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 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 to an early protective immunity of maternal origin and an increase in disease incidence when maternal immunity wanes. The magnitude, type, antigenic diversity and anti-microbial 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 virulent 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 IgG (very high levels) and Shigella LPS were detected in maternal and cord blood sera; efficiency of placental transfer was 100% and 60%, respectively and was associated with 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 a 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 maternal immunity wanes.

Systems approach to define humoral correlates of immunity to Shigella

“…Collectively, these data hint to a critical collaborative role between more persistent IpaB-specific immune responses and OPS-specific functional immunity in protection against shigellosis. The low OPS-specific responses seen in the volunteers in our study are reminiscent of the low OPS seroprevalence in children younger than 2 years of age ( Ndungo et al, 2021 ; Thompson et al., 2016 ), for whom the risk of shigellosis is the highest. In contrast, adults living in endemic regions and constantly exposed to Shigella develop stronger protein- and OPS-specific responses ( Ndungo et al, 2021 ).…”

“…The low OPS-specific responses seen in the volunteers in our study are reminiscent of the low OPS seroprevalence in children younger than 2 years of age ( Ndungo et al, 2021 ; Thompson et al., 2016 ), for whom the risk of shigellosis is the highest. In contrast, adults living in endemic regions and constantly exposed to Shigella develop stronger protein- and OPS-specific responses ( Ndungo et al, 2021 ). The relative contribution of protein- versus OPS-specific immunity in protection against shigellosis remains a critical unanswered question.…”

Cysteine dependent conformation heterogeneity of Shigella flexneri autotransporter IcsA and implications in its function

“…IcsA holds great vaccine candidate potential, as it was demonstrated previously that the level of antibodies to IcsA significantly reduces the risks of shigellosis (37). High levels of anti-IcsA antibodies were also found as one major maternal antibody transferred to infant and may likely contributing to disease prevention during the first months of life (38).…”

“…IcsA holds great vaccine candidate potential, as it was demonstrated previously that the level of antibodies to IcsA significantly reduces the risks of shigellosis (37). High levels of anti-IcsA antibodies were also found as one major maternal antibody transferred to infant and may likely contributing to disease prevention during the first months of life (38). The correlated protection is likely to be through the prevention of early Shigella host cell attachment as was demonstrated previously (11) and not through antibody mediated complement killing (38).…”

“…High levels of anti-IcsA antibodies were also found as one major maternal antibody transferred to infant and may likely contributing to disease prevention during the first months of life (38). The correlated protection is likely to be through the prevention of early Shigella host cell attachment as was demonstrated previously (11) and not through antibody mediated complement killing (38). However, here we show that the binding of IcsAp to the adhesion blocking polyclonal anti-IcsA antibodies can be abolished upon the disruption of the centrally localised cysteine pair in IcsAp that is involved in intramolecular disulfide bond formation.…”