Vaccine research at Novartis Siena

1. Vaccine research at Novartis Siena • Why vaccines? • How does the immune system work? • Historical advances in vaccine development • attenuated/inactivated pathogens • acellular vaccines • conjugate vaccines

2. Major fields of research • MenB, GBS, • GAS, Prophylactic • Chlamydia • Influenza Improved vaccines and • pandemic threat • Adjuvants More potent vaccines • HCV Therapeutic and prophylactic • HIV Therapeutic and prophylactic

3. Perchè vaccini?

4. Global Death Causes 1997 (in 000) Others &Unknown 6250 = 12% Infectious17310 = 33% Respiratory2890 = 6% Perinatal & Maternal 4215 = 8% Circulatory15300 = 29% Cancer6235 = 12%

5. Global Infectious Disease Mortality About 35% of annual deaths are caused by infectious diseases Disease Mortality (000) Acute infection of respiratory tract 4416** Diarrhoea 3115 Tuberculosis 3072** Malaria 2100 Hepatitis B 1156* Measles 1066* HIV 1063 Tetanus neonatorum 459* Pertussis 355* Leishmaniosis 80 Rabies 60* * vaccine preventable disease ** certain share preventable by vaccines Source: Epidem. Bulletin, RKI 1997

8. The success of medical interventions Drop in death rate for diseases prevented or treated with innovative medicines (pharmaceuticals) 1965 – 1999: VACCINATION Infectious Diseases (polio, measles, Hib, HVB, Hib etc) - >97% THERAPEUTICS Rheumatic fever and rheumatic heart disease -75% - 67% Hypertensive heart disease - 61% Ulcer of stomach and duodenum - 41% Ischemic heart disease • Source: EFPIA 1999 – 2002

10. Emerging and diappearing diseases

11. Come funzionano vaccini?

12. Vaccines lead to protection - how? Vaccine APC T cells B cells Ab Protection

13. By inducing an immune response! Vaccine APC T cells B cells Ab Protection

14. The immune response in one slide

15. The immune response in one slide

16. Naïve T cells are primed by antigen presented on activated dendritic cells

17. Principle of T cell help to B cells

18. The immune response at a glance Pathogen “Inflam-mation” APC T cells B cells Ab Inflammation: Cytokines Cell recruitment Neutrophils Monocytes Macrophages Granulocytes Antigen Presenting Cells: Monocytes Macrophages Dendritic cells Protection

19. Vaccines interfere at more than one point Vaccine Adjuvant + Antigen “Inflam-mation” APC T cells B cells Ab Inflammation: Cytokines Cell recruitment Neutrophils Monocytes Macrophages Granulocytes Antigen Presenting Cells: Monocytes Macrophages Dendritic cells Protection adaptive innate

20. Time course of a successful immune response Innate Immunity Adaptive Immunity Response Virus Titer Time Infection Clearance

21. Principle of immunity Naturally acquired immunity: Infection by a pathogen induces an immune response. Two consequences: A: Elimination of the pathogen. B: Immunological memory, i.e. the response to a second infection is faster and more efficient than the first one. The person is immune to the pathogen.

22. vaccine infection

23. vaccine infection

24. vaccine infection

25. vaccine infection

26. Principle of immunity 2 The response to a second infection is faster and more efficient than the first one, due to: increased specific Ab titers increased frequency of Ag-specific (memory) B and T cells more rapid activation and higher functional efficiency of memory B and T cells

27. Principle of vaccines Vaccines mimic the infectious agent, therefore an immune response is mounted, but without experiencing infection/ disease/ complications: Similar but safe

28. Antibodies and B cells

29. Antibodies For most prophylactic vaccines, our primary aim is to induce high concentrations of high affinity antibodies

33. B cell frequencies 10-3-10-4 10-2 10-5 B cell frequencies Response Virus Titer t Clearance Infection

34. Memory B cells Have higher frequency… Produce Abs with higher affinity… Are activated more easily… … than naïve B cells faster, more efficient response

37. T cells

38. The immune response at a glance

43. The immune response at a glance

45. Storia dei vaccini

46. Pre-requisites for vaccine development: in the early 19th century New perception Hippokrates 460-377 a.t. Founder of the theory on miasmae Toxic evaporations of the soil leading to the spread of diseases. E.g. Malaria (mal aire = bad air) At the end of the 18th century Quarrels between „miasmytologists“ and „contagionists“, who believed that disease can be caused by living organisms New basic findings • Pasteur and others • Fermentation is done by living organisms (chemical process) • Process of pasteurization (killing / preserving by heat) • Identification of micro-organisms as causative agents for diseases (infectious agents) • Koch´s postulate Many names of pathogens refer to outstanding scientists: Salmonella typhii Pasteurella pestis Bordetella pertussis Isolation of the pathogen (virus, bacterium) that causes disease Ability to replicate / grow the pathogen

47. Vaccino: simile ma non uguale al patogeno Un vaccino dev’essere il più simile possibile al patogeno ma senza causare danni Variolation: materiale seccato derivato da lesioni provocate da vaiolo veniva usato per vaccinare (ma 3-4% sviluppava la malattia) Jenner: usa materiale dalle lesioni di vaiolo bovino per vaccinare un ragazzo: ha sviluppato la resistenza al vaiolo (quindi il nome “vaccino” = “nella vacca”) Pasteur: usa il virus della rabbia attenuato

48. Smallpox – the scourge of mankind Last reported case of smallpox in 1977 Individual suffering from smallpox The WHO certified the eradication of smallpox in 1980

49. Jennerian approach Smallpox Use of a life animal pathogen with no / low pathogenicity for humans to immunize humans and to protect against the analogous human pathogen Jenner adopted the knowledge that dairymaids who had previously contracted the less severe cowpox never suffered from smallpox In 1796 Jenner immunized a boy with cowpox, after a week of illness the boy was protected against challenge with smallpox Animal pathogen Human pathogen Vaccinate protection against infection Other examples: Mycobacterium bovis (BCG): protection against Mycobacterium tuberculosis Bovine rota virus strains: protection against human rotavirus strains

50. Strong opposition developed against vaccination Introduction of new technologies always causes fears Contemporary cartoon