Vermont Center for Immunobiology and Infectious Disease

Research Lab of Beth Kirkpatrick, M.D.

Overview

Areas of interest: vaccine development, human immunology.

Dr. Kirkpatrick’s work is focused on translational and clinical research. Her experience in clinical trials, clinical immunology and establishing international field sites permits her findings to be tested in a variety of clinical settings, domestic and international. Dr. Kirkpatrick established the clinical and laboratory infrastructure for the Vaccine Testing Center (VTC) at UVM. The VTC is currently conducting a series of phase I clinical trials and immunologic evaluations of attenuated live monovalent and tetravalent Dengue viruses via a 5 year NIH vaccine grant in collaboration with Johns Hopkins and the NIH. Other VTC work has included vaccine development and challenge models for S. Typhi and Campylobacter jejuni infections. Dr. Kirkpatrick (as co-PI with the University of Virginia) and the VTC are also exploring the biologic basis of vaccine underperformance via large field-based studies in Bangladesh and India, funded by the Gates Foundation.

Our team runs a fully functioning unit for performing phase I and II vaccine trials and enteric challenge models at the Vaccine Testing Center (VTC). In general, the VTC focuses on the development of vaccines of importance to global health, including typhoid fever, Campylobacter infections and dengue viral diseases. In 2009, the VTC began a 5- year project with Johns Hopkins University to study new Dengue and West Nile Vaccines. Other collaborators have included biotech companies, the National Institutes of Health and the Department of Defense.

Our laboratories are outfitted for scaled-up clinical immunology and microbiology work. Our staff is trained in current Good Clinical Practices (cGCP) according to FDA E9 specifications and the laboratory operates on Good Laboratory Practices-like (GLP) principles. Laboratories have the capacity for performing the immunogenicity work for multi-site vaccine trials, including specimen processing and storage. We also have the flexibility to add study-specific assays needed for vaccine trials. A detailed description of available equipment is available upon request. Experienced technicians are trained to perform validated immunologic and microbiology assays including: ELISAs, ELISPOT/ ASC/ ALS assays, functional assays of opsonization, PCR, multi-parameter flow cytometry and cell sorting, cytokine analysis (Bioplex), confocal microscopy, plaque-based assays for viral pathogens, bacterial culturing, and inoculum preparation for challenge studies.

Programs & Projects

Typhoid Fever

Salmonella typhi is a gram-negative bacterium that causes a severe febrile illness and is spread through contaminated food and water. The infection spreads in the host via invasion of host macrophages, using a type-III secretion system (TTSS). Despite the presence of vaccines against typhoid fever used for more than 100 years, typhoid fever still infects 15-30 million persons annually, killing 600,000. While the clinical arm of the VTC has been working with biotech partners to develop new typhoid vaccines, the laboratory is focused on understanding correlates of immune protection to S. typhi infection and evaluating the functional immunology of candidate vaccines.

Cryptosporidium infections

Cryptosporidium is an intestinal protozoan infection which causes diarrhea, particularly in young children and immunocompromised individuals (such as persons with Acquired Immunodeficiency Syndrome, AIDS). In developing regions of the world, Cryptosporidium infection is associated with childhood malnutrition, including loss of linear growth/stunting of height. Our laboratory work has focused on how the immune response of young children to this infection contributes to the vicious cycle of diarrhea, infectious diseases and malnutrition.

We have studied the role of host genetic susceptibility and HLA alleles to Cryptosporidium infection. This work was performed as part of a field trial cohort of children in Bangladesh, in collaboration with colleagues at the University of Virginia and the ICDDRB (Dhaka, Bangladesh). Current work is examining the role of mannose-binding lectin genotypes and susceptibility to Cryptosporidium, as well as E. histolytica infections. We are also interested in determining the contribution of the human intestine T-lymphocyte populations to intestinal inflammation, as well as age-dependent changes in the host immune response to intestinal protozoa.

Campylobacter jejuni infections

Campylobacter jejuni is a top cause of food-borne disease in the United States and a common cause of diarrhea in young children globally. It is uniquely associated with post-infectious sequelae, including reactive arthritis, irritable bowel syndrome and, via molecular-mimicry, ascending paralysis (the Guillain-Barré syndrome). Out lab is working to improve serodiagnostic tests for the detection of Campylobacter jejuni infections and to better understand the cellular immune responses to this infection.

Dengue Virus Vaccines

Dengue virus is an RNA virus, transmitted by the Aedes egypti mosquito, which can cause a significant febrile illness (Dengue fever). Most individuals spontaneously recover from primary infection; however secondary, infections are more frequently associated severe complications, including shock and bleeding disorders. Dengue viruses cause 50-100 million infections each year, with 500,000 hospitalizations. Although most infections occur in tropical and subtropical areas, global warming has increased the risk of Dengue becoming a significant risk in areas where the disease was previously eradicated, including the United States. The development of Dengue vaccines is a priority of the National Institutes of Health. Work on dengue vaccines is a new direction for the laboratory and VTC. Over the next five years, the lab will be working with collaborators to better define cellular immune responses to live, attenuated dengue vaccines.

Exploration of the Biologic Basis for Underperformance of Oral Polio and Rotavirus Vaccines in Bangladesh

Oral polio and rotavirus vaccines are significantly less effective in children living in the developing world. Tropical enteropathy, which is associated with intestinal inflammation, decreased absorption and increased permeability, may contribute substantially to oral vaccine failure in developing country settings. Other possible causes of oral vaccine underperformance include malnutrition, interference with maternal or breast milk antibodies, changes in gut microbiota, and genetic susceptibility. The primary hypothesis of this clinical trial is that tropical enteropathy decreases the effectiveness of oral polio and rotavirus vaccines in infants by disrupting gut integrity. The study will enroll 700 healthy infants born in the urban slum of Mirpur, Dhaka, Bangladesh, as well as their mothers, and employ a prospective cohort, 2x2 factorial study design.