VACCINES Current Development & Strategies

1. VACCINESCurrent Development & Strategies Mohd Azmi Mohd Lila, MBA PhD Laboratory of Immunotherapeutics and Vaccines, Institute of Bioscience, Universiti Putra Malaysia

2. Vaccines & Biopharmaceuticals Biopharmaceutical Proteins Replacement Therapy Facilitative Therapy Polygenic Disease Environmental Disease Genetic Disease Acquired Disease Acquired Disease Diabetes Infection Gaucher’s Disease Acute Coronary Syndromes Insulin tPA Glucocerebrosidase Anti-Hep B Vaccine GPIIb/IIIMab EPO Hemophilia A Anti-HIV Vac. Cancers Cancers Factor VIII TB Vaccines, etc Interferon Interferon Cystic Fibrosis Cytokines Cytokines Anti-EGFR MAb CFTR Anti-EGFR MAb Autoimmune Disease Diabetes Skin Damage Cytokines Receptors Insulin EGF Anti-cytokine Mabs

3. Worldwide Biopharmaceutical Products By Development Platform

4. Market Share Versus Sales Growth (USD) For The Ten Major Asian Markets, 1999-2004 20% 15% 10% 5% 0% Indonesia Taiwan Malaysia Singapore Phillipines Growth 1999-2004 (%) South Korea Thailand India China Hong Kong 0 10 20 30 40 Market Share in 2004 (%)

5. Vaccine Production Capacities

6. Vaccines Biopharmaceutical products (human & animals) Prepared from the whole or a part of the disease agent Against disease agents of biological origin Stimulate host defense mechanisms for production of antibody and/or cell-mediated immune response Long period of R&D (7-14 yrs) High investment cost (USD200-800mill.)

7. Vaccines are prepared from • Whole micro-organisms (life or killed) • A part of the organism (sub-unit protein) • With/without adjuvant • Recombinant vaccines (viruses) • Whole cell protein vaccines • DNA vaccines

8. Targets • Viruses • Bacteria • Other microorganisms • Parasites • Self-Antigens • Prions?

9. Desirable Advantages • Safe and easy delivery method • No needles or other delivery tools • Anticipated increase in compliance of volunteers, children and elderly • May induce humoral, mucosal and cell mediated immune responses • Can prepare for long shelf-life packaging

10. Overall rationale, approach and goals in development of a vaccine • Materials: Choose those that have been used in the clinic or approved for clinical use. • Safety: Select components that will achieve the highest level of safety from the lab to the clinic. • Manufacturing: Use methods and materials (e.g.,closed, disposable) expected to increase potential for accelerated regulatory authority approval. • Vaccine delivery: Develop a safer method, e.g., oral delivery for mucosal and systemic immunity. • End-product features: Long shelf life, inexpensive. • Product protection: Patent

11. A Prophylactic & therapeutic vaccines

12. Prophylactic Vaccines Not for a treatment Prevent disease occurrence (epidemics) For mass immunization, for acute onset indications Development of effective multivalent vaccine against the common genotypes Reduction in cost of vaccines to broaden access. Enlarged target populations for vaccination programs.

14. Therapeutic Vaccines • To cure or retard the disease • Application when disease agent is detected • Earlier diagnosis and treatment of infected individuals. • Broadened viral protein (epitope): avoid escape mutations. • Suitable for chronic diseases • Combination of vaccines with other treatments, including antiviral drugs. • Not for mass immunization

15. Estimated that about 1/3 of all cancer patients would benefit from therapeutic vaccines. • Autologous vaccines are the most heavily investigated • Creating personalized vaccines derived from individual patients’ tumor cells. • Creating a hybrid construct in which an autologous antigen is combined with a highly immunogenic molecule

16. Currently available to treat bladder cancer, colorectal cancer, and melanoma. • Future HIV vaccine. • Therapeutic vaccines against human viruses but no products have been commercialized. • Unlikely to be completely effective as monotherapy.

17. Viral Vaccines • HIV/AIDS • Hep B, C • Poliovirus • Flu virus Vaccines • Whole virus • Killed virus • Recombinant virus • Protein sub-unit • Synthetic vaccine

18. 360 million Hepatitis B virus carriers Market size: > USD 1 bill. per annum

19. Vaccines for Bacterial Diseases • T.B. • Meningococcal • Anthrax (Biodefense vaccine) • Vaccines: Lipopolysaccharide (LPS), Outer membrane protein (OMP) • LPS-based vaccines: poor immunity • E.g. Haemophilus Influenzae (Hib), but now synthetic (peptide) vaccine

20. Vaccines for Parasitic Diseases • Identify key target antigens and maximize immune responses. • Malaria: sporozoite, merozoite, erythrocyte surface, toxin, gamete • Shall induce good to excellent immune responses to all known protein targets either at a single stage of the life cycle or at different stages of the parasite life cycle. • Duplicate whole organism-induced immunity with subunit vaccine. • Duplicate immunity elicited by irradiated sporozoite vaccine with whole parasite vaccine.

21. Concerted ‘efforts’ of a vaccine and host immune components

22. Genotype-specific VLP as a vaccine VLP Virus-like particle

23. Genetic Vaccines • Genetic vaccine is emerging as a safe and specific means of eliciting prophylactic and therapeutic immune responses • Immune response mimics to that of its natural infectious agents (antigenic determinants) • Designing an effective genetic vaccine: must consider both the biology of the vaccine vector/antigen combination and the biology of the disease agent.

24. Genetic Vaccines vs Conventional Vaccines

25. Immuno-contraceptive Vaccine

26. Delivery Vehicle • Nanoparticles/Nanocarriers • Immune-enhancers • Specific cell/tissue targeting – magnetic beads technology • Trans-derma & mucosa • Immune-complex approach p64k-EGF anti-cancer vaccine.

27. Why R&D in Vaccine Delivery Vehicle? • Problems in vaccine administration, delivery & efficacy • Lower investment & faster return • Technology leadership in biopharmarmacutical industry • Facing the challenge of the patent regime • Nanoparticles: non-viral carriers

28. Developing A Vaccine

29. Integrated Manufacturing Setup Research PreClinical Development Pilot Plant Clinical trials Manufacturing Filling & Packaging Sales A foundation for maximizing the stakeholder value

30. Cost of Developing A Vaccine • Basic/Fundamental R&D • Applied R&D • Preclinical & clinical trials • Licensure • Manufacturing facility • Marketing • Monitoring

31. Amount Spent by NIH/US by 2002 Malaria Vaccine USD 60 mill AIDS/HIV USD 400 mill

32. A Challenges in R&D • Extreme variation in microbe strains (e.g. HIV, Flu viruses) • Immune response against the disease agent is poorly understood • No animal models for testing of potential vaccines • Accelerated cost!

33. Other challenges • Probability of success: Scientific advancement has no guarantee for development of a safe and effective vaccine. • Size of market: Developed vs developing countries • Clinical trials: • Logistics and Cost: complicated to conduct and expensive. Phase III efficacy trials - large number of participants, for number of years. • Assessing outcome: 5,10,12 years? Efficacy! • Liability: unexpected side-effects e.g. oncogenesis, immunosuppression, and the risks of vaccine-induce infection. • Trial sites: Health care infrastructures and laboratory facilities are not well developed. Risk being accused of using developing country citizens as "guinea pigs"

34. A Other challenges • Vaccine approval: Lack of harmony among national regulatory agencies. Increases the costs to distribute the in more than one country. • Liability: Potential liability exposure e.g., oncogenic potential of the retroviral class of viruses. The fact that when the vaccine is first introduced the tolerance for side-effects will be very low. • Potential price: The future price these groups would be willing to pay for a vaccine is uncertain. A pressure to make a vaccine widely available at below cost for use in developing countries but that developed countries may not be willing to subsidize developing country purchases.

35. A Other challenges • Perceptions of the disease epidemic : A disease affecting marginalized people but do not realize its global scope or its full implications. If the disease and its potential impact were better understood, then there might be more economic and political demand for a solution. • Interest groups: Lobbying efforts have focused on the provision of care, the development of treatments, the development of a cure, and the support of prevention activities. No a strong call for the development of new vaccines and as a result some vaccines are not viewed as a high priority. • Health care: The price controls on health care affect the private sector's investment decisions.

36. THANK YOU