The work, done at the Biodesign Institute at Arizona State University (ASU; Tempe), could be a key step in development of a new means of biological containment that would be a component of a new way to deliver vaccines in animals and humans. If fully developed, the method could be used to administer vaccines to many of those who do not benefit from traditional vaccines because of their cost, because of drug resistance, or because of their limited effects on children.
In the study, published in the July 7 issue of the Proceedings of the National Academy of Sciences, the researchers describe a novel, effective means of biological containment for antigen delivery. The method not only effectively delivers the antigen in the body, but does so in a way that does not infect the body with Salmonella and does not leave any vaccine cells in the environment.
The research team includes scientists formally at Washington University, St. Louis, and Megan Health, Inc., St. Louis, who are now at ASU's Biodesign Institute and the School of Life Sciences.
"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, PhD, director of the Center for Infectious Diseases and Vaccinology at the Biodesign Institute and a professor in ASU's School of Life Sciences. Dr. Curtiss was part of the research team that made the discovery.
He said the research team sought to do this in such a way that no disease symptoms due to Salmonella would arise and a protective immune response would be induced to the pathogen whose protective antigen was delivered by the vaccine construction, in this case against Streptococcus pneumoniae due to an immune response to pneumococcal surface protein A. They also wanted to ensure that there would be "no ability for live bacterial vaccine cells to either persist in vivo or to survive if shed into the environment," Dr. Curtiss said in a statement.
"The biological containment system we developed is sufficient by itself on conferring attenuation, the inability to cause disease symptoms, and ability to deliver an antigen to induce protective immunity," Dr. Curtiss said. "We have high expectations that this delivery system will be safe and effective when administered to animals and humans."
A key to the project, he continued, is "turning a foe into a friend." That foe is the Salmonella bacterium-the leading cause of human food-borne illness. The research team has used genetic know-how to develop 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 diarrhea, gut inflammation, and fluid secretion-while keeping the wherewithal to induce immunity against the bacteria causing pneumonia or other infectious diseases," Dr. Curtiss said. Several in his research team attack the problem from different angles, with some focusing on weakening Salmonella, others boosting the immune response, and others optimizing the self-destruct mechanism.
The research team leader, Wei Kong, PhD, of the Biodesign Institute, discussed the pros and cons of applying a pneumonia antigen. "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."
In experiments, the genetically modified Salmonella bacterium colonizes the lymph tissues of the host and manufactures a protein from the S. pneumoniae bacterium, which then triggers a strong antibody response. Unlike most typical vaccines, the attenuated recombinant Salmonella vaccine, after entry into the immunized individual, serves as its own factory to produce the protective antigens from the S. pneumoniae pathogen. This ability to cause production in the immunized individual dramatically decreases the cost of such vaccines, thus making them affordable for use in the developing world, Dr. Curtiss said.
Nano Trojan Horse Could Aid Drug Delivery
Approach uses a substance found in crab shells
Antioxidants neutralize the harmful effect of free radicals and other reactive chemicals generated in the body and are thought to promote better health. Normally, the human body's antioxidant defense is sufficient, but in individuals with a poor diet or those at risk of developing atherosclerosis, diabetes, or Alzheimer's disease, a nutritional source of antioxidants is required.
Orally delivered antioxidants were easily destroyed by acids and enzymes in the human body; thus, only a small percentage of what is consumed is actually being absorbed, Dr. Larson said in a statement released by the university.
The solution is to design a tiny sponge-like chitosan biopolymeric nanoparticle as a protective vehicle for antioxidants; chitosan is a natural substance found in crab shells. "Antioxidants sit within this tiny Trojan horse, protecting it from attack from digestive juices in the stomach. Once in the small intestine the nanoparticle gets sticky and bonds to the intestinal wall. It then leaks its contents directly into the intestinal cells, which allows them to be absorbed directly into the blood stream," Dr. Larson said.
"We hope that by mastering this technique, drugs and supplements also vulnerable to the digestive process can be better absorbed by the human body," he adds. "For catechins-the class of antioxidants under examination and among the most potent dietary antioxidants-only between 0.1% and 1.1% of the amount consumed makes it into our blood. If we can improve that rate, the benefits are enormous."