new therapeutic and preventive medicines to fight the ebola epidemic: december 2014 status report 16...
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New therapeutic and preventive medicines to fight
the Ebola epidemic: December 2014 Status report
16 December 2014
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Date of
situation report Confirmed Probable Suspected Total Deaths
Guinea 13-Dec 2,115 263 16 2,394 1,518
Liberia 9-Dec 2,946 1,801 3,050 7,797 3,290
Sierra Leone 13-Dec 6,638 79 1,556 8,273 2,033
Total 11,699 2,143 4,622 18,464 6,841
Cumulative EVD cases and deathsCumulative EVD cases and deaths
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Ebola epidemiological curveEbola epidemiological curve*Data represents confirmed cases in patient database and situation report
**For Liberia, laboratory confirmed cases have been available at the country level since 03 November in the situation report
Latest Sitrep13 Dec - GN09 Dec - LB13 Dec - SL
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Ebola epidemiological curveEbola epidemiological curve*Data represents confirmed cases in patient database and situation report
**For Liberia, laboratory confirmed cases have been available at the country level since 03 November in the situation report
Latest Sitrep13 Dec - GN09 Dec - LB13 Dec - SL
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Cumulative EVD infections in health-care workers,as of 16 December 2014
Cumulative EVD infections in health-care workers,as of 16 December 2014
Country Case definition Total Cases* Total Deaths
Guinea Confirmed 103 50
Probable 9 9
Suspected 0 0
Total 112 59
Liberia Confirmed 197 115
Probable 66 29
Suspected 101 39
Total 364 183
Sierra Leone Confirmed 216 105
Probable 38 8
Suspected 57 21
Total 311 134
All countries Confirmed 516 270
Probable 113 46
Suspected 158 60
Total 787 376
Source: Patient database as of 15th December 2014*Includes patients for which outcome data is unavailable
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Development
Testing
Licensure
Plan for use
Accelerating access to vaccines and therapeutics is a high priority
In parallel…
Accelerating access to Ebola vaccines
From research to large scale use
Dr Ana Maria Henao-Restrepo MD MSc
Group Leader, Vaccine Phase 3 trials and early deploymentExperimental Ebola therapeutics and Vaccines
▪ Is the vaccine safe and effective?▪Which of the technologies to be used?▪What is the Target Product Profile and implications?▪How can clinical trial programs be accelerated?
▪What is the benefit-risk profile and can the Vx be used at population level?▪What are the post-licensure activities / surveillance / adverse events?▪What surveillance systems are in place?▪How can we mitigate supply risks and accelerate supply scale-up?
▪What is the most likely supply map in short and long term?▪What are different supply scenarios (dosage, yield, scale-up)?▪What demand scenarios exist (age, geography, stockpile…)? ▪What to do to ensure formulation is as suited to use as possible?
▪What are vaccination strategies to use and why (e.g. ring-vaccination, cohorts, HCPs, high intensity areas, high risk countries)?
▪What are different access scenarios?▪What is the recommended use for the initial vaccine stocks?
▪Who can finance and how?▪How to best organize procurement?▪What is the right framework to think about liability?
▪Mechanism of vaccine administration in different populations?▪How to manage the cold chain and logistics of distribution?▪What are the main drivers of cost and how can they be controlled?
Key issues to consider
A comprehensive scale-up plan
Focus today
Plan
Clinical trials and
tech choice
Regulation
and safety
Supply -demand
Vaccination strategies & Access
Scale-up
Enablers
A
B
C
D
E
F
rVSV-ZEBOV Recombinant vesicular stomatitis virus
It aims to induce EVD-specific immune responses.
Merck/NewLink Pharmaceuticals/Public Health Agency of Canada
ChAd3-ZEBOV Chimpanzee adenovirus 3
It uses a chimpanzee adenovirus that does not grow, containing the gene for EVD surface protein.
GSK/NIAID
Ebola vaccines currently under clinical evaluation
Kanapathipillai R et al. N Engl J Med 2014. DOI: 10.1056/NEJMp1412166
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Ebola recombinant protein Protein Sciences
(1st trimester 2015 )
DNA expressing Ebola glycoprotein with electrophoration. Inovio (2015)
Oral adenovirus 5 Ebola vaccineVaxart
(1st quarter 2015) Alternate rVSV Ebola vaccine
Profectus(mid- 2015)
Recombinant rabies virusThomas Jefferson Univ. (2015)
Adenovirus, lentivirus and influenza virus based Ebola candidates. Russian candidates (2015)
Ebola recombinant nanoparticle with Matrix M adjuvant
Novovax (1st quarter 2015)
Ebola vaccines under Preclinical evaluation
Ad26/Ad35/MVA J&J/Crucell(Jan 2015)
Jan 2015 Dec 2015June 2015
Description, developer(estimated date when clinical testing will start)
HPIV-3 live attenuated Intranasal (two versions), NIAID
(March/April 2015)
Rabies Ebola gp inactivated,Intranasal, NIAID (2015)
Near-term development plan
GMP grade
vaccine
Emergency use under informed consent
Data collection
Large-scale vaccination
Non-affected areas Affected areas
Sept-Nov2014
Non-clinical eval inNHPs
Phase 1Safety and dose selection
1st Quarter 2015
Phase 2aLarge scale safety
Phase 2bPreliminary efficacy
Phase 3 Efficacy
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Ebola vaccines in clinical testing- Phase 1 studies
VRC-USA Bivalent
20 healthy adultsDose-escalation, Safety
Sept 2014 Oct 2014
Oxford-UK Monovalent
60 healthy adultsDose-escalation, Safety
Lausanne-SuisseMonovalent
100 healthy adultsDose-escalation, Safety
WRAIR-USA
30 healthy adultsDose-escalation, Safety
NIAID-USA
30 healthy adultsTwo dose schedule, Safety
Hamburg-Germany
30 healthy adultsDose-selection, Safety
Nov 2014
Lambarene-Gabon
60 healthy adultsDose-selection, Safety
Kilifi-Kenya
40 healthy adultsDose-selection, Safety
Geneva-Suisse
100 healthy adultsDose-selection, Safety
CVD - MaliMonovalent
80 healthy adultsDose-escalation, Safety
rVSV: Phase 1 trials
ChAd3: Phase 1 trials
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Ebola vaccines in clinical testing -Plans for phase 2, 3 studies
Jan- Feb 2015 2nd Q 2015
Phase 2 multisite multi-country
RCT Single common protocol -total of ?3000 including ?500 children, - other special populations?
Possible countries are Ghana, Mali, Cameroon, Nigeria, Senegal, Cote d’Ivoire
Safety, Immunogenicity
Liberia-MonroviaNIH- ChAd3 + rVSV
RCTs3 arm study
Efficacy, Safety
Sierra LeoneCDC(rVSV-ChAd3) Stepped Wedged
Efficacy, Safety
GuineaConsortium (rVSV and?or
ChAd3)Ring Vaccination and FLWs
Efficacy, Safety
Early results of vaccine efficacy
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Initiation of Phase 1 trials for the two most advanced
vaccines
Ebola Vaccines - Key milestones
Sept - Oct 2015 2nd Q 2015Nov-Dec 2015
Agreed protocols (including Phase 3) trials across sites
Preparation started of sites for Phase 3 studies
in Ebola affected countries
Initial safety and immunogenicity
from Phase 1 trials available
Start of Phase 3 trials in Ebola affected
countries
1st quarter 2015
Early results of vaccine efficacy
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There is consensus that the use of whole blood and convalescent blood
serums needs to be considered as
a matter of priority.
Use of convalescent whole blood or plasma collected from patients who have recovered from Ebola virus disease for transfusion as an empirical treatment during outbreaks
Whole blood and convalescent plasmaWhole blood and convalescent plasma
WHO guideline (Sept 2014):Identification of patients recovered from EVD as potential blood donorsInformed consent and selection of donorsDonor’s blood grouping and screening for transfusion-transmissible infectionsBlood collection and donor careLabelling, storage, and transportation of blood and plasma products to sites where transfusion is givenSelection of EVD patients for this interventionClinical transfusion processData collection at the transfusion siteAssessment of effectiveness of this empirical treatment
http://apps.who.int/iris/bitstream/10665/135591/1/WHO_HIS_SDS_2014.8_eng.pdf
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Other Adjacent countries – strengthening preparedness: mtg end FebExpatriated patients – receiving convalescent plasma
Blood ProductsBlood Products
Guinea
Guinea/Belgium/UK/France Guinea/Belgium/UK/France
Deploying imminentlyDeploying imminently
Whole BloodPlasma
Liberia
GovernmentUS (Clin RM/BMFG)
RunningRunning
Whole bloodPlasma
Sierra Leone
GovernmentOthers
RunningPlanning
Whole BloodPlasma
Nigeria
Clin RM To be deployed TBC (IgG?)
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Effective community engagementEffective community engagement
Draft WHO document on key considerations for effective community engagement in blood donation for compassionate use and clinical trials
Document outlines a draft model and key considerations to enable national health authorities, blood transfusion services and trial investigators to effectively engage with communities to prepare EVD survivors and the communities for blood donation and the clinical trials
Aims to help to ensure informed participation of survivors and communities and avoid the additional pressure and anxiety inappropriate and/or insufficient community engagement can place to already vulnerable groups.
WHO Ebola Blood and Plasma Working Group
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Strengthening NBTSStrengthening NBTS
In-depth assessment of BTS conducted in affected countries
The NBTS in affected countries have suffered from a decade of under resourcing; in staff recruitment, staff development, facility maintenance, effective consumables procurement, equipment provision and maintenance
The services were unable to meet the nations’ needs prior to the outbreak - for this emergency the services are not in a position to support either the compassionate use or the clinical trials
Substantial investment is needed to refresh and resource the services during the recovery phase
Country specific plans for system strengthening are developed - training needs are identified – meeting planned for mid-Jan 2015
WHO Ebola Blood and Plasma Working Group
2- Interferes with viral productionTKM 100802Ebola Target two essential viral genes to stop the Ebola from replicating.
AVI 7537 Sarepta Molecules that bind viral RNA, blocking gene function.
Favipiravir T705 Disrupts enzymes that the virus uses to make copies of himself.
BCX4430 Biocryst Disrupts enzymes that the virus uses to make copies of himself.
Brincidofovir Disrupts enzymes that the virus uses to make copies of himself.
4- Bolsters human cellsInterferons - Induce an antiviral state in exposed cells and regulates the immune system
6- Whole blood transfusions and convalescent plasma
Experimental therapies used to treat Ebola Prioritized for consideration based on the availability of NHP efficacy data with a
filovirus challenge and justification for a human dose based on clinical data of the product or comparable products within that class.
Source: Adapted from the Washington Post, Oct 7, 2014
5- Testing existing drugs approved for other purposesAll drugs Screening all licensed drugs.
3- Prevents virus from exiting host cells
1- Targets the virus before it enters the cellZmapp A cocktail of three monoclonal antibodies, which block or neutralises the virus by binding to or coating a different site on the covering or “envelope” of the virus
Hyperimune globulin Antibodies that can neutralize the different EVD strains.
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Zmapp (Mapp)
siRNA/ AVI-7537 (Serepta)
siRNA/ TKM-100802 (Tekmira)
rNAPc2 (ARCA biopharma)
BCX4430 (Biocryst)
Favipirivir/T705 (Fuji/Toyama)
Brincidofovir (Chimerix)
Toremifene
Inteferons
Lamivudine (GSK)
Amiodarone
New Potential Interventions
TherapeuticsTherapeutics
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The ‘stuff’ that is being proposed to WHO for testing in the field…
The ‘stuff’ that is being proposed to WHO for testing in the field…
Vulture Gastric Fluid
Chamomile tea
Ayurvedic oils
Silver suspensions
Bath salts
HIV therapies
Homeopathy
CrystalsVitamins
Micronutrients
Root extracts
Magnets
Electromagnetic waves
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Expert training
Funding for development
Equipment deployment
Integrating development into trials
Understanding the needs
Health System Building/Repair/Development
Health System Building/Repair/Development
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17 tests under investigation (1 approved for procurement)
Others being received
4 main purposes– Identification/ Confirmation– Field test– Entry/Exit tests– Detailed test for data gathering
Need for standards/ standard testing
DiagnosticsDiagnostics
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Ensure there are emergency use regulatory pathways in place;
Ensure there is rapid and proactive cooperation and collaboration between regulators, and also with WHO, to help accelerate development and evaluation of investigational treatments and vaccines;
Drive innovative clinical trial design for situations like the current EVD emergency where traditional clinical trial designs may not be feasible.
Regulators: ICDRA recommendations to Member States
Regulators: ICDRA recommendations to Member States
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Rapidly provide scientific information on the potential therapies and vaccines for EVD, and ensure the information is regularly updated;
Establish and lead a network of regulators globally to address the response to EVD
Facilitate collaborations between regulators in countries where products are being developed and those in countries where the products will be evaluated and, if found safe, used
Regulators: ICDRA recommendations to WHO
Regulators: ICDRA recommendations to WHO
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Research fields include; Therapeutics, Diagnostics, Vaccines, Epidemiology, Virology and Behavioural dynamics
Trans-disciplinary approach
Better future response– Investigating what we could understand about disease
immunopathogenesis, viral progression and viral shedding– This could benefit patient care, infection prevention and control
and contact management– What can we learn about the behavioural dynamics– This could benefit every level of our intervention in country, with
all actions being impacted
ResearchResearch
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Rumours
Interventions without evidential basis
Community engagement (large and small scale)
Awareness
Safety
In the fieldIn the field
“Any man's death diminishes me,Because I am involved in mankind”John Donne
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Back-up slidesBack-up slides
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8. Considerations on operational (non-vaccine) financial needs
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Considerations on operational (non-vaccine) financial needs for roll out of vaccination
strategies
Type of vaccination
strategy
SpecialconsiderationsEbola vaccine
Typicalcampaign
costs
Planning, management and coordination
Possible Ebola Vaccination Strategies
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Mobile teams Ring vaccination
Similar to measles campaigns Health care centre
HCWs in ETCsCommunity basedEbola
responders
Contacts of Ebola
patientsHome-based care takers of
Ebola patients
Target age groups:
Children < 15 yo
Target age groups:
Adults older than 15 yo
Pregnant women
People living
with HIV
Ebola vaccination campaignsPlanning, management, and coordination
35Before campaign During campaign After campaign
High quality microplanning/preparation to identify target population, and to identify logistical and funding requirements
Campaign “readiness dashboards” might be considered
Availability of data for decision making on an hour by hour basis to identify and manage issues and bring reinforcements
Real time tracking and reporting of vaccination team supervision.
Vaccine coverage monitoring
Coordination of data managers at district, regional, national levels
Assessment of vaccine coverage
Evaluation of lessons learned
Drafting guidelines for Ebola vaccination campaign management
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0.2
2.0
Polio Measles HPV
0.6
3.0 3.0
5.0
Estim
ated
co s
t per
pe r
son
vacc
inat
ed (U
SD)
Medical volunteers travel house to house to identify and vaccinate children aged <5 years with oral polio vaccine
Trained health workers work at permanent, temporary or
field posts to vaccinate children aged <5 years with injectable measles vaccine
Trained health workers travel to schools to vaccinate adolescent girls with
injectable HPV vaccine
Typical operational costs of other types
of vaccination campaigns5
4
3
2
1
0
Operational costs of an Ebola vaccine campaign are likely to be higher than those
of other campaigns
Category
Social mobilisation to explain target populationsTraining and supervision for a new “special” vaccineMore human resource requirements may be neededTransport to access remote locations
Immunisation session supplies for vaccine monitoring
Other
Special considerations for an Ebola vaccine campaign plan are pertinent
Category
Cold chain equipment/special logistics
Security and crowd control
Infection control programme and suppliesMonitoring of Adverse Events
Waste management
Stockpiling challenges are more than financing and vaccine supply future outbreaks might involve other strainsphysical/behavioural interventions may continue to be the mainstay of outbreak controltiming of outbreaks is somewhat unpredictableneed international mechanism to manage stockpile
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African Vaccine Regulators Forum (AVAREF): Review of IND application: Protocols, IB, Ethics and informant consentWHO Advisory Committee on Regulatory Emergency Authorization of unlicensed Ebola Vaccines: Review of GMP, evidence on safety and efficacy, programmatic suitability. Time limited authorization for use.
WHO Ebola Vaccines Risk Assessment Group and WHO Global Advisory Committee on Vaccine Safety: Evaluation of safety data and opinion on potential risks and benefits
Strategic and Technical Advisory Committee on Experimental Ebola Therapeutics and Vaccines (STAC-EE): Review of development plan, expert opinion on protocol design, and interpretation of data emerging from trials.
Strategic Advisory Group of Experts: Review of evidence to inform policy considerations for large scale use, if appropriate
Oversight
"The vaccine is not the magic bullet. But when ready, they may be a good part of the effort to turn the tide of this epidemic.”
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Acknowledgements
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