Advanced Vaccination Technologies for Infectious and Chronic Diseases: A guide to Vaccinology

By Vasso Apostolopoulos

The role of vaccines is emerging and even critical to ending infectious and chronic diseases and pandemics alike. The design and development of new vaccines could lead to improved health.

Handbook on Advanced Vaccination Technologies for Infectious and Chronic Disease discusses these new developments and introduces the reader to the current state of the science and the outlook going forward from the discovery of vaccines to the clinical trials of personalized vaccines.

Handbook on Advanced Vaccination Technologies for Infectious and Chronic Diseases is a valuable reference for occupational health professionals whose role involves supervision of immunization programs such as those working in the National Health Service, some sectors of higher education and the pharmaceutical industry.

• Offers comprehensive coverage of different vaccine platforms and their development
• Includes information on the regulatory perspective of vaccine development
• Describes different delivery approaches for vaccinology
• Explains the clinical development of vaccines along with novel platforms
• Covers all recent developments of vaccine production technologies, new types of vaccines, and ongoing research that could prevent future pandemics

• Language: English
• Publisher: Academic Press
• Release date: Mar 25, 2024
• ISBN: 9780443185656

Book preview

Advanced Vaccination Technologies for Infectious and Chronic Diseases

A guide to Vaccinology

Edited by

Vivek P. Chavda

Department of Pharmaceutics and Pharmaceutical Technology, L M College of Pharmacy, Ahmedabad, Gujarat, India

Lalitkumar K. Vora

School of Pharmacy, Queen’s University, Belfast, United Kingdom

Vasso Apostolopoulos

Victoria University, Melbourne, VIC, Australia

Table of Contents

Cover image

Title page

Copyright

Contributors

Biography

Foreword

Preface

Chapter 1. History of vaccination

1. Introduction

2. History of vaccines

3. Basic formulation of vaccines

4. Types of vaccines

5. Different routes of vaccine administration and their immune reactions

6. Vaccine hesitancy

7. Manufacturing procedure

8. Regulation, clinical, and ethics approval

9. Conclusion and future prospects

Chapter 2. Vaccine adjuvants and carriers

1. Vaccine adjuvants

2. Carriers

Chapter 3. Conventional vaccination methods: Inactivated and live attenuated vaccines

1. Background

2. Live attenuated vaccines

3. Inactivated vaccines

4. Conclusion and future directions

Chapter 4. Subunit protein-based vaccines

1. Introduction

2. Subunit-based vaccines, overview

3. Subunit vaccines: Preclinical studies

4. Subunit vaccines: Human clinical trials

5. Subunit vaccines: Approved for human use

6. Mechanism of action of subunit protein-based vaccines

7. Conclusion

Chapter 5. Peptide-based vaccines and altered peptide ligands: Multiple sclerosis paving the way

1. Introduction

2. Linear altered peptide ligands

3. Aza-altered peptide ligand analogs

4. Cyclic altered peptide ligands

5. Citrullinated altered peptide ligands

6. Neuropathic pain

7. Thiopalmitoylation of altered peptide ligands

8. Myelin peptides—Mannan conjugates with or without altered peptide ligands

9. Molecular modeling of altered peptide ligands

10. Conclusions

Chapter 6. Vector-based vaccine delivery and associated immunity: Current status and way forward

1. Introduction

2. Type of vectors harnessing

3. Nanomaterial delivery systems

4. Type(s) and magnitude of the induced immune responses

5. Vaccines on market

6. A look into the future

Chapter 7. It is all in the delivery: How to augment the efficiency of DNA vaccination

1. Preamble

2. History

3. Advantages of DNA vaccines

4. Mechanism of action

5. Current state of DNA vaccines

6. Vaccine vector design

7. Route of delivery

8. Improving the immunogenicity of DNA vaccines

9. Nanoparticle delivery systems

10. Nanoparticle materials

11. Lipids as vaccine adjuvants

12. MPLA adjuvant

13. Concluding remarks

Chapter 8. Plant-based vaccines for emerging infectious diseases

1. Introduction

2. Plant biotechnological-derived virus-like particles as a vaccine

3. Biotechnological methods for transient expression of the desired protein in plants

4. Plant-based VLP vaccines for COVID-19 and influenza

5. Safety considerations for plant-based vaccines

6. Regulatory and legal perspectives on plant-based vaccines

7. Conclusion

8. Expert opinion

Chapter 9. Expression system and purification process for the vaccine production

1. Introduction

2. Expression systems for vaccine production

3. Upstream processing

4. Downstream processing/purification of the vaccines

5. Analytical methods

6. Conclusion and future prospects

Chapter 10. Targeting dendritic cells for antigen delivery in vaccine design

1. Introduction

2. Mannose receptor

3. DEC-205

4. DC-SIGN

5. L-SIGN

6. Langerin

7. MGL

8. Dectin-1

9. Conclusion

Chapter 11. Parenteral vaccine delivery: From basic principles to new developments

1. Introduction

2. History

3. Vaccination programs having a significant impact on global health

4. Types of parenteral vaccines

5. Injection techniques for vaccine administration

6. Production, storage, and distribution of vaccines

7. Guidelines and regulations for vaccine development

8. Future development

9. Conclusion

Chapter 12. Mucosal vaccine delivery

1. Introduction

2. Mucosal immunity

3. Induction of mucosal immune responses

4. Advantages of mucosal vaccines

5. Mucosal vaccine formulations

6. Mucosal vaccine approaches

7. Mucosal vaccines under development

8. Challenges

9. Conclusion

Chapter 13. Personalized vaccines, novel vaccination technologies, and future prospects

1. Introduction

2. Understanding pathology-specific vaccination

3. Tailoring vaccines to individual needs

4. Future vaccine technologies

5. Assessing vaccine efficacy

6. Challenges and opportunities in personalized and future vaccines

7. Conclusion

Chapter 14. The application of nanoparticle-based delivery systems in vaccine development

1. Introduction

2. Types of nanocarriers in vaccine development

3. Lipid NPs

4. Polymer NPs

5. Immunostimulating complexes

6. Emulsions

7. The delivery of nanovaccines

8. NPs-based vaccines in clinical trials

9. Discussion and future directions

10. Conclusion

Chapter 15. Preclinical and clinical development for vaccines and formulations

1. Introduction

2. History of vaccine development

3. Types of vaccines

4. Preclinical development of vaccines

5. Clinical development of vaccines

6. Conclusion

Chapter 16. Regulatory processes involved in clinical trials and intellectual property rights around vaccine development

1. Introduction

2. Clinical trials for vaccines

3. Regulatory authorities regarding vaccine products

4. Global regulatory frameworks

5. Clinical trial management

6. Conclusion

Chapter 17. Vaccine safety, efficacy, and ethical considerations

1. Introduction

2. Vaccine safety

3. Vaccine efficacy

4. Conclusion and future prospects

Chapter 18. Regulatory consideration and pathways for vaccine development

1. Introduction

2. Vaccine development stages with their regulatory considerations

3. Vaccine manufacturing considerations (QC-related aspects)

4. Vaccine regulatory approval pathways

5. Challenges in vaccine development: Why and what to do?

6. Conclusions

Chapter 19. New approaches to vaccines for infectious diseases

1. Introduction

2. Novel vaccine antigens

3. Novel vaccine antigen carrier systems

4. Novel vaccination routes

5. Conclusion

Chapter 20. New approaches to vaccines for cancer

1. Introduction

2. History of cancer vaccines

3. Cancer vaccines based on their application

4. Target antigens for cancer vaccines

5. Vaccine development techniques

6. Adjuvants

7. Vaccine resistance

8. Combination therapy

9. Conclusion

Chapter 21. New approaches to vaccines for autoimmunity

1. Introduction

2. Infection-induced autoimmunity

3. Adjuvant-induced autoimmunity

4. Vaccination and autoimmune disease

5. New-generation vaccines

6. Concluding remarks

Chapter 22. The fast-track development of COVID-19 vaccines

1. Introduction

2. COVID-19 vaccines that were accepted for the emergency use authorization and others under phase 3 clinical trials

3. Immune responses against SARS-CoV-2 vaccines' durability

4. Homologous versus heterologous COVID-19 prime-boost immunization strategies: To mix or not to mix?

5. The rapid development of COVID vaccines compared to traditional vaccines

6. Waning of COVID-19 vaccines immunity

7. Post COVID-19 vaccinations sequelae

8. Challenges and ethics related to the COVID-19 vaccine research

9. Conclusions and recommendations

Chapter 23. Myths and facts about vaccination: Dispelling myths and misconceptions with science

1. Introduction

2. Antivaccine movement and its impact in society

3. Myths and misinformation

4. Spread and susceptibility

5. Facts and measures to prevent the spread of misinformation

6. Justifying the common facts of vaccination

7. Handling of the misinformation

8. Myths and facts of COVID-19 vaccines

9. Conclusion

Chapter 24. Proteogenomics and immunopeptidomics in the development of advanced vaccines

1. Introduction

2. Omics-based technology

3. Proteogenomics

4. Immune peptidomics

5. Challenges in proteogenomics and immunopeptidomics vaccine development

6. Future prospective

7. Conclusion

Chapter 25. Nanoparticle-based vaccines and future vaccine technologies

1. Introduction

2. Types of nanoparticles for vaccine delivery

3. Mechanisms of vaccine delivery by nanoparticles

4. Challenges and limitations

5. Recent advances and future directions

6. Conclusion

Index

Copyright

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Contributors

Devarshi Acharya,     Pharmacy Section, L.M. College of Pharmacy, Ahmedabad, Gujarat, India

Kailash Ahirwar,     Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research (NIPER), Lucknow, Uttar Pradesh, India

Nasima Ahmed,     Department of Pharmaceutical Science, Faculty of Science and Engineering, Dibrugarh University, Dibrugarh, Assam, India

Kale Akanksha,     Vaccine Nanotechnology Laboratory, Center for Drug Delivery Research, College of Pharmacy, Mercer University, Atlanta, GA, United States

Mohsen Akbarian,     School of Dentistry, Marquette University, Milwaukee, WI, United States

Bansal Amit,     Vaccine Nanotechnology Laboratory, Center for Drug Delivery Research, College of Pharmacy, Mercer University, Atlanta, GA, United States

Terrick Andey,     Massachusetts College of Pharmacy and Health Science, Worcester, MA, United States

Vasso Apostolopoulos

Australian Institute for Musculoskeletal Science (AIMSS), Melbourne, VIC, Australia

Institute for Health and Sport, Immunology and Translational Research Group, Victoria University, Melbourne, VIC, Australia

Charles R. Ashby,     Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, NY, United States

Pankti C. Balar

Pharmacy Section, L.M. College of Pharmacy, Ahmedabad, Gujarat, India

Department of Pharmaceutics and Pharmaceutical Technology, L.M. College of Pharmacy, Ahmedabad, Gujarat, India

Santosh Baniya,     Department of Internal Medicine, Metrocity Hospital Pvt.ltd, Pokhara, Nepal

Rajashri Bezbaruah

Institute of Pharmacy, Assam Medical College and Hospital, Dibrugarh, Assam, India

Department of Pharmaceutical Sciences, Faculty of Science and Engineering, Dibrugarh University, Dibrugarh, Assam, India

Praful D. Bharadia,     Department of Pharmaceutics and Pharmaceutical Technology, L. M. College of Pharmacy, Ahmedabad, Gujarat, India

Bedanta Bhattacharjee,     Department of Pharmaceutical Science, Girijananda Chowdhury Institute of Pharmaceutical Science-Tezpur, Sonitpur, Assam, India

Yangchen Doma Bhutia,     Defence Research Laboratory, Tezpur, Assam, India

Christos T. Chasapis,     Institute of Chemical Biology, National Hellenic Research Foundation, Athens, Greece

Vivek P. Chavda,     Department of Pharmaceutics and Pharmaceutical Technology, L.M. College of Pharmacy, Ahmedabad, Gujarat, India

Srusti Dave,     Institute of Pharmacy, Nirma University, Ahmedabad, Gujarat, India

Majid Davidson

Institute for Health and Sport, Victoria University, Melbourne, VIC, Australia

Australian Institute for Musculoskeletal Science (AIMSS), Melbourne, VIC, Australia

Shilpa Dawre,     Department of Pharmaceutics, School of Pharmacy, Vishwakarma University, Pune, Maharashtra, India

Pasupuleti Dedeepya,     Vaccine Nanotechnology Laboratory, Center for Drug Delivery Research, College of Pharmacy, Mercer University, Atlanta, GA, United States

Kangkan Deka,     Department of Pharmacognosy, NETES Institute of Pharmaceutical Science, Guwahati, Assam, India

Nimeet Desai,     Department of Biomedical Engineering, Indian Institute of Technology Hyderabad, Kandi, Telangana, India

Joshi Devyani,     Vaccine Nanotechnology Laboratory, Center for Drug Delivery Research, College of Pharmacy, Mercer University, Atlanta, GA, United States

Martin J. D'Souza,     Vaccine Nanotechnology Laboratory, Center for Drug Delivery Research, College of Pharmacy, Mercer University, Atlanta, GA, United States

Yousra A. El-Maradny

Pharmaceutical and Fermentation Industries Development Center, City for Scientific Research and Technology Applications, Alexandria, Egypt

Microbiology and Immunology, College of Pharmacy, Arab Academy for Science, Technology and Maritime Transport (AASTMT), El-Alamein, Egypt

Adediran Emmanuel,     Vaccine Nanotechnology Laboratory, Center for Drug Delivery Research, College of Pharmacy, Mercer University, Atlanta, GA, United States

Jack Feehan,     Institute for Health and Sport, Immunology and Translational Research Group, Victoria University, Melbourne, VIC, Australia

Jasmine E. Francis,     Bioscience and Food Technology, School of Science, RMIT University, Bundoora, VIC, Australia

Kohtaro Fujihashi

Department of Human Mucosal Vaccinology, Chiba University Hospital, Chiba, Japan

Research Institute of Disaster Medicine, Chiba University, Chiba, Japan

Chiba University Synergy Institute for Futuristic Mucosal Vaccine Research and Development Synergy Institute (cSIMVa), Chiba University, Chiba, Japan

Division of Mucosal Vaccines, International Vaccine Design Center, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan

Department of Pediatric Dentistry, The University of Alabama at Birmingham, Birmingham, AL, United States

Nikitas Georgiou,     Department of Chemistry, Laboratory of Organic Chemistry, National Kapodistrian University of Athens, Athens, Greece

Amol D. Gholap,     Department of Pharmaceutics, St. John Institute of Pharmacy and Research, Palghar, Maharashtra, India

Niva Rani Gogoi,     Department of Pharmaceutical Sciences, Faculty of Science and Engineering, Dibrugarh University, Dibrugarh, Assam, India

Piyush Gondaliya,     Department of Cancer Biology, Mayo Clinic, Jacksonville, FL, United States

Menon Ipshita,     Vaccine Nanotechnology Laboratory, Center for Drug Delivery Research, College of Pharmacy, Mercer University, Atlanta, GA, United States

Keshava L. Jetha

Department of Pharmaceutics and Pharmaceutical Technology, L. M. College of Pharmacy, Ahmedabad, Gujarat, India

Gujarat Technological University, Ahmedabad, Gujarat, India

Bibhuti Bhusan Kakoti,     Department of Pharmaceutical Sciences, Faculty of Science and Engineering, Dibrugarh University, Dibrugarh, Assam, India

Tiba Yamin Kandrikar,     Department of Dermatology, Yerevan State Medical University, Yerevan, Armenia

Braz Gomes Keegan,     Vaccine Nanotechnology Laboratory, Center for Drug Delivery Research, College of Pharmacy, Mercer University, Atlanta, GA, United States

Konstantinos Kelaidonis,     NewDrug/NeoFar PC, Patras Science Park, Patras, Greece

Avinash Khadela,     Department of Pharmacology, L. M. College of Pharmacy, Ahmedabad, Gujarat, India

Shreya Khandelwal,     Department of Anesthesiology and Critical Care, Duke University Medical Centre, Durham, NC, United States

Dharmendra Kumar Khatri

Molecular and Cellular Neuroscience Lab, Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad, Telangana, India

Department of Pharmacology, Shobhaben Pratapbai Patel School of Pharmacy & Technology Management, SVKM’s Narsee Monjee Institute of Management Studies (NMIMS) Deemed-to-University, Mumbai, Maharashtra, India

Anup Kumar,     Pharmacy Section, L. M. College of Pharmacy, Ahmedabad, Gujarat, India

Prashant Kumar,     Department of Pharmaceutical Chemistry, Vaccine Analytics and Formulation Center, University of Kansas, Lawrence, KS, United States

Saloni Malla,     Department of Pharmaceutical Sciences, College of Pharmacy, University of Arkansas for Medical Science, Little Rock, AR, United States

Regash Mariajohn,     American International Medical University, Gros Islet, St Lucia

John M. Matsoukas

NewDrug/NeoFar PC, Patras Science Park, Patras, Greece

Institute for Health and Sport, Immunology and Translational Research Group, Victoria University, Melbourne, VIC, Australia

Department of Physiology and Pharmacology, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada

Department of Chemistry, University of Patras, Patras, Greece

Thomas Mavromoustakos,     Department of Chemistry, Laboratory of Organic Chemistry, National Kapodistrian University of Athens, Athens, Greece

Bhaskar Mazumder,     Department of Pharmaceutical Sciences, Faculty of Science and Engineering, Dibrugarh University, Dibrugarh, Assam, India

Carlos Alberto Calvario Miguela,     Department of Internal Medicine, Universidad Popular Autónoma del Estado de Puebla, Puebla, Mexico

Toshika Mishra,     Department of Biotechnology, Science, Innovation, and Society Research Lab, Hexagon (SMV), Vellore Institute of Technology, Vellore, Tamil Nadu, India

Shail Modi,     Massachusetts College of Pharmacy and Health Science, Worcester, MA, United States

Kalliopi Moschovou,     Department of Chemistry, Laboratory of Organic Chemistry, National Kapodistrian University of Athens, Athens, Greece

Neeha Sultana Nasir,     Primecorp Medical Centre, Dubai, UAE

Arzoo Newar,     Department of Pharmaceutical Science, Girijananda Chowdhury Institute of Pharmaceutical Science-Tezpur, Sonitpur, Assam, India

Kulmira Nurgali

Institute for Health and Sport, Victoria University, Melbourne, VIC, Australia

Department of Medicine Western Health, Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne, Melbourne, VIC, Australia

Australian Institute for Musculoskeletal Science (AIMSS), Melbourne, VIC, Australia

Shreya Pande,     Department of Biomedical Engineering, Indian Institute of Technology Hyderabad, Kandi, Telangana, India

Bhoomika M. Patel,     National Forensic Sciences University, Gandhinagar, Gujarat, India

Vandana Patravale,     Department of Pharmaceutical Sciences and Technology, Institute of Chemical Technology, Mumbai, Maharashtra, India

Abhishek Prasad,     Department of Anesthesiology and Critical Care, Duke University Medical Centre, Durham, NC, United States

Bagwe Priyal,     Vaccine Nanotechnology Laboratory, Center for Drug Delivery Research, College of Pharmacy, Mercer University, Atlanta, GA, United States

Asmaa A. Ramadan

Microbiology and Biotechnology Department, Clinical and Biological Sciences Division, College of Pharmacy, Arab Academy for Science, Technology and Maritime Transport (AASTMT), Alexandria, Egypt

Ministry of Health and Population, Alexandria, Egypt

Dhwani Rana,     Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research (NIPER), Ahmedabad, Gujarat, India

Niloufar Rashidi,     Institute for Health and Sport, Victoria University, Melbourne, VIC, Australia

Nidhi Raval,     University of British Columbia, Vancouver, BC, Canada

Elrashdy M. Redwan

Biological Sciences Department, Faculty of Sciences, King Abdulaziz University, Jeddah, Saudi Arabia

Therapeutic and Protective Proteins Laboratory, Protein Research Department, Genetic Engineering and Biotechnology Research Institute, City for Scientific Research and Technology Applications, New Borg EL-Arab, Alexandria, Egypt

Ayush Rohila,     Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research (NIPER), Lucknow, Uttar Pradesh, India

Damanbhalang Rynjah,     Department of Pharmaceutical Science, Girijananda Chowdhury Institute of Pharmaceutical Science-Tezpur, Sonitpur, Assam, India

Ngurzampuii Sailo,     Department of Pharmaceutical Sciences, Faculty of Science and Engineering, Dibrugarh University, Dibrugarh, Assam, India

Sagar Salave,     Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research (NIPER), Ahmedabad, Gujarat, India

Pallab Sarker,     Department of Medicine, Sher-E-Bangla Medical College, Barisal, Bangladesh

Shah Sarthak,     Vaccine Nanotechnology Laboratory, Center for Drug Delivery Research, College of Pharmacy, Mercer University, Atlanta, GA, United States

Adil Ali Sayyed,     Department of Cancer Biology, Mayo Clinic, Jacksonville, FL, United States

Yesha Shah,     PharmD Section, L. M. College of Pharmacy, Ahmedabad, Gujarat, India

Disha Shah,     PharmD Section, L. M. College of Pharmacy, Ahmedabad, Gujarat, India

Jalpan H. Shah,     Department of Pharmaceutics and Pharmaceutical Technology, L. M. College of Pharmacy, Ahmedabad, Gujarat, India

Vijayanand Sharon,     Vaccine Nanotechnology Laboratory, Center for Drug Delivery Research, College of Pharmacy, Mercer University, Atlanta, GA, United States

Rashi Shukla,     Molecular and Cellular Neuroscience Lab, Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad, Telangana, India

Rahul Shukla,     Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research (NIPER), Lucknow, Uttar Pradesh, India

Patil Smital,     Vaccine Nanotechnology Laboratory, Center for Drug Delivery Research, College of Pharmacy, Mercer University, Atlanta, GA, United States

Peter M. Smooker,     Bioscience and Food Technology, School of Science, RMIT University, Bundoora, VIC, Australia

Shailvi Soni,     Massachusetts College of Pharmacy and Health Science, Worcester, MA, United States

Sajeev Sridhar,     Faculty of Medicine, Masaryk University, Brno, Czech Republic

Lobat Tayebi,     School of Dentistry, Marquette University, Milwaukee, WI, United States

Nikita Tiwari,     Department of Pharmaceutical Sciences and Technology, Institute of Chemical Technology, Mumbai, Maharashtra, India

Amit K. Tiwari,     Department of Pharmaceutical Sciences, College of Pharmacy, University of Arkansas for Medical Science, Little Rock, AR, United States

Dhvani U. Trivedi,     Department of Pharmaceutics and Pharmaceutical Technology, L. M. College of Pharmacy, Ahmedabad, Gujarat, India

Catherine Jia-Yun Tsai

Department of Molecular Medicine & Pathology, School of Medical Sciences, The University of Auckland, Auckland, New Zealand

Maurice Wilkins Centre for Molecular Biodiscovery, Auckland, New Zealand

Department of Human Mucosal Vaccinology, Chiba University Hospital, Chiba, Japan

Mohammad N. Uddin,     Vaccine Nanotechnology Laboratory, Center for Drug Delivery Research, College of Pharmacy, Mercer University, Atlanta, GA, United States

Vladimir N. Uversky

Institute for Biological Instrumentation of the Russian Academy of Sciences, Pushchino, Moscow, Russia

Department of Molecular Medicine, USF Health Byrd Alzheimer's Research Institute, Morsani College of Medicine, University of South Florida, Tampa, FL, United States

Disha Valu,     Drug Product Development, Intas Pharmaceutical Ltd. (Biopharma Division), Ahmedabad, Gujarat, India

Srivatsa Surya Vasudevan,     Department of Otolaryngology - Head and Neck Surgery, Mayo Clinic, Jacksonville, FL, United States

Sruthi Venugopalan,     Department of Infectious Diseases, Duke University School of Medicine, Durham, NC, United States

Lalitkumar K. Vora,     School of Pharmacy, Queen's University Belfast, Belfast, United Kingdom

Suneetha Vuppu,     Department of Biotechnology, Science, Innovation, and Society Research Lab, Hexagon (SMV), Vellore Institute of Technology, Vellore, Tamil Nadu, India

Krupa Vyas,     Department of Pharmaceutics, Khyati College of Pharmacy, Ahmedabad, Gujarat, India

Zonunmawii,     Department of Pharmaceutical Sciences, Faculty of Science and Engineering, Dibrugarh University, Dibrugarh, Assam, India

Nikoletta Zoupanou,     Department of Chemistry, Laboratory of Organic Chemistry, National Kapodistrian University of Athens, Athens, Greece

Biography

Vivek P Chavda is an Assistant Professor (Selection Grade), Department of Pharmaceutics and Pharmaceutical Technology, L M College of Pharmacy, Ahmedabad, Gujarat, India. He is B Pharm and M Pharm Gold medalist at Gujarat Technological University. Before joining to academics, he served to Biologics industry for almost 8 years in the Research and Development of Biologics with many successful regulatory filings. He has more than 170 peer-reviewed national and international publications, 18 book chapters, 10 book chapters under communication, 1 patent in pipeline, and numerous newsletter articles to his credit. His research interests include development of biologics process and formulations, medical device development, nanodiagnostics and noncarrier formulations, long-acting parenteral formulations, and nanovaccines.

Dr. Lalitkumar K. Vora is a Lecturer at the School of Pharmacy, Queen's University, Belfast, UK. He completed his PhD (Pharmaceutics) in 2017 from the Institute of Chemical Technology (ICT), Mumbai, and then he did postdoctoral research on microneedle technologies at Queen's University. He has 150 international publications, 10 book chapters, and 2 granted patents. To date, he has presented over 120 peer-reviewed studies at various international conferences. His research interests include polymeric delivery for biologics, long-acting drug delivery, and microneedle-assisted noninvasive drug/vaccine delivery and diagnosis.

Professor Vasso Apostolopoulos is currently the Vice-Chancellor, Distinguished Fellow (Distinguished Professor), Director of Immunology and Translational Research Group at Victoria University, Australia, and Immunology Program Director at the Australian Institute for Musculoskeletal Science, Australia. Previously, she has held several leadership roles including Pro Vice-Chancellor, Research Partnerships, and Associate Provost. She received her PhD majoring in Immunology in 1995 from the University of Melbourne and the Advanced Certificate in Protein Crystallography from Birkbeck College, University of London. Professor Vasso Apostolopoulos is a world-renowned researcher who has been recognized with over 100 awards for the outstanding results of her research. She has more than 510 research publications and 22 patents to her credit; her interests are in vaccine and drug development for cancer and chronic, infectious, and autoimmune diseases.

Foreword

Vaccines have revolutionized the field of medicine by stimulating immune responses and effectively combating infectious or malignant disease. In this book, the aim is to provide readers with a comprehensive and accessible resource on the various aspects of vaccines from their historical origins to cutting-edge developments, this book covers a wide range of topics, including vaccine adjuvants, formulation, preclinical and clinical trials, delivery methods, and different types of vaccines, including peptide-, protein-, vector-, nucleic acid-, plant-, dendritic cell-, and nanoparticle-based vaccines. As we progress, this book addresses regulatory considerations, novel approaches to vaccine development for cancer, autoimmune diseases, and infectious diseases and provides a glimpse into the prospects of vaccines for the betterment of humanity. In the example of the COVID-19 pandemic, vaccines were developed and acquired emergency use status and rolled out in almost 8–9 months; information regarding fast-track vaccine development, as well as myths, misinformation, and facts, is included.

Throughout this book, the readers can easily grasp the intricacies of vaccine development. The introductory section provides a solid foundation by covering the history of vaccines and key considerations in their development. Global data on vaccine development are also presented to offer a comprehensive overview of the field.

The editors and chapter author contributors have focused on providing well-written chapters containing detailed information on all the topics covered. Their efforts have resulted in a uniquely prepared book (Advanced Vaccination Technologies for Infectious and Chronic Diseases: A Guide to Vaccinology) that will undoubtedly contribute to advancements in the field of vaccine development. This book will serve as a valuable resource for researchers in the field and provide an opportunity for those seeking to expand their knowledge of vaccines.

It was for me a life and thrilling experience to lead with Professor Vasso Apostolopoulos, an international multidisciplinary and multiinstitutional consortium for the development of a therapeutic vaccine against multiple sclerosis. At the end, we were happy recently to see our long-time efforts to be awarded with the approval of a human phase I clinical trial, currently under way, for an immunomodulator developed in our laboratories over 20 years. We hope that this and other efforts worldwide including those included in this book will soon provide the much-needed preventions and treatments for the society for diseases.

John Matsoukas

Professor of Medicinal Chemistry, NewDrug SA, Greece,

Victoria University Australia and University of Calgary, Canada

Preface

A vaccine is a biological preparation that stimulates immune responses, either or both, of the innate and acquired immune systems against infectious or malignant diseases. The safety and efficacy of vaccines have been extensively studied and verified. However, the first questions that arise are how vaccines have been prepared and their mechanisms of action. A vaccine typically contains an agent that resembles a disease-causing microorganism, and vaccines are often made from weakened or killed forms of microbes, viruses, their toxins, or an immunogenic surface protein. Vaccination is one of the most effective methods of preventing infectious diseases. From the exploration of innovative vaccine platforms such as mRNA and viral vectors to the elucidation of immune response mechanisms and the assessment of vaccine safety, this book provides a comprehensive overview of the most exciting and transformative advancements in the field.

As the world continues to grapple with emerging infectious diseases such as COVID-19, antimicrobial resistance, and persistent health disparities, the development and deployment of effective vaccines have become all the more crucial. This book serves as a testament to the tireless efforts of scientists and researchers worldwide who strive to stay ahead of these challenges and ensure a healthier future for all.

The main purpose of this book is to provide systemic information from history to new approaches and myths/misinformation and facts about vaccination. The formulation, mechanism of action, and delivery of different types of vaccines contain information regarding the fast-track development of COVID-19 vaccines. The contributing authors have made the use of distinctive headings, figures, and tables to illustrate the subject of matter. We are grateful to all the authors of the chapters for spending their valuable time on contributing to this book and helping our efforts to translate the progress being made in this area. We sincerely hope that this book will become an important source of knowledge for all investigators wishing to work in this area.

This book contains 25 chapters: Chapter 1 includes all the information regarding the history of vaccine development and introduction on the consideration of vaccine design, Chapter 2 includes information on vaccine adjuvants and carriers for the delivery of a vaccine to its target site, and Chapter 3 includes detailed information regarding conventional vaccination methods such as inactivated and live attenuated vaccines. Now, upcoming chapters contain information regarding the different types of vaccine development and its action. Chapter 4 includes information on subunit protein-based vaccines, Chapter 5 contains information on peptide-based vaccines and their mechanism with altered peptide ligands, Chapter 6 focuses on vector-based vaccine delivery, Chapter 7 includes details of nucleic acid vaccines and the importance of their delivery methodology, and Chapter 8 discusses plant-based vaccines. The expression and purification process of vaccines are described in Chapter 9, Chapter 10 contains details of targeting dendritic cells for antigen delivery, and the route of administration is depicted in Chapter 11 (parenteral route) and Chapter 12 (mucosal delivery). Chapter 13 includes details of personalized vaccines, novel vaccination technologies, and future prospects regarding vaccine development. Currently, in a nanotechnology-based era, nanoparticle-based vaccines are highly effective and are described in Chapter 14. Preclinical and clinical development of vaccines is a crucial part of vaccine development and is described in Chapter 15. The regulatory processes involved in clinical trials, vaccine safety, efficacy, and ethical considerations are described in Chapter 16. Chapter 17 talks about vaccine safety, efficacy, and ethical considerations. The regulatory considerations and pathways for vaccine development are described in Chapter 18. Novel approaches in vaccination for infectious diseases, cancer, and autoimmune diseases were highlighted in Chapters 19–21, respectively. Chapter 22 highlights the pros and cons of fast-track vaccine development. The myths/misinformation and facts regarding vaccination are described in Chapters 23 and 24 contains details of proteogenomics and immunopeptidomes in the development of advanced vaccines. Chapter 25 deals with future vaccine technologies.

We hope that this book will serve as a source of inspiration, knowledge, and guidance for the dedicated professionals working in the field of vaccinology. May it foster further innovation, drive collaboration, and contribute to the ongoing mission of protecting and promoting global health through vaccination.

Vivek P. Chavda (Eds.)

Lalitkumar Vora (Eds.)

Vasso Apostolopoulos (Eds.)

Chapter 1: History of vaccination

Vivek P. Chavda¹, Pankti C. Balar¹,², and Vasso Apostolopoulos³     ¹Department of Pharmaceutics and Pharmaceutical Technology, L.M. College of Pharmacy, Ahmedabad, Gujarat, India     ²Pharmacy Section, L.M. College of Pharmacy, Ahmedabad, Gujarat, India     ³Institute for Health and Sport, Immunology and Translational Research Group, Victoria University, Melbourne, VIC, Australia

Abstract

Vaccine production is the greatest achievement of mankind. It ensures immunization against antigens generating protective and long-term antibody and/or T-cell responses. The development of vaccines started in the 1700s and is still in progress today; earlier records date back to ancient times. With time, several types of vaccines, such as live attenuated vaccines, inactivated vaccines, subunit vaccines, toxoid vaccines, and nucleic acid vaccines, have evolved to facilitate the procedure. Chemical elements other than an antigenic portion, such as preservatives, stabilizers, and antibiotics, are added to the formulation to ensure long-term storage. Despite great vaccine achievements such as eradication of smallpox, eradication of polio in Africa, human papillomavirus vaccine, and measles–mumps–rubella vaccines, there has been much hesitancy, especially in the last 4 years with the COVID-19 pandemic. These pose serious hurdles in achieving herd immunity. This chapter takes us through the history of vaccination, with an outlook on major advancements in vaccination.

Keywords

History; Immunization; Immunotherapy; Production; Vaccine

1. Introduction

Vaccines are among the greatest human health achievements of the last century, saving between 2 and 3 million lives each year [1]. Vaccines alone were responsible for eradicating smallpox, and since the development of the first formal vaccine in the 1700s, over 30 different infectious diseases have been successfully prevented with vaccines [2]. These include polio, meningitis, tetanus, chicken pox, human papillomavirus, and more recently, COVID-19. Vaccines work by inducing an adaptive immune response without inducing disease. This can be achieved in several ways, and vaccine technology continues to pave new paths toward antigen-specific immunity. What began as a technique to prevent communicable diseases has since expanded to include protection against cancer [3–7], autoimmune diseases [8], malaria [9], and even protection against nonimmunogenic disorders such as drug addiction [10–14]. These advances have been made possible by the continuous advancement of novel vaccine development techniques. Nonimmunogenic materials such as psychedelic drugs can be rendered immunogenic through the process of haptenization. Vaccines that do not induce robust antibody and T-cell responses can be enhanced with the use of adjuvants [15,16]. It is even possible to activate specific cells of the innate immune response to aid in the recruitment of adaptive immune cells through specific immunomodulatory molecules. The worldwide vaccine market grew from $12 billion in 2005 to $48 billion in 2015 to over $150 billion during COVID-19.

As of February 2021, 85 vaccines were licensed for use in the United States by the US Food and Drug Administration [17]. These include vaccines against poliomyelitis, measles, whooping cough, and, more recently, hepatitis B (recombinant vaccine) and human papillomavirus [17]. Several vaccines against COVID-19 have also been approved via emergency use authorization for those above 5 years old [17–21]. Vaccines have been used for almost 300 years and have evolved to be highly purified, specific, efficient, and effective. The basic concept, however, remains the same; the body's adaptive immune response is activated to stimulate antigen-specific cellular (T cells) and humoral (antibodies) responses against the chosen antigen. This is done, of course, without inducing the disease itself.

2. History of vaccines

The history of prophylactic introduction to disease can be traced back to before 1000 AD [1]. (Fig. 1.1). At this stage in history, there were no formal vaccine technologies; instead, a process called variolation was used, whereby pustule material from patients with smallpox was used to inoculate healthy individuals, thus inducing a protective immune response. Subsequently, Edward Jenner, a Gloucestershire County general practitioner, noted that milkmaids would contract cowpox with minimal symptoms and consequently were protected against smallpox. The concept of molecular mimicry was established, where one organism mimics another organism. Almost 200 years later, smallpox vaccination became popular, and in the decade 1967–77, worldwide mass vaccinations were introduced, and complete eradication was accomplished by December 9, 1979, the only communicable disease to be eradicated [1].

Louis Pasteur is often credited as the mind behind formal vaccination. His serendipitous observation that chickens inoculated with heat-attenuated Pasteurella multocida or chicken cholera, were immune to subsequent infections would eventually lead to the golden age of immunization [10]. Pasteur went on to develop an anthrax vaccine, proving its efficacy in sheep in 1882, and in 1885, Dr. Emile Roux developed the world's first live-attenuated rabies vaccine [22]. Almost concurrently with Pasteur's live-attenuated vaccines, dead-organism vaccines were being utilized in animal models, although it would take another decade for any clinical potential to be realized [23]. In 1886, Theobald Smith and Daniel Salmon developed the world's first heat-killed vaccine against hog cholera. In the following years, as the 19th century came to a close, heat-killed vaccines were developed against cholera, typhoid, and the plague [23]. Toxoid vaccines would come following the discovery of diphtheria exotoxin. In 1883, Corynebacterium diphtheriae was visualized for the first time by Krebs, and in 1884, Loeffler was able to isolate the bacillus in pure culture [24]. Subsequently, it was noted that although the bacteria were present in local lesions of diphtheria patients, they were not present in remote organs that displayed trademark histopathology associated with the disease. In 1888, Roux and Yersin correlated remote lesions with the presence of heat-inactivated exotoxin produced by the bacillus; 2 years later, von Behring and Kitasato discovered antitoxin in the serum of animals who had been previously infected with and had overcome diphtheria, which could neutralize its toxins [24]. Serum therapy was utilized to vaccinate children against diphtheria until 1923, when Glenny and Hopkins successfully attenuated the toxin into a toxoid, thus allowing for the development of the first toxoid vaccine by Ramon [10,24]. Shortly after, in 1926, a tetanus toxoid vaccine was also similarly developed by Ramon [24].

Figure 1.1  Timeline of the development of vaccines from its conception as variolation to the present day, an outline of some major types of vaccines and when they were developed.

There are many distinct types of adjuvants, which can be broadly classified into three groups: (i) active immunostimulants, which increase the magnitude of the immune response; (ii) carriers, which recruit T cells; and (iii) vehicle adjuvants, which are oil emulsions of liposomes that both stimulate the immune response and create a matrix for antigens [11]. One of the most potent and widely used immunological adjuvants is QS-21, which is a saponin derived from the soap bark tree, or Quillaja Saponaria [14]. Another adjuvant derived from the same tree, known as an immunostimulant complex, or ISCOM, is a matrix of the glycoside Quil A [15].

2.1. New improved vaccines

Despite the efficacy of vaccines made with live, attenuated, dead, or inactivated organisms, many human tragedies occurred, largely because of faulty lab manufacture and handling. As a result, protocols and vaccination safety were enhanced to guarantee appropriate laboratory clean conditions. There is a push for precisely specified vaccinations to increase vaccine protection in addition to cost-effectiveness, efficacy, and stability. The development of vaccines in the last 50 years must adhere to greater criteria of safety and biochemical characterization than they did in the past due to increased public knowledge of health and safety problems. Consequently, new enhanced vaccinations that are precisely specified and highly purified are being developed [25]. The transition from conventional live virus vaccines to theoretically safer but less immunogenic vaccines has led to advancements in fields such as molecular biology, DNA and RNA production, amino acid sequencing of organisms of interest, peptide synthesis, protein production, cell biology, crystallography, immunology, and development of animal models. In the last 30 years, a multitude of technologies and delivery systems have been researched to deliver highly purified antigens to elicit appropriate immune responses. Although safer vaccines have been produced, they lack immunogenic potential.

Advances in technology have allowed for the separation of subunits from organisms and thus the advent of polysaccharide vaccines [10]. The first polysaccharide vaccine was developed against Streptococcus pneumonia in the 1970s. Shortly thereafter, in the 1980s, glycoconjugate vaccines were developed and utilized as a method of maturing polysaccharide-specific B cells. Most notably, a vaccine against Hemophilus influenza type B was developed using glycoconjugate methodology.

Adjuvants represent another leap in vaccine technology. When added to vaccines, adjuvants enhance a specific immune response against a specific antigen [26]. In general, they induce early activation of the innate immune system, which directly correlates with higher end-point antibody titers [27]. Recent acceleration of the development of vaccine adjuvants has seen the number of human-use-approved adjuvants rise to include many different components. These include aluminum salts, toll-like receptor agonists, emulsions, and combination immunopotentiators [27], although aluminum salt-based adjuvants remain the most commonly used in commercial vaccines [16,28].

3. Basic formulation of vaccines

The effectiveness of traditional vaccination formulations is mostly limited to viruses with a conserved antigenic character, such as measles and mumps. Highly mutant pathogens (such as the influenza virus and pneumococcus) have decreased effectiveness, and the necessity to deliver new vaccinations every year or expand the antigenic content of the current vaccines is required. The main issue with traditional vaccinations is that they are ineffective against viruses such as HIV that alter their antigens after infection. A humoral, B-cell-mediated immune response is what conventional vaccinations and the adjuvants included in their formulations are primarily intended to induce [29]. Nevertheless, in several cases, either the pathogen infection and residence site are intracellular, necessitating the usage of cytotoxic T cells for their eradication, or B cells alone are unable to attack the pathogen and require aid from helper T cells. The foundation of the formulation process is the production of solid powder that will be reconstituted before usage [30]. The two main goals in the formulation creation of vaccines are the stability of the completed product, which will impact storage conditions, and the addition of adjuvants, of relevance in subunit-, carbohydrate-, or toxoid-based vaccines to improve their immunogenicity. Although traditional vaccinations have been successful in preventing smallpox and other infections, they have several drawbacks that highlight the need for improved and safer vaccines [29].

With the above data, the formulation of vaccines plays a crucial role in the biological activity of vaccines. Some of the common constituents in vaccines include [31]:

3.1. Adjuvants

Used to exaggerate the response of the body against vaccines to provide an effective immune response. The most used adjuvant is aluminum salts.

3.2. Stabilizers

This moiety, as the name suggests, ensures the effectiveness of vaccine postproduction by ensuring that all the constituents are in the exact concentration as formulated. Commonly used stabilizers are sugar and gelatin [32].

3.3. Preservatives

To ensure the prevention of contamination in the formulation. It is a part of the formulation mostly when it is a multidose container (such as flu vaccines). An example of a preservative used in vaccines is thimerosal [33].

3.4. Residual inactivating ingredient

Residual inactivating ingredient is the substance that is used to either kill viruses or inactivate toxins that are produced during the manufacturing procedure. These are usually added in killed/inactivated types of vaccines. The most used inactivating agent is formaldehyde.

3.5. Residual cell culture materials

Substances such as egg proteins, which were incorporated to provide sufficient material for viruses or bacteria to grow, can be a part of the final formulated vaccine.

3.6. Residual antibodies

Residual antibodies are present in the formulation to avoid any contamination by microbial means during the manufacturing process. The most incorporated antibiotics are kanamycin, neomycin, streptomycin, etc.

4. Types of vaccines

Vaccines, as per the requirement and demand of the disease, age of the target, and type of cell involved in immunization influence the selection of the type of vaccine incorporated for it [25].

4.1. Live attenuated vaccines

A pathogen that has decreased in virulence is used to create attenuated vaccinations. Attenuation is a purposeful weakening. Vaccines that are alive closely resemble illnesses. In vaccination, the pathogen reproduces within the host, and both cellular and humoral immunity are often elicited. Lifelong immunity is frequently attained without the need for booster vaccinations, particularly in the case of viruses [34]. The attenuated viruses reproduce in the body, amplifying the effects of the first dosage and functioning as a series of secondary (booster) vaccines as a result, which accounts for the long-term efficacy. Attenuated vaccinations are risky; however, due to the replicating nature of viruses, bacteria can evolve into more virulent forms. Live vaccinations are not recommended for those with weak immune systems since the attenuated virus or bacterium still has the potential to be infectious. Compared to other kinds of vaccines, live-attenuated vaccines have been used successfully to prevent viral illnesses, including measles, mumps, and rubella [35]. They can be delivered locally, and live attenuated influenza vaccines are efficient without the required adjuvants. Intranasal live attenuated vaccines replicate the progression of infection and the generation of antigens naturally, which sets them apart from locally delivered, replication-incompetent vector- or antigen-based vaccines [36,37].

4.2. Inactive (killed) vaccines

An inactivated/killed vaccine is one made of entire viruses, complete bacteria, or fractions of either that have been produced in culture and subsequently destroyed by physical (heat, radiation, or formalin) and chemical (often formalin) means. Pathogens retain enough of their integrity to be identified by the immune system and trigger an adaptive immune response, even though they are killed and unable to divide. In the case of fractional vaccinations, the organism is further processed to isolate only the components needed for the vaccine. As inactivated vaccines are not active and cannot reproduce, repeated doses are always required [38]. The immunological response often occurs after the second or third dose, not frequently after the first dose. The immunological response is mostly humoral immunity, with little or no cellular immunity, and is quite comparable to a natural infection. Antibody titers against the inactivated antigens decrease with time. Therefore, to boost effectiveness, some inactivated vaccines could need routine additional doses [39]. The benefit is that even in immunocompromised individuals, this vaccination does not result in infectious illness. Examples of inactive vaccines include vaccines for typhoid, diphtheria, tetanus, and polio vaccine (Salk vaccine) [40].

4.3. Viral vector-based vaccines

Viral vector-based vaccines have been shown to induce cellular and humoral immune responses without the need for adjuvants. Over the last 5 decades, several viruses have been developed as vaccine vectors. Genetically altered vectors have been designed and developed to further enhance safety and efficacy, reduce dose, and enable large-scale manufacturing as were noted recently with the generation of viral-vector-based vaccines against SARS-CoV-2 [16,41,42]. Some viral vectors include adenovirus types-5, -26, influenza virus, adenovirus, chimpanzee adenovirus, vesicular stomatitis, lentivirus, poxvirus, and insect-specific virus vectors.

4.4. Subunit vaccines

The foundation of subunit vaccines is microbial fragments. Subunit vaccines only include the pathogen antigenic components required to trigger effective immune responses. A polysaccharide, a nucleic acid, or a protein can all be used as antigens. To cause immunological responses, protein subunits carrying a specific immunogenic product are used instead of the entire viral particle [19,43]. Several subunit vaccines have been developed incorporating toll-like receptors [3,44] or using polysaccharide-subunit conjugated formulations [45].

4.5. Virus-like particle vaccines

Virus-derived structures called virus-like particles, which can self-assemble and resemble virus particles in size and shape but lack genetic material to infect host cells, are called virus-derived structures. Viral structures may be created and rebuilt once viral structural proteins are expressed and self-assembled in a variety of live or cell-free expression systems. Virus-like particle-based vaccines are effective for immunization in various infectious diseases and even cancer [46]. A detailed diagrammatic representation is described in Fig. 1.2.

4.6. Polysaccharide-based vaccines

Polysaccharides are frequently the most abundant allergens on the external surfaces of bacterial cells. The initial action of those numerous infections caused by bacteria due to the innate defenses of people is to damage these polysaccharides, which are crucial in interfacing with the outside world. Many vaccines against carbohydrate antigens have therefore been made or are currently being made [47]. Although many vaccines have been developed using carbohydrate antigens, the low immunogenicity and variety of infectious strains and serovars pose a problem to producers regarding the formulation of antigens. To keep up with changes in human infection rates, vaccines, which may be costly and time consuming, usually focus on prevalent serovars or alter their formulations over time [48].

4.7. Nucleic acid (DNA and RNA)-based vaccine

Nucleic acid vaccines have great potential for therapeutic uses in the treatment of cancer and infectious diseases [49–53]. In contrast to traditional vaccinations, nucleic acid vaccines are both relatively affordable and highly effective. Consequently, nucleic acid immunizations could be advantageous for both sickness prevention and therapy. However, due to their low immunogenicity and fragility, nucleic acid vaccine research has been limited. Several studies have been conducted, increasing research and development for therapeutic applications, to improve their immunogenicity and stability through improved delivery strategies [54]. An antigen-coding gene is inserted into a plasmid derived from bacteria to produce DNA vaccines. Strong promoters, frequently the CMV promoter, must exert control over this process. DNA plasmids are replicated in bacteria that can be selected based on antibiotic resistance via gene-producing resistance indicators by using the prokaryotic origin of replication [55]. In addition to changing humoral immunity, DNA vaccinations may also affect cellular immunity by the addition of appropriate delivery methods such as nanoparticles [56,57] and carriers/adjuvants [56,58–61]. For diagrammatic representation, refer to Fig. 1.3.

Figure 1.2  VLPs are produced by encoding a viral structural protein and expression of viral protein and include self-assembly of the molecule. After that, further procedures included clarification, followed by purification and polishing. The expression of VLPs is performed by moieties such as bacteria, yeast, insect cells, plants, and mammalian cells. It mimics the outer structure of the virus, which ensures immunization against infectious diseases. It also interacts with MHC class 1 and MHC class 2, which initiates antibody-dependent cell-mediated cytotoxicity toward tumor cells. Adopted under CC BY 4 from Ref. [46].

Currently, there are two widely used forms of mRNA vaccines: nonamplifying mRNA and self-amplifying mRNA, which are distinguished based on their various processes. Unlike replication-deficient mRNA constructs, self-amplifying mRNA was developed to prolong and intensify gene of interest (GOI) expression. In addition to encoding antigens, a self-amplifying RNA also contains a sequence similar to that of a replication-competent virus, which enables it to replicate in cells and increase protein synthesis [63]. For instance, the self-amplifying RNA of a virus contains nonstructural genes (nsP1-4), a subgenomic promoter, and a variable GOI that may be altered to modify the coding sequence of the viral structural proteins [64]. For RNA-based vaccines, refer to Fig. 1.4.

Figure 1.3  DNA vaccine eluting both humoral and cellular immunity in the individual. Adopted under CC BY 4 from Ref. [62].

5. Different routes of vaccine administration and their immune reactions

Various routes can be utilized to administer the vaccine. They all hold their pros and cons related to immunization, safety, and other adverse events. Broadly, they can be classified as parenteral and mucosal administration.

5.1. Parenteral administration

The parenteral route includes direct administration of the vaccine into the body without introducing it to enteric circulation. Since the beginning of the vaccine development procedure, it has been the most preferred route. It can be attained by four major routes: intramuscular, intravenous, intrathecal, and subcutaneous. Parenteral drug delivery benefits include the ability to quickly provide a precise dose of medication since liver metabolism is avoided and the medication is injected straight into the tissue and circulatory system. Additionally, people who experience nausea and vomiting, cannot take oral fluids, are taking drugs that might irritate the gastrointestinal system, or are unable to swallow may benefit most from the parenteral route. Parenteral medications administered intravenously have 100% bioavailability compared to the enteral mode of administration, where the drug's bioavailability may vary [65].

5.2. Mucosal administration

Any administration method that targets the mucous membrane is referred to as mucosal administration. The most common mucosal administration methods are oral administration and inhalation. At the primary sites of pathogen infection, mucosal vaccines have the potential to induce strong protective immune responses. The triggering of adaptive immunity at mucosal sites, featuring glandular antibody reactions and tissue-resident T cells, has the potential to stop an infection from starting in the first place, rather than just preventing infection and warding off the onset of disease symptoms [66].

In contrast to systemic immunity, mucosal immunity is triggered by antigens that are found on the mucosal surface of different cavities, which are then taken up by M cells or dendritic cells (DCs) in the mucosal inductive site and trigger immune responses in the mucosal effector site [67]. The ways that M cells and DCs take in antigens differ. In particular, M cells may swallow IgA-antigen complexes to capture antigens in addition to possessing antigen phagocytosis comparable to DC cells. The antigen-secretory IgA (sIgA) complex can attach to M cells via certain receptors when an antigen binds to IgA and causes a conformational change in the IgA molecule. M cells can also give DCs a transcellular route for absorbing antigens [68]. M cells are unable to digest antigens because they lack protein-degrading lysosomes; instead, they pass the antigens they have collected to surrounding APCs (such as DCs and B cells). The collected antigens can only successfully elicit antigen-specific immune responses after completing this essential APC processing. However, in addition to increasing the absorption of DCs, researchers are also interested in targeting M cells with vector design to increase the ability of M cells to take up antigens [69].

Figure 1.4  Mechanism of mRNA vaccines. Adopted under CC BY 4 from Ref. [62].

Another route, such as the genital route, is also an area to emphasize. Given that cervical cancer is the fourth most prevalent malignancy in women, mucosal vaccinations that target the vaginal tract may be able to fight STDs and local tumors. It is obvious that there is a great need for an effective HIV vaccine, and given the virus' intestine tropism, mucosal vaccination techniques are necessary. Furthermore, the rise of multidrug-resistant STDs is concerning and may be thwarted by preventative mucosal vaccination techniques [70].

6. Vaccine hesitancy

Vaccine hesitancy is the fear that many individuals experience before being vaccinated. This phenomenon is very common due to several contributing factors, such as lack of information, prejudices, rumors, illiteracy, and influential acts. A similar thing happened during the COVID-19 pandemic. Globally, there are more than 821 vaccines under trial, 242 candidates, and 80 vaccines that have received approval from at least one nation [71–74]. A study was carried out by a group of scientists to study the hesitancy for vaccination in seven low-income countries, five lower-middle-income countries, and one upper-middle-income country. The average hesitancy ratio was 19.7%, of which the lowest was Burkina Faso and Pakistan (33.5%). The common reason behind acceptance was to protect themselves from the deadly disease, while the fear of adverse events was the reason for disapproval. The opinion of healthcare workers was the most trusted among people [75]. Many countries have laws that state mandatory vaccination in children to ensure immunization. Even while working for society, it has always been a topic to debate. A survey in the United States of America stated that approximately 12% of parents oppose compulsory vaccination [76]. It is well known that parents who are reluctant to vaccinate their children are more concerned with the immediate negative effects or unpleasant incidents brought on by the vaccine, but the range of reluctance also encompasses long-term issues, such as neurologic illnesses. The quantity and timing of the suggested vaccination schedule raise further questions about vaccine safety. Many new vaccinations have been launched recently, and more are on the way [77]. These vaccines will be included in the recommended immunization schedule, and there is a good chance that this number will continue to rise. Parents are concerned about their children's immune systems being overloaded as a result of exposure to too many antigens quickly, which might be damaging rather than beneficial. Some parents are especially concerned about children's overall discomfort and suffering after receiving numerous doses at once [78]. Regardless of the reason, vaccination is crucial in the management of numerous diseases. It helps to attain herd immunity in the population to restrict the spread and prevalence of disease [79].

7. Manufacturing procedure

The production of vaccines consists of several fundamental phases that come together to form the final product. The production of the immune response-inducing antigen is the initial stage. In this phase, either the pathogen itself is produced (for later inactivation or separation of a component) or a recombinant protein generated from the pathogen is produced. Additional techniques are used in developing vaccines; they will be covered later. In cells, viruses may be cultivated. These cells can be either primary cells, such as chicken fibroblasts (used in the production of vaccines against yellow fever and hepatitis A), or continuous cell lines, such as MRC-5 [80]. In bioreactors, bacterial pathogens are grown on a medium designed to maximize antigen output while preserving its integrity. Recombinant protein sequences can be produced in cell culture, yeast, or bacteria. The antigen must then be separated from the substrate and the majority of the milieu that served as its growing environment. This might involve removing free viruses, proteins released by cells, or cells harboring the antigen from the used media. The antigen is then purified in the following phase [81]. This phase may entail many individual steps of column-based chromatography and ultrafiltration for vaccines made of recombinant proteins. An isolated virus may be inactivated for viral vaccination without any additional purification. Employees use specialized protective clothes while working in a highly regulated environment to prevent contamination by ad hoc agents. During operations, important surfaces and the environment are monitored for control. At this step, quality control testing often includes tests for the product's sterility, purity, potency, and other characteristics [80].

The effectiveness of vaccines might be negatively impacted by insufficient distribution and storage methods. Vaccines react differently depending on their makeup to harsh environmental factors, including temperature extremes. Compared to inactivated vaccines and toxic substances, live attenuated vaccines are often more sensitive. The potency of vaccines is designed to last past the maximum dosage that is efficacious in clinical studies with humans. The discharge target vigor may be much higher than the specified end-of-shelf-life standard since the product may deteriorate throughout its 2–3-year shelf life [82].

8. Regulation, clinical, and ethics approval

A novel vaccine candidate goes through a thorough development process after being discovered. Novel vaccine candidates are characterized as either the initial intervention of their sort based on the way it works for shielding or as the first vaccination for a disease. Worldwide regulatory organizations separate this research process into preclinical (animal in vitro and in vivo testing) and clinical (human clinical trials) stages. Clinical evaluations are owned by various entities, such as the World Health Organization (WHO), the European Medicines Agency (EMA), and the United States Food and Drug Administration (US FDA) [83]. Vaccines are administered to healthy persons, as opposed to medications, which are given to the sick; as a result, there should be a very large safety margin. In the United States, the first stage for testing the vaccine is exploratory. This is laboratory-based research that lasts for a duration of 2–4 years. After the initial stage, preclinical studies come into the frame. Preclinical studies evaluate the reliability of the potential vaccine and its immune response, or capacity to elicit an immune response, using tissue-culture or cell-culture methods and animal testing. Mice and monkeys can be included in animal topics. On a normal basis, it lasts for 1–2 years [84]. After this, the crucial stage of clinical studies in human subjects begins. It is carried out in three phases starting from the least individual to moving forward for a greater number of individuals and clinical complications. The company that developed the vaccine will submit a Biologics License Application following a positive Phase III study [85]. The vaccine's labeling will next be approved by the authorities, who will also inspect the manufacturing facility. After receiving a license, the authorities will continue to oversee the vaccine's manufacturing, performing facility inspections and examining the manufacturer's reviews of many vaccinations that were tested for potency, safety, and purity. The licensing authority has the power to test the vaccinations produced by producers on its own. Even after the vaccine is marketed, phase IV trials are carried out by the manufacturing company to ensure the efficacy, tolerability, and other measures of the vaccine (Table 1.1) [101,102].

Table 1.1

9. Conclusion and future prospects

The history of vaccine production started in 1700 and is still a booming topic for research today. It ensures that every individual is exposed to a primary source of antigenic compounds to alleviate the immune system. It leads to the production of an immune response and the capability to fight against the actual antigen whenever exposed. Numerous components, such as stabilizers, preservatives, and adjuvants, are incorporated into the formulation to ensure the effective delivery of vaccines and safety. Even with the advancement of healthcare measures, vaccines remain the priority and area of interest to study. It still holds many miraculous properties to help mankind fly out from the ocean of disease with rainbow colors.

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