Tehran University of Medical Sciences

1. Principle of VaccinologyElhamAhmadnezhadMD. MPH. PhD Student of EpidemiologyFarshidfayyazJahaniMD. MPH. Specialist in Infectious Disease & Tropical Medicine Tehran University of Medical Sciences Vaccinology.

2. Brief History of Lecturers • Elham & Farshid from Tehran, Iran are couple since 3 years ago (2008). Farshid graduated from Medical School in Infectious disease and Tropical medicine’ specialist and Elham now senior student in PhD of Epidemiology. • They have common interest in infectious disease epidemiology then developed some lecturers such as this (Vaccinology). Hope it’s useful for all target groups. Our Email: farshid.fayyazjahani@gmail.com & elhamahmadnezhad@gmail.com Vaccinology.

3. OUTLINE • Introduction & Definition • Vaccination policy option • Mass Vaccination • Surveillance System of Vaccination • Vaccine Development • Vaccine Evaluation • Vaccine Safety • Reporting Immunizations • Reliable Web sits • Vaccine Training Course • Review of National Immunization Coverage Vaccinology.

4. What is Vaccine • Dictionary (Dorland 30th edition 2008) • Attenuated or killed microorganisms or proteins derived from them, administered for the prevention, treatment, or amelioration of infectious diseases • Wikipedia • A vaccine is a biological preparation that improves immunity to a particular disease. A vaccine typically contains an agent that resembles a disease-causing microorganism, and is often made from weakened or killed forms of the microbe. The agent stimulates the body's immune system to recognize the agent as foreign, destroy it, and "remember" it, so that the immune system can more easily recognize and destroy any of these microorganisms that it later encounters. Vaccinology.

5. What is Vaccinology? • Vaccinology is the science of developing vaccines to prevent diseases Vaccinology.

6. Vaccines-Historical Perspective • 7th century- Indian Buddhists' drank snake venom to protect against snake bite. • 10th century- Variolationto prevent smallpox in China and Turkey. • Early 1700s- Variolationintroduced into England. • 1760-70- The Jennerian era. • 1875-1910- Dawn of Immunological Science. • 1910-30- Early bacterial vaccines, toxins and toxoids. • 1930-50- Early viral vaccines: yellow fever and Influenza. • 1950-1970- The tissue culture revolution: poliomyelitis, measles, mumps and rubella. • 1970-1990- Dawn of the molecular era: hepatitis B, Streptococcus pneumonia, Hemophilus influenza B. • Today- Glycoconjugatevaccines, rotavirus vaccine, human papilloma virus vaccine and herpes zoster vaccine. Vaccinology.

7. Aims of Immunisation Programmes • To protect those at highest risk (selective immunisation strategy) or • To eradicate, eliminate or control disease (mass immunisation strategy) Currently, it is estimated that vaccination saves the lives of 3 million children a year • Eradication • Infection (pathogen) has been removed worldwide e.g. smallpox • Elimination • Disease has disappeared from one area but remains elsewhere e.g. polio, measles • Control • Disease no longer constitutes a significant public health problem e.g. neo-natal tetanus Vaccinology.

8. Vaccines Achievements1 • With sanitation and nutrition, vaccines are hailed as one of the most important public health achievements of the 20th century. • The history of vaccinology lends itself to discussion of its progress in terms of periods or eras, in which new advances were made. • Once only targeted against serious childhood diseases, vaccinology has become a tool for preventing infectious diseases or their complications and outcomes in all age groups. • This has seen the number of vaccine-preventable diseases rising to around 26. Vaccinology.

9. Vaccines Achievements2 • “At the end of the 20th century the US Centers for Disease Control and Prevention (CDC) cited vaccination as the number one public health achievement of that century” • “The elimination in 1977 of smallpox as a human disease must rank as one of the major achievements of modern medicine” Vaccinology.

10. The Ideal Vaccine • Immunogenic • Long lasting immunity • Safe • Stable in field conditions • Combined • Single dose • Affordable (and accessible) to all Vaccinology.

11. Categorization of Current Vaccines • Live attenuated:Viruses (oral polio, measles, mumps, rubella, yellow fever), Bacteria (BCG, cholera)- Long lasting immunity, very fragile (cold chain), mutation to pathogenicity • Killed Vaccines: Viruses (hep. A, Salk polio) Bacteria (pertussis, cholera)-intermediate immunity, several doses may be required • Sub-unit vaccines incl:Toxoids: (tetanus, hepb.,occellular vaccines), Conjugate polysacaride vaccines linked with suitable carrier proteins (Hib). Also single or polyvalent vaccines. Vaccinology.

12. Viral Vaccines Vaccinology.

13. Bacterial Vaccines Vaccinology.

14. Target Fungal Vaccines Vaccinology.

15. Target Parasitic Disease • Malaria • Trypanosomiasis • Leishmaniasis • Toxoplasmosis Vaccinology.

16. Selective Vaccination • Vaccine given specifically to those at increased risk of disease: • High risk groups • e.g. Pneumococcal vaccine • Occupational risk • e.g. Hepatitis B, influenza • Travellers • e.g. Yellow fever, rabies, meningitis • Outbreak control • e.g. Hepatitis A. vaccine, measles Vaccinology.

17. Pipelines for Developing Countries Much needed vaccines for the developing world • Malaria • Tuberculosis • HIV • Hookworm • Dengue • EnterotoxigenicEscherichia coli • Shigella Vaccinology.

18. More Possibilities • Therapeutic vaccines: Identification of specific tumor antigens provide immune targets for which immunogenic vaccines may conceivably be designed. Examples: • Leukemia • Breast cancer • Melanoma • Prostate cancer • Colon cancer • Vaccines against autoimmune diseases Vaccinology.

19. Similarities between Vaccines and other Drug • Vaccines are alsomedicines • Potential for adverseeffects • Multipleingredients • Potential for interaction with disease and other medicines • Also need to comply with standards of safety, efficacy and quality Vaccinology.

20. Vaccination Policy Options ? Eradication Activities New Vaccine Introduction Newer Vaccine Research and Development Outbreak vs. routine control of epidemic diseases Vaccinology.

21. Role of disease burden studies in the development and introduction of new and underutilized vaccines • Clinical Evaluation • Study sites • Vaccination schedules & Strategies • Vaccine Utilization • Target groups • Impact • Cost-effectiveness Vaccine Design • Disease Epidemiology • Geographical distribution • Age groups • Seasonality, risk factors Disease-Burden Studies Vaccinology.

22. Mass Vaccination Objective: Make hosts resistant to infection without having to experience disease Vaccinology.

23. Impact of Mass Vaccination Programmes • Reduce size of susceptible population • Reduce number of cases • Reduce risk of infection in population • Reduce contact of susceptible to cases • Lengthening of epidemic cycle -> honeymoon phase • Increase in mean age of infection Vaccinology.

24. No Mass Vaccination Each host in contact with infected host becomes infected (with a certain probability) Vaccinology.

25. Mass Vaccination Outbreak attenuated (or averted) by lack of susceptible hosts Vaccinology.

26. Impact of Mass Immunisation Programme Annual measles notifications & vaccine coveragePoland 1960-2000 Vaccinology.

27. Surveillance of Vaccine Preventable Disease • Vaccine uptake • Vaccine effectiveness • Serological surveillance • Adverse events • Knowledge and attitudes • Vaccine uptake • Disease incidence Vaccinology.

28. Objectives of SurveillanceVaccine Preventable Diseases • Pre-implementation • Estimate burden • Decide vaccination strategy • Post implementation • Monitor impact and effectiveness • Nearing elimination • Identify pockets of susceptible • Certification process Vaccinology.

29. Disease Incidence • Main sources of data • Statutory notification • Laboratory reporting • Death registrations • Other sources • Hospital episodes • Sentinel GP reporting • Paediatric surveillance Vaccinology.

30. Measles Case Definitions • Suspect case • Rash and fever • Probable case • Rash, fever, and either: cough, coryza or conjunctivitis • Laboratory confirmed • Saliva/serum IgM positive Vaccinology.

31. Predictive Value of Notified MeaslesEffect of Change in Incidence Vaccinology.

32. Surveillance of Vaccine Coverage • Vaccine distributed • Vaccine administered • Sampling population assessment e.g. Cluster • Total population assessment (administrative) Number of doses of vaccine given/used Total (target-)population Vaccinology.

33. Use of Administrative Coverage Data • Usually total population • Monitor trends over time • Look for pockets of poor coverage • Compare with disease epidemiology • Estimate vaccine effectiveness Vaccinology.

34. Steps on Vaccine Development1 • Recognize the disease as a distinct entity • Identify etiologic agent • Grow agent in laboratory • Establish in animal model for disease • Identify an immunologic correlate for immunity to the disease- usually serum antibody • Inactivate or attenuate the agent in the laboratory- or choose antigens • Preparecandidate vaccine following GOOD manufacturing Procedures • Evaluatecandidate vaccine(s) for ability to protect animals Vaccinology.

35. Steps on Vaccine Development2 • Prepare protocol(s) for human studies • Apply to MCC for investigational New drug (IND) approval • Phase I human trials- Safety and immugenicity, dose response • Phase II trials- Safety and immugenicity • Phase III trials- Efficacy Vaccinology.

36. Steps on Vaccine Development3 • Submit Product LicensureApplication MCC approval • Advisory Committees review and make recommendations • Marketing Post- Licensure Surveillance for safety and effectiveness (Phase IV) • Long and Complicated process • Usually takes 10-15 years • Many vaccine candidates fail for every success • Costs: $100- $700 million per successful vaccine Vaccinology.

37. Vaccine Evaluation Pre-licensing Randomised, Blinded, Controlled Clinical Trials Vaccine efficacy: Protective Effect under Idealised Conditions RCT: controlled experiments, simple interpretation Post-licensing Observational Studies Vaccine effectiveness: Protective Effect under Ordinary Conditions of a public health programme prone to bias, more complex interpretation Vaccinology.

38. Efficacy, Effectiveness, Impact and Herd Immunity • Efficacy is the direct protection to a vaccinated individual as estimated from clinical trial • Effectiveness is an estimate of the direct protection in a field study post licensure. • Herd Immunityis an indirect effect of vaccination due to reduced disease transmission. • Impact is the population level effect of a vaccination programme. This will depend on many factors such as vaccine coverage, herd immunity and effectiveness. Vaccinology.

39. Basic Calculation of VE % reduction in attack rate of disease in vaccinated (ARV) compared to unvaccinated (ARU) individuals VE (%) = (ARU-ARV) X 100 ARU Where and Consequently, VE = 1-RR (preventive fraction) Vaccinology.

40. IV = 2/10 = 0,2 IU = 9/10 = 0,9 0,9 – 0,2 0,9 VE= = 78% Basic Calculation of VE Vaccinated Unvaccinated Vaccinology.

41. Methods to Assess VE • Pre-licensure: • Randomised control trial (RCT) • Post-licensure:Observational/Field investigation • Screening method • Cohort study • Household contact study • Case-control study Vaccinology.

42. Observational study: Screening Method • Used with Routine Surveillance Data • Take population vaccine coverage (PPV) • Compare with coverage in cases (PCV) VE = 1 - PCV x (1-PPV) (1-PCV) x PPV Vaccinology.

43. Observational study: Screening Method R e l a t i o n s h i p b e t w e e n V E , P P V a n d P C V 1 0 . 8 0 . 6 V E = 6 0 % Proportion of cases vaccinated V E = 8 0 % 0 . 4 V E = 9 0 % V E = 9 5 % 0 . 2 0 0 . 5 0 . 6 0 . 7 0 . 8 0 . 9 1 P r o p o r t i o n o f p o p u l a t i o n v a c c i n a t e d Vaccinology.

44. Potential Pitfalls.... • Case definition; • Vaccine history; • Case ascertainment; • Comparability of vaccinated/unvaccinated groups. Vaccinology.

45. Methodological Issues: Case Definition1 • Lower specificity:Case definition based only on clinical criteria may result in false-positive diagnoses • ARV > ARU VE (%) = (ARU-ARV) X 100 ARU • artificial reduction in VE Vaccinology.

46. Methodological Issues: Case Definition2 Changes in MUMPS vaccine effectiveness Case definition Diagnosis by school nurse ARV 18% (12/67) 89 ARU 28% (77/272) 25% (68/272) VE 37% 52% Kim Farley et al 1985 AJE Vaccinology.

47. Methodological Issues: Case Definition2 Changes in MUMPS vaccine effectiveness Case definition Diagnosis by school nurse Parotitis > 2 days ARV 18% (12/67) 12% (8/67) ARU 28% (77/272) 25% (68/272) VE 37% 52% Kim Farley et al 1985 AJE Vaccinology.

48. Methodological issues: Vaccine History Ascertainment • Avoid misclassification of vaccination status • Equal effort to confirm vaccination status amongst cases and non-cases • Vaccination histories should be documented using GP, clinic, hand-held or computer records • Persons with missing vaccination records should be excluded Vaccinology.

49. Vaccine effectiveness: Post licensure monitoring of VE Post-licensure: maintenance of VE • Problems in vaccine delivery • Cold chain failure, schedule violation, n° of doses, vaccine strain substitution • Epidemiological factors • Pathogen changes • Methodological bias • Selection bias, confounding, chance effects • Low protective efficacy • Bad batch, different target population, alternative patterns of use, vaccine strain used Vaccinology.

50. Summary of VE • Multiple sources of data are valuable to evaluate vaccine programmes • Source of data and case definitions change with stage of vaccination programme • Monitoring VE is integral • VE can be carefully estimated from routine data Vaccinology.