ABSTRACT Local and systemic reactogenic responses to Q-VAX have prevented licensing of this vaccine outside of Australia. These reactogenic responses occur in previously sensitized individuals and have not been well defined at the cellular level, in part because many studies have been done in guinea pigs that have limited molecular tools. We previously characterized a mouse model of reactogenicity where local reaction sites showed an influx of CD8+ and IFNγ-expressing IL17a+ CD4+ T cells consistent with a Th1 delayed-type hypersensitivity. In this study, we determined, using depletion and adoptive transfer experiments, that both anti- Coxiella antibodies and CD4+ T cells were essential for localized reactions at the site of vaccination. Furthermore, IFNγ depletion showed significant histological changes at the local reaction sites demonstrating the essential nature of this cytokine to reactogenicity. In addition to the cells and cytokines required for this response, we determined that whole cell vaccine (WCV) material remained at the site of vaccination for at least 26 weeks post-injection. Transmission electron microscopy (TEM) of these sites demonstrated intact rod-shaped bacteria at 2 weeks post-injection and partially degraded bacteria within macrophages at 26 weeks post-injection. Finally, because small cell variants (SCVs) are an environmentally stable form, we determined that local reactions were more severe when the WCV material was prepared with higher levels of SCVs compared to typical WCV or with higher levels of large cell variant (LCV). These studies support the hypothesis that antigen persistence at the site of injection contributes to this reactogenicity and that anti- Coxiella antibodies, CD4+ T cells, and IFNγ each contribute to this process.

01 Mar 2024·Advanced Healthcare Materials

Synthetic Particulate Subunit Vaccines for the Prevention of Q Fever

Article

Author: Marsh, Ian ; Plain, Karren ; Stenos, John ; Rehm, Bernd H. A. ; Graves, Stephen R. ; Islam, Aminul ; Chen, Shuxiong ; Sam, Gayathri ; Westman, Mark E.

AbstractCoxiella burnetti is an intracellular bacterium that causes Q fever, a disease of worldwide importance. Q‐VAX®, the approved human Q fever vaccine, is a whole cell vaccine associated with safety concerns. Here a safe particulate subunit vaccine candidate is developed that is ambient‐temperature stable and can be cost‐effectively manufactured. Endotoxin‐free Escherichia coli is bioengineered to efficiently self‐assemble biopolymer particles (BPs) that are densely coated with either strings of 18 T‐cell epitopes (COX‐BP) or two full‐length immunodominant antigens (YbgF‐BP‐Com1) all derived from C. burnetii. BP vaccine candidates are ambient‐temperature stable. Safety and immunogenicity are confirmed in mice and guinea pig (GP) models. YbgF‐BP‐Com1 elicits specific and strong humoral immune responses in GPs with IgG titers that are at least 1 000 times higher than those induced by Q‐VAX®. BP vaccine candidates are not reactogenic. After challenge with C. burnetii, YbgF‐BP‐Com1 vaccine leads to reduced fever responses and pathogen burden in the liver and the induction of proinflammatory cytokines IL‐12 and IFN‐γ inducible protein (IP‐10) when compared to negative control groups. These data suggest that YbgF‐BP‐Com1 induces functional immune responses reducing infection by C. burnetii. Collectively, these findings illustrate the potential of BPs as effective antigen carrier for Q fever vaccine development.

28 Dec 2023·The Journal of Physical Chemistry A

Computational Risk Assessment of Persistence, Bioaccumulation, and Toxicity of Novel Flame-Retardant Chemicals

Article

Author: Pandit, Shraddha ; Singh, Prakrity ; Sinha, Meetali ; Yadav, Dhvani ; Parthasarathi, Ramakrishnan

Novel brominated flame retardants (NBFRs) have emerged as chemicals of environmental concern, as they have been widely used as an alternative to polybrominated diphenyl ethers (PBDEs). Considering the similar structural features of NBFRs and PBDEs necessitates a comprehensive investigation to understand the physicochemical relationships of these compounds and their ability to alter biological functions. In this study, we investigated the persistent nature of NBFRs in terms of thyroid-disrupting potential by understanding the structure-stability aspects using density functional theory (DFT)-based reactivity parameters and interactions via molecular docking and molecular dynamics (MD) simulations. The results indicate that the DFT-based stability descriptor (chemical hardness) is associated with the persistent nature of NBFRs. The computed molecular interaction profile revealed prominent interactions between thyroid receptor-β (TR-β) and NBFRs. Stable trajectory and interactions with TR-β were obtained with ATE, p-TBX, PBT, PBEB, and TBBPA-DBPE during 100 ns of MD simulation. The results of these studies have suggested that the presence of a higher number of halogenated atoms increases the stability vis-à-vis the persistence and endocrine disruption potential of NBFRs.

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Indication	Highest Phase	Country/Location	Organization	Date
Pseudomonas Infections	Preclinical	ES	Vaxdyn SL	21 Apr 2023

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