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Potential advantages of booster containing PCV regimen - Professor Shabir Madhi

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This slideset, realized by Professor Shabir Madhi on the occasion of the 11th ISPPD held in Melbourne last April, evaluates the potential advantages of booster containing PCV dosing schedule.
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Potential advantages of booster containing PCV regimen - Professor Shabir Madhi

  1. 1. Professor of Vaccinology University of Witwatersrand, South Africa Director: Medical Research Council: Respiratory and Meningeal Pathogens Research Unit, & DST/NRF Research Chair:: Vaccine Preventable Diseases Shabir Madhi
  2. 2. Company Name Honora ria/ Expens es Consultin g/ Advisory Board Funde d Resea rch Royalt ies/ Patent Stock Option s Owner ship/ Equity Positio n Employ ee Other (please specify) MERCK X GSK X BMGF X X No, nothing to disclose X Yes, please specify:
  3. 3. 3 Systematic review comparing the impact of PCV products and 3-dose schedules on vaccine-type nasopharyngeal carriage (NPC) and invasive pneumococcal disease (IPD) M Deloria-Knoll1, T Pilishvili2, M Ramakrishnan1, M de Cola3, O Cohen1, D Hosangadi1, J Farrar2, J Moisi4, T Cherian3, D Goldblatt5, C Whitney2, KL O’Brien1 Affiliations Systematic review comparing the impact of PCV products and 3-dose schedules on vaccine-type nasopharyngeal carriage (NPC) and invasive pneumococcal disease (IPD) M Deloria-Knoll1, T Pilishvili2, M Ramakrishnan1, M de Cola3, O Cohen1, D Hosangadi1, J Farrar2, J Moisi4, T Cherian3, D Goldblatt5, C Whitney2, KL O’Brien1 Affiliations Systematic review comparing the impact of PCV products and 3-dose schedules on vaccine-type nasopharyngeal carriage (NPC) and invasive pneumococcal disease (IPD) M Deloria-Knoll1, T Pilishvili2, M Ramakrishnan1, M de Cola3, O Cohen1, D Hosangadi1, J Farrar2, J Moisi4, T Cherian3, D Goldblatt5, C Whitney2, KL O’Brien1 Affiliations ISPPD XI; Melbourne Posters: 233, 449, 519, 520
  4. 4.  Rational for a booster containing PCV dosing schedule.  Immunogenicity of 2+1 vs 3+0 PCV dosing schedule.  Focus on early dosing schedule from 6 weeks of age.  Impact of PCV in African countries with different dosing schedules and vaccine formulations.  Pneumococcal colonization in children and adults  Invasive pneumococcal disease
  5. 5. PCV – Current Dosing Schedule Used Source: International Vaccine Access Center (IVAC), Johns Hopkins Bloomberg School of Public Health. VIEW-hub Global Vaccine Introduction and Implementation Report, December 2017. 2+1 (57) 3+0 (59) 3+1 (23) 2+1 and 3+1 (1) Gavi countries • In LMIC, majority implemented a 3+0 dosing schedule, including all in sub-Saharan Africa -except South Africa. • In high-income countries, and Latin America, majority have adopted a 2+1 dosing schedule, except for Australia. • Differences between 2+1 and 3+1 schedules subtle, especially in mature programs with high coverage and indirect effects enhance protection.
  6. 6. 6https://consultations.health.gov.au/ohp-immunisation-branch/infant-pneumococcal-vaccination- schedule-recommend/supporting_documents
  7. 7. Jayasinghe S et al Clin Infect Dis; 2018 Online
  8. 8. Jayasinghe S et al Clin Infect Dis; 2018 Online Increased Odds (2.4- 5.9 fold) of vaccine serotype IPD for PCV7 and PCV13 in Children After 12 months post-primary series compared to incidence within 12 months of vaccination.
  9. 9. Jayashinge S CID 2017: 64: 175-83 (Australia);Landhani SN; Lancet Infect Dis 2018 United Kingdom Australia
  10. 10. Jayashinge S CID 2017: 64: 175-83 (Australia)Landhani SN; Lancet Infect Dis 2018; 18: 441-51; United Kingdom Australia
  11. 11.  Epidemiology of disease: peak incidence <32 weeks vs. ongoing disease in second year of life and beyond (need for booster).  Alignment with existing vaccine schedules.  Vaccine program performance, including coverage at different age-groups.  Efficacy and effectiveness of different schedules, including disease (immunogenicity as a proxy) and colonization.  Economic considerations of reduced dosing schedule and vaccine load.
  12. 12. Whitney C, PIDJ 2014; 33, Suppl 1: S172-175. 33% of IPD in South Africa in children >18 months age South Africa introduced PCV into public immunization program in 2009 using a novel 2+1 (6, 14 and 40 weeks) schedule
  13. 13.  Waning of PCV9 efficacy against IPD in HIV-infected children with 6-10-14 week schedule. Madhi SA et al. Vaccine 2007; 25: 2451-2457
  14. 14. • Median age of serotype 1 cases >20 months. • All serotype 1 cases in children <12 months among placebo recipients vs. similar number serotype I IPD cases between PCV-9 vaccinees and placebo recipients among children >15 months of age. Klugman KP et al. Vaccine 2011; 29: 3372-3373
  15. 15.  Rational for a booster containing PCV dosing schedule.  Immunogenicity of 2+1 vs 3+0 PCV dosing schedule.  Focus on early dosing schedule from 6 weeks of age.  Impact of PCV in African countries with different dosing schedules and vaccine formulations.  Pneumococcal colonization in children and adults  Invasive pneumococcal disease
  16. 16. Spijkerman J et al. JAMA 2013; 310: 930-937 • 2-4-6 superior to 3-5, 2-3-4 and 2-4 schedules for 3, 9 and 11 serotypes, respectively; but inferior to 3-5 for serotype 1. • 3-5 schedule superior to 2-3-4 and 2-4 schedules for 5 and 11 serotypes. • Note: Timing of 1st dose important in 2+1 schedule, in addition to interval between doses. One month post primary series GMC,µg/ml  One month post booster, generally no difference between schedules.  Notably higher GMC to serotype 1 in 3-5 m. than any other schedule.
  17. 17. Jones S et al. PlosOne; 2013; 8: e72794 Note: Even for poorly immunogenic serotypes 6B and 23F, >83% above aggregate correlate of protection (≥0.35µg/ml) in 6-14 wk schedule; and similar to 6-10-14 wks schedule.  IgG GMC similar for 6-14 compared to 6-10-14 weeks schedule for 5 serotypes, lower for one (23F) and higher for one (4). 0 10 20 30 40 50 60 70 80 90 100 4 6B 9V 14 18C 19F 23F %IgG≥35µg/ml Serotypes Post PCV doses at 6 & 10 weeks Post PCV doses at 6 & 14 weeks Post PCV doses at 6,10 & 14 weeks 0,1 1 10 4 6B 9V 14 18C 19F 23F Geometricmeanconcentrations Serotypes Post PCV doses at 6 & 10 weeks Post PCV doses at 6 & 14 weeks Post PCV doses 6, 10 & 14 weeks
  18. 18. Immune response following each of three doses of PCV7 at 6, 14 and 40 weeks age. Jones S et al. PlosOne; 2013; 8: e72794 0,1 1 10 100 4 6B 9V 14 18C 19F 23F Geometricmeanconcentrations Serotypes Post PCV doses at 6 & 10 weeks Post PCV doses at 6 & 14 weeks Post PCV doses 6, 10 & 14 weeks Post PCV doses at 6, 14 and 40 weeks
  19. 19. Hamaluda M et al. Lancet Infect Dis 2015; 15: 405-14 • No difference in GMC or percentage above aggregate correlate of protection after 2 vs. 3 dose primary series. • Similar observation for functional antibody (OPA). • Higher GMC following booster dose of PCV in 2+1 schedule compared to after 3rd dose of primary series. • OPA titers consistently higher following booster dose in 2+1 vs after 3rd dose in 3+0 schedule. Age 18 weeks Age 10 months
  20. 20. Madhi SA et al. Exp Rev Vaccines. 2017; • Generally lower GMC after 2 vs 3 dose primary series. • Similar percent above aggregate correlate of protection following 2 vs. 3 dose primary series. • Similar observation for functional antibody (OPA). • Higher GMC following booster dose of PCV in 2+1 schedule compared to after 3rd dose of primary series. • OPA titers consistently higher following booster dose in 2+1 vs after 3rd dose in 3+0 schedule. Age 18 weeks Age 10 months 1 4 5 6B 7F 9V 4 18C 19F 23F 1 4 5 6B 7F 9V 14 18C 19F 23F 1 4 5 6B 7F 9V 14 18C 19F 23F 1 4 5 6B 7F 9V 4 18C 19F 23F
  21. 21.  Rational for a booster containing PCV dosing schedule.  Immunogenicity of 2+1 vs 3+0 PCV dosing schedule.  Focus on early dosing schedule from 6 weeks of age.  Association of serotype-specific antibody and protection against pneumococcal acquisition.  Impact of PCV in African countries with different dosing schedules and vaccine formulations.  Pneumococcal colonization in children and adults  Invasive pneumococcal disease
  22. 22. Voysey M et al. Clin Infect Dis; 2018; 66: 913-920 Inverse association between serotype-specific antibody concentration and sero-incidence (i.e. proxy for serotype-specific nasopharyngeal acquisition) for all serotypes, except ST-1
  23. 23. Voysey M et al. Clin Infect Dis; 2018; 66: 913-920 Red square: serotype-specific correlate derived from generalized additive methods (i.e. antibody level at which probability of sero-incidence becomes negligible (<5%). Blue circles: serotype-specific correlate derived from Receiver Operating Curve (ROC). Best distinguishes those with protection. Gray bars: Serotype specific correlate against IPD (Andrews et al. Lancet Infect Dis; 2014). Note non-alignment of ROC and GAM estimates indicate less than complete protection for serotype (6B, 9V, 14, 19F and 23F).
  24. 24. Voysey M et al. Clin Infect Dis; 2018; 66: 913-920 Low/Low-middle income High/Upper-middle income Higher antibody concentrations required to protect against infant colonization in Low/Lower-middle Income compared to High/Upper-Middle Settings.
  25. 25.  Rational for a booster containing PCV dosing schedule.  Immunogenicity of 2+1 vs 3+0 PCV dosing schedule.  Focus on early dosing schedule from 6 weeks of age.  Association of serotype-specific antibody and protection against pneumococcal acquisition.  Experience with PCV in African countries with different dosing schedules and vaccine formulations.  Pneumococcal colonization in children and adults  Invasive pneumococcal disease
  26. 26. Lee GM et al. Pediatrics; 2017; 140: 5: 1-7 Scott JR et al. J Infect Dis; 2012; 205: 280-8 American Indians Massachusetts. Children <7 years
  27. 27. 0 2 4 6 8 10 12 14 16 18 20 2009 2011 2013 PercentageVTcolonized 19-45 years PCV7 addPCV13 0 10 20 30 40 50 60 70 80 90 100 2009 2011 2013 PercentageVTcolonized <2 years PCV7 addPCV13 0 10 20 30 40 50 60 70 80 90 100 2009 2011 2013 PercentageVTcolonized 2-4 years PCV7 addPCV13 Nzenze S et al. ISPPD X; Glascow 2016 PCV13 PCV13 PCV13 PCV7PCV7 PCV7
  28. 28. <2 years >25 years Overall -76% (95% CI:-79%,-73%) Rates: (29.2 to 7.0) -45% (95%CI:-48%,-43%) Rates: (10.8 to 5.9) PCV13 Vaccine serotype -94% (95%CI:-96%,-93% Rates: (24.8 to 1.4;) -74% (95%CI:-77%,-72) Rates: (7.3 to 1.9) Non-vaccine serotype 29% (95%CI:+9%,+54%) Rates: (4.3 to 5.6). 15% (95%CI:+7%,+23%) Rates: (3.5 to 4.0) Rates: per 100,000 Note: Inclusive of HIV-infected and HIV-uninfected individuals Courtesy: Anne von Gottberg A et al. ISPPD XI; Melbourne; 2018. Vaccine effectiveness: serotype 1 IPD: Children: 98% (95%CI:91-100%) Adults: 93% (95%CI:89--96%)
  29. 29.  Experience in Australia highlight reality of waning of direct protection and lower indirect effect of a in 3+0 schedule.  Minimal immunological benefit of inclusion of a 10 week dose in 6-10-14 vs. 6-14 week schedule (quantitative or functional antibody); including for serotypes 6B and 23F.  Robust quantitative and qualitative antibody responses following booster dose at 9 months age, likely to enhance protection against vaccine-serotype colonization in toddlers (main source of transmission).  High residual prevalence of vaccine-serotype colonization in Malawian (3+0) children and women compared to in South Africa, 3-5 years post PCV introduction.  2+1 schedule has been highly effective in conferring direct (IPD and pneumonia) and indirect protection in South Africa; including against serotype 1.

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