Vaccines to tackle drug resistant infections An evaluation of R&D opportunities Disclaimer The Boston Consulting Group (BCG) does not provide presentation or other materials, including the accuracy or legal, accounting, or tax advice. Reader is responsible for completeness thereof. obtaining independent advice concerning these matters, which advice may affect the guidance given by BCG. Receipt and review of this document shall be deemed Further, BCG has made no undertaking to update these agreement with and consideration for the foregoing. BCG materials after the date hereof notwithstanding that such does not provide fairness opinions or valuations of market information may become outdated or inaccurate. transactions and these materials should not be relied on or construed as such. These materials serve only as the focus for discussion and may not be relied on as a stand-alone document. 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Changes in hereby waives any rights and claims it may, have at any the underlying data or operating assumptions will clearly time against BCG with regard to the services, this report/ impact the analyses and conclusions. 2 Contents Executive Summary 2 About this project 10 Purpose of this report 10 Summary of methodology 11 Background and context 12 Context of AMR threat 12 Examples of the current landscape of AMR actions 12 Vaccines as a tool for tackling AMR 13 Pathogen comparison 15 Health impact 15 Probability of R&D success 16 Probability of uptake 17 Frameworks for pathogen comparison 18 Pathogen clusters 22 Cross-cutting activities 24 Pathogen-specific information 28 Acinetobacter baumannii 28 Campylobacter 34 Enterobacteriaceae 39 Enterococcus faecium 44 Escherichia coli (enteric) 48 Escherichia coli (urinary) 53 Haemophilus influenzae 58 Helicobacter pylori 63 Klebsiella pneumoniae 69 Mycobacterium tuberculosis 74 Neisseria gonorrhoeae 80 Pseudomonas aeruginosa 86 Salmonella (non-typhoidal) 91 Salmonella Paratyphi 96 Salmonella Typhi 100 Shigella 104 Staphylococcus aureus 108 Streptococcus pneumoniae 114 Bibliography and Acknowledgements 119 Bibliography 119 Acknowledgements 140 Appendix 142 Detailed Methodology 142 Vaccine Pipeline Information 155 Greyscale versions of exhibits 170 1 Executive Summary The role of vaccines in combating antimicrobial resistance (AMR) AMR is a significant and growing problem. Drug resistant infections cause 700,000 deaths per year; this number could rise to 10 million by 2050 1 unless urgent action is taken. Furthermore, this figure does not capture the impact of being unable to safely perform high-risk medical procedures such as complex surgery or chemotherapy. Immediate and coordinated action is required to tackle the threat posed by AMR. Vaccines alone will not be sufficient to achieve this, but they are critical tools that can play an important role when deployed alongside broader activities. A multi-faceted, One Health approach must be used because the emergence of resistance stems from behaviour across human and animal health. The development of new antibiotics and alternative therapeutics, the rational use of antibiotics in human and animal health, more effective use of diagnostics, improvements to water, sanitation and hygiene, and vaccines can all support efforts to combat AMR. However, vaccines do have some unique advantages, and therefore bringing additional, and more effective, vaccines to market could have a huge impact on AMR. Vaccines already play a critical role, with an impressive track-record of reducing AMR 2. Both H. influenzae b and S. pneumoniae vaccines have resulted in a dramatic reduction in disease burden and have been associated with decreased incidence of resistant strains. Additionally, both vaccines have an additional “indirect” effect on AMR by reducing antibiotic usage and therefore selection pressure on pathogens. Evidence shows that universal coverage with 13-valent S. pneumoniae vaccination could avoid 11.4 million days of antibiotic use per year in children under five 3. Vaccines also offer a long-term sustainable approach to infection prevention, because pathogen resistance to vaccines is not common. For example, vaccines against diphtheria and pertussis have been in use for 70 years without resistance developing. Purpose of this report This report seeks to provide an independent, actionable assessment of the potential of vaccines to combat AMR, and encourages greater attention, focus, and funding for vaccine development against pathogens whose resistance to antimicrobial medicines was identified by WHO as posing the greatest threat to human health. By employing a carefully considered prioritisation framework to evaluate these pathogens, this report enables comprehensive comparisons across pathogens. This assessment and prioritisation provides a guide for research priorities, policy focus and investment decisions, while recognising that individuals and institutions have varied areas of focus and seek to interact at different parts of the value chain. Additionally, this report consolidates information on these pathogens, and on the development efforts against them, which is currently fragmented, providing a critical new resource to the community working to address AMR. 2 WHO LIST PROVIDES STARTING POINT FOR COMPARATIVELY ASSESSING VACCINES FOR PATHOGENS WITH HIGH LEVELS OF AMR M. tuberculosis* S. pneumoniae Priority 3: Medium H. influenzae Shigella spp. E. faecium S. aureus Priority 2: High H. pylori Campylobacter spp. Salmonella spp. N. gonorrhoeae A. baumanii P. aeruginosa Priority 1: Critical Enterobacteriaceae: K. pneumoniae, E. coli, Enterobacter spp., Serratia spp., Proteus spp., Providencia spp., Morganella spp. Note: WHO 2017: Global priority list of antibiotic-resistant bacteria to guide research, discovery, and development of new antibiotics; *M. tuberculosis was not subjected to review for inclusion in the WHO priority list. However, it was specifically acknowledged as a globally established priority for which innovative new treatments are urgently needed. e therefore included this pathogen in our analysis. Scope of this report Determining the health impact of a pathogen provides critical information, both for those looking to develop This work used the World Health Organisation (WHO) vaccines and those responsible for establishing and priority pathogen list as a starting point for the funding vaccination programmes. In the context of AMR, assessment: an understanding of the direct health impact of a pathogen It is important to note that additional pathogens, such as needs to be assessed alongside the level of AMR threat influenza virus, contribute to inappropriate antibiotic usage the pathogen causes and the degree to which it drives and selection for AMR, however they were not included in antibiotic use. the assessment at this time. By setting out a robust and durable framework and methodology, this work can be Once a case for vaccine development is established it is taken further in the future by expanding the comparative important to understand how feasible the development set of pathogens and increasing the sophistication of process is likely to be. The robustness of the current individual metrics and indicators. pipeline provides a useful indication of the ease of advancing vaccine candidates and the level of commercial Methodology employed to assess pathogens interest. A more detailed understanding of potential challenges is gained by assessing pathogen biology and Each pathogen was evaluated based on the potential the ease of pre-clinical and clinical programmes. health impact of a vaccine against the pathogen, the probability of R&D success and the probability of vaccine Assuming a vaccine is successfully brought to market, a uptake. The assessment evaluated the development of key question remains about the likelihood of implementing vaccines against all strains of each pathogen – not just a successful vaccination programme. A wide range of those which are resistant to antibiotics. bodies will influence this process, including policy makers, payers and international organisations such as the WHO, This evaluation included the criteria and indicators Gavi and UNICEF – the relative importance of these will summarised on the scorecard on the following page. vary by pathogen. Finally, it is important to identify any This scorecard assessment aims to holistically capture significant barriers that could prevent uptake. the stages of vaccine development and establishing a vaccination programme. A detailed list of sources and methodology for each metric within health impact, probability of R&D success and probability of uptake can be found in the appendix. 3 PATHOGENS ASSESSED ACCORDING TO HEALTH IMPACT, PROBABILITY OF R&D