We have uncovered new cellular mechanisms for adaptive immune responses mediated by glycoconjugate immunization. Following immunization, glycoconjugates undergo enzymatic and oxidative changes resulting in relatively small glycan-peptides being mounted onto MHCII, with the peptide serving as the MHCII anchor and the carbohydrate presented to and recognized by the CD4+T cell (Tcarb). Importantly, the peptide is not recognized by the Tcarb, only the glycan. Presentation of the carbohydrate is the key event required for very robust T cell help in order for the B cell to make very high-titered anti-glycan antibodies. Demystifying the Tcell activation mechanisms of glycoconjugate vaccines was a key step towards designing new-generation vaccines as outlined in this proposal. We learned from our mechanistic studies that the most important feature of an ideal glycoconjugate vaccine is enrichment for these glycan-peptide epitopes. We synthesized a prototype new-generation glycoconjugate vaccine and tested it for immunogenicity and protective capacity in comparison to a traditionally made glycoconjugate vaccine. Our results showed that the new-generation vaccine was 50-100x more immunogenic and protective than the traditional vaccine. In this proposal, we build on our mechanistic studies and develop a translational platform for optimizing carbohydrate-based vaccines to produce a new generation of vaccines applicable to many microbial glycans. There are two Specific Aims: 1) Optimization of the platform construct for glycoconjugate vaccines. In this Specific Aim, we will optimize the carrier peptide, the glycan chain length, and the glycoconjugate construction to establish parameters for a new vaccine platform that can be applied to new vaccines;2) We will translate our basic discoveries and use our vaccine platform to make new vaccines against important pathogens such as Francisella tularensis, Burkholderia mallei and pseudomallei, and Brucella abortus. The approach offers a knowledge-based design that will serve as a platform for a wide variety of glycoconjugate vaccines for diseases where vaccines have not been created and to greatly improve current glycoconjugate vaccines.

Public Health Relevance

Markedly improved glycoconjugate vaccines have great potential to deliver safe and very effective immunity to a host of important pathogens. We will develop a platform for making glycoconjugates ofthe highest immunogenicity through rational design based on a new understanding of the mechanisms controlling immune responses to this class of molecules.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Program--Cooperative Agreements (U19)
Project #
Application #
Study Section
Special Emphasis Panel (ZAI1-LR-M (J1))
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Harvard University
United States
Zip Code
Lorenz, Christian; Dougherty, Thomas J; Lory, Stephen (2016) Transcriptional Responses of Escherichia coli to a Small-Molecule Inhibitor of LolCDE, an Essential Component of the Lipoprotein Transport Pathway. J Bacteriol 198:3162-3175
Markovski, Monica; Bohrhunter, Jessica L; Lupoli, Tania J et al. (2016) Cofactor bypass variants reveal a conformational control mechanism governing cell wall polymerase activity. Proc Natl Acad Sci U S A 113:4788-93
Rajagopal, Mithila; Martin, Melissa J; Santiago, Marina et al. (2016) Multidrug Intrinsic Resistance Factors in Staphylococcus aureus Identified by Profiling Fitness within High-Diversity Transposon Libraries. MBio 7:
Simpson, Brent W; Owens, Tristan W; Orabella, Matthew J et al. (2016) Identification of Residues in the Lipopolysaccharide ABC Transporter That Coordinate ATPase Activity with Extractor Function. MBio 7:
Matano, Leigh M; Morris, Heidi G; Wood, B McKay et al. (2016) Accelerating the discovery of antibacterial compounds using pathway-directed whole cell screening. Bioorg Med Chem 24:6307-6314
Meeske, Alexander J; Riley, Eammon P; Robins, William P et al. (2016) SEDS proteins are a widespread family of bacterial cell wall polymerases. Nature 537:634-638
Pasquina, Lincoln; Santa Maria Jr, John P; McKay Wood, B et al. (2016) A synthetic lethal approach for compound and target identification in Staphylococcus aureus. Nat Chem Biol 12:40-5
Lee, Wonsik; Schaefer, Kaitlin; Qiao, Yuan et al. (2016) The Mechanism of Action of Lysobactin. J Am Chem Soc 138:100-3
Cho, Hongbaek; Wivagg, Carl N; Kapoor, Mrinal et al. (2016) Bacterial cell wall biogenesis is mediated by SEDS and PBP polymerase families functioning semi-autonomously. Nat Microbiol :16172
Meeske, Alexander J; Rodrigues, Christopher D A; Brady, Jacqueline et al. (2016) High-Throughput Genetic Screens Identify a Large and Diverse Collection of New Sporulation Genes in Bacillus subtilis. PLoS Biol 14:e1002341

Showing the most recent 10 out of 17 publications