New Generation Of Vaccine Carriers May Offer Broader Protection
In new studies carried out at the Biodesign Institute of Arizona State University, a Salmonella vaccine carrier has been outfitted with the first multiple-antigen capability to target specific proteins recognized by the body and attacked by the immune system.
Wei Xin has led a team that is using Salmonella as a vaccine delivery vehicle.
The multiple-antigen study was carried out by Wei Xin and colleagues—researchers working in the laboratory of Roy Curtiss, Director of the Center for Infectious Diseases and Vaccinology at the Biodesign Institute. The ongoing research receives funding from the National Institute of Health and through a grant from the Bill and Melinda Gates Foundation. A poster providing a descriptive and visual overview of the research will be presented at the 109th general meeting of the American Society of Microbiology in Philadelphia, Pennsylvania from May 20, 2009.
The work successfully introduces the prospect of broad-spectrum vaccine protection against Streptococcus pneumoniae, including a strategy versatile enough for use against many other lethal infectious diseases. Earlier work by the group had demonstrated the effectiveness of Salmonella as a potent vehicle to deliver a single common disease antigen, due to the bacterium’s tenacious ability to infect the host. A greater challenge has been to equip the Salmonella carrier or vector with additional antigens, which can protect against variant strains of a given pathogen.
The disease target in this case was S. pneumoniae, a causative agent of pneumonia, that kills some 3 million people worldwide each year. Infants, particularly vulnerable to pneumonia, could one day be protected from a wide variety of disease strains, through a salmonella-based vaccine of this kind. Such a vaccine may be produced at minimal cost and delivered orally, making it an attractive alternative to existing methods of protection, particularly in the developing world, where the disease is most rampant. Further, the introduction of multiple antigens holds out the future possibility of a single-dose vaccine to protect against several common infectious diseases simultaneously.
The technique used for the attenuated vaccine involves inserting the disease antigens into the small, circular segment of the Salmonella bacterium’s extrachromosomal DNA, known as a plasmid. It is important for Salmonella to retain the modified plasmid, which it tends to lose over successive generations unless cultured in the presence of antibiotics. Two antibiotic-free “balanced-lethal” host/plasmid systems were developed and constructed for the purpose of stabilizing the expression of multiple foreign antigen genes in a Salmonella vaccine strain and forcing the bacteria to retain the recombinant plasmids. For the first time, the group was able to effectively deliver two pneumococcal antigens known as PspA and PspC, each carried on a separate plasmid within the same Salmonella vaccine strain and to demonstrate in mouse studies that the multi-antigen combination provides more thorough immune protection to S. pneumoniae challenge, when compared with a traditional, single-antigen vaccine or with a combination of two strains, each producing a single antigen. Tests of the plasmid stability showed that it could be effectively retained by the Salmonella carrier for more than 60 generations. Further, by introducing a specific mutation, genetic shuffling among the two plasmids—a factor potentially compromising vaccine effectiveness—could be minimized. The “multi-valent vaccine” was shown to protect mice from otherwise lethal doses of S. pneumoniae.
Additional balanced-lethal host/plasmid systems have been developed to allow for expression of additional antigens. A Salmonella vaccine expressing four S. pneumoniae antigens, PspA, PspC, PcsB and pneumolysin, has been constructed and is currently being tested. Next, the group plans to push the multi-antigen envelope further, with newly engineered Salmonella vaccine carrying six S. pneumoniae antigens, to be tested in mice within the next several months. Team leader Wei Xin stresses that significant molecular hurdles to a much sought-after, multi-antigen vaccine have been overcome. “This is the first time we have successfully introduced a multi-antigen carrier of this kind, and shown that it can be stable and highly effective. The possibilities are exciting.” Director Roy Curtiss concurs, adding “Wei Xin has worked long and hard to achieve this objective of delivering multiple protective pneumococcal antigens in a single vaccine strain.”
Written by
Richard Harth Science Writer Biodesign Institute richard.harth@asu.edu
Media Contact:
Joe Caspermeyer Media Relations Manager & Science Editor joseph.caspermeyer@asu.edu 480-313-2010 (cell)
Media Sources:
Roy Curtiss, PhD
director of the Center for Infectious Diseases and Vaccinology Biodesign Institute rcurtiss@asu.edu
Wei Xin, PhD Assistant Research Scientist Center for Infectious Diseases and Vaccinology Biodesign Institute Wie.Xin@asu.edu
