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. To learn more, visit www.waidid.org!

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

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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.  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. 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. 6https://consultations.health.gov.au/ohp-immunisation-branch/infant-pneumococcal-vaccination-
schedule-recommend/supporting_documents

7. Jayasinghe S et al Clin Infect Dis; 2018 Online

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. Jayashinge S CID 2017: 64: 175-83 (Australia);Landhani SN; Lancet Infect Dis 2018
United Kingdom
Australia

10. Jayashinge S CID 2017: 64: 175-83 (Australia)Landhani SN; Lancet Infect Dis 2018; 18: 441-51;
United Kingdom Australia

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. 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.  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. • 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.  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. 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. 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. 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. 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. 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.  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. 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. 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. 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.  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. 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. 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. <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.  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.