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Leptospirosis Vaccine Development

Award Information
Agency: Department of Health and Human Services
Branch: National Institutes of Health
Contract: 1R41AI174377-01A1
Agency Tracking Number: R41AI174377
Amount: $300,000.00
Phase: Phase I
Program: STTR
Solicitation Topic Code: NIAID
Solicitation Number: PA22-178
Solicitation Year: 2022
Award Year: 2023
Award Start Date (Proposal Award Date): 2023-07-01
Award End Date (Contract End Date): 2025-06-30
Small Business Information
39 Stony Brook Road
Westport, CT 06880-2913
United States
HUBZone Owned: No
Woman Owned: No
Socially and Economically Disadvantaged: No
Principal Investigator
 (917) 545-7262
Business Contact
Phone: (917) 545-7262
Research Institution
NEW HAVEN, CT 06520-8327
United States

 Nonprofit College or University

Summary/abstract. Leptospirosis is a globally important neglected disease caused by pathogenic Leptospira.
It is estimated to cause more than 1 million global cases annually with a 5-20% case-fatality rate, significant
morbidity, and important public health consequences. Currently there is no safe and effective vaccine to
prevent human leptospirosis. LeptoX, Inc. proposes to develop the first human leptospirosis vaccine.
Pathogenic Leptospira are extracellular organisms, but mechanisms by which they exert their pathogenetic
effects were unclear until our discovery of the leptospiral Virulence Modifying (VM) proteins’ cytotoxin function,
followed by our demonstration of the potential for VM proteins to be the antigen components of a pan-
leptospirosis vaccine. Severe human leptospirosis has almost exclusively been reported to be due to strains of
L. interrogans. This proposal focuses on a L. interrogans VM protein-based leptospirosis vaccine, although
cross species protection may be possible. Recently published animal model data demonstrated that as few as
two recombinant VM proteins provide robust cross-serovar protection from disease/death after lethal L.
interrogans challenge in mice. These data indicate strong potential for VM proteins as pan-L. interrogans
protective antigens. In this Phase I, we will optimize dose, delivery and composition of recombinant E. coli-
produced VM proteins in combination with human-compatible adjuvant to determine protective efficacy in the
lethal hamster challenge model of leptospirosis. In Aim 1, we will produce recombinant tagless VM protein
immunogens, analyze their immunogenicity and, in the standard hamster model, compare their protective
efficacy to standard, commercially available bacterin vaccines; contingency experiments will also assess
chemically inactivated wild type proteins and proteins purified from inclusion bodies as alternative forms of the
VM protein immunogen; structural modeling suggests that VM protein disulfide bond-dependent conformation
may not be critical for antigenicity. In Aim 2, we will compare wild type and genetically mutated toxoid-forms of
tagless, recombinant E. coli-produced VM proteins in the lethal hamster model.
Protective immune responses
for both Aims will be assessed by protection from clinical disease and death and by determination of bacterial
load and viability in liver and kidney at various time points. Biomarkers of protective immunity (i.e., antibody
titers against the prototype vaccine antigens and cross-reactivity among serovars and between different
Leptospira species’ VM proteins) will be measured; the putative antibody-mediated protective mechanism of
immunity will be tested by passive transfer experiments. At the end of this Phase I project, we will have
developed final pan-L. interrogans VM-protein-based vaccine prototypes for further animal testing. Following
Phase I, this prototype will be tested in dog clinical trials, which will lead to a first commercial product for these
companion animals. Animal vaccine development will lead towards FDA IND submission for a human
leptospirosis vaccine, upon which strategic partnerships for leptospirosis vaccine development will be formed.

* Information listed above is at the time of submission. *

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