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More than 70 million people worldwide are infected with hepatitis C virus, a major cause of liver cirrhosis, liver failure and hepatocellular carcinoma world-wide. In the last decade, this cancer has emerged as the second leading cause of cancer death and the global burden is increasing by two million new infections per year, mainly due to injection drug use. An effective vaccine will be the most effective means to contain the spread of this virus worldwide. The articles in this Research Topic describe the progress that has been made towards a preventive vaccine and the challenges that still need to be overcome to ultimately achieve this goal.

Conformational epitopes --- humoral immunity --- Conformational structures --- neutralizing antibodies --- Vaccine --- Hepatitis C virus --- hypervariability and flexibility

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In his 1962 book "The Structure of Scientific Revolutions", Thomas Kuhn famously argued that researchers in every field of scientific enquiry always operate under a set of presuppositions known as paradigms that are rarely explicitly stated. In the field of HIV vaccine research, several prevailing paradigms led scientists for many years to pursue unfruitful lines of investigations that impeded significant progress. The uncritical acceptance of reigning paradigms makes scientists reluctant to abandon their mistaken assumptions even when they obtain results that are not consistent with the paradigms. The following five paradigms which disregard the degeneracy of the immune system were particularly harmful. 1) There is a primary and intrinsic epitope specific for each B cell receptor and for the corresponding monoclonal antibody. In reality, there is no single, intrinsic or "real" epitope for any antibody but only a diverse group of potential ligands. 2) Reactions with monoclonal antibodies are more specific than the combined reactivity of polyclonal antibodies. In reality, a polyclonal antiserum has greater specificity for a multiepitopic protein because different antibodies in the antiserum recognize separate epitopes on the same protein, giving rise to an additive specificity effect. By focusing vaccine design on single epitope-Mab pairs, the beneficial neutralizing synergy that occurs with polyclonal antibody responses is overlooked. 3) The HIV epitope identified by solving the crystallographic structure of a broadly neutralizing Mab – HIV Env complex should be able, when used as immunogen, to elicit antibodies endowed with the same neutralizing capacity as the Mab. Since every anti HIV bnMab is polyspecific, the single epitope identified in the complex is not necessarily the one that elicited the bnMab. Since hypermutated Mabs used in crystallographic studies differ from their germline-like receptor version present before somatic hypermutation, the identified epitope will not be an effective vaccine immunogen. 4) Effective vaccine immunogenicity can be predicted from the antigenic binding capacity of viral epitopes. Most fragments of a viral antigen can induce antibodies that react with the immunogen, but this is irrelevant for vaccination since these antibodies rarely recognize the cognate, intact antigen and even more rarely neutralize the infectivity of the viral pathogen that harbors the antigen. 5) The rational design of vaccine immunogens using reverse vaccinology is superior to the trial-and-error screening of vaccine candidates able to induce protective immunity. One epitope can be designed to increase its structural complementarity to one particular bnMab, but such antigen design is only masquerading as immunogen design because it is assumed that antigenic reactivity necessarily entails the immunogenic capacity to elicit neutralizing antibodies. When HIV Env epitopes, engineered to react with a bnMab are used to select from human donors rare memory B cells secreting bnAbs, this represents antigen design and not immunogen design. The aim of this Research Topic is to replace previous misleading paradigms by novel ones that better fit our current understanding of immunological specificity and will help HIV vaccine development.

HIV tolerogenic vaccine --- germline antibodies --- SIV vaccine --- Mucosal vaccine --- Therapeutic vaccine --- vaccine efficacy trials --- neutralizing antibodies --- structure-based reverse vaccinology --- antibody polyspecificity --- bacterial adjuvants

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In his 1962 book "The Structure of Scientific Revolutions", Thomas Kuhn famously argued that researchers in every field of scientific enquiry always operate under a set of presuppositions known as paradigms that are rarely explicitly stated. In the field of HIV vaccine research, several prevailing paradigms led scientists for many years to pursue unfruitful lines of investigations that impeded significant progress. The uncritical acceptance of reigning paradigms makes scientists reluctant to abandon their mistaken assumptions even when they obtain results that are not consistent with the paradigms. The following five paradigms which disregard the degeneracy of the immune system were particularly harmful. 1) There is a primary and intrinsic epitope specific for each B cell receptor and for the corresponding monoclonal antibody. In reality, there is no single, intrinsic or "real" epitope for any antibody but only a diverse group of potential ligands. 2) Reactions with monoclonal antibodies are more specific than the combined reactivity of polyclonal antibodies. In reality, a polyclonal antiserum has greater specificity for a multiepitopic protein because different antibodies in the antiserum recognize separate epitopes on the same protein, giving rise to an additive specificity effect. By focusing vaccine design on single epitope-Mab pairs, the beneficial neutralizing synergy that occurs with polyclonal antibody responses is overlooked. 3) The HIV epitope identified by solving the crystallographic structure of a broadly neutralizing Mab – HIV Env complex should be able, when used as immunogen, to elicit antibodies endowed with the same neutralizing capacity as the Mab. Since every anti HIV bnMab is polyspecific, the single epitope identified in the complex is not necessarily the one that elicited the bnMab. Since hypermutated Mabs used in crystallographic studies differ from their germline-like receptor version present before somatic hypermutation, the identified epitope will not be an effective vaccine immunogen. 4) Effective vaccine immunogenicity can be predicted from the antigenic binding capacity of viral epitopes. Most fragments of a viral antigen can induce antibodies that react with the immunogen, but this is irrelevant for vaccination since these antibodies rarely recognize the cognate, intact antigen and even more rarely neutralize the infectivity of the viral pathogen that harbors the antigen. 5) The rational design of vaccine immunogens using reverse vaccinology is superior to the trial-and-error screening of vaccine candidates able to induce protective immunity. One epitope can be designed to increase its structural complementarity to one particular bnMab, but such antigen design is only masquerading as immunogen design because it is assumed that antigenic reactivity necessarily entails the immunogenic capacity to elicit neutralizing antibodies. When HIV Env epitopes, engineered to react with a bnMab are used to select from human donors rare memory B cells secreting bnAbs, this represents antigen design and not immunogen design. The aim of this Research Topic is to replace previous misleading paradigms by novel ones that better fit our current understanding of immunological specificity and will help HIV vaccine development.

HIV tolerogenic vaccine --- germline antibodies --- SIV vaccine --- Mucosal vaccine --- Therapeutic vaccine --- vaccine efficacy trials --- neutralizing antibodies --- structure-based reverse vaccinology --- antibody polyspecificity --- bacterial adjuvants

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Lassa virus causes Lassa fever disease in several countries in West Africa, where it is estimated to infect up to half million people causing roughly five thousand deaths each year. This deadly virus has also been introduced in multiple occasions into the western world, including the United States, United Kingdom, Netherlands, Sweden, and Germany. Lassa virus infection, which is often misdiagnosed, can lead to a wide range of disease symptoms ranging from mild flu-like symptoms to bleeding disorders, multi-organ failure, and death. Despite some major discoveries made in recent years of research on Lassa fever, there are still many unresolved key issues that hamper the development of effective vaccines and therapies. Some of these issues include a detailed understanding of the viral and participating host factors in completing the virus life cycle, in mediating disease pathogenesis or protection, and in activating or suppressing host immune responses against virus infection. This book is devoted to understanding some of these important issues. Expert and timely contributions in the form of editorial and original research and review articles on Lassa fever viral replication, disease pathogenesis and protection, host immune modulations, and other related hot topics are presented in this publication.

Research & information: general --- Biology, life sciences --- Lassa virus disease (LVD) --- vaccine breadth --- mimicry --- B cell anergy --- conserved antigens --- Fc-gamma receptors --- conformational antigens --- broadly-neutralizing antibodies --- focused immunity --- dominant and subdominant epitopes --- cross-restriction --- Lassa virus --- Z protein --- late domain --- PPXY --- budding --- release --- matrix protein --- phosphorylation --- arenavirus --- mass spectrometry --- viral glycoprotein --- viral entry --- viral fusion --- fusion protein --- Lassa virus vaccine --- ML29 vaccine --- STAT-1-/- mice --- Mopeia virus --- interfering particles --- Lassa fever --- LASV --- virus–host interactions --- entry --- replication --- Lassa vaccine --- replication-deficient MVA vector --- VLP formation --- single-dose efficacy --- cell-mediated immunity --- arenaviruses --- viral hemorrhagic fevers --- animal models --- mammarenavirus --- vaccine --- virulence --- pathogenesis --- innate immunity --- adaptive immunity --- COVID-19

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Lassa virus causes Lassa fever disease in several countries in West Africa, where it is estimated to infect up to half million people causing roughly five thousand deaths each year. This deadly virus has also been introduced in multiple occasions into the western world, including the United States, United Kingdom, Netherlands, Sweden, and Germany. Lassa virus infection, which is often misdiagnosed, can lead to a wide range of disease symptoms ranging from mild flu-like symptoms to bleeding disorders, multi-organ failure, and death. Despite some major discoveries made in recent years of research on Lassa fever, there are still many unresolved key issues that hamper the development of effective vaccines and therapies. Some of these issues include a detailed understanding of the viral and participating host factors in completing the virus life cycle, in mediating disease pathogenesis or protection, and in activating or suppressing host immune responses against virus infection. This book is devoted to understanding some of these important issues. Expert and timely contributions in the form of editorial and original research and review articles on Lassa fever viral replication, disease pathogenesis and protection, host immune modulations, and other related hot topics are presented in this publication.

Research & information: general --- Biology, life sciences --- Lassa virus disease (LVD) --- vaccine breadth --- mimicry --- B cell anergy --- conserved antigens --- Fc-gamma receptors --- conformational antigens --- broadly-neutralizing antibodies --- focused immunity --- dominant and subdominant epitopes --- cross-restriction --- Lassa virus --- Z protein --- late domain --- PPXY --- budding --- release --- matrix protein --- phosphorylation --- arenavirus --- mass spectrometry --- viral glycoprotein --- viral entry --- viral fusion --- fusion protein --- Lassa virus vaccine --- ML29 vaccine --- STAT-1-/- mice --- Mopeia virus --- interfering particles --- Lassa fever --- LASV --- virus–host interactions --- entry --- replication --- Lassa vaccine --- replication-deficient MVA vector --- VLP formation --- single-dose efficacy --- cell-mediated immunity --- arenaviruses --- viral hemorrhagic fevers --- animal models --- mammarenavirus --- vaccine --- virulence --- pathogenesis --- innate immunity --- adaptive immunity --- COVID-19