Shigella spp. cause a severe dysenteric disease that continues to be associated with significant morbidity and mortality, particularly in children under 5 years of age living in less-developed areas of the world. An important observation from the recent Global Enteric Multicenter Study (GEMS) was that the incidence of shigellosis was much lower during early infancy as compared to older children. Shigella accounted for 16.6% of diarrheal cases in infants 0 to 11 months of age, whereas it was responsible for 78.4% of cases in children 2-5 years of age, surpassing all of the other enteric pathogens. We hypothesize that this epidemiological trend reflects the contribution of maternally acquired immunity, which inversely correlates with incidence of disease. Studies from the early 90s reported a protective benefit of breastfeeding but the exact mechanisms have not been explored. In this proposal, we seek to understand the mechanisms by which maternal immunity prevents shigellosis in young infants and identify a novel broadly protective vaccine for toddlers and young children. In preliminary studies, maternal IgG exclusively transferred through placenta or milk and detected in serum of infant mice, conferred protection against lethal Shigella infection. We also observed that Shigella-specific serum IgG had opsonophagocytic (OPA) and serum bactericidal (SBA) activity. We hypothesize that circulating Shigella-specific IgG may cross the mucosal epithelial barrier into the gut where it mediates bacterial clearance following transport by the neonatal fragment C receptor (FcRn). IgG contained in breast milk may likewise be transported through the FcRn across the enterocytes and into the basolateral side, to further limit bacterial spread.
In Aim 1 of this proposal we will determine the maternal immune components that protect infants against shigellosis and investigate the involvement of FcRn in transporting IgG across the mucosal surfaces. Using transgenic mice expressing the human FcRn we will examine the translocation and protective capacity of IgG in human breast milk.
In Aim 2, we will investigate OPA and SBA capacity of Shigella-specific IgG in vaccine recipients and their association with reduced severity of disease. We will also measure kinetics of maternally acquired antibodies in a longitudinal study involving mothers and their infants (followed up to 2 years of age) living in endemic regions. Lastly, using a human enteroid model, we will dissect the components of maternal milk that prevent Shigella infection; particularly FcRn-mediated intestinal translocation of breast milk IgG.
In Aim 3, we will investigate a novel strategy that combines CVD1208S (a live attenuated vaccine) with the invasion plasmid antigen IpaD (a highly conserved type III secretion protein), and the Escherichia coli double mutant heat labile enterotoxin (dmLT) to induce broad protection and strong, long lasting immunity. This work has the potential to uncover a new mechanism involved in protection against shigellosis and a more effective vaccine approach for the protection of children after the waning of maternal immunity.

Public Health Relevance

This project seeks to understand the mechanisms by which maternal immunity prevents shigellosis in young infants, particularly the involvement of the neonatal fragment C receptor (FcRn) in the translocation of Shigella- specific IgG across the mucosal epithelial barrier. We will also investigate a new vaccine strategy that combines a live attenuated organism, a conserved broadly protective antigen (Shigella Type III secretion system protein IpaD) and a clinically advanced adjuvant (E. coli dmLT) for effective immunization of toddlers and young children. This work has the potential to uncover a new mechanism involved in immune responses against shigellosis and a more effective vaccine approach for protecting children beyond the first year of live after the waning of maternal immunity.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI117734-03
Application #
9206438
Study Section
Vaccines Against Microbial Diseases Study Section (VMD)
Program Officer
Mills, Melody
Project Start
2015-02-01
Project End
2020-01-31
Budget Start
2017-02-01
Budget End
2018-01-31
Support Year
3
Fiscal Year
2017
Total Cost
$397,198
Indirect Cost
$120,912
Name
University of Maryland Baltimore
Department
Pediatrics
Type
Schools of Medicine
DUNS #
188435911
City
Baltimore
State
MD
Country
United States
Zip Code
21201
Shimanovich, Avital A; Buskirk, Amanda D; Heine, Shannon J et al. (2016) Functional and Antigen-Specific Serum Antibody Levels as Correlates of Protection Against Shigellosis in a Controlled Human Challenge Study. Clin Vaccine Immunol :
DeLaine, BreOnna C; Wu, Tao; Grassel, Christen L et al. (2016) Characterization of a multicomponent live, attenuated Shigella flexneri vaccine. Pathog Dis 74:
Tennant, Sharon M; Steele, A Duncan; Pasetti, Marcela F (2016) Highlights of the 8th International Conference on Vaccines for Enteric Diseases: the Scottish Encounter To Defeat Diarrheal Diseases. Clin Vaccine Immunol 23:272-81