Bioinformatics for Vaccinology

CONTENTS

Preface

Acknowledgements

Exordium: Vaccines: a Very, Very Short Introduction

1 Vaccines: Their Place in History

Smallpox in History

Variolation

Variolation in History

Variolation Comes to Britain

Lady Mary Wortley Montagu

Variolation and the Sublime Porte

The Royal Experiment

The Boston Connection

Variolation Takes Hold

The Suttonian Method

Variolation in Europe

The Coming of Vaccination

Edward Jenner

Cowpox

Vaccination Vindicated

Louis Pasteur

Vaccination Becomes a Science

Meister, Pasteur, and Rabies

A Vaccine for Every Disease

In the Time of Cholera

Haffkine and Cholera

Bubonic Plague

The Changing Face of Disease

Almroth Wright and Typhoid

Tuberculosis, Koch, and Calmette

Vaccine BCG

Poliomyelitis

Salk and Sabin

Diptheria

Whooping Cough

Many Diseases, Many Vaccines

Smallpox: Endgame

Further Reading

2 Vaccines: Need and Opportunity

Eradication and Reservoirs

The Ongoing Burden of Disease

Lifespans

The Evolving Nature of Disease

Economics, Climate, and Disease

Three Threats

Tuberculosis in the 21st Century

HIV and AIDS

Malaria: Then and Now

Influenza

Bioterrorism

Vaccines as Medicines

Vaccines and the Pharmaceutical Industry

Making Vaccines

The Coming of the Vaccine Industry

3 Vaccines: How They Work

Challenging the Immune System

The Threat from Bacteria: Robust, Diverse, and Endemic

MiCrobes, Diversity, and Metagenomics

The Intrinsic Complexity of the Bacterial Threat

Microbes and Humankind

The Nature of Vaccines

Types of Vaccine

Carbohydrate Vaccines

Epitopic Vaccines

Adjuvants and Vaccine Delivery

Emerging Immunovaccinology

The Immune System

Innate Immunity

Adaptive Immunity

The Microbiome and Mucosal Immunity

Cellular Components of Immunity

Cellular Immunity

The T Cell Repertoire

Epitopes: The Immunological Quantum

The Major Histocompatility Complex

MHC Nomenclature

Peptide Binding by the MHC

The Structure of the MHC

Antigen Presentation

The Proteasome

Transporter Associated with Antigen Processing

Class II Processing

Seek Simplicity and Then Distrust It

Cross Presentation

T Cell Receptor

T Cell Activation

Immunological Synapse

Signal 1, Signal 2, Immunodominance

Humoral Immunity

Further Reading

4 Vaccines: Data and Databases

Making Sense of Data

Knowledge in a Box

The Science of -Omes and -Omics

The Proteome

Systems Biology

The Immunome

Databases and Databanks

The Relational Database

The XML Database

The Protein Universe

Much Data, Many Databases

What Proteins Do

What Proteins Are

The Amino Acid World

The Chiral Nature of Amino Acids

Naming the Amino Acids

The Amino Acid Alphabet

Defining Amino Acid Properties

Size, Charge, and Hydrogen Bonding

Hydrophobicity, Lipophilicity, and Partitioning

Understanding Partitioning

Charges, Ionization, and pKa

Many Kinds of Property

Mapping the World of Sequences

Biological Sequence Databases

Nucleic Acid Sequence Databases

Protein Sequence Databases

Annotating Databases

Text Mining

Ontologies

Secondary Sequence Databases

Other Databases

Databases in Immunology

Host Databases

Pathogen Databases

Functional Immunological Databases

Composite, Integrated Databases

Allergen Databases

Further Reading

Reference

5 Vaccines: Data Driven Prediction of Binders, Epitopes and Immunogenicity

Towards Epitope-Based Vaccines

T Cell Epitope Prediction

Predicting MHC Binding

Binding is Biology

Quantifying Binding

Entropy, Enthalpy, and Entropy-Enthalpy Compensation

Experimental Measurement of Binding

Modern Measurement Methods

Isothermal Titration Calorimetry

Long and Short of Peptide Binding

The Class I Peptide Repertoire

Practicalities of Binding Prediction

Binding Becomes Recognition

Immunoinformatics Lends a Hand

Motif Based Prediction

The Imperfect Motif

Other Approaches to Binding Prediction

Representing Sequences

Computer Science Lends a Hand

Artificial Neural Networks

Hidden Markov Model

Support Vector Machines

Robust Multivariate Statistics

Partial Least Squares

Quantitative Structure Activity Relationships

Other Techniques and Sequence Representations

Amino Acid Properties

Direct Epitope Prediction

Predicting Antigen Presentation

Predicting Class II MHC Binding

Assessing Prediction Accuracy

Roc Plots

Quantitative Accuracy

Prediction Assessment Protocols

Comparing Predictions

Prediction Versus Experiment

Predicting B Cell Epitopes

Peak Profiles and Smoothing

Early Methods

Imperfect B Cell Prediction

References

6 Vaccines: Structural Approaches

Structure and Function

Structure and Function

Types of Protein Structure

Protein Folding

Ramachandran Plots

Local Structures

Protein Families, Protein Folds

Comparing Structures

Experimental Structure Determination

Structural Genomics

Protein Structure Databases

Other Databases

Immunological Structural Databases

Small Molecule Databases

Protein Homology Modelling

Using Homology Modelling Predicting MHC Supertypes Application to Alloreactivity

3D-QSAR

Protein Docking

Predicting B Cell Epitopes with Docking

Virtual Screening

Limitations to Virtual Screening

Predicting Epitopes with Virtual Screening

Virtual Screening and Adjuvant Discovery

Adjuvants and Innate Immunity

Small Molecule Adjuvants

Molecular Dynamics and Immunology

Molecular Dynamics Methodology

Molecular Dynamics and Binding

Immunological Applications

Limitations of Molecular Dynamics

Molecular Dynamics and High Performance Computing

References

7 Vaccines: Computational Solutions

Vaccines and the World

Bioinformatics and the Challenge for Vaccinology

Predicting Immunogenicity

Computational Vaccinology

The Threat Remains

Beyond Empirical Vaccinology

Designing New Vaccines

The Perfect Vaccine

Conventional Approaches

Genome Sequences

Size of a Genome

Reverse Vaccinology

Finding Antigens

The Success of Reverse Vaccinology

Tumour Vaccines

Prediction and Personalised Medicine

Imperfect Data

Forecasting and the Future of Computational Vaccinology

Index