Vaccine responses and immunological memory: what may we learn from immunization failures?

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1 Vaccine responses and immunological memory: what may we learn from immunization failures? Claire-Anne Siegrist Center for Vaccine Immunology University of Geneva, Switzerland

2 Protection against tetanus What? Why?

3 incidence per million Tetanus in the post vaccine era lower income countries: age-specific tetanus incidence Philippines years

4 A few lessons from immunization failures The most frequent vaccine failure is the failure to have been immunized! Non-communicable diseases remain rare even in the absence of vaccine-induced protection

5 Reported cases of diphtheria, Canada, What? Why?

6 Distribution of protective levels of antidiphtheria and tetanus antibodies in the US McQuillan GM, Ann Intern Med % 80% 60% Participants above seroprotection (%) TT-males DT-males TT-females DT-females 40% 20% 0% What? Age (years) Why? So what?

7 Diphtheria cases reported from the African Region (AFR) What? Why? So what?

8 A few lessons from immunization failures The most frequent vaccine failure is the failure to have been immunized! Herd immunity may mask / compensate for individual vaccine failures!

9 Failure of measles prevention in Europe! 2010 Source : Euvac.net

10 What? Why? Measles in Israel : age distribution

11 Measles in Switzerland (n = 2772) : Age distribution N % 23.4% What? Why? % 17.6% 36% 8.3% 6.0% 3.8% % < 1 1 à 4 5 à 9 10 à à à à 39? 40

12 3267 cases (immuniz. records) : 3049 (93%) non immunized 133 (4.1%) 1 dose 63 (1.9%) 2 doses 22 (0.7%)? dose(s) Failure to have been immunized!

13 A few lessons from immunization failures The most frequent vaccine failure is the failure to have been immunized! Herd immunity may mask / compensate for individual vaccine failures! Herd immunity may alter the age distribution of cases towards adulthood measles, rubella!

14 Mumps Outbreak USA May 2, 2006, > 2000 cases College students (median age 21 y) Parotitis: 66% reported cases Reported complications orchitis meningitis encephalitis deafness oophoritis, mastitis, pancreatitis 25 hospitalizations No deaths Cf wild-type mumps Similar observations elsewhere! 77% - 97% of students with 2 vaccine doses!! Why??? Sonja Hutchins, CDC, 2006,

15 Potential explanations for vaccine failure after 2 mumps vaccine doses Primary vaccine failure Secondary vaccine failure Loss of neutralizing Ab Loss of T cell immunity?? Mismatch between vaccine and outbreak strains ( neutralization)? High viral load close contacts (boarding schools)?

16 A few lessons from immunization failures The most frequent vaccine failure is the failure to have been immunized! Herd immunity may mask / compensate for individual vaccine failures! Herd immunity may alter the age distribution of cases towards adulthood measles, rubella! Highly (excessively) attenuated vaccines (mumps) may not induce life-long protection under all circumstances!

17 Role of immune memory in vaccine-induced protection What is needed for protection against hepatitis B?

18 exposure Neutralizing antibodies > 10mIU/ml 4-12 wks Initial viral replication acute infection infection control chronic infection health cirrhosis HCC Prevention of acute hepatitis B : anti-hbsag titer > 10mIU/ml at time of exposure What happens if you have lost vaccine antibodies at time of exposure?

19 exposure Neutralizing antibodies < 10mIU/ml 4-12 wks Initial viral replication Reactivation of memory cells 4-7 days acute infection infection control chronic infection health cirrhosis HCC Acute hepatitis B infection (anti-hbc Abs) Reactivation of vaccine-induced memory cells protect against chronic hepatitis B!

20 A few lessons from immunization failures The most frequent vaccine failure is the failure to have been immunized! Herd immunity may mask / compensate for individual vaccine failures! Herd immunity may alter the age distribution of cases towards adulthood measles, rubella! Highly (excessively) attenuated vaccines (mumps) may not induce life-long protection under all circumstances! Protection may persist after the disappearance of effectors (antibodies / T cells) : demonstrated role for immune memory!

21 exposure Neutralizing antibodies < 10mIU/ml 4-12 wks Initial viral replication Reactivation of memory cells 4-7 days acute infection infection control chronic infection health cirrhosis HCC Why does the EPI schedule include 3 early infant doses of hepatitis B (prime-prime-prime) without a boost?

22 When is memory sufficient or not sufficient for protection? Sufficient Not sufficient And why???

23 Recalling memory responses before the bugs win the race Short incubation Prolonged incubation Hib Pneumococcus Meningococcus Influenza (Ab) Hepatitis B Hepatitis A Time for Ag to reach the LN and reactivate memory cells into Agproducing cells Insufficient memory! Sufficient memory!

24 When is memory sufficient or not sufficient for protection?

25 Recalling memory responses before the bugs win the race Short incubation Prolonged incubation Hib Pneumococcus Meningococcus Influenza (Ab) Hepatitis B Hepatitis A Mucosal only infections HPV!! Pertussis!! Time for Ag to reach the LN and reactivate memory cells into Agproducing cells Insufficient memory! Sufficient memory!

26 A few lessons from immunization failures The most frequent vaccine failure is the failure to have been immunized! Herd immunity may mask / compensate for individual vaccine failures! Herd immunity may alter the age distribution of cases towards adulthood measles, rubella! Highly (excessively) attenuated vaccines (mumps) may not induce life-long protection under all circumstances! Protection may persist after the disappearance of effectors (antibodies / T cells) : demonstrated role for immune memory! Persistence of immune memory may NOT be sufficient to confer protection

27 Does memory last forever?

28 Pertussis outbreak, California 2010 Kaiser Permanente Vaccine Study Center What? years years? DTaP 1-5 Klein NP et al. N Engl J Med 2012;367:

29 Pertussis outbreak, California 2010 Kaiser Permanente Vaccine Study Center Misegades LK JAMA 2012 Waning of immunity 5 years after DTaP5

30 Pertussis outbreak, California 2010 Kaiser Permanente Vaccine Study Center What? years years years? DTaP Tdap Klein NP et al. N Engl J Med 2012;367:

31 Pertussis outbreak, California 2010 Kaiser Permanente Vaccine Study Center Case control study Vaccine efficacy after DTaP 6 69% during 1 year 57% during the 2 nd year Then NO significant efficacy! Klein NP et al. N Engl J Med 2012;367:

32 No/few cases of pertussis in young adults > 18 years?? What? years? years? years? 4. > 18 years? DTaP Tdap Why??

33 Potential explanations for the failure of pertussis vaccines to confer sustained immunity Primary vaccine failures Secondary vaccine failures (ap >> wp) (ap >> wp) Loss of vaccine Ab (rapid) Loss of T cell immunity (Th17) (presumed) Loss of «boostability» with number of ap doses (ap) Lack of natural boosting (ap >> wp?) Mismatch btwn vaccine and outbreak strains (?) Others???

34 A few lessons from immunization failures The most frequent vaccine failure is the failure to have been immunized! Herd immunity may mask / compensate for individual vaccine failures! Herd immunity may alter the age distribution of cases towards adulthood measles, rubella! Highly (excessively) attenuated vaccines (mumps) may not induce life-long protection under all circumstances! Protection may persist after the disappearance of effectors (antibodies / T cells) : demonstrated role for immune memory! Persistence of immune memory may NOT be sufficient to confer protection Memory may not last for ever which implications for vaccine schedules??

35 A few lessons from immunization failures The most frequent vaccine failure is the failure to have been immunized! Much remains to be studied! Herd immunity may mask / compensate for individual vaccine failures! Herd immunity may alter the age distribution of cases towards adulthood measles, rubella! Highly (excessively) attenuated vaccines (mumps) may not induce life-long protection under all circumstances! Protection may persist after the disappearance of effectors (antibodies / T cells) : demonstrated role for immune memory! Persistence of immune memory may NOT be sufficient to confer protection Memory may not last for ever implications for vaccine schedules??