Summary
Shigella is responsible for 190 million annual cases of diarrhoea in low and middle-income countries (LMIC), and estimated 65,000 deaths globally, or 11% of all diarrhoea related child deaths. Presently, no vaccine is available for prevention of Shigella infection but candidate vaccines are under advanced development. Unfortunately, there is insufficient knowledge on when infants in endemic areas get first infected, levels of Shigella-specific antibodies of maternal origin and acquired ones, and what would be the best time window for eventual vaccination.
We propose to utilise existing serum samples from a cohort of Zambian infants recruited to study rotavirus vaccine response from 6 weeks through 24 months of age. We will screen samples collected at 6, 14, 52 & 104 weeks infants age by enzyme-linked immunosorbent assay (ELISA) for antibodies (IgG, IgA & IgM) to Shigella lipopolysaccharide (LPS) antigen. As antibody immune responses have been shown to be important for clinical protection, defining the time at which infants mount immune responses to Shigella in the absence of a vaccine will reveal the time when natural infection emerges and therefore, a potential optimal window for future vaccination.
Roma Chilengi at the Centre for Infectious Disease Research in Zambia has stored serum samples and clinical data on the cohort. Daniel Cohen at University of Tel Aviv has worked extensively on Shigella immunology, and will provide skills transfer to CIDRZ, the LMIC partner. Gad Frankel and team at Imperial College, London has been working on pathogen-host-microbiome interactions during infections with enteric pathogens employing a type III secretion system (T3SS) and on the role IgG antibodies play in protection. Findings from this preparatory work will result in a detailed understanding of the evolution of Shigella-induced immunity in infants naturally exposed to the infection and will be critical for future evaluation of vaccines under advanced clinical development.
Project outcomes
Shigellosis is a leading cause of moderate-to-severe diarrhoea and related mortality in young children in LMICs. Knowledge on naturally acquired immunity can support the development of Shigella candidate vaccines mostly needed in LMICs. We aimed to quantify Shigella-specific antibodies of maternal origin and those naturally acquired in Zambian infants.
Using plasma samples collected from infants at age 6, 14 and 52-weeks were tested for Shigella (S. sonnei and S. flexneri 2a) lipopolysaccharide (LPS) antigen specific immunoglobulin G (IgG) by enzyme-linked immunosorbent assay.
Overall, we found that at 6 weeks infant age, the IgG geometric mean titres (GMT) against S. sonnei (N=159) and S. flexneri 2a (N=135) LPS were high i.e. 312 (95% CI 261-372) and 446 (95% CI 343-580) respectively. At 14 weeks, a decline in IgG GMT was observed for both S. sonnei to 106 (95% CI 89-126), and S. flexneri 2a to 183 (95% CI 147-230). Both S. sonnei and S. flexneri 2a specific IgG GMT continued to wane by 52 weeks infant age as compared to 6 weeks.
From this work we conclude that in our setting, transplacental IgG anti-Shigella LPS is present at high levels in early infancy, and begins to wane by age 14 weeks. We document early exposure and naturally acquired IgG antibodies to S. flexneri 2a and S. sonnei LPS in part of infants between 14 and 52 weeks of age.
These results suggest that a potential timing of vaccination would be after 14 but before 52 weeks of age to ensure early infant protection against shigellosis.