R01AI166682

Evaluation of Memory Responses and Biomarkers from a Phase I Enterotoxigenic Escherichia coli (ETEC) Intramuscular Subunit Vaccine with DMLT Adjuvant

Enterotoxigenic E. coli (ETEC) is a major cause of bacterial infectious diarrhea in children, travelers, and deployed military personnel in risk areas. Therefore, the development of a vaccine would be advantageous for public health. One strategy is to use subunits of colonization factors combined with toxoids of heat-labile toxin (LT). Recently, a first-in-humans safety and immunogenicity Phase 1 vaccine trial (NCT03404674) was conducted. The trial involved dose-escalating intramuscular delivery of CS6-subunit antigen CSSBA combined with LT-R192G/L211A (DMLT). No serious adverse events were reported, and strong humoral immunogenicity was observed in several cohorts, notably related to DMLT dose. However, a complete analysis of clinical trial samples, including humoral and cellular memory, is lacking.

As this vaccine trial indicates, DMLT is not only an LT toxoid but also a potent adjuvant that stimulates immunity to co-delivered antigens. However, there is a gap in our understanding of the molecular mechanisms responsible for initiating vaccination outcomes with antigens co-delivered with DMLT. The objective of this proposal is to expand analysis on serum and PBMC samples from an ETEC Phase 1 clinical trial and to define the key biomarkers and molecular mechanisms directing vaccine outcomes.

In the proposed studies, we aim to explore:

1. How vaccination doses modulated the development of memory, longevity, and diversity of the humoral response.
2. How vaccination altered the development of durable cellular immunity.
3. Whether early signaling events can serve as biomarkers of immunity.
4. What molecular mechanisms during immunization shape vaccination outcomes.

To do so, we will analyze our stored clinical trial samples and perform a number of sophisticated analyses, including transcriptional and metabolomics assays using samples from a related ETEC Phase 2B vaccine efficacy trial. These assays will help us define signatures of vaccine-induced protection, which we will then validate using the Phase 1 trial samples. Additionally, we will validate our findings with cellular analyses and mouse models.

These findings will not only aid in the development of an ETEC vaccine for human use by the parenteral route but also provide mechanistic insight into key events directing vaccination outcomes.

The Administrators Of Tulane Educational Fund

NOT APPLICABLE

93.855 - Allergy and Infectious Diseases Research

National Institute of Allergy and Infectious Diseases (NIAID) [HHS - NIH]

New Orleans, Louisiana 701122632 United States

Single Zip Code

NIH Research Project Grant (Parent R01 Clinical Trial Not Allowed) (PA-20-185)

Amendment Since initial award the End Date has been extended from 08/31/26 to 08/31/27 and the total obligations have increased 418% from $669,587 to $3,467,638.