IMPH Research in Global Health

Examination of Odorant Receptors in Vector Mosquitoes 
Expanded Testing, Linkage, and Treatment for HIV Prevention Among MSM in China
Human Neutralizing Monoclonal Antibodies for Rift Valley Fever Virus 
Increasing Mental Health Research Infrastructure in Southeast Asia 
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 
Targeted Gene Inactivation in Anopeles Gambiae via Artificial Nucleases

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

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

Increasing Mental Health Research Infrastructure in Southeast Asia

This NCD-LIFESPAN project seeks to increase capacity in Southeast Asia, primarily in Vietnam and secondarily in Cambodia, in regards to (a) developing culturally-appropriate, research-based treatments for mental health problems; (b) conducting intervention trials of these treatments; (c) disseminating research results to favorably impact service provision. The NCD-LIFESPAN project builds on two successful ICOHRTA grants, the focus of which has been development of a child- and adolescent-focused, research-oriented PhD Clinical Sciences program at Vietnam National University (VNU). In 2009 our VNU Master's in Clinical Sciences enrolled its first cohort of 15 students, and a second cohort of 15 students in 2010. In addition to providing the curricular foundation for the PhD program, the master's program will be used as a dissemination platform and as a structure for dissemination research for the evidence-based treatment programs developed through the VNU Clinical Psychology program. The NCD-LIFESPAN Specific Aims are to (1) enhance the VNU Clinical Sciences program through: (1a) support for further development of VNU faculty in regards to research, clinical, instructional / mentoring, and administrative expertise; and (1b) development of a Subspecialty in Trauma and PTSD that was identified as of particular need in Vietnam, and Cambodia; and (2) broaden the geographical impact of our program within Vietnam, and Southeast Asia by: (2a) increasing the geographical diversity of our graduate students based within Vietnam, by providing scholarships to students who live a significant distance from the university; and (2b) collaborating with the Psychology Department at the Royal University of Phnom Penh (RUPP), Cambodia, to enhance their graduate program in Clinical Psychology and Trauma Treatment, by providing (2b1) training for RUPP faculty at VNU, (2b2) technical support around curriculum development, and (2b3) funding for small collaborative research projects. Vietnam National University would be LMIC site #1, and the Royal University of Phnom Penh would be LMIC site #2. Read more.

Funding Source: FIC
PI: Bahr Weiss

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.

Targeted Gene Inactivation in Anopeles Gambiae via Artificial Nucleases

The ability to genetically manipulate insect disease vectors such as the malaria vector mosquito Anopheles gambiae remains rudimentary relative to the abundance of molecular tools that are currently available in model insects such as Drosophila. Recently, artificial nucleases have allowed targeted genome editing in species, such as the zebrafish and rat, that previously lacked effective tools. These chimeric nucleases combine a programmable sequence-specific DNA-binding domain with a non-specific nuclease domain to generate a double strand break at a desired genomic locus, which when imprecisely repaired can result in gene inactivation ("knockouts"). If these lesions are generated within the embryonic germline the propagation of targeted mutant alleles is possible. In order to enable this approach for Anopheles gambiae, we will design and optimize a series of custom nucleases targeting a pair of well-characterized odorant receptor (AgOr) genes that play essential roles in olfactory signal transduction. In these studies, we will compare two different programmable nuclease platforms for their efficiency in promoting gene inactivation in the Anopheles germline, with the goal of establishing a robust reverse genetic approach for this organism. The utility of this strategy will be demonstrated by evaluating the effect of various AgOr knockouts on chemosensory responses in adult and larval stage mosquitoes. In addition to advancing our basic knowledge of chemosensory signal transduction in this important disease vector, the proposed studies, if successful, should provide a basis for the laboratory- based application of these and related gene modification tools in Anopheles and a wide range of related vector species. Read more.

Funding source: NIH/NIAID
Pi: Laurence Zwiebel