Contents:

SYNOPSIS 1. Executive summary 2. Clinical need 2.1 Overview 2.2 The disease 2.2.1 Causative agents – dengue viruses 2.2.2 Disease symptoms 2.2.3 Disease pathophysiology 2.3 Incidence 2.3.1 Reported incidence 2.3.2 Estimates of actual incidence 2.4 Transmission 2.4.1 Transmission mechanism 2.4.2 Aedes aegypti 2.4.3 Aedes albopictus 2.5 Populations currently at risk 2.5.1 Relevant populations 2.5.2 Global dengue transmission activity 2.5.3 Risk factors for endemic populations 2.5.4 Endemic countries 2.5.5 Possibly endemic countries 2.5.6 At-risk countries 2.5.7 Global distribution of endemic, possibly endemic and at-risk countries 2.5.8 At-risk travellers 2.5.9 Risk factors for travellers 2.6 Current treatment and prevention options 2.6.1 Current treatment 2.6.2 Current prevention 2.7 Current clinical need 2.8 Summary 3. Scientific / technology background 3.1 Overview 3.2 Virus factors 3.2.1 Humoral immunity to viral components 3.2.2 Cellular immunity to viral components 3.2.3 Genetic variation in dengue viruses 3.2.4 Invasion of host cells by virus 3.2.5 Modulation of host immune response 3.3 Host factors 3.4 Key issues in dengue vaccine development 3.4.1 Surrogate markers of safety and efficacy 3.4.2 Viral interference and immunodominance effects 3.4.3 Clinical considerations 3.5 Early stage approaches to dengue vaccine development 3.5.1 DNA vaccines 3.5.2 Vaccines with attenuating mutations 3.5.3 Subunit vaccines 3.5.4 Prime boost approaches 3.5.5 Other approaches 3.6 Summary 4. Dengue vaccine market: general features 4.1 Overview 4.2 Main stakeholders in vaccine development and procurement 4.2.1 National governments 4.2.2 Non-governmental organisations 4.2.3 Commercial /academic entities involved in vaccine development 4.2.4 Health care providers and healthcare professionals 4.2.5 End-users – vaccinees 4.3 Vaccine purchase and procurement 4.3.1 Public sector vaccine purchase: developed world 4.3.2 Public sector vaccine purchase: developing world 4.3.3 Private sector vaccine purchase: developed world 4.3.4 Private sector vaccine purchase: developing world 4.4 Legal, regulatory and manufacturing issues 4.4.1 Legal 4.4.2 Regulatory 4.4.3 Manufacturing 4.4 Summary 5. Dengue vaccine market: competitive environment 5.1 Overview 5.2 Current dengue vaccine candidates and vaccine sponsors 5.2.1 Outline of main candidate dengue vaccines 5.2.2 Outline of main commercial interests 5.3 Stage of development of main candidate dengue vaccines 5.3.1 NIH / NIAID vaccine 5.3.2 GSK/WRAIR vaccine 5.3.3 Hawaii Biotech vaccine 5.3.4 Inviragen (Shantha)/CDC vaccine 5.3.5 SanofiPasteur / Acambis vaccine 5.3.6 Inovio / VGX vaccine 5.3.7 USAOSG / WRAIR vaccine 5.4 Anticipated market entry of a dengue vaccine 5.5 Target market 5.6 Non-vaccine competition 5.6.1 Dengue therapies 5.6.2 Vector control strategies 5.6 Summary 6. Dengue vaccine market: potential end-user numbers 6.1 Overview 6.2 Potential end-user numbers: public vaccine 6.3 Potential end-user numbers: private vaccine 6.3.1 Travellers from developed economies to endemic countries 6.3.2 Private sector purchase within endemic / possibly endemic countries 6.4 Future growth in potential end-user numbers 6.4.1 2020 public sector projections 6.4.2 2020 private sector projections: endemic / possibly endemic countries 6.4.3 2020 private sector projections: relevant travellers 6.5 Summary 7. Market penetration and revenue projections 7.1 Overview 7.2 Market penetration: public sector vaccine 7.2.1 Countries wishing to introduce a public sector dengue vaccine 7.2.2 Countries able to introduce a public sector dengue vaccine 7.2.3 Appropriate population segments for a public sector dengue vaccine 7.2.4 Coverage estimates 7.2.5 Timing 7.2.6 Public sector market penetration - conclusions 7.3 Market penetration: private sector vaccine 7.3.1 Private sector vaccine: market penetration in endemic / possibly endemic countries 7.3.2 Private sector vaccine: market penetration in developed countries 7.4 Vaccine pricing 7.4.1 Burden of disease studies 7.4.2 Price benchmarking 7.4.3 Conclusions - dengue vaccine pricing in the public and private sectors 7.5 Revenue projections 7.5.1 Key assumptions 7.5.2 Dengue vaccine revenue projections to 2020: private sector, developed world 7.5.3 Dengue vaccine revenue projections to 2020: private sector, developing world 7.5.4 Dengue vaccine revenue projections to 2020: public sector, developing world 7.5.5 Beremans estimate of total 2020 market size for dengue vaccines 7.5.6 Third-party estimates of market size for dengue vaccines 7.5.7 Effect of competition 7.5.8 Other revenue sources 7.6 Summary 8. Expert interviews 8.1 Overview 8.2 Interviewee responses 8.2.1 Is a significant burden of disease likely to follow any spread of albopictus into the developed world? 8.2.2 Are those regions of the developed world that are somewhat at risk of dengue likely to adopt a public sector dengue vaccine, were one to become available? 8.2.3 What is the right immune correlate to measure in assessments of vaccine safety and efficacy? 8.2.4 Could vaccine-induced ADE be a problem for the current generation of dengue vaccine candidates? 8.2.5 When can we expect to see a Phase 3 trial of a candidate dengue vaccine? 8.2.6 When can we expect to see an approved dengue vaccine? 8.2.7 Are the Sanofi and GSK vaccines likely to be aimed at different segments of the paediatric population? 8.2.8 Will any of the current candidate dengue vaccines be applicable to the majority of shortnotice travelers? 8.2.9 How will endemic countries fund the introduction of a public sector dengue vaccine? 8.2.10 Which of the endemic countries are most likely to add a dengue vaccine to the public sector immunisation schedule? 8.2.11 What current developments seem most likely to lead to a step change in dengue prevention or management? 8.2.12 What will the year 2020 look like with regard to dengue incidence, vaccine approval, and vaccine uptake? 8.3 Summary 9. References APPENDICES Appendix 1: Quantitative incidence data by country, 2004-2008 Appendix 2: Reported dengue activity by country, 2004-2008 Appendix 3: Methodology behind population estimates / projections Appendix 4: Interview transcripts A4.1: Prof. Duane Gubler A4.2: Lt-Col. Dr. Stephen Thomas A4.3 Prof. Annelise Wilder-Smith Appendix 5: Dengue vaccine clinical trials Appendix 6: International travel data: correction and adjustment methodology Appendix 7: Spread of endemicity / at-risk status to new countries A7.1 Historical patterns of increased incidence, severity and distribution A7.2 Overview of factors driving the rise in dengue incidence, severity and distribution A7.3 Key factors that drive increases in dengue incidence, severity and distribution A7.3.1 Population growth / urbanisation A7.3.2 International travel and trade: impact on vector distribution A7.3.3 International travel and trade: impact on virus distribution A7.3.4 Climate: impact on dengue transmission A7.3.5 Climate: impact on vector distribution A7.4 Projected patterns of dengue incidence and geographic spread A7.5 Summary Appendix 8: Dengue in travellers A8.1 Overview A8.2 Reports of travel-associated dengue A8.2.1 Dengue in travellers from developed economies A8.2.2 Dengue in travellers from emerging economies A8.3 Trends in travel-associated dengue A8.3.1 Trends in incidence of travel-associated dengue A8.3.2 Trends in severity of travel-associated dengue A8.4 Conclusions – dengue risk in travellers Appendix 9: DTP3 coverage rates for likely adopters of dengue vaccine Appendix 10: Terms and conditions under which this report has been purchased The Figures in the report include the following: - Outline of factors that may influence DHF pathogenesis - Reported dengue incidence 2004-2008 - Global distribution of endemic, possibly endemic and at-risk countries (map) - Market segments in endemic and possibly endemic countries: total population, surviving infants, urban population - Travel from developed economies to dengue transmission regions 2009: endemic, possibly endemic, at-risk destinations - Total population projections 2010-2020 for endemic, possibly endemic and at-risk regions - Urban population projections 2010-2020 for endemic, possibly endemic and at-risk regions - Infant population projections 2010-2020 for endemic, possibly endemic and at-risk regions - Travel from developed economies to endemic and possibly endemic destinations - Putative dengue vaccine introduction: number of countries per year and cumulative total - Yellow fever vaccine introduction [comparator]: number of countries per year and cumulative total - Private sector revenue projections (USD mn): developed world - Private sector revenue projections (USD mn): developing world - Public sector revenue projections (USD mn): developing world - Relative market share: public/private sector, developing world - Relative market share: public/private sector, developed / developing world The Tables in the report include the following: - Number of symptomatic dengue cases by region and by year, 2004-2008 - Countries in which dengue is endemic, by region - Countries which are possibly endemic for dengue, by region - Countries which are at-risk of becoming endemic for dengue, by region - Tiered pricing effects - Clinical trials of vaccine candidate A - Clinical trials of vaccine candidate B - Clinical trials of vaccine candidate C - Clinical trials of vaccine candidate D - Clinical trials of vaccine candidate E - Duration of clinical trials of JE vaccine [comparator] - Dengue vaccine sponsors, vaccine origin, type and description of vaccine, development phase - Demographic data for endemic, possibly endemic and at-risk countries: total population, surviving infants, urban population - Travel from developed economies to dengue transmission regions 2009 - Endemic / possibly endemic countries in which willingness-to-pay studies suggest a market for private sector vaccines - Total population projections 2010-2020 for endemic, possibly endemic and at-risk regions - Urban population projections 2010-2020 for endemic, possibly endemic and at-risk regions - Infant population projections 2010-2020 for endemic, possibly endemic and at-risk regions - Numbers of travellers from developed economies arriving in endemic and possibly endemic destinations - Countries which are both endemic/possibly endemic for dengue and also eligible for GAVI support - Countries which may have both the desire and the means to introduce a public sector dengue vaccine - Early adopters of a new dengue vaccine - Second-phase adopters of a new dengue vaccine - Possible third-phase adopters of public sector dengue vaccine - Countries that may have adopted a public sector dengue vaccine by 2020 grouped by timing of introduction - Order of dengue vaccine roll-out by country in each group based on %DTP coverage - Comparator prices for projecting dengue vaccine price - Key assumptions used in dengue vaccine revenue projection spreadsheets - Private sector revenue projections (USD mn): developed world - Private sector revenue projections (USD mn): developing world - Public sector revenue projections (USD mn): developing world - Quantitative incidence data by country 2004-2008 - Reported dengue activity by country 2004-2008 - Dengue vaccine clinical trials organised by status - Population-based rations for traveller apportionment - Correction factors for travel data - Growth rates for travel projections - DTP3 coverage rates for likely adopters of dengue vaccine

Summary:

This report provides a robustly independent and realistic assessment of the market for dengue vaccines. We emphasise that we are not linked to, or affiliated with, or influenced by, or in any way beholden to any organisation with any interest in promoting dengue vaccines, whether from a commercial perspective, or from a charitable / aid work perspective, or from a public health or any other perspective. There were no conflicts of interest which could have affected our findings or the presentation of our findings. We first assessed and summarised the state of knowledge regarding dengue disease transmission and pathophysiology, by reference to peer-reviewed publications. We then collected publicly available data on reported dengue cases worldwide, and used this to produce a picture of the increased global incidence from 2004-2008, and to derive an estimate of actual cases worldwide. These data also permitted us to identify countries where dengue transmission has been reported, and to categorise countries on the basis of known endemicity, possible endemicity or risk of endemicity. The above allowed us to gain a clear idea of the clinical need associated with dengue. We then reviewed the technical challenges and types of technical approach relevant to dengue vaccine development. This enabled us to provide background detail which is helpful in discussing the various different candidate dengue vaccines that have reached the clinic. Similarly, we examined broad features of the dengue vaccine market, particularly in terms of significant stakeholders, and their influence on the procurement and pricing of some vaccines. This provides useful background to later chapters presenting detailed revenue projections. Next, we identified the main candidate dengue vaccines, focusing on those in clinical development, and summarised the publicly disclosed clinical trials for each vaccine. We also identified the commercial interests in dengue vaccine development, and noted publicly disclosed licensing activity. In addition, we discussed the extent to which clinical trial information on the administration schedules of the different vaccine candidates suggests their applicability to different population segments (e.g. infants vs. travellers). Importantly, we undertook a major exercise to quantify the different populations that might be appropriate for dengue immunisation, namely total populations, urban populations, surviving infant populations, and traveller populations. For traveller populations, this required construction of a detailed model using numerous manipulations, corrections and adjustments of raw travel data to provide defensible estimates of actual traveller numbers from each of 21 different developed countries to each of >100 countries where dengue transmission may occur. In our opinion, this is the most comprehensive and accurate model of international travel available. We also projected relevant population numbers to 2020, to provide a base for revenue projections. We then identified key data which allowed us to make rational and defensible assumptions to apply to our model of dengue vaccine revenue projections. These assumptions (e.g. price, time of market entry, maximum market penetration, rate of market penetration, roll-out per country, etc.) are specified and justified in the text, and enabled an estimation of the market for (i) a private sector vaccine in the developed world (i.e. a travel vaccine); (ii) a private sector vaccine in the developing world; and (iii) a public sector vaccine in the developing world. Finally, we interviewed key experts in the field to obtain third-party views on aspects of the market for dengue vaccines. The report is lengthy, but contains, in addition to the Executive Summary, an extended Summary at the end of each Section. The busy reader may identify all key points by reference to the Summaries, and supplement this as necessary by reference to the text in the main body of each Section. Additional background information is contained in the Appendices.