A phase I/II randomized, double-blinded, placebo-controlled trial of a self-amplifying Covid-19 mRNA vaccine.

Coronavirus disease-19 (Covid-19) pandemic have demonstrated the importantance of vaccines in disease prevention. Self-amplifying mRNA vaccines could be another option for disease prevention if demonstrated to be safe and immunogenic. Phase 1 of this randomized, double-blinded, placebo-controlled trial (N = 42) assessed the safety, tolerability, and immunogenicity in healthy young and older adults of ascending levels of one-dose ARCT-021, a self-amplifying mRNA vaccine against Covid-19.

A single dose of self-transcribing and replicating RNA-based SARS-CoV-2 vaccine produces protective adaptive immunity in mice.

A self-transcribing and replicating RNA (STARR)-based vaccine (LUNAR-COV19) has been developed to prevent SARS-CoV-2 infection. The vaccine encodes an alphavirus-based replicon and the SARS-CoV-2 full-length spike glycoprotein. Translation of the replicon produces a replicase complex that amplifies and prolongs SARS-CoV-2 spike glycoprotein expression.

First-in-Human Phase 1 Study To Assess Safety, Tolerability, and Pharmacokinetics of a Novel Antifungal Drug, VL-2397, in Healthy Adults.

VL-2397 is an antifungal drug with a novel mechanism of action, rapid fungicidal activity, and potent activity against , including azole-resistant strains. VL2397-101, a phase 1 first-in-human, randomized, double-blind, placebo-controlled dose-escalation study, was conducted in healthy adults to determine the safety, tolerability, and pharmacokinetics (PK) of single and multiple ascending intravenous (i.v.

The Siderophore Transporter Sit1 Determines Susceptibility to the Antifungal VL-2397.

VL-2397 (previously termed ASP2397) is an antifungal, aluminum-chelating cyclic hexapeptide with a structure analogous to that of ferrichrome-type siderophores, whereby replacement of aluminum by iron was shown to decrease the antifungal activity of this compound. Here, we found that inactivation of an importer for ferrichrome-type siderophores, termed Sit1, renders resistant to VL-2397. Moreover, expression of the endogenous gene under the control of a xylose-inducible promoter (to uncouple expression from iron repression) combined with C-terminal tagging with a fluorescent protein demonstrated localization of Sit1 in the plasma membrane and xylose-dependent VL-2397 susceptibility.

Population Pharmacokinetic Modeling of VL-2397, a Novel Systemic Antifungal Agent: Analysis of a Single- and Multiple-Ascending-Dose Study in Healthy Subjects.

VL-2397, a novel, systemic antifungal agent, has potent and fungicidal activity against species. Plasma concentrations from a phase 1 study were used to construct a population pharmacokinetic (PPK) model for VL-2397. Healthy subjects aged 18 to 55 years received single doses of VL-2397, ranging from 3 to 1,200 mg, multiple daily doses of 300, 600, or 1,200 mg for 7 days, or 300 mg three times/day for 7 days followed by 600 mg daily for 21 days.

Preclinical evaluation of Vaxfectin-adjuvanted Vero cell-derived seasonal split and pandemic whole virus influenza vaccines.

Increasing the potency and supply of seasonal and pandemic influenza vaccines remains an important unmet medical need which may be effectively accomplished with adjuvanted egg- or cell culture-derived vaccines. Vaxfectin, a cationic lipid-based adjuvant with a favorable safety profile in phase 1 plasmid DNA vaccines trials, was tested in combination with seasonal split, trivalent and pandemic whole virus, monovalent influenza vaccines produced in Vero cell cultures. Comparison of hemagglutination inhibition (HI) antibody titers in Vaxfectin-adjuvanted to nonadjuvanted vaccinated mice and guinea pigs revealed 3- to 20-fold increases in antibody titers against each of the trivalent influenza virus vaccine strains and 2- to 8-fold increases in antibody titers against the monovalent H5N1 influenza virus vaccine strain.

Vaccination with Vaxfectin(®) adjuvanted SIV DNA induces long-lasting humoral immune responses able to reduce SIVmac251 Viremia.

We evaluated the immunogenicity and efficacy of Vaxfectin(®) adjuvanted SIV DNA vaccines in mice and macaques. Vaccination of mice with Vaxfectin(®) adjuvanted SIV gag DNA induced higher humoral immune responses than administration of unadjuvanted DNA, whereas similar levels of cellular immunity were elicited. Vaxfectin(®) adjuvanted SIVmac251 gag and env DNA immunization of rhesus macaques was used to examine magnitude, durability, and efficacy of humoral immunity.

Vaxfectin adjuvant improves antibody responses of juvenile rhesus macaques to a DNA vaccine encoding the measles virus hemagglutinin and fusion proteins.

DNA vaccines formulated with the cationic lipid-based adjuvant Vaxfectin induce protective immunity in macaques after intradermal (i.d.) or intramuscular (i.

A Vaxfectin(®)-adjuvanted HSV-2 plasmid DNA vaccine is effective for prophylactic and therapeutic use in the guinea pig model of genital herpes.

Here we describe studies in the guinea pig model of genital herpes to evaluate a novel plasmid DNA (pDNA) vaccine encoding the HSV-2 glycoprotein D and UL46 and UL47 genes encoding tegument proteins VP11/12 and VP 13/14 (gD2/UL46/UL47), formulated with a cationic lipid-based adjuvant Vaxfectin(®). Prophylactic immunization with Vaxfectin(®)-gD2/UL46/UL47 significantly reduced viral replication in the genital tract, provided complete protection against both primary and recurrent genital skin disease following intravaginal HSV-2 challenge, and significantly reduced latent HSV-2 DNA in the dorsal root ganglia compared to controls. We also examined the impact of therapeutic immunization of HSV-2 infected animals.

In vivo anti-tumor effect of expressing p14ARF-TAT using a FGF2-targeted cationic lipid vector.

Purpose: To develop an efficient and safe strategy to introduce a therapeutic gene into target cells in vivo for cancer therapy. The overall efficiency is based on proper selection of the delivery vector and expressed protein.

Methods: A plasmid coding for a specific cytotoxic fusion peptide, p14ARF-TAT, was evaluated in a xenograft mouse tumor model.

Vaxfectin: a versatile adjuvant for plasmid DNA- and protein-based vaccines.

Importance Of The Field: Many vaccines require the use of an adjuvant to achieve immunity. So far, few adjuvants have advanced successfully through clinical trials to become part of licensed vaccines. Vaxfectin® (Vical, CA, USA) represents a next-generation adjuvant with promise as a platform technology, showing utility with both plasmid DNA (pDNA) and protein-based vaccines.

In vitro cytotoxic activity of cationic paclitaxel nanoparticles on MDR-3T3 cells.

Cationic paclitaxel nanoparticles were developed and the possible delivery mechanism was explored by cellular uptake studies. In vitro cytotoxicity of paclitaxel-loaded nanoparticles was evaluated with NIH-3T3 cells and multidrug resistant MDR-3T3 cells (with active P-glycoprotein). The IC(50)s of paclitaxel nanoparticles, liposomal paclitaxel, and Taxol((R)) on NIH-3T3 cells were 0.

Regulation of adult hematopoietic stem cells fate for enhanced tissue-specific repair.

The ability to control the differentiation of adult hematopoietic stem cells (HSCs) would promote development of new cell-based therapies to treat multiple degenerative diseases. Systemic injection of NaIO(3) was used to ablate the retinal pigment epithelial (RPE) layer in C57Bl6 mice and initiate neural retinal degeneration. HSCs infected ex vivo with lentiviral vector expressing the RPE-specific gene RPE65 restored a functional RPE layer, with typical RPE phenotype including coexpression of another RPE-specific marker, CRALBP, and photoreceptor outer segment phagocytosis.

Development of peptide-targeted lipoplexes to CXCR4-expressing rat glioma cells and rat proliferating endothelial cells.

A peptide analog, 4-fluorobenzoyl-RR-(L-3-(2-naphthyl)alanine)-CYEK-(L-citrulline)-PYR-(L-citrulline)-CR, covalently linked to a phospholipid, was used for targeting a lipid-based gene delivery vehicle to CXCR4(+)-cells. Characterization of transfection activity was done in vitro using a transformed rat glioma cell line (RG2) that expresses CXCR4. The substitution of the targeting lipid at increasing mole percentages in the place of helper lipids yielded a progressive increase in reporter gene expression, reaching a maximum of 2.

IGF binding protein-3 regulates hematopoietic stem cell and endothelial precursor cell function during vascular development.

We asked whether the hypoxia-regulated factor, insulin-like growth factor binding protein-3 (IGFBP3), could modulate stem cell factor receptor (c-kit+), stem cell antigen-1 (sca-1+), hematopoietic stem cell (HSC), or CD34+ endothelial precursor cell (EPC) function. Exposure of CD34+ EPCs to IGFBP3 resulted in rapid differentiation into endothelial cells and dose-dependent increases in cell migration and capillary tube formation. IGFBP3-expressing plasmid was injected into the vitreous of neonatal mice undergoing the oxygen-induced retinopathy (OIR) model.

Feasibility of weekly HIV drug delivery to enhance drug localization in lymphoid tissues based on pharmacokinetic models of lipid-associated indinavir.

Purpose: Compare the simulated pharmacokinetics of lipid-associated and soluble indinavir (IDV) to determine the potential for greater control of virus replication in the lymphoid tissues.

Methods: Two-compartment mathematical models were developed to simulate the human pharmacokinetics of soluble and lipid-associated forms of IDV in the central compartment and the lymphoid tissue. The lipid-associated IDV model was then used to determine the minimum dosing schedule needed to attain central or lymph drug concentrations comparable to the soluble form.

Formation of plasmid-based transfection complexes with an acid-labile cationic lipid: characterization of in vitro and in vivo gene transfer.

Purpose: This study tests the hypothesis that gene transfer efficiency may be improved through the use of transiently stable transfection complexes that degrade within endosomal compartments and promote plasmid escape into the cytosol.

Method: An acid labile cationic lipid, O-(2R-1,2-di-O-(1'Z, 9'Z-octadecadienyl)-glycerol)-3-N-(bis-2-aminoethyl)-carbamate (BCAT), was designed, synthesized, and tested for enhanced gene transfer activity relative to non-labile controls.

Results: The O-alkenyl chains of BCAT were completely hydrolyzed after 4 h incubation in pH 4.