Repertoire of Naturally Acquired Maternal Antibodies Transferred to Infants for Protection Against Shigellosis

Abstract

Shigella is the second leading cause of diarrheal diseases, accounting for >200,000 infections and >50,000 deaths in children under 5 years of age annually worldwide. The incidence of Shigella-induced diarrhea is relatively low during the first year of life and increases substantially, reaching its peak between 11 to 24 months of age. This epidemiological trend hints at an early protective immunity of maternal origin and an increase in disease incidence when maternally acquired immunity wanes. The magnitude, type, antigenic diversity, and antimicrobial activity of maternal antibodies transferred via placenta that can prevent shigellosis during early infancy are not known. To address this knowledge gap, Shigella-specific antibodies directed against the lipopolysaccharide (LPS) and virulence factors (IpaB, IpaC, IpaD, IpaH, and VirG), and antibody-mediated serum bactericidal (SBA) and opsonophagocytic killing antibody (OPKA) activity were measured in maternal and cord blood sera from a longitudinal cohort of mother-infant pairs living in rural Malawi. Protein-specific (very high levels) and Shigella LPS IgG were detected in maternal and cord blood sera; efficiency of placental transfer was 100% and 60%, respectively, and had preferential IgG subclass distribution (protein-specific IgG1 > LPS-specific IgG2). In contrast, SBA and OPKA activity in cord blood was substantially lower as compared to maternal serum and varied among Shigella serotypes. LPS was identified as the primary target of SBA and OPKA activity. Maternal sera had remarkably elevated Shigella flexneri 2a LPS IgM, indicative of recent exposure. Our study revealed a broad repertoire of maternally acquired antibodies in infants living in a Shigella-endemic region and highlights the abundance of protein-specific antibodies and their likely contribution to disease prevention during the first months of life. These results contribute new knowledge on maternal infant immunity and target antigens that can inform the development of vaccines or therapeutics that can extend protection after maternally transferred immunity wanes.

Dynamics of the Gut Microbiome in Shigella -Infected Children during the First Two Years of Life

“…This observation also suggests that Shigella infection is not only dependent on the presence of that organism but is determined by other host-related factors, such as maternal immunity (i.e., antibodies in breast milk) and the individual’s own local innate defenses. We and others have identified placentally acquired maternal antibodies to Shigella antibodies at birth ( 16 , 17 , 41 ). Shigella -specific antibodies have been found in breast milk ( 61 ).…”

“…Participants were recruited as part of a mother-infant cohort in a malaria surveillance study ( 41 ). All of the infants were born between February and November of 2016.…”

“…The study participants were a cohort of children from birth to 2 years of age enrolled in a longitudinal malaria surveillance study in Malawi ( 41 ) who were also monitored for diarrheal disease. Mothers and infants were recruited between January and November of 2016 at Mfera Health Clinic in Chikwawa, Malawi, and they were followed for 2 years.…”

Cysteine-Dependent Conformational Heterogeneity of Shigella flexneri Autotransporter IcsA and Implications of Its Function

“…IcsA holds great vaccine candidate potential because it was demonstrated previously that the level of antibodies to IcsA significantly reduces the risks of shigellosis ( 38 ). High levels of anti-IcsA antibodies were also found as one major maternal antibody transferred to the infant and may likely contribute to disease prevention during the first months of life ( 39 ). The correlated protection is likely to be through the prevention of early Shigella host cell attachment as was demonstrated previously ( 11 ) with adhesion-blocking activity by anti-IcsA antibodies and not through antibody-mediated complement killing ( 39 ).…”

Setup and Characterization of a High-Throughput Luminescence-Based Serum Bactericidal Assay (L-SBA) to Determine Functionality of Human Sera against Shigella flexneri

“…Serotype specificity is determined by the OAg of LPS, therefore immune responses targeting the OAg are likely responsible for protection against shigellosis. Although the OAg-specific immune response has traditionally been quantified by antigen-specific IgG detection through ELISA, presumably a functional readout, such as opsonophagocytosis and/or complement activation, can better determine the effectiveness of antibodies raised upon vaccination [ 32 ]. A recent study reported a strong association between S. flexneri 2a-specific SBA titers in human adult volunteers and reduced clinical disease post-challenge with wild-type organisms [ 13 ], thus supporting the value of this assay to potentially predict vaccine efficacy.…”