Public health impact of pneumococcal conjugate vaccine infant immunization programs: assessment of invasive pneumococcal disease burden and serotype distribution

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Figure 1. Flow chart.

N, number of countries; n, number of citation(s); PCV, pneumococcal conjugate vaccine; PCV7, 7-valent PCV; IPD, invasive pneumococcal disease; VT, vaccine serotype; NVT, non-vaccine serotype. ^aAs defined by the World Bank as countries with a gross national income per capita of $12,476 or more. ^bData from surveillance reports used; ^cNo relevant citations found, but data from surveillance reports used.

Table 1. Characteristics of the included datasets.

Country (region)	Age group	Type of surveillance reporting approach	PCV introduction in NIP	Infant vaccination schedule	Vaccination coverage^b	PPV23 use [37–39]	Study eras			Total PCV (higher valent PCV) program duration
							Pre-PCV	PCV7	HV-PCV
Australia [40,41]	<5 y^a	National, passive, mandatory	PCV7: January 2005 PCV13: July/September 2011^c	3 + 0^d (catchup in <2 y for PCV7 and PCV13)	2011–2014: 90–93% (complete PCV schedule)	Funded nationally for ≥65 y	2003–2004	2009–2010	2014–2015	11 (4)
Canada (Quebec) [42,43]	<5 y^a	Passive province-wide mandatory	PCV7: Dec 2004 PHiD-CV: ~July 2009 PCV13: January 2011	2 + 1 (catchup in <5 y for PCV7)	2010: 95% (complete PCV schedule)	Funded for adults at risk	2001–2004	2007–2008	2013–2014	10 (5)
Denmark [44,45]	<5 and ≥65 y	National, passive mandatory	PCV7: October 2007 PCV13: April 2010	2 + 1 (catchup in <17 m for PCV7)	2011–2013: 89–90% (complete PCV schedule)	Recommended for risk groups with PCV13 since 2012	2000–2007	2009–2010	2014–2015	8 (5)
Finland [46]	<5 and ≥65 y	National, passive mandatory	PHiD-CV: September 2010	2 + 1	2014: 92% (complete PHiD-CV schedule)	Recommended for risk groups	2004–2008	–	2014–2015	5 (5)
France [47–49]	<5 and ≥65 y	National, active	PCV7: June 2006 (2003 in high risk) PCV13: June 2010	2 + 1 (catchup in <2 y for PCV7 and PCV13)	2011–2012: 94% (2 PCV doses)	Recommended for risk groups	2001–2002	2008–2009	2013–2014	11 (4)
Israel [50]	<5 y^a	National, active	PCV7: July 2009 PCV13: November 2010	2 + 1 (catchup in <2 y for PCV7)	December 2011: 33% June 2012: 85% December 2012: 95% (≥2 PCV13 doses)	Recommended for ≥65 y; uptake around 70%	2004/05–2007/08 (epidemiological years)^e	2010/11 (Epidemiological years)^e	2012/13 (Epidemiological years)^e	4 (3)
New Zealand [51–53]	<5 and ≥65 y	National, passive mandatory	PCV7: June 2008 PHiD-CV: October 2011 PCV13: October 2014	3 + 1 (catchup for PCV7)	2012–2014: 92–93% (3 PCV doses)	Recommended for ≥65 y	2006–2007	2010–2011	2014–2015 (<5 y) 2013–2014 (≥65 y)	<5 y: 7 (4) ≥65 y: 6 (3)
Norway [54–58]	≥65 y^a	National, passive mandatory	PCV7: July 2006 PCV13: April 2011	2 + 1 (catchup for PCV7)	2014–2015: 91–93% (complete PCV schedule)	Recommended for risk groups	2004–2005	2009–2010	2014–2015	9 (4)
The Netherlands [59,60]	<5 and ≥65 y	Sentinel and nationwide (for <5 y from 2008) sentinel (for ≥65 y)	PCV7: June 2006 PHiD-CV: May 2011	3 + 1, 2 + 1 (from November 2013)	2011–2013: 95% (complete PCV schedule)	Recommended for risk groups with PCV13	2004/05–2005/06 (Epidemiological years)^f	2009/10–2010/11 (Epidemiological years)^f	2013/14–2014/15 (Epidemiological years)^f	9 (4)
United Kingdom (England and Wales) [61,62]	<5 and ≥65 y	National, passive mandatory (voluntary before 2010)^g	PCV7: September 2006 PCV13: April 2010	2 + 1 (catchup in <2 y for PCV7)	2011–2013: 90–93% (Complete PCV schedule)	Recommended for risk groups, uptake >70%	2000/01–2005/06 (Epidemiological years)^e	2008/09–2009/10 (Epidemiological years)^e	2013/14 (Epidemiological years)^e	8 (4)
US [63–70]	<5 and ≥65 y	Sentinel	PCV7: February 2000 PCV13: February 2010	3 + 1 (catchup in <2 y for PCV7 and <5 y for PCV13)	2010–2012: 76% (3 PCV13 doses); 65% (complete PCV13 schedule)	Recommended for ≥65 y and risk groups <65 y	1998–1999	2008–2009	2013–2014	15 (5)

NIP: National immunization program; PPV23: 23-valent pneumococcal polysaccharide vaccine; PCV7/13: 7/13-valent pneumococcal conjugate vaccine; PHiD-CV: pneumococcal nontypeable Haemophilus influenzae protein D conjugate vaccine; HV-PCV: higher valent PCV (PHiD-CV, PCV13); y: years of age; m: months of age; –: not applicable (PCV7 never introduced). ^aFor the following countries, we could not retrieve the necessary data for adults ≥65 years old: (1) Australia: incidences for VT IPD in the pre-PCV era were not available for the entire population (indigenous and nonindigenous) of adults ≥65 years old in the citations we screened; we could only retrieve incidences of IPD caused by PCV7 serotypes for the pre-PCV era. (2) Quebec: for children <5 years, we used data from several sources [42,43] to estimate the IPD incidence; for adults ≥65 years, we could not retrieve the same information from these sources with the necessary granularity of data. (3) Israel: among the citations we screened that did report IPD data for adults ≥65 years, none had incidences available for the pre-PCV period. For Norway, VT and NVT IPD incidences were not available for children <5 years old. ^bVaccination coverage refers to vaccination with any PCV (PCV7 or higher valent), except when otherwise noted. ^cIn the Northern Territory, PHiD-CV replaced PCV7 from October 2009; in other jurisdictions, PCV13 replaced PCV7 under the national immunization program for infants in July 2011, and in the Northern Territory replaced PHiD-CV from September 2011. ^d3 + 1 schedule in indigenous populations. ^eJuly–June. ^fJune–May. ^gWaight et al. corrected incidences for proportion of samples serotyped, missing age, denominator compared with 2009/10, and for the trend in total IPD up to 2009/10 (after which no trend correction was applied). Note: PCV program duration is calculated from first PCV introduction to the last year used in the analysis.

Figure 2. Invasive pneumococcal disease distribution across analyzed countries or regions by PCV era for children <5 years old.

PCV, pneumococcal conjugate vaccine; Overall IPD, invasive pneumococcal disease due to any pneumococcal serotype; VT IPD, IPD caused by serotypes included in any of the three PCVs, i.e. serotypes 1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F, and 23F; NVT IPD, IPD caused by any other serotype; PCV7, 7-valent PCV; HV-PCV, higher-valent PCV (PHiD-CV, PCV13). Notes: A bubble represents one country. The size of the bubble indicates the number of cases. The center location of the bubble indicates the incidence of the country for the respective analysis period. Rectangles illustrate the mean incidence across analyzed countries (center of rectangle) ± 1 standard deviation (height of rectangle, calculated based on IPD incidences without considering the absolute numbers of cases).

Table 2. Proportion of overall IPD attributed to vaccine serotypes, non-vaccine serotypes, and serotypes 3, 6A, and 19A separately by PCV era in children <5 years old.

	Country (region)	% VT IPD	% NVT IPD	% 19A IPD	% 3 IPD	% 6A IPD
Pre-PCV era	Australia	85.2	6.8	4.3	0.9	NA
	Canada (Quebec)	92.6	7.4	4.1	1.0	NA
	Denmark	90.6	9.4	NA	NA	NA
	Finland	93.7	6.3	9.3	0.9	NA
	France	90.1	9.6	7.0	2.8	NA
	Israel	89.5	10.5	10.1	0.6	NA
	New Zealand	93.2	5.8	6.7	0.6	NA
	The Netherlands	92.2	8.1	6.8	1.3	NA
	United Kingdom (England and Wales)	90.9	9.1	4.2	1.6	NA
	United States	92.3	7.6	NA	NA	NA
PCV7 era	Australia	62.7	31.6	45.2	3.0	NA
	Canada (Quebec)	59.7	40.3	36.0	5.2	NA
	Denmark	76.5	23.5	NA	NA	NA
	Finland	–	–	–	–	–
	France	72.2	27.2	23.5	1.9	NA
	Israel	75.5	24.5	15.2	2.4	NA
	New Zealand	72.6	22.9	20.4	3.6	NA
	The Netherlands	57.6	41.9	18.8	2.6	NA
	United Kingdom (England and Wales)	67.5	32.5	18.4	5.6	NA
	United States	62.6	37.4	NA	NA	NA
HV-PCV era	Australia	34.1	52.6	14.5	8.8	0.2
	Canada (Quebec)	16.1	83.2	9.0	4.5	0.0
	Denmark	9.5	90.5	NA	NA	NA
	Finland	74.0	26.0	42.1	11.9	2.0
	France	19.7	80.3	3.9	1.3	0.0
	Israel	31.9	68.1	8.5	4.8	1.6
	New Zealand	51.4	40.2	24.7	12.9	4.7
	The Netherlands	48.9	51.1	14.6	7.3	0.0
	United Kingdom (England and Wales)	14.6	85.4	2.3	2.6	0.0
	United States	21.1	78.9	NA	NA	NA

IPD: Invasive pneumococcal disease; PCV: pneumococcal conjugate vaccine; PCV7: 7-valent PCV; HV-PCV: higher valent PCV (PHiD-CV, PCV13); % VT IPD: proportion of overall IPD caused by serotypes included in any of the three PCVs, i.e. serotypes 1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F, and 23F; % NVT IPD: proportion of overall IPD caused by any other serotype; % 3, 6A, 19A IPD: proportion of overall IPD caused by serotypes 3, 6A, and 19A, respectively (Note: for New Zealand 6A IPD, refers to IPD caused by serotypes 6A or 6C); –: not applicable (Finland did not introduce PCV7); NA: not available. Proportions were calculated based on incidences of overall, VT, NVT, 3, 6A, and 19A IPD from Supplemental Table 2.

Figure 3. Serotype-specific invasive pneumococcal disease incidence and case counts in the higher-valent PCV era in children <5 years old.

PCV, pneumococcal conjugate vaccine; Overall IPD, invasive pneumococcal disease due to any pneumococcal serotype; NVT IPD, IPD caused by any serotype other than those included in PCVs; 3, 6A, 19A IPD, IPD caused by serotypes 3, 6A and 19A, respectively. ^aData not available for Denmark and US. ^bFor New Zealand, 6A and 6C combined data.

Figure 4. Invasive pneumococcal disease distribution across analyzed countries or regions by PCV era in adults ≥65 years old.

PCV, pneumococcal conjugate vaccine; Overall IPD, invasive pneumococcal disease due to any pneumococcal serotype; VT IPD, IPD caused by serotypes included in any of the three PCVs, i.e. serotypes 1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F, and 23F; NVT IPD, overall IPD caused by any other serotype; PCV7, 7-valent PCV; HV-PCV, higher-valent PCV (PHiD-CV, PCV13). Notes: A bubble represents one country. The size of the bubble indicates the number of cases. The center location of the bubble indicates the incidence of the country for the respective analysis period. Rectangles illustrate the mean incidence across analyzed countries (center of rectangle) ± 1 standard deviation (height of rectangle, calculated based on IPD incidences without considering the absolute numbers of cases).

Table 3. Proportion of overall IPD attributed to vaccine serotypes, non-vaccine serotypes, and serotypes 3, 6A, and 19A separately by PCV era in adults ≥65 years old.

		Country (region)	% VT IPD	% NVT IPD	% 19A IPD	% 3 IPD	% 6A IPD
Pre-PCV era	Denmark		70.2	29.8	NA	NA	NA
	Finland		75.9	24.3	3.9	7.1	NA
	France		77.6	22.4	10.1	9.0	NA
	New Zealand		81.7	18.4	4.4	7.0	NA
	Norway		79.7	20.3	NA	NA	NA
	The Netherlands		75.8	24.2	3.8	5.7	NA
	United Kingdom (England and Wales)		72.7	27.3	3.6	7.2	NA
	United States		73.8	26.2	NA	NA	NA
PCV7 era	Denmark		55.4	44.6	NA	NA	NA
	Finland		–	–	–	–	–
	France		61.4	38.6	14.5	10.9	NA
	New Zealand		55.8	32.9	10.0	5.2	NA
	Norway		55.9	44.1	NA	NA	NA
	The Netherlands		55.4	44.6	9.5	7.2	NA
	United Kingdom (England and Wales)		54.0	46.0	11.3	10.4	NA
	United States		44.2	55.8	NA	NA	NA
HV-PCV era	Denmark		24.8	75.2	NA	NA	NA
	Finland		56.7	43.4	12.9	17.9	3.9
	France		36.5	63.5	11.0	12.0	0.5
	New Zealand		50.5	43.8	14.4	6.3	6.3
	Norway		24.3	75.7	NA	NA	NA
	The Netherlands		37.8	62.2	10.8	6.5	0.2
	United Kingdom (England and Wales)		20.9	79.1	5.3	7.8	0.5
	United States		21.6	78.4	NA	NA	NA

IPD: Invasive pneumococcal disease; PCV: pneumococcal conjugate vaccine; PCV7: 7-valent PCV; HV-PCV: higher valent PCV (PHiD-CV, PCV13); % VT IPD: proportion of overall IPD caused by serotypes included in any of the three PCVs, i.e. serotypes 1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F, and 23F; % NVT IPD: proportion of overall IPD caused by any other serotype; % 3, 6A, 19A IPD: proportion of overall IPD caused by serotypes 3, 6A, and 19A, respectively (Note: for New Zealand 6A IPD, refers to IPD caused by serotypes 6A or 6C); –: not applicable (Finland did not introduce PCV7); NA: not available. Proportions were calculated based on incidences of overall, VT, NVT, 3, 6A, and 19A IPD from Supplemental Table 3.

Figure 5. Serotype-specific invasive pneumococcal disease incidence and case counts in the higher-valent PCV era in adults ≥65 years old.

PCV, pneumococcal conjugate vaccine; Overall IPD, invasive pneumococcal disease due to any pneumococcal serotype; NVT IPD, IPD caused by any serotype other than those included in PCVs; 3, 6A, 19A IPD, IPD caused by serotypes 3, 6A and 19A, respectively.; HV-PCV, higher-valent PCV (PHiD-CV, PCV13). ^aData not available for Denmark, Norway and US. ^bFor New Zealand, 6A and 6C combined data. Note: Serotypes 19A, 3 and 6A are included in PCV13 and not in PHiD-CV.

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