Dr. Beth D. Kirkpatrick
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Infectious Disease ImmunologyThe overarching focus of the work in Dr. Kirkpatrick’s lab and in the Vaccine Testing Center is the concentration on Infectious Diseases of global significance. The Kirkpatrick Lab and the Vaccine Testing Center has two main areas of interest: Vaccine Development: 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. Infectious Disease Immunology: In addition to vaccine testing, the lab is interested in characterizing how the human host responds immunologically to clinically important infectious agents and vaccines. The goal of this work is to gain a better understanding of immunologic responses to vaccines as well as natural infections. Current projects in the lab: 1. 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. 2. 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, http://www.icddrb.org/). 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. 3. 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. 4. 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. 5. 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, 2×2 factorial study design.
 The Vaccine Testing Center Team, December 2010. |
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| Office: 110A Stafford 802 656 0016 Beth.Kirkpatrick@uvm.edu Lab: 110 Stafford Hall 802-656-0016 BACKGROUND
LAB MEMBERS
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SELECTED PUBLICATIONSBD Kirkpatrick, Rasidul Haque, Priya Duggal, Dinesh Mondal, Cathy Larsson, Kristine Peterson, Jasmin Akter, Lauren Lockhart, Salwa Khan, William A Petri, Jr. Association of Cryptosporidium Infection with HLA Class I and II Alleles. Journal Infectious Diseases 2008; 197: 474-478. Lindow JC, Poly F, Tribble DR, Guerry P, Carmolli MP, Baqar S, Porter CK, Pierce KK, Darsley MJ, Sadigh KS, Dill EA; Campylobacter Study Team, Kirkpatrick BD. Caught in the act: in vivo development of macrolide resistance to Campylobacter jejuni infection. J Clin Microbiol. 2010 Aug;48(8):3012-5. Lyon CE, Sadigh KS, Carmolli MP, Harro C, Sheldon E, Lindow JC, Larsson CJ, Martinez T, Feller A, Ventrone CH, Sack DA, DeNearing B, Fingar A, Pierce K, Dill EA, Schwartz HI, Beardsworth EE, Kilonzo B, May JP, Lam W, Upton A, Budhram R, Kirkpatrick BD. In a randomized, double-blinded, placebo-controlled trial, the single oral dose typhoid vaccine, M01ZH09, is safe and immunogenic at doses up to 1.7 x 10(10) colony-forming units. Vaccine. 2010 Apr 30;28(20):3602-8. Carmolli M, Duggal P, Haque R, Lindow J, Mondal D, Petri WA Jr, Mourningstar P, Larsson CJ, Sreenivasan M, Khan S, Kirkpatrick BD. Deficient serum mannose-binding lectin levels and MBL2 polymorphisms increase the risk of single and recurrent Cryptosporidium infections in young children. J Infect Dis. 2009 Nov 15;200(10):1540-7. |
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