Attenuating gene expression (AGE) for vaccine development

Abstract

Live attenuated vaccines are adept in stimulating protective immunity. Methods for generating such vaccines have largely adopted strategies used with Salmonella enterica. Yet, when similar strategies were tested in other gram-negative bacteria, the virulence factors or genes responsible to incapacitate Salmonella often failed in providing the desired outcome. Consequently, conventional live vaccines rely on prior knowledge of the pathogen’s virulence factors to successfully attenuate them. This can be problematic since such bacterial pathogens normally harbor thousands of genes. To circumvent this problem, we found that overexpression of bacterial appendages, e.g., fimbriae, capsule, and flagella, could successfully attenuate wild-type (wt) Salmonella enterica serovar Typhimurium. Further analysis revealed these attenuated Salmonella strains conferred protection against wt S. Typhimurium challenge as effectively as genetically defined Salmonella vaccines. We refer to this strategy as attenuating gene expression (AGE), a simple efficient approach in attenuating bacterial pathogens, greatly facilitating the construction of live vaccines.

Antibodies against In Vivo -Expressed Antigens Are Sufficient To Protect against Lethal Aerosol Infection with Burkholderia mallei and Burkholderia pseudomallei

“…Alternatively, anachronistic overexpression of the batA gene product may attenuate B. mallei. This phenomenon has been reported in the literature as a platform to develop live attenuated vaccines, termed attenuated gene expression (127). The molecular basis of attenuation is not fully understood and varies between model systems.…”

Oral administration of a recombinant attenuated Yersinia pseudotuberculosis strain elicits protective immunity against plague

“…Immunization with Salmonella vaccines synthesizing F1 antigen induced protective immunity against plague [39-43]. However, the virulence of S. typhimurium P1 containing a caf1 expression plasmid was dramatically reduced due to its growth retardation and the disruption of its membrane caused by F1 overexpression [44, 45]. Our observations also showed that the F1 overexpression in Yptb PB1+ strain containing a caf1 expression plasmid severely affected its growth, could not colonize in spleens and livers of mice and barely induced protective immunity against plague (data not shown).…”

Live attenuated vaccines for invasive Salmonella infections

“…[65, 66] Interestingly, instead of deleting genes, some investigators have attenuated bacteria by overexpressing bacterial surface appendages such as flagella and pili using a method termed Attenuated Gene Expression (AGE). [67]…”