Pipeline Insight: Nosocomial Vaccines - Minefield or Goldmine?

Introduction
As the reimbursement status for the cost of hospital-acquired infections is under pressure by payors, interest in preventing these complications at the outset is growing. Nosocomial vaccines offer one route of prevention. This report assesses the clinical pipeline candidates five key nosocomial pathogens and their potential market environment including target population size estimates.

Report Highlights
Highlights
The increasing incidence and severity of nosocomial infections has sparked an interest in preventive strategies such as vaccination. High costs and reimbursement cuts associated with nosocomial infections provide a strong incentive for healthcare stakeholders to invest in infection prevention, providing a strong rationale for vaccine development.

In the highly cost-conscious nosocomials market, a prudent definition of vaccination target groups will be crucial to satisfy the stringent cost-benefit analysis. Whereas patients undergoing planned hospital stays will benefit from vaccination, alternative prevention methods may be preferable for immuno-compromised, newborn and acute patients.

Datamonitor believes that C. difficile vaccines will have the easiest route to market due to the large and well-defined target population and a high unmet need. Vaccines against S. aureus and P. aeruginosa could prove valuable in selected target groups, whereas there is only a limited potential for vaccines against S. epidermidis and enterococcus.
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TABLE OF CONTENTS
ABOUT DATAMONITOR HEALTHCARE 2
About the Infectious Diseases analysis team 2
CHAPTER 1 EXECUTIVE SUMMARY 3
Objective of the analysis 3
Datamonitor insight into the nosocomial vaccines market 3
Contributing experts 5
Related reports 6
Upcoming related reports 6
NOSOCOMIAL INFECTIONS - OVERVIEW OF EPIDEMIOLOGY AND KEY TARGETS FOR VACCINE DEVELOPMENT 8
Summary 8
Patients undergoing hospital stays face an elevated risk of infection 8
Nosocomial infections are a key health concern across the 7MM 9
The risk of infection is highest in intensive care units 11
Nosocomial pneumonia and bloodstream infections have the highest mortality rates 13
S. aureus, P. aeruginosa, S. epidermidis, enterococcus spp. and C. difficile are the most promising vaccine targets 14
CHAPTER 2 FACTORS TO CONSIDER FOR THE ASSESSMENT OF THE OPPORTUNITY FOR NOSOCOMIAL VACCINES 17
Summary 17
A multitude of factors determine the market opportunity for nosocomial vaccines 18
Costs associated with nosocomial infections vary between types of infections 20
Multiple costs arise through nosocomial infections 20
Most costs are directly associated with the increasing length of hospital stay 20
Reimbursement regulations for costs related to nosocomial infections differ across the seven major markets 22
US - Medicare changes on the horizon increase the financial pressure on hospitals 22
Despite common belief, US hospitals lose money on nosocomial infections 22
Medicare will cut reimbursement for certain nosocomial infections from October 2008 23
Japan's prospective payment system needs further amendment to incentivize hospitals effectively 27
Most major European markets operate DRG systems; however, levels of impact differ between countries 27
France 27
Germany 28
Italy 29
Spain 29
The UK 30
Various strategies exist for prevention and prophylaxis of nosocomial infections 33
Antibiotic resistance and worse clinical outcome provide a strong rationale for prevention of nosocomial infections 33
There are three key approaches for prevention of nosocomial infection aiming at different target populations 34
Hygiene and infection-control-based strategies 36
Advantages of hygiene and infection control strategies include a significant reduction in infection rates and hospital costs 38
Disadvantages include lack of efficacy and problems regarding implementation 39
Recommendations surrounding infection prevention vary across the 7MM 41
Immunoglobulins 46
Fast protection and the chance to vaccinate patients undergoing unplanned hospitalization are the key advantages of immunoglobulin-based strategies 46
Unclear efficacy along with limited tolerance and high costs are key concerns linked to immunoglobulin-based prevention strategies 48
Infections caused by staphylococci and Pseudomonas are the main focus of the nosocomial immunoglobulin pipeline 50
Vaccines 52
Long-lasting immunity is the key advantage of vaccines over other methods of prophylaxis 53
Setbacks include efficacy and implementation of vaccination in some key target populations 53
CHAPTER 3 STAPHYLOCOCCUS AUREUS 56
Summary 56
Disease background - S. aureus causes a wide variety of infections, often initiated with commensal carriage of the pathogen 57
Treatment options - S. aureus resistance patterns determine the choice of drug 58
Resistance development - MRSA has become a crucial concern in both hospital and community 58
Epidemiology - elderly and surgical patients are the principal risk groups for S. aureus infection 64
Key risk groups 64
Epidemiology and spread of disease 64
Rationale for vaccine development - high incidence and increasing resistance levels drive interest in vaccines 65
Market potential - a large population would be eligible for vaccination across the 7MM 68
Target population and market opportunity 68
Patients undergoing planned surgery 71
Dialysis 74
Elderly aged 65 years and over 76
Others 78
Pipeline - StaphVAX failure dampens hopes for rapid launch of a S. aureus vaccine 78
Summary 78
StaphVAX (Nabi Biopharmaceuticals) 79
Product profile 79
Clinical trial overview 80
Datamonitor assessment 87
V710 (Merck & Co/Intercell) 88
Product profile 88
Clinical trial data 89
Datamonitor assessment 91
SA75 (VRI plc) 91
Product profile 91
Clinical trial data 92
Datamonitor assessment 93
Assessment of the overall potential of S. aureus vaccines - good prospects, but significant challenges remain 93
CHAPTER 4 STAPHYLOCOCCUS EPIDERMIDIS 96
Summary 96
Disease background - S. epidermidis is mainly associated with medical devices 96
Treatment options - many antibacterial drugs are active against S. epidermidis 97
Resistance development - resistance levels are comparatively low, but have been increasing 97
Epidemiology - patients undergoing implant surgery are at greatest risk of infection 98
Key risk groups 98
Epidemiology and spread of disease 98
Rationale for vaccine development - protection against the next potential ""superbug"" 99
Market potential - orthopedic, ophthalmic and cardiac surgery patients would benefit most from vaccination 101
Target population and market opportunity 101
Implant and device surgery 103
Dialysis 106
Pipeline - no competition for Nabi 108
Summary 108
EpiVAX (Nabi Biopharmaceuticals) 108
Assessment of the overall potential of S. epidermidis vaccines - a combination vaccine with S. aureus is the way forward 109
CHAPTER 5 PSEUDOMONAS AERUGINOSA 113
Summary 113
Disease background - P. aeruginosa causes a wide range of different infections 113
Treatment options - resistances set a limit on therapy approaches 115
Resistance development - increasing non-response to a large variety of drugs makes prevention a key interest 115
Epidemiology - P. aeruginosa is a critical pathogen in the ICU 116
Key risk groups 116
Epidemiology and spread of disease 117
Rationale for vaccine development - resistance is the key driver, but vaccine design will be challenging 120
Market potential - patients with severe respiratory diseases and those at risk of an ICU stay are key target populations 121
Target population and market opportunity 121
Cystic fibrosis patients 122
Chronic obstructive pulmonary disease (COPD) 125
Patients undergoing planned surgery with subsequent pre-planned or highly likely ICU stay 127
Others 132
Pipeline - after many pipeline failures, IC43 looks promising 133
Summary 133
IC43 (Intercell) 135
Product profile 135
Clinical trial data 136
Assessment of the overall potential for P. aeruginosa vaccines 137
CHAPTER 6 CLOSTRIDIUM DIFFICILE 140
Summary 140
Disease background - C. difficile causes severe diarrhea and colitis 140
Treatment - antibiotic drugs are available, but many patients relapse 142
Resistance development - emergence of strain 027 is associated with worse clinical outcomes 142
Epidemiology - the elderly are at greatest risk of C. difficile infection 143
Key risk groups 143
Epidemiology and spread of disease 143
The UK 144
The US 147
Germany 149
Economic burden 150
Rationale for vaccine development - high clinical need is the key driver 150
Market potential - annual peak sales exceeding $1.5 billion are realistic in the elderly population 151
Target population 151
Commercial opportunity 153
Initial market: people in institutionalized care 154
Long-term opportunity: vaccination of all people turning 65 156
C. difficile vaccines pipeline - no competition for Acambis in sight 158
Summary 158
C. difficile vaccine (Acambis) 158
Product profile 158
Clinical trial data 159
Datamonitor assessment 160
Assessment of the overall potential for C. difficile vaccines - C. difficile is a highly promising target for nosocomial vaccination 161
CHAPTER 7 ENTEROCOCCUS SPP. 163
Summary 163
Disease background - E. faecalis and E. faecium are key causes of enterococcal infections 163
Treatment - resistances have limited the efficacy of available antibiotic options 164
Resistance development - VRE is emerging as severe concern 164
Epidemiology - incidence and mortality of enterococcal infections are increasing 168
Key risk groups 168
Epidemiology and spread of disease 169
Rationale for vaccine development 170
Market potential - it will be hard to construct a viable cost-efficacy case for enterococcal vaccination 171
Target population and commercial opportunity 171
Pipeline - no clinical candidates are developed for enterococcal infections yet 173
Summary 173
Assessment of the overall potential for enterococcal vaccines - alternative prevention strategies have better potential 174
APPENDIX A 176
Bibliography 176
APPENDIX B 194
Report methodology 194
About Datamonitor 194
About Datamonitor Healthcare 194
About the Infectious Diseases analysis team 195
Key therapy team members 196
Holger Rovini, Head of Respiratory and Infectious Diseases 196
Hedwig Kresse, Senior Analyst, Infectious Diseases 196
Disclaimer 197
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Table 1: Costs associated with nosocomial infections 20
Table 2: Antibodies against nosocomial infections pipeline, March 2008 51
Table 3: S. aureus - Annual incidence estimates of overall planned surgery and key subtypes in the 7MM, 2008 73
Table 4: S. aureus - Annual incidence estimates of dialysis in the 7MM, 2008 75
Table 5: S. aureus - elderly recurrent and total population sizes in the 7MM, 2008 (million) 77
Table 6: S. aureus vaccine pipeline, January 2008 79
Table 7: StaphVAX - product profile, 2008 80
Table 8: StaphVAX - end-stage renal disease trials, January 2008 82
Table 9: StaphVAX - orthopedic surgery trials, January 2008 83
Table 10: StaphVAX - cardiovascular surgery trials, 2008 83
Table 11: StaphVAX - lot comparison trial, January 2008 84
Table 12: V710 - product profile, 2008 88
Table 13: V710 - clinical trial overview, January 2008 90
Table 14: SA75 - Product profile, 2008 91
Table 15: S. epidermidis - annual incidence estimates of key types of orthopedic/ophthalmic surgery in the 7MM, 2008 105
Table 16: S. epidermidis - annual incidence estimates of key types of cardiac surgery in the 7MM, 2008 106
Table 17: S. epidermidis - annual incidence estimates of dialysis in the 7MM, 2008 107
Table 18: S. epidermidis vaccine pipeline, January 2008 108
Table 19: EpiVAX - Product profile, 2008 108
Table 20: P. aeruginosa - Annual incidence estimates of cystic fibrosis in the 7MM, 2008 123
Table 21: P. aeruginosa - prevalence estimates of different stages of COPD in the 7MM, 2008 126
Table 22: Breakdown of patients at elevated risk of ICU stay (median hospital stay >7 days) by type of procedure and admission in England, 2006 128
Table 23: Pseudomonas aeruginosa- total vaccination target population sizes (7MM) 131
Table 24: P. aeruginosa vaccines - overview of key bacterial targets and candidates, 2008 134
Table 25: P. aeruginosa vaccines - clinical pipeline, January 2008 135
Table 26: Estimated incidence of C. difficile infections across the 7MM 144
Table 27: C. difficile - total recurrent vaccination target population sizes in the 7MM, 2008 (million) 152
Table 28: C. difficile - commercial opportunity and cost-efficacy estimate for vaccination in people undergoing institutionalized care in the 7MM, 2008 155
Table 29: C. difficile - commercial opportunity for annual and cumulative catch-up vaccination in all elderly aged 65 and older in the 7MM, 2008 157
Table 30: C. difficile vaccine pipeline, January 2008 158
Table 31: C. difficile vaccine (Acambis) - product profile, 2008 159
Table 32: Enterococcal vaccine pipeline, January 2008 173

Figure 1: Number of deaths by leading cause of death in the US, 2004 10
Figure 2: Nosocomial infections -most common types of infection in the US, 2007 11
Figure 3: Estimated number of healthcare-associated infections by subpopulation and major site of infection in the US, 2002 12
Figure 4: Rates of healthcare-associated infections by subpopulation and major site of infection in the US, 2002 12
Figure 5: Origin of infection in ICU patients in the 5EU , 1992 13
Figure 6: Deaths associated with healthcare-associated infections in the US, 2002 14
Figure 7: Key ICU infections by causative pathogen in Germany, Spain, France, 2003/2005 15
Figure 8: Factors influencing the assessment of the market opportunity for nosocomial vaccination in the 7MM, 2008 19
Figure 9: Nosocomial infections - additional days spent in hospital by type of infection 21
Figure 10: Hospital costs, reimbursement and losses for central-line BSI and pneumonia - Allegheny General Hospital in the US, 2006 23
Figure 11: Drawbacks of antibiotic therapy and value-added of preventive strategies in nosocomial infections 34
Figure 12: Patient groups likely to benefit from different infection prevention strategies 35
Figure 13: Advantages and disadvantages of hygiene and infection control-based strategies in the prevention and control of nosocomial infections 37
Figure 14: Efficacy assessment of recommended preventive measures for the four most frequent types of nosocomial infection 40
Figure 15: Advantages and disadvantages of immunoglobulin-based strategies in the prevention and control of nosocomial infections 46
Figure 16: Advantages and disadvantages of vaccination strategies in the prevention and control of nosocomial infections 52
Figure 17: MRSA - hospital discharges mentioning MRSA in the US, 1993-2005 59
Figure 18: MRSA - hospital discharges per 100,000 population by age group in the US, 2004 60
Figure 19: MRSA - prevalence among all S. aureus infections in the 5EU, 1999-2006 61
Figure 20: MRSA -proportion of MRSA in ICUs versus other hospital departments in the 5EU, 2006 62
Figure 21: MRSA - incidence in Japan, 1999-2005 (sentinel reporting system) 62
Figure 22: S. aureus - incidence in the 5EU, 2001-06 (sentinel reporting) 65
Figure 23: S. aureus - sizing estimates of key target populations eligible for vaccination in the 7MM, 2008 69
Figure 24: Target group expansion model for S. aureus vaccination 71
Figure 25: S. aureus vaccine development - summary of drivers and resistors, 2008 94
Figure 26: S. epidermidis - sizing estimates of key target populations eligible for vaccination in the 7MM, 2008 103
Figure 27: S. epidermidis vaccine development - summary of drivers and resistors, 2008 111
Figure 28: P. aeruginosa - antibiotic resistance levels across Europe, 2006 116
Figure 29: P. aeruginosa - bacteremia laboratory reports in the UK, 1990-2004 (voluntary reporting) 118
Figure 30: P. aeruginosa - infections in Japan, 1999-2005 (sentinel reports from ~470 hospitals) 118
Figure 31: P. aeruginosa - infections in ICUs in Germany, 2000 and 2005 119
Figure 32: P. aeruginosa - sizing estimates of key target populations eligible for vaccination in the 7MM, 2008 122
Figure 33: P. aeruginosa - potential cost savings through vaccination in cystic fibrosis patients in the 7MM, 2003 124
Figure 34: P. aeruginosa vaccine development - summary of drivers and resistors, 2008 138
Figure 35: C. difficile infection - course of disease 141
Figure 36: Age and sex distribution of C. difficile reports in the UK, January-December 2006 (voluntary surveillance) 145
Figure 37: C. difficile reports for patients aged 65 years and over in the UK, 2000-06 (mandatory and voluntary reports) 146
Figure 38: Deaths related to C. difficile infection in England & Wales, 2001-06 147
Figure 39: C. difficile infections per 100,000 hospital discharges in the US, 1993-2003 148
Figure 40: Annual Clostridium difficile-related mortality rates per million population in the US, 1999-2004 149
Figure 41: C. difficile infections per 100,000 in-hospital patients in Germany, 2000-04 149
Figure 42: C. difficile - possible target group expansion strategy for recurrent opportunity in the 7MM, 2008 (million) 153
Figure 43: C. difficile - market opportunity for vaccination in the 7MM, 2008 154
Figure 44: C. difficile vaccine development - summary of drivers and resistors, 2008 162
Figure 45: Vancomycin-resistant enterococci among ICU patients in the US, 1995-2004 165
Figure 46: E. faecalis /E. faecium susceptibility to vancomycin in England and Wales, 1990-2005 166
Figure 47: E. faecium - vancomycin resistance in Europe, 2001-06 167
Figure 48: Enterococcal infections by age group in the UK, 2005 169
Figure 49: Enterococcal bacteremia reports by type in the UK, 2002-06 170
Figure 50: Enterococcal vaccine development - summary of drivers and resistors, 2008 175
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