Live-Attenuated Shigella Vaccines. Is Encouraging Good Enough?

Abstract

Several strategies have been used to develop vaccines against Shigella infection. Among these, the most tested has been the construction of live attenuated, orally administered vaccine candidates in which defined mutations were introduced in specific genes. Two major options exist: (1) altering key metabolic pathways affecting bacterial growth in tissues or (2) knocking out virulence genes selected upon their expected capacity to affect one or several key steps of the infectious process. In certain cases, the two options have been combined.Live-attenuated Shigella vaccine candidates have shown great promise. They elicited, in general, significant immune responses when administered orally to volunteers. They have the capacity to confer protection by eliciting both mucosal and systemic immune responses, particularly the intestinal production of secretory IgAs directed against the O-antigens, a series of complex surface sugars accounting for the bacterial serotypes, which are known to mediate protection following natural infection. These responses have been measured by evaluating antibody-secreting cells, serum antibody levels, and fecal IgA to O-antigens and individual virulencerelated protein antigens for a dozen of vaccine candidates. Live-attenuated vaccines also offer the potential to elicit strong IFN-g responses, a cytokine that is known to provide protection against Shigella infection. With regard to possible T-cell-mediated responses, much basic research is still warranted to optimize vaccine approaches. Owing to the wide range of Shigella serotypes and subtypes, there is a priori a need for a multivalent vaccine representing the prevalent species and serotypes. The barrier to the use of live vaccine candidates against shigellosis is the issue of multivalency and indications for an average to poor immune responses observed in infants and children in endemic areas. In addition, identification of the correlates of protection is needed to accelerate the development of these vaccines.

The Rising Dominance of Shigella sonnei: An Intercontinental Shift in the Etiology of Bacillary Dysentery

“…As a result of the considerable global burden, low infectious dose [ 4 ], clinical severity, and frequent reports of emerging antimicrobial resistance against first- and, more recently, second-line therapies [ 5 , 6 ], a vaccine against Shigella infections is a growing necessity. Yet, more than a century after the discovery of the agent of bacillary dysentery, there is still neither a licensed vaccine nor agreement on the precise mechanisms that induce Shigella immunity [ 7 ]. Vaccine development is further complicated by the probable need for a multivalent combination of O polysaccharide antigens to protect against a variety of heterogeneously distributed serotypes [ 8 ].…”