Table 2 Open in new tab Quality...

PC vaccines	Quality assessment
LRTI specific mortality^e: Very low outcome specific quality of evidence^f
1 (HIV- children from Klugman et al.¹⁸)	RCT	Not designed to look at effect on mortality	n/a	Only 1 study	9-valent pneumococcal conjugate CRM-197	18	22	0.82 (0.44, 1.52)
All cause mortality^e: Very low outcome specific quality of evidence
2 (HIV- children from Cutts FT et al.¹⁷ and Klugman KP et al.¹⁸)	RCT	Not designed to look at effect on mortality and for 1 study per protocol analysis	Both studies show benefit	Only Africa	9-valent pneumococcal conjugate CRM-197	366	425	0.85 (0.74, 0.98)^g
Radiologically confirmed pneumonia^e: Moderate outcome specific quality of evidence
2 (HIV- children from Cutts FT et al.¹⁷ and Klugman KP et al.¹⁸)	RCT	No major	Heterogeneity from meta-analysis (P = 0.09); both studies show benefit	Only Africa	9-valent pneumococcal conjugate CRM-197	557	802	0.71 (0.58, 0.87)^h
1⁽¹⁹⁾	RCT	No major	n/a	Only 1 study	11-valent pneumococcal sanofi pasteur	119	141	0.84 (0.66, 1.07)
3 (Cuts et al.¹⁷, HIV- children from Klugman et al.¹⁸, Lucero et al.¹⁹)	RCT	See above	Heterogeneity from meta-analysis (P = 0.09); all studies show benefit	Africa, Asia	All valent	676	943	0.74 (0.63, 0.88)
Clinical severe pneumonia^e: Moderate outcome specific quality of evidence
2 (HIV-children from Cutts et al.¹⁷ and Klugman et al.¹⁸)	RCT	No major, for one study per protocol analysis	Both studies show benefit	Only Africa	9-valent pneumococcal conjugate CRM-197	763	854	0.89 (0.81, 0.98)
1⁽¹⁹⁾	RCT	No major	n/a	Only 1 study	11-valent pneumococcal sanofi pasteur	397	383	1.03 (0.90, 1.19)
3 (HIV-children from Cutts et al.¹⁷ and Klugman et al.¹⁸, Lucero et al.¹⁹)	RCT	See above	2 of 3 studies show benefit	Africa, Asia	All valent	1160	1237	0.93 (0.86, 1.01)
Clinical pneumonia^e: Moderate outcome specific quality of evidence
2 (HIV-children from Cutts et al.¹⁷ and Klugman et al.¹⁸)	RCT	No major, for one study per protocol analysis	Heterogeneity from meta-analysis (P = 0.08); both studies show benefit	Only Africa	9-valent pneumococcal conjugate CRM-197	2738	2965	0.89 (0.80, 0.99)
1⁽¹⁹⁾	RCT	No major	n/a	Only 1 study	11-valent pneumococcal sanofi pasteur	1093	1080	1.08 (0.93, 1.10)
3 (Cutts et al.¹⁷, HIV- children from Klugman et al.¹⁸, Lucero et al.¹⁹)	RCT	See above	Heterogeneity from meta-analysis (P = 0.03); 2 of 3 studies show benefit	Africa, Asia	All valent	3831	4045	0.93 (0.85, 1.02)

PC vaccines	Quality assessment
LRTI specific mortality^e: Very low outcome specific quality of evidence^f
1 (HIV- children from Klugman et al.¹⁸)	RCT	Not designed to look at effect on mortality	n/a	Only 1 study	9-valent pneumococcal conjugate CRM-197	18	22	0.82 (0.44, 1.52)
All cause mortality^e: Very low outcome specific quality of evidence
2 (HIV- children from Cutts FT et al.¹⁷ and Klugman KP et al.¹⁸)	RCT	Not designed to look at effect on mortality and for 1 study per protocol analysis	Both studies show benefit	Only Africa	9-valent pneumococcal conjugate CRM-197	366	425	0.85 (0.74, 0.98)^g
Radiologically confirmed pneumonia^e: Moderate outcome specific quality of evidence
2 (HIV- children from Cutts FT et al.¹⁷ and Klugman KP et al.¹⁸)	RCT	No major	Heterogeneity from meta-analysis (P = 0.09); both studies show benefit	Only Africa	9-valent pneumococcal conjugate CRM-197	557	802	0.71 (0.58, 0.87)^h
1⁽¹⁹⁾	RCT	No major	n/a	Only 1 study	11-valent pneumococcal sanofi pasteur	119	141	0.84 (0.66, 1.07)
3 (Cuts et al.¹⁷, HIV- children from Klugman et al.¹⁸, Lucero et al.¹⁹)	RCT	See above	Heterogeneity from meta-analysis (P = 0.09); all studies show benefit	Africa, Asia	All valent	676	943	0.74 (0.63, 0.88)
Clinical severe pneumonia^e: Moderate outcome specific quality of evidence
2 (HIV-children from Cutts et al.¹⁷ and Klugman et al.¹⁸)	RCT	No major, for one study per protocol analysis	Both studies show benefit	Only Africa	9-valent pneumococcal conjugate CRM-197	763	854	0.89 (0.81, 0.98)
1⁽¹⁹⁾	RCT	No major	n/a	Only 1 study	11-valent pneumococcal sanofi pasteur	397	383	1.03 (0.90, 1.19)
3 (HIV-children from Cutts et al.¹⁷ and Klugman et al.¹⁸, Lucero et al.¹⁹)	RCT	See above	2 of 3 studies show benefit	Africa, Asia	All valent	1160	1237	0.93 (0.86, 1.01)
Clinical pneumonia^e: Moderate outcome specific quality of evidence
2 (HIV-children from Cutts et al.¹⁷ and Klugman et al.¹⁸)	RCT	No major, for one study per protocol analysis	Heterogeneity from meta-analysis (P = 0.08); both studies show benefit	Only Africa	9-valent pneumococcal conjugate CRM-197	2738	2965	0.89 (0.80, 0.99)
1⁽¹⁹⁾	RCT	No major	n/a	Only 1 study	11-valent pneumococcal sanofi pasteur	1093	1080	1.08 (0.93, 1.10)
3 (Cutts et al.¹⁷, HIV- children from Klugman et al.¹⁸, Lucero et al.¹⁹)	RCT	See above	Heterogeneity from meta-analysis (P = 0.03); 2 of 3 studies show benefit	Africa, Asia	All valent	3831	4045	0.93 (0.85, 1.02)

Table 2

Quality assessment of studies of PC conjugate vaccines on pneumonia related outcomes

PC vaccines	Quality assessment
				Directness		No of events
No of studies (ref.)	Design	Limitations^a	Consistency^b	Generalizability to population of interest^c	Generalizability to intervention of interest^d	Intervention	Control	RR (95% CI)
LRTI specific mortality^e: Very low outcome specific quality of evidence^f
1 (HIV- children from Klugman et al.¹⁸)	RCT	Not designed to look at effect on mortality	n/a	Only 1 study	9-valent pneumococcal conjugate CRM-197	18	22	0.82 (0.44, 1.52)
All cause mortality^e: Very low outcome specific quality of evidence
2 (HIV- children from Cutts FT et al.¹⁷ and Klugman KP et al.¹⁸)	RCT	Not designed to look at effect on mortality and for 1 study per protocol analysis	Both studies show benefit	Only Africa	9-valent pneumococcal conjugate CRM-197	366	425	0.85 (0.74, 0.98)^g
Radiologically confirmed pneumonia^e: Moderate outcome specific quality of evidence
2 (HIV- children from Cutts FT et al.¹⁷ and Klugman KP et al.¹⁸)	RCT	No major	Heterogeneity from meta-analysis (P = 0.09); both studies show benefit	Only Africa	9-valent pneumococcal conjugate CRM-197	557	802	0.71 (0.58, 0.87)^h
1⁽¹⁹⁾	RCT	No major	n/a	Only 1 study	11-valent pneumococcal sanofi pasteur	119	141	0.84 (0.66, 1.07)
3 (Cuts et al.¹⁷, HIV- children from Klugman et al.¹⁸, Lucero et al.¹⁹)	RCT	See above	Heterogeneity from meta-analysis (P = 0.09); all studies show benefit	Africa, Asia	All valent	676	943	0.74 (0.63, 0.88)
Clinical severe pneumonia^e: Moderate outcome specific quality of evidence
2 (HIV-children from Cutts et al.¹⁷ and Klugman et al.¹⁸)	RCT	No major, for one study per protocol analysis	Both studies show benefit	Only Africa	9-valent pneumococcal conjugate CRM-197	763	854	0.89 (0.81, 0.98)
1⁽¹⁹⁾	RCT	No major	n/a	Only 1 study	11-valent pneumococcal sanofi pasteur	397	383	1.03 (0.90, 1.19)
3 (HIV-children from Cutts et al.¹⁷ and Klugman et al.¹⁸, Lucero et al.¹⁹)	RCT	See above	2 of 3 studies show benefit	Africa, Asia	All valent	1160	1237	0.93 (0.86, 1.01)
Clinical pneumonia^e: Moderate outcome specific quality of evidence
2 (HIV-children from Cutts et al.¹⁷ and Klugman et al.¹⁸)	RCT	No major, for one study per protocol analysis	Heterogeneity from meta-analysis (P = 0.08); both studies show benefit	Only Africa	9-valent pneumococcal conjugate CRM-197	2738	2965	0.89 (0.80, 0.99)
1⁽¹⁹⁾	RCT	No major	n/a	Only 1 study	11-valent pneumococcal sanofi pasteur	1093	1080	1.08 (0.93, 1.10)
3 (Cutts et al.¹⁷, HIV- children from Klugman et al.¹⁸, Lucero et al.¹⁹)	RCT	See above	Heterogeneity from meta-analysis (P = 0.03); 2 of 3 studies show benefit	Africa, Asia	All valent	3831	4045	0.93 (0.85, 1.02)

PC vaccines	Quality assessment
				Directness		No of events
No of studies (ref.)	Design	Limitations^a	Consistency^b	Generalizability to population of interest^c	Generalizability to intervention of interest^d	Intervention	Control	RR (95% CI)
LRTI specific mortality^e: Very low outcome specific quality of evidence^f
1 (HIV- children from Klugman et al.¹⁸)	RCT	Not designed to look at effect on mortality	n/a	Only 1 study	9-valent pneumococcal conjugate CRM-197	18	22	0.82 (0.44, 1.52)
All cause mortality^e: Very low outcome specific quality of evidence
2 (HIV- children from Cutts FT et al.¹⁷ and Klugman KP et al.¹⁸)	RCT	Not designed to look at effect on mortality and for 1 study per protocol analysis	Both studies show benefit	Only Africa	9-valent pneumococcal conjugate CRM-197	366	425	0.85 (0.74, 0.98)^g
Radiologically confirmed pneumonia^e: Moderate outcome specific quality of evidence
2 (HIV- children from Cutts FT et al.¹⁷ and Klugman KP et al.¹⁸)	RCT	No major	Heterogeneity from meta-analysis (P = 0.09); both studies show benefit	Only Africa	9-valent pneumococcal conjugate CRM-197	557	802	0.71 (0.58, 0.87)^h
1⁽¹⁹⁾	RCT	No major	n/a	Only 1 study	11-valent pneumococcal sanofi pasteur	119	141	0.84 (0.66, 1.07)
3 (Cuts et al.¹⁷, HIV- children from Klugman et al.¹⁸, Lucero et al.¹⁹)	RCT	See above	Heterogeneity from meta-analysis (P = 0.09); all studies show benefit	Africa, Asia	All valent	676	943	0.74 (0.63, 0.88)
Clinical severe pneumonia^e: Moderate outcome specific quality of evidence
2 (HIV-children from Cutts et al.¹⁷ and Klugman et al.¹⁸)	RCT	No major, for one study per protocol analysis	Both studies show benefit	Only Africa	9-valent pneumococcal conjugate CRM-197	763	854	0.89 (0.81, 0.98)
1⁽¹⁹⁾	RCT	No major	n/a	Only 1 study	11-valent pneumococcal sanofi pasteur	397	383	1.03 (0.90, 1.19)
3 (HIV-children from Cutts et al.¹⁷ and Klugman et al.¹⁸, Lucero et al.¹⁹)	RCT	See above	2 of 3 studies show benefit	Africa, Asia	All valent	1160	1237	0.93 (0.86, 1.01)
Clinical pneumonia^e: Moderate outcome specific quality of evidence
2 (HIV-children from Cutts et al.¹⁷ and Klugman et al.¹⁸)	RCT	No major, for one study per protocol analysis	Heterogeneity from meta-analysis (P = 0.08); both studies show benefit	Only Africa	9-valent pneumococcal conjugate CRM-197	2738	2965	0.89 (0.80, 0.99)
1⁽¹⁹⁾	RCT	No major	n/a	Only 1 study	11-valent pneumococcal sanofi pasteur	1093	1080	1.08 (0.93, 1.10)
3 (Cutts et al.¹⁷, HIV- children from Klugman et al.¹⁸, Lucero et al.¹⁹)	RCT	See above	Heterogeneity from meta-analysis (P = 0.03); 2 of 3 studies show benefit	Africa, Asia	All valent	3831	4045	0.93 (0.85, 1.02)

^aLimitations include comments on such aspects as blinding, placebo, how valid is the measure (i.e. self reported incidence vs. active case detection) for each study included.

^bConsistency is a summary measure of the heterogeneity of the meta-analysis and a short description applying judgment based on the overall directionality of the effect.

^cGeneralizability to population of interest examines the age of the children and the regions the studies were conducted in for each meta-analysis.

^dGeneralizability to intervention of interest examines how direct the intervention is measured.

^eOutcome definition for each study described in Supplementary Table 2b.

^fMore information about the quality grades is presented in Supplementary Table b.

^gMantel-Haenszel pooled RR, fixed effect meta-analysis.

^hDerSimonian-Laird pooled RR, random effect meta-analysis. The bold value indicates the fact that this outcome was used to infer the effect of Hib vaccines on pneumonia mortality.

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