Research from the Arizona State University Biodesign Institute describes efforts to improve the effectiveness of a Recombinant Attenuated Salmonella Vaccine (RASV) by modifying its ability to survive the hostile environment of the stomach.
The researchers demonstrated experimental strategies to restore acid resistance in several Salmonella vaccine strains, thereby improving their ability to survive low pH conditions in the stomach. The improved survival rate allows more of the bacterial cells to continue their infection sequence, colonizing intestinal tissues and generating a strong immune response.
Further, the acid resistant vaccine strains may behave more like unmodified Salmonella, which are cued by low pH conditions to prepare for the later stages of the infection process by up-regulating a key suite of genes involved in host interactions. These factors, the authors suggest, may significantly improve the effectiveness of Salmonella vaccines.
These results were recently published in the Journal of Bacteriology.
“Even though wild-type strains of Salmonella are quite capable of surviving the acidic environment of the stomach, it is surprisingly difficult to deliver a live Salmonella vaccine orally,” Brenneman says. “Many vaccines have mutations that leave them especially vulnerable to low pH, which means a large proportion of the vaccine cells are killed before they reach the intestine and thus are unable to do their job of delivering vaccine targets to the immune system. We’re trying to compensate for that increased acid sensitivity by increasing expression of the normal acid resistance systems.”
At the Biodesign Institute’s Center for Infectious Diseases and Vaccinology at ASU, researchers have been harnessing Salmonella’s impressive ability to infiltrate human tissues and stimulate immune responses, producing Salmonella-based vaccines targeting a range of illnesses. One such vaccine – developed by the group and currently in Phase I FDA trials – targets infant pneumonia, a disease that continues to kill some 2 million people per year, many of them in the developing world.
Such vaccines are attractive for a number of reasons. They can typically be produced much more cheaply than conventional vaccines, they may be delivered orally rather than through injection and can confer long-term immunity without the requirement of a subsequent booster dose. Further, Salmonella powerfully stimulates both cellular and humoral immunity, producing a robust, systemic response in the vaccine recipient.
The basic idea behind RASVs is to genetically retool the Salmonella bacterium in such a way that it retains its strong, immunogenic properties without causing illness. It is then outfitted with antigens for the particular disease the vaccine is designed to protect against. This Trojan-horse method introduces the disease antigens hidden in the Salmonella carrier, which then stimulate the immune responses.
But as the authors of the current study explain, the promising technique—potentially applicable for vaccines against virtually any pathogen—is not without its challenges. One of the most significant hurdles concerns the ability of Salmonella to survive the harsh environment of the stomach, where highly acidic (low pH) conditions prevail.
Read the rest of the story at the Biodesign Institute.
