Robert W. Frenck, MD
Dr. Robert Frenck, along with Dr. David Bernstein, directs the NIH funded Vaccine Treatment Evaluation Unit (VTEU) contract. Over the past year, the VTEU has focused largely on improving vaccines against influenza, and Dr. Frenck has helped oversee the conduct of these trials.
Dr. Frenck received a DoD-sponsored grant to develop a challenge model of Shigella sonnei. The model is a first step in a program to test vaccines to prevent S. sonnei infections, a major cause of shigellosis in industrialized nations. The first cohort of the study is complete and the remainder of the study has a projection completion date of early 2017. Once the model is developed, Dr. Frenck has plans to use the model to test various vaccines against S. sonnei.
Dr. Frenck has received various grants from vaccine manufacturers to test their vaccines as part of the path to licensure. Included among the vaccines are influenza, pathogenic E. coli, C. difficile and S. aureus.
Dr. Frenck continues to maintain a research focus on clinical trials with special interest in enteric diseases.
David I. Bernstein, MD, MA
The NIH funded vaccine treatment evaluation unit (VTEU), led by Dr. David Bernstein continued to be active. Clinical studies recently completed included evaluations of altered dosing schedules for the human papillomavirus (HPV) vaccine in adolescent girls, a study of an enterotoxigenic Escherichia coli (ETEC) vaccine provided by several routes of administration, a study of a Shigella vaccine, and a new treatment for bacterial vaginosis (BV). Another priority area for the NIH and the VTEUs has been influenza vaccines including the study of bird flu vaccines and attempts to develop more broadly protective vaccines that could eliminate the need for yearly vaccinations. Current trials are underway for an H5N1 and an H7N9 influenza vaccine as well as prime boost strategies designed to induce broadly protective antibodies.
Dr. Bernstein’s interest in herpes vaccines also continued with both preclinical and clinical studies of a therapeutic vaccine for genital herpes. This vaccine, originally shown by our group to reduce recurrences and recurrent virus shedding in an animal model was also effective in a clinical trial. The manuscript, recently submitted by Dr. Bernstein described a trial in subjects with recurrent genital herpes that showed vaccine induced reductions in clinical recurrences and for the first time recurrent HSV-2 shedding, the most common source for the spread of this virus. Work was also published by us describing an animal model evaluation of a vaccine for congenital cytomegalovirus (CMV) that utilized LCMV as a vector for two CMV proteins.
Rebecca C. Brady, MD
Dr. Rebecca Brady is the medical director of the Ohio American Academy of Pediatrics Maximizing Office Based Immunization (MOBI) Program. The expansion of this program now includes specialized modules and quality improvement activities. She continues as the contributing section editor for Infectious Diseases, an American Academy of Pediatrics Grand Rounds publication. Dr. Brady also served as co-investigator for many clinical studies performed at the Gamble Program for Clinical Studies, Cincinnati Children's Division of Infectious Diseases. She led the Division of Infectious Diseases in a quality improvement project to improve review of immunization records for all new patients seen in the infectious diseases clinics. This project provided American Board of Pediatrics Maintenance of Certification Part IV credit. Together with Jennifer Huggins (Division of Rheumatology), she has grant funding from Pfizer for the project, “Connecting the Silos: A Partnership to Improve Immunization Rates among Adolescents with High-Risk Chronic and Immunocompromising Conditions”. She serves as the Cincinnati Children's Division of Infectious Diseases representative for the education of medical students and residents.Beverly L. Connelly, MD
The collaborative efforts of the infection control program, directed by Dr. Beverly Connelly, aligned with the institutional strategic goals to reduce healthcare associated infections (HAIs). Hand hygiene activities focused on incorporating the World Health Organization’s “My 5 Moments of Hand Hygiene” into everyday practice throughout the medical center and on further developing teams for monitoring and improvement. The program also partnered with the central line associated bloodstream infections (CLABSIs) improvement group to identify opportunities for simplification of protocols and standardization of care surrounding central line use across all units. With successful implementation of the CLABSI One Standard during FY 16, we expect to see reduced variation in practice and reductions in CLABSI rates. Collaborative efforts and standardization of processes helped maintain a low rate of surgical site infections (SSIs) in FY 16. The program partnered with Emergency Preparedness, Occupational Safety and Environmental Health (OSEH), Employee Health, and the Divisions of Emergency Medicine and Critical Care Medicine to capitalize on “ebola learnings” to meet the Ohio Department of Health requirements for Assessment Hospitals. This work moves Cincinnati Children's toward a more universal preparedness model. During FY 16, the program established stronger collaborative relationships with OSEH and Plant Engineering in the area of water safety. The institution moved toward a more robust water safety plan with the assistance of an outside consultant. We look to add additional Cu/Ag legionella prevention at select satellite locations in FY17. Our air quality and safety program moved forward in FY 16, bringing sampling capabilities in-house. This program can now expand surveillance activities in FY 17 to better support state-of-the-art prevention programs with our construction contractors.Lara Danziger-Isakov, MD, MPH
Dr. Lara Danziger-Isakov continues her role as protocol chair for three studies in the Clinical Trials in Organ Transplantation in Children (CTOTC) funded by the National Institute of Allergy and Infectious Diseases (NIAID). One study evaluates the interaction between respiratory viral infections and the development of allo – and autoimmunity after pediatric lung transplantation, while the second assesses the impact of B-cell induction on the development of allo- and autoimmunity and early graft dysfunction in pediatric lung transplant recipients. The final study assesses perceived barriers to adherence after pediatric solid organ transplantation. She was re-appointed to the Steering Committee to CTOTC and named as co-chair of the Adherence, Growth & Development and QOL Subcommittee that is launching a new study to assess the impact of post-traumatic stress symptoms on adherence and outcomes after solid organ transplantation (SOT).
Dr. Danziger-Isakov has expanded her work in SOT in collaboration with the Studies in Pediatric Liver Transplantation (SPLIT) to evaluate current practices for cytomegalovirus prevention and in collaboration with a multi-center pediatric infectious disease collaborative to evaluate the epidemiology and impact of respiratory viral infections after SOT and hematopoietic stem cell transplantation. A focus on quality improvement has led to significant improvements in pre-transplant infectious disease risk assessment and post-transplant vaccination rates.
Monica M. McNeal, MS
Ms. McNeal is the associate director for the Laboratory for Specialized Clinical Studies (LSCS) in the Division of Infectious Diseases, which provides lab support for clinical studies involving vaccine trials, vaccine development and surveillance studies. The laboratory has been, and continues to be, the central laboratory supporting the development of past and present live oral rotavirus vaccines. Rotavirus vaccines continue to be an important aspect in improving child health worldwide. Ms. McNeal has continued to support rotavirus vaccine trials conducted in numerous countries around the world in association with nonprofit organizations and industrial sponsors. Some of those studies involve determining how to improve efficacy of rotavirus vaccines in developing countries in Asia and Africa by looking at vaccination schedules, booster doses and the effect of breast feeding.
The laboratory continues to support the development of non-living rotavirus vaccines by developing and validating assays for clinical trials. The first ever human vaccine trial using a non-living rotavirus vaccine in children and infants, took place in Africa with a publication ready for submission. The laboratory is also involved in supporting influenza vaccines, analyzing samples from clinical trials conducted in the US. Additional projects include using animal models to investigate the effects of malnutrition on oral rotavirus vaccines, detecting the pathogens causing community acquired pneumonia presenting to the ED, rotavirus vaccine effectiveness in conjunction with the Center for Disease Control and Prevention (CDC) and establishing assays to quantitate norovirus shedding in immunocompromised patients. Ms. McNeal continues to support the clinical trials run by the Gamble program including Shigella and Escherichia coli (ETEC) vaccine trials, by establishing new assays and providing laboratory support.
Grant C. Paulsen, MD
Dr. Grant Paulsen maintains a focus on clinical research and trials, with a special interest in prevention of post-transplant infections, vaccination following organ transplant, and treatment and prevention of viral infections in immunocompromised patients. Research in pre-transplant Methicillin Resistant Staphylococcus aureus (MRSA) screening is aimed at determining the effect of screening, and use of targeted peri-operative prophylactic antibiotics on early post-transplant infections. He is also investigating the safety and efficacy of live viral vaccines, such as varicella and MMR, following liver transplantation. In addition, Dr. Paulsen serves as sub-investigator for a number of ongoing clinical studies in immunocompromised patients as well as clinical trials with Cincinnati Children's Vaccine and Treatment Evaluation Unit (VTEU).Joseph E. Qualls, PhD
Research in the Qualls laboratory has focused on the contribution of intracellular L-arginine synthesis on immune cell function. L-arginine is a semi-essential amino acid, meaning it isn't synthesized to sufficient amounts in our bodies during “stressful” conditions – including infection and other disease states. In addition to serving as a building block for protein synthesis, microbicidal nitric oxide (NO) production by macrophages and for T lymphocyte proliferation requires this amino acid. When L-arginine is limiting, these cells rely on L-arginine synthesis from L-citrulline, to sustain their respective functions. Mice that cannot convert L-citrulline to L-arginine in immune cells of hematopoietic lineage are impaired at clearing M. bovis BCG and M. tuberculosis infection in vivo. One project, funded by the American Heart Association, aims to define the metabolic consequences of L-citrulline in mycobacteria-infected macrophages. We published the first study stemming from this award, defining differential metabolic pathways of imported L-arginine, and L-arginine synthesized from intracellular L-citrulline in macrophages (Rapovy et al. The Journal of Immunology. 2015). Additionally, the preliminary data from these studies suggest control of mycobacterial is dependent on macrophage L-citrulline metabolism, and supplementing mice with commercially available L-citrulline enhances host defense to mycobacteria infection. These exciting findings resulted in a pilot award from Cincinnati Children's, and led to a new five-year grant from the NIH/NIAID (1 R01 AI116668-01A1) to study the implication and therapeutic potential of L-citrulline metabolism in models of virulent tuberculosis disease.
A doctoral candidate in the laboratory, Shannon (Rapovy) Lange, is studying the necessity of L-citrulline metabolism during T cell function. Although previous studies have shown that L-citrulline can rescue T cell proliferation in L-arginine scarce environments in vitro, the contribution of L-citrulline on T cell function in vivo is not addressed. Shannon has recently established a novel mouse model to probe the necessity and mechanism of L-citrulline metabolism in T cells, and experiments testing this during homeostasis and disease in vivo are underway. Preliminary data from these studies suggest that proliferation of mycobacterial-specific CD4+ T cells might not depend on L-citrulline. However, the survival of mycobacterial-specific CD4+ T cells with intact L-citrulline metabolism is far superior compared to those unable to metabolize L-citrulline. This project was partially funded by the American Association of Immunologists, which supported Mrs. Lange’s stipend for 2015-2016.
Nancy M. Sawtell, PhD
Most of the human population world-wide is and will remain infected with herpes simplex virus (HSV). At its core, this relationship hinges on the ability of the virus to aggressively replicate in the epithelial cells at the site of infection, transport into the nervous system through the axons innervating the infection site, and enter a repressed state called latency. Periodically, the latent viral program in rare neurons switches to the lytic cycle and infectious progeny and transport back to the body surface followed by rounds of replication in mucosal epithelium and virus shedding with the potential for transmission to new hosts. This facet of the viral life cycle, called reactivation, results in inflammation in the nervous system and serious outcomes including blindness and encephalitis. In addition, HSV infection contributes to diabetes, cardiovascular, neurodegenerative diseases and increases the probability of HIV infection.
No effective vaccine is available, and no therapy eliminates latency or prevents the early stages of reactivation. One long-term goal of ongoing research in the Sawtell lab is to find interventions for recurrent HSV episodes by defining the host and viral mechanisms that control the establishment and reactivation of HSV-1 latency. Interaction between the virus and the sensory neuron represents a pivot point where largely unknown mechanisms lead to a latent or a lytic infection in the neuron. Recent discoveries in the lab have identified several key features as to how to establish latency in vivo. Their studies could have a major impact on vaccine and gene transfer vector design, and may lead to a new class of therapeutics. Through the use of a mouse genetic reference population, they have identified a locus on mouse chromosome 16 that regulates HSV neurovirulence as well as the severity of herpetic stromal keratitis. Their studies are the first to demonstrate that the virus’ interaction with the nervous system contributes to its ability to cause corneal opacity and blindness and have led to a novel hypothesis regarding the initiation of stromal disease. In related studies, “genomics squared” analysis to explore the interaction of both viral and host genetics in herpetic disease have been initiated. In a project funded by NASA, the Sawtell lab is conducting studies to determine the long term outcomes of latent HSV in the central nervous system and the effects of stress and exposure to galactic cosmic radiation on HSV related pathology in the brain. These studies will not only define risks to astronauts and but also model HSV induced CNS damage (potentially increasing dementia risks) occurring in the aging population. Finally, a new NIH funded project exploits virally encoded miRNAs to regulate HSV reactivation in vivo.
Elizabeth P. Schlaudecker, MD, MPH
Dr. Elizabeth Schlaudecker’s research continues to focus on the immunologic responses to maternal immunization. Her recent work has demonstrated shifts in antibody isotype responses after influenza vaccination during pregnancy. With the mentorship and support of Dr. Sing Sing Way in the Division of Infectious Diseases, and Dr. Fred Finkelman in the Division of Immunology, she has revealed an altered isotype profile in pregnant women compared to non-pregnant women consistent with a decreased response to the vaccine. She is also investigating a sequential versus simultaneous administration of influenza and tetanus, diphtheria, and acellular pertussis (Tdap) vaccines in pregnant women with the Centers for Disease Control and Prevention (CDC), as well as immunologic responses to immunization in breast milk with Cincinnati Children's Vaccine and Treatment Evaluation Unit (VTEU).Samir S. Shah, MD, MSCE
Dr. Shah’s research team focuses on improving efficiency and effectiveness of care of hospitalized children with a particular emphasis on respiratory tract infections. Several ongoing studies will determine the comparative effectiveness of different antibiotic regimens for community-acquired pneumonia and identify biomarkers that predict illness severity in children with community-acquired pneumonia and bronchiolitis. Recently published research identified factors associated a higher risk of treatment failure in children hospitalized with pneumonia. Dr. Shah is also PI on a parallel group randomized trial determining the efficacy of home nursing visits in improving outcomes after hospitalization for acute illnesses such as pneumonia and bronchiolitis.Mary A. Staat, MD, MPH
Through Dr. Staat’s large epidemiology and surveillance program developed in 1997; she has optimized methods of detecting the changes and manifestations of infectious diseases of children within Hamilton County which has allowed her to compare local findings to national trends. Using unique methods, Dr. Staat has conducted studies to determine the population-based rates of Hamilton County hospitalizations and emergency department visits for many pediatric infectious diseases. These studies have resulted the determination of disease burdens as well as effectiveness of vaccines including rotavirus and influenza. Dr Staat currently is heading a trial funded by the Center for Disease Control and Prevention (CDC) to examine intussusception associated with rotavirus vaccine as well as two studies funded through the Vaccine and Treatment Evaluation Unit (VTEU) contract to evaluate the ability of mupirocin to decrease colonization of S aureus in infants, and to evaluate the treatment of children with community acquired pneumonia.
Dr. Staat has also utilized data from her large international adoption center to publish studies to assist in the development of evidence-based guidelines for internationally adopted children. In addition to studies in the field of infectious diseases, Dr. Staat and her colleagues have begun to explore the differences in neurological function between adopted and birth children using neuroimaging and psychological testing.
Ming Tan, PhD
Dr. Tan has two major research focuses: 1) elucidation of complex norovirus-host interactions, and 2) development of combinational subunit vaccines against enterically transmitted viruses. Dr Tan demonstrated that histo-blood group antigens (HBGAs) are critical attachment factors that affect the host susceptibility and host ranges of noroviruses. He discovered the mechanisms by which noroviruses enhance their HBGA binding capabilities which in turn results in the expansion of the target populations for norovirus. These studies led to the finding that human noroviruses changed their host factors from human HBGAs to porcine-specific glycans thus shifting host specificity from humans to pigs.
Utilizing the “P” particle that he discovered in norovirus, Dr Tan has developed three P domain-based polymers used as combinational vaccines and vaccine platforms. Several promising vaccine candidates were developed using the “P” particle technology, and three have moved to preclinical animal trials. In summary, Dr. Tan research outcomes shed light onto virus-host interactions and evolution of norovirus and offer new strategies for vaccine development against noroviruses and other infectious pathogens.
