Relationship between immune response to pneumococcal conjugate vaccines in infants and indirect protection after vaccine implementation

Figures & data

Figure 1. Three levels of protection elicited by PCVs against disease caused by VT pneumococci.

(1) Acquisition of circulating neutralizing antibodies (i.e. serotype-specific immunoglobulin G). (2) Prevention of VT NP acquisition following exposure to the pathogen. (3) Prevention of person-to-person transmission of VT pneumococci. Levels 1 and 2 represent protection of the vaccinated individual, often referred to as direct protection. Level 3 is referred to as indirect or herd protection. NP = nasopharyngeal; PCV = pneumococcal conjugate vaccine; VT = vaccine serotype.

Figure 2. Differences in inferiority observed when measuring the proportion of children achieving concentrations above threshold vs geometric mean antibody concentrations: A comparison between PCV10 and PCV7.

(a) After the third primary vaccine dose, PCV10 was noninferior to PCV7 for most serotypes using the proportion of subjects achieving a titer of ≥0.20 µg/mL response; the only exceptions were serotypes 6B and 23F. (b) PCV10 was inferior to PCV7 for most serotypes when measuring the geometric mean concentrations of anti-polysaccharide immunoglobulin G; the only exception was serotype 19F. Solid bars, data from Wysocki J, et al. Pediatr Infect Dis J 2009 [34]. Hatched bars, data from Vesikari T, et al. Pediatr Infect Dis J 2009 [35]. ELISA = enzyme-linked immunosorbent assay; PCV = pneumococcal conjugate vaccine; PCV7 = 7-valent PCV; PCV10 = 10-valent PCV.

Figure 3. Carriage studies examining the efficacy of CRM₁₉₇-conjugated vaccines (i.e. PCV7/PCV13) and protein-D conjugated vaccines (i.e. PCV10/PCV11).

(a) All published studies in which PCV was administered as three infant doses, and carriage was measured around 12 months of age, before the toddler dose. (b) All published studies in which PCVs were administered at either two or three doses during infancy, and a booster was administered at around 12 months of age. The age when carriage was measured appears on the y-axis. Several age points were often used for the same study. The circled endpoints are for studies in which children received two doses in infancy. For all others, children received three infant doses. Each circle represents the endpoint efficacy of the vaccine measured against placebo or control vaccine; error bars represent CIs. Adapted from Fleming-Dutra KE, et al. Pediatr Infect Dis J 2014 [55]. Studies on y-axes correspond to: (a) Prymula R, et al. Vaccine 2009 [57]; (b) GlaxoSmithKline COMPAS Study 109563 (10PN-PD-DIT-028) [61]; (c) Vesikari T. European Congress of Clinical Microbiology and Infectious Diseases 2013, Berlin, Germany [56]; (d) Cheung YB, et al. Pediatr Infect Dis J 2009 [58]; (e) Russell FM, et al. Clin Vaccine Immunol 2010 [48]; (f) Dagan R, et al. Clin Infect Dis 2013 [42]; (g) O’Brien KL, et al. J Infect Dis 2007 [59]; (h) Prymula R, et al. Vaccine 2011 [62]; and (i) van Gils EJ, et al. JAMA 2009 [60]. *Data are for the additional six serotypes in PCV13 plus 6C combined. PCV = pneumococcal conjugate vaccine; PCV7 = 7-valent PCV; PCV9 = 9-valent PCV; PCV10 = 10-valent PCV; PCV11 = 11-valent PCV; PCV13 = 13-valent PCV; VT = vaccine serotype.

Table 1. Immunogenicity of serotypes 19A and 6A using OPA assays from clinical studies comparing PCV7, PCV10, and PCV13.

	Serotype 19A OPA GMT (95% CI)		Serotype 6A OPA GMT (95% CI)
Vaccine Administered	Primary Series	Booster Dose	Primary Series	Booster Dose
PCV7 vs PCV10 Studies
PCV10 [68]	10.9 (8.4, 14.3)	64.9 (44.6, 94.5)	188.9 (139.8, 255.3)	196.1 (134.6, 285.9)
PCV7 [68]	5.3 (4.2, 6.7)	15.5 (8.1, 29.9)	358.0 (213.4, 600.5)	1415.7 (891.2, 2248.9)
PCV10 [35]	8.6 (7.1, 10.5)	29.2 (22.3, 38.3)	40.9 (31.4, 53.3)	254.8 (202.8, 320.1)
PCV7 [35]	4.5 (3.9, 5.3)	11.1 (7.3, 17.0)	83.3 (51.6, 134.3)	872.7 (597.1, 1275.7)
PCV10* [34]	7.1 (5.6, 9.0)	18.9 (13.0, 27.4)	100.9 (65.9, 154.6)	293.7 (217.9, 395.8)
PCV7* [34]	4.1 (3.9, 4.2)	8.7 (6.6, 11.4)	231.5 (155.1, 345.4)	1166.4 (877.2, 1550.9)
PCV10^† [74]	10.6 (7.9, 14.2)	89.3 (58.9, 135.4)	-	-
PCV7^† [74]	4.2 (3.8, 4.7)	8.7 (5.4, 14.2)	-	-
PCV10^‡ [74]	10.1 (7.8, 13.1)	70.7 (45.3, 110.4)	-	-
PCV7^‡ [74]	4.0 (4.0, 4.0)	20.3 (8.8, 46.8)	-	-
PCV10 [75]	9.0 (6.9, 11.7)	-	-	-
PCV7 [75]	4.9 (4.4, 5.4)	-	-	-
PCV7 vs PCV13 Studies
PCV13 [69]	152 (105, 220)	1024 (774, 1355)	980 (783, 1226)	2242 (1707, 2945)
PCV7 [69]	7 (5, 8)	268 (164, 436)	100 (66, 152)	539 (375, 774)
PCV13 [70]	442 (361, 543)	1349 (1089, 1672)	1228 (883, 1708)	2502 (1916, 3266)
PCV7 [70]	7 (5, 9)	59 (37, 94)	122 (74, 202)	501 (341, 736)
PCV13 [71]	557 (493.1, 628.9)	1287 (1109.0, 1494.1)	4882 (4206.4, 5665.3)	5799 (4938.7, 6808.4)
PCV7 [71]	9 (7.3, 12.0)	24 (17.3, 34.5)	456 (301.0, 691.3)	1047 (711.2, 1542.0)
PCV10 vs PCV13 Studies
PCV13 [72]	-	-	2832.0 (2212.8, 3624.4)	5200.7 (4134.9, 6541.3)
PCV10 [72]	-	-	36.5 (22.6, 59.0)	146.4 (87.6, 244.6)
PCV13 [73]	-	4516 (3031, 6729)	-	18,094 (13,293, 24,629)
PCV10 [73]	-	285 (139, 585)	-	2888 (1812, 4602)

GMT = geometric mean titer; OPA = opsonophagocytic activity; PCV = pneumococcal conjugate vaccine; PCV7 = 7-valent PCV; PCV10 = 10-valent PCV; PCV13 = 13-valent PCV.

*Reported with coadministered Haemophilus influenzae type b meningococcal serogroup C (Hib-MenC).

^†Data from Filipino infants.

^‡Data from Polish infants.

Figure 4. Cross-protection induced by cross-reactive serotype antigens does not provide a similar level of protection to that elicited by the specific serotype antigen against serotype 19A carriage: results of two double-blind studies.

(a) Results of a double-blind study comparing PCV13 and PCV7 for 19A carriage in Israel. Adapted from Dagan R, et al. Clin Infect Dis 2013 [42]. (b) Results of a study comparing the efficacy of PCV10 and PCV7 on 19A carriage in the Netherlands. Adapted from van den Bergh MR, et al. Clin Infect Dis 2013 [83]. PCV = pneumococcal conjugate vaccine; PCV7 = 7-valent PCV; PCV10 = 10-valent PCV; PCV13 = 13-valent PCV.

Table 2. Postlicensure PCV10 and PCV13 studies assessing the effect of vaccination on serotype 19A, 6A, and 6C carriage.

Study Location	Study Period	Age Group, n	Serotype 19A Carriage	Serotype 6A Carriage	Serotype 6C Carriage
PCV10 Studies
Kenya [87]	2009–2012 (PCV10 included in NIP in 2011)	All age groups, 2031	Carriage increased from 2009–2012*	Carriage increased from 2009–2012*	Only two isolates detected during study period
Brazil [88]	Dec 2010–Feb 2011 (PCV10 included in NIP in 2010)	7–11 mo and 15–18 mo, 1287	Serotype 19A was second highest among non-PCV10 serotypes (6.3%)	Serotype 6A was highest among non-PCV10 serotypes (9.8%)	Serotype 6C was third highest among non-PCV10 serotypes (5.9%)
Brazil [103]	Mar–Aug 2010 and Jun 2013 (PCV10 included in NIP in 2010)	12–23 mo, 901	Pre-PCV10: 1.8% Post-PCV10: 5.1%	Pre-PCV10: 4.2% Post-PCV10: 4.0%	Pre-PCV10: 1.8% Post-PCV10: 11.2%
Australia [89]	Sep 2008–Dec 2012 (PCV10 included in NIP in 2009 in Northern Territories)	0–6 y, 421 (PCV7) and 443 (PCV10)	PCV7 group: 10% PCV10 group: 8%	Serotype 6A was sixth most common serotype identified in PCV7 group; not in top 10 serotypes in PCV10 group	Serotype 6C was fifth most common serotype in both groups
New Zealand [101]	May–Nov 2011 May–Nov 2014 (PCV10 included in NIP in late 2011)	<36 mo, 935	May–Nov 2011: 15% May–Nov 2014: 22%	May–Nov 2011: <5% May–Nov 2014: <5%	May–Nov 2011: 5% May–Nov 2014: 12%
Netherlands [83]	Apr 2008–Dec 2010 (PCV7 included in NIP in Mar 2006; PCV10 introduced in Mar 2011)	5–24 mo, 260 (PCV7) and 520 (PCV10)	PCV7: 30.8% PCV10: 28.1%	Similar between PCV7 and PCV10 groups	NR
Netherlands [102]	Autumn/winter 2010/2011 and autumn/winter 2012/2013 (PCV7 included in NIP in Mar 2006; PCV10 introduced in Mar 2011)	11–24 mo, 1169	In 2012/2013, 19A carriage reduced significantly in children aged 24 mo vaccinated with PCV7, but not significant in children aged 11 mo vaccinated with PCV10	NR (assay did not distinguish between 6A and 6B)	NR (assay did not distinguish between 6C and 6D)
Finland [86]	Feb 2009–Dec 2011 (PCV10 included in NIP in Sep 2010)	6 wk–18 mo, 6178	PCV10 (3 + 1 schedule), across all visits: 1.8% Control across all visits: 3.4%	PCV10 (3 + 1 schedule), across all visits: 6.7% Control across all visits: 6.2%	PCV10 (3 + 1 schedule): <5% Control: 1.4%
Fiji [108]	Jul 2012–Dec 2012 Jul 2013–Dec 2013 Jul 2014–Dec 2014 Jul 2015–Dec 2015 (PCV10 included in NIP in Oct 2012)	5–8 wk, 2006 12–23 mo, 2004 2–6 y, 2052 (Approx. 500 subjects were sampled each year in each age group)	5–8 wk: 2012: 0.42%; 2015: 2.08% 12–23 mo: 2012: 1.01%; 2015: 2.83% 2–6 y: 2012: 1.37%; 2015: 2.96%	5–8 wk: 2012: 1.04%; 2015: 1.66% 12–23 mo: 2012: 3.85%; 2015: 3.04% 2–6 y: 2012: 3.33%; 2015: 1.38%	NR
Iceland [109]	2009–2015 (PCV10 included in NIP in 2011)	<4 y, 1224	2009–2012: 5.0% 2013–2015: 3.6%	2009–2012: 8.3% 2013–2015: 5.7%	2009–2012: 0.9% 2013–2015: 6.5%
Brazil [110]	2010–2013 (PCV10 included in NIP in 2010)	12–23 mo, 901	2010: 1.8% 2013: 5.1%	2010: 4.2% 2013: 4.0%	2010: 1.8% 2013: 11.2%
Kenya [111]	2009–2017 (PCV10 included in NIP in 2011)	<5 y, 1409	2009–2010: 1.75%* 2011–2017: 6.25%*	2009–2010: 6.75%* 2011–2017: 6.25%*	NR
PCV13 Studies
United States [90]	2001–2011 (PCV13 included in NIP in 2010)	<7 y, 5380	Decline from 2009–2011*	Decline from 2009–2011*	Decline from 2009–2011*
United States [91]	Jul 2010–Jun 2012 (PCV13 included in NIP in 2010)	<5 y, 4330	Year 1: 3 per 100 children Year 2: <1 per 100 children	2010: <5 per 1000 children; after beginning of 2012: no further 6A carriage identified	2 per 100 children; no apparent increase or decrease over time
United States [92]	Jul 2010–Jun 2013 (PCV13 included in NIP in 2010)	6–59 mo, 2048	Jul–Dec 2010: 26% Jan–Jun 2013: 3%	Jul–Dec 2010: 0.8% Jan–Jun 2013: not detected	Jul–Dec 2010: 8% Jan–Jun 2013: 1%
Italy [93]	Sep–Dec 2011 (PCV13 included in NIP in 2010)	3–59 mo, 1312^†	Unvaccinated: 9% PCV7: 12% PCV13: 0%	Unvaccinated: 5% PCV7: 1% PCV13: 0%	Unvaccinated: 14% PCV7: 8% PCV13: 5%
France [94]	Oct 2010–May 2011 (PCV13 included in NIP in 2010)	6–24 mo, 943	PCV7: 15.4% PCV13: 7.5% (P< 0.001)	PCV7: 0 PCV13: 0.5%	PCV7: 8.4% PCV13: 3.7% (P= 0.003)
France [95]	1999–2012^‡ (PCV13 included in NIP in 2010)	3–40 mo, 343 (2008) and 365 (2012)	2008: 15.5% 2012: 6.5%	NR	2008: NR 2012: 5.3%
Portugal [96]	2006–2011 (PCV13 licensed in 2010)	0–6 y, 448	2006: 7.7% 2007: 11.8% 2009: 14.6% 2010: 13.1% 2011: 5.3%	2006: 12.0% 2007: 7.3% 2009: 1.9% 2010: 1.0% 2011: 2.8%	2006: 4.1% 2007: 5.4% 2009: 8.1% 2010: 17.6% 2011: 7.4%
Israel [107]	Jul 2009–Dec 2014 (PCV7 included in NIP in Jul 2009; PCV13 gradually replaced PCV7, without a further catchup, in Nov 2010)	<5 y, 10,702	Nov 2009–Jun 2010: 6.3% Jul 2014–Dec 2014: 2.0%	Nov 2009–Jun 2010: 5.1% Jul 2014–Dec 2014: 0.1%	NR
Israel [42]	Feb 2008–Sep 2011 (PCV7 included in NIP in Jul 2009; PCV13 gradually replaced PCV7, without a further catchup, in Nov 2010)	2–24 mo, 934 (PCV7) and 932 (PCV13)	PCV7: 24.6% PCV13: 14.3%	PCV7: 16.5% PCV13: 9.9%	PCV7: 6.2% PCV13: 2.9%
Gambia [98]	Mar–Jun 2011 (in children who received three PCV7 doses) and Mar–Jun 2012 (in children who received three PCV13 doses); PCV7 introduced into EIP second half of 2009; PCV13 replaced PCV7 in Jun 2011	6–11 mo, 339 (PCV7) and 350 (PCV13)	PCV7: 8.3% PCV13: 6.3% (3 y after PCV7 introduction)	PCV7: 15.3% PCV13: 5.7%	NR
Sweden [104]	2004 and 2011–2013 (PCV7 introduced in NIP in Oct 2007; replaced with PCV13 in Jan 2010)	1–5 y, 719 at daycare centers (2004); 0–5 y, 2161 (2011–2013)	Slight (<1%) increase* (<5% of isolates both before and after PCV introduction)	>10% decrease* (~12% of isolates before PCV introduction and <5% after PCV introduction)	NR for pre-PCV period and ~5% of isolates after PCV introduction*
United Kingdom [99]	Jul 2012 and Mar 2013 (PCV7 introduced into NIP in 2006; replaced by PCV13 April 2010)	1–5 y and their household members, 217 households (683 participants)	Carried by only one adult (26 y; unvaccinated)	NR	NR
United Kingdom [106]	Oct–Mar 2006/2007 to Oct–Mar 2012/2013 (PCV7 introduced into NIP in 2006; replaced by PCV13 April 2010)	≤4 y, 2267 swabs	2006/2007: ~5% 2012/2013: not detected*	2006/2007: ~10%* 2012/2013: 2.6%	2006/2007: ~5% 2012/2013: ~5%*
Australia [100]	Feb 2010–Aug 2013 (PCV13 included in NIP in 2011 in Northern Territories)	0–6 y, 511 (PCV10) and 140 (PCV13)	PCV10: 8% PCV13: not detected	PCV10: not detected PCV13: not detected	PCV10: 5% PCV13: not detected
Australia [105]	Aug 2008–Nov 2014 (PCV7 included in NIP for Aboriginal children in 2001; replaced by PCV13 in Jul 2011)	All Aboriginal age groups; 2824 swabs, 60 nose-blown samples, 1 unknown	Pre-PCV13: 6.6% Post-PCV13: 3.4%	Pre-PCV13: 4.3% Post-PCV13: 2.5%	Pre-PCV13: 8.5% Post-PCV13: 4.1%
Lao PDR [115]	Nov 2013 – Feb 2014 Nov 2015 – Feb 2016 (PCV13 was included in the Lao PDR NIP in late 2013)	5–8 wk, 498 (pre-PCV13) and 502 (post-PCV13) 12–23 mo, 503 (pre-PCV13) and 507 (post-PCV13)	5–8 wk: No significant change 12–23 mo: No significant change	5–8 wk: Pre-PCV13: 2.2% Post-PCV13: 0.6% 12–23 mo: Pre-PCV13: 6.4% Post-PCV13: 3.0%	5–8 wk: No significant change 12–23 mo: Pre-PCV13: 3.2% Post-PCV13: 1.2%

EIP = expanded immunization program; NIP = national immunization program; NR = not reported for individual serotype; PCV = pneumococcal conjugate vaccine; PCV7 = 7-valent PCV; PCV10 = 10-valent PCV; PCV13 = 13-valent PCV.

*Trend based on graph; specific numbers not provided in the reference.

^†From these children, 1295 nasopharyngeal specimens were collected.

^‡Only results for 2008 and 2012 are presented here.

Table 3. Impact of PCV10 and PCV13 against IPD caused by serotypes 19A, 6A, and 6C across all ages in countries with robust surveillance.

Country	Year Vaccine Introduced	Age Group	Cases or Incidence*
			Serotype 19A IPD (Year)	Serotype 6A IPD (Year)	Serotype 6C IPD (Year)
PCV10
Finland [126]	2010	<5 y	Cases (2009) 8 (2016) 15	Cases (2009) 4 (2016) 0	Cases (2009) 0 (2016) 1
		≥5 y	Cases (2009) 21 (2016) 151	Cases (2009) 22 (2016) 117	Cases (2009) 6 (2016) 44
Netherlands [127,146]	2011	<5 y	Incidence (2010–2011) <2 (2015–2016) <1.5 Cases (2009–2011) 7 (2013–2014) 0	Incidence (2010–2011) 0 (2015–2016) 0 Cases (2008–2011) 2 (2011–2014) 0	Incidence (2010–2011) 0 (2015–2016) 0 Cases (2008–2011) 0 (2011–2014) 1
		≥65 y	Incidence (2010–2011) <5 (2015–2016) 5 Cases (2009–2011) 63 (2013–2014) 33	Incidence (2010–2011) <1 (2015–2016) 0	Incidence (2010–2011) 0.5 (2015–2016) <1.5
Chile [140,141]	2011	<2 y	Cases (2007) 12 (5%) (2015) 15 (19%)	Cases (2007) 15 (6%) (2015) 3 (4%)	NR
		All ages	Cases (2007) 28 (3%) (2015) 78 (12%)	Cases (2007) 39 (4%) (2015) 13 (2%)	NR
Australia [142,143]	2009	<5 y	Cases (2009) 100 (2016) 20	Cases (2009) 5 (2016) 1	Cases (2009) 5 (2016) 1
		≥5 y	Cases (2009) 221 (2016) 105	Cases (2009) 22 (2016) 2	Cases (2009) 53 (2016) 50
New Zealand [118]	2011	<5 y	Cases (2011) 13 (2016) 15	Cases (2011) 1^† (2016) 0	Cases (2011) NR (2016) 1
		≥5 y	Cases (2011) 50 (2016) 63	Cases (2011) 23^† (2016) 1	Cases (2011) NR (2016) 17
Brazil [149]	2010	<5 y	Cases (2005–2009) 44 (2011–2015) 126 (2016–2017) 92	NR	NR
		5–49 y	Cases (2005–2009) 43 (2011–2015) 104 (2016–2017) 87	NR	NR
		≥50 y	Cases (2005–2009) 17 (2011–2015) 87 (2016–2017) 73	NR	NR
Austria [148]	2012	<5 y	IRR (2009–2011) 0.42 (2013–2014) 0.73 (2015–2016) 1.87	IRR (2009–2011) 0.21 (2013–2014) 0.98 (2015–2016) NR	NR
		≥50 y	IRR (2009–2011) 0.34 (2013–2014) 1.17 (2015–2016) 1.63	IRR (2009–2011) 0.26 (2013–2014) 0.63 (2015–2016) 0.55	NR
Colombia [151]	2011^‡	<12 mo	Isolates (2009) 2 (2015) 10	Isolates (2009) 3^† (2015) 4	Isolates (2009) NR (2015) 2
		12–23 mo	Isolates (2009) 0 (2015) 5	Isolates (2009) 0^† (2015) 1	Isolates (2009) NR (2015) 0
		24–59 mo	Isolates (2009) 3 (2015) 16	Isolates (2009) 1^† (2015) 2	Isolates (2009) NR (2015) 1
PCV13
United States [134]	2010	<5 y	Cases (2009–2010) 205 (2012–2013) 13	Cases (2009–2010) 1 (2012–2013) 0	Cases (2009–2010) 8 (2012–2013) 3
		5–17 y	Cases (2009–2010) 19 (2012–2013) 7	Cases (2009–2010) 2 (2012–2013) 1	Cases (2009–2010) 7 (2012–2013) 3
		≥18 y	Cases (2009–2010) 473 (2012–2013) 161	Cases (2009–2010) 44 (2012–2013) 6	Cases (2009–2010) 185 (2012–2013) 152
Israel [145]^§	2010	<5 y	Cases (2009–2010) 33 (2014–2016) 1	Cases (2009–2010) 15 (2014–2016) 2	NR
		≥18 y	Incidence (2009–2010) 0.65 (2014–2015) 0.50 Cases (2009–2010) 31 (2014–2015) 20	Incidence (2009–2010) 0.35 (2014–2015) 0.05 Cases (2009–2010) 16 (2014–2015) 2	Incidence (2009–2010) 0.10 (2014–2015) 0.20
United Kingdom^‖	2010	<5 y	Cases (2009) 93 (2014) 14	Cases (2009) 2 (2014) 0	NR
		≥5 y	Cases (2009) 511 (2014) 268	Cases (2009) 96 (2014) 16	NR
New Zealand [118]	2014	<5 y	Incidence (2014) 5.5 (2016) NA Cases (2014) 17 (2016) 15	Incidence NA Cases (2014) NR for single serotype (2016) 0	Incidence NA Cases (2014) NR for single serotype (2016) 1
		≥5 y	Incidence (2014) 5–64 y, 1.1 ≥65 y, 4.6 (2016) NA Cases (2014) 70 (2016) 63	Incidence NA Cases (2014) NR for single serotype (2016) 1	Incidence NA Cases (2014) NR for single serotype (2016) 17
Sweden [104]	2010	All ages	Incidence (2009–2010 vs 2011–2014) RR = 0.67; 95% CI: 0.44, 1.04	Incidence (2009–2010 vs 2011–2014) RR = 0.66; 95% CI: 0.34, 1.29	Incidence (2009–2010 vs 2011–2014) RR = 0.85; 95% CI: 0.44, 1.63
Australia [142,143]	2011	<5 y	Cases (2011) 106 (2016) 20	Cases (2011) 1 (2016) 1	Cases (2011) 8 (2016) 1
		≥5 y	Cases (2011) 273 (2016) 105	Cases (2011) 8 (2016) 2	Cases (2011) 91 (2016) 50
Norway [136]	2011	<5 y	Isolates (2009) 5 (2010) 7 (2011) 10 (2012) 0	Isolates (2009) 0 (2010) 1 (2011) 0 (2012) 0	Isolates (2009) 0 (2010) 2 (2011) 3 (2012) 1
		≥5 y	Isolates (2009) 50 (2010) 72 (2011) 81 (2012) 53	Isolates (2009) 29 (2010) 13 (2011) 10 (2012) 6	Isolates (2009) 7 (2010) 30 (2011) 38 (2012) 24
Ireland [144]	2010	<5 y	Isolates (2009) 3 (2016) 3	Isolates (2009) NR (2016) 0	Isolates (2009) NR (2016) 0
		≥5 y	Isolates (2009) 18 (2016) 26	Isolates (2009) NR (2016) 0	Isolates (2009) NR (2016) 6
South Africa [147]	2011	<2 y	Incidence (2005–2008) 4.5 (2011) 3.1 (2012) 1.3 Isolates (2005–2008) 94 (2011) 67 (2012) 29	Incidence (2005–2008) 6.3 (2011) 2.4 (2012) 0.9 Isolates (2005–2008) 131 (2011) 52 (2012) 20	NR
		25–44 y	Incidence (2005–2008) 1.2 (2011) 1.2 (2012) 0.8 Isolates (2005–2008) 166 (2011) 184 (2012) 128	Incidence (2005–2008) 0.8 (2011) 0.7 (2012) 0.4 Isolates (2005–2008) 110 (2011) 117 (2012) 66	NR
Taiwan [150]	2011	≤5 y	Incidence (2008–2009) 2.19 (2010–2012) 9.01 (2013–2017) 2.77	Incidence (2008–2009) 0.68 (2010–2012) 1.02 (2013–2017) 0.21	NR

IPD = invasive pneumococcal disease; IRR = incidence rate ratio; PCV = pneumococcal conjugate vaccine; PCV10 = 10-valent PCV; PCV13 = 13-valent PCV; NA = not available; NR = not reported.

*Incidence reported per 100,000 population.

^†6A and 6C not distinguished for analysis.

^‡As reported in Leal et al. [152].

^§R. Dagan, The Pediatric Infectious Disease Unit, Soroka University Medical Center, Beer-Sheva, Israel, personal communication, 4/9/2018.

^‖E. Miller, Immunisation Department Health Protection Agency, Center for Infections, London, UK, personal communication, 4/18/2016.

Figure 5. Differential impact on serotype 19A IPD post-PCV10 vs post-PCV13 implementation in six countries: three countries post-PCV13 introduction (Israel, United States, United Kingdom) and three countries post-PCV10 introduction (Chile, New Zealand, Finland).

(a) Number of cases of serotype 19A IPD in children <5 years of age between 2004 and 2016. (b) Number of cases of serotype 19A IPD in individuals ≥5 years of age between 2004 and 2016. Vertical dashed lines denote the implementation year of PCV7, PCV10, or PCV13. Vaccination with PCV10 was conducted in Chile and Finland per 3 + 1 and 2 + 1 schedules, respectively. Data are adapted from (a) Israel National Surveillance. Personal communication to Ron Dagan; (b) Moore MR, et al. Lancet Infect Dis 2015 [134]; (c) S. Ladhani, Pediatric Infectious Disease, Public Health England, London, UK, personal communication, 12/30/2017; (d) Pan American Health Organization. SIREVA II (Sistema de Redes de Vigilancia de los Agentes Responsables do Neumonias y Meningitis Bacterianas) [125]; (e) Public Health Surveillance. Information for New Zealand Public Health Action. Invasive Pneumococcal Disease Reports [118]; and (f) National Institute for Health and Welfare. Incidence of Invasive Pneumococcal Disease in Finland [126]. *Number of cases (scale) per country differs. ^†Threshold for Chile is <2 years and ≥2 years of age. ^§Surveillance years may span January–December or July–June. IPD = invasive pneumococcal disease; PCV = pneumococcal conjugate vaccine; PCV7 = 7-valent PCV; PCV10 = 10-valent PCV; PCV13 = 13-valent PCV.

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