Inactivated Oral Cholera Vaccine - Rodney Carbis 5th Asian Vaccine Conference Hanoi 12-14 June 2015
←
→
Page content transcription
If your browser does not render page correctly, please read the page content below
Inactivated Oral Cholera Vaccine
Rodney Carbis
5th Asian Vaccine Conference
Hanoi 12-14 June 2015
Vision An affordable cholera vaccine for those most in need
Cholera - disease burden
Cholera is endemic in 51 countries in sub-Saharan Africa and Asia
Plus 18 countries where cholera occurs sporadically
1.4 billion people at risk
Estimated 1.4 – 4.3 million cases annually
With 28,000 to 140,000 deaths
Cholera Outbreak In Haiti – The World Health
Organization has announced today that an unknown
type of cholera has killed dozens of people in Haiti in
the last few days.
Need for a safe, high quality affordable vaccine
Cholera - bacteria
Vibrio cholerae
Serogroups O1 and O139
Pathogenic strains always produce toxin
Serogroup O1 is subdivided into serotypes Inaba and Ogawa based on
the O antigen (polysaccharide antigen associated with LPS).
Two biotypes based on biochemical reactions: classical and El Tor.
Protection from infection
Cholera infection – 90% protection from subsequent attacks for up to 3 years.
The ability to stimulate local intestinal immunity is considered critical in
providing protection
– Local intestinal sIgA against lipopolysaccharide (LPS) prevents colonization and
multiplication of the bacteria
– Local intestinal sIgA against cholera toxin protects against toxin induced fluid
secretion
Model of cholera toxin
Model of antibody binding to cholera O-specific antigen
Cholera vaccine available in 2003
VaBiotech Vietnam SBL Sweden
$1.00 per course of vaccination €35 per course of vaccination
VaBiotech ORC-Vax Compliance with WHO recommendations? Reference: Draft WHO guidelines for production and control of inactivated cholera vaccine Two potential problems identified 1. Antigen quantification method was not accurate. 2. Removal of cholera toxin and no assay to detect residual toxin. Steps taken to improve safety and quality Reformulation • Removed toxin hyper-producing strain and replaced with an equivalent serogroup (O1 Inaba). • Increased the dose of the O1 Ogawa component. Quality Control • Introduced an ELISA to quantify O antigen component of LPS. • Introduced an ELISA to quantify residual cholera toxin.
Cholera Vaccine
Reformulation of Vabiotech Vaccine
SONLA
Strain Old New Non Endemic
30 100
Formalin inactivated 90
25 80
El Tor Inaba (Phil 6973) 5 x 1010 600 EU 70
20
60
15 50
Heat inactivated 40
10
30
Classical Inaba (Cairo 48) - 300 EU 20
5
10
0 0
Formalin inactivated Old New Old New
Classical Inaba (569B) 2.5 x 1010 - GMF increase Seroconversion
30 100
Heat inactivated 90
25
Classical Ogawa (Cairo 2.5 x 1010 300 EU 80
20 70
50) 60
15 50
Formalin inactivated 40
10
Classical Ogawa (Cairo - 300 EU 30
5 20
50)
10
0 0
Formalin inactivated Adults Children
Adults Children
0139 (4260B) 5x 1010 600 EU KOLKATA
Endemic
Seed bank
Ready for Technology Transfer
Expansion of Cell numbers
in Shaker Flask Culture
Seed
Fermentation Serial passage at high dilution to ensure
absence of BSE
Production
Fermentation
Eliminated passage on solid agar
Inactivation
(if formaldehyde)
Concentration
Diafiltration
Increased washing during diafiltration
Inactivation - removal of small amounts of toxin
(if heat) Eliminated centrifugation
Bulk monovalent
concentrates
New QC assays
Formulation LPS (Antigen) and Toxin
Fill and Finish
Shanchol
Indication: 2 doses orally
Technology transfer to Shantha administered 2 weeks apart; to
subjects above 1 year of age.
No buffer required.
Shanchol licensed in India in Feb 2009
WHO Prequalification obtained 28th Sept 2011.
Cost of Goods analysis completed - price of $1.85 considered fair.
Capacity – 2,500,000 doses per yearClinical trials with Shanchol
Trial Study size Result
5 year efficacy (Kolkata) Overall 65% efficacy after 5 years
Cluster randomized placebo 66,360 43% in 1-5 year olds
controlled
Dose interval study (Kolkata) No difference in response if second
356
Double blind placebo controlled dose given 4 wks versus 2 wks later
Booster response (Kolkata) Boosting after 6 years restored
Open label control 426 antibody levels to those seen after
primary dosing
Odisha demonstration trial 74% efficacy (1 year follow up)
Mass vaccination / effectiveness 32,000 Vaccination feasible using existing
infrastructure
Bridging study in Africa (Addis Good immune responses outside of
216
Ababa) Asia
Single dose study (Dhaka) Measurement of response after a
205,661
Double blind placebo controlled single dose. Analysis underway.Supply issues Yield improvement - fed batch fermentation • Using a fed batch fermentation the cell density at the end of fermentation can be increased greater than 3 fold. Increases capacity of existing manufacturing facilities. • No need for additionally capital equipment, should decrease cost of goods and thus increase vaccine affordability.
Ensuring supply Technology transfer of manufacturing and Technology transfer of manufacturing and quality control to EuBiologics (Korea). quality control to Incepta (Bangladesh).
Ensuring supply Technology transfer of two new ELISA based assays to VaBiotech and the Vietnamese NRA. • O antigen component of the LPS • Cholera Toxin assay
Shantha - Shanchol
Licensed and WHO prequalified
Capacity: approx. 2 million doses per annum
Ongoing work (IVI):
Use of booster dose at 5 year
Interval between 2 doses: up to 4 weeks
Bridging immunogenicity in African population
Efficacy of single dose in endemic population
Immunogenicity and safety in Infants
Co administration with OPV and other EPI vaccinesEubiologics -Euvichol
EuBiologics: (South Korean manufacturer)
• 100 L scale (capacity of approx. 5 million doses per annum)
• Submission of dossier to KFDA: Oct 2014
• Export only approval/license: Dec 2014
• Submission of PQ application Jan 2015
Working on increasing capacity
• 600 L scale bulk
• 25 million doses/ yearIncepta
• Incepta: (Bangladeshi manufacturer)
• Technology Transfer completed at IVI: July 2014
• Scale up to 100 L: Sep 2014
• Production of 3 GMP Batch: 2015
• Toxicology: 2015
• Clinical evaluation: 2015
• Licensure in Bangladesh: 2016
• Issues/Benefit
• Non Functional NRA
• High quality vaccine for local use
• Cost about 1 US$/doseVabiotech - mORCVAX
Licensed for use in Vietnam
Vietnamese National Regulatory Authority has now been
recognized as functional by the WHO
Important step for Vietnamese manufacturers as they can now
apply for WHO pre-qualification of their vaccines.
IVI and Vabiotech will work together to achieve pre-
qualification of their Oral Cholera Vaccine.
An important step for the Vietnamese vaccine industryTHANKS TO….. Donors • Bill and Melinda Gates Foundation • Governments of Korea, Sweden and Kuwait Collaborators • Centers for Disease Control, USA • ICDDR, Bangladesh • ICMR/NICED, India • RMRC Odisha • Médecins Sans Frontières, Switzerland • Epicentre, France • NIHE, Vietnam • SBL/Crucell, Sweden • Shantha Biotechnics, India • University of Gothenburg, Sweden • Eubiologics, Korea • VABIOTECH, Vietnam • World Health Organization • GAVI …. and our entire team of epidemiologists, social scientists, data managers, and laboratory scientists at the IVI
You can also read
