Detoxified O-Specific Polysaccharide (O-SP)–Protein Conjugates: Emerging Approach in the Shigella Vaccine Development Scene

Abstract

Shigella is the second most common cause of moderate to severe diarrhea among children worldwide and of diarrheal disease-associated mortality in young children in low-and middle-income countries. In spite of many years of attempts to develop Shigella vaccines, no licensed vaccines are yet available. Injectable conjugate vaccines made of the detoxified lipopolysaccharide (LPS) of S. flexneri 2a, S. sonnei, and S. dysenteriae type 1 covalently bound to protein carriers were developed in the early 1990s by John B. Robbins and Rachel Schneerson at the US National Institutes of Health. This approach was novel for a disease of the gut mucosa, at a time when live, rationally attenuated oral vaccine strains that intended to mimic Shigella infection and induce a protective local immune response were extensively investigated. Of keystone support to Shigella glycoconjugates development were the findings of a strong association between pre-existent serum IgG antibodies to S. sonnei or S. flexneri 2a LPS and a lower risk of infection with the homologous Shigella serotypes among Israeli soldiers serving in field units. In view of these findings and of the successful development of the pioneering Haemophilus influenzae type b conjugate vaccines, it was hypothesized that protective immunity may be conferred by serum IgG antibodies to the O-Specific Polysaccharide (O-SP) following parenteral delivery of the conjugates. S. sonnei and S. flexneri 2a glycoconjugates induced high levels of serum IgG against the homologous LPS in phase I and II studies in healthy volunteers. The protective efficacy of a S. sonnei detoxified LPS-conjugate was further demonstrated in field trials in young adults (74%) and in children older than three years of age (71%), but not in younger ones. The evaluation of the Shigella conjugates confirmed that IgG antibodies to Shigella LPS are correlates of protection and provided solid basis for the development of a new generation of glycoconjugates and other injectable LPS-based vaccines that are currently in advanced stages of clinical evaluation.

Development of Shigella conjugate vaccines targeting Shigella flexneri 2a and S. flexneri 3a using a simple platform-approach conjugation by squaric acid chemistry

“…These vaccines display OSP in an immunologically relevant manner, are functional as judged by serotype-specific bactericidal activity, and are protective in virulent challenge models. Studies performed in humans over 20 years ago in endemic regions noted that serum antibody responses and antibody secreting cell (ASC) responses to LPS and invasion plasmid antigens (Ipas) occur following shigellosis [ 6 , 52 - 54 ], and an association was noted between serum antibody responses and protection against shigella, especially LPS/OSP responses [ 6 - 8 ]. Such antibody responses have been associated with protection against challenge in both animal and human volunteer studies [ 22 , 55 - 57 ].…”

“…A number of shigella vaccines are in various stages of development, including ones based on conjugation, to develop immune responses to the OSP component of Shigella spp LPS [ 6 , 8 , 10 - 36 ]. We have previously described the use of an inexpensive conjugation vaccine technology based on squaric acid chemistry to directly link bacterial O-specific polysaccharides recovered from Vibrio cholerae to a recombinant fragment of tetanus toxin heavy chain (rTTHc) to produce a cholera conjugate vaccine (CCV) [ 37 - 41 ].…”

Development of the Shigella flexneri 2a, 3a, 6, and S. sonnei artificial Invaplex (Invaplex AR ) vaccines

“…Shigella vaccine approaches that are in clinical development include live attenuated vaccines (NCT04242264; 42 ) and subunit vaccine efforts ( 43 , 44 ). For the most part, Shigella vaccine approaches focus on the delivery of the serotype-defining Shigella LPS or O-SP, which has been suggested as a protective antigen ( 45 , 46 ). Building on earlier clinical studies by Robbins and co-workers using O-SP conjugate vaccines, are recent approaches delivering the O-specific polysaccharide with either bioconjugates ( 47 ) or synthetic conjugates ( 48 ) which have advanced to clinical studies in target populations (NCT02646371 and NCT04602975).…”

Recent updates on correlates of vaccine-induced protection

“…In a review published in 2007 Levine et al (59) wrote that "Identification of protection is arguably the most crucial catalyst needed to accelerate the development of effective Shigella vaccines," but added that no clear correlate had been identified. Multiple candidate vaccines against shigella continue to be studied, including those containing the surface O antigen, antibodies to which are one proposed correlate (60,61). In a detailed analysis Clarkson et al (62) conclude that there are multiple CoPs, which may differ from one species to another.…”