Leptospirosis, a spirochetal disease, is a leading zoonotic cause of morbidity and mortality worldwide. It has traditionally been a rural-based disease of subsistence farmers and pastoralists, but the investigations of Yale University and Oswaldo Cruz Foundation (Fiocruz) in Brazil have raised awareness that leptospirosis has emerged as a cause of rat-borne epidemics in urban slum populations. Moreover, leptospirosis causes life- threatening disease and has become a major cause worldwide of pulmonary hemorrhage syndrome and acute kidney injury. To date, there is no effective prevention or control for leptospirosis in resource-poor settings. An effective vaccine would provide synergistic health and societal benefits by preventing transmission and disease in domestic animals and the risk of spill-over infections in humans. The major challenge has been developing a vaccine that protects against the nine species and >200 serovars which are agents for leptospirosis. In addition, a key knowledge gap for vaccine development is whether naturally-acquired immunity to reinfection occurs in humans. Our field investigations in Brazil have addressed this question and now provide the first evidence that naturally-acquired infection confers immunity against reinfection in populations residing in high- transmission slum settings. Furthermore, we produced motility-deficient mutant strains of L. interrogans and found that immunization with this attenuated strain conferred cross-protective immunity to infection with homologous and heterologous serovars in experimental animals. We developed novel whole L. interrogans proteome arrays to interrogate the immune response to infection and found that immunization with the attenuated strain in animals, as well as naturally acquired infection in humans, induce antibodies to a restricted repertoire of Leptospira proteins. These findings form the basis for our proposal, which builds on the infrastructure created in Brazil through NIH support since 1996, which includes a community site mobilized for long-term cohort studies, diagnostic and vaccine research laboratories, and a multidisciplinary team of collaborators. We propose to integrate field studies on the natural history with animal models of immunity, thus creating the opportunity to test hypotheses generated from our investigations of human populations. Our proposal aims to identify vaccine candidates and evaluate the feasibility of a universal vaccine approach for leptospirosis. In the 1st project aim, we will determine prospectively whether naturally-acquired infection in a cohort of slum residents induces robust anti-Leptospira protein responses and whether these responses are correlates of immunity to reinfection. In the 2nd project aim, we will identify the specific Leptospira proteins which elicit naturally-acquired and attenuated vaccine-mediated immunity and determine whether immunization with these antigens confers cross-protective immunity in animals. We expect to identify, as outcome of this proposal, novel human correlates of immunity and vaccine candidates for leptospirosis, which in turn will yield new intervention strategies for this important yet neglected infectious disease problem.

Public Health Relevance

There is no effective prevention or control for leptospirosis, which is a life-threatening bacterial disease and a leading zoonotic cause of mortality and morbidity among impoverished subsistence farmers and urban slum dwellers. The proposed research will integrate field studies of urban slum populations in Brazil with investigations of experimental animal models of immunity to identify human correlates for naturally-acquired immunity to the disease and vaccine candidates for this important yet neglected disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI121207-04
Application #
9606056
Study Section
Clinical Research and Field Studies of Infectious Diseases Study Section (CRFS)
Program Officer
Mukhopadhyay, Suman
Project Start
2015-12-01
Project End
2020-11-30
Budget Start
2018-12-01
Budget End
2019-11-30
Support Year
4
Fiscal Year
2019
Total Cost
Indirect Cost
Name
Yale University
Department
Public Health & Prev Medicine
Type
Schools of Medicine
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520
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Adhikarla, Haritha; Wunder Jr, Elsio A; Mechaly, Ariel E et al. (2018) Lvr, a Signaling System That Controls Global Gene Regulation and Virulence in Pathogenic Leptospira. Front Cell Infect Microbiol 8:45
Casanovas-Massana, Arnau; Pedra, Gabriel Ghizzi; Wunder Jr, Elsio A et al. (2018) Quantification of Leptospira interrogans Survival in Soil and Water Microcosms. Appl Environ Microbiol 84:
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Nabity, Scott A; Hagan, José E; Araújo, Guilherme et al. (2018) Prospective evaluation of accuracy and clinical utility of the Dual Path Platform (DPP) assay for the point-of-care diagnosis of leptospirosis in hospitalized patients. PLoS Negl Trop Dis 12:e0006285
Dhewantara, Pandji Wibawa; Mamun, Abdullah A; Zhang, Wen-Yi et al. (2018) Epidemiological shift and geographical heterogeneity in the burden of leptospirosis in China. Infect Dis Poverty 7:57
Owers, Katharine A; Odetunde, Juliana; de Matos, Rosan Barbosa et al. (2018) Fine-scale GPS tracking to quantify human movement patterns and exposure to leptospires in the urban slum environment. PLoS Negl Trop Dis 12:e0006752

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