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Principal Investigator: Olivia Steele-Mortimer
Organization: NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES
Fiscal Year: 2020
Award: $356,012
Funding agency: National Institute of Allergy and Infectious Diseases
Live recombinant attenuated Salmonella vaccines (RASV) have been used to protect against Typhoid fever and can be used to deliver foreign antigens or DNA plasmids. We are developing an RASV platform as a therapeutic vaccine for breast cancer and also as a delivery system for DNA antiviral vaccines. RASVs can be delivered orally, are inexpensive to produce and can elicit both mucosal and systemic immune responses. The breast cancer project is a collaboration with Dr Alana Welm at the Huntsman Institute. Dr Welm has several different in vivo models for metastasis in mice, including a model where human tumors can be transplanted into mice and go on to reproduce the same metastasis as seen in the patient. In order to test the functionality of the RASV strains, before adapting them as cancer vaccines, we are first testing them in a Lassa virus infection model. Lassa virus is an BSL4 level human pathogen that causes significant morbidity and infection in West Africa. Vaccination is an effective way to prevent disease in humans but it has little to no effect on the amount of virus in the environment since the natural host of this zoonotic disease is a rodent, Mastomys natalensis, which is ubiquitous and highly commensal in Lassa endemic areas. As a way to control zoonotic spread of the disease we will develop an RASV to deliver a DNA-vaccine, in the form of a plasmid, into Mastomys natalensis. For the last three years we have focused on designing and making novel RASV strains. This involves introducing multiple attenuating mutations in Salmonella enterica serovar Typhmurium (Salmonella Typhimurium), which must be done sequentially making it a rather laborious process. We now have several RASV strains that have been sequenced and have been tested in vitro, to show that they can infect epithelial cells but are attenuated in intracellular replication and able to deliver the recombinant plasmid to the cytosol of the host cell. Working with our collaborator Kyle Rosenke (Laboratory of Virology) we are starting to test a Lassa RASV in M. natalensis. We are also looking at ways to optimize delivery of the plasmid and subsequent expression of the viral glycoprotein in mammalian cells. This RASV platform is now also being used to develop a SARS-CoV-2 vaccine using the prefusion variant of the spike glycoprotein as an antigen.
Terms: <2019 novel coronavirus><2019-nCoV><Abdominal Typhus><Africa><Antigens><Antineoplastic Vaccine><Antiviral Agents><Antiviral Drugs><Antivirals><Area><Attenuated><Body Tissues><Brain><Brain Nervous System><Breast Cancer><COVID-19><COVID19><Cancer Vaccines><Cell Body><Cells><Collaborations><Cricetinae><Cytosol><DNA><DNA Vaccines><Deoxyribonucleic Acid><Development><Disease><Disorder><Encephalon><Enteric Fever><Environment><Epithelial Cells><Genetic Alteration><Genetic Change><Genetic defect><Glycoproteins><Goals><Hamsters><Hamsters Mammals><Human><Immune response><Immunological response><Infection><Institutes><Laboratories><Lassa fever virus><Lassa virus><Liver><Lung><Lung Respiratory System><Mammalian Cell><Mastomys><Metastasis><Metastasize><Metastatic Lesion><Metastatic Mass><Metastatic Neoplasm><Metastatic Tumor><Mice><Mice Mammals><Modeling><Modern Man><Morbidity><Morbidity - disease rate><Mucosa><Mucosal Tissue><Mucous Membrane><Murine><Mus><Mutation><Naked DNA Vaccines><Neoplasm Metastasis><Neoplasm Vaccines><Oral><Patients><Plasmids><Process><Recombinant DNA Vaccines><Recombinants><Research Institute><Rodent><Rodentia><Rodents Mammals><S enterica><S enterica serovar Typhimurium><S typhimurium><S. enterica><S. enterica serovar Typhimurium><S. typhimurium><SARS-CoV-2><SARS-CoV2><SARS-associated coronavirus 2><SARS-coronavirus-2><SARS-related coronavirus 2><Salmonella><Salmonella Vaccines><Salmonella enterica><Salmonella enterica serovar Typhimurium><Salmonella typhimurium><Salmonellosis Vaccines><Secondary Neoplasm><Secondary Tumor><Severe acute respiratory syndrome coronavirus 2><System><Testing><Tissues><Transplantation><Tumor Vaccines><Typhoid><Typhoid Fever><Vaccination><Vaccines><Variant><Variation><Viral><Viral Antigens><Viral Diseases><Virus><Virus Diseases><Wuhan coronavirus><Zoonoses><Zoonotic><Zoonotic Infection><anti-viral agents><anti-viral drugs><anti-virals><bone><breast cancer vaccine><cancer metastasis><corona virus disease 2019><coronavirus disease 2019><design><designing><develop a vaccine><development of a vaccine><developmental><genome mutation><hepatic body system><hepatic organ system><host response><human pathogen><immunogen><immunoresponse><in vitro testing><in vivo Model><malignant breast neoplasm><malignant breast tumor><novel><plasmid DNA><prevent><preventing><pulmonary><therapeutic vaccine><transplant><treatment vaccines><tumor><tumor cell metastasis><vaccine development><vaccine evaluation><vaccine for cancer><vaccine for the treatment><vaccine for treatment><vaccine formulation><vaccine screening><vaccine testing><viral infection><virology><virus antigen><virus infection><virus-induced disease>