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Research Project: Characterization of the Pathogenesis and Antigen Expression in Spirochete Diseases

Location: Infectious Bacterial Diseases Research

Title: A live attenuated-vaccine model confers cross-protective immunity against different species of the Leptospira genus

item WUNDER, ELSIO - Yale University
item ADHIKARLA, HARITHA - Yale University
item HAMOND, CAMILA - Yale University
item OWERS, KATIE - Yale University
item LIANG, LI - University Of California
item RODRIGUES, CAMILA - University Of California
item BISHT, VIMLA - Yale University
item Nally, Jarlath
item Alt, David
item REIS, MITERMAYER - Oswaldo Cruz Foundation
item DIGGLE, PETER - Lancaster University
item FELGNER, PHILIP - University Of California
item KO, ALBER - Yale University

Submitted to: eLife
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 12/23/2020
Publication Date: 1/26/2021
Citation: Wunder, E.A., Adhikarla, H., Hamond, C., Owers, K., Liang, L., Rodrigues, C.B., Bisht, V., Nally, J.E., Alt, D.P., Reis, M.G., Diggle, P.J., Felgner, P.L., Ko, A.I. 2021. A live attenuated-vaccine model confers cross-protective immunity against different species of the Leptospira genus. eLife. 10:e64166.

Interpretive Summary: Pathogenic species of Leptospira cause leptospirosis, a global disease that is transmitted from animals to humans. Leptospires survive in the kidney of domestic and wild animal species, which act as reservoir hosts of infection, and excrete leptospires via urine. Leptospirosis can be caused by more than 200 serovars of Leptospira, but current vaccine strategies only contain up to 5 serovars. In order to overcome this limitation, we evaluated a novel mutant live Leptospira to determine if it could work as a vaccine that protects against more than 1 serovar of Leptospira. The mutant was evaluated in two different animal models of infection and results indicated that immunized animals were protected from acute lethal infection and reduced levels of renal colonization.

Technical Abstract: Leptospirosis is the leading zoonotic disease in terms of morbidity and mortality worldwide with a great health and economic impact in both humans and animals. Effective prevention is urgently needed as rapid urbanization, climate change and drivers of disease transmission continue to intensify. The key challenge has been developing a widely-applicable vaccine that protects against the 13 different pathogenic species and >300 serovars that can cause leptospirosis, providing a major public health benefit and opportunity to leverage One Health approaches. Live attenuated mutants that can boost immunity and induce protection are enticing vaccine candidates and poorly explored in the field. We evaluated a recent characterized motility-deficient mutant lacking the expression of a flagellar protein, FcpA. Although the fcpA- mutant has lost its ability to penetrate mucous membranes and cause disease, a transient bacteremia prior to clearance by the host immune response was observed. In two animal models, immunization with a single dose of the fcpA- mutant was sufficient to induce robust anti-protein antibodies response that promoted interspecies protection against death and colonization. Furthermore, characterization of the immune response identified a small repertoire of biologically relevant proteins that are highly conserved among pathogenic Leptospira species and potential correlates of cross-protective immunity.