An mRNA vaccine candidate encoding H5HA clade 2.3.4.4b protects mice from clade 2.3.2.1a virus infection.

Highly pathogenic avian influenza (HPAI) H5 viruses from different clades have been circulating globally, threatening wild/domestic birds and mammals. Given frequent spillovers and high mortality among mammals, coupled with our inability to predict which clade of H5 virus has pandemic potential, cross-clade protective HPAI H5 vaccines are urgently needed. Here, we demonstrate the applicability of a lipid nanoparticle-based mRNA vaccine modality to induce cross-protective immunity against lethal HPAI virus infection.

An mRNA vaccine encoding the SARS-CoV-2 receptor-binding domain protects mice from various Omicron variants.

Here, we assessed the efficacy of a lipid nanoparticle-based mRNA vaccine candidate encoding the receptor-binding domain (LNP-mRNA-RBD) in mice. Mice immunized with LNP-mRNA-RBD based on the ancestral strain (ancestral-type LNP-mRNA-RBD) showed similar cellular responses against the ancestral strain and BA.5, but their neutralizing activity against BA.

DS-5670a, a novel mRNA-encapsulated lipid nanoparticle vaccine against severe acute respiratory syndrome coronavirus 2: Results from a phase 2 clinical study.

Background: DS-5670a is a vaccine candidate for coronavirus disease 2019 (COVID-19) harnessing a novel modality composed of messenger ribonucleic acid (mRNA) encoding the receptor-binding domain (RBD) from the spike protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) encapsulated in lipid nanoparticles. Here, we report the safety, immunogenicity, and pharmacokinetic profile of DS-5670a from a phase 2 clinical trial in healthy adults who were immunologically naïve to SARS-CoV-2.

Methods: The study consisted of an open-label, uncontrolled, dose-escalation part and a double-blind, randomized, uncontrolled, 2-arm, parallel-group part.

Fever Responses Are Enhanced with Advancing Age during Respiratory Syncytial Virus Infection among Children under 24 Months Old.

The most important risk factor for severe respiratory syncytial virus (RSV) infection is considered young age due to the immature immune system. The risk at young age is reported greater for RSV than for other respiratory infectious agents. Based on the strong association between young age and severity of RSV infection due to immature immunity, we aimed to assess whether there were any age-related differences in fever responses, as one clinical aspect of the immune response.

Age-Specific Profiles of Antibody Responses against Respiratory Syncytial Virus Infection.

Respiratory syncytial virus (RSV) is one of the most prevalent causative agents of lower respiratory tract infections worldwide, especially in infants around 3 to 4months old. Infants at such a young age have maternally-transferred passive antibodies against RSV but do not have active immune systems efficient enough for the control of RSV infection. In order to elucidate age-specific profiles of immune responses against RSV protection, antibody responses were examined by using blood samples in both acute and convalescent phases obtained from child patients and adult patients.

Ligand-induced Ordering of the C-terminal Tail Primes STING for Phosphorylation by TBK1.

The innate immune protein Stimulator of interferon genes (STING) promotes the induction of interferon beta (IFN-β) production via the phosphorylation of its C-terminal tail (CTT) by TANK-binding kinase 1 (TBK1). Potent ligands of STING are, therefore, promising candidates for novel anti-cancer drugs or vaccine adjuvants. However, the intrinsically flexible CTT poses serious problems in in silico drug discovery.

Efficient antigen delivery to the draining lymph nodes is a key component in the immunogenic pathway of the intradermal vaccine.

Background: It has been clinically demonstrated that intradermal (ID) vaccines have a potential to confer a superior immunogenic profile compared to intramuscular (IM) or subcutaneous (SC) vaccines. In terms of distribution of a vaccine antigen depending on the administration routes, at least two independent immunogenic pathways of the vaccines have been proposed: (1) the antigen recognition by the immune cells present at the vaccine-administered site and (2) the antigen recognition by the lymph node (LN)-resident immune cells through the lymphatic flow from the vaccine-administered site after the antigen is directly delivered into the draining LNs.

Objective: In order to clarify the key components for the immunogenic pathway of the ID vaccine, the correlation between the kinetics of the antigen distribution to the draining LNs and antibody responses to the antigen were evaluated.

Superior immunogenicity profile of the new intradermal influenza vaccine compared to the standard subcutaneous vaccine in subjects 65 years and older: A randomized controlled phase III study.

Background: Although the elderly are at high risk for influenza, the immunogenicity in the elderly is lower than that in younger adults. We developed the new type of seasonal influenza vaccine with the novel intradermal (ID) injection system. In the previous exploratory phase I/II study of the ID vaccine with a dose of 15 μg HA per strain showed the superior immunogenicity profile to that of the standard subcutaneous (SC) injection vaccine in subjects aged 20 years and older.

Immunogenicity and safety of the new intradermal influenza vaccine in adults and elderly: A randomized phase 1/2 clinical trial.

Background: Recent clinical evidence indicates that an intradermal (ID) delivery of vaccines confers superior immunogenicity as compared to a standard intramuscular or subcutaneous (SC) delivery.

Methods: In this exploratory study, 600 healthy adults were randomized to 6 study groups with subgroups of young adults (20-64 years old) and older adults (65 years and older). The subjects were either injected by a novel ID injection system with a single dose of 6, 9, or 15 μg HA or two doses (21 days apart) of 15 μg HA per strain or injected by an SC injection method with a single or two doses (21 days apart) of 15 μg HA per strain.

Role of Extrachromosomal Histone H2B on Recognition of DNA Viruses and Cell Damage.

Histones are essential components of chromatin structure, and histone modification plays an important role in various cellular functions including transcription, gene silencing, and immunity. Histones also play distinct roles in extrachromosomal settings. Extrachromosomal histone H2B acts as a cytosolic sensor to detect double-stranded DNA (dsDNA) fragments derived from infectious agents or damaged cells to activate innate and acquired immune responses in various cell types.

Recognition of damage-associated molecular patterns related to nucleic acids during inflammation and vaccination.

All mammalian cells are equipped with large numbers of sensors for protection from various sorts of invaders, who, in turn, are equipped with molecules containing pathogen-associated molecular patterns (PAMPs). Once these sensors recognize non-self antigens containing PAMPs, various physiological responses including inflammation are induced to eliminate the pathogens. However, the host sometimes suffers from chronic infection or continuous injuries, resulting in production of self-molecules containing damage-associated molecular patterns (DAMPs).

Innate Immune Signaling by, and Genetic Adjuvants for DNA Vaccination.

DNA vaccines can induce both humoral and cellular immune responses. Although some DNA vaccines are already licensed for infectious diseases in animals, they are not licensed for human use because the risk and benefit of DNA vaccines is still controversial. Indeed, in humans, the immunogenicity of DNA vaccines is lower than that of other traditional vaccines.

Demonstration of innate immune responses in the thyroid gland: potential to sense danger and a possible trigger for autoimmune reactions.

Background: Autoimmune thyroid disease is an archetypal organ-specific autoimmune disorder that is characterized by the production of thyroid autoantibodies and lymphocytic infiltration into the thyroid. However, the underlying mechanisms by which specific thyroid antibodies are produced are largely unknown. Recent studies have shown that innate immune responses affect both the phenotype and the severity of autoimmune reactions.

Guidelines for the use and interpretation of assays for monitoring autophagy.

In 2008 we published the first set of guidelines for standardizing research in autophagy. Since then, research on this topic has continued to accelerate, and many new scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding.

Intracellular inflammatory sensors for foreign invaders and substances of self-origin.

In order to survive, all organisms must recognize and eliminate foreign invaders such as infectious pathogens, chemicals, ultraviolet rays, metabolites and damaged or transformed self-tissues, as well as allogenic organs in cases of transplantation. Recent research in innate immunity has elucidated that there are versatile inflammatory sensors on spatiotemporal 'sentry duty' that recognize substances derived from both 'nonself' and 'self', e.g.

Novel strategies to improve DNA vaccine immunogenicity.

DNA vaccines can induce both humoral and cellular immune responses in animals. Some DNA vaccines are already licensed for infectious diseases such as West Nile virus encephalitis in horses. When used in humans, however, DNA vaccines suffer from lower immunogenicity profiles.

Fragments of genomic DNA released by injured cells activate innate immunity and suppress endocrine function in the thyroid.

Activation of innate and acquired immune responses, which can be induced by infection, inflammation, or tissue injury, may impact the development of autoimmunity. Although stimulation of cells by double-stranded DNA (dsDNA) has been shown to activate immune responses, the role of self-genomic DNA fragments released in the context of sterile cellular injury is not well understood. Using cultured thyroid cells, we show that cell injury prompts the release of genomic DNA into the cytosol, which is associated with the production of type I interferons, inflammatory cytokines, and chemokines.

NLRP4 negatively regulates autophagic processes through an association with beclin1.

Although more than 20 putative members have been assigned to the nucleotide-binding and oligomerization domain-like receptor (NLR) family, their physiological and biological roles, with the exception of the inflammasome, are not fully understood. In this article, we show that NLR members, such as NLRC4, NLRP3, NLRP4, and NLRP10 interact with Beclin1, an important regulator of autophagy, through their neuronal apoptosis inhibitory protein, MHC class II transcription activator, incompatibility locus protein from Podospora anserina, and telomerase-associated protein domain. Among such NLRs, NLRP4 had a strong affinity to the Beclin1 evolutionally conserved domain.

Modulation of intracellular signaling using protein-transduction technology.

Protein-transduction technology is one of the most promising therapeutic tools for the control of intracellular events. A number of studies have demonstrated that minimal and efficient protein-transduction domains (PTDs) can act as a peptide vector to transfer bioactive cargo molecules from outside to inside the cell. PTD-mediated transduction has the ability to cross the blood-brain barrier, with transduction taking place in most tissues and cell types in vivo.

C/EBP{delta} and STAT-1 are required for TLR8 transcriptional activity.

Toll-like receptor 8 (TLR8), which is expressed primarily in myeloid cells, plays a central role in initiating immune responses to viral single-stranded RNA. Despite the great interest in the field of TLR8 research, very little is known in terms of TLR8 biology and its transcriptional regulation. Here, we describe the isolation of the hTLR8 promoter and the characterization of the molecular mechanisms involved in its regulation.

Expression of Toll-like receptor 9 in renal podocytes in childhood-onset active and inactive lupus nephritis.

Background: Childhood-onset systemic lupus erythematosus (SLE) is frequently complicated with lupus nephritis (LN), which is characterized by the deposition of DNA-containing immune complex to the glomerulus. Toll-like receptor 9 (TLR9), capable of recognizing the microbially derived CpG oligonucleotide, plays a crucial role in the innate immunity. TLR9 is also assumed to be related to the aetiology of SLE in the recognition of anti-DNA antibody-containing immune complex, but this remains controversial.

Immunogenicity of whole-parasite vaccines against Plasmodium falciparum involves malarial hemozoin and host TLR9.

Although whole-parasite vaccine strategies for malaria infection have regained attention, their immunological mechanisms of action remain unclear. We find that immunization of mice with a crude blood stage extract of the malaria parasite Plasmodium falciparum elicits parasite antigen-specific immune responses via Toll-like receptor (TLR) 9 and that the malarial heme-detoxification byproduct, hemozoin (HZ), but not malarial DNA, produces a potent adjuvant effect. Malarial and synthetic (s)HZ bound TLR9 directly to induce conformational changes in the receptor.

Extrachromosomal histone H2B mediates innate antiviral immune responses induced by intracellular double-stranded DNA.

Fragments of double-stranded DNA (dsDNA) forming a right-handed helical structure (B-DNA) stimulate cells to produce type I interferons (IFNs). While an adaptor molecule, IFN-beta promoter stimulator 1 (IPS-1), mediates dsDNA-induced cellular signaling in human cells, the underlying molecular mechanism is not fully understood. Here, we demonstrate that the extrachromosomal histone H2B mediates innate antiviral immune responses in human cells.