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    The O-Ag Antibody Response to Francisella Is Distinct in Rodents and Higher Animals and Can Serve as a Correlate of Protection.

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    Author
    Shoudy, Lauren E
    Namjoshi, Prachi
    Giordano, Gabriela
    Kumar, Sudeep
    Bowling, Jennifer D
    Gelhaus, Carl
    Barry, Eileen M
    Hazlett, Allan J
    Hazlett, Brian A
    Cooper, Kristine L
    Pittman, Phillip R
    Reed, Douglas S
    Hazlett, Karsten R O
    Show allShow less

    Date
    2021-12-20
    Journal
    Pathogens (Basel, Switzerland)
    Publisher
    MDPI AG
    Type
    Article
    
    Metadata
    Show full item record
    See at
    https://doi.org/10.3390/pathogens10121646
    Abstract
    Identifying correlates of protection (COPs) for vaccines against lethal human (Hu) pathogens, such as Francisella tularensis (Ft), is problematic, as clinical trials are currently untenable and the relevance of various animal models can be controversial. Previously, Hu trials with the live vaccine strain (LVS) demonstrated ~80% vaccine efficacy against low dose (~50 CFU) challenge; however, protection deteriorated with higher challenge doses (~2000 CFU of SchuS4) and no COPs were established. Here, we describe our efforts to develop clinically relevant, humoral COPs applicable to high-dose, aerosol challenge with S4. First, our serosurvey of LVS-vaccinated Hu and animals revealed that rabbits (Rbs), but not rodents, recapitulate the Hu O-Ag dependent Ab response to Ft. Next, we assayed Rbs immunized with distinct S4-based vaccine candidates (S4ΔclpB, S4ΔguaBA, and S4ΔaroD) and found that, across multiple vaccines, the %O-Ag dep Ab trended with vaccine efficacy. Among S4ΔguaBA-vaccinated Rbs, the %O-Ag dep Ab in pre-challenge plasma was significantly higher in survivors than in non-survivors; a cut-off of >70% O-Ag dep Ab predicted survival with high sensitivity and specificity. Finally, we found this COP in 80% of LVS-vaccinated Hu plasma samples as expected for a vaccine with 80% Hu efficacy. Collectively, the %O-Ag dep Ab response is a bona fide COP for S4ΔguaBA-vaccinated Rb and holds significant promise for guiding vaccine trials with higher animals.
    Keyword
    Francisella
    O-Antigen
    animal models
    humans
    rabbits
    rodents
    Identifier to cite or link to this item
    http://hdl.handle.net/10713/17606
    ae974a485f413a2113503eed53cd6c53
    10.3390/pathogens10121646
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