The majority of moderate to severe diarrheal cases in children ages 2-5 years living in Asia and Sub- Saharan Africa are attributed to Shigella. Recurrence of infection results in death or long-term disability. No vaccine is currently available. While multiple candidates have been developed, only a few have been tested in humans for safety and immunogenicity. However, their protective efficacy remains unknown. No immune correlates of protection have been established, which poses a hindrance to Shigella vaccine development efforts. An additional challenge is the lack of standardized immunological assays that could be used to harmonize data from different clinical studies. The goal of this application is to establish and validate serological assays that can predict efficacy of Shigella vaccine candidates in humans. Our preliminary data supports the hypothesis that antibodies with anti-microbial activity and a distinct profile of antigen-specific antibodies in serum from vaccinated subjects can be predictive of vaccine efficacy.
In Aim 1, we will develop and validate assays to measure the anti-microbial functionality of anti- Shigella antibodies (serum bactericidal, opsonophagocytic killing and inhibition of macrophage and neutrophil toxicity) using serum samples from trials in which healthy human adult subjects received the Sfl2aWC candidate vaccine or a placebo. We will examine vaccine-induced antibody and clinical data (i.e. disease) post-challenge with S. flexneri 2a to identify a distinct serological profile that can be indicative of vaccine efficacy.
In Aim 2, we will develop a high throughput multiplex ELISA to measure multiple Shigella-specific antibodies [e.g. Invasion plasmid antigens (Ipa) IpaB, IpaC and IpaD, VirG and strain specific LPS] in a single well. Serum from Sfl2aWC vaccine recipients before and after vaccination and before and after challenge will be tested with this new MSD ELISA to determine a potential association between antigen-specific antibodies and protection against disease.
In Aim 3, we will adapt the assays determined to correlate with enhanced protection in humans and apply them in guinea pig and mouse studies. Identification of animal models for which the same serological readouts predict a protective outcome would be a critical advance for pre-clinical vaccine assessment as such models would more closely resemble vaccine performance in humans. This application involves a partnership between leading researchers of Shigella pathogenesis, vaccine development and immunology from the University of Maryland, Baltimore (UMB), the Walter Reed Army Institute of Research (WRAIR), and The John Hopkins University (JHU) and this work has the potential to develop technology and reagents that will facilitate vaccine development efforts.

Public Health Relevance

The goal of this proposal is to develop serological assays to measure Shigella vaccine-induced antibodies that exhibit functional, anti-microbial activity (bactericidal, opsonophagocytic killing and inhibition of macrophage/neutrophil toxicity) and antibodies specific to multiple Shigella antigens (by means of a high throughput multiplex ELISA). These assays will be applied to serum samples from human volunteers immunized with the leading inactivated whole cell S. flexneri 2a vaccine candidate (Sfl2aWC) and challenged with virulent S. flexneri 2a to identify immunogenicity measurements that can predict vaccine efficacy. Because of the lack of firm immune correlates of protection against shigellosis, such measurements will significantly advance vaccine development efforts.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
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Special Emphasis Panel (ZAI1)
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Mills, Melody
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University of Maryland Baltimore
Schools of Medicine
United States
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