Yutai Zhao

Background/Objectives: Shigella is the leading bacterial cause of diarrheal disease worldwide. Although multiple vaccine candidates are under development and in clinical trials, no Shigella vaccine is currently available on the market. Shigella comprises four species: S. dysenteriae, S. flexneri, S. boydii, and S. sonnei. S. flexneri has been recognized as the most prevalent species, particularly in low- and middle-income countries (LMICs), and the top serotypes are S. flexneri 2a, 3a and 6. Conversely, S. sonnei has a single serotype and predominates in high-income countries (HICs). Invasion plasmid antigen B (IpaB) is a critical virulence factor of Shigella type III secretion system (T3SS) that is highly conserved across Shigella serotypes. Here, we report the development of a Shigella quadrivalent O-polysaccharide-IpaB conjugate vaccine candidate (IVT Shigella-04). Methods: IVT Shigella-04 contains O-polysaccharides (O-PS) from S. flexneri 2a, 3a, 6, and S. sonnei, each individually conjugated to recombinantly expressed IpaB as the carrier protein using 1-cyano-4-dimethylaminopyridinium tetrafluoroborate (CDAP) chemistry. The immunogenicity of IVT Shigella-04 was evaluated in a rabbit immunization model. Results: Baseline (day 0) IgG concentrations were low for all four Shigella serotypes (p < 0.001) by day 42, reaching 67.96 µg/mL (2a), 91.56 µg/mL (3a), 371.31 µg/mL (6), and 11.00 µg/mL (sonnei). Consistently, serum bactericidal activity (SBA) at day 42 increased 13-fold (2a), 34-fold (3a), 63-fold (6), and 224-fold (sonnei) relative to baseline (day 0). Conclusions: IVT Shigella-04 elicited robust serotype-specific humoral and functional immune responses in preclinical models, supporting its further development toward clinical evaluation.

Background/Objectives: Group B Streptococcus (GBS) is a significant cause of perinatal infection in neonates and infants. Complications could include neonatal sepsis and meningitis, preterm birth, stillbirth, or death. Though no GBS vaccine is currently licensed, maternal immunization is expected to be a highly effective strategy to address invasive GBS disease—particularly in low- and middle-income countries (LMICs), where the disease burden is the greatest and access to existing interventions is limited. In this study, we present a novel hexavalent GBS vaccine candidate with a unique combination of serotypes (ST)—Ia, Ib, II, III, V, and VII—that could be an efficacious and cost-effective intervention, with the broadest coverage of 99% against circulating serotypes globally. Methods: The 6-valent conjugate vaccine candidate, GBS-06, is developed using a novel approach by linking the six polysaccharides (PS) to recombinant cross-reactive material 197 (rCRM197) carrier protein derivatized with a hydrazide-polyethylene glycol-hydrazide (HZ-PEG-HZ) linker. A repeat-dose GLP toxicology study with GBS-06 was conducted at the highest clinical dose of 20 µg in rabbits with saline as the placebo control. Results: The results reveal induction of robust anti-capsular polysaccharide-specific IgG responses against each of the six serotypes after each dose with the highest antibody GMCs at Day 49 following the third dose. Conclusions: Hence, this work is the first demonstration of strong immunogenicity achieved using a linker (HZ-PEG-HZ) for GBS glycoconjugate vaccine development. The positive data from the study have strong implications in the advancement of the candidate for evaluation in clinical trials and provide a licensure pathway for maternal immunization.