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The recent success of cancer immunotherapies has highlighted the benefit of harnessing the immune system for cancer treatment. Vaccines have a long history of promoting immunity to pathogens and, consequently, vaccines targeting cancer neoantigens have been championed as a tool to direct and amplify immune responses against tumours while sparing healthy tissue. In recent years, extensive preclinical research and more than one hundred clinical trials have tested different strategies of neoantigen discovery and vaccine formulations. However, despite the enthusiasm for neoantigen vaccines, proof of unequivocal efficacy has remained beyond reach for the majority of clinical trials. In this Review, we focus on the key obstacles pertaining to vaccine design and tumour environment that remain to be overcome in order to unleash the true potential of neoantigen vaccines in cancer therapy.Personalized neoantigen vaccines offer the potential to boost immune response a patient against their specific cancer antigens. Here, Katsikis, Ishii and Schliehe discuss the challenges that currently limit this therapeutic approach, including those related to neoantigen selection and adjuvants, and post-vaccine challenges such as the immunosuppressive tumour microenvironment. Moreover, they consider solutions that could help to overcome these obstacles.

mRNA vaccines such as those used to prevent COVID-19 owe part of their success to methylation that masks immunostimulatory properties of the mRNA, but the immunological mechanisms of adjuvanticity are unclear. Two new studies reveal distinct mechanisms for innate sensing of this hidden adjuvant.

Spike protein mutation Leu455Ser is a hallmark mutation of JN.1: we have recently shown that HK.3 and other flip variants carry Leu455Phe, which contributes to increased transmissibility and immune escape ability compared with the parental EG.5.1 variant.5 Here, we investigated the virological properties of JN.1. KJI and KS are supported in part by AMED SCARDA Japan Initiative for World-leading Vaccine Research and Development Centers UTOPIA and by AMED SCARDA Program on R&D of new generation vaccine including new modality application. KS received funding from the AMED Research Program on HIV/AIDS, JST CREST, JSPS Core-to-Core Program, The Tokyo Biochemical Research Foundation, and The Mitsubishi Foundation; received consulting fees from Moderna Japan and Takeda Pharmaceutical; and honoraria for lectures from Gilead Sciences, Moderna Japan, and Shionogi & Co. JI received funding from JST PRESTO and JSPS KAKENHI Grant-in-Aid for Early-Career Scientists; and received consulting fees and honoraria for lectures from Takeda Pharmaceutical.

Key Points To elicit protective adaptive immune responses, vaccines must efficiently trigger the innate immune system. It is becoming increasingly apparent that microbial and host nucleic acids serve as important activators of the innate immune system in both currently available and experimental vaccines. Microbial and host nucleic acids may be recognized, respectively, as pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs) by a complex machinery of innate immune receptors. The activation of these receptors either directly or indirectly has an impact on the activity of antigen-presenting cells and on subsequent adaptive immune responses. The deconstruction of the mechanisms of action of many live attenuated vaccines is revealing that the sensing of microbial nucleic acids makes an important contribution to the immunogenicity of these vaccines. Innate immune detection of host DNA and of the nucleic acid metabolite uric acid may have a role in the adjuvant properties of aluminium salts, the most widely used type of vaccine adjuvant. Nucleic acid-sensing mechanisms may be directly harnessed by novel adjuvant molecules. Several vaccines containing such molecules are currently in the preclinical and early clinical stages of development. It is becoming increasingly clear that the activation of the innate immune system by host or microbial nucleic acids contributes to the immunogenicity of many vaccines. This article describes the receptors and signalling pathways that are involved in sensing nucleic acids and discusses the implications for current and future vaccination strategies. The demand is currently high for new vaccination strategies, particularly to help combat problematic intracellular pathogens, such as HIV and malarial parasites. In the past decade, the identification of host receptors that recognize pathogen-derived nucleic acids has revealed an essential role for nucleic acid sensing in the triggering of immunity to intracellular pathogens. This Review first addresses our current understanding of the nucleic acid-sensing immune machinery. We then explain how the study of nucleic acid-sensing mechanisms not only has revealed their central role in driving the responses mediated by many current vaccines, but is also revealing how they could be harnessed for the design of new vaccines.

Systemic inflammation mediated by Plasmodium parasites is central to malaria disease and its complications. Plasmodium parasites reside in erythrocytes and can theoretically reach all host tissues via the circulation. However, actual interactions between parasitized erythrocytes and host tissues, along with the consequent damage and pathological changes, are limited locally to specific tissue sites. Such tissue specificity of the parasite can alter the outcome of malaria disease, determining whether acute or chronic complications occur. Here, we give an overview of the recent progress that has been made in understanding tissue-specific immunopathology during Plasmodium infection. As knowledge on tissue-specific host-parasite interactions accumulates, better treatment modalities and targets may emerge for intervention in malaria disease.

Double-stranded DNA (dsDNA) derived from pathogen- or host-damaged cells triggers innate immune responses when exposed to cytoplasm. However, the machinery underlying the primary recognition of intracellular dsDNA is obscure. Here we show that the DNA damage sensor, meiotic recombination 11 homolog A (MRE11), serves as a cytosolic sensor for dsDNA. Cells with a mutation of MRE11 gene derived from a patient with ataxia-telangiectasia–like disorder, and cells in which Mre11 was knocked down, had defects in dsDNA-induced type I IFN production. MRE11 physically interacted with dsDNA in the cytoplasm and was required for activation of stimulator of IFN genes (STING) and IRF3. RAD50, a binding protein to MRE11, was also required for dsDNA responses, whereas NBS1, another binding protein to MRE11, was dispensable. Collectively, our results suggest that the MRE11–RAD50 complex plays important roles in recognition of dsDNA and initiation of STING-dependent signaling, in addition to its role in DNA-damage responses.

How alum acts as a vaccine adjuvant continues to perplex. Here Marichal et al . now report that alum induces host cell death and release of genomic DNA, which acts as an endogenous damage-associated molecular pattern that stimulates antibody and T cell responses Aluminum-based adjuvants (aluminum salts or alum) are widely used in human vaccination, although their mechanisms of action are poorly understood. Here we report that, in mice, alum causes cell death and the subsequent release of host cell DNA, which acts as a potent endogenous immunostimulatory signal mediating alum adjuvant activity. Furthermore, we propose that host DNA signaling differentially regulates IgE and IgG1 production after alum-adjuvanted immunization. We suggest that, on the one hand, host DNA induces primary B cell responses, including IgG1 production, through interferon response factor 3 (Irf3)-independent mechanisms. On the other hand, we suggest that host DNA also stimulates 'canonical' T helper type 2 (T H 2) responses, associated with IgE isotype switching and peripheral effector responses, through Irf3-dependent mechanisms. The finding that host DNA released from dying cells acts as a damage-associated molecular pattern that mediates alum adjuvant activity may increase our understanding of the mechanisms of action of current vaccines and help in the design of new adjuvants.

Type I interferons are central mediators for antiviral responses. Using high-throughput functional screening of interferon inducers, we have identified here a molecule we call interferon-β promoter stimulator 1 (IPS-1). Overexpression of IPS-1 induced type I interferon and interferon-inducible genes through activation of IRF3, IRF7 and NF-κB transcription factors. TBK1 and IKKi protein kinases were required for the IPS-1-mediated interferon induction. IPS-1 contained an N-terminal CARD-like structure that mediated interaction with the CARD of RIG-I and Mda5, which are cytoplasmic RNA helicases that sense viral infection. 'Knockdown' of IPS-1 by small interfering RNA blocked interferon induction by virus infection. Thus, IPS-1 is an adaptor involved in RIG-I- and Mda5-mediated antiviral immune responses.

The occurrence of diseases characterized by irregular spinal alignment, such as kyphosis, lordosis, scoliosis, and dropped head syndrome (DHS) is increasing, particularly among older adults. DHS is characterized by an excessive forward tilt of the head and neck, causing the head to droop. Although it is believed that muscle activity plays a role in both the onset and treatment of DHS, the underlying mechanisms remain unclear. To elucidate the mechanism, we used a human body finite element model, which included the erector spinae muscle group, and a muscle controller with fixed legs for spinal posture stabilization. The model replicated muscle activation levels during the maintenance of an upright posture under gravity, similar to those obtained from experimental data. Parametric simulations to investigate the effect of each spinal muscle impairment on upright posture with and without compensatory activities of the other muscles suggest that trunk extensors; the multifidus L1-S and longissimus thoracis muscles, and hip flexors; psoas major and iliacus muscles play an integral role in maintaining an upright posture. These findings support the results of a rehabilitation study that reported that exercises targeting the trunk, psoas muscles, and cervical extensors could improve global spinal alignment and clinical outcomes in DHS.

When animals are infected with helminthic parasites, resistant hosts show type II helper T immune responses to expel worms. Recently, natural helper (NH) cells or nuocytes, newly identified type II innate lymphoid cells, are shown to express ST2 (IL-33 receptor) and produce IL-5 and IL-13 when stimulated with IL-33. Here we show the relevant roles of endogenous IL-33 for Strongyloides venezuelensis infection-induced lung eosinophilic inflammation by using Il33–/– mice. Alveolar epithelial type II cells (ATII) express IL-33 in their nucleus. Infection with S. venezuelensis or intranasal administration of chitin increases in the number of ATII cells and the level of IL-33. S. venezuelensis infection induces pulmonary accumulation of NH cells, which, after being stimulated with IL-33, proliferate and produce IL-5 and IL-13. Furthermore, S. venezuelensis infected Rag2–/– mice increase the number of ATII cells, NH cells, and eosinophils and the expression of IL-33 in their lungs. Finally, IL-33–stimulated NH cells induce lung eosinophilic inflammation and might aid to expel infected worms in the lungs.