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Global Women’s Health Agenda
“Global Health Technologies: Innovative and multidisciplinary research & development to combat
neglected tropical diseases"
Maria Elena Bottazzi PhD FASTMHAssociate Dean and Professor
Deputy Director, TCH Center for Vaccine Development
Plenary 4: Merck Sponsored Presentation
Learning Objectives
1. Review and update what are the neglected tropical diseases (NTDs), their burden and distribution
2. Review and update the research and development and public health activities that impact the control of diseases that affect adolescent and young adult women’s reproductive health
3. Learn what is the product development partnership model for the development of public health interventions
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Disclosure
No conflicts to disclose
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The Convergence of ‘Global Health’
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The Global Health 2035 report, a roadmap to achieve dramatic health gains within one
generation.
In 2013…..
“Grand convergence” in global health =
Scale-up of health technologies and strengthening health systems
Up to 24% economic return to investing in health
http://www.undp.org/content/undp/en/home/librarypage/mdg/the-millennium-development-goals-report-2014.html
The Millennium Development Goals
2000 - 2015
Millennium
Development
Goals
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Expanded use of vaccines
• 83% reduction in measles deaths
• 82% reduction in tetanus deaths
• 57% reduction in diphtheria/pertussis deaths
• 45% reduction in Hib deaths
Development of new vaccines
• Pneumococcal disease (36% reduction in deaths)
• Rotavirus (63% reduction in deaths)
Progress on Millennium Development Goal 42.5 million childhood lives saved
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Progress on Millennium Development Goal 6
19 million lives saved from AIDS
30% reduction in Malaria
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MDG6: “Other Diseases”
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The Neglected Tropical Diseases (NTDs)
17 diseases or tropical infections
149 endemic countries worldwide
Highly prevalent among the poor
Poverty promoting
Chronic
High morbidity but low mortality
Huge burdens on maternal and child health
Stigmatizing
Disabling (growth delays, blindness or disfigurement)
Ancient afflictions
http://www.who.int/neglected_diseases/about/en/
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What Ails You doesn’t Necessarily Kill You
Disease DALYsDiarrheal 89 millionHIV/AIDS 82 millionMalaria 82 millionTuberculosis 49 millionMeningitis 29 millionNTDs 26 million
Disability-adjusted Life YearsDALYs = YLLs + YLDs
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10 Major Successes + Big Gains!
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Global Women's Health Agenda
• Average life expectancy at birth increased by 6.6 years for women
• Positive changes in social determinants of maternal health
• Efforts made worldwide and nationally to decrease maternal mortality
• A shifting profile: women’s burden of disease• HIV/AIDS still increased in rank as a cause of death – the 7th most
common cause of death
• Increase in death and disability caused by NCDs
• Communicable, perinatal, and nutritional diseases are still among the main causes of death and disability
“Most obstetricians and gynecologists do not routinely think about tropical infectious diseases nor see them as central or
perhaps even relevant to their clinical practices”
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NTDs and Women’s Health
Helminth infections cause adverse pregnancy outcomes and impaired women’s reproductive health
• Hookworm Disease• Risk of severe anemia, higher mortality, and
experiencing poor neonatal outcome
• Schistosomiasis• Linked to horizontal transmission of human
immunodeficiency virus (HIV)
Chagas disease
• Vertical transmission occurs in an average of 4.7% of all affected pregnancies
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The World has Changed since the Years 2000-2015
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• Neglected diseases of the poor living amidst wealth
• A new framework for global science policy and the poverty-related diseases
Most NTDs Occur among the Poor in Wealthy (G20) Countries!!
NTDs in the G20 (plus Nigeria)
77% Leprosy
71% Food-borne trematodiases
67% Leishmaniasis
61% Dengue
61% Chagas disease
60% Lymphatic filariasis
50% Helminth infections
http://g20.org/English/
“The Blue Marble”—an international symbol of peace and healing—photographed by Astronauts, Eugene Cernan, Ronald Evans, and Jack Schmitt, December 7, 1972
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http://foreignpolicy.com/2013/03/25/the-disease-next-door/
Global Health & Disease in the 2020s
New World Order• Perception of anti-
science• Regional conflicts• Climate change• Economic downturn• US/UK Retreat from
Globalization, China’s neo-Silk Road
• Blue Marble Health
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“The Global Health WHACK-A-MOLE”
Urbanization/DeforestationPopulation Growth
Anthropocene Forces
Forces and Drivers
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ISIS-Occupied Syria, Iraq, Libya, & Yemen
Venezuela
Southern Europe
Malaria in Greece and Italy
Schistosomiasis in Corsica
Dengue in Portugal
WNV, Chikungunya in Spain, Italy, France
The AmericasZikaChikungunyaDengue
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The Rise of Emerging + Neglected Diseases in the “New Texas”
Leading TX NTDs• Toxocariasis 700,000
• Trichomoniasis 450,000
• Chagas disease 37,000
• WNV 183-1,900
• Intestinal protozoan 1,000
• Cysticercosis 195-754
• Murine Typhus >100
• Dengue, Zika, Chikungunya
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Hotez PJ (2017) The Rise of Neglected Tropical Diseases in the ‘New Texas’
Poverty in Texas
South Texas “Colonias” Shaghayegh Tajvidi
Chagas disease transmission in Texas
Transmitted by “Kissing
bug”
Causes progressive heart
failure
Identification of autochthonous & imported Chagas disease cases• 1 per 6500 blood donors in Texas screen
positive for Chagas antibodies• 47% (16 out of 34) of blood donors in
Texas suspected locally acquired disease
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Hookworm disease in Alabama
Am. J. Trop. Med. Hyg., 97(5), 2017, pp. 1623–1628
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Lancet. 2015 Aug 22; 386 (9995):743-800.
9 Failures or Minimal Gains!
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An integrated approach for the control of NTDs
Nature Medicine 14, 365 - 367 (2008)
Texas Children’s Hospital Center for Vaccine Development Product Development Partnership (PDP) Model
+ 18 years track record
Partnering with the academic, public and private sectors to leverage expertise
Advancing R&D and product development that focuses on capacity building, infrastructure development and knowledge-sharing to meet LMIC policies and WHO PQ requirements
COMMITTED TO:
• Achieving improved health outcomes in the most cost-effective manner possible
• Early inclusion and understanding of LMICs needs and preferences
• Incentivizing disease-endemic country ownership
• Building self-reliance and sustainability
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Vaccine Development Portfolio
Phase I-IIIDiscovery Preclinical
Human Hookworm
Vaccine Initiative
SchistosomiasisVaccine Initiative
LeishmaniaVaccine Initiative
Chagas Vaccine Initiative
Sars/MersVaccine Initiative
Ascaris and Asthma
Helminth Vaccine and Diagnostics
Oncho Vaccine & Adjuvant
WNV and CHK Preclinical
Testing
Trichuris and Immunology
AMR Bacterial
Pathogens
Research
Molecular Epidemiology
Bacterial Pathogenesis
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Human Hookworm Vaccine (HHV) Initiative
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Bringing vaccines to those in need
India - EU Partnership funded by EuropeAID
Public Health Value
Proposition Strategy
Adapted from Gessner et al., Vaccine 35 (2017) 6255–6263
Human Hookworm Burden of Disease and Public Health Needs Assessment
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• Infects more than 470 million people
• Ranks NUMBER ONE in terms of Years Lost from Disability
• Among the TOP THREE in terms of DALYs (4.1 DALYs using 2010 disability weight estimates)
• Prevalent Worldwide – Overlap with Malaria in Africa
• Causes anemia, malnutrition, physical and developmental delays, hence reductions in future wage earnings
Bartsch et al (2016), Hotez PJ et al. (2010) ; Murray et al, (2012); Smith and Brooker, (2010); Keenan JD et al., (2013) Brooker et al., (2007), Brooker et al., (2006); Smith et al., (2010)
7 million pregnant women in sub-Saharan Africa with hookworm
Up to one-third of pregnant women
• Reduced birthweight• Increased perinatal
child mortality• Increased maternal
mortality
HHV can complement conventional MDA
Lee et al., (2012); Bartsch et al. (2016) Smith et al., (2010)
No overall effect of BMZABZ 1.89 g/l increase in mean Hb
MBZ no apparent impact
Current treatment: Small molecule drugs
• Do not prevent re-infection
• Lack of improvement in hookworm anemia
• Low cure rates and variable efficacy, increasing drug failure
• After widespread MDA hookworm infection has remained almost unchanged (13% over the last decade – GBD 2016)
• A survey of NTD experts concluded that prevention will not be feasible using MDA alone – a vaccine is a strategic necessity
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Candidate Pipeline Prioritization and Evaluation
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Prioritized from a pipeline of >12 candidates
Applied a matrix evaluation and scoring system:• Potential safety risk assessment• Production and scalability feasibility• Stability assessment• Preclinical efficacy• Known function/structure
HHV comprised of TWO Recombinant Proteins from the adult worm
Na-Glutathione S-transferase-1 (Na-GST-1)
Na-Aspartic Protease-1 (Na-APR-1)
Vaccine formulationRecombinant protein adsorbed to Alhydrogel® +/- immuno-stimulants (TLR Agonists – GLA-AF or CpG10104)
Hotez PJ, Bethony JM, Diemert DJ, et al. 2011. https://www.ncbi.nlm.nih.gov/books/NBK62497/
Clinical Development
A series of Phase I clinical trials have been conducted in the USA, Brazil, and Gabon
Tested alone and in co-administration
Tested in adult volunteers from non-endemic and endemic areas and in children from an endemic area• Na-GST-1 vaccine tested in 160 volunteers• Na-APR-1 vaccine in 70 volunteers• Co-administration in 110 adult volunteers• Co-administration in 48 children volunteers
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TARGET PRODUCT PROFILE
Recombinant protein-based vaccine
• 1-2 recombinant antigens + adjuvant
• 2 or 3 doses
• Intramuscular injection
To prevent moderate and heavy hookworm infections caused by Necator americanus
• Prevention of hookworm-related iron-deficiency anemia & related sequelae
Pre-school and school-aged children (< 10 years)
Vaccinations incorporated into existing mass drug administration programs
In these studies, the vaccine was consistently found to be safe, well tolerated and induced anti-Na-GST-1 & anti-Na-APR-1 IgG antibodies
Ongoing Clinical ActivitiesControlled Human Hookworm Infection (CHHI) model • Developed in US under US FDA IND• Established the NaL3PU at GWU: Necator americanus
infectious Larvae 3 Production Unit • US hookworm-naïve adults N = up to 30• Single application of 25, 50, or 75 L3 larvae• Tolerable and quantifiable infection status & intensity
Phase 2: Vaccination + CHHI Study• Randomized, placebo-controlled trial• 48 Healthy, hookworm-naïve adults in US
• Na-GST-1/Alhydrogel®
• Na-GST-1/Alhydrogel® + GLA-AF
• Na-GST-1/Alhydrogel® + CpG 10104
• Infectivity controls (injected with placebo)
• Challenge with 50 Larvae
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Schistosomiasis Vaccine Initiative
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• Schistosomiasis is a chronic parasitic infection caused by Schistosoma blood flukes
• Infection is associated with high mortality and morbidity:
• 280K deaths occur annually
• 252M people are chronically infected with schistosomeworms: ~800M people are at risk
• >90% of people at risk live in Africa
• Schistosomiasis is caused by 3 main worm species:
• S. haematobium - common in Africa / Middle East and manifests in the genitourinary system
• S. mansoni – common in Africa / S. America and manifests in the GI and hepatic system
• S. japonicum – common in Asia and impacts the hepatic system – causes ~1% of infections
Impact of Schistosomiasis
Infection may significantly increase chances of maternal mortality, HIV burden and other high socioeconomic impacts
Stakeholders are increasingly recognizing that current tactics alone may not be sufficient to control infection
WHO, NIH, Am J Trop Med Hyg. (2011); Acta Tropica (2000), Urology (2012), Tropical Medicine Intl Health (2013), Lancet Infectious Diseases (2014), InTech (2012), BJUI (2010), L.E.K. analysis
Impact of schistosomiasis
5-7 million incremental HIV patients in Africa
Risk of HIV contraction among women
~160,000 more bladder cancer patients
annually
Increased chance of bladder cancer
~$1 billion annual loss due to disability / lost
work
Decreased work output
9-10 million infected pregnant women in
Africa
Risk of maternal mortality
$10-20 billion spent on less effective ART
Decreased efficacy of HIV ART
~$20 billion in incremental spend on lifetime treatment costs
4-8 million more patients with
hepatic fibrosis
Liver damage
Infection during pregnancy may lead to severe anemia, increased infant / maternal mortality
rate, and congenital infection
Significantly lowers the IQ of affected children
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Migrating eggs cause granulomas, mucosal erosions and ulcerations, contact bleeding
Most commonly affects cervix and vagina
Infertility, dyspareunia, postcoital bleeding, abdominal pain
Zimbabwe OR = 3 increase in HIV/AIDSKjetland et al. AIDS 2006
Tanzania OR = 4 increase in HIV/AIDSDowns et al. AJTMH 2011
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Schistosoma haematobium
Poggensee and Feldmeier, Acta Tropica 2001; 79(3): 193-210.Photo: Kjetland EF et al., Am J Trop Med Hyg 2005; 72(3):311-9.
Schistosoma haematobiumin the genital tract
Ongoing DevelopmentVaccine comprised of recombinant protein
• Sm-Tetraspanin-2 (Sm-TSP-2)Vaccine formulation
• Sm-TSP-2 adsorbed to Alhydrogel® +/-immuno-stimulant (TLR Agonist – GLA-AF)
A Phase I clinical trial has been conducted in the USA - Tested in 60 adult volunteers
Ongoing a randomized, controlled, double blind Phase 1b dose-escalating clinical trial in up to 48 healthy adult volunteers from an endemic area in Brazil
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In the completed study, the vaccine was consistently found to be safe, well tolerated and induced anti-Sm-TSP-2 IgG antibodies
Chagas Disease
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Therapeutic Chagas Disease Vaccine
Increased Ag-specific IFNγDecreased T. cruzi burdenDecreased Cardiac fibrosis
Could an immuno-therapy be used to modulate and/or balance the host immunological response against chronic Chagas?
Could an immuno-therapy contribute to bridging the drug efficacy gap?
Could an immuno-therapy benefit drug treatments by bridging their tolerability gap?
Tc24- 24kDa Trypanosoma CruziFlagellar Calcium Binding Protein TLR4 agonist:
P P
E6020
(Eisai)
Candidate Antigen Candidate Adjuvant
+
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Questions?
More information:
https://www.texaschildrens.org/departments/vaccine-development
https://www.bcm.edu/departments/pediatrics/sections-divisions-centers/tropical-medicine/research/vaccine-development
email: [email protected]
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