Search

Identifying suitable animal models and standardizing preclinical methods are important for the generation, characterization, and development of new vaccines, including those against Francisella tularensis. Non-human primates represent an important animal model to evaluate tularemia vaccine efficacy, and the use of correlates of vaccine-induced protection may facilitate bridging immune responses from non-human primates to people. However, among small animals, Fischer 344 rats represent a valuable resource for initial studies to evaluate immune responses, to identify correlates of protection, and to screen novel vaccines. In this study, we performed a comparative analysis of three Fischer rat substrains to determine potential differences in immune responses, to evaluate methods used to quantify potential correlates of protection, and to evaluate protection after vaccination. To this end, we took advantage of data previously generated using one of the rat substrains by evaluating two live vaccines, LVS and F. tularensis SchuS4-ΔclpB (ΔclpB). We compared immune responses after primary vaccination, adaptive immune responses upon re-stimulation of leukocytes in vitro, and sensitivity to aerosol challenge. Despite some detectable differences, the results highlight the similarity of immune responses to tularemia vaccines and challenge outcomes between the three substrains, indicating that all offer acceptable and comparable approaches as animal models to study Francisella infection and immunity. [ABSTRACT FROM AUTHOR]

Objective: To determine the in vitro antiviral activity of oral care products containing stabilized chlorine dioxide toward infectious viruses that harbor in the oral cavity. Specfically, severe acute respiratory syndrome coronavirus‐2 (SARS‐CoV‐2), SARS‐CoV, human coronavirus (HCoV) 229E, influenza A (H3N2), rhinovirus type 14, adenovirus type 5, and herpes simplex virus (HSV) type 1 and 2 were examined. Methods: Validated in vitro suspension virucidal assays were used. Test product was mixed with the test virus for 30, 60, or 120 s, neutralized with sodium thiosulfate, serially diluted in dilution medium in a 96‐well plate and incubated in a carbon dioxide incubator for 7 days. The 50% Tissue Culture Infectious Dose per milliliter was determined. Results: Two rinses, one oral spray and one fluoride toothpaste showed log reduction of severe acute respiratory syndrome coronavirus‐2 ranging from 1.81 to 2.98 and of influenza A from 2.58 to 4.13, respectively, within 30 s of contact time; similar results were obtained at 60 s. Further, the Ultra Sensitive rinse showed 0.19, 0.75, 1.58, 1.75, 2.66, and 3.24 log reduction of severe acute respiratory syndrome coronavirus, human coronavirus 229E, rhinovirus type 14, adenovirus type 5, and herpes simplex virus type 1 and type 2, respectively, within 30 s of contact time. Conclusion: Stabilized chlorine dioxide containing ClōSYS® oral care products reduced the viral load of multiple viruses within 30 s. The results warrant further investigation for potential in vivo applications. [ABSTRACT FROM AUTHOR]

Many bacterial species use secreted quorum-sensing autoinducer molecules to regulate cell density- and growth phase-dependent gene expression, including virulence factor production, as sufficient environmental autoinducer concentrations are achieved. Bacillus anthracis, the causative agent of anthrax, contains a functional autoinducer (AI-2) system, which appears to regulate virulence gene expression. To determine if the AI-2 system is necessary for disease, we constructed a LuxS AI-2 synthase-deficient mutant in the virulent Ames strain of B. anthracis. We found that growth of the LuxS-deficient mutant was inhibited and sporulation was delayed when compared with the parental strain. However, spores of the Ames luxS mutant remained fully virulent in both mice and guinea pigs. [ABSTRACT FROM AUTHOR]

Inhalation of small numbers of Francisella tularensis subspecies tularensis (Ftt) in the form of small particle aerosols causes severe morbidity and mortality in people and many animal species. For this reason, Ftt was developed into a bona fide biological weapon by the USA, by the former USSR, and their respective allies during the previous century. Although such weapons were never deployed, the 9/11 attack quickly followed by the Amerithrax attack led the U.S. government to seek novel countermeasures against a select group of pathogens, including Ftt. Between 2005–2009, we pursued a novel live vaccine against Ftt by deleting putative virulence genes from a fully virulent strain of the pathogen, SCHU S4. These mutants were screened in a mouse model, in which the vaccine candidates were first administered intradermally (ID) to determine their degree of attenuation. Subsequently, mice that survived a high dose ID inoculation were challenged by aerosol or intranasally (IN) with virulent strains of Ftt. We used the current unlicensed live vaccine strain (LVS), first discovered over 70 years ago, as a comparator in the same model. After screening 60 mutants, we found only one, SCHU S4 ΔclpB, that outperformed LVS in the mouse ID vaccination-respiratory-challenge model. Currently, SCHU S4 ΔclpB has been manufactured under current good manufacturing practice conditions, and tested for safety and efficacy in mice, rats, and macaques. The steps necessary for advancing SCHU S4 ΔclpB to this late stage of development are detailed herein. These include developing a body of data supporting the attenuation of SCHU S4 ΔclpB to a degree sufficient for removal from the U.S. Select Agent list and for human use; optimizing SCHU S4 ΔclpB vaccine production, scale up, and long-term storage; and developing appropriate quality control testing approaches. [ABSTRACT FROM AUTHOR]