Deadly salmonella designed to administer vaccines in the body

Washington, July 9 : Scientists at the Biodesign Institute, affiliated to Arizona State University, claim to have made a significant advance towards developing a biologically engineered organism that can effectively deliver an antigen in the body.

In their study report, appearing in the online edition of the Proceedings of the National Academy of Sciences, the researchers say that they have been able to use live salmonella bacterium as the containment/delivery method for an antigen.

They are of the opinion that their work may pave the way for novel techniques to administer vaccines to many of those who do not benefit from traditional vaccines because of several causes-viz., cost, drug resistance, or limited effects on children.

"Regulated programmed lysis of recombinant Salmonella in host tissues to release protective antigens and confer biological containment," read the research paper.

The researchers claim that their method effectively delivers the antigen in a way that does not infect the body with salmonella, and does not leave any vaccine cells in the environment.

"Our goal is to design, engineer and evaluate a live bacterial (using salmonella) antigen delivery system that would display regulated delayed lysis in vivo after invasion into and colonizing internal lymphoid tissues in an immunized individual," said Roy Curtiss, director of the Center for Infectious Diseases and Vaccinology at the Biodesign Institute and a professor in ASU's School of Life Sciences.

"We wanted to do this in a way so that no disease symptoms due to salmonella would arise, a protective immune response would be induced to the pathogen whose protective antigen was delivered by the vaccine construction (in this case against S. pneumoniae due to an immune response to PspA), and there would be no ability for live bacterial vaccine cells to either persist in vivo or to survive if shed into the environment," he added.

Curtiss says that the key to the new approach is "turning a foe into a friend": salmonella being the foe because it is known to be the leading cause of human food-borne illness.

Through genetic know-how, his team has developed a variety of ways to tame salmonella in the lab, and use it as a delivery vector for vaccines.

"We try to genetically modify the salmonella bacterium to eliminate its harmful effects-the diarrhoea, gut inflammation and fluid secretion-while keeping the wherewithal to induce immunity against the bacteria causing pneumonia or other infectious diseases," the researcher said.

Speaking about the application of a pneumonia antigen, team leader Wei Kong, of the Biodesign Institute, said: "If we tried to use live Streptococcus pneumoniae causing pneumonia for a vaccine, we would obviously kill the patient. The benefit of a live vaccine that uses a weakened form of salmonella, is that the salmonella can be taken up through the intestinal lining and stimulate an immune response by using just a portion of the bacteria causing pneumonia that itself is not deadly."

The experiments showed the genetically modified Salmonella enterica bacterium to colonize the lymph tissues of the host, and manufacture a protein from the S. pneumoniae bacterium, which then triggered a strong antibody response.

Unlike most vaccines that are entirely manufactured by a vaccine company, according to the researchers, the attenuated recombinant salmonella vaccine after entry into the immunized individual serves as its own factory to produce the protective antigens (proteins) from the S. pneumoniae pathogen.

Curtiss believes that this ability dramatically decreases the cost of such vaccines to make them affordable for use in the developing world.

He said that an important factor for the research team was to genetically program the S. enterica bacterium to destroy itself so that it was not released into the environment.

"Biological containment systems are important to address the potential risk posed by any unintentional release of the modified salmonella into the environment," he said.

The salmonella life cycle is balanced to allow enough time to enter the body and build an immune response, while leading to cell death by bursting the cells and preventing the vaccine strain from spreading into the environment.

"The data show that the system we have devised results in cell lysis in the absence of arabinose and clearance of the strain from host tissues," the researchers said.

"More importantly, our strain was fully capable of delivering a test antigen and inducing a robust immune response comparable to that of a vaccine strain without this containment system, thereby demonstrating that this system has all of the features required for biological containment of a recombinant attenuated salmonella vaccine," they added.

ANI