Optimization of the Synthesis and Conjugation of the Methyl Rhamnan Tip of A-Band Polysaccharide and Immunogenicity Evaluation for the Continued Development of a Potential Glycoconjugate Vaccine.

is an antimicrobial-resistant bacterium that has no vaccine approved for human use. Additionally, it has been identified by the World Health Organization as a priority pathogen for novel vaccines and therapeutic development. We previously developed a synthetic mimic of the A-band polysaccharide tip that showed promise in terms of immunogenicity for use as a glycoconjugate vaccine.

Synthesis and Immunogenicity of a Methyl Rhamnan Pentasaccharide Conjugate from A-Band Polysaccharide.

was added to the World Health Organization's priority pathogen list for research and development of new antibiotics in 2017. Alongside the development of new antibiotics to fight antimicrobial-resistant , vaccines would be an appealing addition to the toolbox health professionals have against this bacteria, which causes life-threatening respiratory infections. Recently, the structure of a novel immunogenic terminal carbohydrate moiety on the cell surface of was elucidated, consisting of a 3--methyl (1→4)-α-d-rhamnan pentasaccharide.

d--β-d-heptose Phosphate 7--Modifications.

Pathogen-associated molecular patterns activate the immune system via pattern recognition receptors. Recently, newly discovered pathogen-associated molecular patterns, d--β-d-heptose phosphate and d--β-d-heptose 1,7-biphosphate, were shown to induce a TRAF-interacting protein with a forkhead-associated domain-dependent immune response in human embryonic kidney cells and colonic epithelial cells. Concurrently, ADP-heptose was shown to bind α-kinase 1 and activate TIFA via phosphorylation leading to an immune cascade to ultimately activate NF-κB.

Assessment of stability of sulphated lactosyl archaeol archaeosomes for use as a vaccine adjuvant.

Archaeosomes, composed of sulphated lactosyl archaeol (SLA) glycolipids, have been proven to be an effective vaccine adjuvant in multiple preclinical models of infectious disease or cancer. In addition to efficacy, the stability of vaccine components including the adjuvant is an important parameter to consider when developing novel vaccine formulations. To properly evaluate the potential of SLA glycolipids to be used as vaccine adjuvants in a clinical setting, a comprehensive evaluation of their stability is required.

Archaeal glycolipid adjuvanted vaccines induce strong influenza-specific immune responses through direct immunization in young and aged mice or through passive maternal immunization.

Vaccine induced responses are often weaker in those individuals most susceptible to infection, namely the very young and the elderly, highlighting the need for safe and effective vaccine adjuvants. Herein we evaluated different archaeosome formulations as an adjuvant to the H1N1 influenza hemagglutinin protein and compared immune responses (anti-HA IgG and hemagglutination inhibition assay titers) as well as protection to an influenza A virus (strainA/PuertoRico/8/1934H1N1)homologous challenge to those generated using a squalene-based oil-in-water nano-emulsion, AddaVax™ in a murine model. The impact of age (young adult vs aged) on vaccine induced immune responses as well as the protection in pups due to the transfer of maternal antibodies was measured.

A comparison of the immune responses induced by antigens in three different archaeosome-based vaccine formulations.

Archaeosomes are liposomes composed of natural or synthetic archaeal lipids that can be used as adjuvants to induce strong long-lasting humoral and cell-mediated immune responses against entrapped antigen. However, the entrapment efficiency of antigen within archaeosomes constituted using standard liposome forming methodology is often only 5-40%. In this study, we evaluated different formulation methods using a simple semi-synthetic archaeal lipid (SLA, sulfated lactosyl archaeol) and two different antigens, ovalbumin (OVA) and hepatitis B surface antigen (HBsAg).

Sulfated archaeol glycolipids: Comparison with other immunological adjuvants in mice.

Archaeosomes are liposomes traditionally comprised of total polar lipids (TPL) or semi-synthetic glycerolipids of ether-linked isoprenoid phytanyl cores with varied glyco- and amino-head groups. As adjuvants, they induce robust, long-lasting humoral and cell-mediated immune responses and enhance protection in murine models of infectious disease and cancer. Traditional total polar lipid (TPL) archaeosome formulations are relatively complex and first generation semi-synthetic archaeosomes involve many synthetic steps to arrive at the final desired glycolipid composition.

On the Ability of Formaldehyde to Act as a Tethering Catalyst in Water.

The low concentration issue is a fundamental challenge when it comes to prebiotic chemistry, as macromolecular systems need to be assembled via intermolecular reactions, and this is inherently difficult in dilute solutions. This is especially true when the reactions are challenging, and reactions that proceeded more rapidly could have dictated chemical evolution. Herein we establish that formaldehyde is capable of catalyzing, via temporary intramolecularity, a challenging reaction in water at low concentrations, thus providing an alternative to other approaches that can either lead to higher concentrations or higher effective molarities.

Electrocatalytic generation of H from neutral water in acetonitrile using manganese polypyridyl complexes with ligand assistance.

A Mn(i) tris(2-pyridylmethyl)amine complex fac-[Mn(κ-tpa) (CO)]OTf carries out electrocatalytic hydrogen evolution from neutral water in acetonitrile. Bulk electrocatalytic studies showed that the catalyst functions with a moderate Faradaic efficiency and turn over frequency. DFT computations support the role of the tpa ligand as a shuttle to transfer of protons to the metal center.