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PERAN SAINS DALAM PANDEMI
Amin Soebandrio
Many unknowns including
• Disease and its optimal management
• Virus reservoirs (the origin?)
• Virus evolution
• Transmission and epidemiology
Urgent need to develop safe and effective countermeasures that can be available, accessible and suitable for use in populations most in need
5/23 /2020 2
State-of-the-art
In-house RT-PCR detection in place
Ready-to-use formulations on research use only basis available,
in vitro diagnostic-qualified products in the pipeline
Virus isolation capacities available in reference centers
Generic sequencing capacities widely available
Virus isolates available under minimal material transfer agreements
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Required Capacities
PreventPredict
Detect
Resp
onse
Report
5/23 /2020 4
VACCINE TECHNOLOGIES
5/23 /2020 5
Old Technology
6 5 / 23 / 2020
• Grow in animals (vaccinia in calves for smallpox; rabbit brains for rabies)
• Simple bacterial culture (Cholera vibrio) then inactivation
• Grow in eggs (influenza, vaccinia) then inactivate
Live attenuated virus vaccines
5/23 /2020
• Previous preparation:
• Passage at low temperature
• Chemical mutagenesis and selection of mutants with desired phenotype*
• Passage in heterologous tissues
7
MODERN MOLECULAR BIOLOGYHAS OFFERED NEW APPROACHES TO MAKE VACCINES
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Virosome
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Clone gene from virus or bacteria and express this protein antigen in yeast, bacteria or mammalian cells in culture
Cloned gene
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Cloned protein antigenshave pluses and minuses
Pluses
• Easily manufactured and often
relatively stable
• Cannot “revert” to recreate pathogen
Minuses
• Poorly immunogenic
• Poor T cell response
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Virus Vector
Clone gene from virus or bacteria Into genome of another virus (adenovirus, canary pox, vaccinia) and use this live virus as vaccine
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Viral vectors have pluses and minuses
Pluses
• Infects human cells but some do not replicate
• Better presentation of antigen
• Generate T cell response
Minuses
• Can cause bad reactions
• Can be problems with pre-exisiting immunity to virus
• Often can only accommodate one or two antigens
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Reassortment (1)
Courtessy of National Institute of Allergy
and Infectious Diseases (NIAID)
5/23 /2020 14
Reassortment (2)
Courtessy of National Institute of Allergy
and Infectious Diseases (NIAID)
5/23 /2020 15
Reverse Genetics (1)
Frontiers in Bioscience 4912-4924, May 1, 20085 /23 /2020 16
Reverse Genetic (2)
Courtessy of National Institute of Allergy
and Infectious Diseases (NIAID)
5/23 /2020 17
Recombinant protein vaccines• Advantages :
• no risk of infection (residual live virus) • no side-effect (JEV) • Codon optimized
• Disadvantage : • Identification of the right immunogen• High production of rec. protein (promoter and gene amplification
• Separation of the protein from host cell proteins and DNA (secreted protein) • Gentle procedure to purify proteins without denaturation: Purification using immunoaffinity (MAb) or IMAC (His tag)
or lectin chromatography, physical separation: maintain the 3D structure and function for Nt Ab induction• Several injections• Choice of adjuvant
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Recombinant antigens
Expression systems
• Bacteria
• Yeast
• Mammalian cells
• Insect cells
• Avian cells
• Plants
• DNA ( Gene gun. B and T cell response)
Type of antigens
• Particulate (VLP) • Soluble (monomeric or dimeric) • Fusion protein
• Chimeric
19
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Overview of Potential SARS-CoV-2 Vaccine Platforms
Amanat and Krammer, SARS-CoV-2 Vaccines: Status Report, Immunity (2020), https://doi.org/10.1016/j.immuni.2020.03.007
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Overview of Vaccine Production Platforms and Technologies for SARS-CoV-2
Amanat and Krammer, SARS-CoV-2 Vaccines: Status Report, Immunity (2020), https://doi.org/10.1016/j.immuni.2020.03.007
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Pipeline of COVID-19 vaccine candidates by technology platform.
https://www.nature.com/articles/d41573-020-00073-55/23 /2020 22
Profile of COVID-19 vaccine developers by type and geographic location.
https://www.nature.com/articles/d41573-020-00073-5
5/23 /2020 23
CLINICAL-PHASE VACCINE CANDIDATES FOR COVID-19 Candidate Vaccine characteristics Lead developer Status
mRNA-1273LNP-encapsulated mRNA vaccine
encoding S proteinModerna Phase I (NCT04283461)
Ad5-nCoVAdenovirus type 5 vector that
expresses S proteinCanSino Biologicals Phase I (NCT04313127)
INO-4800DNA plasmid encoding S protein
delivered by electroporationInovio Pharmaceuticals Phase I (NCT04336410)
LV-SMENP-DC
DCs modified with lentiviral
vector expressing synthetic
minigene based on domains of
selected viral proteins;
administered with antigen-specific
CTLs
Shenzhen Geno-Immune Medical
InstitutePhase I (NCT04276896)
Pathogen-specific aAPC
aAPCs modified with lentiviral
vector expressing synthetic
minigene based on domains of
selected viral proteins
Shenzhen Geno-Immune Medical
InstitutePhase I (NCT04299724)
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5/23 /2020 24
Difference between Traditional Vaccine Development and Development Using a Pandemic Paradigm.
https://www.nejm.org/doi/full/10.1056/NEJMp20056305/23 /2020 25
HERD IMMUNITY
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5/23/2020 27
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