Abstract
Shigella is the second most deadly diarrheal disease among children under five years of age, after rotavirus, with high morbidity and mortality in developing countries. Currently, no vaccine is widely available, and the increasing levels of multidrug resistance make Shigella a high priority for vaccine development. The single-component candidate vaccine against Shigella sonnei (1790GAHB), developed using the GMMA technology, contains the O antigen (OAg) portion of lipopolysaccharide (LPS) as active moiety. The vaccine was well tolerated and immunogenic in early-phase clinical trials. In a phase 1 placebo-controlled dose escalation trial in France (NCT02017899), three doses of five different vaccine formulations (0.06/1, 0.3/5, 1.5/25, 3/50, 6/100 µg of OAg/protein) were administered to healthy adults. In the phase 1 extension trial (NCT03089879), conducted 2–3 years following the parent study, primed individuals who had undetectable antibody levels before the primary series received a 1790GAHB booster dose (1.5/25 µg OAg/protein). Controls were unprimed participants immunized with one 1790GAHB dose. The current analysis assessed the functionality of sera collected from both studies using a high-throughput luminescence-based serum bactericidal activity (SBA) assay optimized for testing human sera. Antibodies with complement-mediated bactericidal activity were detected in vaccinees but not in placebo recipients. SBA titers increased with OAg dose, with a persistent response up to six months after the primary vaccination with at least 1.5/25 µg of OAg/protein. The booster dose induced a strong increase of SBA titers in most primed participants. Correlation between SBA titers and anti-S. sonnei LPS serum immunoglobulin G levels was observed. Results suggest that GMMA is a promising OAg delivery system for the generation of functional antibody responses and persistent immunological memory.
Highlights
Diarrheal diseases continue to be a major cause of death worldwide, with approximately 1.6 million fatalities estimated in 2017 [1]
Baseline serum bactericidal activity (SBA) geometric mean titer (GMT) were below the lower limit of quantification (LLOQ) in the 0.06/1 and 0.3/5 groups and were 55 and 58 at D29, respectively
At six months following the third dose (D225), GMTs were below the LLOQ in the 0.06/1 group, 61 in the 0.3/5 group, 276 in the 1.5/25 group, 167 in the 3/50 group, and 189 in the 6/100 group
Summary
Diarrheal diseases continue to be a major cause of death worldwide, with approximately 1.6 million fatalities estimated in 2017 [1]. Mortality rates from diarrheal diseases have decreased since 1990 [1], diarrhea morbidity remains high, in low- and middle-income countries, lacking relevant microbiological diagnostics, water quality, and sanitation, and adequate health-care facilities and treatment interventions are not accessible [2, 3]. Shigella is the second leading cause of diarrheal disease after rotavirus and is the main pathogen associated with diarrhea in children under five years of age in developing countries [7,8,9]. Shigella has been associated with diarrhea in adults, with increased disease incidence in the elderly [10]. It is a leading cause of diarrhea in travelers and military personnel [11,12,13]
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