Vaccines for neglected pathogens : strategies, achievements and challenges : focus on leprosy, leishmaniasis, melioidosis and tuberculosis

This book reviews successes and (remaining) challenges in vaccine development for the selected Neglected Tropical Diseases (NTD) of Leprosy, Leishmaniasis, Meliodoisis and Tuberculosis, which are a continuous burden for millions of people in affected areas worldwide. Written by frontline researchers, the volume deep-dives into different vaccine strategies, provides biotechnological background information and also tackles animal models in NTD therapeutics research. By bringing together state-of-the-art expert knowledge, the book contributes to the aim of ultimately ending the epidemics of neglected tropical diseases, complying with UN Sustainable Development Goal 3, Health and Well-Being. The volume highlights the activities of the research network VALIDATE (VAccine deveLopment for complex Intracellular neglecteD pAThogEns), funded by the Medical Research Council in the UK. The four NTDs discussed in the book were selected as these are in the focus of VALIDATE’s research. The book targets scientists and clinicians working on NTDs, as well as all readers with a background in biomedicine and interest in vaccine development. This is an open access book. Contents Chapter 1: Introduction 1.1 Neglected Tropical Diseases and the VALIDATE Pathogens 1.2 Book Synopsis References Chapter 2: The VALIDATE Network: Accelerating Vaccine Development for Tuberculosis, Leishmaniasis, Melioidosis and Leprosy 2.1 Introduction 2.2 VALIDATE’s Focus Pathogens 2.2.1 Tuberculosis (TB) 2.2.2 Leishmaniasis 2.2.3 Melioidosis 2.2.4 Leprosy (Hansen’s Disease) 2.3 VALIDATE: Outputs and Successes 2.3.1 Pump-Priming Funding 2.3.2 Fellowships 2.3.2.1 Dr. Jomien Mouton, Stellenbosch University (South Africa): Identification of Latency Associated Antigens and Biosignatures Associated with Mycobacterium tuberculosis 2.3.2.2 Dr. Rachel Tanner, University of Oxford (UK): Characterising the BCG-Induced Antibody Response to Inform the Design of Improved Vaccines Against M. tuberculosis, M. leprae and M. bovis 2.3.3 Training Grants 2.3.4 Mentoring 2.3.5 ECR Career Development Network 2.3.6 Information Dissemination 2.3.7 Events 2.3.8 Outreach 2.3.9 Data Sharing 2.3.10 Equipment Exchange 2.4 The Future of VALIDATE References Part I: Leprosy and Buruli Ulcer Chapter 3: A Current Perspective on Leprosy (Hansen’s Disease) 3.1 Introduction 3.2 Disease Transmission and Infection 3.3 Disease Classification and Pathophysiology 3.4 Diagnosis and Treatment 3.5 Challenges and Future Direction 3.5.1 The WHO Roadmap 3.5.2 Stigma and Discrimination 3.5.3 Alternative Therapies 3.5.4 Animal and Ex Vivo Models 3.5.5 Diagnostics 3.5.6 M. leprae Vaccine 3.6 Conclusions References Chapter 4: Leprosy Vaccines: Developments for Prevention and Treatment 4.1 Introduction 4.2 The BCG Vaccine Has Variable Protection Against Leprosy 4.3 The Recombinant BCG Vaccines to Improve Efficacy Against Leprosy 4.4 The Cross-Reactivity and Subunit Leprosy Vaccines 4.5 Vaccine and Drug Combinatory Therapy 4.6 Conclusion and Vaccine Outlook References Chapter 5: Current Progress and Prospects for a Buruli Ulcer Vaccine 5.1 Buruli Ulcer 5.1.1 Epidemiology and Transmission 5.1.2 Clinical Presentations and Current Treatments 5.2 Mycobacterium ulcerans 5.2.1 Mycolactone 5.2.2 Immune Response to M. ulcerans Infection 5.3 Vaccine Candidates 5.3.1 Human Studies with BCG 5.3.2 Mouse Studies of BU Vaccine Candidates 5.3.2.1 Whole Bacteria Vaccines 5.3.2.2 Subunit Vaccines for BU 5.4 Prospects References Part II: Tuberculosis Chapter 6: Correlates of Protection from Tuberculosis 6.1 Introduction 6.2 Innate Immunity 6.2.1 Early Clearance and a Role for Innate Immunity 6.2.2 Mononuclear Phagocytes 6.2.3 Natural Killer Cells 6.2.4 Neutrophils 6.2.5 Donor Unrestricted T Cells 6.2.6 Trained Innate Immunity 6.3 Conventional T Cells 6.3.1 CD4+ T Cells 6.3.1.1 IFN-γ Producing CD4+ T Cells 6.3.1.2 Polyfunctional CD4+ T Cells 6.3.1.3 Th17 Cells 6.3.2 CD8+ T Cells 6.4 Humoral Immunity 6.4.1 B Cells 6.4.2 Antibodies 6.5 Approaches to Identifying Correlates of Protection 6.5.1 Preclinical Models 6.5.1.1 Murine Models 6.5.1.2 Guinea Pigs 6.5.1.3 Cattle 6.5.1.4 Non-human Primates (NHPs) 6.5.1.5 Novel Humanized Animal Models 6.5.2 Clinical Studies 6.5.2.1 Clinical TB Vaccine Trials 6.5.2.2 Observational Studies 6.5.3 Controlled Human Infection Models 6.5.3.1 PPD CHIMs 6.5.3.2 BCG CHIMs 6.5.3.3 Other CHIM Models 6.5.4 Mycobacterial Growth Inhibition Assays 6.6 Conclusion References Chapter 7: Animal Models of Tuberculosis 7.1 Introduction 7.2 Mouse (Order Rodentia, Family Muridae, Mus musculus) 7.3 Rat (Order Rodentia, Family Muridae, Rattus norvegicus) 7.4 Rabbit (Order Lagomorpha, Family Leporidae, Oryctolagus cuniculus) 7.5 Zebrafish (Order Cypriniformes, Family Cyprinidae, Subfamily Danioninae, Danio rerio) 7.6 Cattle (Order Artiodactyla, Family Bovidae, Subfamily Bovinae, Bos taurus) 7.7 Guinea Pigs (Order Rodentia, Family Caviidae, Cavia, C. porcellus) 7.8 Non-Human Primates 7.9 Other Models 7.9.1 Cat (Order Carnivora, Family Felidae, Felis catus) 7.9.2 Dog (Order Carnivora, Family Canidae, Canis familiaris) 7.9.3 Deer (Order Artiodactyla, Family Cervidae, Genus cervus) 7.9.4 Minipig (Order Artiodactyla, Family Suidae, Sus domesticus) 7.9.5 Fruit Fly (Order Diptera, Family Drosophilidae, Drosophila melanogaster) 7.10 Conclusions and Perspectives References Chapter 8: BCG: Past, Present and Future Direction 8.1 History of BCG 8.2 Evolution and Genetics of BCG Vaccines 8.3 Immunogenicity of BCG 8.3.1 Innate Immune Responses 8.3.2 Adaptive Immune Response 8.3.3 Trained Immunity 8.4 Efficacy of BCG Against TB 8.4.1 Reasons for Variable BCG Efficacy 8.4.2 BCG Revaccination 8.4.3 Measuring BCG Protection? 8.5 Efficacy of BCG Against Other Infections 8.5.1 BCG and Other Mycobacterial Infections 8.5.2 BCG “Non-Specific” Immunity 8.5.3 BCG and COVID-19 Disease 8.6 BCG and Non-Communicable Diseases 8.6.1 BCG and Cancer 8.6.2 BCG and Allergic, Autoimmune and Inflammatory Diseases 8.7 Safety and Adverse Effects of BCG 8.8 BCG Future Directions 8.8.1 Recombinant BCG 8.8.2 Route of Administration 8.9 Conclusions References Chapter 9: The Role of Fermentation in BCG Manufacture: Challenges and Ways Forward 9.1 The BCG Vaccine: History and Approval 9.2 How Is BCG Vaccine Cultured and Manufactured: Fundamental Limitations? 9.3 Could Fermentation Be an Approach for BCG Vaccine Production? 9.4 BCG Product Characterisation 9.5 Regulatory Considerations 9.6 Concluding Remarks References Chapter 10: Progress in the Development of New Vaccines Against Tuberculosis 10.1 Immunological Characteristics and Markers for Mycobacterium tuberculosis 10.2 Approaches for TB Vaccine Development 10.3 Live Attenuated TB Vaccines 10.4 Inactivated TB Vaccines 10.5 Subunit TB Vaccines with Adjuvants 10.6 Recombinant TB Vaccines 10.7 Recombinant Vaccine Candidates Based on M. tuberculosis-Specific Antigens 10.8 Routes of Vaccine Delivery 10.9 Conclusion References Part III: Leishmaniasis Chapter 11: Visceral and Tegumentary Leishmaniasis 11.1 Introduction 11.2 What Are Visceral Leishmaniasis and Tegumentary Leishmaniasis? 11.3 The Global Distribution of VL and TL 11.4 Current Treatment Regimens for VL and TL 11.5 An Introduction to Vaccine Development for VL and TL 11.6 Conclusions References Chapter 12: The Utility of a Controlled Human Infection Model for Developing Leishmaniasis Vaccines 12.1 Introduction 12.1.1 Leishmaniasis: A Vaccine-Preventable Disease 12.1.2 The Case for Controlled Human Infection 12.2 Historical Perspective of Experimental Human Infections with Leishmania 12.2.1 The Early Years and Leishmanization: From Community to Mass Usage 12.2.2 Using Leishmanization for Vaccine Evaluation 12.3 Ethical, Regulatory and Scientific Advances to Incorporate in a Modern-Day CHIM 12.3.1 The Importance of Vector Transmission 12.3.2 Regulatory Standards and Other Risk Mitigation 12.4 A Leishmania major CHIM Initiated by Sand Fly Bite 12.5 Accommodating Diversity: Leishmania CHIMs in Endemic Country Settings 12.5.1 CHIMs Using Other Leishmania Strains (Including Genetically Modified Strains) 12.5.2 Sand Fly Diversity and Other Confounders 12.6 Prospects References Chapter 13: Vaccines for Canine Leishmaniasis 13.1 Introduction 13.2 Diagnosis of CanL 13.3 Treatment of CanL 13.4 Immune Responses in CanL 13.5 CanL Vaccines 13.5.1 Leish-Tec® Vaccine 13.5.2 Leishmune® Vaccine 13.5.3 CaniLeish® Vaccine 13.5.4 LetiFend® Vaccine 13.5.5 New Unlicensed Vaccine Candidates for CanL 13.6 Conclusions References Chapter 14: Vaccine Development for Human Leishmaniasis 14.1 History of Human Leishmaniasis Vaccines 14.2 Strategies to Vaccine Design: Where Are Good Candidates to Be Found and How Do We Explore Their Potential? 14.3 Immunological Insights into Vaccine Development 14.4 Lessons from the COVID Era: What Have We Learned, and How Can We Translate It to Leishmania Vaccines? 14.5 Conclusions References Part IV: Melioidosis Chapter 15: Vaccine Development Against Melioidosis 15.1 Melioidosis 15.2 Pathogenesis and Host Response 15.3 Vaccine Development 15.3.1 Live-Attenuated Vaccines 15.3.2 Inactivated Whole-Cell Vaccines 15.3.3 Subunit Vaccines 15.4 Conclusions References