Effectiveness and impact of the 10-valent pneumococcal conjugate vaccine, PHiD-CV: review of clinical trials and post-marketing experience

Figures & data

Figure 1. ‘Focus on the Patient’ section to contextualize, highlight, and discuss the impact of the primary findings of our review.

Table 1. Characteristics of clinical trials that evaluated the impact of PHiD-CV.

Country (study name)	Trial registry number	Vaccines	Vaccination schedule^a	Clinical end points reported	Time period	PCV in NIP before study start?	Ref.
Double-blind, randomized controlled trials
Finland (FinIP)	NCT00861380	PHiD-CV vs. HBV/HAV	Enrollment age <7 mo: 3 + 1 or 2 + 1 Enrollment age 7–11 mo: 2 + 1 Enrollment age 12–18 mo: 2-dose catch-up	IPD, pneumonia, tympanostomy tube placements, outpatient antibiotic prescriptions (AOM) Indirect effects on IPD, pneumonia, NPC^b	2009–2012	No	[10,46,56,57,74,75,98,102,103,109]
Argentina, Panama, Colombia (COMPAS)	NCT00466947	PHiD-CV vs. HBV/HAV	3 + 1: 2, 4, 6, 15–18 mo	CAP, AOM, culture-confirmed IPD, NPC	2007–2011	No	[12,72]
Finland (Study 053: nested within FinIP)	NCT00839254	PHiD-CV vs. HBV/HAV	As for FinIP	FinIP end points plus AOM and NPC	2009–2011	No	[11]
Kenya (Study 070)	NCT01028326	PHiD-CV vs. HAV	2-dose catch-up, 12–59 mo	NPC	2010	No	[13]
Single-blind, randomized
The Netherlands (Study 027)	NCT00652951	PHiD-CV vs. 7vCRM	3 + 1: 2, 3, 4, 11–13 mo	NPC	2008–2010	Yes (7vCRM)	[15]
Open-label, non-randomized
Czech Republic (Study 014)	NCT00496015	PHiD-CV vs. MenACWY-TT	3 + 1: 3, 4, 5, 12–15 mo	NPC	2007–2009	No	[14]

^a3 + 1: three priming doses plus booster dose; 2 + 1: two priming doses plus booster dose.

^bNPC analyses performed as satellite study to FinIP effectiveness trial (NCT01925222).

AOM: acute otitis media; CAP: community-acquired pneumonia; COMPAS: Clinical Otitis Media and PneumoniA Study; FinIP: Finnish Invasive Pneumococcal disease trial; IPD: invasive pneumococcal disease; NIP: national immunization program; NPC: nasopharyngeal carriage; PCV: pneumococcal conjugate vaccine; mo: months of age.

HBV: hepatitis B vaccine; HAV: hepatitis A vaccine; MenACWY-TT: quadrivalent meningococcal serogroups A, C, W-135, Y tetanus toxoid conjugate vaccine; 7vCRM: 7-valent pneumococcal CRM-conjugate vaccine.

Table 2. Characteristics of post-marketing effectiveness and impact studies of PHiD-CV. Effectiveness studies compared vaccinated and unvaccinated individuals exposed to the same PHiD-CV vaccination program while impact studies compared the same population before and after the introduction of PHiD-CV in the national immunization program.

Country, specific area	Data source	PHiD-CV vaccination schedule^a	Outcomes reported	Date PHiD-CV introduced	Ref.
Effectiveness studies
Finland	National infectious disease register	2 + 1: 3, 5, 12 mo	IPD	September 2010	[20]
The Netherlands	National surveillance	3 + 1: 2, 3, 4, 11 mo	IPD	May 2011 (prior 7vCRM use)	[38]
Sweden, 2 counties	National and regional registers	2 + 1: 3, 5, 12 mo	AOM-related diagnoses and comorbidities	2010 (prior 7vCRM use)	[81]
Brazil, 10 states	Laboratory and hospital surveillance	3 + 1: 2, 4, 6, 12 mo or 1-dose catch-up at 12–23 mo	IPD	March–September 2010	[23,24]
Brazil, Goiânia	Laboratory and hospital surveillance	3 + 1: 2, 4, 6, 12 mo or 1-dose catch-up at 12–23 mo	NPC	June 2010	[92]
Chile	National surveillance	3 + 1: 2, 4, 6, 12 mo From 2012, 2 + 1: 2, 4, 12 mo	Pneumonia hospitalizations, pneumonia mortality	January 2011	[59]
Canada, Quebec	Provincial public health register	2 + 1: 2, 4, 12 mo	IPD	June 2009 (prior 7vCRM use)	[34]
Impact studies
Countries where PHiD-CV was not preceded by 7vCRM in NIP
Finland	National infectious disease and health-care registers	2 + 1: 3, 5, 12 mo	IPD, pneumonia, pneumococcal meningitis, tympanostomy tube placements, outpatient antibiotic prescriptions (AOM) Indirect effects on IPD, pneumonia	September 2010	[18,19,21,22,47,62,79,104,105,110]
Iceland	National infectious disease register and National Drug Prescription Database	2 + 1: 3, 5, 12 mo	IPD, pneumonia hospital visits/admissions, AOM hospital visits/admissions, antibiotic prescriptions (AOM), NPC Indirect effects on IPD, NPC	April 2011	[28,29,82,83,94]
Brazil	Laboratory and hospital surveillance	3 + 1: 2, 4, 6, 12 mo or 1-dose catch-up at 12–23 mo	IPD, pneumonia hospitalizations, pneumonia mortality, pneumococcal meningitis, AOM outpatient visits, NPC Indirect effects on IPD, meningitis	March–September 2010	[25–27,58,61,63,64,68,85,92,93,96,106–108]
Chile	Hospital surveillance	3 + 1: 2, 4, 6, 12 mo From 2012, 2 + 1: 2, 4, 12 mo	Pneumonia hospitalizations, AOM emergency department visits	January 2011	[60,84]
Mozambique	Hospital surveillance	3 + 0: 2, 3, 4 mo	IPD, pneumonia, pneumococcal meningitis	April 2013	[31,32,69]
Kenya, Kilifi	District hospital records	3 + 0: 6, 10, 14 wk or 2-dose catch-up at <5 y	IPD, pneumonia, pneumonia hospitalizations, NPC Indirect effect on NPC	January 2011	[30,66,95]
Kenya, Kibera	Population-based surveillance	3 + 0: 6, 10, 14 wk or 2-dose catch-up at <5 y	Pneumonia mortality	January 2011	[67]
Countries where PHiD-CV was preceded by 7vCRM in NIP
The Netherlands	Laboratory surveillance	3 + 1: 2, 3, 4, 11 mo	IPD Indirect effects on IPD, pneumonia	May 2011	[36,37,111]
Sweden, proportion of 21 counties	National register	2 + 1: 3, 5, 12 mo	IPD, pneumonia hospitalizations, AOM, AOM-related diagnoses and surgical procedures	2010	[39,71,80]
Canada, Quebec	Provincial public health register	2 + 1: 2, 4, 12 mo	IPD, bronchiolitis and pneumonia hospitalizations, AOM hospital visits	June 2009	[33,70,86]
Australia, Northern Territory	Regional surveillance	3 + 1: 2, 4, 6, 18 mo	NPC, middle ear discharge	October 2009	[8]
New Zealand	National laboratory surveillance	3 + 1: 6 wk, 3, 5, 15 mo	IPD	July 2011	[35]
Voluntary surveillance
Brazil	SIREVA II	3 + 1: 2, 4, 6, 12 mo or 1-dose catch-up at 12–23 mo	IPD	March–September 2010	[9,16]
Chile	SIREVA II	3 + 1: 2, 4, 6, 12 mo From 2012, 2 + 1: 2, 4, 12 mo	IPD	January 2011	[16]
Colombia	SIREVA II	2 + 1: 2, 4, 12 mo	IPD	January 2012 (prior 7vCRM use)	[16]

^a3 + 1: three priming doses plus booster dose; 2 + 1: two priming doses plus booster dose.

AOM: acute otitis media; IPD: invasive pneumococcal disease; NIP: national immunization program; NPC: nasopharyngeal carriage; SIREVA II: Latin American laboratory network for passive surveillance of bacterial pneumonia and meningitis pathogens; wk/mo/y: weeks/months/years of age.

7vCRM: 7-valent pneumococcal CRM-conjugate vaccine.

Figure 2. Countries in which studies were conducted to assess the efficacy or effectiveness of PHiD-CV against invasive pneumococcal disease (IPD), pneumonia, and acute otitis media (AOM).

^aAntimicrobial purchases and tympanostomy tube placement in Finland; AOM-related diagnoses and surgical procedures in Sweden; antimicrobial purchases in Iceland.^bStudy 053 was not powered to evaluate AOM end points and the assessment was affected by a randomization error.COMPAS: Clinical Otitis Media and PneumoniA Study; FinIP: Finnish Invasive Pneumococcal disease trial; 7vCRM: 7-valent pneumococcal CRM-conjugate vaccine; 2 + 1/3 + 1/3 + 0, PHiD-CV infant vaccination schedules (two or three primary doses with or without booster dose).

Table 3. Efficacy and effectiveness of PHiD-CV against invasive pneumococcal disease (IPD) in vaccinated or vaccine-eligible infants and young children.

Country (study name)	Vaccination schedule^a	Age at follow-up	Time period, target vs. control	End point	Decrease vs. control (95% CI)	Number of cases^b	Incidence^b	Ref.
Double-blind, randomized controlled trials
Finland (FinIP)^c	Infant 3 + 1, 2 + 1	2–38 mo	2009–2012, PHiD-CV vs. HBV	VT IPD	3 + 1: 100% (83, 100) 2 + 1: 92% (58, 100)	0 vs. 12 1 vs. 12	0 vs. 56 5 vs. 56	[10]
				Overall IPD	3 + 1 and 2 + 1 combined: 93% (75, 99)	2 vs. 14	5 vs. 66	[10]
				Patient-file verified non-laboratory-confirmed IPD	3 + 1: 63% (34, 80) 2 + 1: 80% (60, 92)	16 vs. 43 8 vs. 43	82 vs. 200 36 vs. 200	[46]
				Register-based non-laboratory-confirmed IPD or unspecified sepsis	3 + 1: 38% (13, 56) 2 + 1: 62% (43, 75)	55 vs. 87 32 vs. 87	275 vs. 422 151 vs. 422	[46]
Argentina, Panama, Colombia (COMPAS)^c,d	Infant 3 + 1	2–35 mo	2007–2011, PHiD-CV vs. HBV/HAV	VT IPD	100% (77, 100)	0 vs. 18	0 vs. 0.1^e	[12]
				Overall IPD	67% (22, 86)	7 vs. 21	0.1 vs. 0.2^e
Effectiveness studies
Countries where PHiD-CV was not preceded by 7vCRM in NIP
Finland	Infant 2 + 1	3–42 mo	2010–2013, vaccinated vs. unvaccinated	VT IPD	98% (72, 100)	1 vs. 8	NR	[20]
Brazil: matched case-control	Infant 3 + 1, toddler 1-dose catch-up	3–53 mo	2010–2012, vaccinated vs. unvaccinated	VT IPD	84% (66, 92)	NA	NA	[23]
				19A IPD	82% (11, 96)	NA	NA
Brazil: indirect cohort	Infant 3 + 1, toddler 1-dose catch-up	3–53 mo	2010–2012, PHiD-CV vaccination (≥1 dose) in VT or vaccine-related IPD vs. NVT IPD	VT IPD	73% (44, 87)	NA	NA	[24]
				19A IPD	71% (17, 90)	NA	NA
				6A IPD	51% (−52, 84)	NA	NA
Countries where PHiD-CV was preceded by 7vCRM in NIP
The Netherlands: indirect cohort	Infant 3 + 1	2–54 mo	NR, PHiD-CV vaccination (≥1 dose) vs. unvaccinated	VT IPD	89% (41, 98)	NA	NA	[38]
				19A IPD	61% (−79, 92)	NA	NA
Canada, Quebec	Infant 2 + 1	2–59 mo	2005–2013, vaccinated vs. unvaccinated	VT IPD + 6A IPD	97% (84, 99)	NA	NA	[34]
				19A IPD	71% (24, 89)	NA	NA
Impact studies
Countries where PHiD-CV was not preceded by 7vCRM in NIP
Finland	Infant 2 + 1	3–78 mo	2010–2016 (post) vs. 2002–2008 (pre)	VT IPD	94% (92, 96)	23 vs. 391	1.9 vs. 32.3	[19]
				Overall IPD	79% (74, 83)	114 vs. 520	9.2 vs. 42.9
				19A IPD	26% (−13, 51) 68% −257%	39 vs. 51 <24 mo: 14 vs. 44 ≥24 mo: 25 vs. 7	3.1 vs. 4.2
				6A IPD	95% (75, 100)	1 vs. 19	0.1 vs. 1.6
Finland	Infant 2 + 1	3–42 mo	2010–2013 (post) vs. 2003–2008 (pre)	Register-based non-laboratory-confirmed IPD or unspecified sepsis	34% (29, 39)	791 vs. 2333	237 vs. 359	[47]
Finland	Infant 2 + 1	<2 y	2010–2014 (post) vs. 1995–1999 (pre)	Pneumococcal meningitis	46%	14 vs. 26	2.3 vs. 4.3	[21]
Finland	Infant 2 + 1	<5 y	2014 (post) vs. 2009 (pre)	Invasive isolates	76%	8 vs. 33	NR	[22]
Iceland	Infant 2 + 1	<2 y	2011–2013 (post) vs. 2008–2010 (pre)	VT IPD	87%	2 vs. 15	NR	[28]
				Overall IPD	82%	4 vs. 22	14 vs. 77
Iceland	Infant 2 + 1	<2 y	2012–2015 (post) vs. 2009–2011 (pre)	Overall IPD	93%	1 vs. 14	2.8 vs. 48.3	[29]
Kenya, Kilifi	Infant 3 + 0, 2-dose catch-up for <5 y	<5 y	2013–2016 (post) vs. 2003–2010 (pre)	VT IPD	96%	1.0 vs. 24.4	NR	[30]
				Overall IPD	78%	7.0 vs. 32.5	NR
Brazil	Infant 3 + 1, toddler 1-dose catch-up	2–23 mo	2011–2013 (post) vs. 2008–2009 (pre)	VT IPD	2–11 mo: 58% 12–23 mo: 62%	72 (31%) vs. 157 (74%) 27 (31%) vs. 151 (81%)	NA	[25]
Brazil	Infant 3 + 1, toddler 1-dose catch-up	2 mo–4 y	2014–2015 (post) vs. 2005–2009 (pre)	VT meningitis	83%	13 vs. 580	NA	[27]
				VT IPD (non-meningitis)	87%	15 vs. 461
Mozambique	Infant 3 + 0	<5 y	2014–2016 (post) vs. 2008–2012 (pre)	VT IPD	96% (79, 100)	NR	7 vs. 111 (2016 vs. 2008)	[32]
				Overall IPD	73% (39, 92)	NR	41 vs. 235 (2016 vs. 2008)
Mozambique	Infant 3 + 0	<5 y	2015 (post) vs. 2013 (pre)	VT meningitis	100%	0 vs. 48	NR	[31]
				Overall pneumococcal meningitis	98%	3 (2%) vs. 124 (34%)	NR
Brazil (SIREVA II)	Infant 3 + 1, toddler 1-dose catch-up	<2 y	2011–2012 (post) vs. 2007–2009 or 2010^f (pre)	VT IPD	75%	43.5 vs. 171	NR	[16]
				Overall IPD	46%	118.5 vs. 219	NR
				19A IPD	6%	7.5 vs. 8	NR
				6A IPD	38%	8 vs. 13	NR
Brazil (SIREVA II)	Infant 3 + 1, toddler 1-dose catch-up	<2 y	2011–2015 (post) vs. 2005–2009 (pre)	19A IPD	270% increase	NR (12.2% vs. 3.3%)	NR	[9]
Chile (SIREVA II)	Infant 3 + 1, 2 + 1	<2 y	2012 (post) vs. 2007–2010 or 2010^f (pre)	VT IPD	79%	36 vs. 173.8	NR	[16]
				Overall IPD	62%	91 vs. 240.5	NR
				19A IPD	41%	8 vs. 13.5	NR
				6A IPD	72%	5 vs. 18	NR
Countries where PHiD-CV was preceded by 7vCRM in NIP
The Netherlands	Infant 3 + 1	<2 y	2009–2011 (mostly 7vCRM), 2011–2013 (mostly PHiD-CV) or 2013–2014 (PHiD-CV vaccinated) vs. 2004–2006 (pre-7vCRM)	7vCRM-type IPD	2009–2011: 98% 2011–2013: 96% 2013–2014: 100%	0.3 vs. 16.7 0.7 vs. 16.7 0 vs. 16.7	NA NA NA	[36]
The Netherlands	Infant 3 + 1	<5 y	2013–2014, 2014–2015, 2015–2016 (PHiD-CV vaccinated) vs. 2010–2011 (mostly 7vCRM vaccinated)	Overall IPD	2013–2014: 56% 2014–2015: 22% 2015–2016: 44%	NR	4 vs. 9 7 vs. 9 5 vs. 9	[37]
Sweden	Infant 2 + 1	<5 y	2013–2016 (PHiD-CV vaccinated) vs. 2007 (pre-7vCRM)	Overall IPD	64%	NR	5.7 vs. 15.7	[39]^g
				6A IPD	80%	NR	0.4 vs. 2.0
				19A IPD	Infinity	NR	1.1 vs. 0
Canada, Quebec	Infant 2 + 1	6–30 mo	2009–2011 (PHiD-CV-vaccinated) vs. 2007–2009 (7vCRM vaccinated)	Overall IPD	43%	23 vs. 40	31 vs. 56	[33]
				19A IPD	33%	10 vs. 15	13 vs. 21
New Zealand	Infant 3 + 1	<2 y	October 2012–September 2013 (PHiD-CV-vaccinated) vs. October 2011–September 2012 (mostly 7vCRM vaccinated)	Overall IPD	40%	25 vs. 42	NR	[35]
				19A IPD	47%	8 vs. 15	NR
				6A IPD	50%	1 vs. 2	NR
Colombia (SIREVA II)	Infant 2 + 1	<2 y	2012 (PHiD-CV vaccinated) vs. 2007–2010 or 2010^f (7vCRM vaccinated)	VT IPD	74%	20 vs. 78	NR	[16]
				Overall IPD	59%	43 vs. 103.8	NR
				19A IPD	43%	2 vs. 3.5	NR
				6A IPD	−200%	3 vs. 1	NR

^a3 + 1: three priming doses plus booster dose; 2 + 1: two priming doses plus booster dose.

^bNumber of cases is average number per year or number in specified time periods. Percentages indicate proportion of samples that tested positive for S. pneumoniae (any or indicated serotype[s]). Incidence is incidence/100,000 person-years, except where indicated.

^cData for intent-to-treat analysis (follow-up any time from first vaccination).

^dData for first episodes.

^ePercentage, calculated as number of first episodes during follow-up period divided by number of children, multiplied by 100.

^fFor 6A IPD in Brazil, Chile, and Colombia, 2010 was used as control, i.e. the first year that a distinction between serotypes 6A and 6C was made.

^gAn expression of concern has been raised relating to the publication by Naucler et al. [40]. Following receipt of additional information, the authors are reanalyzing the data and their impact on the published study results.

CI: confidence interval; COMPAS: Clinical Otitis Media and PneumoniA Study; FinIP: Finnish Invasive Pneumococcal disease trial; mo/y: months/years of age; NA: not applicable because of study design; NIP: national immunization program; NVT IPD: IPD due to non-vaccine serotypes; NR: not reported; overall IPD: IPD due to any pneumococcal serotype; SIREVA II: Latin American laboratory network for passive surveillance of bacterial pneumonia and meningitis pathogens; VT IPD: IPD due to vaccine serotypes; 7vCRM-type IPD: IPD due to serotypes included in 7vCRM; 19A/6A IPD: IPD due to vaccine-related serotype 19A or 6A; post: after PHiD-CV was introduced; pre: before PHiD-CV was introduced.

HBV: hepatitis B vaccine; HAV: hepatitis A vaccine; 7vCRM: 7-valent pneumococcal CRM-conjugate vaccine.

Table 4. Efficacy and effectiveness of PHiD-CV against pneumonia in vaccinated or vaccine-eligible infants and young children in countries where PHiD-CV was the first PCV introduced in the national immunization program.

Country (study name)	Vaccination schedule^a	Age at follow-up	Time period, target vs. control	End point	Decrease vs. control (95% CI)	Ref.
Double-blind, randomized controlled trials
Finland (FinIP)^b	Infant 3 + 1, 2 + 1	2–38 mo	2009–2011, PHiD-CV vs. HBV	Hospital-diagnosed pneumonia	3 + 1: 25% (3, 43) 2 + 1: 28% (6, 45)	[56]
				Hospital-treated primary pneumonia	3 + 1: 25% (−2, 44) 2 + 1: 30% (4, 48)
				Hospital-diagnosed pneumonia with radiologic confirmation	3 + 1: 28% (−0.5, 48) 2 + 1: 29% (0.6, 49)	[57]
				Hospital-diagnosed pneumonia with WHO-defined consolidation	3 + 1: 47% (24, 64) 2 + 1: 43% (19, 61)
Argentina, Panama, Colombia (COMPAS)^b,c	Infant 3 + 1	2–35 mo	2007–2011, PHiD-CV vs. HBV/HAV	CAP with WHO-defined consolidation	23% (9, 36)	[12]
				Likely bacterial CAP	18% (6, 29)
Effectiveness studies
Chile	Infant 3 + 1	2–26 mo	2010–2013, vaccinated vs. unvaccinated	Pneumonia hospitalizations and deaths	11% (9, 14)	[59]
				Bacterial/unspecified pneumonia hospitalizations and deaths	21% (17, 24)
				Bacterial pneumonia deaths	72% (9, 92)
Impact studies
Finland	Infant 2 + 1	3–42 mo	Children born 2010–2013 (post) vs. 2003–2008 (pre)	Hospital-diagnosed pneumonia Hospital-treated primary pneumonia	13% (9, 16) 23% (18, 28)	[62]
Iceland	Infant 2 + 1	<24 mo	2011–2013 (post) vs. 2008–2010 (pre)	Pneumonia hospital visits/admissions	<12 mo: 30% (11, 45) 12–23 mo: 23% (10, 34)	[65]
Brazil, Goiânia	Infant 3 + 1, toddler 1-dose catch-up	2–35 mo	2011–2013 (post), vs. 2007–2009 (pre)	Pneumonia hospitalizations (X-ray confirmed)	23% (22, 24) 2–23 mo: 25% (25, 26) 24–35 mo: 12% (11, 13)	[64]
Brazil, 5 cities	Infant 3 + 1, toddler 1-dose catch-up	2–24 mo	2010–2011 (post) vs. 2005–2009 (pre)	Pneumonia hospitalizations	2–29% (city-dependent)^d	[58]
Brazil	Infant 3 + 1, toddler 1-dose catch-up	<48 mo	2011–2015 (post) vs. 2005–2009 (pre)	Pneumonia hospitalizations	<12 mo: 27% (18, 36) 12–23 mo: 17% (9, 26) 2–4 y: 22% (13, 30)	[68]
Brazil	Infant 3 + 1, toddler 1-dose catch-up	<48 mo	2011–2012 (post) vs. 2002–2009 (pre)	Pneumonia hospitalizations	13%	[63]
Brazil	Infant 3 + 1, toddler 1-dose catch-up	2–23 mo	2011–2012 (post) vs. 2005–2009 (pre)	Pneumonia mortality	17%^e	[61]
Chile	Infant 2 + 1	<24 mo	2012–2013 (post) vs. 2009–2010 (pre)	Pneumonia hospitalizations	56%	[60]
Mozambique	Infant 3 + 0	<2 y	2014–2016 (post) vs. 2010–2012 (pre)	Pneumonia (X-ray confirmed)	64% (33, 87)	[69]
Kenya, Kilifi	Infant 3 + 0 or 2-dose catch-up at <5 y	<5 y	2002–2015; post vs. pre	Pneumonia (X-ray confirmed)	48%	[66]
Kenya, Kibera	Infant 3 + 0 or 2-dose catch-up at <5 y	<5 y	2013, 2014 (post) vs. 2009–2010 (pre)	Pneumonia mortality	2013: 41% 2014: 43%	[67]

^a3 + 1: three priming doses plus booster dose; 2 + 1: two priming doses plus booster dose.

^bData for intent-to-treat analysis (follow-up any time from first vaccination).

^cData for first episodes.

^dEstimated by comparing percentage changes in hospitalizations for pneumonia vs. hospitalizations for non-respiratory causes.

^eEstimated by comparing pneumonia vs. all respiratory causes.

CAP: community-acquired pneumonia; CI: confidence interval; COMPAS: Clinical Otitis Media and PneumoniA Study; FinIP: Finnish Invasive Pneumococcal disease trial; post: after PHiD-CV was introduced; pre: before PHiD-CV was introduced; WHO: World Health Organization; mo/y: months/years of age.

HBV: hepatitis B vaccine; HAV: hepatitis A vaccine.

Table 5. Efficacy and effectiveness of PHiD-CV against acute otitis media (AOM) or AOM-related end points in vaccinated or vaccine-eligible infants and young children in countries where PHiD-CV was the first PCV introduced in the national immunization program.

Country (study name)	Vaccination schedule^a	Age at follow-up	Time period, target vs. control	End point	Decrease vs. control (95% CI)	Ref.
Double-blind, randomized controlled trials
Finland (FinIP)^b	Infant 3 + 1, 2 + 1	2–35 mo	2009–2011, PHiD-CV vs. HBV	Antimicrobial purchases^c	3 + 1: 8% (−1, 15) 2 + 1: 8% (0, 15)	[74]
				Tympanostomy tube placement	3 + 1: 14% (−4, 29) 2 + 1: 13% (−5, 28)	[75]
Panama (COMPAS)^b,d	Infant 3 + 1	2–33 mo	2007–2011, PHiD-CV vs. HBV/HAV	Clinical AOM	19% (4, 31)	[12,72]
				<24 mo	24% (9, 37)
				Mild	2% (−27, 24)
				Moderate	18% (−6, 36)
				Severe	33% (−21, 62)
				Pneumococcal	56% (22, 75)
				Vaccine serotype	70% (30, 87)
Finland (Study 053)^e	Infant 3 + 1, 2 + 1	2–22 mo	2009–2011, PHiD-CV vs. HBV	Parent-reported physician-diagnosed AOM	≥1 AOM episode: 3 + 1: 6% (−3, 14) 2 + 1: 7% (−3, 17) All AOM episodes: 3 + 1: 3% (−10, 14) 2 + 1: 10% (−4, 23)	[11]
Effectiveness study
Iceland	Infant 2 + 1	<3 y	Children born 2011–2014 (post) vs. 2005–2010 (pre)	Antimicrobial prescriptions for AOM	20% (15, 25)	[83]
Impact studies
Finland	Infant 2 + 1	3–54 mo	Children born 2010–2014 (post) vs. 2004–2008 (pre)	Tympanostomy tube placement	15% (13,17)	[79]
				Antimicrobial purchases^c	18% (17, 18)
Iceland	Infant 2 + 1	<3 y	Children born 2011–2015 (post) vs. 2005–2010 (pre)	All-cause AOM primary care visits	22% (12, 31)	[82]
Brazil, Goiânia	Infant 3 + 1, toddler 1-dose catch-up	2–23 mo	2011–2015 (post) vs. 2008–2010 (pre)	All-cause AOM outpatient visits	43% (41, 45)	[85]
Chile	Infant 2 + 1	<24 mo	2012–2015 (post) vs. 2007–2010 (pre)	AOM emergency department visits	32%	[84]

^a3 + 1: three priming doses plus booster dose; 2 + 1: two priming doses plus booster dose.

^bData for intent-to-treat analysis (follow-up any time from first vaccination).

^cAntimicrobials recommended for treatment of AOM or upper respiratory infections.

^dData for first episodes.

^eStudy 053 was not powered to evaluate AOM and the assessment was affected by a randomization error.

CI: confidence interval; COMPAS: Clinical Otitis Media and PneumoniA Study; FinIP: Finnish Invasive Pneumococcal disease trial; OM: otitis media; post: after PHiD-CV was introduced; pre: before PHiD-CV was introduced.

HBV: hepatitis B vaccine; HAV: hepatitis A vaccine; PCV13: 13-valent pneumococcal CRM-conjugate vaccine.

Figure 3. Impact of PHiD-CV vaccination on nasopharyngeal carriage of vaccine pneumococcal serotypes (VT) and non-vaccine serotypes (NVT) in (a) Panama (COMPAS) [72], (b) Finland (study 053: AOM/carriage study nested in FinIP trial) [11], (c) the Czech Republic (study 014: non-randomized study with age-matched controls) [14], and (d) the Netherlands (study 027: randomized study of children immunized with PHiD-CV or 7vCRM) [15].

*Pneumococcal serotypes included in PHiD-CV (serotypes 1, 4, 5, 6B, 7F, 9V, 14, 18C, 19F, and 23F).

Figure 4. Indirect effects of PHiD-CV on invasive pneumococcal disease (IPD), meningitis, and pneumonia in vaccine-ineligible children and adults estimated from post-marketing impact studies in Finland, the Netherlands, Iceland, and Brazil. Further information on the analyses conducted is provided in Supplementary Table 2.

diag: diagnosed; lab: laboratory; overall IPD: IPD due to any pneumococcal serotype; pneumococcal meningitis: meningitis due to any pneumococcal serotype; VT IPD: IPD due to vaccine serotypes; VT meningitis: meningitis due to vaccine serotypes; mo: months; y: years. Error bars represent 95% confidence intervals.

Palmu AA, Jokinen J, Borys D, et al. Effectiveness of the ten-valent pneumococcal Haemophilus influenzae protein D conjugate vaccine (PHiD-CV10) against invasive pneumococcal disease: a cluster randomised trial. Lancet. 2013;381:214–222.

 PubMed Web of Science ®Google Scholar

Palmu AA, Jokinen J, Nieminen H, et al. Vaccine effectiveness of the pneumococcal Haemophilus influenzae protein D conjugate vaccine (PHiD-CV10) against clinically suspected invasive pneumococcal disease: a cluster-randomised trial. Lancet Respir Med. 2014;2:717–727.

 PubMed Web of Science ®Google Scholar

Kilpi T, Palmu AA, Puumalainen T, et al. Effectiveness of the 10-valent pneumococcal Haemophilus influenzae protein D conjugate vaccine (PHiD-CV10) against hospital-diagnosed pneumonia in infants - FinIP trial. 31st Annual Meeting of the European Society for Paediatric Infectious Diseases; 2013 May 28–Jun 1; Milan, Italy.

 Google Scholar

Kilpi T, Jokinen J, Puumalainen T, et al. Effectiveness of pneumococcal Haemophilus influenzae protein D conjugate vaccine against radiologically confirmed pneumonia. 54th Interscience Conference on Antimicrobial Agents and Chemotherapy; 2014 Sep 5–9; Washington, DC.

 Google Scholar

Palmu AA, Jokinen J, Nieminen H, et al. Effect of pneumococcal Haemophilus influenzae protein D conjugate vaccine (PHiD-CV10) on outpatient antimicrobial purchases: a double-blind, cluster randomised phase 3–4 trial. Lancet Infect Dis. 2014;14:205–212.

 PubMed Web of Science ®Google Scholar

Palmu AA, Jokinen J, Nieminen H, et al. Effectiveness of the ten-valent pneumococcal conjugate vaccine against tympanostomy tube placements in a cluster-randomized trial. Pediatr Infect Dis J. 2015;34:1230–1235.

 PubMed Web of Science ®Google Scholar

Palmu AA, Toropainen M, Kaijalainen T, et al. Direct and indirect effectiveness of the 10-valent pneumococcal conjugate vaccine against carriage in a cluster randomized trial. Pediatr Infect Dis J. 2017;36:1193–1200.

 PubMed Web of Science ®Google Scholar

Palmu AA, Jokinen J, Ruokokoski E, et al. Indirect impact of pneumococcal Haemophilus influenzae protein-D conjugate vaccine (PHiD-CV10) on suspected non-confirmed invasive pneumococcal disease (IPD) in cluster-randomized trial. 9th International Symposium on Pneumococci & Pneumococcal Diseases; 2014 Mar 9–13; Hyderabad, India.

 Google Scholar

Kilpi T, Palmu AA, Ruokokoski E, et al. Indirect impact of pneumococcal Haemophilus influenzae protein-D conjugate vaccine (PHiD-CV10) on invasive pneumococcal disease (IPD) in a clinical trial. 8th World Congress of the World Society for Pediatric Infectious Diseases; 2013 Nov 19–22; Cape Town, South Africa.

 Google Scholar

Palmu A, Jokinen J, Puumalainen T, et al. Indirect impact of pneumococcal Haemophilus influenzae protein D-conjugate vaccine (PHiD-CV10) on hospital-diagnosed pneumonia in cluster-randomized trial. 33rd Annual Meeting of the European Society for Paediatric Infectious Diseases; 2015 May 12–16; Leipzig, Germany.

 Google Scholar

Tregnaghi MW, Sáez-Llorens X, López P, et al. Efficacy of pneumococcal nontypable Haemophilus influenzae protein D conjugate vaccine (PHiD-CV) in young Latin American children: a double-blind, randomized controlled trial. PLoS Med. 2014;11:e1001657.

 PubMed Web of Science ®Google Scholar

Sáez-Llorens X, Rowley S, Wong D, et al. Efficacy of 10-valent pneumococcal non-typeable Haemophilus influenzae protein D conjugate vaccine against acute otitis media and impact on nasopharyngeal carriage in Panamanian children - a randomized controlled trial. Human Vacc Immunother. 2017;13:1213–1228.

 PubMed Web of Science ®Google Scholar

Vesikari T, Forsten A, Seppä I, et al. Effectiveness of the 10-valent pneumococcal non-typeable Haemophilus influenzae protein D-conjugated vaccine (PHiD-CV) against carriage and acute otitis media - a double-blind randomized clinical trial in Finland. J Pediatric Infect Dis Soc. 2016;5:237–248.

 PubMed Web of Science ®Google Scholar

Hammitt LL, Ojal J, Bashraheil M, et al. Immunogenicity, impact on carriage and reactogenicity of 10-valent pneumococcal non-typeable Haemophilus influenzae protein D conjugate vaccine in Kenyan children aged 1–4 years: a randomized controlled trial. PLoS One. 2014;9:e85459.

 PubMed Web of Science ®Google Scholar

van den Bergh MR, Spijkerman J, Swinnen KM, et al. Effects of the 10-valent pneumococcal nontypeable Haemophilus influenzae protein D-conjugate vaccine on nasopharyngeal bacterial colonization in young children: a randomized controlled trial. Clin Infect Dis. 2013;56:e30–e39.

 PubMed Web of Science ®Google Scholar

Prymula R, Hanovcova I, Splino M, et al. Impact of the 10-valent pneumococcal non-typeable Haemophilus influenzae Protein D conjugate vaccine (PHiD-CV) on bacterial nasopharyngeal carriage. Vaccine. 2011;29:1959–1967.

 PubMed Web of Science ®Google Scholar

Rinta-Kokko H, Auranen K, Palmu A, et al. Effectiveness of 10-valent pneumococcal conjugate vaccine (PCV10) against invasive pneumococcal disease (IPD) during ongoing national vaccination programme (NVP) in Finland. 9th International Symposium on Pneumococci & Pneumococcal Diseases; 2014 Mar 9–13; Hyderabad, India.

 Google Scholar

Knol MJ, Van der Ende A, Sanders L, et al. Vaccine effectiveness of 10-valent pneumococcal conjugate vaccine against invasive pneumococcal disease: indirect cohort design. 10th International Symposium on Pneumococci and Pneumococcal Diseases; 2016 Jun 26–30; Glasgow, UK.

 Google Scholar

Talarico C, Feng Y, Medin E, et al. Impact of pneumococcal conjugate vaccines (PCVs) on otitis media incidence in Swedish children. 11th International Symposium on Pneumococci and Pneumococcal Diseases; 2018 Apr 15–19; Melbourne, Australia.

 Google Scholar

Domingues CM, Verani JR, Montenegro Renoiner EI, et al. Effectiveness of ten-valent pneumococcal conjugate vaccine against invasive pneumococcal disease in Brazil: a matched case-control study. Lancet Respir Med. 2014;2:464–471.

 PubMed Web of Science ®Google Scholar

Verani JR, Domingues CM, Moraes JC. Indirect cohort analysis of 10-valent pneumococcal conjugate vaccine effectiveness against vaccine-type and vaccine-related invasive pneumococcal disease. Vaccine. 2015;33:6145–6148.

 PubMed Web of Science ®Google Scholar

Andrade AL, Ternes YM, Vieira MA, et al. Direct effect of 10-valent conjugate pneumococcal vaccination on pneumococcal carriage in children Brazil. PLoS One. 2014;9:e98128.

 PubMed Web of Science ®Google Scholar

Diaz J, Terrazas S, Bierrenbach AL, et al. Effectiveness of the 10-valent pneumococcal conjugate vaccine (PCV-10) in children in Chile: A nested case-control study using nationwide pneumonia morbidity and mortality surveillance data. PLoS One. 2016;11:e0153141.

 PubMed Web of Science ®Google Scholar

Deceuninck G, De Serres G, Boulianne N, et al. Effectiveness of three pneumococcal conjugate vaccines to prevent invasive pneumococcal disease in Quebec, Canada. Vaccine. 2015;33:2684–2689.

 PubMed Web of Science ®Google Scholar

Jokinen J, Rinta-Kokko H, Siira L, et al. Impact of ten-valent pneumococcal conjugate vaccination on invasive pneumococcal disease in Finnish children - a population-based study. PLoS One. 2015;10:e0120290.

 PubMed Web of Science ®Google Scholar

Rinta-Kokko H, Palmu AA, Auranen K, et al. Long-term impact of 10-valent pneumococcal conjugate vaccination on invasive pneumococcal disease among children in Finland. Vaccine. 2018;36:1934–1940.

 PubMed Web of Science ®Google Scholar

Polkowska A, Toropainen M, Ollgren J, et al. Bacterial meningitis in Finland, 1995–2014: a population-based observational study. BMJ Open. 2017;7:e015080.

 PubMedGoogle Scholar

Sihvonen R, Siira L, Toropainen M, et al. Streptococcus pneumoniae antimicrobial resistance decreased in the Helsinki Metropolitan Area after routine 10-valent pneumococcal conjugate vaccination of infants in Finland. Eur J Clin Microbiol Infect Dis. 2017;36:2109–2116.

 PubMed Web of Science ®Google Scholar

Palmu AA, Kilpi TM, Rinta-Kokko H, et al. Pneumococcal conjugate vaccine and clinically suspected invasive pneumococcal disease. Pediatrics. 2015;136:e22–e27.

 PubMed Web of Science ®Google Scholar

Palmu AA, Rinta-Kokko H, Nohynek H, et al. Impact of ten-valent pneumococcal conjugate vaccine on pneumonia in Finnish children in a nation-wide population-based study. PLoS One. 2017;12:e0172690.

 PubMed Web of Science ®Google Scholar

Palmu AA, Rinta-Kokko H, Nohynek H, et al. Impact of national ten-valent pneumococcal conjugate vaccine programme on reducing antimicrobial use and tympanostomy tube placements in Finland. Pediatr Infect Dis J. 2018;37:97–102.

 PubMed Web of Science ®Google Scholar

Palmu AA, Rinta-Kokko H, Nuorti JP, et al. A pneumococcal conjugate vaccination programme reduced clinically suspected invasive disease in unvaccinated children. Acta Paediatr. 2018. DOI:10.1111/apa.14335

 Web of Science ®Google Scholar

Nuorti JP, Rinta-Kokko H, Toropainen M, et al. Invasive pneumococcal disease among adults after routine infant conjugate vaccination in Finland - implications for vaccination policy. 9th International Symposium on Pneumococci & Pneumococcal Diseases; 2014 Mar 9–13; Hyderabad, India.

 Google Scholar

Okasha O, Rinta-Kokko H, Palmu AA, et al. Population-level impact of infant 10-valent pneumococcal conjugate vaccination on adult pneumonia hospitalisations in Finland. Thorax. 2018;73:262–269.

 PubMed Web of Science ®Google Scholar

Erlendsdóttir H, Haraldsson A, Hrafnkelsson B, et al. An early reduction of invasive pneumococcal infections after PCV-10 immunisation. Poster session presented at: 9th International Symposium on Pneumococci and Pneumococcal Diseases; 2014 Mar 9–13; Hyderabad, India.

 Google Scholar

Kristinsson KG, Erlendsdóttir H, Quirk S, et al. Effect of pneumococcal vaccination on invasive pneumococcal disease in Iceland 2009–2015. Poster session presented at: 26th European Congress of Clinical Microbiology and Infectious Diseases; 2016 Apr 9–12; Amsterdam, The Netherlands.

 Google Scholar

Sigurdsson S, Eythorsson E, Hrafnkelsson B, et al. Reduction in all-cause acute otitis media in children less than three years of age in primary care following pneumococcal vaccination with PHiD-CV10: A whole population study. Clin Infect Dis. 2018. DOI:10.1093/cid/ciy233

 PubMed Web of Science ®Google Scholar

Eyþorsson ES, Sigurdsson S, Hrafnkelsson B, et al. Pneumococcal vaccination in Iceland: PHiD-CV10 effectiveness against AOM associated antimicrobial prescriptions in children under three years of age. 11th International Symposium on Pneumococci and Pneumococcal Diseases; 2018 Apr 15–19; Melbourne, Australia.

 Google Scholar

Sigurdsson S, Erlendsdóttir H, Quirk SJ, et al. Pneumococcal vaccination: direct and herd effect on carriage of vaccine types and antibiotic resistance in Icelandic children. Vaccine. 2017;35:5242–5248.

 PubMed Web of Science ®Google Scholar

Andrade AL, Minamisava R, Policena G, et al. Evaluating the impact of PCV-10 on invasive pneumococcal disease in Brazil: A time-series analysis. Hum Vaccin Immunother. 2016;12:285–292.

 PubMed Web of Science ®Google Scholar

Brandileone MC, Almeida SCG, Minamisava R, et al. Distribution of invasive Streptococcus pneumoniae serotypes before and 5 years after the introduction of 10-valent pneumococcal conjugate vaccine in Brazil. Vaccine. 2018;36:2559–2566.

 PubMed Web of Science ®Google Scholar

Afonso ET, Minamisava R, Bierrenbach AL, et al. Effect of 10-valent pneumococcal vaccine on pneumonia among children, Brazil. Emerg Infect Dis. 2013;19:589–597.

 PubMed Web of Science ®Google Scholar

Minamisava R, Sgambatti S, Morais-Neto OL, et al. Impact of PCV10 introduction on pneumonia mortality rates in Brazil: a time series analysis. 9th International Symposium on Pneumococci & Pneumococcal Diseases; 2014 Mar 9–13; Hyderabad, India.

 Google Scholar

Scotta MC, Veras TN, Klein PC, et al. Impact of 10-valent pneumococcal non-typeable Haemophilus influenzae protein D conjugate vaccine (PHiD-CV) on childhood pneumonia hospitalizations in Brazil two years after introduction. Vaccine. 2014;32:4495–4499.

 PubMed Web of Science ®Google Scholar

Sgambatti S, Minamisava R, Bierrenbach AL, et al. Early impact of 10-valent pneumococcal conjugate vaccine in childhood pneumonia hospitalizations using primary data from an active population-based surveillance. Vaccine. 2016;34:663–670.

 PubMed Web of Science ®Google Scholar

Andrade AL, Afonso ET, Minamisava R, et al. Direct and indirect impact of 10-valent pneumococcal conjugate vaccine introduction on pneumonia hospitalizations and economic burden in all age-groups in Brazil: A time-series analysis. PLoS One. 2017;12:e0184204.

 PubMed Web of Science ®Google Scholar

Sartori AL, Minamisava R, Bierrenbach AL, et al. Reduction in all-cause otitis media-related outpatient visits in children after PCV10 introduction in Brazil. PLoS One. 2017;12:e0179222.

 PubMed Web of Science ®Google Scholar

Brandileone MC, Zanella RC, Almeida SCG, et al. Effect of 10-valent pneumococcal conjugate vaccine on nasopharyngeal carriage of Streptococcus pneumoniae and Haemophilus influenzae among children in Sao Paulo, Brazil. Vaccine. 2016;34:5604–5611.

 PubMed Web of Science ®Google Scholar

Neves FPG, Cardoso NT, Snyder RE, et al. Pneumococcal carriage among children after four years of routine 10-valent pneumococcal conjugate vaccine use in Brazil: the emergence of multidrug resistant serotype 6C. Vaccine. 2017;35:2794–2800.

 PubMed Web of Science ®Google Scholar

Caierão J, Cunha G, d’Azevedo PA, et al. Distribution of pneumococcal serotypes after introduction of 10-valent conjugate vaccine: a study involving adults with invasive disease, Porto Alegre, Brazil. 8th International Symposium on Pneumococci and Pneumococcal Diseases; 2012 Mar 11–15; Iguaçu Falls, Brazil.

 Google Scholar

Lobo PR, Azevedo J, Silva E, et al. Epidemiology of pneumococcal meningitis in the metropolitan region of Salvador, Brazil, before and after the introduction of PCV10. Poster session presented at: 9th International Symposium on Pneumococci and Pneumococcal Diseases; 2014 Mar 9–13; Hyderabad, India.

 Google Scholar

Fernández VJP, Goecke HC, von Borries C, et al. Incidence of admissions due to pneumonia in children under 24 months old before and after the introduction of the 10-valent pneumococcal conjugate vaccine into the National Immunization Program of Chile. Rev Chil Pediatr. 2015;86:168–172. Spanish.

 PubMed Web of Science ®Google Scholar

Rosenblut A, Rosenblut M, Garcia K, et al. Frequency of acute otitis media in children under 24 months of age before and after the introduction of the 10-valent pneumococcal conjugate vaccine into the national immunization program in Chile. Pediatr Infect Dis J. 2018;37:132–134.

 PubMed Web of Science ®Google Scholar

Nhantumbo AA, Weldegebriel G, Katsande R, et al. Surveillance of impact of PCV-10 vaccine on pneumococcal meningitis in Mozambique, 2013–2015. PLoS One. 2017;12:e0177746.

 PubMed Web of Science ®Google Scholar

Massora S, Mucavele H, Lessa F, et al. Impact of 10-valent pneumococcal conjugate vaccine (PCV10) on invasive pneumococcal disease among children in Mozambique, 2008–2016. 11th International Symposium on Pneumococci and Pneumococcal Diseases 2018 Apr 15–19; Melbourne, Australia.

 Google Scholar

Mucavele H, Massora S, Lessa F, et al. Impact of 10-valent pneumococcal conjugate vaccine on radiologically confirmed pneumonia among children in Mozambique 11th International Symposium on Pneumococci and Pneumococcal Diseases; 2018 Apr 15–19; Melbourne, Australia.

 Google Scholar

KEMRI Wellcome Trust. Pneumococcal conjugate vaccine impact study (PCVIS) [internet]. Kenya: KWTRP; 2017 [cited 2017 Nov 29]. Available from: http://kemri-wellcome.org/programme/pcvis-2/

 Google Scholar

Silaba M, Ooko M, Bottomley C, et al. The impact of 10-valent pneumococcal conjugate vaccine (PCV10) on the incidence of radiologically-confirmed pneumonia and on pneumonia hospitalizations among children in Kilifi, Kenya. 10th International Symposium on Pneumococci and Pneumococcal Diseases; 2016 Jun 26–30; Glasgow, UK.

 Google Scholar

Hammitt LL, Akech DO, Morpeth SC, et al. Population effect of 10-valent pneumococcal conjugate vaccine on nasopharyngeal carriage of Streptococcus pneumoniae and non-typeable Haemophilus influenzae in Kilifi, Kenya: findings from cross-sectional carriage studies. Lancet Glob Health. 2014;2:e397–e405.

 PubMed Web of Science ®Google Scholar

Verani J, Bigogo G, Muema S, et al. Pneumonia-related mortality among children in an urban slum in Nairobi, Kenya following 10-valent pneumococcal conjugate vaccine introduction. 10th International Symposium on Pneumococci and Pneumococcal Diseases; 2016 Jun 26–30; Glasgow, UK.

 Google Scholar

Knol MJ, Wagenvoort GHJ, Sanders EAM, et al. Invasive pneumococcal disease 3 years after introduction of 10-valent pneumococcal conjugate vaccine, the Netherlands. Emerg Infect Dis. 2015;21:2040–2044.

 PubMed Web of Science ®Google Scholar

Netherlands Reference Laboratory for Bacterial Meningitis (AMC/RIVM). Pneumokokken [internet]. Amsterdam: RIVM; 2017 [cited 2017 Nov 29]. Available from: http://www.rivm.nl/Onderwerpen/P/Pneumokokken

 Google Scholar

Vestjens SMT, Wagenvoort GHJ, Grutters JC, et al. Changes in pathogens and pneumococcal serotypes causing community-acquired pneumonia in The Netherlands. Vaccine. 2017;35:4112–4118.

 PubMed Web of Science ®Google Scholar

Naucler P, Galanis I, Morfeldt E, et al. Comparison of the impact of Pneumococcal Conjugate Vaccine 10 or Pneumococcal Conjugate Vaccine 13 on invasive pneumococcal disease in equivalent populations. Clin Infect Dis. 2017;65:1780–1789.

 PubMed Web of Science ®Google Scholar

Berglund A, Ekelund M, Fletcher MA, et al. All-cause pneumonia hospitalizations in children <2 years old in Sweden, 1998 to 2012: impact of pneumococcal conjugate vaccine introduction. PLoS One. 2014;9:e112211.

 PubMed Web of Science ®Google Scholar

Gisselsson-Solen M. Trends in otitis media incidence after conjugate pneumococcal vaccination; a national observational study. Pediatr Infect Dis J. 2017;36:1027–1031.

 PubMed Web of Science ®Google Scholar

De Wals P, Lefebvre B, Markowski F, et al. Impact of 2+1 pneumococcal conjugate vaccine program in the province of Quebec, Canada. Vaccine. 2014;32:1501–1506.

 PubMed Web of Science ®Google Scholar

Zhou Z, Deceuninck G, Boucher F, et al. Impact of two pneumococcal conjugate vaccines on hospitalizations for lower-tract respiratory infections (LRTI) in Quebec, Canada. 9th International Symposium on Pneumococci & Pneumococcal Diseases; 2014 Mar 9–13; Hyderabad, India.

 Google Scholar

De Wals P, Fratu R, Defay F, et al. Frequency of visits for otitis media in Quebec: face-to-nape comparison of children exposed to PCV-7 or PHiD-CV. 31st Meeting of the European Society for Paediatric Infectious Diseases; 2013 May 28–Jun 1; Milan, Italy.

 Google Scholar

Leach AJ, Wigger C, Hare K, et al. Reduced middle ear infection with non-typeable Haemophilus influenzae, but not Streptococcus pneumoniae, after transition to 10-valent pneumococcal non-typeable H. influenzae protein D conjugate vaccine. BMC Pediatr. 2015;15:162.

 PubMed Web of Science ®Google Scholar

Institute of Environmental Science & Research Limited. Public health surveillance information for New Zealand public health action - invasive pneumococcal disease reports [internet]. New Zealand: Ministry of Health; 2014 [cited 2017 Nov 29]. Available from: https://surv.esr.cri.nz/surveillance/IPD.php

 Google Scholar

Almeida SC, Cassiolato AP, Amorim CS, et al. Increase in 19A and 6C serotypes after 5 years of PCV10 routine immunization in Brazil. 10th International Symposium on Pneumococci and Pnemococcal Diseases; 2016 Jun 26-30; Glasgow, UK.

 Google Scholar

Pan American Health Organization. SIREVA II regional reports [internet]. Washington (DC): PAHO; 2012 [cited 2017 Nov 29]. Available from: http://www.paho.org/hq/index.php?option=com_content&view=article&id=5536&Itemid=3966&lang=en

 Google Scholar

Schooley RT. Expression of concern relating to Naucler et al. Clin Infect Dis. 2018. DOI:10.1093/cid/ciy316

 Google Scholar

Sigurdsson S, Kristinsson KG, Erlendsdóttir H, et al. Decreased incidence of respiratory infections in children after vaccination with ten-valent pneumococcal vaccine. Pediatr Infect Dis J. 2015;34:1385–1390.

 PubMed Web of Science ®Google Scholar