Development of Salmonella vaccines for breast cancer and viruses

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Cancer vaccines are considered either therapeutic (treating an existing cancer) or prophylactic (which prevent cancer from developing in healthy people). Our goal is to develop a therapeutic vaccine for breast cancer. Breast cancer metastasis, when cells from the original tumor spread to other organs, is what usually kills patients. This vaccine would stimulate the immune system to discover and destroy metastatic cells. This project is a collaboration with Dr Alana Welm at the Oklahoma Medical Research Foundation. 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. We are developing a novel recombinant attenuated Salmonella vaccine (RASV) for this project. In order to test the functionality of the RASV strains, before adapting them as cancer vaccines, we will first test them in a viral 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 two 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.