Building blocks to success in malaria elimination

Proven Successes in Global Health – case studies Eradicating smallpox Preventing HIV/STDs in Thailand Trachoma in Morocco Health in Mexico Infant diarrhea deaths in Egypt Onchocerciasis in Africa Polio in the Americas TB in China Safe motherhood in Sri Lanka Guinea worm control in Africa and Asia Tobacco use in Poland Measles in Southern Africa Hib in Chile and Gambia Iodine deficiency in China Flouridation in Jamaica Chagas in Southern Cone through vector control Fertility in Bangladesh Source: Levine, R., Millions Saved: Proven Successes in Global Health, Center for Global Health, What Works Working Group, 2005

Proven Successes in Global Health – common elements Technical consensus about the appropriate biomedical or public health approach Technological innovation with an effective delivery system, at a sustainable price Predictable, adequate funding from both international and local sources Political leadership and champions Good management on the ground Effective use of information This slide shows common themes that were identified in the analysis, Millions Saved by Ruth Levine of the Center for Global Development, which analyzed 17 successes in global health. From this analysis, six “Elements of Success” emerged – common features of most or all of the 17 case studies. The MV TRM process was originated to develop the technical consensus described in the first bullet and stimulate technological innovations described in the second bullet. However, if we are successful as a community in developing an effective roadmap, the other four elements of success will also come. The Malaria Vaccine TRM has the potential to cultivate these elements of success for malaria vaccines. Source: Levine, R., Millions Saved: Proven Successes in Global Health, Center for Global Health, What Works Working Group, 2005 . www.cgdev.org/globalhealth

Transformations: Control vs. Elimination/Eradication Goal - Control Goal – E/E Prevent death – RTS,S Case management Risk groups such as malaria in pregnancy, severe malaria Scale up existing interventions – LLINs, ACTs, IRS Prevent transmission – TBVs, SERPAC, etc. Simplify toolbox – single dose treatment, avoid and prevent resistance Make tough decisions Refocus R&D targets MalERA

The inquiry agenda in support of malaria elimination Complex systems – both biology and health systems Fonts: Header: 28pt (black); sub-header 24 pt (blue); Lign up: Header or sub-header (if used) lined up with lower end of STI text Font in bullet lists: 24, 21, 18 pt decreasing with each indent Color codes: Blue (sub-header): R 65; G 91; B 155 Blue (dark): R 51; G 51; B 153 Green (dark): R 0; G 115; B 71 Red: R 255; G 51; B 0 Red (dark): R 176; G 29; B 65 “Malaria systems” “Health systems” 25/04/2017 from Marcel Tanner

Summary of proposed key responses PLoS Medicine 25 January 2011 Summary of proposed key responses Control Scalling for impact (SUFI) Sustaining control (SC) Prevention of reintroduction Pre-elimination Elimination Single Encounter Radical Cure and Prophylaxis drug suitable for MDA SERCaP / MDA VIMT Vaccine (s) that Interrupt Malaria Transmission Diagnostics + New Diagnostics (individual, community/MDA) Surveillance as an intervention Vector Control/TPP for outdoor populations Surveillance as an Intervention Modeling Intervention Mixes inc. CEA Sustained Vectorial Capacity Reduction Tool HSR Predictive modeling allowing strategic and operational, including costing, assessment of combining different control and elimination strategies Essential R&D backbone, enabling technologies and platforms Continuous culture of P. vivax Biology of liver stages Genomic and proteomic platforms Approaches and tools for measuring transmission Framework and tool for effectiveness decay analysis and health system integration Harmonization of data bases, model outputs, user interface Training Minimal Enabling Framework for Health Systems Readiness 25/04/2017

Synergy of connected system-level interventions Decentralization,& local ownership Household health surveillance New communication tools District Health Profiles District Health Accounts SWAp Basket 1$ per capita New planning & management skills New mix of services; higher coverage, quality, & utilization Community voice tool 25/04/2017 Source: MOHSW TEHIP Tanzania

Decentralisation 25/04/2017 National Government MoH NGOs MoH Regional Health Authorities District Health System Self-help Groups / Community Based Organisations (formal and informal) Communities / Families / Citizens Traditional Health System National Government Regional / Province Government Local / District Government Private Sector 25/04/2017

From Efficacy to Effectiveness Health System Factors / Partnership The systems context From Efficacy to Effectiveness Efficacy 80% X Access x 80% Health System Factors / Partnership X Targeting Accuracy x 80% X Provider Compliance x 75% X Consumer Adherence X 75% = Effectiveness = 29%

System effectiveness of ALU in Rufiji Tanzania 1000 simple malaria fevers Sought care Individual behaviour Health system behaviour Sought care within 24 h Individual & drug behaviour Accessed ACT provider within 24 h Correctly diagnosed or prescribed ACT stocked in 110 cases successfully treated Adhered to treatment Treatment effective 413 lost 12 lost 2 lost 50 lost 64 lost 101 lost 248 lost 890 failures to treat effectively 25/04/2017 10

Real time mHealth monitoring of ACT supply chains.. We have good drugs for malaria! But a continuing challenge of global, national and local responses to antimalarial drug procurement and supply chain system realities. Current situation in 5,126 public health facilities in Tanzania on Oct 5th, 2012 Red if a stock out this week Green if in stock this week Surveillance in place Modern Approaches M-Health with incentives but Action is lacking Training Understanding Management… Source: SMS for Life Tanzania

Source: NMCP-Tanzania Malaria Prevalence: 2012 ACT-Stockouts: 2012 Source: NMCP-Tanzania 25/04/2017

Research Priorities: Surveillance - Response Systems (SRS) Dynamic mapping of „pockets“ of transmission and/or reintroduction Capturing population dynamics Analyses of M&E data and modeling to optimize SRS Parasite – Man – Vectors Sampling in space and time Design and validate with use of (i) evidence from programs and (ii) modeling (intervention mixes) effective response packages tailored to different transmission settings and levels Use of new technologies (m/e-health, diagnostics) Validation, validation, validation…alongside with programs

IPTc now Seasonal Mass Chemoprophylaxis Field implementation Guide published (English and French) 3 workshops (2012, 2013) have been organized by WHO in collaboration with the UCAD / LSHTM, and RBM/WARN that provided countries with support and to guide SMC planning and implementation. 9 countries have adopted and added it in their strategy Large scale implementation yet to start due to funding constraints, small scale implementation ongoing in a few countries (Mali, Senegal, Niger, Nigeria) Challenges in sourcing pre-qualified medicines Based on implementation plans developed by the WARN eligible countries (9 countries), 19 million children can potentially benefit from SMC during the next three malaria seasons (up to 2016).

Global changes in malaria incidence rate, 2000-2010 World Health Organization 25 April, 2017 Global changes in malaria incidence rate, 2000-2010 This slide and the next one are animated – all you have to do is click once and it will run through from 2000 to 2010 Incidence per 1000 population Unfortunately, the legend is a bit hard to read, so: Darkest green: 0 Light green: 0-1 Yellow: 1-10 Orange: 10-50 Red: >50 2010 2000

Global changes in malaria death rate, 2000-2010 World Health Organization 25 April, 2017 Global changes in malaria death rate, 2000-2010 2010 2000

Extent of malaria transmission: 1945 Select Topics Hypothetical phasing scenario Extent of malaria transmission: 1945 Malaria transmission No Malaria transmission Source: Malaria Elimination: Geography, finance, and economics, presentation by Prof. Sir Richard Feachem, at ASTMH 7 Dec 2008.

Extent of malaria transmission: 2008 Select Topics Hypothetical phasing scenario Extent of malaria transmission: 2008 Malaria transmission No Malaria transmission Planning for elimination or eliminating Source: Malaria Elimination: Geography, finance, and economics, presentation by Prof. Sir Richard Feachem, at ASTMH 7 Dec 2008.

Funding and investments Global need: GMAP estimates Malaria implementation and R&D combined will require $5-7B per year through 2020 Millions US$ 6,939 6,094 5,837 5,558 3,838 Implementation R&D 2009 2010 2015 2020 2025 Source: Roll Back Malaria Global Malaria Action Plan (RBM GMAP) published September 2008

Globally, total malaria spend estimated to be ~$3b in 2010 H Funding and investments Globally, total malaria spend estimated to be ~$3b in 2010 Millions US$ Does not include potential future commitments Implementation: Global Fund Implementation: World Bank 3,494 Implementation: PMI 3,296 Implementation: Other 3,102 R&D: BMGF 2,960 2,878 R&D: NIH 2,645 2,696 R&D: Other 2,215 1,604 1,496 1,117 888 370 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 Note: Implementation spend assumes all committed spend will be disbursed. Implementation includes World Bank, Global Fund, PMI and Other USAID, Other International Donors, Local Country Spend, and Private Household Spend. R&D spend includes BMGF, NIH and "Other R&D Spend" 1. BMGF implementation spend is assumed to be all captured in donation to Global Fund and is not listed out separately. Global Fund also includes Round Commitments, RCC Funding, and AMFm additional funding.2. Assumed that 2007 spend (sourced from GFinder report) will remain constant through 2015. Prior to 2007, estimates from 2007 Malaria Strategy work. Total of US$468m assumed to remain constant 2007 – 2015. Source: WHO Malaria Report 2008, Global Fund Pledges (website), GMAP report, USAID website (www.usaid.gov/our_work/global_health/home/Funding/funding_rd.html), PMI website, World Bank website, George Institute G-Finder Report for year 2007 and 2008

2013 World Malaria Report Impact from GFATM, PMI, national investments in malaria Decrease in 45% mortality since 2000 – about 627K Greatest impact in highest burden countries 50% access to LLINs BUT: Still have 200M +/- cases Gains are fragile – documented resurgence Resistance in Thai-Cambodia-Myanmar

WHO Malaria Situation Room – focus on meeting 2015 goals Nigeria Democratic Republic of the Congo Tanzania Uganda Mozambique Côte d’Ivoire Ghana Burkina Faso Cameroon Niger

Malaria – the post 2015 agenda Global transitions World Bank – focus on extreme poverty What comes after the MDGs – High Level UN Panel Chronic Disease agenda – Does health remain on the agenda? Eradication framework BMGF strategy – focus on transmission, Ho is based on strategic use of drugs at scale MalERA research agenda

IVCC Progress To Date

New medicines for Malaria Eradication Replacing three days ACT and 14 days primaquine with a simpler therapy Overcoming concerns about resistance Post treatment Protection Fast killing Radical cure Transmission blocking SERCaP single exposure radical cure and prophylaxis Alonso P et al.,(2011) A research agenda for malaria eradication: drugs PLoS Med. Jan 25;8

Global Portfolio of Antimalarial Medicines Registration Preclinical Research Translational Development Phase IIa Phase I Lead Optimisation Phase IV Phase IIb/III 1 Project Novartis Artesunate for injection Guilin Coartem®-D Aminopyridines UCT 3 Projects GSK KAE609 OZ439 (Monash/UNMC/ STI) Pyramax Shin Poong/ University of Iowa ELQ-300 (USF/ OHSU-VAMC) 21A092 (DrexelMed/UW) KAF156 DSM265 (UTSW/UW/ Monash) Eurartesim® Sigma-Tau Whole cell leads AstraZeneca Tafenoquine P218 DHFR (Biotec/Monash/ LSHTM) Tetraoxane Liverpool STM/Liverpool Uni Paediatric Shin Poong/ University of iowa Orthologue Leads Sanofi Heterocycles Dundee Included in MMV portfolio post registration SP-AQ ASAQ Winthrop sanofi /DNDi MMV390048 (UCT) dUTPase inhibitors Medivir DOS Broad Institute Imidazolidinediones WRAIR RKA182 Liverpool STM NPC-1161-B University of Mississippi SAR116242 Palumed Mefloquine Artesunate Farmaguinhos/DNDi SAR97276 Ferroquine Fosmidomycin Piperaquine Jomaa Pharma GmbH Methylene Blue AQ Uni. Heidelberg AQ13 Immtech Artesunate i.r. WHO/TDR Artemisone UHKST Antimalarial Actelion DF02 Dilafor CDRI 97-78 Ipca N-tert butyl isoquine Liverpool STM/GSK ARCO Naphthoquine/ Artemisinin Arterolane/PQP Ranbaxy ArtiMist™ Proto Pharma OSDD Univ Sydney DHODH UTSW/UW/Monash Oxaboroles Anacor SJ557733 St Jude/Rutgers NDH2 Long Duration Leads Merck Serono HKMT IC/ CNRS Non MMV Nauclea pobeguinii DRC/Antwerp Argemone mexicana Mali/Geneva

MVI’s current portfolio feasibility studies translational projects vaccine candidates Antigen Delivery Preclinical Phase 1/2a Phase 2b Phase 3 Antigen discovery (Seattle BioMed) pDNA (Inovio/UPenn) Translational research RTS,S-AS01 (GSK) Multivalent pDNA/ adenovirus (NMRC/Oxford U) Multivalent ChAd63/MVA (Oxford U) Antigen discovery (NMRC) Pfs25 (NIAID, Fraunhofer CMB) PvDBPII (ICGEB/MVDP) RTS,S-AS01/ ChAd63/MVA-TRAP (Oxford U/GSK) CSP RI conjugates (NYU/Merck) Translational development RTS,S-AS01 delayed fractional dose (GSK/WRAIR) B cell targets (Seattle BioMed, JHU, NIAID, WRAIR, NMRC) Pfs25-EPA-Alhydrogel® (NIAID) Antigen discovery (NIAID) Pfs25-VLP-Alhydrogel® (Fraunhofer CMB) EBA-Rh (WEHI/Gennova) MVI identifies potentially promising malaria vaccine candidates and approaches, then… MVI systematically move candidates and approaches through the development process. This is MVI’s portfolio of vaccine projects today. As the products move from the left to the right, they become closer to reality. [For the world as whole, there are about 40 malaria vaccine projects in either the preclinical or clinical phase.] Since 2003, MVI has moved more than three dozen projects through the pipeline, including 12 into human testing. One of them has made it to the last stages of development before licensure: RTS,S. Phase 3 trial is designed to confirm and safety and efficacy of a vaccine, to confirm the results of previous, but much smaller studies. This is a major achievement and a testament to the power of the product development partnership model. RTS,S, which is under development through a partnership between the MVI program and GSK Vaccines, is the only vaccine candidate to advance so far in the development pipeline. PvDBP3-5 (WEHI) AnAPN1 (JHU) Pre-erythrocytic Blood-stage Transmission-blocking P. falciparum vaccines: P. vivax vaccines:

Estimated declines in malaria mortality rates from 2000-2012: 45% globally 49% in WHO African Region Estimated 3.3 million lives saved (69% in 10 countries with highest burden in 2000)

Estimated declines in malaria mortality rates among children <5 years of age from 2000-2012: 51% globally 54% in WHO African Region 90% of lives saved (3 million) among children <5 years of age

Estimated declines in malaria case incidence rates, 2000-2012: 29% globally 31% in WHO African Region

A range of players in Malaria Funding and investments A range of players in Malaria Multilaterals Foundations Research and Academia Clinton Foundation Private sector Donor Countries NGOs Malaria-Endemic Countries

IT ALWAYS SEEMS IMPOSSIBLE… UNTIL IT IS DONE Nelson Mandela