Effect of Two Unique Nanoparticle Formulations on the Efficacy of a Broadly Protective Vaccine Against Pseudomonas Aeruginosa

Howlader, Debaki Ranjan; Das, Sayan; Lu, Ti; Hu, Gang; Varisco, David J.; Dietz, Zackary K.; Walton, Sierra P; Ratnakaram, Siva Sai Kumar; Gardner, Francesca M.; Ernst, Robert K.; Picking, William D.; Picking, Wendy L.

doi:10.3389/fphar.2021.706157

Cited by 14 publications

(20 citation statements)

References 32 publications

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“…Formulation will be required prior to use in humans since monomeric subunit proteins are often not protective in humans (25,26). We have determined that formulation of L-PaF, the Pseudomonas aeruginosa homologue of L-DBF, reduces the required antigen by 10-fold or more (27).…”

Section: Intranasal L-dbf Stimulates Dose Dependent Immune Responses and Protection In Micementioning

confidence: 99%

L-DBF Elicits Cross Protection Against Different Serotypes of Shigella spp

Das

Howlader

et al. 2021

Front. Trop. Dis

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Shigellosis is a severe diarrheal disease caused by members of the genus Shigella, with at least 80 million cases and 700,000 deaths annually around the world. The type III secretion system (T3SS) is the primary virulence factor used by the shigellae, and we have previously demonstrated that vaccination with the type T3SS proteins IpaB and IpaD, along with an IpaD/IpaB fusion protein (DBF), protects mice from Shigella infection in a lethal pulmonary model. To simplify the formulation and development of the DBF Shigella vaccine, we have genetically fused LTA1, the active subunit of heat-labile toxin from enterotoxigenic E. coli, with DBF to produce the self-adjuvanting antigen L-DBF. Here we immunized mice with L-DBF via the intranasal, intramuscular, and intradermal routes and challenged them with a lethal dose of S. flexneri 2a. While none of the mice vaccinated intramuscularly or intradermally were protected, mice vaccinated with L-DBF intranasally were protected from lethal challenges with S. flexneri 2a, S. flexneri 1b, S. flexneri 3a, S. flexneri 6, and S. sonnei. Intranasal L-DBF induced both B cell and T cell responses that correlated with protection against Shigella infection. Our results suggest that L-DBF is a candidate for developing an effective serotype-independent vaccine against Shigella spp.

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Section: Intranasal L-dbf Stimulates Dose Dependent Immune Responses and Protection In Micementioning

confidence: 99%

L-DBF Elicits Cross Protection Against Different Serotypes of Shigella spp

Das

Howlader

et al. 2021

Front. Trop. Dis

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“…L-PaF, BECC438b, and ME were prepared as previously described ( 9 , 10 ). The sequence for the C-terminus of ExlA (residues 1361-1651) was cloned into pET-15b to be expressed with an N-terminal histidine tag (HT).…”

Section: Methodsmentioning

confidence: 99%

Development of a nano-emulsion based multivalent protein subunit vaccine against Pseudomonas aeruginosa

Howlader,

Mandal,

et al. 2024

Front. Immunol.

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Pseudomonas aeruginosa (Pa) is an opportunistic bacterial pathogen responsible for severe hospital acquired infections in immunocompromised and elderly individuals. Emergence of increasingly drug resistant strains and the absence of a broad-spectrum prophylactic vaccine against both T3SA+ (type III secretion apparatus) and ExlA+/T3SA- Pa strains worsen the situation in a post-pandemic world. Thus, we formulated a candidate subunit vaccine (called ExlA/L-PaF/BECC/ME) against both Pa types. This bivalent vaccine was generated by combining the C-terminal active moiety of exolysin A (ExlA) produced by non-T3SA Pa strains with our T3SA-based vaccine platform, L-PaF, in an oil-in-water emulsion. The ExlA/L-PaF in ME (MedImmune emulsion) was then mixed with BECC438b, an engineered lipid A analogue and a TLR4 agonist. This formulation was administered intranasally (IN) to young and elderly mice to determine its potency across a diverse age-range. The elderly mice were used to mimic the infection seen in elderly humans, who are more susceptible to serious Pa disease compared to their young adult counterparts. After Pa infection, mice immunized with ExlA/L-PaF/BECC/ME displayed a T cell-mediated adaptive response while PBS-vaccinated mice experienced a rapid onset inflammatory response. Important genes and pathways were observed, which give rise to an anti-Pa immune response. Thus, this vaccine has the potential to protect aged individuals in our population from serious Pa infection.

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“…(B) A >60% vaccine efficacy was used as a targeted cut-off value (right). (32,35). In this study, ME proved to be a more effective adjuvant for enhancing the immune response against Shigella infection.…”

Section: B Amentioning

confidence: 99%

Impact of the TLR4 agonist BECC438 on a novel vaccine formulation against Shigella spp.

Lu,

Das,

Howlader

et al. 2023

Front. Immunol.

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Shigellosis (bacillary dysentery) is a severe gastrointestinal infection with a global incidence of 90 million cases annually. Despite the severity of this disease, there is currently no licensed vaccine against shigellosis. Shigella’s primary virulence factor is its type III secretion system (T3SS), which is a specialized nanomachine used to manipulate host cells. A fusion of T3SS injectisome needle tip protein IpaD and translocator protein IpaB, termed DBF, when admixed with the mucosal adjuvant double-mutant labile toxin (dmLT) from enterotoxigenic E. coli was protective using a murine pulmonary model. To facilitate the production of this platform, a recombinant protein that consisted of LTA-1, the active moiety of dmLT, and DBF were genetically fused, resulting in L-DBF, which showed improved protection against Shigella challenge. To extrapolate this protection from mice to humans, we modified the formulation to provide for a multivalent presentation with the addition of an adjuvant approved for use in human vaccines. Here, we show that L-DBF formulated (admix) with a newly developed TLR4 agonist called BECC438 (a detoxified lipid A analog identified as Bacterial Enzymatic Combinatorial Chemistry candidate #438), formulated as an oil-in-water emulsion, has a very high protective efficacy at low antigen doses against lethal Shigella challenge in our mouse model. Optimal protection was observed when this formulation was introduced at a mucosal site (intranasally). When the formulation was then evaluated for the immune response it elicits, protection appeared to correlate with high IFN-γ and IL-17 secretion from mucosal site lymphocytes.

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Effect of Two Unique Nanoparticle Formulations on the Efficacy of a Broadly Protective Vaccine Against Pseudomonas Aeruginosa

Cited by 14 publications

References 32 publications

L-DBF Elicits Cross Protection Against Different Serotypes of Shigella spp

L-DBF Elicits Cross Protection Against Different Serotypes of Shigella spp

Development of a nano-emulsion based multivalent protein subunit vaccine against Pseudomonas aeruginosa

Impact of the TLR4 agonist BECC438 on a novel vaccine formulation against Shigella spp.

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