Saturday, November 23, 2024
11/23/2024
SUMMARY: Identifying effective vaccines and their correlates of protection (COPs) for highly lethal human (Hu) pathogens is problematic. Tularemia (rabbit fever), a severe zoonoses caused by Francisella tularensis (Ft), is a prime example. Studies conducted in the 1960s revealed that Hu vaccination with the attenuated Live Vaccine Strain (LVS) of Ft provided partial protection against low-dose aerosol challenge with virulent Ft SchuS4 (S4); however, protection against higher challenge doses (~2,000 CFU) was subpar and no surrogate markers of Hu protection were developed. Since the 1960s, no further Hu vaccine-efficacy trials have been performed and the bulk of tularemia vaccine research has relied on inbred rodent models. Currently, there are two unmet needs: i) vaccines that protect against high-dose aerosol challenge with S4 and ii) Hu-relevant COPs to guide future clinical trials as envisioned by the FDA Animal Rule. To advance vaccine candidates and their COPs, studies are needed in higher outbred models that faithfully replicate Hu responses. We used murine and rabbit (Rb) models to identify 2 lead vaccine candidates (S4ΔaroD and S4Δ guaBA) that were effective against aerosols of WT S4 (target dose ~2,000 CFU). Our two strains along with WT LVS and an externally developed mutant (S4clpB) were all found to provide various degrees of vaccine-mediated protection. However, S4aroD was the only vaccine that provided significantly greater protection than LVS. The S4aroD-mediated protection was robust (75%) up to challenge doses of ~20,000 CFU. During these experiments, we also collected pre-challenge sera from individual Rbs. Following challenge outcome, retrospective analysis of these sera identified putative COPs that predict S4 challenge outcome with statistical significance. Our long-term goal is to foster advancement of the most effective Ft vaccine candidate to Hu clinical trials. Our immediate objectives are to determine how well the S4aroD-mediated protection and COPs observed in Rbs translate to non-human primates (NHP). We have formulated the following Aims: Aim 1. Vaccine efficacy in the NHP model and Aim 2. Correlate analysis of NHP samples. To further Hu translation, we have secured an invaluable resource: ~150 plasma from LVS-vaccinated Hu banked prior to the pause in the US Army’s Special Immunization Program. The combined bacteriology, vaccinology, aerobiology and biostatistics expertise within this consortium makes us exclusively well-positioned to complete these studies; our productivity in the prior cycle (>20 publications) documents our ability to achieve our goals. By the end of these studies, we will have determined the efficacy of S4aroD-vaccination against S4 aerosol challenge regarding both NHP mortality and morbidity. We will have performed a head-to-head comparison with LVS vaccination and determined if COPs developed in Rbs are also predictive in NHPs. We envision that pivotal vaccine efficacy and correlate data developed in the NHP model will place S4ΔaroD on the cusp of translation to advanced development and Hu-clinical trials.
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