Microfluidic-Chip-Based Formulation and In Vivo Evaluations of Squalene Oil Emulsion Adjuvants for Subunit Vaccines.

Background: Adjuvants play a crucial role in improving the immunogenicity of various antigens in vaccines. Squalene-in-water emulsions are clinically established vaccine adjuvants that improve immune responses, particularly during a pandemic. Current manufacturing processes for these emulsion adjuvants include microfluidizers and homogenizers and these processes have been used to produce emulsion adjuvants to meet global demands during a pandemic.

In vivo evolution of env in SHIV-AD8-infected rhesus macaques after AAV-vectored delivery of eCD4-Ig.

eCD4-immunoglobulin (Ig) is an HIV entry inhibitor that mimics the engagement of both CD4 and CCR5 with the HIV envelope (Env) protein, a property that imbues it with remarkable potency and breadth. However, env is exceptionally genetically malleable and can evolve to escape a wide variety of entry inhibitors. Here we document the evolution of partial eCD4-Ig resistance in SHIV-AD8-infected rhesus macaques (RMs) treated with adeno-associated virus vectors encoding eCD4-Ig.

Synthesis of Janus All- Tetrafluorocyclohexanes Carrying 1,4-Diether Motifs.

Nucleophilic aromatic substitutions (SAr) of alkoxides on pentafluoroaryl ethers are explored as a first step in a synthesis sequence to generate all- 2,3,5,6-tetrafluorocyclohexyl-1,4-dialkyl ethers . The SAr reaction was explored both experimentally and theoretically to rationalize // selectivities. -Butyl deprotection of products followed by phenol alkylations introduces versatility to the synthesis.

Exploring Fluorinase Substrate Tolerance at C-2 of SAM.

The fluorinase enzyme (EC 2.5.1.

Conformational Analysis Explores the Role of Electrostatic Nonclassical CF···HC Hydrogen Bonding Interactions in Selectively Halogenated Cyclohexanes.

The conformational equilibria of selectively halogenated cyclohexanes are explored both experimentally (VT-NMR) for 1,1,4,-trifluorocyclohexane and by computational analysis (M06-2X/aug-cc-pVTZ level), with the latter approach extending to a wider range of more highly fluorinated cyclohexanes. Perhaps unexpectedly, is preferred over the conformation by Δ = 1.06 kcal mol, contradicting the accepted norm for substituents on cyclohexanes.

The scientific journey of a novel adjuvant (AS37) from bench to bedside.

A decade ago, we described a new approach to discover next generation adjuvants, identifying small-molecule immune potentiators (SMIPs) as Toll-like receptor (TLR)7 agonists. We also optimally formulated these drugs through adsorption to aluminum salts (alum), allowing them to be evaluated with a range of established and early-stage vaccines. Early proof-of-concept studies showed that a TLR7 agonist (TLR7a)-based SMIP, when adsorbed to alum, could perform as an effective adjuvant for a variety of different antigens, in both small and large animals.

3'--β-Glucosyl-4',5'-didehydro-5'-deoxyadenosine Is a Natural Product of the Nucleocidin Producers and .

3'--β-Glucosyl-4',5'-didehydro-5'-deoxyadenosine is identified as a natural product of and . It is also generated by direct β-glucosylation of 4',5'-didehydro-5'-deoxyadenosine with the enzyme NucGT. The intact incorporation of oxygen-18 and deuterium isotopes from (±)[1-O,1-H]-glycerol into C-5' of nucleocidin and its related metabolites precludes 3'--β-glucosyl-4',5'-didehydro-5'-deoxyadenosine as a biosynthetic precursor to nucleocidin .

Aryl (β,β',β″-Trifluoro)--butyl: A Candidate Motif for the Discovery of Bioactives.

The (β,β',β″-trifluoro)--butyl (TFTB) group has received very little attention in the literature. This work presents a direct synthesis of this group and explores its properties. The TFTB group arises when the methyl groups of a -butyl moiety are exchanged for fluoromethyl groups.

Aluminum Adjuvants-'Back to the Future'.

Aluminum-based adjuvants will continue to be a key component of currently approved and next generation vaccines, including important combination vaccines. The widespread use of aluminum adjuvants is due to their excellent safety profile, which has been established through the use of hundreds of millions of doses in humans over many years. In addition, they are inexpensive, readily available, and are well known and generally accepted by regulatory agencies.

Disordered alcohol and substance use in Irish farmers: A cross-sectional survey.

Purpose: Farming is a high-pressure occupation. Populations of farmers face significant health risks, including injury, mental illness, and in some cases, heavy alcohol use. However, there is little research on farmers' use of substances beyond alcohol.

Broadly neutralizing antibodies against sarbecoviruses generated by immunization of macaques with an AS03-adjuvanted COVID-19 vaccine.

The rapid emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants that evade immunity elicited by vaccination has placed an imperative on the development of countermeasures that provide broad protection against SARS-CoV-2 and related sarbecoviruses. Here, we identified extremely potent monoclonal antibodies (mAbs) that neutralized multiple sarbecoviruses from macaques vaccinated with AS03-adjuvanted monovalent subunit vaccines. Longitudinal analysis revealed progressive accumulation of somatic mutation in the immunoglobulin genes of antigen-specific memory B cells (MBCs) for at least 1 year after primary vaccination.

[3-Meth-oxy-5-(meth-oxy-carbon-yl)isoxazol-4-yl](4-meth-oxy-phen-yl)iodo-nium 2,2,2-tri-fluoro-acetate.

A new isoxazole-based iodo-noium salt, CHINO ·CFO , has been synthesized and structurally characterized. In the crystal, ions are linked by short I⋯O contacts to form a neutral tetra-ion aggregate. These combine with C-H⋯F and C-H⋯O inter-actions to form double-layered two-dimensional sheets in the (001) plane.

The Emergence and Properties of Selectively Fluorinated 'Janus' Cyclohexanes.

This account describes the evolution of a research programme that started by linking fluoromethylene (-CHF-) groups along aliphatic chains and then progressing to alicyclic rings with contiguous fluorine atoms. Different stereoisomers of aliphatic chains tend to adopt low polarity conformations. In order to force polar conformations, the programme began to address ring systems and in particular cyclohexanes, to restrain conformational freedom and co-aligned C-F bonds.

MRI/PET multimodal imaging of the innate immune response in skeletal muscle and draining lymph node post vaccination in rats.

The goal of this study was to utilize a multimodal magnetic resonance imaging (MRI) and positron emission tomography (PET) imaging approach to assess the local innate immune response in skeletal muscle and draining lymph node following vaccination in rats using two different vaccine platforms (AS01 adjuvanted protein and lipid nanoparticle (LNP) encapsulated Self-Amplifying mRNA (SAM)). MRI and FDG PET imaging were performed temporally at baseline, 4, 24, 48, and 72 hr post Prime and Prime-Boost vaccination in hindlimb with Cytomegalovirus (CMV) gB and pentamer proteins formulated with AS01, LNP encapsulated CMV gB protein-encoding SAM (CMV SAM), AS01 or with LNP carrier controls. Both CMV AS01 and CMV SAM resulted in a rapid MRI and PET signal enhancement in hindlimb muscles and draining popliteal lymph node reflecting innate and possibly adaptive immune response.

Extremely potent pan-sarbecovirus neutralizing antibodies generated by immunization of macaques with an AS03-adjuvanted monovalent subunit vaccine against SARS-CoV-2.

Unlabelled: The rapid emergence of SARS-CoV-2 variants that evade immunity to vaccination has placed a global health imperative on the development of therapeutic countermeasures that provide broad protection against SARS-CoV-2 and related sarbecoviruses. Here, we identified extremely potent pan-sarbecovirus antibodies from non-human primates vaccinated with an AS03 adjuvanted subunit vaccine against SARS-CoV-2 that recognize conserved epitopes in the receptor binding domain (RBD) with femtomolar affinities. Longitudinal analysis revealed progressive accumulation of somatic mutation in the immunoglobulin genes of antigen-specific memory B cells for at least one year following primary vaccination.

Maturation of Aluminium Adsorbed Antigens Contributes to the Creation of Homogeneous Vaccine Formulations.

Although aluminium-based vaccines have been used for almost over a century, their mechanism of action remains unclear. It is established that antigen adsorption to the adjuvant facilitates delivery of the antigen to immune cells at the injection site. To further increase our understanding of aluminium-based vaccines, it is important to gain additional insights on the interactions between the aluminium and antigens, including antigen distribution over the adjuvant particles.

A Self-Emulsified Adjuvant System Containing the Immune Potentiator Alpha Tocopherol Induces Higher Neutralizing Antibody Responses than a Squalene-Only Emulsion When Evaluated with a Recombinant Cytomegalovirus (CMV) Pentamer Antigen in Mice.

The development of new vaccine adjuvants represents a key approach to improvingi the immune responses to recombinant vaccine antigens. Emulsion adjuvants, such as AS03 and MF59, in combination with influenza vaccines, have allowed antigen dose sparing, greater breadth of responses and fewer immunizations. It has been demonstrated previously that emulsion adjuvants can be prepared using a simple, low-shear process of self-emulsification (SE).

Contribution of Hyperconjugation and Inductive Effects to the -anomeric Effect in 4-Substituted Methoxycyclohexanes.

The importance of electrostatic nonconventional hydrogen bonds (NCHBs) to the -anomeric effect of 4-substituted methoxycyclohexanes is evaluated using theory [natural bond orbital (NBO)] to deconvolute electrostatic from other contributing effects. There is an interesting interplay between σ → σ hyperconjugation and the electropositive charge on 3,5-axial hydrogens (H). In essence, better σ (or π) acceptors increase the charge on 3,5-CH, which in turn strengthens CH···OMe NCHB interactions.

Systems analysis of human responses to an aluminium hydroxide-adsorbed TLR7 agonist (AS37) adjuvanted vaccine reveals a dose-dependent and specific activation of the interferon-mediated antiviral response.

The candidate Adjuvant System AS37 contains a synthetic toll-like receptor agonist (TLR7a) adsorbed to alum. In a phase I study (NCT02639351), healthy adults were randomised to receive one dose of licensed alum-adjuvanted meningococcal serogroup C (MenC-CRM) conjugate vaccine (control) or MenC-CRM conjugate vaccine adjuvanted with AS37 (TLR7a dose 12.5, 25, 50 or 100 µg).

Identification of Genes Essential for Fluorination and Sulfamylation within the Nucleocidin Gene Clusters of Streptomyces calvus and Streptomyces virens.

The gene cluster in Streptomyces calvus associated with the biosynthesis of the fluoro- and sulfamyl-metabolite nucleocidin was interrogated by systematic gene knockouts. Out of the 26 gene deletions, most did not affect fluorometabolite production, nine abolished sulfamylation but not fluorination, and three precluded fluorination, but had no effect on sulfamylation. In addition to nucI, nucG, nucJ, nucK, nucL, nucN, nucO, nucQ and nucP, we identified two genes (nucW nucA), belonging to a phosphoadenosine phosphosulfate (PAPS) gene cluster, as required for sulfamyl assembly.