Pneumococcal polysaccharide vaccines: Systematic review and meta-analysis of randomised controlled efficacy trials

Transcription

1 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

2 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

3 Meta-analyses vary in 1) Populations studied 2) Outcomes considered 3) Quality of analysis - only 5 report heterogeneity in all analyses 3

4 Methods: Search > In June/July 2007: Embase/ Medline (searched for RCTs) Cochrane References lists IndMed AIM LILACS > Key words: Pneumococcal vaccine/ immunisation Polysaccharide 4

5 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

6 Data extraction > Study population / country > Interventions > Sample size, loss to follow up > Outcomes > Methodological quality of the trial Concealment of allocation sequence Blinding 6

7 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

8 Data extraction > Extraction of all items in duplicate > Blinded assessment of study quality > Discrepancies resolved by consensus 8

9 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

10 Summary of outcomes Outcome No of trials reporting this outcome Combined n of study population for this outcome Definitive pneumococcal pneumonia Presumptive p pneumonia Pneumonia, all causes Bronchitis Mortality all cause Mortality due to pneumonia Mortality due to pneumoc infection 4 16, Bacteraemia 8 32, Combined number of cases in both vaccinees and controls Meningitis None of the studies reported meningitis as an outcome Otitis media Adverse events Many of the studies reported only a comment, eg no serious side effects were reported 10

11 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

12 valency by start of project Valency of vaccine year trial started

13 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

14 Trial countries

15 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

16 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 (034, 057) 85/ / (43, 66) 3 Austrian (035, 058) 83/93 182/80 55 (42, 65) 13 Smit a (044, 091) 37/983 1/ (9, 56) 6 Austrian a (100, 149) 154/607 4/ (-49, -0) Riley (049, 117) 36/ /60 24 (-17, 51) Smit b (032, 142) 9/540 28/ (-42, 68) Austrian b (083, 116) 268/ / (-16, 17) Davis (019, 194) 4/50 7/53 39 (-94, 81) Gaillat (011, 048) 9/937 31/ (52, 89) Douglas (030, 592) 4/426 3/ (-492, 70) Simberkoff (092, 204) 56/15 41/ (-104, 8) Koivula (083, 157) 73/ /73 - (-57, 17) Örtqvist (083, 159) 63/339 57/ (-59, 17) Honkanen (091, 148) 5/ / (-48, 9) French (119, 300) 50/667 26/ (-200, -19) Zhogolev a (0, 237) 4/99 8/5 27 (-137, 77) Zhogolev c (0, 033) 24/990 90/ (67, 86) Zhogolev b (020, 046) 27/422 85/ (54, 80) Alfageme (065, 141) 43/300 45/300 4 (-41, 35) Steentoft (031, 164) 11/37 5/ 29 (-64, 69) Overall (I-squared = 891%, p = 0000) 074 (057, 094) 1185/ / (6, 43) NOTE: Weights are from random effects analysis Reduced risk Increased risk 16

17 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/ /426 48/60 116/ (-492, 70) 24 (-17, 51) -16 (-48, 9) Simberkoff (092, 204) 56/15 41/ (-104, 8) French (119, 300) 50/667 26/ (-200, -19) Austrian b (083, 116) 268/ / (-16, 17) Kaufman (034, 057) 85/ / (43, 66) 3 Gaillat (011, 048) 9/937 31/ (52, 89) Koivula (083, 157) 73/ /73 - (-57, 17) Smit b (032, 142) 9/540 28/ (-42, 68) Zhogolev a (0, 237) 4/99 8/5 27 (-137, 77) Zhogolev c (0, 033) 24/990 90/ (67, 86) Smit a (044, 091) 37/983 1/ (9, 56) 6 Austrian (035, 058) 83/93 182/80 55 (42, 65) 13 Davis (019, 194) 4/50 7/53 39 (-94, 81) Alfageme (065, 141) 43/300 45/300 4 (-41, 35) Örtqvist (083, 159) 63/339 57/ (-59, 17) Austrian a (100, 149) 154/607 4/ (-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/ / (6, 43) NOTE: Weights are from random effects analysis Reduced risk Increased risk 17

18 All cause pneumonia By developing/developed By trial country setting Pneumococcal polysaccharide vaccination Study ID RR (95% CI) vaccinees controls efficacy (%) valency Developed Kaufman (034, 057) 85/ / (43, 66) 3 Austrian b (083, 116) 268/ / (-16, 17) Austrian a (100, 149) 154/607 4/ (-49, -0) Douglas (030, 592) 4/426 3/ (-492, 70) Gaillat (011, 048) 9/937 31/ (52, 89) Simberkoff (092, 204) 56/15 41/ (-104, 8) Davis (019, 194) 4/50 7/53 39 (-94, 81) Koivula (083, 157) 73/ /73 - (-57, 17) Örtqvist (083, 159) 63/339 57/ (-59, 17) Honkanen (091, 148) 5/ / (-48, 9) Alfageme (065, 141) 43/300 45/300 4 (-41, 35) Steentoft (031, 164) 11/37 5/ 29 (-64, 69) Subtotal (I-squared = 829%, p = 0000) 089 (070, 1) 915/ / (-, 30) Developing Austrian (035, 058) 83/93 182/80 55 (42, 65) 13 Smit a (044, 091) 37/983 1/ (9, 56) 6 Riley (049, 117) 36/ /60 24 (-17, 51) Smit b (032, 142) 9/540 28/ (-42, 68) French (119, 300) 50/667 26/ (-200, -19) Subtotal (I-squared = 863%, p = 0000) 076 (047, 5) 215/ / (-25, 53) Undefined Zhogolev c (0, 033) 24/990 90/ (67, 86) Zhogolev a (0, 237) 4/99 8/5 27 (-137, 77) Zhogolev b (020, 046) 27/422 85/ (54, 80) Subtotal (I-squared = 532%, p = 0118) 029 (018, 047) 55/ / (53, 82) Overall (I-squared = 891%, p = 0000) 074 (057, 094) 1185/ / (6, 43) NOTE: Weights are from random effects analysis Reduced risk Increased risk 18

19 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/ (063, 1) 58/387 45/300 57/365 4 (-41, 35) (-, 37) 189 (119, 300) 50/667 26/ (-200, -19) 189 (119, 300) 50/667 26/ (-200, -19) 133 (030, 592) 4/ (030, 592) 4/426 3/426 3/ (-492, 70) -33 (-492, 70) 045 (035, 058) 83/ (032, 142) 9/ /80 28/ (42, 65) 32 (-42, 68) (044, 091) 37/ (0, 033) 24/ (0, 237) 4/99 1/ /787 8/5 37 (9, 56) 79 (67, 86) 27 (-137, 77) (020, 046) 27/422 85/ (54, 80) 042 (029, 061) 184/4527 5/ (39, 71) 044 (034, 057) 85/ (100, 149) 154/ (083, 116) 268/ /4033 4/ / (43, 66) -22 (-49, -0) 2 (-16, 17) 3 0 (011, 048) 9/937 31/ (52, 89) 137 (092, 204) 56/15 41/ (-104, 8) 1 (083, 157) 73/ /73 - (-57, 17) 115 (083, 159) 63/ (091, 148) 5/ / / (-59, 17) -16 (-48, 9) 090 (067, 0) 853/ / (-20, 33) 076 (049, 117) 36/ /60 24 (-17, 51) 076 (049, 117) 36/ /60 24 (-17, 51) 074 (057, 094) 1185/ / (6, 43) 19

20 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/ / (43, 66) (035, 058) 83/93 182/80 55 (42, 65) (032, 142) 9/540 28/ (-42, 68) 063 (044, 091) 37/983 1/ (9, 56) 6 2 (100, 149) 154/607 4/ (-49, -0) 0 (011, 048) 9/937 31/ (52, 89) 061 (019, 194) 4/50 7/53 39 (-94, 81) 1 (083, 157) 73/ /73 - (-57, 17) 116 (091, 148) 5/ / (-48, 9) 189 (119, 300) 50/667 26/ (-200, -19) 073 (0, 237) 4/99 8/5 27 (-137, 77) 021 (0, 033) 24/990 90/ (67, 86) 030 (020, 046) 27/422 85/ (54, 80) 096 (065, 141) 43/300 45/300 4 (-41, 35) 064 (046, 090) 747/ / (10, 54) 076 (049, 117) 36/ /60 24 (-17, 51) 098 (083, 116) 268/ / (-16, 17) 133 (030, 592) 4/426 3/ (-492, 70) 137 (092, 204) 56/15 41/ (-104, 8) 115 (083, 159) 63/339 57/ (-59, 17) 071 (031, 164) 11/37 5/ 29 (-64, 69) 102 (088, 118) 438/ /770-2 (-18, ) 074 (057, 094) 1185/ / (6, 43) NOTE: Weights are from random effects analysis Reduced risk Increased risk 20

21 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/ (011, 048) 9/ (020, 046) 27/ / /749 85/ (43, 66) 77 (52, 89) 70 (54, 80) (0, 237) 4/ (0, 033) 24/990 8/5 90/ (-137, 77) 79 (67, 86) 096 (065, 141) 43/ (031, 164) 11/ (027, 067) 203/ (035, 058) 83/93 45/300 5/ 428/ /80 4 (-41, 35) 29 (-64, 69) 57 (33, 73) 55 (42, 65) (044, 091) 37/983 1/ (9, 56) (032, 142) 9/ (083, 116) 268/ / / (-42, 68) 2 (-16, 17) 1 (083, 157) 73/ /73 - (-57, 17) 116 (091, 148) 5/ (058, 1) 615/ / / (-48, 9) 19 (-, 42) 076 (049, 117) 36/ /60 24 (-17, 51) 2 (100, 149) 154/607 4/ (-49, -0) 133 (030, 592) 4/426 3/ (-492, 70) 137 (092, 204) 56/15 41/ (-104, 8) 061 (019, 194) 4/50 7/53 39 (-94, 81) 115 (083, 159) 63/339 57/ (-59, 17) 189 (119, 300) 50/667 26/ (-200, -19) 119 (097, 147) 367/ / (-47, 3) 074 (057, 094) 1185/ / (6, 43) NOTE: Weights are from random effects analysis Reduced risk Increased risk 21

22 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 (001, 164) 0/300 5/ (-64, 99) Subtotal (I-squared = %, p = ) 009 (001, 164) 0/300 5/ (-64, 99) Not reported to be double blind, placebo-controlled MacLeod (050, 097) 60/ / (3, 50) 4 Austrian (029, 058) 44/93 106/80 59 (42, 71) 13 Smit a (0, 049) 9/983 38/ (51, 88) 6 Smit b (001, 048) 1/540 16/ (52, 99) Klastersky (008, 199) 2/26 4/21 60 (-99, 92) 17 Koivula (051, 141) 26/ /73 15 (-41, 49) Honkanen (080, 182) 52/ / (-82, 20) Subtotal (I-squared = 798%, p = 0000) Reported to be double blind, placebo-controlled 054 (033, 086) 194/ / (, 67) Simberkoff (053, 216) 16/15 15/ (-116, 47) Davis (026, 10763) 2/50 0/ (-10663, 74) Örtqvist (064, 236) 19/339 16/352 - (-136, 36) Subtotal (I-squared = 00%, p = 0593) 0 (075, 192) 37/ / (-92, 25) Overall (I-squared = 744%, p = 0000) 064 (043, 096) 1/ / (4, 57) NOTE: Weights are from random effects analysis Reduced risk Increased risk 22

23 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/ / (17, 66) (089, 6) 2/ /749-6 (-26, 11) 098 (071, 137) 57/300 58/300 2 (-37, 29) 086 (060, 1) 321/ /5082 (-, 40) 096 (064, 145) 45/ (080, 2) 152/ (082, 118) 197/86 47/ /73 213/ (-45, 36) 1 (-22, 20) 2 (-18, 18) 079 (063, 099) 133/ (060, 143) 35/ /60 43/ (1, 37) 7 (-43, 40) 065 (030, 139) 10/ (050, 101) 51/ /470 71/ (-39, 70) 29 (-1, 50) 4 (103, 149) 211/15 171/ (-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/ /656 0 (-19, 16) 094 (080, 110) 674/ / (-10, 20) 094 (084, 105) 1192/ / (-5, 16) NOTE: Weights are from random effects analysis Reduced risk Increased risk

24 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 (0, 620) 4/62 2/37-19 (-520, 77) Simberkoff (005, 553) 1/15 2/ (-453, 95) Leech (013, 7663) 1/92 0/ (-7563, 87) Klastersky (005, 16) 1/26 1/21 19 (-1116, 95) 17 Örtqvist (002, 177) 1/339 5/ (-77, 98) Honkanen (007, 191) 2/ / (-91, 93) French (067, 326) 15/667 10/ (-226, 33) Austrian a 1980 (Excluded) 0/607 0/693 Overall (I-squared = 00%, p = 0503) 098 (055, 175) 25/ / (-75, 45) NOTE: Weights are from random effects analysis Reduced risk Increased risk 24

25 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 Publication year 101 ( ) ( ) Year study started 100 ( ) ( ) valency b valent - Other valencies 107 ( ) 093 ( ) 070 ( ) 071( ) Concealment of allocation c Adequate 156 ( ) 111 ( ) Blinding d - Not describd as doubleblind, controlled 191 (1-326) ( ) Tau 2 - Described as double blind, controlled Study population e 276 ( ) ( ) Respiratory 089 ( ) 171 ( ) - HIV patients 2 ( ) 156 ( ) - Children 149 ( ) 1 ( ) - Miners/soldiers 048 ( ) 052 ( ) - >10 years old in PNG Trial setting f 085 ( ) ( ) Industrialized countries 116 ( ) 146 ( ) - Other 040 ( ) 080 ( ) 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

26 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

27 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