mRNA Vaccines

Preface
Contents
230 mRNA-Based Vaccines and Mode of Action
	Abstract
	1 Introduction
		1.1 Established Vaccination Approaches
		1.2 Novel Vaccination Approaches
	2 mRNA Technology
		2.1 5′ Cap Structure
		2.2 Untranslated Regions (UTR) of mRNA
		2.3 3′End of the mRNA
		2.4 ORF Optimization and Global Modifications
	3 Mode of Action of mRNA Vaccines
		3.1 Innate Immune Sensors Detecting mRNAs
		3.2 Immune Activation by mRNA Vaccines (Adjuvancy vs. Overactivation)
		3.3 Adaptive Immune Response
			3.3.1 Humoral Immunity
			3.3.2 Cellular Immunity
	4 Conclusion
	Acknowledgements
	References
233 Self-amplifying mRNA-Based Vaccine Technology and Its Mode of Action
	Abstract
	1 Introduction
	2 Self-amplifying mRNA: From Viruses to Synthetic Vaccines
		2.1 Self-amplifying mRNA Biology and Mechanistic Clues from the Alphavirus Self-amplification Pathway
		2.2 Main Characteristics of Synthetic Self-Amplifying mRNA Vaccines
	3 Decoding the Balance Between Innate and Adaptive Immune Responses for Potent Self-amplifying mRNA Vaccines
		3.1 Mechanistic Insights from Alphaviruses: Immune Recognition and Evasion of IFN-Mediated Defenses
		3.2 Innate Immune Response to Synthetic Self-amplifying mRNA Vaccines
		3.3 Self-adjuvanting Effect of the Self-amplifying mRNA
	4 Recent Advances and Optimization Approaches of Self-amplifying mRNA Vaccines
	5 Conclusions and Perspectives
	Acknowledgements
	References
217 Formulation and Delivery Technologies for mRNA Vaccines
	Abstract
	1 Introduction
	2 Administration Routes for mRNA Vaccines
	3 Delivery Strategies for mRNA Vaccines
		3.1 Delivery Carriers of mRNA Vaccines
			3.1.1 Lipid-based Delivery
			3.1.2 Polymer-based Delivery
			3.1.3 Peptide-based Delivery
			3.1.4 Virus-Like Replicon Particle
			3.1.5 Cationic Nanoemulsion
		3.2 Naked mRNA Vaccines
		3.3 Dendritic Cells-Based mRNA Vaccines
		3.4 Co-delivery of mRNA Vaccines
			3.4.1 Co-delivery of mRNAs to Assemble Protein Complexes
			3.4.2 Co-delivery of mRNAs Encoding Multiple Antigens
			3.4.3 Co-delivery of mRNAs Encoding Antigens and Immunostimulatory Proteins
	4 Current Challenges and Future Perspectives
	5 Conclusion
	Acknowledgments
	References
202 Messenger RNA-Based Vaccines Against Infectious Diseases
	Abstract
	1 Introduction
	2 mRNA Vaccine Formats and Delivery Materials
		2.1 Optimization of mRNA Production
		2.2 mRNA Vaccine Types
		2.3 Delivery Materials for mRNA Vaccines
	3 Preclinical and Clinical Application of Infectious Disease mRNA Vaccines
		3.1 Influenza Virus mRNA Vaccines
		3.2 HIV-1 mRNA Vaccines
		3.3 Zika and Other Flavivirus mRNA Vaccines
		3.4 Rabies mRNA Vaccines
		3.5 Ebola Virus mRNA Vaccines
		3.6 Other mRNA Vaccines Against Viruses
		3.7 mRNA Vaccines Against Bacteria
		3.8 mRNA Vaccines Against Parasites (Malaria, Leishmania, Toxoplasma)
	4 Passive Immunization with mRNA-Encoded Monoclonal Antibodies Against Infectious Diseases
	5 Conclusions and Future Perspective
	Acknowledgements
	References
222 Advances in Development of mRNA-Based Therapeutics
	Abstract
	1 Introduction
	2 Delivery Platforms for mRNA Therapeutics
	3 In Vitro Synthesis of mRNA Molecules
	4 Clinical Application of mRNA Therapeutics
		4.1 mRNA in Cancer Immunotherapy
		4.2 Cancer Vaccine
			4.2.1 Tumor-Associated Antigen (TAA)-Based Cancer Vaccine
			4.2.2 Neoantigens Antigen-Based Cancer Vaccine
			4.2.3 Dendritic Cell Vaccine
		4.3 Therapeutic mRNA Encoding Cytokines and Other Immune-Modulating Factors
		4.4 CAR-T Cells
		4.5 mRNA Vaccines in Infectious Diseases
		4.6 mRNA in Protein Replacement Therapy
			4.6.1 Local Injection-Based Protein Replacement Therapy
				Myocardial Infarction
				Diabetes Foot
			4.6.2 Liver Diseases
			4.6.3 Lung Diseases
		4.7 Genome Editing
	5 Conclusions
	References
259 Clinical Development of mRNA Vaccines: Challenges and Opportunities
	Abstract
	1 Introduction
	2 Development of Nucleic Acid-Based Vaccines
	3 Clinical Experience with mRNA Vaccines
		3.1 SARS-CoV-2: mRNA-1273 and BNT162b2
		3.2 Other Infectious Disease Vaccines
	4 Key Questions for mRNA Vaccine Clinical Development
		4.1 Do Correlates of Protection Generated by Conventional Vaccines Apply to mRNA Vaccines?
		4.2 Are Packaged mRNA Vaccines Considered an Adjuvanted Vaccine?
		4.3 mRNA Lends Itself to the Development of Combination Vaccines - What are the Implications?
		4.4 mRNA Is a Platform Technology: Does Accumulated Safety Data with One mRNA Vaccine Predict Safety to an Unrelated mRNA Vaccine?
	5 Summary
	References
220 Regulatory Considerations on the Development of mRNA Vaccines
	Abstract
	1 Introduction
	2 RNA Vaccine Development
	3 Production Limitations
	4 Product Quality Issues
		4.1 Chemistry, Manufacture and Controls (CMC) of Drug Substance
		4.2 Identity
		4.3 Consistency of Production
		4.4 Purity of the DS
		4.5 Stability of the DS
		4.6 CMC of Drug Product (DP)
		4.7 Potency Determination
		4.8 Stability of the DP
	5 Potential Safety Issues
		5.1 Immunogenicity of RNA
		5.2 Reactogenicity of RNA
		5.3 Self-Amplifying mRNA (SAM) Vaccines
	6 Safety Evaluation
		6.1 Toxicity
		6.2 Genotoxicity
		6.3 Biodistribution and Retention of the DP
		6.4 Adjuvant Versus Delivery Vehicle
	7 Concluding Remarks
	Acknowledgements
	References