New therapeutic and
preventive medicines to fight
the Ebola epidemic:
December 2014 Status report
16 December 2014
Cumulative EVD cases and deaths
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
11,699
2,143
4,622
18,464
6,841
Total
2|
3|
Ebola 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 Sitrep
13 Dec - GN
09 Dec - LB
13 Dec - SL
4|
Ebola 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 Sitrep
13 Dec - GN
09 Dec - LB
13 Dec - SL
5|
Cumulative EVD infections in health-care workers,
as of 16 December 2014
Country
Guinea
Liberia
Sierra Leone
All countries
6|
Case definition
Total Cases*
Total Deaths
103
50
Probable
9
9
Suspected
0
0
Total
112
59
Confirmed
197
115
Probable
66
29
Suspected
101
39
Total
364
183
Confirmed
216
105
Probable
38
8
Suspected
57
21
Total
311
134
Confirmed
516
270
Probable
113
46
Suspected
158
60
Total
787
376
Confirmed
Source: Patient database as of 15th December 2014
*Includes patients for which outcome data is unavailable
7|
8|
Accelerating access to vaccines
and therapeutics is a high priority
In parallel…
Development
Testing
Licensure
Plan for use
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
deployment
Experimental Ebola therapeutics and Vaccines
A comprehensive scale-up plan
Key issues to consider
A
B
Clinical
trials and
tech
choice
Regulation
and safety
C
Supply demand
D
Vaccination
strategies
& Access
E
F
Scale-up
Enablers
▪ 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?
Focus
today
▪ 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?
▪ 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?
▪ Who can finance and how?
▪ How to best organize procurement?
▪ What is the right framework to think about
liability?
Plan
Ebola vaccines currently under
clinical evaluation
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
Kanapathipillai R et al. N Engl J Med 2014. DOI: 10.1056/NEJMp1412166
Ebola vaccines under Preclinical evaluation
Adenovirus, lentivirus and influenza virus based
Ebola candidates. Russian candidates (2015)
HPIV-3 live attenuated
Intranasal (two versions), NIAID
(March/April 2015)
Ebola recombinant nanoparticle
with Matrix M adjuvant
Novovax
(1st quarter 2015)
Oral adenovirus 5 Ebola vaccine
Vaxart
(1st quarter 2015)
Ebola recombinant protein
Protein Sciences
(1st trimester 2015 )
Recombinant rabies virus
Thomas Jefferson Univ. (2015)
DNA expressing Ebola glycoprotein with
electrophoration. Inovio (2015)
Rabies Ebola gp inactivated,
Intranasal, NIAID (2015)
Alternate rVSV Ebola vaccine
Profectus
(mid- 2015)
Description, developer
(estimated date when clinical
testing will start)
Ad26/Ad35/MVA
J&J/Crucell
(Jan 2015)
Jan 2015
June 2015
13
Dec 2015
Near-term development plan
Nonclinical
eval in
NHPs
GMP
grade
vaccine
Phase 1
Phase 2a
Phase 2b
Safety and
dose selection
Large scale
safety
Preliminary
efficacy
Phase 3
Efficacy
Sept-Nov
2014
1st Quarter
2015
Emergency use
under informed consent
Data collection
Non-affected areas
Large-scale
vaccination
Affected areas
Ebola vaccines in clinical testingPhase 1 studies
NIAID-USA
Kilifi-Kenya
30 healthy adults
Two dose schedule, Safety
40 healthy adults
Dose-selection, Safety
WRAIR-USA
Lambarene-Gabon
30 healthy adults
Dose-escalation, Safety
60 healthy adults
Dose-selection, Safety
Oxford-UK
Monovalent
60 healthy adults
Dose-escalation, Safety
Lausanne-Suisse
Monovalent
100 healthy adults
Dose-escalation, Safety
Geneva-Suisse
VRC-USA
Bivalent
20 healthy adults
Dose-escalation, Safety
CVD - Mali
Monovalent
80 healthy adults
Dose-escalation, Safety
rVSV: Phase 1 trials
ChAd3: Phase 1 trials
Sept 2014
Oct 2014
100 healthy adults
Dose-selection, Safety
Hamburg-Germany
30 healthy adults
Dose-selection, Safety
Nov 2014
15
Ebola vaccines in clinical testing Plans for phase 2, 3 studies
Guinea
Consortium (rVSV and?or
ChAd3)
Ring Vaccination and FLWs
Phase 2 multisite multicountry
RCT
Single common protocol
Efficacy, Safety
total of ?3000 including ?500
children,
- other special populations?
Sierra Leone
CDC(rVSV-ChAd3)
Stepped Wedged
Efficacy, Safety
Possible countries are Ghana,
Mali, Cameroon, Nigeria,
Senegal, Cote d’Ivoire
Safety, Immunogenicity
Liberia-Monrovia
NIH- ChAd3 + rVSV
RCTs
3 arm study
Efficacy, Safety
Jan- Feb 2015
Early results of
vaccine efficacy
2nd Q 2015
16
Ebola Vaccines - Key milestones
Preparation started of
sites for Phase 3 studies
in Ebola affected
countries
Agreed protocols
(including Phase 3)
trials across sites
Initiation of Phase 1
trials for the two
most advanced
vaccines
Start of Phase 3 trials in
Ebola affected
countries
Early results of
vaccine efficacy
Initial safety and
immunogenicity
from Phase 1 trials
available
Sept - Oct 2015 Nov-Dec 2015
17
1st quarter 2015 2nd Q 2015
Whole blood and convalescent plasma
WHO guideline (Sept 2014):
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
Identification of patients recovered
from EVD as potential blood donors
Informed consent and selection of
donors
Donor’s blood grouping and screening
for transfusion-transmissible
infections
Blood collection and donor care
Labelling, storage, and transportation
of blood and plasma products to sites
where transfusion is given
Selection of EVD patients for this
intervention
Clinical transfusion process
Data collection at the transfusion site
Assessment of effectiveness of this
empirical treatment
http://apps.who.int/iris/bitstream/10665/135591/1/WHO_HIS_SDS_2014.8_eng.pdf
18 |
Blood Products
Guinea
Guinea/Belgium/UK/France
Guinea/Belgium/UK/France
Deploying imminently
Deploying imminently
Whole Blood
Plasma
Running
Running
Whole blood
Plasma
Running
Planning
Whole Blood
Plasma
To be deployed
TBC (IgG?)
Liberia
Government
US (Clin RM/BMFG)
Sierra Leone
Government
Others
Nigeria
Clin RM
Other Adjacent countries – strengthening preparedness: mtg end Feb
Expatriated patients – receiving convalescent plasma
19 |
Effective 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.
20 |
WHO Ebola Blood and Plasma Working Group
Strengthening 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
21 |
WHO Ebola Blood and Plasma Working Group
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.
e: Adapted from the Washington Post, Oct 7, 2014
1- Targets the virus before it enters the cell
Zmapp
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
4- Bolsters human cells
Interferons - Induce an antiviral state in
exposed cells and regulates the immune system
Antibodies that can neutralize
the different EVD strains.
5- Testing existing
drugs approved for
other purposes
3- Prevents virus from
exiting host cells
All drugs Screening all
licensed drugs.
6- Whole blood transfusions
and convalescent plasma
2- Interferes with viral production
TKM 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.
Therapeutics

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
23 |
The ‘stuff’ that is being proposed to WHO for
testing in the field…
Vulture Gastric Fluid
Silver suspensions
Chamomile tea
Micronutrients
Ayurvedic oils
Crystals
Homeopathy
Bath salts
Magnets
Electromagnetic waves
24 |
Vitamins
HIV therapies
Root extracts
Health System
Building/Repair/Development
 Expert training
 Funding for development
 Equipment deployment
 Integrating development into trials
 Understanding the needs
25 |
Diagnostics
 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
26 |
Regulators: ICDRA recommendations to
Member States
 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.
27 |
Regulators: ICDRA
recommendations to WHO
 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
28 |
Research
 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
29 |
In the field
 Rumours
 Interventions without evidential basis
 Community engagement (large and small scale)
 Awareness
 Safety
30 |
“Any man's death diminishes me,
Because I am involved in mankind”
John Donne
Back-up slides
31 |
8. Considerations on operational (non-vaccine)
financial needs
32
Considerations on operational (non-vaccine) financial
needs for roll out of vaccination strategies
Typical
campaign
costs
Special
considerations
Ebola vaccine
Type of
vaccination
strategy
Planning, management and coordination
33
Possible Ebola Vaccination Strategies
Ring vaccination
Mobile teams
CommunityHCWs in ETCs
based
Ebola
responders
Target age
groups:
Adults older
than 15 yo
Target age
groups:
Children
<
15 yo
Similar to measles campaigns
Contacts of
Home-based
Ebola
patients care takers of
Ebola
patients
Pregnant
women
People
living
with HIV
Health care centre
34
Ebola vaccination campaigns
Planning, management, and coordination
Availability of data for
decision making on an hour
by hour basis to identify and
manage issues and bring
reinforcements
High quality
microplanning/preparatio
n to identify target
population, and
to identify logistical and
funding requirements
Campaign “readiness
dashboards” might be
considered
Before campaign
Real time tracking and
reporting of vaccination team
supervision.
Assessment of vaccine
coverage
Vaccine coverage monitoring
Evaluation of lessons
learned
Coordination of data
managers at district, regional,
national levels
Drafting guidelines for
Ebola vaccination
campaign management
During campaign
After campaign
35
Typical operational costs of other types
of vaccination campaigns
5
5.0
4
3
2
3.0
3.0
2.0
1
0.6
0
0.2
Polio
Medical volunteers travel
house to house to identify
and vaccinate children aged
<5 years with oral polio
vaccine
Measles
Trained health workers work at
permanent, temporary or field
posts to vaccinate children aged
<5 years with injectable measles
vaccine
HPV
Trained health workers travel to
schools to vaccinate adolescent
girls with injectable HPV vaccine
36
Operational costs of an Ebola vaccine campaign
are likely to be higher than those of other
campaigns
Category
Social mobilisation to explain target populations
Training and supervision for a new “special” vaccine
More human resource requirements may be needed
Transport 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 supplies
Monitoring of Adverse Events
Waste management
Stockpiling challenges are more
than financing and vaccine supply
future outbreaks might involve other strains
physical/behavioural interventions may
continue to be the mainstay of outbreak
control
timing of outbreaks is somewhat unpredictable
need international mechanism to manage
stockpile
39
Oversight
African Vaccine Regulators Forum (AVAREF): Review of IND application: Protocols,
IB, Ethics and informant consent
WHO 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
40
"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.”
41
Acknowledgements
42