Antiviral Therapeutics - Technologies, markets and companies

• Publication date: February 2012

This report reviews the current state-of-art of antiviral approaches including vaccines, pharmaceuticals and innovative technologies for delivery of therapeutics. The introduction starts with a practical classification of viral diseases according to their commercial importance. Various antiviral approaches are described including pharmaceuticals and molecular biological therapies such as gene therapy and RNA interference (RNAi) as well as vaccine...

This report reviews the current state-of-art of antiviral approaches including vaccines, pharmaceuticals and innovative technologies for delivery of therapeutics. The introduction starts with a practical classification of viral diseases according to their commercial importance. Various antiviral approaches are described including pharmaceuticals and molecular biological therapies such as gene therapy and RNA interference (RNAi) as well as vaccines for virus infections. Expert opinion is given about the current problems and needs in antiviral therapy. SWOT (strengths, weaknesses, opportunities and threats) analysis of antiviral approaches is presented against the background of concept of an ideal antiviral agent.

A novel feature of this report is the use of nanotechnology in virology and its potential for antiviral therapeutics. Interaction of nanoparticles with viruses are described. NanoViricides are polymeric micelles, which act as nanomedicines to destroy viruses. Various methods for local as well as systemic delivery of antiviral agents and vaccines are described. Nanobiotechnology plays an important role in improving delivery of antivirals. Advantages and limitations of delivery of gene-based, antisense and RNAi antiviral therapeutics are discussed.

Anti-influenza measures applicable to human as well as avian forms are described including the recent epidemic of swine flu. Resistance can develop against neuraminidase inhibitors although it is less than that with adamantanes. Considering these problems, there is need for a more effective agent. Investigations into alternative anti-influenza target will probably expand in the coming years. These include the development of mechanisms to inhibit fusion between the virus envelope and the cell membrane.

After a discussion of current therapies of AIDS/HIV and their limitations, new strategies in development of antiviral agents are described. Drug resistance and toxicities are emerging as major treatment challenges. Based on a review of technologies and drugs in development, it can be stated that there are good prospects are of finding a cure for HIV/AIDS in the next decade.

Hepatitis viruses are described with focus on hepatitis C virus (HCV) and hepatitis B virus (HBV). Despite the presence of numerous drug candidates in the anti-HCV pipeline, and the commitment of major R&D resources by many pharmaceutical companies, it might still take several years for any new anti-HCV drugs to reach the market. Although many companies are focusing their efforts on developing viral inhibitors, cellular targets in the host are beginning to emerge as attractive possibilities because they might enable the development of broad-spectrum antiviral drugs with less chance for developing viral resistance.

Various commercially important viruses include herpes simplex (HSV) and human papilloma virus (HPV). There a number of treatments but HSV is not destroyed completely and remains dormant and activates from time to time to cause various clinical manifestations. There is discussion about the role of HPV in cervical cancer and vaccines available now seem to be adequate in preventing HSV-induced cervical cancer. There is no effective vaccine for respiratory syncytial virus (RSV) although monoclonal antibody (MAb) treatment is useful for prophylaxis and reducing the clinical manifestations. There is a need for an agent to eliminate this virus.

Various viruses that either occur in epidemics or in tropics and some naturally emerging infectious diseases are described, e.g. viral hemorrhagic fevers such as dengue and West Nile virus infection. These are a constant threat and impossible to anticipate. Some of these lack antiviral agents or vaccines for prevention. Although these include some of the most serious viral disorders, the development of antiviral agents for these is not commercially attractive. Current research and approaches to these virus infections are discussed.

Markets for antivirals are considered according to viruses and diseases caused by them and also according to management approaches: antiviral drugs, vaccines, MAbs and innovative approaches that include immunological and use of other technologies such as gene therapy, antisense, RNAi and nanobiotechnology. Antiviral markets are estimated starting with 2010 with projections up to the year 2020.

Profiles of 178 companies that are involved in developing various technologies and products are profiled and with 161 collaborations. These include major pharmaceutical companies (13), those developing antiviral therapeutics (107) as well as viral vaccine companies (58). The report is supplemented with 49 tables, 11 figures and 450 references from the literature.

Therapy Industry

TABLE OF CONTENTS

0. Executive Summary 17
1. Introduction to Virology 19
Introduction 19
Virus databases 19
A practical classification of viruses 19
Pathomechanism of viral diseases relevant to therapy 20
Intrinsic host defense against retroviruses 21
Life cycle of virus as basis for antiviral approaches 22
Genetic switch in virus infections 22
Emerging viruses 23
Viral-induced cancer 23
Prophylaxis versus therapy 24
Economic impact of viral diseases 25
Historical landmarks in the development of antiviral therapies 25
2. Antiviral Approaches 27
Classification 27
Antiviral drug discovery and development 27
Viral versus cellular targets for antiviral therapy 27
Antivirals based on double-stranded RNA activated caspase oligomerizer 29
Antimicrobial peptides 29
Immunological approaches 29
Basics of immune regulation in relation to viruses 29
Effect of viruses on the immune system 30
Latent viral infections and the immune system 30
Immunomodulating agents 31
Amplification of innate immunity 31
Blocking the effects of thromboxane A2 on thromboxane receptor 31
Enhancers of immune system 32
Promoting immune-mediated clearance of a chronic viral infections 32
Immunoglobulins 32
Bovine lactoferrin 33
Quercetin 33
Monoclonal antibodies 34
Bavituximab 34
Treatment of viral infection with radiolabeled MAbs 35
Limitations of MAbs and measures to overcome these 35
Interferon-based approaches 35
Novel antiviral approaches 36
Squalamine 36
Synthetic modified hypericin compounds 36
Targeting Toll-like receptors 36
Potential and drawbacks of TLR-ligands in viral diseases 37
Inhibition of viral transport from cytoplasm into the cell nucleus 38
Nitric Oxide based antiviral therapeutics 38
Gene therapy for viral infections 38
Antisense approaches to viral infections 39
Antisense oligonucleotides 39
Limitations of antisense oligonucleotides as antivirals 40
NEUGENE antisense 40
RNAi 40
RNAi screens of viral genomes 41
RNAi for treatment of viral infections 41
Promise and pitfalls of RNAi gene therapy 42
Management of rapidly evolving pathogens 42
Personalized medicine and viral diseases 42
An integrated approach to viral diseases 43
Current problems and needs in antiviral therapy 43
3. Vaccines for Virus Infections 45
Introduction 45
Types of vaccines 46
Live attenuated virus vaccines 46
DNA vaccines 46
Nanotechnology-based vaccines 47
Recombinant viral vaccines 48
Synthetic peptides as vaccines 48
Virosomes 49
Vaccines based on reverse genetics 49
Virus-like particles 49
Routine vaccination in children against viral infections 50
Personalized vaccines 50
Limitations of vaccines 50
Neurological complications of vaccination 51
Expert opinion on antiviral vaccines 51
4. Role of Nanotechnology in Developing Antiviral Agents 53
Introduction 53
Study of interaction of nanoparticles with viruses 53
Nanoparticle antiviral agents 54
Silver nanoparticles 54
Fullerenes 54
Nanoviricides 55
Role of micelles in nanopharmaceuticals 55
Some physicochemical characteristics common to polymeric micelles 55
Structure and function of nanoviricides 56
Mechanism of action of NanoViricides 56
Advantages of NanoViricides 57
5. Delivery of Antivirals 59
Introduction 59
Methods of delivery of antiviral agents 59
Local application of antivirals 59
Systemic delivery of of protein-polymer antiviral drugs 60
Controlled delivery of antivirals 60
Targeted delivery of antivirals 60
Delivery of antivirals to the brain across the blood-brain barrier 61
Antiviral vaccine delivery systems 61
Minicell vaccine delivery 61
Transnasal delivery of vaccines by Newcastle disease virus as vector 61
Transdermal delivery of vaccines 62
CELLECTRA® electroporation device 62
Intramuscular electroporation for delivery of DNA vaccine 62
HIV/AIDS vaccination by transdermal application 62
Transdermal vaccines for influenza 63
Use of nanotechnology for improving delivery of antivirals 63
Macrophage-based nanoformulated antiretroviral therapy 64
Improvement of antiviral vaccine delivery by nanotechnology 65
Bacterial spores for delivery of vaccines 65
Liposomal antiviral vaccine preparations 65
Nanoparticles for DNA vaccines 65
Chitosan-derived nanoparticles for vaccine delivery 66
Use gold nanorods for delivery of RNA immune activator molecules 66
Proteosomes™ as vaccine delivery vehicles 66
Polymeric micellae for delivery of DNA vaccine 66
“Smart” nanoparticles for delivery of vaccines 67
Nanospheres for controlled release of viral antigens 67
Nanocoating for local viricidal effect 67
Delivery of gene-based antiviral drugs 68
Limitations of delivery of gene, RNAi and antisense therapies 68
Systemic delivery of NanoViricides 68
Concluding remarks on delivery of antiviral agents 69
6. Competitive Assessment of Antiviral Approaches 71
Introduction 71
An ideal antiviral agent 71
SWOT analysis 71
Concluding remarks 74
7. Influenza Viruses 75
Introduction 75
Clincal features of influenza 75
Colds due to rhinovirus 75
Effects of influenza on the respiratory system 76
Effect of avian influenza on the nervous system 76
Epidemiology 76
Supermap of avian influenza 76
Influenza A 77
Avian influenza affecting humans 77
Human influenza versus avian influenza 78
H1N1 influenza 79
Immune system and influenza 80
Immune Epitope Database and Analysis Resources 80
Anti-influenza approaches 81
Pharmaceuticals 81
Neuraminidase inhibitors 81
Mechanism of action 81
Tamiflu 82
Zanamivir 82
CS-8958 82
Peramivir 83
Resistance to neuraminidase inhibitors 83
Adverse effects of neuraminidase inhibitors 84
Other drugs for influenza 85
Adamantanes 85
Probenecid 85
Current recommendations for the use of antiviral agents for influenza 85
Vaccines 86
Seasonal influenza vaccines 86
Live attenuated influenza vaccine vs. inactivated vaccine 86
Vaccines for H1N1 influenza 87
Current status of influenza vaccines 88
Current recommendations for influenza vaccination 88
Current status of vaccine preparedness against seasonal influenza 88
Current status of vaccine preparedness against H5N1 89
Limitations, needs and challenges of influenza vaccines 89
Limitations of current influenza vaccines 89
Needs of influenza vaccines 90
Problems with demand and supply of influenza vaccines 91
Problems with access to virus samples 91
FluVac project for development of pandemic influenza vaccine 91
Influenza vaccines for multiple strains of the disease 92
Universal influenza vaccines 92
Future prospects of influenza vaccines 92
Application of new technologies for influenza vaccines 93
Adjuvants 93
Cell culture-derived influenza vaccines 94
DNA vaccines for avian influenza 95
Epitope-based vaccines for influenza 95
Gene-based vaccines for influenza 96
Live attenuated vaccines 96
MAbs for passive immunization against avian influenza 96
M2e-based human influenza A vaccine. 96
Pre-pandemic split antigen H5N1 vaccine 97
Recombinant-protein based influenza vaccines 97
Synthetic avian influenza vaccine 98
Viral vectors for influenza vaccination 99
Virus-like particles as influenza vaccines 99
RNAi-based approaches 100
Inhibition of influenza virus by siRNAs 100
Limitations of RNAi approach to influenza 101
Challenges and future prospects of siRNAs for influenza 101
Antisense approaches 102
NEUGENE® antisense for inhibition of multiple strains of influenza A 102
Nanoviricides against influenza 102
Other innovative approaches 103
Abatacept 103
Polymeric coatings to inactivate influenza virus 103
Cytotoxic therapy 103
Cyanovirin 104
Fludase 104
Multiferon® 104
Pyrrolidine dithiocarbamate 105
T-705 105
Value of antivirals in preventing spread of influenza after exposure 105
Resistance to influenza therapy and efforts to overcome it 105
NIAID Centers of Excellence for research on pandemic influenza viruses 106
Research on influenza viruses at Bayer 106
Concluding remarks and future prospects 107
8. AIDS/HIV 109
Introduction 109
Epidemiology 109
Current concepts of pathomechanisms 109
Decoding the structure of an entire HIV genome 110
Genentic basis of resistance against HIV 110
Host-pathogen interactions that regulate HIV-1 replication 110
Pathogenesis of AIDS 111
Visualization of the interaction of HIV-1 proteins with target cells 112
Viral latency in HIV 112
Complications of AIDS 113
AIDS and the nervous system 113
Opportunistic infections in AIDS 113
Coexistent HIV-1 and HSV-2 114
Coexistent hepatitis virus infections with HIV 114
HIV and HBV 115
HIV and HCV 115
AIDS wasting syndrome 116
Current therapies 116
Aim of anti-HIV drugs 117
Efavirenz 118
Tipranavir 118
Enfuvirtide 119
Darunavir 119
Impact of antiretroviral treatment on transmission of HIV 119
Postexposure prophylaxis against HIV 120
Limitations of current therapies 121
Adverse effects of antiretroviral therapy 121
Drug resistance in AIDS 122
Effect of interruption of HIV treatment 123
Reservoirs of HIV Infection 123
Persistance of low-level viremia in HIV-1 patients on retroviral therapy 123
Reconsideration of abandoned therapies for AIDS 123
Therapies in development 123
Drugs in development for HIV/AIDS 124
Nucleoside reverse transcriptase inhibitors 125
Apricitabine 125
Non-nucleoside reverse transcriptase inhibitors 125
Etravirine 125
IDX899 125
Novel protease inhibitors 126
Overcoming HIV-1 resistance to PIs 126
PPL-100 127
Entry inhibitors targeting CCR5 receptor 127
Maraviroc 128
SP-01A 128
MAbs targeting CCR5 receptor 128
PRO 140 129
Ibalizumab 129
Integrase inhibitors 130
Raltegravir (Isentress) 130
Elvitegravir (GS 9137) 131
S/GSK1349572 131
S/GSK1265744 132
Design of fusion inhibitor peptides against enfuvirtide-resistant HIV-1 132
Maturation inhibitors 132
Blocking of pre-integration complex translocation 133
Immune enhancers 133
Pyrimidinediones 133
Novel combinations of drugs for prevention of AIDS 134
Truvada 134
Combination of raltegravir, enfuvirtide, and darunavir 134
Other innovative antiviral approaches against HIV/AIDS 134
Enhancing immune response by blockade of PD-1 receptor 134
IL-2 as adjunct to antiretroviral therapy 135
A filtration device for HIV-1 as an adjunct to the immune system 135
In vitro evaluation of antiviral drug activity 135
Methods for sustaining antiviral activity 136
Selective targeting of ITK to block multiple steps of HIV replication 136
Drugs from natural sources 136
Anti-HIV activity of drugs that stimulate cholesterol efflux 137
Antiviral hyperactivation-limiting therapeutics 137
Blocking of HIV budding by DC-SIGN protein 137
ATR kinase as a target for anti-HIV drug discovery 138
Nanoviricides for HIV/AIDS 138
Prophylactic measures to prevent HIV infection 138
Microbicidal agents for local application in HIV/AIDS 139
Currently investigated microbicidals against HIV and their limitations 139
CCR5 receptor blockers 140
PSC-Rantes and recombinant chemokine analogs 140
HIV-1 entry inhibitor griffithsin as a topical microbicide 141
Nanotechnology-based topical microbicides 141
Next generation microbicides for HIV 141
Intracellular immunization in HIV 142
Engineered cellular proteins such as soluble CD4s 142
Intracellular antibodies 142
Selection of T-cell vaccine antigens 142
Glycoprotein 120 as target for neutralizing HIV-1 antibodies 143
Anti-rev single chain antibody fragment 143
Gene therapy strategies in HIV/AIDS 143
Inhibition of HIV-1 replication by lentiviral vectors 144
VRX496 (Lexgenleucel-T) 144
Insertion of protective genes into target cells 145
Use of genes to chemosensitize HIV-1 infected cells 145
Autocrine interferon-? production by somatic cell gene therapy 145
HIV/AIDS vaccines 145
Cell-based vaccines for HIV 146
Delivery of HIV vaccine by an adenoviral vector 147
DNA vaccines for HIV/AIDS 147
Epitope-based DNA vaccines against HIV 148
Gene transfer for HIV vaccination 149
Limitations and needs of HIV vaccines 149
Recombinant HIV proteins 149
Vaccination after discontinuation of antiretroviral treatment 149
Innovations in HIV/AIDS vaccine 150
Attenuated rabies virus-based vaccine for HIV 150
Combination of a prime vaccine and booster vaccine 150
Dendritic cell-based vaccine for HIV 151
DermaVir 151
Early control of HIV by an effector memory T cell vaccine 151
MVA nef vaccine 152
Peptide-based vaccine for HIV 152
Personalized vaccine for HIV 152
Transdermal nanoparticles for immune enhancement in HIV 152
Vaccine to prevent HIV entry at the mucosal level 153
Cell therapy for HIV/AIDS 153
hESCs converted to T-cells for treatment of HIV infection 153
Transplantation of genetically modified hematopoietic cells 154
Transplantation of genetically modified T cells 154
Overlapping Peptide-pulsed Autologous Cells 155
Antisense approaches to AIDS 155
Antisense oligodeoxynucleotides 155
Antisense efforts with PNA constructs 155
RNA decoys 156
Ribozymes 156
RNAi applications in HIV/AIDS 157
A multiple shRNA approach for silencing of HIV-1 157
Aptamer-mediated delivery of anti-HIV siRNAs 158
Bispecific siRNA constructs 158
Role of the nef gene during HIV-1 infection and RNAi 158
siRNA-directed inhibition of HIV-1 infection 159
Synergistic effect of snRNA and siRNA 159
Targeting CXCR4 with siRNAs 160
Targeting CCR5 with siRNAs 160
Concluding remarks on RNAi approach to HIV/AIDS 161
Companies involved in developing gene therapy for HIV/AIDS 161
Conclusions regarding gene therapy of HIV/AIDS 162
Testing for new anti-HIV therapies 162
Personalized approach to management of HIV 162
Differences in response of the body to HIV 163
Variations in action of drugs on HIV 163
Drug-resistance in HIV 163
Replication Capacity measurement 164
Role of biomarkers in management of HIV/AIDS 164
Prevention of adverse reactions to antiviral drugs 164
Nanoviricides as a personalized approach to HIV 165
Concluding remarks and future prospects 165
9. Hepatitis Viruses 167
Introduction 167
Hepatitis delta virus infection 167
Hepatitis A virus infection 167
Hepatitis E virus infection 168
Epidemiology 168
Structure of the HEV 168
HEV vaccines 168
Epidemiology of HBV 169
Pathogenesis of HBV-induced liver disease 169
Current approaches to management of HBV 170
Entecavir 170
Adefovir dipivoxil 171
Telbivudine 171
Pegylated interferon-alpha 171
Limitations of current therapies and needs of HBV 171
Personalized management of HBV 172
Innovations in the management of HBV 172
Tenofovir disoproxil fumarate 172
Hepatitis B immune globulins 173
Nabi-HB 173
HepaGam B 173
Hepatitis B vaccine composed in a novel nanoemulsion adjuvant 173
Innovative pharmaceuticals for HBV 174
Clevudine 174
HepDirect prodrugs 174
Monoclonal antibodies for HBV 175
RNAi-based therapy of HBV 175
Personalized treatment of hepatitis B 176
Concluding remarks and future prospects of management of hepatitis B 176
Epidemiology of HCV 176
HCV characteristics 177
Pathomechanism of HCV infection 177
Mechanism of HCV entry 177
HCV and the immune system 177
Mechanism of HCV replication and response to interferon 178
Current approaches to management of HCV 178
Interferon therapy for HCV 178
Limitations of current HCV therapies 179
Novel approaches to HCV 179
HCV protease inhibitors 180
Boceprevir 180
Narlaprevir (SCH 900518) 180
Telaprevir (Incivek) 181
Small molecule HCV protease inhibitors 181
Innovations in interferon therapy for HCV 181
AlbIFN-?2b 182
Directed evolution of gene-shuffled IFN-? for treatment of HCV 182
GEA007.1 182
Omega DUROS 182
PEG-IFN-? 183
Personalizing interferon therapy of HCV 183
Innovative ribavirin-based treatments 184
Targeted delivery of hemoglobin-ribavirin conjugate for HCV 184
Taribavirin 184
Nucleoside polymerase inhibitor 184
Valopicitabine 184
Host cell targets for hepatitis C therapy 185
SP-10 185
NS5a inhibitors 186
Compounds targeting HCV receptor E2 186
Cyclophilin inhibitors 186
Alisporivir 187
Methylene blue 187
Naringenin 187
Nitazoxanide 188
Cyclosporine and analogues as anti-HCV agents 188
Clemizole and HCV 189
RNAi-based approaches to HCV 189
Use of adenoviral vectors for RNAi 189
siRNAs for HCV 190
Limitations and drawbacks of siRNA therapy for HCV 190
Role of miRNA in viral infections 191
miR-122 antagonists 191
Therapeutic vaccine for HCV 191
Clinical trials of HCV therapeutics 192
Limitations to the development of effective anti-HCV therapeutics 192
Causes of treatment failure in chronic hepatitis C 192
HCV drug resistance 193
Personalized management of HCV infection 193
Role of sequencing in personalized management of HCV 194
Concluding remarks about HCV therapy 195
Future needs in HCV therapy 195
10. Miscellaneous Commercially Important Virus Infections 197
Introduction 197
Herpes viruses 197
Herpes simplex virus 197
Treatment of HSV-1 197
Acyclovir 197
Vaccines for HSV 198
Antisense therapy for HSV-1 198
Herpes simplex virus 2 and genital herpes 198
Famciclovir 199
Intravaginal microbicidal agents for HSV-2 199
Vaccines for HSV-2 199
Herpes simplex keratitis 200
Herpes simplex encephalitis 200
Limitations of current HSV therapies 201
Herpes zoster virus 201
Herpes zoster and chicken pox 201
Epidemiology of herpes zoster 201
Treatment of herpes zoster 202
Herpes zoster vaccine 202
Cytomegalovirus 202
Valganciclovir hydrochloride 203
T-cell therapy for CMV 203
Vaccine for CMV 203
Gene therapy of CMV 203
Antisense approach to CMV 204
siRNA treatment of CMV 204
Epstein-Barr virus 205
Human papilloma virus 205
Epidemiology 205
Vaccines for HPV 205
Gardasil 206
Cervarix 206
Vaccine based on fusion proteins of HPV envelope 206
DNA vaccine VGX-3100 207
Limitations of HPV vaccines 207
Antivirals for HPV 208
Imiquimod 208
Novel approaches against HPV 208
Intrabody strategies for the treatment of HPV 208
A novel peptide to inhibit HPV 209
Heat shock protein-based antivirals 209
Respiratory syncytial virus 209
Epidemiology 209
Current management of RSV 210
Palivizumab 210
Innovative anti-RSV products in development 210
RSV604 210
MDT-637 210
RNAi approach to RSV 211
Vaccines for RSV 211
BCG as a vaccine against RSV 211
Oral DNA vaccine for RSV 211
Other respiratory viruses 212
Parainfluenzavirus type 3 212
Human metapneumovirus 212
Gastrointestinal viruses 213
Noroviruses 213
Concluding remarks 214
11. Viruses with High Impact but Low Commercial Significance 215
Introduction 215
Chikungunya fever 215
Coxsackie virus 215
Japanese encephalitis 216
Vaccines for JE 216
Parvovirus 217
Polyomavirus JC 217
Rabies 217
Rabies vaccines 218
Recombinant viral vaccines for rabies 218
DNA vaccine against rabies 219
Rabies immune globulin 219
Monoclonal antibodies for rabies 219
NanoViricides approach for rabies 219
The Milwaukee protocol for rabies 220
Rotavirus 220
Epidemiology 220
Vaccines against rotavirus 221
Viral hemorrhagic fevers 221
Dengue 222
Antivirals in development 222
Dengue vaccines 223
Genetic elimination of dengue vector mosquitoes 224
Ebola virus 224
Development of antiviral drugs for Ebola 225
DNA vaccine for Ebola 225
Lassa fever 226
Marburg hemorrhagic fever 226
Yellow fever 227
Vaccines for yellow fever 227
Sequencing of Aedes aegypti genome and control of yellow fever 227
Crimean-Congo hemorrhagic fever 228
West Nile virus 228
Epidemiology 228
Pathogenesis 229
Treatment of West Nile neuroinvasive disease 229
Vaccines against WNV 229
Innovative treatments for WNV 230
Western equine encephalitis 230
Sporadic virus epidemics 230
Coronavirus/severe acute respiratory syndrome 230
Therapeutic approaches to SARS 231
MAbs for SARS 231
siRNA treatment of SARS 232
Zoonotic viral infections 232
Vaccines for zoonotic viral diseases 232
Virus bioterrorism and biowarfare 232
Small pox as a biological weapon 233
Status of small pox vaccination 233
Strategies against virus bioterrorism and biowarfare 234
Increasing resistance by stimulating innate immune mechanisms 234
Nanoviricides for combating viral bioterrorism 234
Concluding remarks 235
12. Markets for Antivirals 237
Introduction 237
Markets according to disease 237
Influenza market 237
HIV/AIDS market 238
Hepatitis B and C markets 239
Markets according to products and approaches 239
Market values of monoclonal antibodies for viral diseases 239
Market values of vaccines for viral diseases 239
Markets for vaccines against HPV 240
Markets for other antiviral vaccines 240
Markets according to geographical areas 241
Emerging markets for antiviral therapeutics 241
Geographical distribution of HIV/AIDS market 242
Unmet needs in antivirals 242
Policies regarding conquered viral diseases 243
Future of polio vaccine 243
Policies concerning HPV vaccine for prevention of cervical cancer 244
HPV vaccine in developing countries 244
Future prospects of innovative approaches 245
US Government support of antiviral efforts 246
US Government support for R & D in avian influenza vaccines 246
US Government support for developing anti-bioterrorism agents 246
The European Union support of antiviral research 247
European Commission’s research support for anti-HIV/AIDS programs 247
European Commission's support anti-influenza programs 248
Collaboration of biotechnology companies with big pharma 249
Strategies for marketing 249
13. Companies 251
Introduction 251
Top companies 251
Profiles of pharmaceutical companies 252
Profiles of antiviral companies 268
Profiles of viral vaccine companies 382
Collaborations 450
14. References 457

List of Tables
Table 1 1: A practical classification of viruses 19
Table 1 2: Vaccines vs therapeutics for viral diseases 25
Table 1 3: Historical landmarks in the development of antiviral therapies 25
Table 2 1: Classification of antiviral strategies 27
Table 2 2: Viral vs cellular targets for discovery of antivirals 28
Table 2 3: Viruses amenable to antisense oligonucleotides 39
Table 2 4: Inhibition of viral replication by RNAi 41
Table 3 1: Types of vaccines for viral diseases 46
Table 4 1: Role of nanobiotechnology in virology 53
Table 5 1: Methods of delivery of antiviral agents 59
Table 5 2: Role of nanotechnology for improving delivery of antivirals 64
Table 5 3: Commercially available liposomal antiviral vaccines 65
Table 6 1: SWOT of monoclonal antibodies 71
Table 6 2: SWOT of agents that prevention viral entry into cells 72
Table 6 3: SWOT of drugs interfering with intracellular replication 72
Table 6 4: SWOT of protease inhibitors 72
Table 6 5: SWOT of integrase inhibitors 72
Table 6 6: SWOT of maturation inhibitors 72
Table 6 7: SWOT of neuraminidase inhibitors 73
Table 6 8: SWOT of targeting Toll-like receptors (TLRs) 73
Table 6 9: SWOT of topical antivirals agents against viral infections 73
Table 6 10: SWOT of gene therapy, antisense oligonucleotides, RNAi 73
Table 6 11: SWOT of vaccines 73
Table 6 12: SWOT of NanoViricides 74
Table 7 1: Anti-influenza approaches 81
Table 7 2: Antiviral drugs used for influenza 81
Table 7 3: Various approaches to production of influenza vaccines 93
Table 8 1: Drugs in clinical development for HIV/AIDS 124
Table 8 2: Strategies for gene therapy of AIDS 143
Table 8 3: Classification of HIV/AIDS vaccines in clinical trials 145
Table 8 4: Companies involved in developing gene therapy for HIV/AIDS 161
Table 9 1: Innovations in the treatment of HBV 172
Table 9 2: Innovations for management of HCV 180
Table 9 3: Antiviral agents for HCV targeting host cells 185
Table 9 4: HCV drugs in clinical trials 192
Table 10 1: Methods of delivery of acyclovir 197
Table 11 1: Strategies against virus bioterrorism and biowarfare 234
Table 12 1: Worldwide market for all antiviral approaches 2011-2021 237
Table 12 2: Markets for antivirals according to virus infections 2011-2021 237
Table 12 3: Markets values of all drugs for HIV/AIDS 2011-2021 238
Table 12 4: Market values of monoclonal antibodies for viral diseases 2011-2021 239
Table 12 5: Market values of vaccines for viral diseases 2011-2021 240
Table 12 6: Markets for antiviral drugs according to geographical areas 2011-2021 241
Table 12 7: Markets for antiviral vaccines according to geographical areas 2011-2021 241
Table 12 8: Emerging markets for antiviral drugs according to countries 2011-2021 241
Table 12 9: Emerging markets for antiviral vaccines according to countries 2011-2021 242
Table 13 1: Top five antiviral companies 251
Table 13 2: Roche antiviral products in development 258
Table 13 3: Collaborations of antiviral companies 450

List of Figures
Figure 1 1: Varieties of host and cell responses to viral infections 21
Figure 1 2: Cycle of infection and replication of a retrovirus 22
Figure 1 3: Viral-induced cancer 24
Figure 2 1: An integrated approach to viral diseases 42
Figure 4 1: Schematic representation of NanoViricide attacking a virus particle 57
Figure 7 1: Evolution of mutations associated with virulence/drug resistance in H5N1 78
Figure 7 2: Mechanism of development of resistance to oseltamivir 84
Figure 8 1: Mode of action of some current anti-HIV drugs 117
Figure 9 1: Steps of HBV replication and site of action of various drugs 169
Figure 9 2: Omega DUROS device for interferon delivery in chronic hepatitis C 183
Figure 12 1: Unmet needs in antivirals 243