Shigella Vaccines: The Continuing Unmet Challenge

Abstract

Shigellosis is a severe gastrointestinal disease that annually affects approximately 270 million individuals globally. It has particularly high morbidity and mortality in low-income regions; however, it is not confined to these regions and occurs in high-income nations when conditions allow. The ill effects of shigellosis are at their highest in children ages 2 to 5, with survivors often exhibiting impaired growth due to infection-induced malnutrition. The escalating threat of antibiotic resistance further amplifies shigellosis as a serious public health concern. This review explores Shigella pathology, with a primary focus on the status of Shigella vaccine candidates. These candidates include killed whole-cells, live attenuated organisms, LPS-based, and subunit vaccines. The strengths and weaknesses of each vaccination strategy are considered. The discussion includes potential Shigella immunogens, such as LPS, conserved T3SS proteins, outer membrane proteins, diverse animal models used in Shigella vaccine research, and innovative vaccine development approaches. Additionally, this review addresses ongoing challenges that necessitate action toward advancing effective Shigella prevention and control measures.

Keywords: Shigella spp.; conjugate; live attenuated; shigellosis; subunit; type III secretion system; vaccines; whole killed.

Figure 1

Timeline of vaccine development against Shigella infection. This figure illustrates key milestones in the field of Shigella research and vaccine development, highlighting breakthroughs and advances achieved over the years. Figure created using BioRender.com (accessed on 17 October 2023).

Figure 2

Shigella pathogenesis. (Left) Stepwise evasion of the host immune system by Shigella during its journey from ingestion to the colonization of the intestine. This figure highlights key mechanisms employed by Shigella to evade immune detection and clearance at various stages of infection. (Right) Detailed depiction of the process of Shigella invasion into host cells via genetic changes and acquisition of virulence plasmids (right top) providing insights into the intricate mechanisms by which Shigella breaches the host epithelial barrier and initiates intracellular replication by using the type III secretion system (T3SS) or enterotoxins (right middle), leading to infection and pathogenesis (right bottom). The straight arrows at the top represent mechanisms, while the straight arrows in the middle indicate different infections. Curved arrows in the middle and bottom denote the release of toxins. Figure created using BioRender.com (accessed on 17 October 2023).

Figure 3

Current Shigella vaccines in development. This figure provides an overview of the diverse vaccine candidates currently under development against Shigella infections. Each vaccine candidate is displayed along with its corresponding target antigens. Figure created with BioRender.com (accessed on 17 October 2023).

Figure 4

Animal models for vaccine development against Shigella infection. (Left) Various challenge routes can be used in mouse models. The figure outlines different routes, such as (A) intranasal delivery, (B) intraperitoneal injection, and (C) oral administration. (Right) Non-mouse animal models employed in Shigella vaccine development research. This includes (D,G) primate models, (E) rabbit models, and (F) guinea pig models. Each offers unique advantages and insights into Shigella pathogenesis and vaccine responses. Figure created using BioRender.com (accessed on 17 October 2023).