bluuebunny/crossref_metadata_2025_split huggingface dataset:
Pan-filovirus monoclonal antibody cocktail protects against lethal challenge with Marburg virus in non-human primates.
Authors: Prugar Laura I. , Dorosky Danielle , Holtsberg Frederick , Shulenin Sergey , Vu Hong , Howell Katy , Bakken Russell , Brannan Jennifer , Dye John M. , Aman M. Javad 
Published: January 2023

Abstract
While disregarded in the past, the use of antibody therapeutics in the treatment of filovirus infection has been gaining traction in recent years. Early studies in our lab with the treatment of non-human primates (NHPs) with polyclonal antibodies from convalescent NHPs demonstrated protection against challenges with a lethal dose of Ebola virus (EBOV). Successes with monoclonal antibody (mAb) cocktails such as ZMapp™ have encouraged the development of a cocktail that may be protective against multiple species of filovirus. This may ultimately allow for the prepositioning of a single cocktail in filovirus prone locations, rather than storing and maintaining multiple cocktails at each location. We have previously described three antibodies, FVM04 and CA45, which can neutralize multiple species of ebolavirus, and MR191, which can neutralize marburgviruses, and have shown efficacy in rodent and NHP models of filovirus disease. In this study, we evaluated the efficacy of a pan-ebolavirus cocktail (FVM04+CA45) in combination with the Marburg virus specific mAb MR191 in a pan-filovirus cocktail (FVM04+CA45+MR191), in the NHP model of Marburg virus disease. Both the pan-ebolavirus and pan-filovirus cocktails have been shown to be efficacious against lethal challenge with Sudan virus (SUDV) or EBOV in the rhesus macaque model. These data are the first to demonstrate protective efficacy of MR191 as part of a pan-filovirus cocktail against MARV in the NHP model of disease.
Comparing NKT cell therapy to oseltamivir phosphate (Tamiflu®) for controlling pandemic H1N1 influenza
Authors: Artiaga Bianca Libanori , Yang Guan , Loeb Julia , Richt Jürgen , Abbott Jeffrey , Lednicky John , Driver John 
Published: January 2023

Abstract
The continuing global burden of disease from influenza infections reveals an urgent need for new approaches that more efficiently protect and potentially avoid the emergence of drug-resistant strains over time. One strategy could be to therapeutically target natural killer T (NKT) cells, an innate-like lymphocyte subset capable of inducing potent antiviral immune responses. We previously reported that disease outcome is significantly improved when influenza-infected pigs are intranasally treated with the NKT cell superagonist α-galactosylceramide (αGC). Here, we compared the protective effects of αGC to 7DW8-5, an αGC derivative that promotes pro-inflammatory immune responses, as well as oseltamivir phosphate (Tamiflu®), a neuraminidase inhibitor used to treat and prevent influenza. A total of 20 pigs challenged with H1N1 A/California/04/2009 (CA04) (4 per group) were administered vehicle, 7DW8-5, or αGC and Tamiflu®, alone or in combination. Four other pigs were mock infected and vehicle treated. Symptoms, viral shedding and peripheral blood leukocytes were measured for 7 days post infection (dpi). Pigs were then euthanized to examine viral titers and immune responses in the airway and lymphoid organs. Pigs treated with αGC and 7DW8-5 but not Tamiflu restored weight gain of infected pigs to the level of un-infected animals. All treatments eliminated virus shedding by 2 dpi compared to infected and untreated pigs that continued to shed virus throughout the study. So far, our results suggest that NKT cell therapy is similar to Tamiflu® for reducing the severity and transmission of influenza infections in pigs. Thus, it may be possible to use NKT cell superagonists to limit the spread of influenza viruses amongst swine and humans.
Sequential and liver-targeting activation of T cells overcomes PDL1-mediated viral persistence
Authors: Liu Longchao , Peng Hua , Fu Yang-Xin 
Published: January 2023

Abstract
Breaking the immune tolerance induced by persistence of hepatitis B virus (HBV) to achieve viral clearance has been challenging due to the unique liver tolerant microenvironment. In this study, we explored whether liver-targeted therapeutic strategies are able to reverse liver tolerant microenvironment. Using an adenovirus vaccine expressing mouse LIGHT (CD258) and HBsAg (Ad-L-H) to target liver, we observed that immunization of Ad-L-H induced a robust antigen-specific T-cell response in naïve mice, especially accumulated in liver. By adoptively transferring primed splenocytes to carrier mice, we demonstrated that Ad-L-H but not conventional vaccine primed T cells were sufficient to control HBV in carrier mice lacking endogenous T cells. However, in immune competent carrier mice, adoptively transferred antigen-specific T cells expressed high level of PD1 and failed to clear HBV. Finally, sequential combination of liver targeted immunization with anti-PDL1 blockage resulted in protective immunity. In conclusion, targeting liver with sequential vaccine and checkpoint blockade is a novel strategy for controlling HBV in the tolerant host.
Development of novel C type lectin receptor agonists as Th17-inducing adjuvants for next generation TB vaccines
Authors: Smith Alyson J. , Buhl Cassandra , Child Robert , Ettenger George , Schoener Roman , Burkhart Daivd J. , Ryter Kendal , Evans Jay T. 
Published: January 2023

Abstract
Mycobacterium tuberculosis (Mtb), the causative pathogen of tuberculosis (TB), is one of the leading causes of death among adults. Extensively drug resistant TB is an emerging threat shown to be spreading as a result of transmission; as such it could benefit greatly from the development of a new, effective vaccine. Mtb is structurally composed of many immunostimulatory elements, including trehalose 6,6′-dimycolate (TDM). It has recently been shown that these cell wall lipids act to stimulate the immune system through engagement of the innate, C type lectin receptor Mincle. Because of their potent immune stimulating properties these compounds have come into focus as potential vaccine adjuvants but are limited due to toxicity concerns. Therefore, we created a library of synthetic trehalose-based compounds with varying structures and assessed their ability to modulate innate immunity in human and mouse immune cells. We optimized the acyl chain configuration for maximal immune stimulation in human cells and discovered divergent structure-activity-relationships between murine and human responses. We also assessed the ability of the compounds to induce a Th17-favorable cytokine profile from primary human cells. Finally, in vivo studies of the optimal in vitro determined compound demonstrated good Th17-inducing activity against a candidate Mtb recombinant antigen. Our data demonstrates the species and structure-specific activity of our novel compounds and clearly highlights the necessity of multi-species structure-activity evaluation for potential therapeutic molecules even at the earliest stages of investigation. As well this study demonstrates the clear potential for Mincle agonist compounds for use as vaccine adjuvants.
Use of GLA-nanoalum as an effective adjuvant for a therapeutic ID93 TB vaccine
Authors: Baldwin Susan L. , Larsen Sasha E. , Reese Valerie A. , Pecor Tiffany , Granger Brian , Khandhar Amit , Fox Christopher B. , Reed Steven G. , Coler Rhea N. 
Published: January 2023

Abstract
Tuberculosis (TB) caused by the intracellular bacterium Mycobacterium tuberculosis (Mtb) reportedly killed 1.3 million people in 2016 and is the leading cause of death caused by a single infectious organism. Increasingly worrisome is the ability of Mtb to develop extensive drug resistance. According to the 2017 WHO global TB report, there were 600,000 new rifampicin-resistant cases in 2016, and almost half a million cases with multiple drug resistant (MDR) TB. The development of new host-targeted therapeutic strategies that prevent the outgrowth of resistant mutants and/or modulate the immune response to combat Mtb infection and/or reduce disease pathology is one solution to prevent the generation of antibacterial resistance and treat drug resistant (DR)-TB. Here we evaluate a novel nanoalum adjuvant formulation containing a synthetic TLR4 agonist, glucopyranosyl lipid adjuvant (GLA), with our clinical ID93 protein as an immunotherapeutic vaccine. We show that immunotherapy with ID93+GLA-nanoalum is effective against Mtb when given as an adjunct to drug treatment in a mouse TB therapy model.
-Intranasal immunization with Bacillus anthracis spore antigens sensitizes mice to death from inhalational anthrax in a B cell-dependent manner
Authors: Weilhammer Dina R. , Dunkle Alexis D. , Fischer Nicholas O. , Gilmore Sean F. , Blanchette Craig , Peters Sandra , Boone Tyler , Lehmann Doerte , Hoeprich Paul , Driks Adam , Rasley Amy 
Published: January 2023

Abstract
There is considerable interest in developing an improved Bacillus anthracis (BA) vaccine that would provide broader, more rapid protection of naïve populations. Here, we investigate intranasal (i.n.) immunization as a method of inducing a mucosal immune response against BA spore antigens (BAAs) to facilitate early recognition and clearance. Nanolipoprotein particles (NLPs) were used as a nanoparticle platform for co-localized delivery of multiple spore proteins in conjunction with monophosphoryl lipid A (MPLA) adjuvant via i.n. immunization in mice. Immunization with BAA-MPLA-NLP constructs induced robust IgG and IgA responses in serum and in bronchoalveolar lavage. Surprisingly, when challenged with fully virulent BA, mice immunized with BAA-MPLA-NLPs died significantly faster than unimmunized mice. This hastened time to death following i.n. immunization was not antigen or adjuvant specific, nor related to the NLP platform, as similar results were observed using cholera toxin and CpG as adjuvants co-administered with BAAs in the absence of NLPs. Previous work has shown that B cells can traffic BA spores from the lungs to the lung-draining lymph nodes. Therefore, we investigated a role for B cells in sensitizing immunized mice to BA challenge. B cells in the lung increased following i.n. immunization, and depletion of B cells from immunized mice prior to challenge reversed the sensitized phenotype. Spore binding to B cells was enhanced by pre-incubation of spores with immune sera in a manner that was dependent upon the exosporium protein BclA. These results suggest i.n. immunization is not tenable as a protective strategy against inhalational anthrax due to an unexpected consequence of B cell expansion following immunization.
Novel cyclin D1-based DC vaccine inhibits TNBC tumor growth
Authors: Gibb Matthew James , Kroll Mitchell , Su Qingtai , Zurawski Sandy , Zurawski Gerard , Igyarto Botond 
Published: January 2023

Abstract
Triple-negative breast cancer (TNBC) is an aggressive histological subtype with limited treatment options and very poor prognosis after the failure of standard chemotherapeutic regimens. Immunotherapies activating the patient’s own immune system to fight various types of cancer are emerging as a powerful alternative and complement to standard chemotherapy and radiation therapy. Since dendritic cells (DCs) regulate every aspect of adaptive immune responses, we sought to generate DC vaccines that target TNBC. Recently, we found that targeting CD40 on DCs induced superior anti-tumor cytotoxic T cell responses compared to targeting other DC receptors. In the quest to find tumor-specific (overexpressed) antigens, we recently identified the cell cycle protein, cyclin D1, as a potential antigen for a DC-targeting-based vaccine against TNBC. Cyclin D1 is overexpressed in many tumors, including TNBC, and we found that cyclin D1-specific effector T cells could be readily expanded from the blood of TNBC patients or normal human donors. To test whether targeting cyclin D1 to DCs through CD40 can control tumor growth, we implemented a novel TNBC mouse model in our laboratory. This consists of a transgenic mouse expressing human CD40 in a C57BL/6 background and a recently characterized syngeneic EO771-LMB metastatic breast cancer cell line with TNBC characteristics. We found that in a therapeutic setting, targeting cyclin D1 (highly conserved between mice and humans) to DCs through CD40 led to significant inhibition of tumor growth in mice.
Thus, these data suggest that cyclin D1-based DC-targeting vaccines could be a novel immunotherapeutic candidate for TNBC.
Augmenting vaccine immunogenicity through the use of natural human anti-Rha antibodies and monoclonal Fc domains
Authors: Hossain Md Kamal , Vartak Abhishek , Sucheck Steven , Wall Katherine Ann 
Published: January 2023

Abstract
In order to obtain an effective cellular and humoral immune response, a vaccine construct has to be captured, processed and presented by antigen presenting cells (APCs) through their major histocompatibility complex (MHC) molecules. One effective way to enhance antigen presentation is through an antibody-dependent antigen uptake mechanism by targeting FcγR receptors of APCs that can bind with the Fc portion of an immune complexed antibody. Anti-Rhamnose (Anti-Rha) antibody is among the most common natural anti-carbohydrate antibodies present in human serum. Therefore, rhamnose can be utilized as a targeting moiety for a rhamnose-containing vaccine to prepare an effective vaccine formulation. Binding rhamnose of a rhamnose-containing vaccine with murine anti-Rha antibody has previously been proven effective for capturing and processing of antigen by APCs via stimulatory Fc receptors. We show that human anti-Rha antibodies enhance the uptake of rhamnose-containing antigen by murine APCs in vitro. In-vivo, passive transfer of human anti-Rha antibodies into mice improves the priming of T cells to Rha-antigen. We synthesized and tested an anti-cancer vaccine containing a lipoglycopeptide cancer antigen in a Rha-bearing liposome and demonstrated improved immunogenicity. Also, we showed that direct conjugation of the Fc domain of an antibody to a liposomal vaccine instead of rhamnose can be a good approach for efficient uptake and presentation, as we can bypass the need for anti-Rha antibodies. A liposomal vaccine bearing IgG3Fc has been found to be equally effective as the Rha-vaccine at priming CD4+ T cells. Priming of CD8+ T cells for IFN-γ release and tumor cytotoxicity was promising in comparison to anti-Rha antibody targeting.
Efficient generation of MCC oncoprotein-specific CD4+ T cells for potential adoptive immunotherapy
Authors: Davies Sarah I. , Chang Mark J. , Whitehill Gregory , Koklanaris Eleftheria , Ito Sawa , Brownell Isaac , Buck Christopher , Barrett John , Muranski Pawel 
Published: January 2023

Abstract
Merkel Cell Carcinoma (MCC) is an aggressive skin tumor caused by Merkel Cell Polyomavirus (MCV) in ~80% of cases that responds poorly to standard chemotherapies. Virus positive tumors have a low mutational burden, and are driven by alternatively spliced T-antigens (TAG), small T (sT) and truncated large T antigen (LTT). These intracellular proteins are constitutively expressed in MCC tumors and are required for tumor survival. We hypothesized that MCV TAG can be targeted by cytotoxic T lymphocytes for potential use as an adoptive T cell immunotherapy to treat MCC. Peripheral blood T cells were stimulated with autologous dendritic cells pulsed with overlapping peptide libraries derived from MCV sT and LTT in the presence of a pro-inflammatory cytokine cocktail (IL-1β, IL-6, IL-7, IL-15, IL-21, IL-23, and TGFβ). This culturing method increases yields by 6 fold of antigen-specific T cells that produce TNFα and IFNγ, from both MCC subjects and healthy donors. These expanded TAG-specific cells are predominately CD4+ cells of a memory phenotype that expresses low levels of PD-1, but no expression of IL-17A. Growing evidence suggests that CD4+ Th1 and Th17 cells can have potent anti-tumor activities, especially against MHC class II positive tumors. Three virus-positive and two virus-negative MCC cell lines were tested for HLA-DR expression by flow cytometry. We found that MCC cell lines, both virus positive and virus negative, can be induced to express HLA-DR in a dose-dependent fashion in response to IFNγ in vitro. These results suggest that MCC virus positive tumors can likely be directly recognized and destroyed by adoptively transferred Th1 or Th17 CD4+ T cells and offers a promising avenue for adoptive T cell immunotherapy as a MCC treatment.
Gp96-Ig/Costimulator Combination Platform Improves T Cell Priming, Enhances Immunity and Memory
Authors: Gonzalez Louis E. , Giffin Louise , Rose Jason , Fromm George , Da Silva Suresh , Schreiber Taylor H. , Jasuja Rahul , Hutchins Jeff 
Published: January 2023

Abstract
The recent excitement in the field of immuno-oncology has been driven largely by the clinical success of checkpoint inhibitors. However, 60–90% of patients are still failing to respond to these therapies. It is widely believed that approaches targeting multiple facets of the immune system, including combinations with checkpoint inhibition and costimulator agonism, will be required to improve patient outcomes. Heat Biologics has developed a next generation T cell activating platform called ComPACT (COMbination Pan-Antigen Cytotoxic Therapy) that incorporates expression of a tumor antigen chaperone (gp96-Ig) and a T cell costimulator (OX40L-Ig) within a single vaccine cell line to effectively prime and boost antigen-specific CD4+ and CD8+ T cells. Furthermore, ComPACT stimulates activation of CD127+KLRG1- memory precursor cells, and lacks the toxic systemic inflammatory cytokine production and proliferation of non-specific CD4+ T cells and Tregs observed with systemic administration of OX40 agonist antibodies. ComPACT also led to high frequencies of IFNγ+, TNFα+, granzyme B+ and IL-2+ antigen-specific CD8+ T cells at both priming and boosting.
Here, we have further assessed ImPACT and ComPACT-OX40L in combination with the anti-PD1 checkpoint inhibitor and with expression of an additional cell-secreted T cell costimulator, TL1A-Ig. We show that these treatments synergize effectively to amplify antigen-specific T cells and program a memory response. The combination of ComPACT-OX40L/TL1A with αPD1 or αPD-L1 may therefore translate into an efficacious approach generate long lasting memory in immuno-oncology settings.
Alum adjuvant is more effective than MF59 in promoting early germinal center formation in response to peptide-protein conjugates and enhancing efficacy of candidate vaccines against opioid abuse in adult and old mice
Authors: Pravetoni Marco , Robinson Christine , Schmiel Shirdi E. , Mueller Daniel L. 
Published: January 2023

Abstract
Heroin and prescription opioid abuse and overdose have been declared a national emergency in the United States. Compared to current medications, vaccines provide a complementary long-lasting, safe and cost-effective therapeutic strategy. Since the efficacy of vaccines against drugs of abuse is contingent upon achieving high antibody levels in immunized subjects, this study tested whether vaccines against oxycodone were more effective when formulated in the well-established aluminum hydroxide or the squalene-based oil-in-water emulsion MF59 adjuvant. Alum was more effective in inducing early expansion of hapten-specific germinal center (GC) B cells, and in inducing oxycodone-specific serum IgG antibodies that were effective in blocking oxycodone-induced motor activity in BALB/c adult mice. Alum was also more effective than MF59 in promoting early, but not late, differentiation of antigen-specific MHCII-restricted GC-Tfh cells in C57Bl/6 adult mice immunized with a model peptide-protein conjugate vaccine. Finally, alum and MF59 adjuvants displayed equivalent stimulation of hapten-specific B cells and peptide-specific T cells in old mice. Alum was significantly more effective, or at least equivalent to MF59 in eliciting protective responses against the highly-abused prescription opioid oxycodone and inducing early germinal center formation in response to hapten and peptide antigens in both adult and aging mice.
Development of a mesothelin-based prophylactic vaccine against ovarian cancer
Authors: Scholler Nathalie , Sharma Khushboo , Yin Catherine , Kamat Kalika , Fernando Romaine Ingrid , Sei Shizuko , Shoemaker Robert H. , Stein Paul L. , Sambucetti Lidia 
Published: January 2023

Abstract
Mesothelin is a tumor-associated antigen overexpressed in ovarian cancer and normally expressed by mesothelial linings. While mesothelin function remains to be fully elucidated, the lack of phenotype of mesothelin-knockout mice makes it plausible that mesothelin can safely serve as a vaccine target. We designed a new vaccination strategy based on mesothelin targeting with activation of type I IFN signaling via cyclic dinucleotides (CDN). Vaccines first combined human mesothelin protein with alum- vs. CDN-based adjuvants. C57Bl/6 mice received a priming immunization followed by 2 boosts; two weeks later, immunized mice were injected orthotopically with luciferase-transduced mouse ovarian cancer cells (Luc-ID8). More than 2/3 of the mesothelin/CDN-immunized mice were protected against invasive cancer and presented increased cytotoxic T cells (CTL) and plasmacytoid dendritic cells in spleens. Effector memory T cells were also increased and MDSC were profoundly decreased in peritoneal lavages after immunization with mesothelin +/− CDN compared with all the other groups. IFNγ ELISPOT assays performed with protected animal splenocytes stimulated with mesothelin peptides identified 2 immunogenic regions. We next tested a peptide-based subunit vaccine derived from mouse mesothelin sequence. Immunization and 2 boosts of 25-mer peptides with CDN were sufficient to mount an immune response against 2 overlapping mouse mesothelin peptides. Immunizations with peptide pools mapping in the immunogenic regions are currently assessed for protection against Luc-ID8 growth and progression. Peptide-based prophylactic vaccination against ovarian cancer may be possible in combination with adjuvants that trigger cellular immunity.
Development of adjuvant scaffolds from small molecule contact allergens
Authors: Kimani Flora , Kim Seong-Min , Esser-Kahn Aaron 
Published: January 2023

Abstract
Small molecule contact allergens are an understudied class of immunostimulatory compounds that have the potential of being developed into adjuvants. Vaccines remain the most effective tool in preventing disease and adjuvants serve to make vaccines more efficacious by activating the innate immunity. To develop contact allergens molecules as adjuvants, we began by first elucidating the mechanism of allergic contact hypersensitivity. Using contact allergens and their analogues we wanted to define the structural elements necessary for the activation of immune cells. Our initial experiments sought to correlate sensitization potential to chemical reactivity where the latter influenced the initial phase of sensitization, hapten formation. We showed that there is a non-linear relationship between the rate of reactivity of the compounds and the ability to induce IL-8 expression on THP-1 cells. This result suggested that contact allergens modify specific target proteins and hence sterics, as well as electronic nature of the contact allergen, play an important role. Using the insights from this initial study we are developing probes that will allow the identification of the hapten-protein complex formed during the sensitization process in order to understand the recognition mechanism of this complex to immune cell receptors. We envision this study as the first step towards the development of potent adjuvants from contact allergen scaffolds. Additionally, the elucidation of the protein targets of small molecule contact allergens will reveal therapy avenues for the treatment of allergic contact hypersensitivity.