. Pacific STEP-UP aims to seed and shape a culture that values scientific research as the means to address health issues in these communities. Accordingly, we propose three aims - Specific Aim 1. Recruit best qualified high school students (11th and 12th graders) from the seven US State and Territories in the Pacific into the STEP-UP Summer Research Program, and track the cohortÃ¢??s academic progress for a minimum of 5 years. Specific Aim 2. Provide individualized summer research experience (and related education and training) that stresses local community or population relevance to the Pacific STEP-UP interns. Provide STEP-UP alumni with follow up, and research-focused, mentoring extending for 9 months. Specific Aim 3. Seed and cultivate interests in laboratory sciences in the Pacific high schools while strengthen local collegesÃ¢?? capacity to enable and sustain laboratory and community based research; all in support of the Pacific STEP-UP training program by expanding the application pool and research opportunities.
NIH/NIAID / R21AI129465, 08 November 2016 - 31 October 2018
Under Attack: Modulation of the Blood-Testes Barrier by Zika Virus: The ongoing epidemic of Zika virus (ZIKV) infection has caused severe unexpected clinical outcomes, including increased risk of sexual transmission. Currently, there is no vaccines or specific therapeutic measures to combat ZIKV infection. Therefore, there is an urgent need for models to understand ZIKV pathogenesis. Understanding how ZIKV gains entry into immune-privileged sites, such as the testes and clarifying the role of inflammatory mediators in facilitating this process will provide new knowledge for the development of strategies to prevent virus-testes entry and sexual transmission.
NIH/NINDS / R21NS099838, 01 September 2016 - 31 August 2018
Defining the Function of Schlafen4 in the Pathogenesis of Flavivirus Encephalitis: Members of the Flavivirus genus are leading causes of epidemic encephalitis worldwide and continue to spread globally. There is no approved antiviral therapeutic agent available for treatment of flavivirus infections. This study will investigate the function of Schlafen4 in West Nile virus and Japanese encephalitis virus replication and pathogenesis, using novel mouse models. Results from our study will delineate a new antiviral pathway and identify a novel host antiviral target for treatment of flavivirus encephalitis.
NIH/NIEHS / R21ES027230, 01 September 2016 - 31 August 2018
Pathogenesis of Life Threatening Box Jellyfish Envenomation and Irukandji Syndrome: Box jellyfish stings pose a public health threat in tropical and subtropical coastal areas. Irukandji syndrome is a complex, potentially life-threatening clinical sequelae of box jellyfish envenomation. The proposed exploratory research will clarify the role of the jellyfish pore-forming protein (or porin) in Irukandji syndrome. This improved understanding will guide the development of more effective treatments.
NIH/NIAID / R21AI123913, 10 March 2016 - 28 February 2018
Functional Characterization of Essential Burkholderia pseudomallei Virulence Regulators: Burkholderia pseudomallei (Bp), a facultative intracellular pathogen, is a tier 1 select agent due to its potential use as a bioweapon and the often fatal disease it causes, melioidosis. Melioidosis has a wide variety of symptoms that affects essentially every tissue of the body. The varieties in clinical manifestations is due to th fact that Bp is genetically diverse among species and has a wide array of virulence mechanisms used to establish disease In order to develop effective vaccines and treatment strategies, the molecular pathogenesis of Bp must be elucidated. To date, only a handful of pathogenesis mechanisms have been described, for a bacterium with a very large and diverse genome of >7 mega base pairs. Through our innovative approach of transcriptionally profiling single Bp cells at different stages of infection, we have identified four hypothetical regulators essential for complete Bp pathogenesis in vivo. To study the pathogenic processes and the genes controlled by these regulators we propose Aim 1, which will identify the regulation networks and characterize their roles in pathogenesis. This will shed light on the regulation of either known virulence pathways and/or novel virulence pathways adding to the complete understanding of the Bp intracellular lifecycle. Aim 2 proposes the mechanistic characterization of these novel transcriptional regulators by determining DNA-regulator interactions across the entire genome. This analysis will allow for identification of binding motifs for each regulator and validate their function. Taken together, the proposed aims will greatly enrich the understanding of Bp infection within the host that can lead to the development of novel vaccine and therapeutic strategies. The overall methodology used in this proposal has broad applicability to study other medically significant facultative intracellular pathogens.
NIH/NIAID / R01AI119185, 28 August 2015 - 31 July 2019
Defining a Protective Ebola Vaccine in Non-human Primates: The overall goal of this project is to develop a non-replicating recombinant subunit Ebola virus (EBOV) vaccine that can safely and reliably protect at-risk populations against EBOV infections. This vaccine is based on highly purified recombinant EBOV subunit proteins expressed by stably transformed Drosophila Schneider 2 (S2) cells. A key advantage of this production system is the ability to consistently produce large quantities of pure, stable, and properly folded viral proteins. Purification by immunoaffinity chromatography is essential for the highly efficient production and is being facilitated by the use of plant-expressed monoclonal antibodies. Fine tuning of antigen dosing, immunization schedule, and adjuvant selection allow the rapid inclusion of new or modified targets into a core vaccine formulation to allow the formulation of a broadly protective vaccine in the future. This core formulation will have a safety profile only achievable with the use of highly purified subunit proteins. This research is divided into three Specific Aims: In Aim 1, the ideal adjuvant for the EBOV GP (lead antigen) will be selected with a specific focus on achieving consistent humoral immunity in non-human primates (NHPs). Aim 2 will evaluate the ability of EBOV VP24 and VP40 antigens to enhance efficacy of the lead candidate formulation in primates as previously observed in rodent studies. This is followed by evaluation of durability of the selected final formulation. Aim 3 will be addressed concurrently with Aims 1 and 2. It will focus on detailed analysis of the humoral and cellular immune responses using conventional methods as well as the peptide-array based "immunosignature" technology. As we will have the samples from our three NHP efficacy studies, the sample size should be adequate for us to correlate challenge outcome with the immunologic readouts leading toward identification of a universal immunosignature for a protective EBOV vaccine that can be used for future clinical development.
Hawaii Community Foundation / 15ADVC-75878, 15 July 2015 - 14 January 2017
West Nile Virus NS2B-NS3 Heterodimer as a Potential Target for Antiviral Drug Development: The goal of this project is to elucidate the regulatory mechanisms controlling NS3 recruitment to the replication organelle in order to develop an effective therapeutic to attenuate the disease process of West Nile virus infection.
Department of Defense, U.S. Army Medical Research Acquisitions Administration / W81XWH-15-R-0015, 13 July 2015 - 12 July 2017
US Army Medical Research Institute of Infectious Diseases (USAMRIID) Requirement to Develop, Produce and Deploy MAGPIX-Based Immunoassays: The goal of this project is to produce filovirus antigens for conducting Magpix-based immunoassays.
NIH/NIGMS / P30GM114737, 01 July 2015 - 30 June 2020
Pacific Center for Emerging Infectious Diseases Research: The principal objective of the Phase III COBRE for emerging infectious diseases is to enhance the conditions that accelerate the pace of scientific discovery, heighten research productivity and increase competitiveness for extramural funding. The objective will be achieved (1) by enhancing the growth and sustainability of the COBRE core resources in biocontainment, bioinformatics and molecular and cellular immunology, which are grounded in the triad of customized and collaborative service, research and development, and education and training; and (2) by developing and implementing a COBRE Small Grants Program, without borders, that fosters collaborations and partnerships, data and resource sharing and additional opportunities for mentoring and specialized training across IDeA-funded centers to improve human health and reduce disease burden.
Chun Foundation / 0, 12 June 2015 - 15 August 2016
Improve Long-term Immunity to Childhood Pertussis Vaccination: This proposal is focused on improvement of acellular vaccines for Bordetella pertussis, commonly known as whooping cough. While current vaccines are initially effective, immunity wanes over time, creating a pool of potential carriers for this disease. These carriers pose a risk of exposure of infants to pertussis. The current project will utilize novel vaccine adjuvants, compounds that enhance the immune response to vaccines, to induce a more durable immunity to B. pertussis. The basic hypothesis is that memory B cells, key players in protective immunity, will be activated more efficiently by pertussis antigens in the presence of specific Toll-like receptor (TLR) ligands. Peripheral blood B cells from human volunteers will be stimulated in culture with Bordetella pertussis antigens in combination with various TLR ligands. Stimulated B cells will be analyzed for proliferation, expression of activation markers, and production of cytokines. Increased memory B cells responses will be indicative of a more robust immune response to "booster" immunization and will provide evidence for the use of TLR ligands as adjuvants for acellular pertussis vaccines.
NIH/NIAID / R21AI109449, 19 December 2014 - 30 November 2016
Immunity to Placental Malaria: Persistence of Antibodies to VAR2CSA: How long does immunity to placental malaria persist in women, especially in women who receive intermittent preventive treatment (IPT) during one or more pregnancies? This question is being asked by researchers, clinicians and public health policy officials concerned with the care of pregnant women exposed to malaria. The question is particularly relevant since transmission of malaria is decreasing in many parts of the world and antibodies (Ab) and T cell responses to P. falciparum antigens quickly decline in the absence of boosting. Plasmodium falciparum malaria is severe in pregnant women because infected erythrocytes express VAR2CSA, a protein that binds to chondroitin sulfate A on trophoblasts, causing infected erythrocytes to accumulate in the placenta. As a result, inflammation and pathology occur, increasing the risk of miscarriages, premature deliveries, and low birth weight babies. Fortunately, antibodies (Ab) to VAR2CSA improve pregnancy outcomes. However, little is known about the induction and maintenance of long-lived plasma cells and memory B cells (MBC) to VAR2CA. Data suggest that the response to VAR2CSA differs from other malarial antigen and that memory may be produced during a single pregnancy. The proposed study seeks to characterized the B cell memory response to VAR2CSA and determine how long it persists in two groups of women, i.e., those who do not become pregnant again and those who receive IPT over several pregnancies. The study will take place in Yaounde, Cameroon. Since 2009, we have followed women monthly throughout pregnancy who received IPT. Among these women, >430 women had substantial Ab levels to VAR2CSA at delivery. We propose to conduct a cross-sectional follow-up study in 2015 and measure Ab levels and number of MBC to VAR2CSA in these women and again in 2016 in those who remained positive; thereby monitoring maintenance of immunity over a 1.5 to 8 year period. If immunity persists >8 years, women enrolled in our previous studies (1995-2005) can be studied, extending the period from 1.5 to 20 years. Scientists with expertise in clinical trials, Ab responses to VAR2CSA, and modeling of Ab half-life will conduct the study. The study tests an innovative hypothesis that Ab to VAR2CSA persist for >30 years in women who have >35% high avidity Ab to VAR2CSA at delivery compared to <3 years in women who have <35% high avidity Ab. Ab levels to full-length VAR2CA (FV2), the 6 Duffy-like binding domains, polymorphic variants, Ab avidity to FV2, number of MBC, and clinical data will be used to define the long-lasting memory response and factors that contribute to it. Results will provide key information on how long long-lived plasma cells and MBC to VAR2CSA persist; determine if Ab levels to VAR2CSA in multigravidae who have high Ab levels are maintained or declined if they receive IPT in subsequent pregnancies; and establish if an association exists between high avidity Ab and long-term memory to VAR2CSA. If true, a diagnostic test based on avidity to VAR2CSA could be developed for determining the immune status of pregnant women.
NIH/NIAID / R01AI110769, 01 April 2014 - 31 March 2019
Mature Virus-like Particles as a New Strategy for Dengue Virus Vaccines: Despite considerable effort and progress in developing tetravalent vaccines against the four serotypes of dengue virus (DENV), one of the major unmet challenges is the difficulty in eliciting balanced neutralizing (NT) antibodies (Abs) against all four serotypes and to lower the risk of antibody-dependent enhancement (ADE), mediated mainly by cross-reactive and weakly or non-NT Abs. Studies of human Abs after DENV infection have shown the immunodominance of cross-reactive and weakly or non-NT Abs recognizing the fusion loop (FL) of envelope (E) protein over the type-specific and potent NT Abs, and the presence of cross-reactive and weakly or non-NT anti-precursor membrane (prM) Abs. Whether such immunodominance can be modulated to induce potent NT Abs without cross-reactive and weakly or non-NT Abs remains unknown. We recently found a DNA vaccine expressing mature DENV particles induced potent NT Abs with minimal cross-reactive, weakly or non-NT Abs, suggesting that specific modulation of DENV particles might induce superior Ab responses. Our long-term goal is to develop a safe and effective DENV vaccine. The objective of the proposed research is to understand the immunodominance of DENV E protein and to test whether mature or FL-modified mature DENV particles can induce potent NT Abs without cross-reactive, weakly or non-NT Abs. The central hypothesis is that mature DENV particles induce potent NT Abs, less anti-FL Abs and no anti-prM Abs, thus reducing the risk of ADE compared with mixed DENV particles. The objective will be achieved by the three specific aims: The first specific aim is to define the E protein epitopes and the accessibility, binding avidity and NT potency of a large panel of anti-E mAbs on mature, mixed and immature DENV particles. We hypothesize that differential epitope accessibility and binding avidity of anti-E Abs to different DENV particles may account for the immunodominance of E protein. The second aim is to demonstrate the superiority of DNA vaccines expressing mature DENV particles, over DNA vaccines expressing mixed particles, in eliciting potent NT Abs and minimal potential enhancing Abs and providing protection in outbred mice and AG129 mice, a well-established dengue murine model. The third aim is to demonstrate the superiority of DNA vaccines expressing FL-modified mature DENV particles, over DNA vaccines expressing non-modified mature DENV particles, in eliciting potent NT Abs and minimal potential enhancing Abs and providing protection in murine models. The significance of the proposed research rests on its detailed understanding of the immunodominance of DENV E protein and on the demonstration that such immunodominance can be modulated by mature and FL-modified DENV particles to induce potent NT Abs and minimal infection-enhancing Abs. This represents a novel strategy for DENV vaccine design and cannot be achieved by all current DENV particle-based candidate vaccines. The proposed research can be translated to several more advanced DENV vaccine candidates as the second generation of "safe and effective" DENV vaccines.
NIH/NIAID / R21AI105286, 01 March 2014 - 28 February 2016
Defining Immunity to Placental Malaria using a Multi-assay Predictive Model: In developing countries, young pregnant women are at risk of spontaneous abortions, premature deliveries and low birth weight babies if they become infected with malaria. Fortunately, over several pregnancies they acquire antibodies that protect them from the severe effects of malaria, but there is no way to predict if a woman has adequate levels of protective antibodies. The goal of this project is to develop a multi-assay method that will predict early in pregnancy a womanÃ¢??s level of immunity, thereby allowing physicians to provide improve health care for pregnant women exposed to malaria; a goal embraced by NIAID, NIH.
NIH/NIMHD / T37MD008636, 01 December 2013 - 30 November 2018
International Biomedical Research Training for Hawaiian & Pacific Island Students: The Department of Tropical Medicine, Medical Microbiology and Pharmacology (T3MP) has a long-term investment in training students from ethnically underrepresented backgrounds in tropical medicine with the goal of increasing the number of research career professionals who are Hawaiians, Pacific Islanders and Filipinos. Through the T3MP STEP-UP program, we have set up laboratories in Guam, Saipan and Yap and begun to train high school students from the Pacific. High school students from these sites and Hawaii spend summers conducting directed research at the University of Hawaii. Similarly, we recently developed training programs in Cameroon, Thailand, and China for graduate and post-doctoral fellows. To fill the gap of undergraduate student international research training, we now apply for the NIMHD Minority Health and Health Disparities International Research Training (T37) grant to complete our pipeline of training efforts from high school through careers in biomedical research. The goal of this training grant is to teach underrepresented minority students in Hawaii, primarily of Hawaiian, Pacific Island and Filipino descent, basic concepts in biomedical research. The program is designed for nine undergraduate and one graduate student annually to conduct research in Cameroon and Thailand and learn about global health disparities. The program supports NIH's goal of encouraging minority and other underrepresented students to seek careers in biomedical research.
NIH/NIGMS / R01GM103580, 01 September 2013 - 30 June 2017
Functional Genomics of Single- and Mixed-Species Biofilms in Spatiotemporal Scale : Bacteria of the oral, genital, respiratory, and gut microbiomes can exist as host- associated biofilm communities and biofilm-related infections are among the most serious diseases treated by clinicians. Bacterial associations and dynamics within the microenvironments of the biofilm structure are poorly understood on a global level. Global gene-expression dynamics of whole biofilms have been studied on the temporal scale, which lacks the resolution to decipher bacterial physiology and interactions within the microenvironments of biofilm. Thus, global gene-expression dynamics vary in two dimensions, space and time, which modulate the physiology of bacteria within their biofilm microenvironments. We have made recent advances in transcriptome analysis of single-cells have made fine-resolution functional genomic analysis of bacteria within their microenvironments possible. Our preliminary data of Pseudomonas aeruginosa (Pa) single-species biofilm has yielded many interesting aspects of this bacterium in its biofilm microenvironments and its organized spatial gene-expression pattern that make- up the living and functioning biofilm as a whole. Herein, we further proposed single- and mixed-species biofilm models of Pa and Burkholderia cenocepacia (Bc) to begin the process of unraveling the spatiotemporal global gene-expression pattern that contributes to the physiological- and interactions-dynamics of bacteria within their biofilm microenvironments. Aim 1 will determine the global gene-expression dynamics and physiology of Pa and Bc within mature single-species biofilms and Aim 2 will determine the global gene-expression dynamics, physiology, and interactions of Pa and Bc within mixed-species biofilms spatiotemporally in vitro, with validation in vivo. Upon completion of these studies, we expect to discover numerous answers to mysterious questions regarding the dynamics of bacterial physiology, interaction, and cooperation within microenvironments of single- and mixed-species biofilms at a global level. This will serve as a foundation and framework to further study the functional genomics of other host- associated biofilm communities and many important biofilm-related infections leading to novel treatment strategies.
NIH/FIC / R25TW009345, 06 April 2012 - 31 March 2017
Northern/Pacific Global Health Research Fellows Training Consortium : The goal of this project is to provide outstanding mentored research training to post-doctorate trainees and doctoral students at six international partner institutions with robust clinical research programs and exceptional histories of training Fogarty International Clinical Research Scholars and Fellows and strengthen global health research programs to help globalize the research portfolios of all of the sponsoring NIH ICs, and develop sustainable multidisciplinary partnerships between the four Consortium institutions and institutions in the six international partnering countries.
NIH/NIDDK / R25DK078386, 01 April 2012 - 31 March 2017
Pacific High Schools STEP-UP to Biomedical Research: The University of Hawaii, John A. Burn School of Medicine, proposes to develop a summer biomedical research training and education program for the underrepresented minority high school students in the Pacific region. This program will encompass the State of Hawaii, the US-affiliated (flagged) territories of American Samoa, Guam, and the Commonwealth of Northern Mariana Islands; and the US-associated (non-flagged) territories that include the Republic of Palau, the Federated States of Micronesia, and the Republic of the Marshall Islands. These Pacific communities constitute the most concentrated populations of underrepresented Pacific Islanders, with success rates of higher educational attainment well below national averages, and well known burdens of disease disparities that are relevant to NIDDK. The research training program we propose will be unprecedented in most of the targeted Pacific communities where biomedical research infrastructures and health research education are nonexistent. Our short-term goal is to raise awareness of biomedical research and career pathways in high school students, with the long-term objective of establishing a steady pipeline of underrepresented young students with interests and readiness in pursuing biomedical sciences education and, ultimately, research careers relevant to NIDDK's mission. To begin to address these goals, our proposed program, "Pacific High Schools STEP-UP to Biomedical Research" will focus on four Specific Aims. Aim 1 is to recruit annually 20 high school students (underrepresented; 11 /12 Grade) from Hawaii, Am. Samoa, Guam, CNMI, FSM, Republic of Palau, and Republic of Marshall Islands to Pacific STEP-UP. Aim 2 is to provide the Pacific STEP-UP students high- quality, hands-on research experience related to NIDDK mission, and research-related education over the summer period at JABSOM. Aim 3 is to introduce and stir interests in biomedical research by providing local exposure to molecular biology laboratory techniques and related scientific concepts in the form of mini- workshops to targeted high school teachers and students in Am. Samoa, CNMI, and Republic of Marshall Islands. Finally, Aim 4 is to recruit at least 20 scientists at JABSOM with research related to NIDDK mission areas as mentors for STEP-UP students (Aim 1), and develop a mentoring plan for the STEP-UP students. We will evaluate the impact of our program in terms of increasing Native Hawaiian and Pacific Islanders to pursue higher education in biomedical sciences, particularly in areas relevant to NIDDK's mission. PUBLIC HEALTH RELEVANCE: One of the Healthy People 2020's goals is to eliminate health disparity. It is widely known that health disparity occurs among underrepresented minority populations and this is no exception for Native Hawaiians and other Pacific Islanders (NHOPI). It is also widely accepted that research on diseases that disproportionately affect minorities may be best take on by scientists of the same minority background because they are more sensitive to ethnic and cultural issues that are contributory to the disease processes. Unfortunately, the number of underrepresented minorities engage in biomedical research is much lower that the general population. The proposed research education program will address this deficiency by targeting underrepresented high school students in all US affiliated Pacific communities and provide opportunities for biomedical research experience. The goals and objectives is to inform, raise interests and awareness of biomedical research careers in these populations in order to create and sustain a pipeline of underrepresented individuals with likelihood of pursuing biomedical research careers.
NIH/FIC / D43TW009074, 01 August 2011 - 30 July 2016
Training of Cameroonian Scientists in Research on Malaria: Malaria, caused by Plasmodium falciparum, is one of the three major infectious diseases in the world today. The introduction of control measures including insecticide-treated bednets, rapid diagnostic tests, and intermittent preventative treatment (IPT) have reduced the prevalence of malaria in a number of African countries, yet malaria remains highly endemic in central Africa where public health resources are poor. At highest risk of severe infections are pregnant women and young children. More than ever, well-trained African scientists are needed to monitor the changing landscape as the malaria picture rapidly changes. Scientists in Cameroon are actively engage in research on malaria, but additional expertise and faculty are needed to identify malaria- related problems as they arise and design strategies to solve them. Therefore, the purpose of this application is to help young Cameroonian scientists acquired the skills necessary for conducting research on malaria, with a focus on malaria in pregnant women and infants. In 1994, scientists at the University of Yaoundi 1, Cameroon, and Georgetown University began collaborating on malaria at the Biotechnology Center (BTC). Through continuous NIH grant support and a training grant from the Maternal and Child Health Research Training Program (MCHRT), a group of 5 full- time faculty members, >6 well-trained technicians, and ~40 students are conducting research at the BTC. Previous trainees wish to return after completing their post-doctoral and residency programs in the USA. This application proposes ways to help the malaria group at the BTC acquire the critical mass and expertise it needs to develop a long-term sustainable research program on malaria. The specific goal of the application is to provide expertise that is currently lacking at the BTC that would supplement on-going research. Areas of training include 1) use of anti-malarial drugs (pharmacokinetics, evolution of parasite-drug resistance, and clinical trial design), 2) immunology of the placenta, with emphasis on flow cytometry, 3) co-infections between malaria and other diseases, 4) use of ultrasound for monitoring fetal development, and 5) vector biology. The program includes training of 3 PhD-level and 4 MS-level students, mentoring of returning clinicians(s) in OB/GYN and infectious diseases, and training of local physicians in ultrasound. Three in-country workshops designed and conducted by former FIC trainees are proposed. These training activities will significantly contribute to the long-term goal of creating a group of scientists at the BTC whose research will continue to improve the health care of pregnant women and their newborns.
NIH/NIGMS / P20GM103516, 16 September 2010 - 30 June 2015
Pacific Center for Emerging Infectious Diseases Research: The overall goal of this five-year project is to establish a translational science center of research excellence for new, emerging and re-emerging infectious diseases aimed at developing rapid diagnostics, innovative drugs and affordable vaccines for vector-borne and zoonotic infectious diseases of regional importance and global concern.
International Vaccine Institute/Pediatric Dengue Vaccine Initiative / Cooperative Research Agreement, 01 April 2010 - 31 December 2010
ELISA based assay for detection of neutralizing antibodies in polyclonal dengue antisera: The main objective of this project is to develop a prototype capture-ELISA using virus-like particles to detect neutralizing antibodies in polyclonal human sera after dengue virus infection or vaccination.
NIH/NIAID / R01AI075057, 08 August 2008 - 31 July 2014
Intraspecies Transmission and Infectivity of Insectivore-Borne Hantaviruses: The major goal of this collaborative project is to determine the intraspecies transmission of a newly recognized hantavirus and to ascertain its importance to human health and disease.
NIH/NIAID / 5 R01 AI075057-03 , 08 August 2008 - 31 July 2012
Intraspecies Transmission and Infectivity of Insectivore-Borne Hantaviruses: The major goal of this project is to determine the intraspecies transmission of a newly recognized hantaviruses and to ascertain its importance to human health and disease.
NIH/NIAID / 5 U01 AI078213-03 , 01 August 2008 - 31 July 2013
Multiplex Serodiagnostic Protein Microarray: The goal of this project is to fabricate a protein microarray chip containing 678 antigens from emerging infectious diseases and biodefense agents, and to probe serum obtained from different regions of the world where these diseases are endemic to determine the true prevalence of infection.
NIH/NINDS / 5 R03 NS060647-02 , 15 May 2008 - 30 April 2012
Migration of Polyomavirus JC Across the Blood-Brain Barrier: The goal of this project is to identify cellular and molecular mechanisms underlying migration of JCV across the blood-brain barrier.
NIH/NIDDK / 5 R25 DK078386-05, 01 April 2007 - 31 March 2012
High School Students STEP-UP to Biomedical Research: The goal of this project is to provide research exposure and training for high school students of ethnic minority or the socio-economically disadvantaged.
NIH/NIMH / 5 R25 MH080661-05 , 01 February 2007 - 31 January 2012
Translational Research in Neuro-AIDS and Mental Health (TR-NAMH): The goal of this project is to improve research capacity by developing mentoring programs for doctoral and post doctoral candidates and junior faculty, whose research focuses on Neuro-AIDS disparity issues.
NIH/NCRR / 5 G12 RR003061-25, 01 August 2006 - 31 July 2011
Research Outcomes Accelerating Discoveries for Medical Applications and Practice: Activity 3- Tropical Infectious Diseases Detection and Prevention This RCMI activity responds to an urgent local, regional and national need to detect exotic infectious diseases that may be introduced to Hawaii and the continental United States from Asia.
NIH/NCRR / 5 P20 RR018727-07 , 30 September 2003 - 30 June 2015
Pacific Center for Emerging Infectious Diseases Research: The overall goal of this project is to develop a center of research excellence for emerging infectious diseases of relevance to the Asia-Pacific Region.