Clinical trials of Shigella vaccines: two steps forward and one step back on a long, hard road

Abstract

More than 50 years of research has yielded numerous Shigella vaccine candidates that have exemplified both the promise of vaccine-induced prevention of shigellosis and the impediments to developing a safe and effective vaccine for widespread use, a goal that has yet to be attained. This Review discusses the most advanced strategies for Shigella vaccine development, the immune responses that are elicited following disease or vaccination, the factors that have accelerated or impeded Shigella vaccine development and our ideas for the way forward.At the end of the 19th century, as epidemics of bacillary dysentery accompanied by high mortality spread across Japan, the young microbiologist Kiyoshi Shiga examined dysenteric stools and isolated a bacterium that was agglutinated by serum from convalescent patients but not from patients with acute disease [1][2][3] (FIG. 1). That bacterium -known today as Shigella dysenteriae 1 -was the first identified member of the genus Shigella. Four Correspondence to M.L. mlevine@medicine.umaryland.edu. Competing interests statement:The authors declare no competing financial interests. Links NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author ManuscriptShigella species (or groups) are now recognized: S. dysenteriae (group A), which has 15 serotypes; Shigella flexneri (group B), which has 14 classical serotypes and subserotypes; Shigella boydii (group C), which has 20 serotypes; and Shigella sonnei (group D), which has single serotype 4 (TABLE 1).There has been resurgent interest in Shigella as a human pathogen, driven by the availability of more precise data on the disease burden 5-8 , emerging antibiotic resistance 9,10 and the fact that mucosally invasive Shigella, which often cause dysentery (gross blood in diarrhoeal stools), are less amenable to the salutary effects of oral rehydration than non-invasive pathogens that cause watery diarrhoea, such as Vibrio cholerae and enterotoxigenic Escherichia coli. The target populations for the use of Shigella vaccines include infants and young children in developing countries (in which the peak incidence occurs at 12-47 months of age and the S. flexneri serotypes predominate) 5-7 .S. dysenteriae 1, which produces Shiga toxin and typically carries R factors that encode resistance to multiple antibodies, waxes and wanes as a cause of epidemic severe disease in the world's least developed countries [11][12][13][14] Few bacterial pathogens have had their pathogenesis or interactions with mammalian tissues elucidated so precisely at the cellular and subcellular levels as Shigella spp. 20,21 Nevertheless, progress in attaining safe and effective Shigella vaccines has faltered. Herein, we review recent and old clinical trials that have evaluated the safety, immunogenicity and efficacy of candidate Shigella vaccines. We relate the bassis for the most popular strategies (BOX 2), the relevance of the different immune responses measured, the factors that have favoured or impeded vaccine development and, most importantly, the less...

Causes of Impaired Oral Vaccine Efficacy in Developing Countries

“…Ty21a offers moderate efficacy against typhoid fever (reported at 48% over 3 years in a recent systematic review [13]), although there is no evidence to suggest that this is lower than protection offered to travelers from high-income, non-endemic countries [14,15]. One live-attenuated Shigella vaccine candidate was reactogenic and immunogenic when administered to North-American adults; however, when the same vaccine was tested in Bangladesh, it elicited no adverse reactions and failed to induce a serological response in any recipient [16,17]. Poor immunogenicity has also been observed for an oral-killed cholera vaccine among children in Nicaragua compared with Sweden [18].…”

Towards a non-living vaccine against Shigella flexneri: From the inactivation procedure to protection studies

“…Current vaccines strategies against Shigella can be grouped into two fundamental approaches: live-attenuated vaccines and nonliving vaccines [6][7][8]. While the essential concern regarding live attenuated candidates is to find the appropriate balance between immunogenicity and acceptable side effects, different scenery appears for inactivated whole cell or subunit vaccines.…”

“…In the absence of an existing effective vaccine and the ever-increasing frequency of antimicrobial-resistant Shigella strains worldwide, Shigellosis has become a major source of concern [5]. Several candidate shigellosis vaccines are currently in development including live attenuated, inactivated whole cell, or subunit vaccines [6][7][8]. Considering intrinsic risk of living vaccines, the non-living vaccine alternative, including either inactivated whole-cell or acellular approaches, results the safest direction.…”

Safety and immunogenicity of an intranasal Shigella flexneri 2a Invaplex 50 vaccine

“…The lack of a clear correlate of protection for Shigella vaccines has hampered vaccine development over the past several decades [8,10,11]. Even so, the importance of the serotype specific LPS antigen is widely recognized and included as a component of all vaccine approaches actively being pursued.…”