Determinants of immune responses predictive of protection against shigellosis in an endemic zone: a systems analysis of antibody profiles and function.

Background: Shigella is the third leading global cause of moderate or severe diarrhoea among children younger than 5 years globally, and is the leading cause in children aged 24-59 months. The mechanism of protection against Shigella infection and disease in endemic areas is uncertain. We aimed to compare the Shigella-specific antibody responses in individuals living in Shigella-endemic and non-endemic areas, and to identify correlates of protection in a Shigella-endemic location.

Putative correlates of protection against shigellosis assessing immunomarkers across responses to S. sonnei investigational vaccine.

Shigella spp. are a leading bacterial cause of diarrhea. No widely licensed vaccines are available and there is no generally accepted correlate of protection.

GMP manufacture of Shigella flexneri 2a Artificial Invaplex (Invaplex) and evaluation in a Phase 1 Open-label, dose escalating study administered intranasally to healthy, adult volunteers.

Shigella species cause severe disease among travelers to, and children living in, endemic countries. Although significant efforts have been made to improve sanitation, increased antibiotic resistance and other factors suggest an effective vaccine is a critical need. Artificial Invaplex (Invaplex) is a subunit vaccine approach complexing Shigella LPS with invasion plasmid antigens.

Development of the 2a, 3a, 6, and artificial Invaplex (Invaplex) vaccines.

The artificial invasin complex (Invaplex) vaccine is a subunit approach that effectively induces robust immunogenicity directed to serotype-specific lipopolysaccharide and the broadly conserved IpaB and IpaC proteins. One advantage of the vaccine approach is the ability to adjust the constituents to address suboptimal immunogenicity and to change the serotype targeted by the vaccine. As the vaccine moves through the product development pipeline, substantial modifications have been made to address manufacturing feasibility, acceptability to regulatory authorities, and developing immunogenic and effective products for an expanded list of serotypes.

Shigella-Controlled Human Infection Models: Current and Future Perspectives.

Shigella-controlled human infection models (CHIMs) are an invaluable tool utilized by the vaccine community to combat one of the leading global causes of infectious diarrhea, which affects infants, children and adults regardless of socioeconomic status. The impact of shigellosis disproportionately affects children in low- and middle-income countries (LMICs) resulting in cognitive and physical stunting, perpetuating a cycle that must be halted. Shigella-CHIMs not only facilitate the early evaluation of enteric countermeasures and up-selection of the most promising products but also provide insight into mechanisms of infection and immunity that are not possible utilizing animal models or in vitro systems.

From Concept to Clinical Product: A Brief History of the Novel Invaplex Vaccine's Refinement and Evolution.

The invasin complex or Invaplex vaccine is a unique subunit approach to generate a protective immune response. Invaplex is a large, macromolecular complex consisting of the major antigens: lipopolysaccharide (LPS) and the invasion plasmid antigen (Ipa) proteins B and C. Over the past several decades, the vaccine has progressed from initial observations through pre-clinical studies to cGMP manufacture and clinical evaluations.

Efficacy, safety, and immunogenicity of the 1790GAHB GMMA candidate vaccine: Results from a phase 2b randomized, placebo-controlled challenge study in adults.

Background: Shigellosis accounts for substantial morbidity and mortality worldwide and is the second most common cause of moderate and severe diarrhoea in children.

Methods: This phase 2b study (NCT03527173), conducted between August 2018 and November 2019, evaluated vaccine efficacy (VE), safety, and immunogenicity of a GMMA candidate vaccine (1790GAHB) in adults, using a 53 G controlled human infection model. Participants (randomized 1:1) received two doses of 1790GAHB or placebo (GAHB-Placebo), at day (D) 1 and D29, and an oral challenge of 53 G at D57.

-Specific Immune Profiles Induced after Parenteral Immunization or Oral Challenge with Either Shigella flexneri 2a or Shigella sonnei.

spp. are a leading cause of diarrhea-associated global morbidity and mortality. Development and widespread implementation of an efficacious vaccine remain the best option to reduce -specific morbidity.

Immune response characterization in a human challenge study with a Shigella flexneri 2a bioconjugate vaccine.

Background: Diarrheal diseases are a leading cause of global morbidity and mortality affecting all ages, but especially children under the age of five in resource-limited settings. Shigella is a leading contributor to diarrheal diseases caused by bacterial pathogens and is considered a significant antimicrobial resistance threat. While improvements in hygiene, and access to clean water help as control measures, vaccination remains one of the most viable options for significantly reducing morbidity and mortality.

Immune Response Characterization after Controlled Infection with Lyophilized Shigella sonnei 53G.

is a major cause of moderate to severe diarrhea largely affecting children (<5 years old) living in low- and middle-income countries. Several vaccine candidates are in development, and controlled human infection models (CHIMs) can be useful tools to provide an early assessment of vaccine efficacy and potentially support licensure. A lyophilized strain of 53G was manufactured and evaluated to establish a dose that safely and reproducibly induced a ≥60% attack rate.

Establishment of a Controlled Human Infection Model with a Lyophilized Strain of Shigella sonnei 53G.

Controlled human infection models (CHIMs) are useful for vaccine development. To improve on existing models, we developed a CHIM using a lyophilized preparation of strain 53G produced using current good manufacturing practice (cGMP). Healthy adults were enrolled in an open-label dose-ranging study.

Consensus Report on Shigella Controlled Human Infection Model: Immunological Assays.

Moderate to severe diarrhea caused by Shigella is a global health concern due to its substantial contribution to morbidity and mortality in children aged <5 years in low- and middle-income countries. Although antibiotic treatment can be effective, emerging antimicrobial resistance, limited access, and cost affirm the role of vaccines as the most attractive countermeasure. Controlled human infection models (CHIMs) represent a valuable tool for assessing vaccine efficacy and potentially accelerating licensure.

Assembly, Biochemical Characterization, Immunogenicity, Adjuvanticity, and Efficacy of Artificial Invaplex.

The native Invaplex (Invaplex) vaccine and adjuvant is an ion exchange-purified product derived from the water extract of virulent species. The key component of Invaplex is a high-molecular-mass complex (HMMC) consisting of the lipopolysaccharide (LPS) and the invasin proteins IpaB and IpaC. To improve product purity and immunogenicity, artificial Invaplex (Invaplex) was developed using recombinant IpaB and IpaC proteins and purified LPS to assemble an HMMC consisting of all three components.

Improving chances for successful clinical outcomes with better preclinical models.

In order to avoid expensive clinical failures, better and more predictive animal models of vaccine efficacy are needed to screen Shigella and ETEC vaccine candidates for protective efficacy. The 2016 Vaccines Against Shigella and ETEC (VASE) Conference included a workshop focused on the strengths and weaknesses of current models, particularly in terms of the correlation to vaccine efficacy in human clinical trials. Workshop presenters shared information on existing preclinical animal models for assessing the immunogenicity and protective efficacy of Shigella and ETEC vaccines.

Safety and Immunogenicity of a Candidate Bioconjugate Vaccine against Shigella flexneri 2a Administered to Healthy Adults: a Single-Blind, Randomized Phase I Study.

Several candidate vaccines against Shigella spp. are in development, but the lack of a clear correlate of protection from challenge with the induction of adequate immune responses among the youngest age groups in the developing world has hampered Shigella vaccine development over the past several decades. Bioconjugation technology, exploited here for an Shigella flexneri 2a candidate vaccine, offers a novel and potentially cost-effective way to develop and produce vaccines against a major pathogen of global health importance.