Pneumococcal polysaccharide vaccines: Systematic review and meta-analysis of randomised controlled efficacy trials Pippa Scott, Anke Huss, Matthias Egger Institute of Social & Preventive Medicine (ISPM) University of Bern Switzerland egger@ispmunibech, pscott@ispmunibech
Background > At least 16 meta-analyses (+ countless reviews) > Four reviews of these meta-analyses have been published > These reviews stress Difficulty in accurate diagnosis and incomplete investigation of all cases Errors in data extraction Low power Inclusion/exclusion of trials affect findings 2
Meta-analyses vary in 1) Populations studied 2) Outcomes considered 3) Quality of analysis - only 5 report heterogeneity in all analyses 3
Methods: Search > In June/July 2007: Embase/ Medline (searched for RCTs) Cochrane References lists IndMed AIM LILACS > Key words: Pneumococcal vaccine/ immunisation Polysaccharide 4
Inclusion/ exclusion > Included: RCTs Comparing polysaccharide pneumococcal vaccine (PPV) with placebo/ no intervention/ other vaccine Reporting on relevant disease outcomes > Excluded RCTs if: Outcome was antibody response only PPV was used only as a booster after the conjugate vaccine Study population consisted only of children < 2 years Uncontrolled studies Observational studies Animal / lab studies 5
Data extraction > Study population / country > Interventions > Sample size, loss to follow up > Outcomes > Methodological quality of the trial Concealment of allocation sequence Blinding 6
Definitions > Allocation concealment - Where the persons allocating participants to interventions are unaware of which group the person is being allocated to, thus limiting potential for intervention groups to be systematically different at baseline (selection bias) Blinding - Where trial participants and/or trial staff are unaware of which intervention was given, thus limiting the potential for differences in outcome ascertainment between the intervention groups (ascertainment bias) 7
Data extraction > Extraction of all items in duplicate > Blinded assessment of study quality > Discrepancies resolved by consensus 8
Results: Trial flow 516 studies identified: 269 Embase and Medline 7 Cochrane 63 from references lists 22 LILACS 1 AIM IndMed excluded: 73 duplicates 73 conjugate vaccine only 202 were not RCT s 74 a did not report clinically relevant outcomes (usually antibody response only) 1 PPV used as booster only 1 conference proceedings 1 only children up to 9 month of age 91 potentially eligible trials identified after screening of title and abstract 65 Excluded after screening the full text: 40 were not RCT s 8 were only conference proceedings, editorials or short letters 6 did not report clinically relevant outcomes 5 reported a follow-up of a subpopulation only, or of an earlier trial phase, or an additional data analysis 2 were in children under 2 yrs of age 2 used PPV only as booster vaccination 1 reported only pilot phase of trial Included 27 publications, reporting 31 trials (2 with 2 trials, 1 with 3 trials) 9
Summary of outcomes Outcome No of trials reporting this outcome Combined n of study population for this outcome Definitive pneumococcal pneumonia 2 794 7 Presumptive p pneumonia 11 56564 589 Pneumonia, all causes 20 83517 2729 Bronchitis 4 20589 1689 Mortality all cause 51098 96 Mortality due to pneumonia 10 39117 251 Mortality due to pneumoc infection 4 16,041 18 Bacteraemia 8 32,869 50 Combined number of cases in both vaccinees and controls Meningitis None of the studies reported meningitis as an outcome Otitis media 5 18 170 Adverse events Many of the studies reported only a comment, eg no serious side effects were reported 10
Study characteristics I > Years Publications between 1941 and 2006 Some up to 15 years delay between trial and publication > Control interventions Placebo (19) No intervention (8) Other vaccine (7) (3 trials had placebo and vaccine control groups) > Total sample size (all studies) 107,000 54,500 vaccinees, 52,500 controls > Total number of cases: wide range All-cause mortality: 96 cases (1192 in vacc, 04 in controls) Definitive pneumococcal pneumonia: 7 (2 in vacc, 5 in controls) 11
valency by start of project Valency of vaccine 2 6 1935 1945 1955 1965 1975 1985 1995 2005 year trial started
Sample > Study population COPD patients (4) Children (9) Adults, some including elderly, chronic illness (6) Hospitalised, living in a home (3), Young gold miners (3), HIV+ developing (1), Soldiers (4) PNG aged > 10 (1) > Demographics 20/31 (65%) report range and/or mean age 20/31 (65%) report sex distribution 13
Trial countries
Quality I > Concealment of allocation Reported by / 31 (45%) In 9 we thought it was adequate (30%) > Blinding 13 (42%) reported a double-blind design and were placebocontrolled 10 (32%) did not report double-blinding, but were placebocontrolled 8 (26%) were unblinded and not placebo-controlled 15
All cause pneumonia All cause pneum Sorted by trial by start yearof study Pneumococcal polysaccharide vaccination Study ID RR (95% CI) vaccinees controls efficacy (%) valency Kaufman 1947 044 (034, 057) 85/4750 164/4033 56 (43, 66) 3 Austrian 1976 045 (035, 058) 83/93 182/80 55 (42, 65) 13 Smit a 1977 063 (044, 091) 37/983 1/2036 37 (9, 56) 6 Austrian a 1980 2 (100, 149) 154/607 4/693-22 (-49, -0) Riley 1977 076 (049, 117) 36/5946 48/60 24 (-17, 51) Smit b 1977 068 (032, 142) 9/540 28/1135 32 (-42, 68) Austrian b 1980 098 (083, 116) 268/6782 274/6818 2 (-16, 17) Davis 1987 061 (019, 194) 4/50 7/53 39 (-94, 81) Gaillat 1985 0 (011, 048) 9/937 31/749 77 (52, 89) Douglas 1984 133 (030, 592) 4/426 3/426-33 (-492, 70) Simberkoff 1986 137 (092, 204) 56/15 41/1150-37 (-104, 8) Koivula 1997 1 (083, 157) 73/1364 69/73 - (-57, 17) Örtqvist 1998 115 (083, 159) 63/339 57/352-15 (-59, 17) Honkanen 1999 116 (091, 148) 5/13980 116/945-16 (-48, 9) French 2000 189 (119, 300) 50/667 26/656-89 (-200, -19) Zhogolev a 2003 073 (0, 237) 4/99 8/5 27 (-137, 77) Zhogolev c 2003 021 (0, 033) 24/990 90/787 79 (67, 86) Zhogolev b 2003 030 (020, 046) 27/422 85/405 70 (54, 80) Alfageme 2006 096 (065, 141) 43/300 45/300 4 (-41, 35) Steentoft 2006 071 (031, 164) 11/37 5/ 29 (-64, 69) Overall (I-squared = 891%, p = 0000) 074 (057, 094) 1185/41857 1544/41660 26 (6, 43) NOTE: Weights are from random effects analysis 5 25 5 1 2 4 8 Reduced risk Increased risk 16
All cause pneumonia By % of controls with pneumonia Pneumococcal polysaccharide vaccination Sorted by incidence of pneumonia in controls over study period Study ID RR (95% CI) vaccinees controls efficacy (%) valency Douglas 1984 Riley 1977 Honkanen 1999 low 133 (030, 592) 076 (049, 117) 116 (091, 148) 4/426 36/5946 5/13980 3/426 48/60 116/945-33 (-492, 70) 24 (-17, 51) -16 (-48, 9) Simberkoff 1986 137 (092, 204) 56/15 41/1150-37 (-104, 8) French 2000 189 (119, 300) 50/667 26/656-89 (-200, -19) Austrian b 1980 098 (083, 116) 268/6782 274/6818 2 (-16, 17) Kaufman 1947 044 (034, 057) 85/4750 164/4033 56 (43, 66) 3 Gaillat 1985 0 (011, 048) 9/937 31/749 77 (52, 89) Koivula 1997 1 (083, 157) 73/1364 69/73 - (-57, 17) Smit b 1977 068 (032, 142) 9/540 28/1135 32 (-42, 68) Zhogolev a 2003 073 (0, 237) 4/99 8/5 27 (-137, 77) Zhogolev c 2003 021 (0, 033) 24/990 90/787 79 (67, 86) Smit a 1977 063 (044, 091) 37/983 1/2036 37 (9, 56) 6 Austrian 1976 045 (035, 058) 83/93 182/80 55 (42, 65) 13 Davis 1987 061 (019, 194) 4/50 7/53 39 (-94, 81) Alfageme 2006 096 (065, 141) 43/300 45/300 4 (-41, 35) Örtqvist 1998 115 (083, 159) 63/339 57/352-15 (-59, 17) Austrian a 1980 2 (100, 149) 154/607 4/693-22 (-49, -0) Zhogolev b 2003 Steentoft 2006 high 030 (020, 046) 071 (031, 164) 27/422 11/37 85/405 5/ 70 (54, 80) 29 (-64, 69) Overall (I-squared = 891%, p = 0000) 074 (057, 094) 1185/41857 1544/41660 26 (6, 43) NOTE: Weights are from random effects analysis 5 25 5 1 2 4 8 Reduced risk Increased risk 17
All cause pneumonia By developing/developed By trial country setting Pneumococcal polysaccharide vaccination Study ID RR (95% CI) vaccinees controls efficacy (%) valency Developed Kaufman 1947 044 (034, 057) 85/4750 164/4033 56 (43, 66) 3 Austrian b 1980 098 (083, 116) 268/6782 274/6818 2 (-16, 17) Austrian a 1980 2 (100, 149) 154/607 4/693-22 (-49, -0) Douglas 1984 133 (030, 592) 4/426 3/426-33 (-492, 70) Gaillat 1985 0 (011, 048) 9/937 31/749 77 (52, 89) Simberkoff 1986 137 (092, 204) 56/15 41/1150-37 (-104, 8) Davis 1987 061 (019, 194) 4/50 7/53 39 (-94, 81) Koivula 1997 1 (083, 157) 73/1364 69/73 - (-57, 17) Örtqvist 1998 115 (083, 159) 63/339 57/352-15 (-59, 17) Honkanen 1999 116 (091, 148) 5/13980 116/945-16 (-48, 9) Alfageme 2006 096 (065, 141) 43/300 45/300 4 (-41, 35) Steentoft 2006 071 (031, 164) 11/37 5/ 29 (-64, 69) Subtotal (I-squared = 829%, p = 0000) 089 (070, 1) 915/30717 956/29004 11 (-, 30) Developing Austrian 1976 045 (035, 058) 83/93 182/80 55 (42, 65) 13 Smit a 1977 063 (044, 091) 37/983 1/2036 37 (9, 56) 6 Riley 1977 076 (049, 117) 36/5946 48/60 24 (-17, 51) Smit b 1977 068 (032, 142) 9/540 28/1135 32 (-42, 68) French 2000 189 (119, 300) 50/667 26/656-89 (-200, -19) Subtotal (I-squared = 863%, p = 0000) 076 (047, 5) 215/9629 405/11319 24 (-25, 53) Undefined Zhogolev c 2003 021 (0, 033) 24/990 90/787 79 (67, 86) Zhogolev a 2003 073 (0, 237) 4/99 8/5 27 (-137, 77) Zhogolev b 2003 030 (020, 046) 27/422 85/405 70 (54, 80) Subtotal (I-squared = 532%, p = 0118) 029 (018, 047) 55/1511 183/1337 71 (53, 82) Overall (I-squared = 891%, p = 0000) 074 (057, 094) 1185/41857 1544/41660 26 (6, 43) NOTE: Weights are from random effects analysis 5 25 5 1 2 4 8 Reduced risk Increased risk 18
All cause pneumonia By study population Study ID RR (95% CI) vaccinees controls efficacy (%) valency COPD or brochogenic carcinoma Davis 1987 Steentoft 2006 Alfageme 2006 Subtotal (I-squared = 00%, p = 0665) HIV positive French 2000 Subtotal (I-squared = %, p = ) Children Douglas 1984 Subtotal (I-squared = %, p = ) Miners or soldiers Austrian 1976 Smit b 1977 Smit a 1977 Zhogolev c 2003 Zhogolev a 2003 Zhogolev b 2003 Subtotal (I-squared = 742%, p = 0002) Chronic illness or elderly Kaufman 1947 Austrian a 1980 Austrian b 1980 Gaillat 1985 Simberkoff 1986 Koivula 1997 Örtqvist 1998 Honkanen 1999 Subtotal (I-squared = 889%, p = 0000) >10yo in Papua New Guinea Riley 1977 Subtotal (I-squared = %, p = ) Overall (I-squared = 891%, p = 0000) NOTE: Weights are from random effects analysis 061 (019, 194) 4/50 7/53 39 (-94, 81) 071 (031, 164) 11/37 5/ 29 (-64, 69) 096 (065, 141) 43/300 088 (063, 1) 58/387 45/300 57/365 4 (-41, 35) (-, 37) 189 (119, 300) 50/667 26/656-89 (-200, -19) 189 (119, 300) 50/667 26/656-89 (-200, -19) 133 (030, 592) 4/426 133 (030, 592) 4/426 3/426 3/426-33 (-492, 70) -33 (-492, 70) 045 (035, 058) 83/93 068 (032, 142) 9/540 182/80 28/1135 55 (42, 65) 32 (-42, 68) 13 063 (044, 091) 37/983 021 (0, 033) 24/990 073 (0, 237) 4/99 1/2036 90/787 8/5 37 (9, 56) 79 (67, 86) 27 (-137, 77) 6 030 (020, 046) 27/422 85/405 70 (54, 80) 042 (029, 061) 184/4527 5/5988 58 (39, 71) 044 (034, 057) 85/4750 2 (100, 149) 154/607 098 (083, 116) 268/6782 164/4033 4/693 274/6818 56 (43, 66) -22 (-49, -0) 2 (-16, 17) 3 0 (011, 048) 9/937 31/749 77 (52, 89) 137 (092, 204) 56/15 41/1150-37 (-104, 8) 1 (083, 157) 73/1364 69/73 - (-57, 17) 115 (083, 159) 63/339 116 (091, 148) 5/13980 57/352 116/945-15 (-59, 17) -16 (-48, 9) 090 (067, 0) 853/29904 896/28213 10 (-20, 33) 076 (049, 117) 36/5946 48/60 24 (-17, 51) 076 (049, 117) 36/5946 48/60 24 (-17, 51) 074 (057, 094) 1185/41857 1544/41660 26 (6, 43) 19
All cause pneumonia By adequate By concealment of allocation Pneumococcal polysaccharide vaccination Study ID RR (95% CI) vaccinees controls efficacy (%) valency Unclear Kaufman 1947 Austrian 1976 Smit b 1977 Smit a 1977 Austrian a 1980 Gaillat 1985 Davis 1987 Koivula 1997 Honkanen 1999 French 2000 Zhogolev a 2003 Zhogolev c 2003 Zhogolev b 2003 Alfageme 2006 Subtotal (I-squared = 915%, p = 0000) Adequate Riley 1977 Austrian b 1980 Douglas 1984 Simberkoff 1986 Örtqvist 1998 Steentoft 2006 Subtotal (I-squared = 92%, p = 0357) Overall (I-squared = 891%, p = 0000) 044 (034, 057) 85/4750 164/4033 56 (43, 66) 3 045 (035, 058) 83/93 182/80 55 (42, 65) 13 068 (032, 142) 9/540 28/1135 32 (-42, 68) 063 (044, 091) 37/983 1/2036 37 (9, 56) 6 2 (100, 149) 154/607 4/693-22 (-49, -0) 0 (011, 048) 9/937 31/749 77 (52, 89) 061 (019, 194) 4/50 7/53 39 (-94, 81) 1 (083, 157) 73/1364 69/73 - (-57, 17) 116 (091, 148) 5/13980 116/945-16 (-48, 9) 189 (119, 300) 50/667 26/656-89 (-200, -19) 073 (0, 237) 4/99 8/5 27 (-137, 77) 021 (0, 033) 24/990 90/787 79 (67, 86) 030 (020, 046) 27/422 85/405 70 (54, 80) 096 (065, 141) 43/300 45/300 4 (-41, 35) 064 (046, 090) 747/27182 1116/26890 36 (10, 54) 076 (049, 117) 36/5946 48/60 24 (-17, 51) 098 (083, 116) 268/6782 274/6818 2 (-16, 17) 133 (030, 592) 4/426 3/426-33 (-492, 70) 137 (092, 204) 56/15 41/1150-37 (-104, 8) 115 (083, 159) 63/339 57/352-15 (-59, 17) 071 (031, 164) 11/37 5/ 29 (-64, 69) 102 (088, 118) 438/675 428/770-2 (-18, ) 074 (057, 094) 1185/41857 1544/41660 26 (6, 43) NOTE: Weights are from random effects analysis 5 25 5 1 2 4 8 Reduced risk Increased risk 20
By blinding All cause pneumonia By blinding Study ID RR (95% CI) vaccinees controls efficacy (%) valency Unblinded Kaufman 1947 Gaillat 1985 Zhogolev b 2003 Zhogolev a 2003 Zhogolev c 2003 Alfageme 2006 Steentoft 2006 Subtotal (I-squared = 825%, p = 0000) Not described as double blind;placebo/vaccine controlled Austrian 1976 Smit a 1977 Smit b 1977 Austrian b 1980 Koivula 1997 Honkanen 1999 Subtotal (I-squared = 875%, p = 0000) Described as double blind;also controlled Riley 1977 Austrian a 1980 Douglas 1984 Simberkoff 1986 Davis 1987 Örtqvist 1998 French 2000 Subtotal (I-squared = 399%, p = 06) Overall (I-squared = 891%, p = 0000) 044 (034, 057) 85/4750 0 (011, 048) 9/937 030 (020, 046) 27/422 164/4033 31/749 85/405 56 (43, 66) 77 (52, 89) 70 (54, 80) 3 073 (0, 237) 4/99 021 (0, 033) 24/990 8/5 90/787 27 (-137, 77) 79 (67, 86) 096 (065, 141) 43/300 071 (031, 164) 11/37 043 (027, 067) 203/7535 045 (035, 058) 83/93 45/300 5/ 428/6431 182/80 4 (-41, 35) 29 (-64, 69) 57 (33, 73) 55 (42, 65) 13 063 (044, 091) 37/983 1/2036 37 (9, 56) 6 068 (032, 142) 9/540 098 (083, 116) 268/6782 28/1135 274/6818 32 (-42, 68) 2 (-16, 17) 1 (083, 157) 73/1364 69/73 - (-57, 17) 116 (091, 148) 5/13980 081 (058, 1) 615/252 116/945 790/25887-16 (-48, 9) 19 (-, 42) 076 (049, 117) 36/5946 48/60 24 (-17, 51) 2 (100, 149) 154/607 4/693-22 (-49, -0) 133 (030, 592) 4/426 3/426-33 (-492, 70) 137 (092, 204) 56/15 41/1150-37 (-104, 8) 061 (019, 194) 4/50 7/53 39 (-94, 81) 115 (083, 159) 63/339 57/352-15 (-59, 17) 189 (119, 300) 50/667 26/656-89 (-200, -19) 119 (097, 147) 367/9180 326/9342-19 (-47, 3) 074 (057, 094) 1185/41857 1544/41660 26 (6, 43) NOTE: Weights are from random effects analysis 5 25 5 1 2 4 8 Reduced risk Increased risk 21
Presumptive pneumococcal pneumonia Presumptive pneumococcal By blinding pneumonia Pneumococcal polysaccharide vaccination Study ID RR (95% CI) vaccinees controls efficacy (%) valency Unblinded, not placebo-controlled Alfageme 2006 009 (001, 164) 0/300 5/300 91 (-64, 99) Subtotal (I-squared = %, p = ) 009 (001, 164) 0/300 5/300 91 (-64, 99) Not reported to be double blind, placebo-controlled MacLeod 1945 069 (050, 097) 60/8586 85/8449 31 (3, 50) 4 Austrian 1976 041 (029, 058) 44/93 106/80 59 (42, 71) 13 Smit a 1977 024 (0, 049) 9/983 38/985 76 (51, 88) 6 Smit b 1977 006 (001, 048) 1/540 16/550 94 (52, 99) Klastersky 1986 040 (008, 199) 2/26 4/21 60 (-99, 92) 17 Koivula 1997 085 (051, 141) 26/1364 33/73 15 (-41, 49) Honkanen 1999 0 (080, 182) 52/13980 40/945-20 (-82, 20) Subtotal (I-squared = 798%, p = 0000) Reported to be double blind, placebo-controlled 054 (033, 086) 194/26972 322/25903 46 (, 67) Simberkoff 1986 107 (053, 216) 16/15 15/1150-7 (-116, 47) Davis 1987 529 (026, 10763) 2/50 0/53-429 (-10663, 74) Örtqvist 1998 1 (064, 236) 19/339 16/352 - (-136, 36) Subtotal (I-squared = 00%, p = 0593) 0 (075, 192) 37/1534 31/1555-20 (-92, 25) Overall (I-squared = 744%, p = 0000) 064 (043, 096) 1/28806 358/27758 36 (4, 57) NOTE: Weights are from random effects analysis Reduced risk 5 25 5 1 2 4 8 Increased risk 22
All cause mortality All-cause mortality By blinding Pneumococcal polysaccharide vaccination Study ID RR (95% CI) vaccinees controls efficacy (%) valency Unblinded, not placebo-controlled Kaufman 1947 Gaillat 1985 Alfageme 2006 Subtotal (I-squared = 757%, p = 0016) Not reported to be double blind, placebo-controlled Austrian b 1980 Koivula 1997 Subtotal (I-squared = 00%, p = 0908) Reported to be double blind, placebo-controlled Riley 1977 Austrian a 1980 Riley 1981 Riley 1986 Simberkoff 1986 Davis 1987 Leech 1987 Örtqvist 1998 French 2000 Subtotal (I-squared = 492%, p = 0046) Overall (I-squared = 458%, p = 0031) 053 (034, 083) 32/4750 51/4033 47 (17, 66) 3 106 (089, 6) 2/937 175/749-6 (-26, 11) 098 (071, 137) 57/300 58/300 2 (-37, 29) 086 (060, 1) 321/5987 284/5082 (-, 40) 096 (064, 145) 45/6782 099 (080, 2) 152/1364 098 (082, 118) 197/86 47/6818 166/73 213/8291 4 (-45, 36) 1 (-22, 20) 2 (-18, 18) 079 (063, 099) 133/5946 093 (060, 143) 35/607 170/60 43/693 21 (1, 37) 7 (-43, 40) 065 (030, 139) 10/401 071 (050, 101) 51/2445 18/470 71/2417 35 (-39, 70) 29 (-1, 50) 4 (103, 149) 211/15 171/1150-24 (-49, -3) 1 (060, 218) /50 13/53 - (-118, 40) 058 (022, 149) 6/92 11/97 42 (-49, 78) 108 (065, 177) 29/339 28/352-8 (-77, 35) 100 (084, 119) 185/667 182/656 0 (-19, 16) 094 (080, 110) 674/11692 707/11900 6 (-10, 20) 094 (084, 105) 1192/25825 04/25273 6 (-5, 16) NOTE: Weights are from random effects analysis 5 25 5 1 2 4 8 Reduced risk Increased risk
Bacteraemia, septicaemia or invasive pneumococcal disease Bacteraemia Sorted by start of study Pneumococcal polysaccharide vaccination Study ID RR (95% CI) vaccinees controls efficacy (%) valency John 1984 119 (0, 620) 4/62 2/37-19 (-520, 77) Simberkoff 1986 050 (005, 553) 1/15 2/1150 50 (-453, 95) Leech 1987 316 (013, 7663) 1/92 0/97-216 (-7563, 87) Klastersky 1986 081 (005, 16) 1/26 1/21 19 (-1116, 95) 17 Örtqvist 1998 021 (002, 177) 1/339 5/352 79 (-77, 98) Honkanen 1999 037 (007, 191) 2/13980 5/945 63 (-91, 93) French 2000 148 (067, 326) 15/667 10/656-48 (-226, 33) Austrian a 1980 (Excluded) 0/607 0/693 Overall (I-squared = 00%, p = 0503) 098 (055, 175) 25/16918 25/15951 2 (-75, 45) NOTE: Weights are from random effects analysis 5 25 5 1 2 4 8 Reduced risk Increased risk 24
Univariable and multivariable meta-regression analysis of the effect of pneumococcal polysaccharide vaccine on the risk of pneumonia from all causes in 20 trials Univariable analysis Multivariable analysis a Variable Ratio of relative risks* (95%CI) Tau 2 Ratio of relative risks* (95%CI) Nil 03116 03116 Publication year 101 (099-103) 03243 101 (099-102) 01638 Year study started 100 (098-102) 033 100 (099-102) 01731 valency b 03510 01758 - valent - Other valencies 107 (049-233) 093 (045-192) 070 (036-134) 071(038-131) Concealment of allocation c 02919 01659 - Adequate 156 (083-293) 111 (063-195) Blinding d - Not describd as doubleblind, controlled 191 (1-326) 01520 188 (108-330) 01659 Tau 2 - Described as double blind, controlled Study population e 276 (160-478) 01929 262 (141-490) 00054 - Respiratory 089 (039-204) 171 (097-302) - HIV patients 2 (067-672) 156 (075-325) - Children 149 (021-1068) 1 (015-045) - Miners/soldiers 048 (027-087) 052 (038-073) - >10 years old in PNG Trial setting f 085 (027-265) 01929 064 (0 32-131) 01027 - Industrialized countries 116 (066-205) 146 (087-245) - Other 040 (018-092) 080 (033-195) a Adjusted for blinding and concealment of allocation For these two variables, adjusted results reported are those from the model containing these two variables alone b Compared to valent PPV c Adequate compared to unclear/inadequate group d Compared to unblinded e Compared to elderly/chronically ill f Compared to trials in developing countries * Relative risk with characteristic divided by relative risk without characteristic Ratios above 10 correspond to a larger relative risk for trials with characteristic and hence a smaller apparent benefit of the vaccine Trials described as double blind and using placebo or another vaccine in the control group show a less beneficial effect than unblended trials, for example 25
Meta-regression > All-cause pneumonia Almost all heterogeneity explained by blinding,concealment of allocation and study population Beneficial effects in healthy young adults should be interpreted with caution - groups contain only older trials (generally poorer reporting) and trials from Russia (poor description of randomisation methods in this paper) 26
Conclusions 1 > High degree of heterogeneity between trials > Heterogeneity partly explained by quality > In trials with higher quality Little evidence of a protective effect of the polysaccharide pneumococcal vaccine in preventing Presumptive pneumococcal pneumonia, All-cause pneumonia and All-cause mortality Bacteraemia 27