Development of a Universal Vaccine Against Leptospirosis

PROJECT SUMMARY Leptospirosis, an emerging infectious disease, is a leading zoonotic cause of morbidity and mortality worldwide, conveying the greatest burden to subsistence farmers and urban slum populations. In the US and other industrialized countries, there is increasing awareness of leptospirosis as the cause of disease among inner-city

populations, military personnel, and individuals engaged in swimming and water sports. Leptospirosis is an environmentally transmitted disease caused by spirochetes belonging to forty-one pathogenic species (P1 and P2) of the genus Leptospira. Leptospirosis causes life-threatening disease in humans and domestic animals and

has a major economic impact on livestock animals worldwide. To date, there is no effective prevention and control for leptospirosis. The major challenge has been developing a vaccine that protects against all the genetically diverse pathogenic species and >300 serovars which are potential agents for leptospirosis. All attempts to identify

leptospiral vaccine candidates that can be used as a widely-applicable vaccine has failed. This crucial knowledge gap has hampered the development of an effective universal vaccine that can provide synergistic health and societal benefits by preventing transmission and disease in domestic animals and the risk of spill-over infections

in humans. Our work has been focused on closing those gaps. Recently, we evaluated a motility-deficient mutant strain of Leptospira and found that immunization with this attenuated strain conferred cross-protective immunity in experimental animals, with antibodies against proteins being immune-correlates for this cross-protection.

Furthermore, a multi-recombinant protein construct based on four targets identified from our attenuated-vaccine model elicited cross-protection against death and renal colonization. In this proposal, we hypothesize that our multi-recombinant protein candidate induces a strong humoral immune response that correlates with cross-

protection on multiple animal models. Further, we hypothesize that this cross-protection is determined by a strong immune response against specific B-cell epitopes conserved among pathogenic species of Leptospira spp. We will vaccinate hamsters, mice and rats and determine the efficacy of out recombinant-protein construct to elicit

cross-protection for death and/or renal colonization, and characterize their immunogenicity based on B and T cell responses. We will then apply a high throughput, random bacterial peptide display technology and a cryo-EM- based approach to identify epitope binding specificities with single amino acid resolution. Those epitopes will be

then validated and selected based on their immunogenicity and cross-protective characteristics among different strains of pathogenic Leptospira spp. to establish a universal multi-epitope construct against leptospirosis. The results obtained by the characterization of our multi-recombinant protein vaccine would expand the work to

confirm that a universal vaccine against leptospirosis is feasible. We expect to identify a potential generalizable candidate for leptospirosis, which can be advanced for process development and clinical trials for human and veterinary use, yielding new intervention strategies for this important yet neglected infectious disease problem.