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Cancer vaccines, which are designed to amplify tumour-specific T cell responses through active immunization, have long been envisioned as a key tool of effective cancer immunotherapy. Despite a clear rationale for such vaccines, extensive past efforts were unsuccessful in mediating clinically relevant antitumour activity in humans. Recently, however, next-generation sequencing and novel bioinformatics tools have enabled the systematic discovery of tumour neoantigens, which are highly desirable immunogens because they arise from somatic mutations of the tumour and are therefore tumour specific. As a result of the diversity of tumour neoepitopes between individuals, the development of personalized cancer vaccines is warranted. Here, we review the emerging field of personalized cancer vaccination and discuss recent developments and future directions for this promising treatment strategy.

Aside from centrally induced trained immunity in the bone marrow (BM) and peripheral blood by parenteral vaccination or infection, evidence indicates that mucosal-resident innate immune memory can develop via a local inflammatory pathway following mucosal exposure. However, whether mucosal-resident innate memory results from integrating distally generated immunological signals following parenteral vaccination/infection is unclear. Here we show that subcutaneous Bacillus Calmette–Guérin (BCG) vaccination can induce memory alveolar macrophages (AMs) and trained immunity in the lung. Although parenteral BCG vaccination trains BM progenitors and circulating monocytes, induction of memory AMs is independent of circulating monocytes. Rather, parenteral BCG vaccination, via mycobacterial dissemination, causes a time-dependent alteration in the intestinal microbiome, barrier function and microbial metabolites, and subsequent changes in circulating and lung metabolites, leading to the induction of memory macrophages and trained immunity in the lung. These data identify an intestinal microbiota-mediated pathway for innate immune memory development at distal mucosal tissues and have implications for the development of next-generation vaccine strategies against respiratory pathogens.Parenteral BCG vaccination has been shown to drive innate immune memory responses that can affect the response to pathogens other than mycobacteria. Here the authors show an innate immune memory mechanism whereby subcutaneous BCG vaccination alters the intestinal microbiome and in turn can train alveolar macrophages in the lungs.

Key Points Human immune system composition and function are highly variable between healthy individuals, but they are relatively stable over time within a given individual. Human immune systems vary as a consequence of heritable and non-heritable influences, but non-heritable influences explain most of the variation. Understanding the specific factors that shape an individual's immune system is key for understanding immune competence and risk of immune-mediated and infectious diseases. This Review provides a comprehensive overview of the influences on human immune system variation. Systems immunology analyses have revealed that variations between individuals are mainly due to non-heritable influences such as age, sex, microbiota and the environment. The human immune system is highly variable between individuals but relatively stable over time within a given person. Recent conceptual and technological advances have enabled systems immunology analyses, which reveal the composition of immune cells and proteins in populations of healthy individuals. The range of variation and some specific influences that shape an individual's immune system is now becoming clearer. Human immune systems vary as a consequence of heritable and non-heritable influences, but symbiotic and pathogenic microbes and other non-heritable influences explain most of this variation. Understanding when and how such influences shape the human immune system is key for defining metrics of immunological health and understanding the risk of immune-mediated and infectious diseases.

The adaptive immune response to influenza virus infection is multifaceted and complex, involving antibody and cellular responses at both systemic and mucosal levels. Immune responses to natural infection with influenza virus in humans are relatively broad and long-lived, but influenza viruses can escape from these responses over time owing to their high mutation rates and antigenic flexibility. Vaccines are the best available countermeasure against infection, but vaccine effectiveness is low compared with other viral vaccines, and the induced immune response is narrow and short-lived. Furthermore, inactivated influenza virus vaccines focus on the induction of systemic IgG responses but do not effectively induce mucosal IgA responses. Here, I review the differences between natural infection and vaccination in terms of the antibody responses they induce and how these responses protect against future infection. A better understanding of how natural infection induces broad and long-lived immune responses will be key to developing next-generation influenza virus vaccines.Developing universal influenza virus vaccines will require understanding how broad and long-lived antibody responses to natural infection with influenza A virus are generated, a topic that has benefited greatly from technologies that enable the analysis of single human B cells.

Key Points Messenger RNA (mRNA) is a pivotal molecule of life, involved in almost all aspects of cell biology. As the subject of basic and applied research for more than 5 decades, mRNA has only recently come into the focus as a potentially powerful drug class able to deliver genetic information. Synthetic mRNA can be engineered to resemble mature and processed mRNA molecules as they occur naturally in the cytoplasm of eukaryotic cells and to transiently deliver proteins. Recent advances addressed challenges inherent to this drug class and provided the basis for a broad spectrum of applications Besides cancer immunotherapies and infectious disease vaccines novel approaches such as in vivo delivery of mRNA to replace or supplement proteins, mRNA-based induction of pluripotent stem cells, or mRNA-assisted delivery of designer nucleases for genome engineering rapidly emerged and entered into pharmaceutical development. This Review gives a comprehensive overview of the current state of mRNA drug technologies, their applications and crucial aspects relevant to mRNA based drug discovery and development. The therapeutic potential of in vitro -transcribed mRNA (IVT mRNA) extends from prophylactic and therapeutic vaccines to applications such as protein replacement and genome engineering. In this Review, the authors describe the recent developments in the IVT mRNA field, discuss the class-specific challenges with regards to translating IVT mRNA into a biopharmaceutical, and provide an overview of IVT mRNA drugs in development for different indications. In vitro transcribed (IVT) mRNA has recently come into focus as a potential new drug class to deliver genetic information. Such synthetic mRNA can be engineered to transiently express proteins by structurally resembling natural mRNA. Advances in addressing the inherent challenges of this drug class, particularly related to controlling the translational efficacy and immunogenicity of the IVTmRNA, provide the basis for a broad range of potential applications. mRNA-based cancer immunotherapies and infectious disease vaccines have entered clinical development. Meanwhile, emerging novel approaches include in vivo delivery of IVT mRNA to replace or supplement proteins, IVT mRNA-based generation of pluripotent stem cells and genome engineering using IVT mRNA-encoded designer nucleases. This Review provides a comprehensive overview of the current state of mRNA-based drug technologies and their applications, and discusses the key challenges and opportunities in developing these into a new class of drugs.

Key Points Outer membrane vesicles (OMVs) are bacterial nanoparticles that are naturally produced during bacterial growth both in vitro and in vivo . OMVs can interact with many host cell types — including mucosal epithelial cells, myeloid cells and cells distal to the site of OMV entry — and thus have a range of inflammatory outcomes. Clinical studies have demonstrated the presence of OMVs in host tissues, suggesting that they have potentially pathogenic roles in various infectious diseases, particularly in those of a chronic nature. OMVs may also be important as previously unrecognized mediators of the inflammatory pathologies that accompany certain infectious diseases of idiopathic origin. OMVs can enter non-phagocytic human epithelial cells via multiple mechanisms including lipid raft-dependent and lipid raft-independent endocytosis, in addition to dynamin-dependent and dynamin-independent mechanisms. When they are present inside cells, OMVs migrate to early endosomes and are detected by the host intracellular immune receptor nucleotide-binding oligomerization domain-containing protein 1 (NOD1), which results in the induction of autophagy and the generation of a pro-inflammatory response. When OMVs are within epithelial cells, their protein cargo is processed and OMV peptides are released in exosomes. These peptide-laden exosomes can then be taken up by professional antigen-presenting cells and presented to T cells, resulting in the generation of antigen-specific adaptive immune responses. In addition to their pro-inflammatory effects, OMVs can modulate or even suppress immune cell responses through their direct effects on host cells. Evidence is also emerging that OMVs produced by commensal bacteria may have roles in immune tolerance and other physiological functions of benefit to the host. OMVs are highly stable, non-infectious and genetically tractable nanoparticles that contain the major immunogenic proteins of the parent bacterium and are able to elicit responses from both arms of the immune system, thus making them highly suited as vaccines and adjuvants. Outer membrane vesicles (OMVs) are produced by bacteria and can interact with leukocytes and other host cells to shape the immune response during infection. OMVs can have both pro-inflammatory and anti-inflammatory effects; in this Review, the authors discuss how they may contribute to human diseases and also their potential as vaccine adjuvants. Gram-negative bacteria shed extracellular outer membrane vesicles (OMVs) during their normal growth both in vitro and in vivo . OMVs are spherical, bilayered membrane nanostructures that contain many components found within the parent bacterium. Until recently, OMVs were dismissed as a by-product of bacterial growth; however, findings within the past decade have revealed that both pathogenic and commensal bacteria can use OMVs to manipulate the host immune response. In this Review, we describe the mechanisms through which OMVs induce host pathology or immune tolerance, and we discuss the development of OMVs as innovative nanotechnologies.

The coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the most formidable challenge to humanity in a century. It is widely believed that prepandemic normalcy will never return until a safe and effective vaccine strategy becomes available and a global vaccination programme is implemented successfully. Here, we discuss the immunological principles that need to be taken into consideration in the development of COVID-19 vaccine strategies. On the basis of these principles, we examine the current COVID-19 vaccine candidates, their strengths and potential shortfalls, and make inferences about their chances of success. Finally, we discuss the scientific and practical challenges that will be faced in the process of developing a successful vaccine and the ways in which COVID-19 vaccine strategies may evolve over the next few years.This Review outlines the guiding immunological principles for the design of coronavirus disease 2019 (COVID-19) vaccine strategies and analyses the current COVID-19 vaccine landscape and the challenges ahead.

The development of effective vaccines against bacterial lung infections requires the induction of protective, pathogen-specific immune responses without deleterious inflammation within the pulmonary environment. Here, we made use of a polysaccharide-adjuvanted vaccine approach to elicit resident pulmonary T cells to protect against aerosol Mycobacterium tuberculosis infection. Intratracheal administration of the multistage fusion protein CysVac2 and the delta-inulin adjuvant Advax™ (formulated with a TLR9 agonist) provided superior protection against aerosol M. tuberculosis infection in mice, compared to parenteral delivery. Surprisingly, removal of the TLR9 agonist did not impact vaccine protection despite a reduction in cytokine-secreting T cell subsets, particularly CD4 + IFN-γ + IL-2 + TNF + multifunctional T cells. CysVac2/Advax-mediated protection was associated with the induction of lung-resident, antigen-specific memory CD4 + T cells that expressed IL-17 and RORγT, the master transcriptional regulator of Th17 differentiation. IL-17 was identified as a key mediator of vaccine efficacy, with blocking of IL-17 during M. tuberculosis challenge reducing phagocyte influx, suppressing priming of pathogen-specific CD4 + T cells in local lymph nodes and ablating vaccine-induced protection. These findings suggest that tuberculosis vaccines such as CysVac2/Advax that are capable of eliciting Th17 lung-resident memory T cells are promising candidates for progression to human trials.

One strategy to counter the rise of antimicrobial resistance is the development of vaccines against resistant pathogens, preventing further infection and spread of antimicrobial resistance. Antimicrobial resistance (AMR) and the associated morbidity and mortality due to bacterial pathogens have been increasing globally to alarming levels. The World Health Organization (WHO) has called for global action on AMR, supported worldwide by governments, health ministries and health agencies. Many potential solutions to stem AMR are being discussed and implemented. These include increases in antimicrobial stewardship, investment in research and development to design new classes of antibiotics, and reduction of antibiotic use in rearing of livestock. However, vaccines as tools to reduce AMR have historically been under-recognized in these discussions, even though their effectiveness in reducing disease and AMR is well documented. This review article seeks to highlight the value of vaccines as an additional modality to combat AMR globally, using select examples. It also will provide perspectives on how vaccines could be more effectively used in this effort.

Although antiviral drugs and vaccines have reduced the economic and healthcare burdens of influenza, influenza epidemics continue to take a toll. Over the past decade, research on influenza viruses has revealed a potential path to improvement. The clues have come from accumulated discoveries from basic and clinical studies. Now, virus surveillance allows researchers to monitor influenza virus epidemic trends and to accumulate virus sequences in public databases, which leads to better selection of candidate viruses for vaccines and early detection of drug-resistant viruses. Here we provide an overview of current vaccine options and describe efforts directed toward the development of next-generation vaccines. Finally, we propose a plan for the development of an optimal influenza vaccine. The universal flu vaccine remains elusive, but there are several strategies that scientists can take to develop one, including closer monitoring of viral evolution.