Polysaccharide and conjugate vaccine responses

Transcription

1 Hyporesponsiveness Kim Mulholland Murdoch Childrens Research Institute, Melbourne London School of Hygiene and Tropical Medicine, UK University of Melbourne, Australia

2 Hyporesponsiveness Reduced or absent response to an antigen due to prior exposure st described in animals following administration of pneumococcal polysaccharide st described in humans with whole cell pertussis vaccine given at birth Other examples: Hib vaccines administered to neonates Meningococcus following PS vaccine Described in a child following pneumococcal meningitis (Pitchichero) Pneumococcus following PS vaccine Related issue: Vaccines that led to increased susceptibility to the target infection RSV, IM measles, malaria, pneumococcal PS in HIV+, GAS, C. trachomatis

3 Polysaccharide and conjugate vaccine responses PS vaccines Non-T dependent responses Poorly immunogenic in infants Some exceptions Conjugate vaccines T-dependent responses Immunogenic in infants Jan Poolman; Ray Borrow; Expert Review of Vaccines 0, 0, DOI: 0.586/erv..8 Copyright 0 Expert Reviews Ltd

4 Meningococcus Group A Behaves like a T-dependent antigen Group B PS poorly immunogenic, probably unsafe Group C and others PS vaccine leads to hyporesponsiveness in children and adults

5 Prior PS vaccine leads to poor responses in subsequent doses Published in: Jan Poolman; Ray Borrow; Expert Review of Vaccines 0, 0, DOI: 0.586/erv..8 Copyright 0 Expert Reviews Ltd

6 Pneumococus key questions Is pneumococcal PS vaccine safe for infants and young children? Is repeated PS vaccine desirable in adults? How can PS and conjugate vaccines be used for adults?

7 Fiji pneumococcal Project NIH funded 550 infants enrolled to receive: pneumococcal conjugate vaccine in, or 3 dose schedules All were randomized to receive, or not receive PPV at months All children received small (0%) dose of PPV at 7 months as an immunological probe PPV vaccinated infants had good booster responses to PPV vaccine, but All were hyporesponsive to subsequent PPV challenge

8 Post primary responses to 0,, or 3 doses of PCV - ELISA GMT (μg/ml) * * * 4 6B 9V 4 8C 9F 3F 0 doses dose doses 3 doses * Significant difference between doses and 3 doses (p<0.0)

9 An\body levels to PCV- 7 serotypes weeks a^er mths PS booster GMT (μg/ml) 90 * * * 0 doses dose doses 30 3 doses 0 0 * 0 4 6B 9V 4 8C 9F 3F * One dose recipients significantly higher than 3- dose recipients (P<0.05)

10 An\body levels to non- PCV- 7 serotypes following mths booster PS vaccine GMT (μg/ml) F 8 9N 0A A F 5B 7F 9A 0 F 33F PS no PS

11 Antibody levels to non-pcv-7 serotypes before and 4 weeks after micro (0%) dose of PS at 7 months a) No PS at months GMT (µg/ml) pre-micro PS post-micro PS F 8 9N 0A A F 5B 7F 9A 0 F 33F

12 Antibody levels to non-pcv-7 serotypes before and 4 weeks after micro (0%) dose of PS at 7 months GMT (µg/ml) b) PS at months pre-micro PS post-micro PS 3 5 7F 8 9N 0A A F 5B 7F 9A 0 F 33F

13 Pre- vs post- 7m mpps an\- serotype 6B levels Serotype 6B Post mpps, Log Ab concentration Pre mpps, Log Ab concentration O = no 3vPPS at m + = 3vPPS at m

14 Pneumococcal immuniza\on - NT Indigenous children born between /4/000 and 3/0/004 CID 00,50:

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17 Conclusions of FiPP Pneumococcal vaccination is a high priority in Fiji and the Pacific Two doses of PCV as a primary series produces similar immunity to 3 doses Possible exception of type 6A, 3F A single dose of PCV produces better priming than or 3 doses Led to current investigations with + schedules Pneumococcal polysaccharide vaccine as a booster for PCV produces almost complete hyporesponsiveness

18 Follow up Countries considering PCV + PPV schedules did not proceed with these Australia dropped the PPV booster for Indigenous children PCV vaccine introduced into Fiji in 0 WHO sub-committee formed to evaluate Appropriate PCV schedules Revised global EPI schedule NIAID grant to follow up PPV recipients

19 Safety followup of PPV recipients Risk of pneumococcal illness no increased risk Carriage patterns no change in carriage of pneumococci Immunological response to PCV3

20 Serotype-specific IgG PPS v no PPS groups (ALL) PCV3 serotypes (except 6A) 000 PPS no PPS 00 Serotype-specific IgG GMC ( ± 95%CI) B 7F 9V 4 8C 9A 9F 3F PRE-PCV3

21 Serotype-specific IgG PPS v no PPS groups (ALL) PCV3 serotypes (except 6A) 000 PPS no PPS 00 Serotype-specific IgG GMC ( ± 95%CI) B 7F 9V 4 8C 9A 9F 3F POST-PCV3

22 Impact of second dose of PS in adults (n=5) ST4 ST4 ST pre dose post dose pre dose post dose JAMA 999;8(3):43-48

23 The PIPPA study (Vaccine 07;35:908-95) Question: Does repeat PPS vaccination of Indigenous Australian adults lead to hyporesponsiveness Three groups: Indigenous first dose PPS (n=60) Indigenous nd dose PPS (n=0) Non-indigenous first dose PPS (n=5)

24 The PIPPA study (Vaccine 07;35:908-95) Question: Does repeat PPS vaccination of Indigenous Australian adults lead to hyporesponsiveness Three groups: Indigenous first dose PPS (n=60) Indigenous nd dose PPS (n=0) Non-indigenous first dose PPS (n=5)

25 PIPPA participants with adequate response by number of serotypes and group Vaccine 07;35:908-95

26 ELISA antibodies Licciardi et al, submitted S e ro ty p e 6 B p o s t- 3 v P P V S e ro ty p e 6 B p o s t- 3 v P P V Indigenous st dose ᐃ Indigenous nd dose O non-indigenous st dose S e ro ty p e 6 B p re - 3 v P P V S e ro ty p e 6 B p re - 3 v P P V S e ro ty p e 4, p o s t- 3 v P P V S e ro ty p e 4, p o s t- 3 v P P V S e ro ty p e 4, p re - 3 v P P V S e ro ty p e 4, p re - 3 v P P V

27 Opsonophagocytic antibodies Licciardi et al, submitted S e ro ty p e 6 B p o s t- 3 v P P V S e ro ty p e 6 B, p o s t- 3 v P P V Indigenous st dose ᐃ Indigenous nd dose O non-indigenous st dose S e ro ty p e 6 B, p re - 3 v P P V S e ro ty p e 6 B, p re - 3 v P P V S e ro ty p e 4, p o s t- 3 v P P V S e ro ty p e 4, p o s t- 3 v P P V S e ro ty p e 4, p re - 3 v P P V S e ro ty p e 4, p re - 3 v P P V

28 Are some serotypes more likely to cause hyporesponsiveness? Serotype 3 Some evidence of negative efficacy with PPV Failed in the V PCV, PHiD-CV (precursor of PCV0, Synflorix) Seems not to work in PCV3

29 Hyporesponsiveness to serotype 3 following - valent PCV-Protein D (precursor of PCV0) Boosted by PS PCV at -5 mths only Response to PCV following,3,4 mths schedule, boosted At -5 months Published in: Jan Poolman; Ray Borrow; Expert Review of Vaccines 0, 0, DOI: 0.586/erv..8 Copyright 0 Expert Reviews Ltd

30 Conclusions Meningococcus Repeated Men C PS vaccination hyporesponsiveness Clinical implications unknown Pneumococcus Severe infections can hyporesponsiveness In young children PPS vaccine hyporesponsiveness for all STs Resolves within 4 years Clinical implications unknown PCV s have not led to hyporesponsiveness Exception may be ST3 with PCV0 precursor In adults repeated PPS may hyporesponsiveness for some STs No evidence that this is a clinical problem

31 Thoughts about adult pneumococcal immunization.. Pnc vaccination of seniors will become much more important In a community with a stable infant PCV program, the risk for adults from PCV vaccine-type pneumococci is very small In the UK today: Increasing disease due to non-pcv3 types 8, F, F, 4F, 33F and others most are present in 3V PPV Most cases are in older adults Protection by herd immunity may merge into increased risk due to serotype replacement Research is urgently needed to re-define optimal vaccination strategies for seniors in Australia PCV/PPV combinations Whole cell vaccine Protein vaccines New conjugate vaccines