Research Progress of Aluminum Phosphate Adjuvants and Their Action Mechanisms.

Although hundreds of different adjuvants have been tried, aluminum-containing adjuvants are by far the most widely used currently. It is worth mentioning that although aluminum-containing adjuvants have been commonly applied in vaccine production, their acting mechanism remains not completely clear. Thus far, researchers have proposed the following mechanisms: (1) depot effect, (2) phagocytosis, (3) activation of pro-inflammatory signaling pathway NLRP3, (4) host cell DNA release, and other mechanisms of action. Having an overview on recent studies to increase our comprehension on the mechanisms by which aluminum-containing adjuvants adsorb antigens and the effects of adsorption on antigen stability and immune response has become a mainstream research trend. Aluminum-containing adjuvants can enhance immune response through a variety of molecular pathways, but there are still significant challenges in designing effective immune-stimulating vaccine delivery systems with aluminum-containing adjuvants. At present, studies on the acting mechanism of aluminum-containing adjuvants mainly focus on aluminum hydroxide adjuvants. This review will take aluminum phosphate as a representative to discuss the immune stimulation mechanism of aluminum phosphate adjuvants and the differences between aluminum phosphate adjuvants and aluminum hydroxide adjuvants, as well as the research progress on the improvement of aluminum phosphate adjuvants (including the improvement of the adjuvant formula, nano-aluminum phosphate adjuvants and a first-grade composite adjuvant containing aluminum phosphate). Based on such related knowledge, determining optimal formulation to develop effective and safe aluminium-containing adjuvants for different vaccines will become more substantiated.

Design of a Novel and Potent Multi-Epitope Chimeric Vaccine against Human Papillomavirus (HPV): An Immunoinformatics Approach.

In the current era, our experience is full of pandemic infectious agents that no longer threaten the major local source but the whole globe. One such infectious agent is HPV, a sexually transmitted disease that can cause various clinical disorders, including benign lesions and cervical cancer. Since available vaccines still need further improvements in order to enhance efficacy, our goal was to design a chimeric vaccine against HPV using an immunoinformatics approach. For designing the vaccine, the sequence of HPV was retrieved, and then phylogenetic analysis was performed. Several CTL epitopes, HTL epitopes, and LBL epitopes were all predicted using bioinformatics tools. After checking the antigenicity, allergenicity, and toxicity scores, the best epitopes were selected for vaccine construction, and then physicochemical and immunological properties were analyzed. Subsequently, vaccine 3D structure prediction, refinement, and validation were performed. Molecular docking and dynamics simulation techniques were used to explore the interactions between the Toll-like receptor 2 and the modeled vaccine construct. To ensure the vaccine protein was expressed at a higher level, the construct was computationally cloned into the pET28a (+) plasmid. The molecular docking and simulation results showed that our designed vaccine is stable, of immunogenic quality, and has considerable solubility. Through in silico immune simulation, it was predicted that the designed polypeptide vaccine construct would trigger both humoral and cellular immune responses. The developed vaccine showed significant affinity for the TLR2 receptor molecule. However, additional laboratory research is required to evaluate its safety and efficacy.

RIP1 kinase inhibitor halts the progression of an immune-induced demyelination disease at the stage of monocyte elevation.

Demyelination in the central nervous system (CNS) underlies many human diseases, including multiple sclerosis (MS). We report here the findings of our study of the CNS demyelination process using immune-induced [experimental autoimmune encephalomyelitis (EAE)] and chemical-induced [cuprizone (CPZ)] mouse models of demyelination. We found that necroptosis, a receptor-interacting protein 3 (RIP3) kinase and its substrate mixed lineage kinase domain-like protein (MLKL)-dependent cell death program, played no role in the demyelination process, whereas the MLKL-dependent, RIP3-independent function of MLKL in the demyelination process initially discovered in the peripheral nervous system in response to nerve injury, also functions in demyelination in the CNS in these models. Moreover, a receptor-interacting protein 1 (RIP1) kinase inhibitor, RIPA-56, blocked disease progression in the EAE-induced model but showed no effect in the CPZ-induced model. It does so most likely at a step of monocyte elevation downstream of T cell activation and myelin-specific antibody generation, although upstream of breakdown of the blood-brain barrier. RIP1-kinase dead knock-in mice shared a similar result as mice treated with the RIP1 inhibitor. These results indicate that RIP1 kinase inhibitor is a potential therapeutic agent for immune-mediated demyelination diseases that works by prevention of monocyte elevation, a function previously unknown for RIP1 kinase.

Mixed Lineage Kinase Domain-like Protein MLKL Breaks Down Myelin following Nerve Injury.

Successful regeneration of severed peripheral nerves requires the breakdown and subsequent clearance of myelin, tightly packed membrane sheaths of Schwann cells that protect nerve fibers and harbor nerve growth-inhibitory proteins. How Schwann cells initiate myelin breakdown in response to injury is still largely unknown. Here we report that, following sciatic nerve injury, MLKL, a pseudokinase known to rupture cell membranes during necroptotic cell death, is induced and targets the myelin sheath membrane of Schwann cells to promote myelin breakdown. The function of MLKL in disrupting myelin sheaths requires injury-induced phosphorylation of serine 441, an activation signal distinct from the necroptosis-inducing phosphorylation by RIP3 kinase. Mice with Mlkl specifically knocked out in Schwann cells showed delayed myelin sheath breakdown. Lack of MLKL reduced nerve regeneration following injury, whereas overexpression of MLKL accelerated myelin breakdown and promoted the regeneration of axons.