The Future of Vaccines

1. The Future of Vaccines WHO TechNet Consultation 30 Nov. - 2 Dec. 2010, Malaysia Jules Millogo, MD, MSc Director, International Organizations Merck & Co., Inc., USA On behalf of International Federation of Pharmaceutical Manufacturers & Associations (IFPMA)

2. The long road leading to the development of a Vaccine Research(Inc. Immunology) Pre-ClinicalDevelopment(Inc. Formulation Science) ClinicalDevelopment (Inc. Post Marketing Surveillance) Transfer Process to Manufacturing BuildFacility x x Up to 50-100 M$ Up to 10-20 M$ Up to 500-1 B$ x x x 2-4 years > 1 year 2-3 years 1-10 years

3. Current Vaccine-Preventable Diseases • Bacterial diseases: • Cholera • Diphtheria • Haemophilusinfluenzae type b infections • Meningococcal infections • Pertussis • Pneumococcal infections • Tetanus • Tuberculosis • Typhoid fever • Viral diseases: • Hepatitis A • Hepatitis B • Human Papillomavirus • Influenza • Japanese Encephalitis • Measles • Mumps • Poliomyelitis • Rabies • Rotavirus diseases • Rubella • Tick born encephalitis • Varicella • Yellow fever

4. Current Vaccine Landscape Adolescent / Adult Vaccines Pediatric Vaccines • Tetanus-diphtheria-pertussis (Tdap) • Meningococcal • HPV / Cervical Cancer • Shingles (Herpes Zoster) • H1N1 Flu (Swine Flu) • Influenza (Seasonal Flu) • Hepatitis A and B • Pneumococcal (polysaccharide) • Inactivated Polio • Live attenuated Polio • Haemophilus influenzae type b (Hib) • Diphtheria • Tetanus • Pertussis (Whooping Cough) • Pneumococcal (conjugate) • Rotavirus • Measles / Mumps / Rubella • Varicella • Hepatitis A / B • Tuberculosis (BCG) • Yellow Fever • Influenza (Seasonal Flu) • * Combo vaccines available including Diphtheria, Tetanus, Pertussis, HIB, Hep B antigens Travel / Regional Vaccines • Japanese Encephalitis (JE) • Lyme Disease • Rabies • Typhoid Fever • Smallpox • Monkeypox • Anthrax • BCG Vaccine in use in many countries outside the U.S. • Routine vaccine in some countries

5. “Old” and “New” Vaccine Timeline HIV/AIDS TB Malaria Dengue Mening (conj) HPV Rotavirus Pneumo (conj) Cholera Typhoid Hib (conj) HepB Influenza Rubella YF JE Measles Tetanus Polio Pertussis Diphtheria // // 1960 1980 2000 Future Underutilised Vaccines Traditional EPI Source: WHO 2006

6. Vaccines of the Future Smoking Addiction Grass Allergy Pollen Allergy Diabetes ETEC Infection (traveler’s diarrhea) Leishmaniasis Malaria Shigellosis Alzheimer disease Ebola Hepatitis C and E Hypertension HIV/AIDS Methicillin Resistant Staphylococcus Aureus Multiple Sclerosis Obesity Parkinson Disease Vaccines in phase III trial Vaccines in Phase I trial

7. A Special Challenge:HIV Vaccine Development Usual vaccine: attenuated virus or “virus-like” antigen stimulates the production of antibodies able to prevent natural infection HIV virus DOES NOT stimulate the production of protective antibodies Unclear how to develop a HIV vaccine that can induce protective (neutralizing) antibodies HIV mutates very rapidly & continually, escaping any immune response Other ways to stimulate immune system: T cells T cells may not prevent infection, but could inhibit disease progression 7

8. HIV Vaccines: Recent Developments • The Merck “Step Study” developed a T cell-based vaccine, but this approach failed • Knowledge of what happened in that trial may help scientists create a more effective vaccine • The recent Thai HIV “prime-boost” vaccine trial produced modest results – the vaccine reduced the chances of infection by 30% • If the mechanism of protection can be understood - it might be possible to develop a better vaccine • Recently, scientists have discovered rare & unusual, but apparently effective antibodies against HIV • The major technical challenge is to develop a vaccine that can induce such antibodies

9. Innovative Vaccine Technologies in Development • Sources include: The Jordan Report (2007), and: • http://www.intercell.com/main/forvaccperts/technologies/vaccine-patch/ (accessed 10/29/2010) • http://www.nsf.gov/od/lpa/nsf50/nsfoutreach/htm/n50_z2/pages_z3/16_pg.htm (accessed 10/29/2010) • http://online.wsj.com/article/SB10001424052748703503804575083611168442980.html (accessed 10/29/2010)

10. Future Technologies for Vaccine Administration Novel vaccine administration technologies in clinical development Intra- / transdermal vaccine administration Mucosal vaccine administration Trans-dermal patches Needle-free injection (liquid, solid, powder) Oral Microneedles Intranasal Pulmonary

11. Factors influencing Development of Novel Administration Technologies • Challenging regulatory pathway • Limited knowledge of molecular mechanisms of vaccine delivery, posing a potential safety risk • Stability issues • Oligopoly structure of the vaccines market, restricting options for licensing deals and alliances • Increasing cost consciousness of healthcare payers • Shortage of funding for biotech companies as result of the economic downturn • Improved vaccine efficacy, particularly in challenging age groups (elderly, newborns) • Government and NGO support for specific indications (e.g. biodefense, childhood vaccines for developing countries) • Additional market opportunities particularly for emerging / developing countries, mass vaccination campaigns • Reduction of vaccination inconvenience, contamination, disease transmission between patients DRIVERS RESISTORS

12. Conclusions on Delivery Mechanisms • Continuing quest for safer, more convenient delivery routes. • Antigen stability, safety and efficacy are the key development hurdles. • New generation needle-free injectors could provide a valuable option for mass immunization. • Big potential for transdermal patches and microneedles routes. Dose reproducibility and antigen formulation remain to be resolved. • Oral and intranasal administration still reliable. Pulmonary vaccination appears less promising.

13. Programmatic Suitability Challenges for Future Vaccines • Multidose vaccines vials: rarely used in developed countries   • Use of Preservatives for MDV vaccines: concerns about stability, potency, AEFI • Combination/ multivalent vaccines : Compatibility between antigens, interference in immune responses, AEFI profile, country preferences. • Thermostability issues- not only technological, but also regulatory.  • Critical role of WHO/Industry dialogue to ensure availability and affordability of appropriate vaccines

14. IFPMA Strategy: Work with WHO to Improve Access to Vaccines & Education • Work with WHO through existing consultation mechanisms to identify public health priorities- especially in LMIC and Developing Countries • Ensure affordability of vaccines thanks to the Tiered pricing mechanism • Participate in Private-Public Partnerships, innovative financing mechanisms, etc • Develop specific efforts to facilitate the availability and access to vaccines (training, education grants, infrastructure building)

15. Tiered pricing based on: Economic status of the country (GNI/capita) Volume of the contract Duration of the contract Tiered pricing allows: Availability Affordability Sustainability *All research-based vaccines companies fully respect competition policies, laws and regulations worldwide. Strategies to Improve Vaccine Access: Tiered Pricing

16. Strategies to Improve Vaccine Access: Tech Transfer & Joint Venture Programs