Center of Biomedical Research Excellence
Barbara Lohman-Payne, Ph.D., Assistant Research Professor
HIV Exposed Uninfected Infant Immunity
The incidence of HIV-1 infection is slowing globally, thanks to broadening implementation of antiretroviral treatment to infected individuals and programs targeting populations at risk of infection with prophylaxis. However, UNAIDS reports indicate that more than half of HIV-1 infected adults in sub-Saharan Africa are women of childbearing age. The availability of antiretroviral treatment to pregnant HIV-1 infected women has reduced the rates of mother-to-child transmission and simultaneously increased the rates of children born uninfected with HIV, but not unexposed. Epidemiologic studies of these HIV-1 exposed uninfected (EU) infants consistently report that these infants have increased morbidity and mortality during the first 2 years of life compared to unexposed infants, even in research settings of improved quality of medical care, infant growth monitoring and nutritional counseling. While early reports found minimal differences in morbidity and mortality between HIV-1 EU compared to HIV-1 unexposed infants, recent studies noted appreciable increases in morbidity and mortality in EU infants: 2-3 fold higher mortality rates and 20-30% more sick clinic visits and hospitalization. Reduced placental transfer of maternal antibody may explain vulnerability during infancy. However, persistent morbidity beyond the neonatal period was noted in EU infants and it is not clear why EU infants have continued elevated risk throughout the first year of life. The main focus of my research aims to uncover the mechanisms contributing to the infant vulnerabilities. One hypothesis we are exploring is that in utero HIV-1 exposure alters the TCR repertoire in infants and leaved a durable imprint on the developing immune system. We are interested in evaluating the role of maternal viral load, immune activation and plasma cytokine environment on the neonatal immune repertoire present at birth by measuring cord blood TCR diversity through amplification of the CDR3 region followed by sequence analysis of expanded clones. Dr. Payne’s current research interest at the Institute for Immunology and Informatics at the University of Rhode Island is the impact of HIV exposure in infants who remain uninfected. Recent epidemiologic evidence points to persistent immumologic deficiencies in exposed infants that cannot be fully explained by reduced maternal immunity subsequently transferred to their infants. She aims to evaluate the impact of HIV exposure by comparing T-cell receptor (TCR) repertoire size and diversity present in cord blood of infants born to HIV-1 infected women compared to the repertoire size and diversity present in cord blood of HIV unexposed infants. Dr. Payne and her colleagues will further explore the relationship between TCR changes present and after routine childhood vaccinations.
Carey L. Medin, Ph.D., Assistant Research Professor
Understanding viral-host interactions that are modulated during DENV infections
Dengue virus (DENV) is a mosquito-borne human pathogen of global medical importance. DENV causes an acute febrile illness that, in some patients, is associated with a life-threatening plasma leakage syndrome, dengue hemorrhagic fever (DHF). It is thought that secondary heterotypic dengue virus infections are more likely to produce DHF. While there is ongoing debate regarding the contribution of different mechanisms in dengue illness, there is substantial evidence supporting both viral and host factors in disease pathogenesis.
Several studies indicate that an increase in viremia during DENV infection correlates with severity of disease. In order for a virus to productively infect a cell it must be efficient at highjacking cellular mechanisms and avoid detection by the innate immune sensors. The research focus if this project is to investigate cellular organelle changes such as autophagosomes, lysosome, mitochondria, endoplasmic reticulum and peroxisomes during DENV infection in order to identify related cellular mechanisms that are modulated by DENV to enhance its own propagation. The significance of these studies will lead to a better understanding of cellular targets by DENV, which can identify new potential therapeutics to reduce viral levels during infection and lessen the severity of disease.
Ian Michelow, M.D., Assistant Professor
Development of a novel vaccine candidate for pediatric falciparum malaria
Malaria affects nearly one-half of the world’s population and causes more than 600,000 deaths each year. Immunologically immature children bear the greatest burden of morbidity and mortality, and represent a key target group for vaccine development efforts. Historically, selection of malaria vaccine candidates has been empiric, unsystematic, and limited to a small portfolio.
Therefore, our laboratory established a transformative high-throughput platform to screen a Plasmodium falciparum complementary DNA bacteriophage library that displays potentially the entire proteome of blood stage parasites. Our laboratory previously identified 10 immunoreactive antigens that were uniquely recognized by antibodies in plasma from resistant but not susceptible children. There is evidence that at least three of these antigens (MSP-3, MSP-7 and RAMA) as well as a novel protein that arrests parasite maturation (PfSEA-1; Science 2014) have protective functions in pre-clinical or clinical studies.
The objective of the current proposal is to fully characterize an additional vaccine candidate, Clone 10 using the infrastructure and expertise of the Center for International Health Research at Rhode Island Hospital/Brown University and the University of Rhode Island. We hypothesize that Clone 10 represents a novel blood-stage malaria target that induces a robust and protective immune response in children. We will assess its potential effectiveness as a vaccine using state-of-the-art in vitro and translational techniques that were successful in our laboratory previously. Specifically, we will characterize the role of Clone 10 in red blood cell invasion and schizogeny by performing immunolocalization studies on infected red blood cells, and invasion/growth inhibition assays to determine the role of anti-Clone 10 antibodies in mediating resistance.
We will also assess whether the findings can be translated to a model of lethal murine malaria using Clone 10-homologue DNA and protein subunit vaccines derived from Plasmodium berghei (ANKA) to induce immunity. We will then validate the generalizability of protective human immune responses against Clone 10 and other candidate antigens in an independent cohort of Tanzanian children, and investigate potential single nucleotide polymorphisms in Clone 10 from P. falciparumfield isolates from Tanzania.
In summary, we will fully characterize a novel rationally identified blood stage malaria antigen. The deliverables of this project will be a potential Plasmodium falciparum vaccine candidate ready for non-human primate and human challenge experiments.
Christian Nixon, M.D., Assistant Professor
Cellular Effector Mechanisms Elicited by Novel Malaria Vaccine Candidate PfSEA-1
The overall aim of this project is to determine the functional significance of antibody targeted cellular and complement responses to a novel pediatric malaria vaccine candidate antigen, PfSEA-1. P. falciparum malaria is a leading cause of morbidity and mortality in developing countries, infecting hundreds of millions of individuals and killing over one million children in sub-Saharan Africa each year . Of the 100 vaccine candidates currently under investigation, more than 60% are based on only four parasite antigens – a fact that has caused considerable concern.
We discovered PfSEA-1 using our whole proteome differential screening method in a search for new vaccine candidates for pediatric falciparum malaria. We interrogated the P. falciparum blood stage proteome with plasma from resistant and susceptible two yr old children to identify parasite proteins that are the targets of protective antibody responses. Our study subjects participated in the Mother Offspring Malaria Studies (MOMS) project, which is based at Muheza Designated District Hospital (DDH), in north eastern Tanzania.
We will specifically employ cellular bioassays including the monocyte monolayer assay and antibody-dependent cellular inhibition assay to determine the role of cellular effector mechanisms in anti-PfSEA-1 mediated immunity. In addition, we will develop a high through-put PfSEA-1 specific growth inhibition assay that will guide ongoing immune-epidemiology and ultimately vaccine trials for this novel vaccine candidate. Together these data will support future efforts to conduct Phase I clinical trials in humans and constitute significant progress on the pathway toward a vaccine for falciparum malaria.