Toward a Shigella Vaccine: Opportunities and Challenges to Fight an Antimicrobial-Resistant Pathogen

Abstract

Shigellosis causes more than 200,000 deaths worldwide and most of this burden falls on Low- and Middle-Income Countries (LMICs), with a particular incidence in children under 5 years of age. In the last decades, Shigella has become even more worrisome because of the onset of antimicrobial-resistant strains (AMR). Indeed, the WHO has listed Shigella as one of the priority pathogens for the development of new interventions. To date, there are no broadly available vaccines against shigellosis, but several candidates are being evaluated in preclinical and clinical studies, bringing to light very important data and information. With the aim to facilitate the understanding of the state-of-the-art of Shigella vaccine development, here we report what is known about Shigella epidemiology and pathogenesis with a focus on virulence factors and potential antigens for vaccine development. We discuss immunity after natural infection and immunization. In addition, we highlight the main characteristics of the different technologies that have been applied for the development of a vaccine with broad protection against Shigella.

Keywords: AMR; O-antigens; Shigella; lipopolysaccharides; type III secretion system; vaccines.

Figure 1

Major pathogens responsible for diarrhea in children under 5 years old. Each ball reports the number of deaths from diarrhea attributed to each pathogen in 2016 (data source: https://ourworldindata.org/diarrhoeal-diseases) (accessed on 23 January 2023). ETEC: Enterotoxigenic E. coli, EPEC: Enterotopathogenic E. coli.

Figure 2

Infectious cycle of Shigella.

Figure 3

Shigella diarrhea mortality rate (deaths per 100,000). Data from [28].

Figure 4

Global drug treatment against Shigella infection over the years and increase in antibiotic resistance developed to these drugs.

Figure 5

Biosynthesis of LPS moieties expressed on the membrane surface of Shigella bacteria (A). Structures of Shigella O-antigens and core regions (B). KDO: 3-deoxy-D-manno-2-octulosonic acid; Hep: L-glycero-D-manno-heptose; GlcN: glucosamine; GlcNAc: N-Acetylglucosamine; Rha: Rhamnose; GalA: galacturonic acid; GalNAc: N-Acetylgalactosamine; AltNAcA: N-Acetyl-amino altruronic acid; FucNAc: N-Acetyl-L-fucosamine; cmpx: complex; G4C: group 4 capsule; HMW: high molecular weight; MMW: medium molecular weight; LMW: low molecular weight.