bluuebunny/crossref_metadata_2025_split huggingface dataset:
Immunogenicity of a Purified Inactivated Zika Virus Vaccine Candidate in Humans is Diminished by Priming with a Yellow Fever or Japanese Encephalitis Virus Vaccine: Elucidating Immunologic Interference between Flavivirus Vaccines
Authors: Modjarrad Kayvon , Koren Michael , Lin Leyi , Sondergaard Erica , De La Barrera Rafael , Eckels Kenneth , Krebs Shelly , Eller Michael , Costanzo Margaret , Joyce Gordon , Dussupt Vincent , Gromowski Gregory D , Storme Casey , Amare Mihret , Jarman Richard G , Thomas Stephen , Michael Nelson 
Published: January 2023

Abstract
In response to the 2016 Zika virus (ZIKV) outbreak, we developed a purified, formalin-inactivated, Alum-adjuvanted ZIKV vaccine (ZPIV) candidate that was protective in animal models and advanced to human testing in four phase 1 clinical trials. We have previously reported the interim analysis of three trials. Here we present the final analysis of a phase 1, placebo controlled, double-blind trial of ZPIV. Seventy-five flavivirus-naïve adults—divided into three groups of 25—were randomly assigned to receive three 5μg doses of ZPIV or placebo at days 1, 29 and 196. Group 1 only received ZPIV, while Groups 2 and 3 first received either licensed Japanese encephalitis (IXIARO®) or yellow fever (YF-VAX®) vaccine two-months prior to receiving ZPIV. Immune responses were assessed by a live-virus microneutralization assay. ZPIV was well tolerated across groups. Group 1 exhibited neutralizing antibody (nAb) geometric mean titers (GMT) of 101 and 511 after the 2nd and 3rd doses. GMTs in Groups 2 and 3 were significantly lower at 11.8 and 6.6 after two doses, and 174 and 79 after the 3rd dose. There were no differences in binding antibody titers or in antibody affinity maturation across groups. These data suggest that flavivirus vaccine priming of B cells directed antibodies toward non-neutralizing epitopes and that decline in ZIKV nAb titers did not reflect overall decrements in B cell responses. Other studies have shown prior dengue virus infection boosts subsequent ZIKV responses. These results indicate the interplay of flavivirus immunity is contextual and likely specific to the mode and timing of antigen presentation. More studies are needed to investigate these factors, so as to optimize the rational use of vaccines against co-endemic flaviviruses.
Glycolipid-peptide vaccination induces liver-resident memory CD8+ T cells that protect against malaria
Authors: Holz Lauren , Chua Yu Cheng , Anderson Regan , Draper Sarah , Compton Benjamin , Chan Susanna , Mathew Juby , de Menezes Maria , Cozijnsen Anton , Mollard Vanessa , McFadden Geoffrey , Painter Gavin , Heath William R 
Published: January 2023

Abstract
Liver resident-memory CD8+ T cells (TRM cells) can kill liver-stage Plasmodium-infected cells and prevent malaria, but simple vaccines for generating this important immune population are lacking. Here, we report the development of a fully synthetic self-adjuvanting glycolipid-peptide conjugate vaccine designed to efficiently induce liver TRM cells. Upon cleavage in vivo, the glycolipid-peptide conjugate vaccine releases an MHC I-restricted peptide epitope (to stimulate Plasmodium-specific CD8+ T cells) and an adjuvant component, the NKT cell agonist a-galactosylceramide (a-GalCer). Following transfer of a transgenic CD8+ T cell population, a single dose of this vaccine induced substantial numbers of intrahepatic CD8+ T cells expressing canonical markers of liver TRM cells (CD69, CXCR6 and CD101), and these cells could be further increased in number upon vaccine boosting. We show that modifications to the peptide, such as addition of proteosomal-cleavage sequences or epitope-flanking sequences, or the use of alternative conjugation methods to link the peptide to the glycolipid, improved liver TRM cell generation and led to the development of a vaccine able to induce sterile protection in C57BL/6 mice against P. berghei sporozoite challenge after a single dose. Incorporation of a cognate malaria antigen into the vaccine resulted in the generation of large numbers of long-lived liver TRM cells derived from the endogenous T cell population that were capable of providing sterile immunity. Our findings describe an ideal synthetic vaccine platform for generating large numbers of liver TRM cells for effective control of liver-stage malaria and, potentially, a variety of other hepatotropic infections
Development of a chlamydial vaccine for koalas : Protection against infection and disease
Authors: Timms Peter 
Published: January 2023

Abstract
Wild koala populations continue to experience serious declines as a result of several threatening factors including, (i) loss of habitat, (ii) motor vehicle trauma; (iii) dog attacks; (iv) Chlamydia. Chlamydial infections are associated with diseases ranging from ocular disease leading to blindness, as well as urinary and genital tract disease, leading to female infertility. Modeling shows that targeting chlamydial disease would have a major impact on stabilising population decline. Our studies have demonstrated that koalas can be safely immunized with a vaccine containing a mixture of chlamydial major outer membrane protein (MOMP) antigens combined with a single dose subcutaneous regime. We conducted a wild koala field trial and observed strong, specific and long-lasting immune responses in the vaccinated koalas; high titre antibody responses (as measured by ELISA and also in vitro neutralisation) as well as Chlamydia-specific cytokine responses (interferon-gamma and IL-17 in particular). For animals which were Chlamydia PCR positive at the time of vaccination, we observed a significant reduction in their infection PCR load. We also observed protection from progression to clinical disease in the vaccinated animals. We also conducted a small trial to vaccinate animals which already have clinical signs of ocular disease. Instead of the normal practice of administering antibiotics (chloramphenicol, daily for 28 days, which severely disrupts the animal’s gut microbiome) we vaccinated four animals with a single dose, 3-MOMP vaccine. For all vaccinated animals, their Chlamydia PCR load decreased, and for 6 of the 7 animals, ocular disease regressed and the animals could be released back into the wild without further treatment.
Increased immune cell infiltration contribute to enhanced protective immunity following co-delivery of VCG Chlamydia vaccine with Flt3L
Authors: Richardson Shakyra S , Lundy Stephanie , Dye Kamran , Omosun Yusuf , Eko Francis 
Published: January 2023

Abstract
Chlamydia trachomatis remains the commonest bacterial cause of sexually transmitted infections worldwide and can lead to pelvic inflammatory disease and infertility. Although antibiotics are effective against Chlamydia, most infections are asymptomatic suggesting the use of an effective vaccine may be the best approach for preventing these infections and the associated sequelae. We previously showed rectal (IR) immunization was a viable mucosal route for inducing female genital tract immunity and that the Fms-like tyrosine kinase 3-ligand (Flt3L; FL) enhanced the protective immunity of a Vibrio cholerae ghost (VCG)-based Chlamydia vaccine. However, the mechanism of immune enhancement was not investigated. In this study, we investigated if differences in the type and number of immune cells infiltrating mucosal and systemic tissues of mice could account for the observed immune enhancement following immunization. Mice were immunized IR with rVCG co-expressing the C. trachomatis polymorphic membrane protein D (PmpD) and porin B (PorB) proteins (rVCG-PmpD/PorB) with and without FL. Vaccine evaluation was based on measurement of IFN-γ cytokine, T cell proliferation, protection against intravaginal infection, and the differential profile of immune cells infiltrating mucosal and systemic tissues of mice using flow cytometry. The results showed co-delivery of vaccine with FL significantly enhanced IFN-γ levels and proliferation of splenic CD4+ immune T cells, as well as increased infiltration of immune cells in the spleen and genital tract tissues of mice. The results indicate the increased immune cell infiltration contribute to the enhanced protective immunity following co-delivery of VCG vaccine with FL.
Identification of toxicity and efficacy against new staphylococcal enterotoxin B subunit vaccine
Authors: Sim Euni , Kim Nayoung , Son Wonrak , Lee Minhoon , Hong Sungyoul , Shin YoungKee , Choi JunYoung 
Published: January 2023

Abstract
Staphylococcus aureus (S. aureus) bacteria, the gram-positive coccus and occurring irregular clusters, have the power to produce many types of enterotoxin. It is known as a foodborne poisoning agent as well as being a potential inhaled bioterrorism agent. Previously we confirmed the structure of modified-S. aureus enterotoxin B (SEB) vaccine candidate (ABN701) that can induce neutralization of antigen activity and also elicit humoral and cellular immune response. In this study, we studied the immunization efficacy and toxicity of ABN701 in various animal models. ABN701 was immunized in a dose dependent manner to BalB/C mouse and rabbit and about 20 ug ABN701 can induce an immune response in these models. Through the adjuvant tests, aluminum-composed adjuvant triggered more antibody inducement in mice and rabbit. The immunized BalB/C mouse were challenged with the SEB toxin and survived against 20LD50 SEB toxin treatment. Emesis is one of the most important evaluation factors for SEB vaccine development because emesis is related to SEB toxin symptom. House musk shrew mouse (Suncus Murinus) is widely known to be sensitive to various emetic drug evaluation and a new experimental animal model for SEB toxin related emesis. We confirmed that ABN701 did not cause emesis while SEB toxin cause emesis in this model. We also immunized ABN701 to monkey and showed no emesis symptom, but induced an effective immune response. In this study, we identified that ABN701 can induce an immune response in mouse, rabbit and monkey and ABN701 do not have toxicity related to emesis in the House musk shrew mouse model and monkey model.
An outer membrane vesicle-adjuvanted oral vaccine protects against lethal, oral Salmonella infection
Authors: Harrell Jaikin , Kurtz Jonathan R , Bauer David L , Gellings Patrick , Morici Lisa , McLachlan James B 
Published: January 2023

Abstract
Non-typhoidal salmonellosis, caused by Salmonella enterica serovar Typhimurium (S. Typhimurium) is a common disease worldwide that can be contracted from contact with contaminated food, water, or animal carriers. Salmonellosis is characterized by mild gastrointestinal distress resulting in diarrhea, chills, fever, abdominal cramps, head and body aches, nausea, and vomiting; however, increasing incidences of antibiotic resistant invasive non-typhoidal Salmonella infections makes this a global threat requiring novel treatment strategies such next-generation vaccines. The goal of the current study was to formulate a novel vaccine platform against Salmonella infection that could be delivered orally. To accomplish this, we created a vaccine consisting of Burkolderia pseudomallei outer membrane vesicles (OMVs) which have been shown to act as potent immune mediators and are currently being explored as adjuvants for the next generation of vaccines. We show here that adding OMVs to a heat-killed oral Salmonella vaccine protects against a lethal oral challenge with S. Typhimurium. We show that anti-Salmonella antibodies are induced in response to immunization and demonstrate that bacterial burdens are lessened when OMVs are included in the vaccine. We are currently exploring whether CD4 helper T cells are induced and can contribute to the observed protection as these cells are known to be essential mediators of protective anti-Salmonella immunity. This study represents a new, oral vaccine approach to combatting the increasing problem of invasive Salmonella infections.
Two for one: Identification of P. aeruginosa and B. pertussis Cross-species Antigens
Authors: Blackwood Catherine B , Kilic Emel Sen , Weaver Kelly , Boehm Dylan T , Hall Jesse , Wong Ting , Malkowski Aaron , Witt William T , Damron F. Heath , Barbier Mariette 
Published: January 2023

Abstract
Development of effective vaccines requires logical design and formulation of two main components: antigens and adjuvants. Some compounds, called immunogens, can assume both of these roles. Notably, Bordetella pertussis (Bp) and some of its antigenic products have been found to adjuvant immune responses to other vaccines or vaccine components. We chose to explore this ability by using B. pertussis and pertussis toxin as adjuvants for a whole cell vaccine (WCV) against Pseudomonas aeruginosa (Pa). Pa is a highly antibiotic resistant Gram-negative opportunistic pathogen for which there are no approved vaccines or immunotherapies. We formulated vaccines containing Pa with Bp or pertussis toxin to determine if these components could modulate the immune response to PaWCV, as measured by quantification of bacterial burden and immune cell response after an acute pneumonia challenge. We determined that these additions to the PaWCV were associated with increased clearance of bacteria after challenge and increased Pa-binding immunoglobulins in the blood and airway. Additionally, we determined that the BpWCV alone was sufficient to induce protection from acute Pa infection. This correlated with production of antibodies that bind Pa, indicating that there is at least one cross-reactive antigen that could be providing protection. Through utilization of immunoblotting of protein fractions of Pa and mass spectroscopy, we identified this protective antigen. It will be used to formulate a subunit vaccine and tested for efficacy in protection from Pseudomonas infection. This type of cross-protection is novel within the field and could lead to the identification of a protective antigen against P. aeruginosa in B. pertussis.
Impact of viral sensitizer-enhanced oncolytic virus immunotherapy on the anti-tumor immune response
Authors: Alluqmani Nouf N. , Bergeron Anabel , Chen Andrew , Khan Sarwat , Forbes Nicole , Arulanandam Rozanne , Souza Christiano , Crans Debbi C. , Diallo Jean-Simon 
Published: January 2023

Abstract
Oncolytic viruses (OVs) have emerged as promising anticancer treatment platforms, able to specifically replicate in and kill cancer cells. OVs also have immunostimulatory effects, promoting antitumor immune responses, and several strategies have been developed in combination with OVs to stimulate cancer-specific immune responses. Viral sensitizers (VSes) are molecules that alter the tumor antiviral response in order to improve the efficacy of OVs. Such compounds can improve OV spread, transgene expression, and promote long-term antitumor immunity in various tumor models. A major objective of our study is to investigate the impact of VSes compounds on T-cells and other immune cells in the context of OV therapy and cancer vaccination strategies employing OVs. Results to date, VSes in combination with OVs significantly improve the therapeutic efficacy in syngeneic murine carcinoma tumor models. Additionally, we performed peptide-MHC-class I pentameric complexes staining to evaluate the kinetics of the T cell mediated anti-tumor immune response in vivo, our data illustrated that this combination therapy induced the production of antigen specific CD8+ T cells. We screened for chemokine and cytokine secretion using multiplex assay, and we found significant increases in IFN-γ, GM-CSF, and IL-12, 24 hour and 5 days post the treatment. We currently aim to phenotype the tumor microenvironment in order to understanding the mechanism that modulates the anti-tumor immunity using flow cytometry. We anticipate that unraveling the impact of VSes on the immunological response to OV therapy will lead to better understanding of mechanism contributing to its efficacy and improve our ability to successfully translate our findings to the clinic.
N2 / Ar plasma acts as a switch from apoptosis to necroptosis by degradation of MAVS aggregates
Authors: You Young Suk , Choi Jae Hoon , Kim Chul-Ho 
Published: January 2023

Abstract
Inflammatory responses play an important role in cancer progression and cell survival. For this reason, cancer can be treated by targeting an inflammatory response. Previously we reported that nonthermal plasma, which is a mixture of energy particles including electrons, ions and radicals, has anti-inflammatory and anti-cancer efffects. However, the underlying mechanisms how N2/Ar plasma induces cell death is largely unknown. In this study, we investigated whether N2/Ar plasma induces apoptosis or necroptosis in HNC cells. Inflammation-related proteins and mitochondrial MAVS proteins were elevated in HNC patient samples. TCGA data also showed low survival rates for HNC patients with increased inflammatory responses. We observed that the inflammatory response and expression of mitochondrial MAVS protein decreased when N2/Ar plasma was treated in the HNC cells. In addition, N2/Ar plasma treatment reduced the inflammatory response and MAVS protein expression and induced necroptosis. Finally, it was also confirmed that the increase of RIP3 decreases the expression of mitochondrial MAVS, inhibits apoptosis and induces necroptosis. This results suggest that, in HNC cells, N2/Ar plasma may act as a molecular switch from apoptotic cell death to necrototic cell death by regulating MAVS aggregates.
Cyclooxygenase-2 dependent prostaglandin E2 signaling through the EP3 receptor is required for cell-mediated immunity to Listeria monocytogenes
Authors: McDougal Courtney E , Theisen Erin , Sauer John-Demian 
Published: January 2023

Abstract
The bacterial pathogen Listeria monocytogenes (Lm) is being developed as a cancer immunotherapeutic platform due to its ability to elicit robust CD8+ T cell responses. Though the role of cytokines in Lm-stimulated immunity is well studied, the role of eicosanoids, lipid modulators of inflammation, is unclear. We previously demonstrated that cyclooxygenase-2 (COX-2) dependent prostaglandin E2 (PGE2) is essential for optimal T-cell priming. Antigen specific T cells and protective immunity were decreased following either treatment with the COX-2 inhibitor celecoxib or immunization of mice deficient in microsomal PGE2 synthase-1. Analysis of splenic eicosanoid levels revealed an upregulation of PGE2 twelve hours post immunization and administration of exogenous PGE2 at this time restored immunity during COX-2 inhibition. To understand how PGE2 impacts T-cell priming we assessed the role of the receptors EP1–4 in mediating this response using small molecule agonists and antagonists. EP3 blockade impaired immune responses while the use of an EP3 specific agonist restored immunity during COX-2 inhibition, suggesting that PGE2 signaling through EP3 is critical for T-cell priming. Conversely, consistent with its predicted inverse role in cAMP signaling, EP4 blockade enhanced responses, providing a mechanism by which to improve Listeria-based immunotherapeutics. Ongoing studies with floxed COX-2, EP3 and EP4 mice will illuminate the cell types producing and responding to PGE2. In conclusion, PGE2 signaling through EP3 is necessary Lm-stimulated immunity while EP4 signaling is detrimental. Further understanding these signaling pathways and where they function will be key to optimizing Lm as therapeutic platform.
Exploring γδ T cells for use in non-MHC restricted immunotherapy
Authors: Schriefer Kalyn , Chang Dan , Garett-Engele Phillip , Li Lixia , Spooner Ed , Monslow Morgan , Killough Jason , Lieberman Linda , Mohammadi Sina , Sana Theodore , Wyche Thomas , Guo Amanda , Howell Bonnie , Peterson Vanessa , Martinelli Roberta 
Published: January 2023

Abstract
γδ T cells are a unique subset of T cells found in both blood (Vδ2) and tissues (Vδ1). Unlike canonical αβ T cells that recognize peptide antigens through MHC class I/II molecules, γδ T cells recognize lipids and metabolites presented by non-MHC molecules. γδ T cells are highly cytotoxic and can rapidly kill both infected and cancer cells. Their cytotoxicity and lack of MHC restriction makes γδ T cells a promising target for allogeneic cell transfer therapy. In collaboration with MRL Oncology and ID/Vax we are investigating γδ T cells as a potential “off-the-shelf” cell transfer therapy. The ESC is currently optimizing ex vivo expansion protocols for both Vδ1 and Vδ2 T cells. Vδ2 cells rapidly expand from PBMCs after exposure to Zometa/IL-2, and are efficient cancer killers in vitro. To assess activation state, targeted metabolomics analysis was performed during Vδ2 expansion, and displayed significant differences in glutamate utilization, lactic acid, myo-inositol, and several essential and non-essential amino acids. We have also isolated and expanded Vδ1 T cells from PBMCs and human tissues (colon). These cells express high levels of NKG2D, which is suggestive of cytotoxic potential and we are currently assessing their cancer cell killing capacity in vitro. In collaboration with GpGx, we are identifying the dominant T-cell receptor (TCR) repertoires present in these populations by performing sc-TCRseq, sc-REAPseq, and comprehensive immunophenotyping. The results of these assays will be used to identify the optimum expansion protocol as well as to inform on the mechanisms underlying γδ T cell cancer targeting.
Characterization of a novel type NK cell line KHYG-1 carrying EGFRvIII-specific CAR in glioblastoma cells
Authors: Morimoto Takayuki , Nakazawa Tsutomu , Natsume Atsushi , NIshimura Fumihiko , Matsuda Ryosuke , Murakami Toshiharu , Nakamura Mitsutoshi , Nakagawa Ichiro , Motoyama Yasushi , Park Young-Soo , Tsujimura Takahiro , Wakabayashi Toshihiko , Nakase Hiroyuki 
Published: January 2023

Abstract

Background
Natural killer (NK) cells are considered potential antitumor effector cells. The aim of this study was to establish a novel type of a chimeric antigen receptor (CAR)-NK cell line (CAR-KHYG-1) specific for epidermal growth factor receptor variant III (EGFRvIII)-expressing glioblastoma (GBM) cells and investigate the antitumor effects of EGFRvIII-specific-CAR-expressing KHYG-1 (EvCAR-KHYG-1) in vitro and in vivo.

Materials and Methods
EvCAR-KHYG-1 was established by lentiviral-based transduction of the EvCAR gene and magnetic bead-based purification of EvCAR-expressing NK cells. The antitumor effects of EvCAR-KHYG-1 were evaluated using growth inhibition and apoptosis detection assays on GBM cell lines (EGFRvIII-expressing and non-expressing U87MG glioma cells). Cytokine production was determined by cytometric beads array. In vivo xenograft assays were performed in NOG mice subcutaneously implanted with EGFRvIII-expressing U87MG (Ev-U87MG).

Results
EvCAR-KHYG-1 inhibited GBM cell-growth via apoptosis in an EGFRvIII-expression specific manner in vitro. In addition, EvCAR-KHYG-1 produced IL-2, INF-γ and TNF-α on Ev-U87MG cells. In vivo xenograft assays showed that EvCAR-KHYG-1 did not decrease the volume of subcutaneous tumors but inhibited the occupancy of cancer cells in the subcutaneous tumor.

Discussion
EvCAR-KHYG-1 enhanced antitumor effects and produced Th1-type cytokines on EGFRvIII-expressing GBM cells, but did not inhibit progression of subcutaneous GBM cell-derived tumors to induce a pseudo progression pathological phenotype.

Conclusion
A novel type CAR-NK cell line was established. In vivo experiments are required to determine ways it can be used to inhibit tumor progression.