Vaccine and Antibody Prof Roshan Perera
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Transcript of Vaccine and Antibody Prof Roshan Perera
PROF. ROSHAN PERERAKDU-CARE
INSTITUTE FOR COMBINATORIAL ADVANCED RESEARCH & EDUCATIONGENERAL SIR JOHN KOTELAWALA DEFENCE UNIVERSITY
Emerging Biotechnologies for the Development and Manufacture of
Antibodies, Vaccines and Biosimilar Products
Active and passive immunity
Active immunity: long-lasting protection (memory), multiple effector mechanisms activated, lag time
Passive immunity: rapid protection, short duration
Abbas, Lichtman and Pillai. Cellular and Molecular Immunology, 7th edition, 2011
Types of Vaccines & Adjuvants
Vaccines– Inactivated– Live attenuated– Chimeric– Toxoid– Subunit– recombinant– Conjugate– DNA
AdjuvantsInorganic compounds: alum, aluminum hydroxide, aluminum phosphate, calcium phosphate hydroxide
Mineral oil: paraffin oil
Bacterial products: killed bacteria Bordetella pertussis, Mycobacterium bovis, toxoids
Nonbacterial organics: squalene, thimerosal
Delivery systems: detergents (Quil A)
Cytokines: IL-1, IL-2, IL-12
Challenges in modern vaccinology
• Polymorphism of antigens• Variable immune responses• Antigenic competition/interference in multivalent constructs• Inability to enhance the immunogenicity of highly purified or recombinant
antigens • Reduce the amount of antigen or the number of immunizations needed for
protective immunity • Improve the efficacy of vaccines in newborns, the elderly or immuno-
compromised persons• A major challenge in modern vaccinology is the development of robust methods
to selectively induce a strong immune response against self-proteins, or to increase the immunogenicity of specific epitopes in foreign antigens that can elicit neutralizing antibodies, but which are not immunodominant.
The goal of vaccination is to provide long-term protection against infection through the generation of a strong immune response to the administered antigen
Vaccines: the Phase III efficacy trials
• Malaria: RTS,S by GSK/US Army - efficacy 49%
• HIV: RV144, tested the “prime-boost” combination of two vaccines: ALVAC® HIV vaccine (the prime) and AIDSVAX® B/E vaccine (the boost). US Military - efficacy 31.2%
• Dengue: CYD-TDV by Sanofi Pasteur - efficacy 56.5%
Strategic Goal: To develop 80% or more efficacious vaccine and antibody candidates
INPIRATION
Natural & Unnatural Amino Acids
Genetically Incorporated Unnatural Amino AcidsNatural Amino Acids
IDEATION
Immunochemical termination of self-tolerance
A view of mTNF-trimer
pNO2Phe
Serum titers for C57BL/6 mice immunization
—TNF is an important mediator in inflammation, immune responses (i.e. rheumatoid arthritis) and infection-related phenomena
—but prolonged overexpression leads to severe toxicity, which limits the use of TNF as an anticancer agent
INVENTION
• Immunization (5 g antigen/mouse)
• 23 C57BL/6 mice (age: 15 weeks)
• LPS dose 8.5 mg/kg on day 1
0 1 2 3 4 5 6 7 80
20
40
60
80
100WT_mTNFWT_mod_mTNF
PBS
days
Surv
ival
(%)
mTNF-Y86NO2F (n=8)mTNF-wt (n=8)PBS (n=7)
Lipopolysaccharide (LPS) challenge
—This immunization efficiently protects mice against a lipopolysaccharide (LPS) induced lethality.—Due to the close structure similarity, the elicited antibodies can cross-react with the corresponding self-protein.
~90% survival rate
~10% survival rate
—The septic shock induced by LPS is known to involve in the production and release of TNF
INVENTION
Summary
• —Mice immunized with this pNO2Phe containing protein generate a strongly neutralizing antibody response that effectively cross-reacts with wild-type mTNF,
• —immunization efficiently protects mice against a lipopolysaccharide (LPS) induced lethality.
• —These results strongly suggest that self-proteins bearing a unique NO2 group, a highly immunogenic moiety not found in natural occurring proteins, will be recognized as foreign antigens by the immune system.
• —This approach should provide a general method for breaking immune tolerance of self-proteins and the productions of vaccines.
H2N CO2H
NO2
p-nitrophenylalanine (pNO2Phe)
INVENTION
National Immunization Programme
• The estimated cost of vaccines procured by the government of Sri Lanka is over Rs. 400 million/year.
• Every year the cost of vaccine is increasing substantially.
• Antibody treatment is also an expensive affair (i.e. Rs 70,000/injection for Rheumatoid arthritis)
Development of Vaccine Candidates, Monoclonal Antibodies and Protein Therapeutics in Sri Lanka
A GMP certified vaccine and antibody production plant with recombinant technology should be set up in Sri Lanka for:
1. Production of high quality disease specific monoclonal antibodies and virology (infectious) reagents for research and diagnostics.
2. Production of antibodies for snake venom and rheumatoid arthritis.
3. Development of vaccine candidates for rabies4. Production of Biosimilar products
Preclinical & Clinical Trials
KDU-CARE and KDU University Hospital ($222 million project)
IMPLEMENTATION