A systematic review of invasive pneumococcal disease vaccine failures and breakthrough with higher-valency pneumococcal conjugate vaccines in children

Figures & data

Figure 1. Plain language summary.

Figure 2. Selection of publications in the systematic review. AOM, acute otitis media; IPD, invasive pneumococcal disease; n, number of records; PCV(9/13), (9/13-valent) pneumococcal conjugate vaccine; PCV10, pneumococcal non-typeable Haemophilus influenzae protein D-conjugate vaccine.

Table 1. Characteristics of included studies

Author [ref]	Study period (PCV10/PCV13 assessment)	Country (Region)	PCV	Schedule	Study design	Age of cases
Agier [23]	2010–2014	France	PCV13	2+1	National pharmacovigilance survey	≤6 years^a
Almeida [24]	2012–2014	Portugal	PCV13	3+1	Retrospective, observational; hospital records (1 hospital)	≤5 years
Andrews [25]^b	2010–2018	United Kingdom (England)	PCV13	2+1	Case-control (indirect cohort); enhanced, national, laboratory-based, surveillance	≤9 years^a
Antachopoulos [26]	2012	Greece	PCV7/ PCV13	3+1	Descriptive analysis, national, laboratory-based, passive surveillance	≤6 years^a
Asner [27]	2011–2015	Switzerland	PCV7/ PCV13	2+1	Prospective, national, observational cohort; hospital records (10 hospitals)	<17 years^a
Blyth [28]	2012–2017	Australia	PCV13	3+0	Descriptive analysis of vaccine failures; national, laboratory-based, passive surveillance	<5 years
Cohen [29]^b	2012–2014	South Africa	PCV13	2+1	Case-control; national, laboratory-based, active surveillance (sentinel hospitals)	≤5 years
Corcoran [47]	2012–2018	Ireland	PCV7/ PCV13	2+1	Descriptive analysis; national, laboratory-based, enhanced surveillance	≤6 years^a
De Wals [30]	2011–2016	Canada (Quebec)	PCV13	2+1	Descriptive analysis; provincial and sentinel, laboratory-based surveillance	<5 years
Deceuninck [6]^b	2009–2013	Canada (Quebec)	PCV7/ PCV10/ PCV13	2+1	Case-control; provincial, laboratory-based, surveillance	<5 years
Diawara [31]	2011–2014	Morocco (Casablanca)	PCV10/ PCV13	2+1	Descriptive analysis; laboratory-based, passive surveillance (1 hospital)	≤5 years
Dominguez [32]^b	2012–2016	Spain (Barcelona)	PCV13	3+1	Case-control; hospital records (3 hospitals)	<5 years
Godot [33]	2011–2013	France	PCV13	2+1	Descriptive analysis; national hospital-based active surveillance	<5 years
Guevara [34]^b	2010–2014	Spain (Navarra)	PCV10/ PCV13	3+1	Population-based cohort with nested case-control; active, laboratory-based surveillance	<5 years
Harboe [35]	2011–2013	Denmark	PCV13	2+1	Population-based cohort; national, laboratory-based surveillance	<2 years
Jayasinghe [36]^b	2011–2014	Australia	PCV13	3+0	Case-control; national, passive, laboratory-based surveillance	<4 years
Latasa [37]^b	2010–2015	Spain (Madrid)	PCV13	3+1	Case-control; regional, laboratory-based surveillance	≤5 years
Mackenzie [38]	2013–2014	Gambia (Upper River Region)	PCV13	3+0	Prospective observational; population-based surveillance	≤2 years
Madhi [39]	2013	France	PCV13	2+1	Case report	3 years
Moore [41]^b	2010–2014	United States	PCV13	3+1	Case-control; active, sentinel laboratory-based surveillance (13 sites)	<5 years
Novak [42]	2012	Sweden	PCV13	2+1	Case report	1 year
Okonji [43]	2012–2014	Czechia	PCV10/ PCV13	3+1/(2+1)	Descriptive analysis; national, laboratory-based surveillance	<5 years
Ong [44]	2009–2014	Singapore	PCV13	2+1	Retrospective; hospital records (1 hospital)	≤5 years
Sütçü [45]	NA	Turkey	PCV13	3+1	Case report	2 years
van der Linden [46]^b	2010–2015	Germany	PCV10/ PCV13	3+1	Case-control (indirect cohort); national, laboratory-based surveillance	<2 years
Verani [9]^b	2010–2012	Brazil	PCV10	3+1	Case-control (indirect cohort); laboratory-based surveillance (10 states)	<5 years

Additional information is provided in Supplementary Table 1. ^aThese studies were included despite a wider age range, because most cases occurred in children ≤5 years old. ^bIncluded in sub-analysis on case-control studies. NA, not available; PCV7/13, 7/13-valent pneumococcal conjugate vaccine; PCV10, pneumococcal non-typeable Haemophilus influenzae protein D-conjugate vaccine.

Table 2. Breakthrough IPD cases and vaccine failures identified in the included studies

Author [ref]	PCV (schedule)	N IPD (PCV-vaccinated)	Breakthrough cases	Serotypes in breakthrough cases (n)	Vaccine failures	Serotypes in vaccine failures (n)
Agier [23]	PCV13 (2+1)	54	NA	NA	16	19A (5), 19F (5)^a
Almeida [24]	PCV13 (3+1)	9	3	2 doses: 19A (1) 3 doses: 3 (2)	4	3 (4)
Andrews [25]^b	PCV13 (2+1)	2,642	158	1 dose: 1 (11), 3 (19), 5 (1), 6A (3), 6B (1), 6C (5), 7F (13), 14 (1), 19A (19), 19F (3), 23F (1) 2 doses: 1 (2), 3 (24), 6A (2), 6B (1), 6C (6), 7F (5), 14 (1), 18C (2), 19A (29), 19F (8), 23F (1)	90	1 (6), 3 (36), 6B (1), 6C (4), 7F (4), 9V (2), 18C (1), 19A (26), 19F (8), 23F (2)
Antachopoulos [26]^c	PCV7/PCV13 (3+1)	NA	0	0	5	Catch-up: 3 (5)
Asner [27]	PCV7/PCV13 (2+1)	25	NA	NA	11	3 (11)^d
Blyth [28]	PCV13 (3+0)	1,147	NA	NA	241	1 (1), 3 (96), 6A (1), 7F (1), 14 (1), 18C (1), 19A (93), 19F (46), 23F (1)
Cohen [29]^b	PCV13 (2+1)	230	38	1 dose: 1 (1), 5 (1), 6A (6), 6B (1), 19A (1), 19F (3), 23F (2) 2 doses: 1 (1), 3 (1), 4 (3), 6A (2), 6B (6), 19A (5), 19F (4), 23F (1)	7	3 (1), 5 (1), 19A (3), 19F (2)
Corcoran [47]	PCV7/PCV13 (2+1)	NA	5	2 doses PCV7 + 1 dose PCV13: 19A (2) 1 dose PCV7 + 2 doses PCV13: 19A (1) 2 doses PCV13: 19A (2)	8	3 (1), 6B (1), 7F (1), 19A (5)
De Wals [30]^c	PCV13 (2+1)	NA	21	1 dose: 3 (1), 19A (1) 2 doses: 3 (1), 19A (18)	9	3 (3), 19A (6)
Deceuninck [6]^b	PCV7/PCV10/PCV13 (2+1)	128	PCV10 or PCV7 + PCV10: 22 PCV13: 10	PCV10: 1 dose: 7F (1), 19A (9) 2 doses: 6A (1), 19A (11) PCV13: 1 dose: 3 (1) 2 doses: 19A (9)	PCV10: 4 PCV10 + PCV13:2	PCV10: 19A (4) PCV10 + PCV13: 19A (2)
Diawara [31]	PCV10/PCV13 (2+1)	18	PCV10: 5 PCV13: 5	PCV10: 1 dose: 1 (1), 6B (1) 2 doses: 1 (1), 6B (1), 14 (1) PCV13: 1 dose: 7F (1) 2 doses: 3 (1), 6B (1), 9V (1), 14 (1)	0	0
Dominguez [32]^b	PCV13 (3+1)	75	17	1, 2 or 3 doses: 1 (2), 3 (10), 19A (5)	15	1 (1), 3 (12), 14 (1), 19A (1)
Godot [33]	PCV13 (2+1)	NA	12	1 dose: 7F (2), 19A (2), 19F (1) 2 doses: 19A (5), 19F (2)	1	19A (1)
Guevara [34]^b	PCV10/PCV13 (3+1)	18	0	0	3	PCV10 + PCV13: 19A (1) PCV13: 3 (2)
Harboe [35]	PCV13 (2+1)	NA	1	2 doses: 3 (1)	0	0
Jayasinghe [36]^b,e	PCV13 (3+0)	256	60	1 or 2 doses: 3 (12), 6C (4), 7F (1), 19A (33), 19F (10)	26	3 (7), 7F (1), 19A (14), 19F (4)
Latasa [37]^b	PCV13 (3+1)	173	14	2 or 3 doses: 1 (3), 3 (1), 19A (9), 19F (1)	6	Catch-up: 1 (2), 3 (2), 19A (1), 23F (1)
Mackenzie [38]	PCV13 (3+0)	NA	1	2 doses: 23F (1)	5	1 (2), 14 (2), 19A (1)
Madhi [39]	PCV13 (2+1)	NA	NA	NA	1	3 (1)
Moore [41]^b	PCV13 (3+1)	487	86 (failure or breakthrough) ≥1 dose: 3 (25), 6C (4), 7F (2), 9V (1), 14 (1), 19A (50), 19F (3)
Novak [42]	PCV13 (2+1)	NA	NA	NA	1	3 (1)
Okonji [43]	PCV10/PCV13 (3+1/2+1)	NA	PCV10: 1 PCV13: 1	PCV10 3 primary doses: 14 (1) PCV13 3 primary doses: 3 (1)	PCV10: 4 PCV13: 2	PCV10: 1 (3), 14 (1) PCV13: 1 (1), 3 (1)
Ong [44]	PCV13 (2+1)	NA	NA	NA	3	3 (1), 19A (2)
Sütçü [45]	PCV13 (3+1)	NA	NA	NA	1	9V (1)
van der Linden [46]^b	PCV10/PCV13 (3+1)	339	PCV10: 5 PCV13: 24	PCV10: 2 doses: 19A (2) 3 doses: 14 (1), 19A (2) PCV13: 1 dose: 19A (4), 19F (1) 2 doses: 3 (1), 7F (1), 19A (1), 19F (1) 3 doses: 1 (2), 3 (4), 19A (9)	PCV10: 2 PCV13: 2	PCV10: 6B (1), 19F (1) PCV13: 3 (1), 19A (1)
Verani [9]^b	PCV10 (3+1)	187	92 (failure or breakthrough) ≥1 dose: 6A (16), 6B (16), 14 (28), 18C (6), 19A (15), 19F (4), 23F (7)

Additional information is provided in Supplementary Table 1. ^aSerotype-specific information was only provided for the two most common serotypes. ^bIncluded in sub-analysis on case-control studies. ^cStudy only assessed serotype 3 cases (Antachopoulos et al.) or serotype 3 and 19A cases (De Wals et al.). ^dIn addition to these 11 vaccine failures, one case of serotype 3, one of 6B, one of 14, three of 19A and two with undisclosed PCV13 serotypes were reported after ≥1 dose, but these could not be classified as either vaccine failure or breakthrough (number of doses not specified). ^eOnly serotypes with case counts of ≥5 were provided. IPD, invasive pneumococcal disease; N IPD (PCV-vaccinated), total number of IPD cases in children vaccinated with ≥1 dose of PCV reported in the study; n, number of cases per serotype; NA, not available; PCV(7/13), (7/13-valent) pneumococcal conjugate vaccine; PCV10, pneumococcal non-typeable Haemophilus influenzae protein D-conjugate vaccine.

Figure 3. Vaccine failures and breakthrough IPD cases after PCV13 or PCV10, reported for each serotype in the included studies, shown as proportions of the total vaccine failures or breakthrough cases across serotypes. Panel a shows vaccine failures, and breakthrough cases after receipt of ≥1 dose or ≥2 doses of PCV13 or PCV10. Panel b shows breakthrough cases after receipt of exactly 1, 2 or 3 doses of PCV13 or PCV10. IPD, invasive pneumococcal disease; N, total number of reported vaccine failures or breakthrough cases after the indicated number of doses, including only cases with serotype information available; PCV13, 13-valent pneumococcal conjugate vaccine; PCV10, pneumococcal non-typeable Haemophilus influenzae protein D-conjugate vaccine.

Figure 4. Vaccine failures after receipt of a 2+1, 3+0 or 3+1 PCV13 or PCV10 schedule reported for each serotype in the included studies, shown as proportions of the total vaccine failures across serotypes. 2+1, schedule consisting of 2 primary doses and a booster; 3+0, schedule consisting of 3 primary doses; 3+1, schedule consisting of 3 primary doses and a booster; N, total number of reported vaccine failures after the indicated schedule, including only cases with serotype information available; PCV13, 13-valent pneumococcal conjugate vaccine; PCV10, pneumococcal non-typeable Haemophilus influenzae protein D-conjugate vaccine.

Figure 5. Vaccine failures or breakthrough IPD cases after PCV13 or PCV10 reported for each serotype in the included case-control studies. Panel a shows vaccine failure or breakthrough cases per serotype (as explained for panels b to d) as a proportion of all failure or breakthrough cases across case-control studies; N values indicate the latter. Panel b shows the number of vaccine-serotype IPD cases per study and serotype in children who received ≥1 dose of PCV13 or PCV10 (vaccine failures and breakthrough). Panel c shows the number of vaccine failures per study and serotype. Panel d shows the number of breakthrough cases per study and serotype. *Vaccine failure data were only available for children 7–24 months of age who received a 2-dose catch-up schedule. IPD, invasive pneumococcal disease; PCV13, 13-valent pneumococcal conjugate vaccine; PCV10, pneumococcal non-typeable Haemophilus influenzae protein D-conjugate vaccine.

Figure 6. Percentage of the total number of vaccine failures or breakthrough IPD cases after PCV13 or PCV10 associated with each serotype. ≥1 dose refers to all vaccine-serotype IPD cases after receipt of ≥1 dose of either PCV13 or PCV10, including those that could not be classified as either vaccine failure or breakthrough (i.e. with no further information on the exact number of doses received, which was the case for two PCV13 studies: Asner et al. [27], Moore et al. [41], and one PCV10 study accounting for a high proportion of all cases: Verani et al. [9]). IPD, invasive pneumococcal disease; N, total number of reported vaccine failures, breakthrough cases or vaccine-serotype IPD cases after receipt of ≥1 dose of either PCV13 or PCV10, including only cases with serotype information available and excluding cases where children had received a mixed PCV13/PCV10 schedule; PCV13, 13-valent pneumococcal conjugate vaccine; PCV10, pneumococcal non-typeable Haemophilus influenzae protein D-conjugate vaccine.

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