A systematic literature review and network meta-analysis feasibility study to assess the comparative efficacy and comparative effectiveness of pneumococcal conjugate vaccines

Figures & data

Figure 1. Flow diagram of search results and study selection.

ISPPD, International Symposium on Pneumococci and Pneumococcal Diseases; RCT, randomised controlled trial; SLR, systematic literature review.

Table 1. Key study characteristics.

Author	Study design	Country	Arm name	Vaccine administered	N	Schedule	Dose
Black, 2000 Kaiser Permanente trial	RCT	US (Northern California)	PCV-7/intervention	Heptavalent pneumococcal conjugate, PCV-7	18,927	at 2, 4, 6 and 12 to 15 months of age	≥1 dose
			MCV/placebo	meningococcus type C conjugate vaccine	18,941	at 2, 4, 6 and 12 to 15 months of age	≥1 dose
Black, 2002 Kaiser Permanente trial	RCT	US (Northern California)	PCV-7/intervention	Heptavalent pneumococcal conjugate, PCV-7	18,927	at 2, 4, 6 and 12 to 15 months of age	≥1 dose
			MCV/placebo	meningococcus type C conjugate vaccine	18,941	at 2, 4, 6 and 12 to 15 months of age	≥1 dose
Shinefield, 2002 Kaiser Permanente trial	RCT	US (Northern California)	PCV-7/intervention	Heptavalent pneumococcal conjugate, PCV-7	18,927	at 2, 4, 6 and 12 to 15 months of age	≥1 dose
			MCV/placebo	meningococcus type C conjugate vaccine	18,941	at 2, 4, 6 and 12 to 15 months of age	≥1 dose
Tregnaghi, 2014 COMPAS, NCT00466947	RCT	Argentina, Panama, Colombia	PHiD-CV group	ten-valent pneumococcal non-typeable Haemophilus influenzae protein D conjugate vaccine (PHiD-CV)	23,821	3 + 1 PHiD-CV + DTPa-HBV-IPV/Hib at approx. 2, 4, 6 months and PHiD-CV + DTPa-IPV/Hib at 15–18 months	3 + 1
			Control group	Recombinant hepatitis B vaccine and hepatitis A vaccine	23,821	3 + 1 Hep B + DTPa-IPV/Hib at approx. 2, 4, 6 months and Hep A + DTPa-IPV/Hib at 15–18 months	3 + 1
Andrews, 2011	Indirect cohort	England and Wales	VT-IPD case	PCV-7	1,228	2-dose routine, at 2 and 4 months (evaluated for cases 5 months to <14 months); 2 dose older infants, at 3 and 8 months (evaluated for cases 5 months to <14 months); 2-dose routine + 1 (evaluated for cases ≥14 months); 2 dose older infants + 1 (evaluated for cases ≥14 months); 1-dose catch-up (evaluated for cases ≥14 months)	≥1 dose
			Non-VT-IPD control	PCV-7	1,228	2-dose routine, at 2 and 4 months (evaluated for cases 5 months to <14 months); 2-dose older infants, at 3 and 8 months (evaluated for cases 5 months to <14 months); 2-dose routine + 1 (evaluated for cases ≥14 months); 2-dose older infants + 1 (evaluated for cases ≥14 months); 1-dose catch-up (evaluated for cases ≥14 months)	≥1 dose
Andrews, 2014	Indirect cohort	England, Wales, Northern Ireland	VT-IPD case	PCV-13	716	2 + 1 schedule at 2, 4, and 12 months	≥1 dose
			Non-VT-IPD control	PCV-13	716	2 + 1 schedule at 2, 4, and 12 months	≥1 dose
De Serres, 2012	Indirect cohort	USA	VT-IPD case	PCV-7	1,447	according to age schedule	≥1 dose
			Non-VT-IPD control	PCV-7	1,233	according to age schedule	≥1 dose
Miller, 2011	Indirect cohort	England and Wales	VT-IPD case	PCV-13	264	according to age schedule, recommended schedule is 2 + 1 at 2, 4 and 13 months	≥ 1 dose
			Non-VT-IPD control	PCV-13	ND	according to age schedule, recommended schedule is 2 + 1 at 2, 4 and 13 months	≥ 1 dose
Ruckinger, 2010	Indirect cohort	Germany	VT-IPD case	PCV-7	30	according to age schedule, the recommended schedule is 3 + 1 at 2, 3, 4 and 11–14 months	≥1 dose
			Non-VT-IPD control	PCV-7	72	according to age schedule, the recommended schedule is 3 + 1 at 2, 3, 4 and 11–14 months	≥1 dose
van der Linden, 2016	Indirect cohort	Germany	VT-IPD case	PCV-7, PCV-13	617	according to age schedule, the recommended schedule is 3 + 1 at 2, 3, 4 and 11–14 months	≥1 dose
			Non-VT-IPD control	PCV-7, PCV-13	617	according to age schedule, the recommended schedule is 3 + 1 at 2, 3, 4 and 11–14 months	≥1 dose
Verani, 2015	Indirect cohort	Brazil	VT-IPD case	PHiD-CV	147	according to age, recommended PHiD-CV schedule includes 3 primary doses (2, 4, 6 months) + 1 booster (12 months). Catch-up schedules for children aged 3–11 months at the time of introduction included one to three primary doses (based on age) plus a booster dose; a single dose was recommended for children aged 12–23 months	≥1 dose
			VT-IPD case	PHiD-CV	75	according to age, recommended PHiD-CV schedule includes 3 primary doses (2, 4, 6 months) + 1 booster (12 months). Catch-up schedules for children aged 3–11 months at the time of introduction included one to three primary doses (based on age) plus a booster dose; a single dose was recommended for children aged 12–23 months	≥1 dose
			Non-VT-IPD control	PHiD-CV	94	according to age, recommended PHiD-CV schedule includes 3 primary doses (2, 4, 6 months) + 1 booster (12 months). Catch-up schedules for children aged 3–11 months at the time of introduction included one to three primary doses (based on age) plus a booster dose; a single dose was recommended for children aged 12–23 months	≥1 dose
Barricarte, 2007	Case-control	Spain	IPD case	PCV-7	85	3 PCV-7 doses, if the first dose occurred at 2–6 months of age; 2 doses, if the first dose occurred at 7–23 months of age; and 1 dose, if the first dose occurred at ≥24 months of age; a booster in the second year was also required for children who began vaccination before 12 months of age	≥1 dose
			Non-IPD control	PCV-7	425	3 PCV-7 doses, if the first dose occurred at 2–6 months of age; 2 doses, if the first dose occurred at 7–23 months of age; and 1 dose, if the first dose occurred at ≥24 months of age; a booster in the second year was also required for children who began vaccination before 12 months of age	≥1 dose
Ciruela, 2013	Case-control	Spain	IPD case	PCV-7	293	according to age schedule. PCV-7 has not been introduced into Spanish routine vaccination schedules (except for the community of Madrid in 2006), although the Spanish Paediatric Association recommends its use in children aged <2 years, with doses at 2, 4, 6 and 12–15 months. Schedule assumed to be 3 + 1 at months 2, 4, 6, and a booster at 12–15 months	≥1 dose
			Non-IPD control	PCV-7	782	according to age schedule. PCV-7 has not been introduced into Spanish routine vaccination schedules (except for the community of Madrid in 2006), although the Spanish Paediatric Association recommends its use in children aged <2 years, with doses at 2, 4, 6 and 12–15 months. Schedule assumed to be 3 + 1 at months 2, 4, 6, and a booster at 12–15 months	≥1 dose
Cohen, 2014	Case-control	South Africa	IPD case	PCV-7	237	2 + 1 schedule at 6 weeks, 14 weeks and 9 months	≥1 dose
			Non-IPD control	PCV-7	928	2 + 1 schedule at 6 weeks, 14 weeks and 9 months	≥1 dose
Deceuninck, 2010	Case-control	Canada	IPD case	PCV-7	298	Recommended schedule is 2 + 1 at 2, 4, and 12 months	≥1 dose
			Non-IPD control	PCV-7	4,549	Recommended schedule is 2 + 1 at 2, 4, and 12 months	≥1 dose
Deceuninck, 2015	Case-control	Canada	IPD case	PCV-7, PHiD-CV and PCV-13	889	Recommended schedule is 2 + 1 at 2, 4, and 12 months for PCV-7. For PHiD-CV and PCV-13, the recommended schedule is 2 + 1 at 2, 4 and 12 months	≥1 dose
			Non-IPD control	PCV-7, PHiD-CV and PCV-13	7,962	Recommended schedule is 2 + 1 at 2, 4, and 12 months for PCV-7. For PHiD-CV and PCV-13, the recommended schedule is 2 + 1 at 2, 4 and 12 months	≥1 dose
Domingues, 2014	Case-control	Brazil	IPD case	PHiD-CV	398	3 + 1, with three primary doses at 2, 4, and 6 months and a booster at 12 months	≥1 dose
			Non-IPD control	PHiD-CV	1,258	3 + 1, with three primary doses at 2, 4, and 6 months and a booster at 12 months	≥1 dose
Dominguez, 2011	Case-control	Spain	IPD case	PCV-7	293	Complete vaccination schedule is 3 doses at 2, 4, and 6 months and a fourth dose at 15 months, or 2 doses at least two months apart in children aged 12–23 months, or a single dose in children aged >24 months	≥1 dose
			Non-IPD control	PCV-7	751	Complete vaccination schedule is 3 doses at 2, 4, and 6 months and a fourth dose at 15 months, or 2 doses at least two months apart in children aged 12–23 months, or a single dose in children aged >24 months	≥1 dose
Fortunato, 2015	Case-control	Italy	IPD case	PCV-7 and PCV-13	39	3 PCV-13 doses at 3, 5–6, and 11–13 months of age. Children who had received one or two doses of PCV-7 completed their immunisation series with PCV-13. One PCV-13 catch-up dose was recommended for children fully vaccinated with PCV-7	≥3 doses
			Non-IPD control	PCV-7 and PCV-13	117	3 PCV-13 doses at 3, 5–6, and 11–13 months of age. Children who had received one or two doses of PCV-7 completed their immunisation series with PCV-13. One PCV-13 catch-up dose was recommended for children fully vaccinated with PCV-7	≥3 doses
Guevara, 2016	Case-control	Spain	IPD case	PCV-13	34	3 + 1, 3 doses at 2, 4, and 6 months and a booster dose at 12–15 months	≥1 dose
			Non-IPD control	PCV-13	272	3 + 1, 3 doses at 2, 4, and 6 months and a booster dose at 12–15 months	≥1 dose
Moore, 2016	Case-control	USA	IPD case	PCV-7, PCV-13	1,344	according to age schedule and the recommended schedule has 4 doses. PCV-7 was introduced in 2000, using a schedule of doses at 2, 4, 6 and 12–15 months of age. In 2010, PCV-13 replaced PCV-7 in the USA infant immunisation schedule	≥1 dose
			Non-IPD control	PCV-7, PCV-13	14,296	according to age schedule and the recommended schedule has 4 doses. PCV-7 was introduced in 2000, using a schedule of doses at 2, 4, 6 and 12–15 months of age. In 2010, PCV-13 replaced PCV-7 in the USA infant immunisation schedule	≥1 dose
Picon, 2013	Case-control	Uruguay	VT-IPD case	PCV-7	44	2 + 1 (2, 4, and 12 months) and a catch-up campaign with two doses (15 and 17 months)	≥1 dose
			Non-VT-IPD control	PCV-7	637	2 + 1 (2, 4, and 12 months) and a catch-up campaign with two doses (15 and 17 months)	≥1 dose
Pilishvili, 2010	Case-control	USA	IPD/VT-IPD case	PCV-7	1,267	≥1 dose	≥1 dose
			Non-IPD/non-VT-IPD control	PCV-7	8,018	≥1 dose	≥1 dose
Su, 2016	Case-control	Taiwan	IPD case	PCV-7, PHiD-CV and PCV-13	555	3 + 1 schedule, or one dose of catch-up schedule, or two doses of catch-up schedule, or 2 + 1 schedule	≥1 dose
			Non-IPD control	PCV-7, PHiD-CV and PCV-13	2,092	3 + 1 schedule, or one dose of catch-up schedule, or two doses of catch-up schedule, or 2 + 1 schedule	≥1 dose
von Mollendorf, 2015	Case-control	South Africa	IPD case	PCV-7	486	≥2 doses	≥2 doses
			Non-IPD control	PCV-7	2,037	≥2 doses	≥2 doses
Whitney, 2006	Case-control	USA	IPD case	PCV-7	1,267	≥1 dose, different schedules are possible but the recommended schedule is 3 + 1 at 2, 4, 6 and 12–15 months	≥1 dose
			Non-IPD control	PCV-7	8,018	≥1 dose, different schedules are possible	≥1 dose

Figure 2. Summary of risk of bias assessment for (a) RCTs using the Cochrane risk of bias tool and (b) non-RCTs using the Newcastle-Ottawa scale.

RCT, randomized controlled trial.

Figure 3. Overall network for included studies.

PCV-7, 7-valent pneumococcal conjugate vaccine; PCV-13, 13-valent pneumococcal conjugate vaccine; PHiD-CV, pneumococcal non-typeable Haemophilus influenzae protein D conjugate vaccine; RCT, randomized controlled trial. *It cannot be assumed that exposure is solely PCV-13

Table 2. Subject characteristics reported across studies.

Study	Age	Sex	Race^a	CM	Premature birth	IC	Urban/rural
RCT
Kaiser Permanente trial^Citation17-Citation19					●
COMPAS trial^Citation20	●	●	●	●			●
Indirect cohort studies
Andrews 2011^Citation21		●	●	●	●
Andrews 2014^Citation22
De Serres 2012^Citation23		●		●
Miller 2011^Citation24
Ruckinger 2010^Citation25	●	●		●
van der Linden 2016^Citation26		●
Verani 2015^Citation27	●			●	●	●
Case-control studies
Barricarte 2007^Citation28		●					●
Ciruela 2013^Citation29		●		●		●
Cohen 2014^Citation30	●	●		●	●
Deceuninck 2010^Citation31			●	●	●
Deceuninck 2015^Citation32
Domingues 2014^Citation33	●	●		●	●	●
Dominguez 2011^Citation34		●		●
Fortunato 2015^Citation35		●
Guevara 2016^Citation36	●	●		●	●		●
Moore 2016^Citation37	●	●	●	●	●	●
Picon 2013^Citation38	●	●
Su 2016^Citation39	●	●		●
von Mollendorf 2015^Citation40				●
Whitney 2006, Pilishvili 2010^Citation41,Citation42	●	●	●	●	●	●

^a% caucasian CM, co-morbidities; IC, immunocompromised; RCT, randomised controlled trial

Figure 4. Summary of context, outcomes, and impact for health-care providers.

Table

AOM	acute otitis media
CDSR	Cochrane Database of Systematic Reviews
CIQ	Comité sur l’immunisation du Québec
CM	co-morbidities
IC	immunocompromised
DTPa-HBV-IPV/Hib	diphtheria, tetanus, acellular pertussis, hepatitis B, inactivated poliomyelitis, and Haemophilus influenzae type b
IPD	invasive pneumococcal disease
ISPPD	International Symposium on Pneumococci and Pneumococcal Diseases
MCV	meningococcus type C conjugate vaccine
NACI	National Advisory Committee on Immunization
NMA	network meta-analysis
PCV	pneumococcal conjugate vaccine
PCV-7	7-valent pneumococcal conjugate vaccine
PCV-13	13-valent pneumococcal conjugate vaccine
PHiD-CV	pneumococcal non-typeable Haemophilus influenzae protein D conjugate vaccine
PICOS	Population, Intervention, Comparators, Outcomes, Study design
RCT	randomised controlled trial
SAGE	Strategic Advisory Group of Experts on Immunization
VT	vaccine-type
WHO	World Health Organization

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