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INTRODUCTION• Streptococcus pneumoniae is an important cause of severe bacterial infections in children in their first
years of life.1 – Nasopharyngeal (NP) colonization is a prerequisite for the development of pneumococcal disease and is responsible for transmission of pneumococci to other individuals.
• NP colonization of vaccine-type serotypes is reduced by pneumococcal conjugate vaccines (PCVs) by prevention of NP acquisition of vaccine-type pneumococci.
• Prior studies have shown that there is an association between increasing serum antipolysaccharide immunoglobulin G (IgG) concentrations after vaccination with PCVs and decreasing probability of acquisition for some vaccine serotypes.3-5
– In fact, serum IgG concentrations higher than that defined by the World Health Organization (WHO) as being sufficient to prevent invasive pneumococcal disease (ie, 0.35 µg/mL6,7) may be required to reduce NP colonization; these levels may differ between serotypes.8
• A large 13-valent PCV (PCV13) and 7-valent PCV (PCV7) study conducted in Israel in 2 ethnic populations (Bedouin and Jewish) provided sufficient NP acquisition and immunogenicity data for the 7 common serotypes (4, 6B, 9V, 14, 18C, 19F, 23F) and the PCV7 cross-reacting serotype 6A (which is in PCV13 only) to further investigate these associations between NP acquisition and serum IgG levels as well as the influence of ethnicity on these associations.9
METHODS• Immunogenicity and NP carriage methodology was previously described.9
• To achieve an appropriate sample size, data for the 7 common serotypes (4, 6B, 9V, 14, 18C, 19F, 23F) and the cross-reacting serotype 6A were combined from the PCV13 and PCV7 arms of the study (N=1410–1530 healthy subjects).
• A logistic regression model assessed the rate of new NP acquisitions as a function of the logarithm of IgG concentrations 1 month after the infant series; this was also adjusted by ethnicity.
• For each serotype, the subjects with NP acquisition were selected. – From these, the 50th, 75th, and 90th percentiles (and corresponding distribution-free CIs) were calculated for reduction in NP acquisition based on their IgG values at 7 months of age (1 month after the infant series).
– Additionally, the percentage of subjects experiencing NP acquisition for whom the IgG levels were ≥0.35 µg/mL was calculated.
CONCLUSIONS• This study shows that achieving higher
IgG levels by vaccination with PCV has a substantial effect on prevention of NP carriage, which may influence the incidence of subsequent pneumococcal disease by direct protection and herd effects.
• Despite the different NP acquisition rates observed in the 2 ethnic groups, which were due to differences in exposure to pneumococci, the dynamics of reduction of NP acquisition by increasing IgG concentrations were generally similar across ethnic groups for most serotypes studied.
• The data show that serum IgG concentrations higher than that defined by WHO to prevent invasive pneumococcal disease (ie, 0.35 µg/mL6,7) are required to reduce NP colonization; these levels differ between serotypes.
OBJECTIVES• To investigate the association between pneumococcal NP acquisition and IgG antibody concentrations for
PCV13 and PCV7 common serotypes 4, 6B, 9V, 14, 18C, 19F, 23F, and cross-reacting serotype 6A • To investigate the variability of immune responses and NP colonization in 2 ethnic groups (Bedouin and
Jewish) relative to exposure rates • To determine IgG concentrations required to achieve the 50th, 75th, and 90th percentile for reduction in
NP acquisition by serotype
REFERENCES1. World Health Organization. Wkly Epidemiol Rec. 2007;82:93-104.
2. Simell B, et al. Expert Rev Vaccines. 2012;11:841-855.
3. Simell B, et al. Clin Vaccine Immunol. 2012;19:1618-1623.
4. Dagan R, et al. J Infect Dis. 2005;192:367-376.
5. Millar EV, et al. Clin Infect Dis. 2007;44:1173-1179.
6. Jodar L, et al. Vaccine. 2003;21:3265-3272.
7. World Health Organ Tech Rep Ser. 2005;927:1-154.
8. Goldblatt D, et al. J Infect Dis. 2005;192:387-393.
9. Dagan R, et al. Clin Infect Dis. 2013;57:952-962.
ACKNOWLEDGMENTSThis study was supported by Pfizer Inc. Medical writing support was provided by Nicole Gudleski O’Regan, PhD, of Complete Healthcare Communications, Inc., and was funded by Pfizer Inc.
RESULTSFigure 1. Predicted Acquisition Rates by Serotype-Specific IgG Concentrations*
Serotype 23F
0
10
20
40
30
Pred
icte
d A
cqui
sitio
n R
ate
s, %
IgG Concentration, µg/mL
0.01 0.1 1 10 1000.35 µg/mL
50th Percentile3.3 (2.3–4.4)
90th Percentile1.8 (1.0–3.0)
Serotype 19F
0
10
20
40
30
Pred
icte
d A
cqui
sitio
n R
ate
s, %
IgG Concentration, µg/mL
0.01 0.1 1 10 1000.35 µg/mL
50th Percentile10.0 (8.6–11.7)
90th Percentile8.5 (6.5–11.0)
Serotype 14
0
10
20
40
30
Pred
icte
d A
cqui
sitio
n R
ate
s, %
IgG Concentration, µg/mL
0.01 0.1 1 10 1000.35 µg/mL
50th Percentile4.7 (3.7–6.0)
90th Percentile3.5 (2.5–5.0)
0
10
20
40
0.01 0.1 1 10 100
Serotype 6B
30
Pred
icte
d A
cqui
sitio
n R
ate
s, %
IgG Concentration, µg/mL
0.35 µg/mL
50th Percentile5.8 (4.7–7.2)
90th Percentile4.2 (2.9–6.0)
0.001 0.01 0.1 1 10 100
Serotype 6A
IgG Concentration, µg/mL
0
10
20
40
30
Pred
icte
d A
cqui
sitio
n R
ate
s, %
0.35 µg/mL
50th Percentile9.8 (8.3–11.5)
90th Percentile6.5 (4.9–8.7)
IgG=immunoglobulin G.*Predicted acquisition rate (95%CI) corresponding to the 50th and 90th percentile of the observed IgG concentrations using a logistic regression model; WHO protection threshold for invasive pneumococcal disease (0.35 μg/mL) is marked.
• New NP acquisition rates decreased as IgG concentrations increased for serotypes 6A, 14, and 23F (P<0.001), 6B (P=0.010), and 19F (P=0.089; Figure 1).
• For serotypes 4, 9V, and 18C, the slopes were negative, showing a similar trend, although P values were not significant (P=0.474, 0.582, and 0.4488, respectively); NP colonization and IgG responses were numerically lower for these serotypes than for the other serotypes.
• There were significant differences in the model between Bedouin and Jewish populations for all serotypes (covariate P≤0.007) except serotype 4, for which acquisition was low (9/1530).
– Despite higher NP acquisition rates in Bedouin children compared with Jewish children, serotype-specific immune responses were similar across ethnic groups.
– The dynamics of the decreasing NP acquisition rates by increasing IgG concentrations were similar between the 2 ethnic groups for most serotypes (Figure 2)
• The percentage of subjects with NP acquisition at or above the WHO-defined efficacy threshold of 0.35 µg/mL ranged between 81.5%−100% for the PCV13/PCV7 common serotypes and 65.8% for the cross-reacting serotype 6A.
Figure 2. Predicted Acquisition Rates by Serotype-Specific IgG Concentrations and by Ethnicity*
JewishBedouin
Ethnicity
0
10
20
30
40 Serotype 6A
Pred
icte
d A
cqui
sitio
n R
ate
s, %
IgG Concentration, µg/mL
0.001 0.01 0.1 1 10 1000.35 µg/mL
50th Percentile – Bedouin13.5 (10.6–17.1)
50th Percentile – Jewish 7.9 (6.3–9.9)
90th Percentile – Bedouin8.2 (5.2–12.8)
90th Percentile – Jewish 5.5 (3.7–8.0)
10
20
30
40
0
Serotype 6B
Pred
icte
d A
cqui
sitio
n R
ate
s, %
IgG Concentration, µg/mL
0.01 0.1 1 10 1000.35 µg/mL
50th Percentile – Bedouin9.9 (7.4–13.0)
50th Percentile – Jewish 3.8 (2.7–5.3)
90th Percentile – Bedouin7.6 (4.7–12.1)
90th Percentile – Jewish 2.4 (1.4–4.3)
0
10
20
30
40 Serotype 23F
Pred
icte
d A
cqui
sitio
n R
ate
s, %
IgG Concentration, µg/mL
0.01 0.1 1 10 1000.35 µg/mL
50th Percentile – Bedouin4.3 (2.7–6.8)
50th Percentile – Jewish
2.5 (1.7–3.7) 90th Percentile – Bedouin1.4 (0.5–3.5)
90th Percentile – Jewish 2.0 (1.0–3.9)
0
10
20
30
40
Pred
icte
d A
cqui
sitio
n R
ate
s, %
IgG Concentration, µg/mL
Serotype 19F
0.01 0.1 1 10 1000.35 µg/mL
50th Percentile – Bedouin14.5 (11.6–17.9)
50th Percentile – Jewish 7.7 (6.2–9.6)
90th Percentile – Bedouin13.9 (9.5–19.8)
90th Percentile – Jewish 6.2 (4.2–8.9)
10
20
30
40
0
Serotype 14
Pred
icte
d A
cqui
sitio
n R
ate
s, %
IgG Concentration, µg/mL
0.01 0.1 1 10 1000.35 µg/mL
50th Percentile – Bedouin7.8 (5.6–10.6)
50th Percentile – Jewish 3.3 (2.3–4.7)
90th Percentile – Jewish 2.2 (1.3–3.7)
90th Percentile – Bedouin6.6 (4.1–10.3)
IgG=immunoglobulin G.*Predicted acquisition rate (95%CI) corresponding to the 50th and 90th percentile of the observed IgG concentrations using a logistic regression model; WHO protection threshold for invasive pneumococcal disease (0.35 μg/mL) is marked.
• Higher serum IgG concentrations were required to achieve the 50th, 75th, and 90th percentile reduction in NP acquisition for each serotype (Table 1). – To achieve the 90th percentile in reduction of NP acquisition, IgG concentrations ranged from 2.48 (serotype 18C) to 17.69 (serotype 14).
Table 1. IgG Concentrations Corresponding to Selected Reductions in NP Acquisition Percentiles by Serotype
IgG Concentration (95% CI*) Corresponding to Selected Percentile of Acquisition, µg/mL
SerotypeAcquisition at IgG Concentration
≥0.35 µg/mL, % 50th Percentile 75th Percentile 90th PercentilePCV7 4 100 1.83 (0.78–3.58) 3.10 (1.83–4.11) 4.11 (3.10–4.11) 6B 88.2 2.06 (1.30–2.97) 3.96 (3.45–7.42) 9.35 (7.40–15.48) 9V 100 1.46 (0.80–1.76) 2.07 (1.55–3.76) 3.76 (2.14–4.33) 14 94.9 5.58 (4.30–6.66) 8.38 (6.79–12.18) 17.69 (11.87–30.16) 18C 100 1.56 (0.86–1.95) 2.17 (1.74–2.67) 2.48 (2.17–3.17) 19F 99.3 2.47 (2.16–2.84) 3.70 (3.24–4.43) 7.16 (4.62–9.21) 23F 81.5 0.88 (0.60–1.20) 1.53 (1.20–2.97) 2.97 (1.88–5.12)Additional 6A 65.8 0.61 (0.49–0.91) 1.55 (1.22–1.96) 3.79 (2.64–6.52)IgG=immunoglobulin G; NP=nasopharyngeal; PCV7=7-valent pneumococcal conjugate vaccine.*Distribution-free 95% CI.
Modeling of Nasopharyngeal Acquisition as a Function of Anticapsular Serum Antibody Concentrations and of Ethnicity After Vaccination With Pneumococcal Conjugate Vaccines
Ron Dagan,1 Christine Juergens,2 James Trammel,3 Scott Patterson,4 David Greenberg,1 Noga Givon-Lavi,1 Nurith Porat,1 William C. Gruber,5 Daniel A. Scott 51Pediatric Infectious Disease Unit, Soroka University Medical Center and the Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel; 2Pfizer Pharma GmbH, Berlin, Germany; 3inVentiv Health Clinical, Princeton, NJ, USA; 4Pfizer Inc, Collegeville, PA, USA; 5Pfizer Inc, Pearl River, NY, USA
Presented at IDWeek 2014; October 8–12, 2014; Philadelphia, PA
1106
For additional information, please contact:Ron Dagan, MD
Pediatric Infectious Disease UnitSoroka University Medical Center
Beer-Sheva, IsraelTel.: +972-8-6400547Fax: +972-8-6232334
Email: [email protected]
