Table of Contents

Preface xiii

Acknowledgements xv

Exordium xvii

1 Vaccines: Their place in history 1

Smallpox in history 1

Variolation 3

Variolation in history 5

Variolation comes to Britain 6

Lady Mary Wortley Montagu 9

Variolation and the Sublime Porte 11

The royal experiment 13

The boston connection 14

Variolation takes hold 17

The Suttonian method 18

Variolation in Europe 19

The coming of vaccination 21

Edward Jenner 23

Cowpox 26

Vaccination vindicated 28

Louis Pasteur 29

Vaccination becomes a science 30

Meister, Pasteur and rabies 31

A vaccine for every disease 33

In the time of cholera 34

Haffkine and cholera 36

Bubonic plague 37

The changing face of disease 39

Almroth wright and typhoid 40

Tuberculosis, Koch, and Calmette 43

Vaccine BCG 44

Poliomyelitis 46

Salk and Sabin 47

Diphtheria 49

Whooping cough 50

Many diseases, many vaccines 51

Smallpox: Endgame 53

Further reading 54

2 Vaccines: Need and opportunity 55

Eradication and reservoirs 55

The ongoing burden of disease 57

Lifespans 57

The evolving nature of disease 59

Economics, climate and disease 60

Three threats 60

Tuberculosis in the 21st century 61

HIV and AIDS 62

Malaria: Then and now 63

Influenza 64

Bioterrorism 65

Vaccines as medicines 67

Vaccines and the pharmaceutical industry 68

Making vaccines 70

The coming of the vaccine industry 70

3 Vaccines: How they work 73

Challenging the immune system 73

The threat from bacteria: Robust, diverse, and endemic 74

Microbes, diversity and metagenomics 75

The intrinsic complexity of the bacterial threat 76

Microbes and humankind 77

The nature of vaccines 78

Types of vaccine 80

Carbohydrate vaccines 82

Epitopic vaccines 82

Vaccine delivery 83

Emerging immunovaccinology 84

The immune system 85

Innate immunity 86

Adaptive immunity 88

The microbiome and mucosal immunity 90

Cellular components of immunity 90

Cellular immunity 93

The T cell repertoire 93

Epitopes: The immunological quantum 94

The major histocompatibility complex 95

MHC nomenclature 97

Peptide binding by the MHC 98

The structure of the MHC 99

Antigen presentation 101

The proteasome 101

Transporter associated with antigen processing 103

Class II processing 103

Seek simplicity and then distrust it 104

Cross presentation 105

T cell receptor 106

T cell activation 108

Immunological synapse 109

Signal 1, signal 2, immunodominance 109

Humoral immunity 110

Further reading 112

4 Vaccines: Data and databases 113

Making sense of data 113

Knowledge in a box 114

The science of -omes and -omics 115

The proteome 115

Systems biology 116

The immunome 117

Databases and databanks 118

The relational database 119

The XML database 119

The protein universe 120

Much data, many databases 122

What proteins do 122

What proteins are 124

The amino acid world 124

The chiral nature of amino acids 127

Naming the amino acids 130

The amino acid alphabet 132

Defining amino acid properties 134

Size, charge and hydrogen bonding 135

Hydrophobicity, lipophilicity and partitioning 136

Understanding partitioning 139

Charges, ionization, and pka 140

Many kinds of property 143

Mapping the world of sequences 146

Biological sequence databases 147

Nucleic acid sequence databases 148

Protein sequence databases 149

Annotating databases 150

Text mining 151

Ontologies 153

Secondary sequence databases 154

Other databases 155

Databases in immunology 156

Host databases 156

Pathogen databases 159

Functional immunological databases 161

Composite, integrated databases 162

Allergen databases 163

Further reading 165

Reference 165

5 Vaccines: Data driven prediction of binders, epitopes and immunogenicity 167

Towards epitope-based vaccines 167

T cell epitope prediction 168

Predicting MHC binding 169

Binding is biology 172

Quantifying binding 173

Entropy, enthalpy and entropy-enthalpy compensation 174

Experimental measurement of binding 175

Modern measurement methods 177

Isothermal titration calorimetry 178

Long and short of peptide binding 179

The class I peptide repertoire 180

Practicalities of binding prediction 181

Binding becomes recognition 182

Immunoinformatics lends a hand 183

Motif based prediction 184

The imperfect motif 185

Other approaches to binding prediction 186

Representing sequences 187

Computer science lends a hand 188

Artificial neural networks 188

Hidden Markov models 190

Support vector machines 190

Robust multivariate statistics 191

Partial least squares 191

Quantitative structure activity relationships 192

Other techniques and sequence representations 193

Amino acid properties 194

Direct epitope prediction 195

Predicting antigen presentation 196

Predicting class II MHC binding 197

Assessing prediction accuracy 199

ROC plots 202

Quantitative accuracy 203

Prediction assessment protocols 204

Comparing predictions 206

Prediction versus experiment 207

Predicting B cell epitopes 208

Peak profiles and smoothing 209

Early methods 210

Imperfect B cell prediction 211

References 212

6 Vaccines: Structural approaches 217

Structure and function 217

Types of protein structure 219

Protein folding 220

Ramachandran plots 221

Local structures 222

Protein families, protein folds 223

Comparing structures 223

Experimental structure determination 224

Structural genomics 226

Protein structure databases 227

Other databases 228

Immunological structural databases 229

Small molecule databases 230

Protein homology modelling 231

Using homology modelling 232

Predicting MHC supertypes 233

Application to alloreactivity 235

3D-QSAR 236

Protein docking 238

Predicting B cell epitopes with docking 238

Virtual screening 240

Limitations to virtual screening 241

Predicting epitopes with virtual screening 243

Virtual screening and adjuvant discovery 244

Adjuvants and innate immunity 245

Small molecule adjuvants 246

Molecular dynamics and immunology 248

Molecular dynamics methodology 249

Molecular dynamics and binding 249

Immunological applications 250

Limitations of molecular dynamics 251

Molecular dynamics and high performance computing 252

References 253

7 Vaccines: Computational solutions 257

Vaccines and the world 257

Bioinformatics and the challenge for vaccinology 259

Predicting immunogenicity 260

Computational vaccinology 261

The threat remains 262

Beyond empirical vaccinology 262

Designing new vaccines 263

The perfect vaccine 264

Conventional approaches 265

Genome sequences 266

Size of a genome 267

Reverse vaccinology 268

Finding antigens 269

The success of reverse vaccinology 271

Tumour vaccines 273

Prediction and personalised medicine 275

Imperfect data 276

Forecasting and the future of computational vaccinology 277

Index 283

About the Author

Dr Darren R Flower, Reader in Pharmacy, School of Life and Health Sciences, University of Aston, Birmingham, UK.

Reviews

“It pulls a number of different disciplines into a concise review that illustrates the potential we have in science to change our world.” (Doody's, April 2009)
"This book may well serve as a first line of reference for all biologists and
computer scientists. This textbook would be an excellent addition to the bookshelf of most scientists who encounter vaccinology in the drug discovery and development processes." ( Virology Journal - October -2009)