scholarly journals A deimmunized and pharmacologically optimized Toll-like receptor 5 agonist for therapeutic applications

2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Vadim Mett ◽  
Oleg V. Kurnasov ◽  
Ivan A. Bespalov ◽  
Ivan Molodtsov ◽  
Craig M. Brackett ◽  
...  
Keyword(s):  
Immune Response ◽  
Neutralizing Antibodies ◽  
De Novo ◽  
Therapeutic Potential ◽  
Phase 1 ◽  
Immune Memory ◽  
T Cell Epitopes ◽  
Toll Like Receptor ◽  
Radiation Induced ◽  
Toll Like Receptor 5

AbstractThe Toll-like receptor 5 (TLR5) agonist entolimod, a derivative of Salmonella flagellin, has therapeutic potential for several indications including radioprotection and cancer immunotherapy. However, in Phase 1 human studies, entolimod induced a rapid neutralizing immune response, presumably due to immune memory from prior exposure to flagellated enterobacteria. To enable multi-dose applications, we used structure-guided reengineering to develop a next-generation, substantially deimmunized entolimod variant, GP532. GP532 induces TLR5-dependent NF-κB activation like entolimod but is smaller and has mutations eliminating an inflammasome-activating domain and key B- and T-cell epitopes. GP532 is resistant to human entolimod-neutralizing antibodies and shows reduced de novo immunogenicity. GP532 also has improved bioavailability, a stronger effect on key cytokine biomarkers, and a longer-lasting effect on NF-κB. Like entolimod, GP532 demonstrated potent prophylactic and therapeutic efficacy in mouse models of radiation-induced death and tissue damage. These results establish GP532 as an optimized TLR5 agonist suitable for multi-dose therapies and for patients with high titers of preexisting flagellin-neutralizing antibodies.

Phase 1 Clinical Trial of a Conditionally Replication-Defective Human Cytomegalovirus (CMV) Vaccine in CMV-Seronegative Subjects

2019 ◽  
Vol 220 (3) ◽  
pp. 411-419 ◽  
Author(s):  
Stuart P Adler ◽  
Nicole Lewis ◽  
Anthony Conlon ◽  
Mark P Christiansen ◽  
Mohamed Al-Ibrahim ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Injection Site ◽  
Human Cytomegalovirus ◽  
Neutralizing Antibodies ◽  
De Novo ◽  
Phase 1 ◽  
Vaccine Dose ◽  
Genetically Engineered ◽  
Clinical Trial Registration ◽  
Viral Shedding

Abstract Background A conditionally replication-defective human cytomegalovirus (CMV) vaccine (V160) derived from AD169 and genetically engineered to express CMV pentameric complex (gH/gL/pUL128/pUL130/pUL131) was developed and evaluated for phase 1 vaccine safety and immunogenicity in CMV-seronegative and CMV-seropositive adults. Methods Subjects received 3 doses of V160 or placebo on day 1, month 1, and month 6. Four vaccine dose levels, formulated with or without aluminum phosphate adjuvant, were evaluated. Injection-site and systemic adverse events (AEs) and vaccine viral shedding were monitored. CMV-specific cellular and humoral responses were measured by interferon-gamma ELISPOT and virus neutralization assay up to 12 months after last dose. Results V160 was generally well-tolerated, with no serious AEs observed. Transient, mild-to-moderate injection-site and systemic AEs were reported more frequently in vaccinated subjects than placebo. Vaccine viral shedding was not detected in any subject, confirming the nonreplicating feature of V160. Robust neutralizing antibody titers were elicited and maintained through 12 months postvaccination. Cellular responses to structural and nonstructural viral proteins were observed, indicating de novo expression of viral genes postvaccination. Conclusions V160 displayed an acceptable safety profile. Levels of neutralizing antibodies and T-cell responses in CMV-seronegative subjects were within ranges observed following natural CMV infection. Clinical Trial Registration . NCT01986010.

scholarly journals Immunomodulatory nanogels overcome restricted immunity in a murine model of gut microbiome–mediated metabolic syndrome

2019 ◽  
Vol 5 (3) ◽  
pp. eaav9788 ◽  
Author(s):  
Matthew J. Mosquera ◽  
Sungwoong Kim ◽  
Hao Zhou ◽  
Tina T. Jing ◽  
Marysol Luna ◽  
...  
Keyword(s):  
Metabolic Syndrome ◽  
Immune Response ◽  
Germinal Center ◽  
Gut Microbiome ◽  
Wild Type Mouse ◽  
Toll Like Receptor ◽  
Vaccine Response ◽  
Independent Manner ◽  
Immunological Responses ◽  
Toll Like Receptor 5

Biomaterials-based nanovaccines, such as those made of poly(lactic-co-glycolic acid) (PLGA), can induce stronger immunity than soluble antigens in healthy wild-type mouse models. However, whether metabolic syndrome can influence the immunological responses of nanovaccines remains poorly understood. Here, we first show that alteration in the sensing of the gut microbiome through Toll-like receptor 5 (TLR5) and the resulting metabolic syndrome in TLR5−/− mice diminish the germinal center immune response induced by PLGA nanovaccines. The PLGA nanovaccines, unexpectedly, further changed gut microbiota. By chronically treating mice with antibiotics, we show that disrupting gut microbiome leads to poor vaccine response in an obesity-independent manner. We next demonstrate that the low immune response can be rescued by an immunomodulatory Pyr-pHEMA nanogel vaccine, which functions through TLR2 stimulation, enhanced trafficking, and induced stronger germinal center response than alum-supplemented PLGA nanovaccines. The study highlights the potential for immunomodulation under gut-mediated metabolic syndrome conditions using advanced nanomaterials.

scholarly journals CBLB502, a Toll-like receptor 5 agonist, offers protection against radiation-induced male reproductive system damage in mice†

2018 ◽  
Vol 100 (1) ◽  
pp. 281-291 ◽  
Author(s):  
Hao Bai ◽  
Feifei Sun ◽  
Ganggang Yang ◽  
Lei Wang ◽  
Quanyi Zhang ◽  
...  
Keyword(s):  
Reproductive System ◽  
Male Reproductive System ◽  
Toll Like Receptor ◽  
Radiation Induced ◽  
Toll Like Receptor 5

A Porcine Reproductive and Respiratory Syndrome Virus Vaccine Candidate Based on PRRSV Glycoprotein 5 and the Toll-Like Receptor 5 Agonist Salmonella typhimurium Flagellin

2015 ◽  
Vol 25 (1) ◽  
pp. 56-59 ◽  
Author(s):  
Hongqin Song ◽  
Dan Xiong ◽  
Jing Wang ◽  
Xianyue Zhai ◽  
Guangcheng Liang
Keyword(s):  
Salmonella Typhimurium ◽  
Neutralizing Antibodies ◽  
Expression Vectors ◽  
Respiratory Syndrome Virus ◽  
Toll Like Receptor ◽  
Pcr Method ◽  
Overlap Pcr ◽  
Toll Like Receptor 5 ◽  
Cellular Immune ◽  
Glycoprotein 5

Glycoprotein 5 (GP5) from porcine reproductive and respiratory syndrome virus (PRRSV) is a key inducer of neutralizing antibodies. A truncated GP5 gene lacking the signal peptide and transmembrane sequences was amplified via an overlap PCR method and inserted into prokaryotic expression vectors, pET32a or pGEX-6p-1, to add an His or GST tag, respectively. His-tagged GP5 was induced with IPTG, verified by SDS-PAGE and Western blotting, and purified to serve as an immunogen accompanied with the <i>Salmonella typhimurium</i> flagellin (FliC), a Toll-like receptor 5 (TLR5) agonist. Levels of TLR5 and cytokine mRNAs in spleens of mice following injection with FliC were detected by qRT-PCR to verify the activation of innate immunity. FliC was used as an adjuvant and administered with the GP5 to C57BL/6 mice via intraperitoneal injection. Coadministration of GP5 with FliC induced a significantly enhanced GP5-specific IgG and IFN-&#947; response compared with administration of GP5 alone, and the GP5-specific titer in the GP5 + FliC coadministration group was elevated almost twofold after the third immunization. These results indicate that FliC is an effective adjuvant, increasing the induction of antibodies against GP5 with the induction of both humoral and cellular immune responses.

scholarly journals Role of Toll-like receptor 5 in the innate immune response to acute P. aeruginosa pneumonia

2009 ◽  
Vol 297 (6) ◽  
pp. L1112-L1119 ◽  
Author(s):  
Amy E. Morris ◽  
H. Denny Liggitt ◽  
Thomas R. Hawn ◽  
Shawn J. Skerrett
Keyword(s):  
Immune Response ◽  
Innate Immune Response ◽  
Innate Immune ◽  
Bacterial Clearance ◽  
Toll Like Receptor ◽  
Monocyte Chemoattractant Protein 1 ◽  
Monocyte Chemoattractant ◽  
Monocyte Chemoattractant Protein ◽  
High Inoculum ◽  
Toll Like Receptor 5

Pseudomonas aeruginosa is a leading cause of hospital-acquired pneumonia and an important pathogen in patients with chronic lung disease, such as cystic fibrosis and bronchiectasis. The contribution of Toll-like receptor 5 (TLR5) to the innate immune response to this organism is incompletely understood. We exposed wild-type and TLR5-deficient ( Tlr5−/−) mice to aerosolized P. aeruginosa at low and high inocula and assessed bacterial clearance, lung inflammation, and cytokine production 4 and 24 h after infection. Bacterial clearance was impaired in Tlr5−/−mice after low-inoculum, but not high-inoculum, infection. Early bronchoalveolar accumulation of neutrophils was reduced in Tlr5−/−mice after low- and high-dose infection. Cytokine responses, including markedly impaired monocyte chemoattractant protein-1 production 4 h after low- and high-inoculum challenge, were selectively altered in Tlr5−/−mice. In contrast, there was no impairment of bacterial clearance, neutrophil recruitment, or monocyte chemoattractant protein-1 production in Tlr5−/−mice after infection with a nonflagellated isotypic strain of P. aeruginosa . Thus TLR5-mediated recognition of flagellin is involved in activating pulmonary defenses against P. aeruginosa and contributes to antibacterial resistance in a manner that is partially inoculum dependent. These data are the first to demonstrate a unique role for TLR5 in the innate immune response to P. aeruginosa lung infection.

The innate immune response to bacterial flagellin is mediated by Toll-like receptor 5

Nature ◽  
2001 ◽  
Vol 410 (6832) ◽  
pp. 1099-1103 ◽  
Author(s):  
Fumitaka Hayashi ◽  
Kelly D. Smith ◽  
Adrian Ozinsky ◽  
Thomas R. Hawn ◽  
Eugene C. Yi ◽  
...  
Keyword(s):  
Immune Response ◽  
Innate Immune Response ◽  
Innate Immune ◽  
Toll Like Receptor ◽  
Toll Like Receptor 5

scholarly journals Strong immunogenicity of heterologous prime-boost immunizations with the experimental vaccine GRAd-COV2 and BNT162b2 or ChAdOx1-nCOV19

2021 ◽  
Author(s):  
Chiara Agrati ◽  
Stefania Capone ◽  
Concetta Castilletti ◽  
Eleonora Cimini ◽  
Giulia Matusali ◽  
...  
Keyword(s):  
Immune Response ◽  
Single Dose ◽  
Neutralizing Antibodies ◽  
Small Sample Size ◽  
Phase 1 ◽  
Vaccination Campaign ◽  
Small Sample ◽  
Vaccine Platform ◽  
Ideal Tool ◽  
Cellular Immune

Here we report on the humoral and cellular immune response in eight volunteers who autonomously chose to adhere to the Italian national COVID-19 vaccination campaign more than 3 months after receiving a single administration GRAd-COV2 vaccine candidate in the context of the phase 1 clinical trial. We observed a clear boost of both binding/neutralizing antibodies as well as T cell responses upon receipt of the heterologous BNT162b2 or ChAdOx1-nCOV19 vaccines. These results, despite the limitation of the small sample size, support the concept that a single-dose of an adenoviral vaccine may represent an ideal tool to effectively prime a balanced immune response, which can be boosted to high levels by a single dose of a different vaccine platform.

scholarly journals EXTH-39. HEXON SWAPPING MITIGATES ANTI-VIRAL IMMUNE RESPONSE DURING BRAIN TUMOR VIROTHERAPY

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii95-ii95
Author(s):  
Dong Ho Shin ◽  
Teresa Nguyen ◽  
Hong Jiang ◽  
Sagar Sohoni ◽  
Sumit Gupta ◽  
...  
Keyword(s):  
Immune Response ◽  
Brain Tumor ◽  
Immune Responses ◽  
Neutralizing Antibodies ◽  
Phase 1 ◽  
Malignant Gliomas ◽  
Oncolytic Viruses ◽  
Comparable Efficacy ◽  
Host Immune System ◽  
Serotype 5

Abstract Cancer virotherapy is a paradigm-shifting treatment modality based on the capabilities of virus-mediated oncolysis to elicit an anti-tumor immune response. Phase 1 and 2 clinical trials have demonstrated the safety and efficacy of our oncolytic adenovirus DNX-2401 (Delta-24-RGD) for patients with recurrent malignant gliomas. While a subset of the patients showed significant benefits, our goal is to improve the response rate. Clearance of the therapeutic virus by dominant anti-viral immune responses may contribute to the observed limits of the virotherapy. Adenovirus serotype 5 that provides the backbone of most oncolytic adenoviruses is highly prevalent in the human population and neutralizing antibodies against the capsid protein hexon may inhibit viral infection and replication. In this study, we showed using immunofluorescence that in mice bearing orthotopic syngeneic glioblastoma GSC005 treated with Delta-24-RGD, IgG antibodies crossed the disrupted blood-brain barrier and infiltrated the brain tumor parenchyma to colocalize with the viral hexon, suggesting that the systemic immune response may eradicate the virus within the infected tumor. To overcome this obstacle, we generated a chimeric virus called Delta-24-RGD-H43m with hexon hypervariable regions replaced with those from a lesser prevalent serotype 43 to avoid recognition by antibodies generated against serotype 5. The molecular swapping of the hexon did not significantly interfere with virion assembly nor attenuate its anti-glioma effect. Thus, the two viruses showed comparable efficacy in vitro (P= 0.568) and in vivo for animals without prior virus exposures (P= 0.228). Importantly, Delta-24-RGD-H43m evaded neutralizing antibodies generated against Delta-24-RGD and maintained its oncolytic ability (P&lt; 0.0001). We conclude that hexon swapping strategies may improve virotherapy by alleviating the dominant immune response against the virus. Despite limited understanding of the interaction between oncolytic viruses and the host immune system, further research on strategies to circumvent virus-specific immune responses should aid the development of enhanced, glioma-targeted virotherapies.

scholarly journals Strong immunogenicity of heterologous prime-boost immunizations with the experimental vaccine GRAd-COV2 and BNT162b2 or ChAdOx1-nCOV19

npj Vaccines ◽  
2021 ◽  
Vol 6 (1) ◽  
Author(s):  
Chiara Agrati ◽  
Stefania Capone ◽  
Concetta Castilletti ◽  
Eleonora Cimini ◽  
Giulia Matusali ◽  
...  
Keyword(s):  
Immune Response ◽  
Single Dose ◽  
Neutralizing Antibodies ◽  
Small Sample Size ◽  
Phase 1 ◽  
Vaccination Campaign ◽  
Small Sample ◽  
Vaccine Platform ◽  
Ideal Tool ◽  
Cellular Immune

AbstractHere we report on the humoral and cellular immune response in eight volunteers who autonomously chose to adhere to the Italian national COVID-19 vaccination campaign more than 3 months after receiving a single-administration GRAd-COV2 vaccine candidate in the context of the phase-1 clinical trial. We observed a clear boost of both binding/neutralizing antibodies as well as T-cell responses upon receipt of the heterologous BNT162b2 or ChAdOx1-nCOV19 vaccines. These results, despite the limitation of the small sample size, support the concept that a single dose of an adenoviral vaccine may represent an ideal tool to effectively prime a balanced immune response, which can be boosted to high levels by a single dose of a different vaccine platform.

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