Poly-N-acetyl glucosamine (PNAG) is a 0-1-6 linked surface polysaccharide that is expressed by a broad range of bacterial pathogens, including Staphylococcus aureus, Escherichia coli, and Yersinia pestis. It has high potential to be a widely protective vaccine against a diverse array of pathogens, but specific glycoforms, notably ones lacking acetate substituents on the amino groups of the glucosamine monosaccharide are needed to produce optimal immunity. Additionally, active and passive vaccination strategies targeting PNAG have moved into early clinical development, but the utility of this antigen as a single component vaccine is likely to be suboptimal, Furthermore, pathogen-derived PNAG antigen may be suboptimal for synthesizing vaccines that elicit the most effective protective antibody response. Finally, producing conjugate vaccines using an array of different carrier proteins can be time consuming and expensive. To address these issues, synthetic oligoglucosamine glycoforms will be produced that can be easily stored and readily conjugated to a variety of recombinant carrier proteins derived from targeted pathogens. These vaccines will be evaluated for engendering protection against methicillin-resistant S. aureus (MRSA), enterohemorrhagic E. coli (EHEC) O157 and similar Shiga toxin (STX)-prpducing strains, and Y. pestis. Moreover, these PNAG-based vaccines will also be evaluated for the ability to prevent mucpsal colonization as well as pneumonia, two critical interventions that have not yet been tested. PNAG-based conjugate vaccines will be paired with recombinant proteins specific to each of the pathogens to determine if additive, synergistic or possibly even inhibitory immune effects can be engendered by multicomponent preparations. Conjugate vaccines for MRSA will contain synthetic PNAG oligosaccharides plus capsular polysaccharide types 5 (CP5) and 8 (CP8). Carrier protein antigens will include those that contribute to protective immunity, such as alpha-hemolysin toxoid (Hla) or clumping factor B (ClfB). Vaccines for EHEC will include conjugates of synthetic PNAG oligosaccharides and STX. Synthetic PNAG oligoglucosamines conjugated to LcrV, F1 capsule or a fusion protein of these will be used to target Y. pestis. We will investigate the type of immune effectors generated by immunization and evaluate their functionality for the prevention of mucosal colonization and infection by these pathogenic bacteria.

Public Health Relevance

Effective vaccines were the most successful public health development of the 20th century. This project will continue progress into the 21st century by evaluating vaccines for significant human pathogens, including Staphylococcus aureus, food-borne E. coli and infections caused by the plague bacillus, Yersinia pestis. These bacteria share a structure on their surface that is being tested as a vaccine that could be effective against these, as well as other, serious bacterial infections.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Specialized Center--Cooperative Agreements (U54)
Project #
5U54AI057159-10
Application #
8441650
Study Section
Special Emphasis Panel (ZAI1-DDS-M)
Project Start
Project End
Budget Start
2013-03-01
Budget End
2014-02-28
Support Year
10
Fiscal Year
2013
Total Cost
$410,003
Indirect Cost
$127,293
Name
Harvard University
Department
Type
DUNS #
047006379
City
Boston
State
MA
Country
United States
Zip Code
02115
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