Development of Salmonella vaccines for cancer and viruses

National Institute Of Allergy And Infectious Diseases

Investigators

Abstract

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 have tested them in a Lassa virus infection model. Lassa virus is a 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 have developed an RASV to deliver a DNA-vaccine, in the form of a plasmid, into Mastomys natalensis. 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 have tested a SARS-CoV-2 vaccine, using the prefusion variant of the spike glycoprotein as an antigen, in mice and hamsters.