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Pneumococcal polysaccharide vaccine: a systematic review of clinical effectiveness in adults
Vaccine 20 (2002) 2166–2173
Review
Pneumococcal polysaccharide vaccine: a systematic review of clinical effectiveness in adults Lorna Watson a,∗ , Brenda J. Wilson b , Norman Waugh c a
c
Department of Public Health Medicine, Grampian Health Board, Aberdeen, UK b Department of Public Health, University of Aberdeen, Aberdeen, UK Wessex Institute for Health Research and Development, University of Southampton, Southampton, UK Received 19 June 2001; received in revised form 28 January 2002; accepted 5 February 2002
Abstract Pneumococcal polysaccharide vaccine is recommended in western countries for individuals at high risk of pneumococcal illness. We undertook a systematic review of randomised controlled trials of pneumococcal vaccine in adults, to determine the effects on clinical outcomes. Results: In industrialised populations, no benefit was detected for outcomes other than pneumococcal bacteraemia, and this did not reach statistical significance. In non-industrial populations, clear benefit was demonstrated for mortality and all-cause pneumonia. Conclusion: Benefit from pneumococcal vaccination depends on the baseline risk of infection and characteristics of a given population. Evidence from randomised trials for widespread adult vaccination in industrial countries is lacking. © 2002 Elsevier Science Ltd. All rights reserved. Keywords: Vaccination; Pneumococcal; Review
1. Introduction Pneumococcal illness remains a serious public health problem around the world despite medical advances [1]. It is a major cause of pneumonia, meningitis and septicaemia, as well as less serious infections, in developed and developing populations, and mortality remains high. The most vulnerable groups are the very young, the very old and those with predisposing co-morbidities, including immunosuppression and chronic organ dysfunction [2]. The pneumococcal polysaccharide vaccine has been licensed for twenty years in the US and UK. The vaccine contains 23 of the commoner serotypes of pneumococcal infection, covering around 90% of invasive infections. Its overall efficacy is quoted as ‘probably 60–70%’ in preventing pneumococcal pneumonia, but less in the presence of immunosuppression or in children under 2 years [3]. The US Advisory Committee on Immunisation Practices (ACIP) recommend use of pneumococcal polysaccharide vaccine in ∗ Corresponding author. Present address: Public Health Medicine, Information and Statistics Division, Trinity Park House, South Trinity Road, Edinburgh EH5 3SQ, Scotland, UK. Tel.: +44-131-552-6255; fax: +44-131-551-1392. E-mail address: [email protected] (L. Watson).
people over 65, as well as persons at high risk of pneumococcal infection due to co-morbidity [4,5]. In the UK, vaccination is recommended for patients with chronic organ dysfunction and immunosuppression [3]. Around 8% of the UK population fulfils this definition. Immunisation rates in adults in the UK have been low, but have increased in the past few years [6]. Much of the evidence for the efficacy of the vaccine has been derived from ecological and observational studies [7–9]. Meta-analyses have produced inconsistent recommendations: Fine and colleagues failed to find definitive evidence of vaccine efficacy in ‘high risk’ groups [10], but Hutchison et al. [11] concluded that the vaccine was efficacious against the specific serotypes included in the preparation, with no evidence of poorer efficacy in immunocompromised subjects. This conflicting evidence led us to re-examine the evidence of effectiveness of the vaccine by conducting an updated systematic review and meta-analysis, with a focus firstly on those groups in which vaccination is recommended in UK and US guidance, and secondly on endpoints which are clinically relevant, rather than proxy indicators. We also wished to examine whether differences in the epidemiology of pneumococcal infection in industrialised and less industrialised countries appeared to affect vaccine effectiveness [12–14].
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2. Methods
2.3. Data extraction and quality assessment
2.1. Identification of relevant trials
Two observers independently extracted data and methodological details from the unmasked published reports [16] and a third checked data from a sample of reports. Each report was scored by two reviewers using Jadad’s system [17], in which one point is allocated for each of randomisation, blinding, and description of withdrawals, and an additional point added for each of well described methods of randomisation and blinding. Points were subtracted for clearly inadequate randomisation or blinding. The maximum possible score was five points, and we took studies scoring <3 to be to be of low methodological quality. Any disagreements were resolved by discussion.
We carried out a literature search using the following electronic databases: Medline 1966 to March 1999; Embase 1980 to March 1999; the Cochrane Controlled Trials Register; CINAHL; the Inter-Dec database; ASSIA; Grey Literature databases; SIGLE. Internet sources were also accessed, including Medscape, the Centers for Disease Control, dotPharmacy, WebDoctor, InPharma. Medline searches were updated in May 2000. For Medline searches we used the medical subject headings “pneumococcal infection”, “immunisation” and “bacterial vaccines”, as part of a standard search based on that developed by the Cochrane Collaboration [15]. Animal studies were excluded and there was no language restriction. Citations of relevant articles were reviewed. Bibliographies of publications such as HMSO Immunisation against Infectious Disease 1996 [3] and medical reference textbooks were also searched. The Science Citation Index was used to trace any articles quoting a previous meta-analysis. We approached the vaccine manufacturers, Pasteur– Merieux and Lederle, for any unpublished data that might be relevant. We contacted the authors of trials published in the last few years and asked if they were aware of further studies. We approached experts, including epidemiologists from the Scottish Centre for Environment and Environmental Health, medical officers in the UK Department of Health, and members of the Joint Committee on Vaccines and Immunisation, for contacts or knowledge of further trials.
2.4. Grouping of studies Studies were grouped first for comparison between subjects from industrialised and non-industrialised populations. For studies set in industrialised countries, two further groups were examined: (a) persons with chronic organ dysfunction or immunosuppression (the JCVI definition of “high risk”) [6] and (b) all persons over 65 years (the ACIP definition of “older age”) [8]. We performed a sensitivity analysis, comparing the findings from all studies with those confined to studies with a quality score of ≥3. 2.5. Statistical methods Calculations were done with Revman 4.0.4 software [18], and results were expressed as relative risks using both random effects and fixed effects models. Statistical heterogeneity was tested with the Chi-square test.
2.2. Inclusion criteria 3. Results We included in the review studies which fulfilled the following criteria:
3.1. Studies identified
(a) Participants had to be adults. (b) Participants had to be randomised to an intervention group which received the vaccine or a control group which did not. We did not include newer conjugate vaccines, which are not generally available, nor trials of a prototype vaccine in the 1940s, as it was likely to be significantly different in composition from modern vaccines. (c) The outcome measures had to be clinically relevant, e.g. death, bacteraemia or other invasive infection of a normally sterile body site. We accepted all-cause pneumonia as defined by combinations of clinical and radiographic changes. We did not accept pneumococcal pneumonia if the diagnosis relied significantly on potentially unreliable tests such as naso-pharyngeal aspirates. (d) Data on outcomes of interest had to be reported in numerical format, including numerator and denominator data.
We identified 16 studies, presented in 12 published reports, which satisfied the inclusion criteria; one report was identified from citations alone (Fig. 1). Table 1 summarises the characteristics of the studies included. Clinical outcomes for which meaningful data were reported from more than one study were: all-cause pneumonia, pneumococcal pneumonia, pneumococcal bacteraemia, and overall mortality. These are summarised in Table 2. The three trials carried out by Austrian et al. [29] were not reported fully, and no definition of their category “putative pneumococcal pneumonia” was given. Although these trials had positive results for other outcomes, we could not include them in this meta-analysis. Very few individual trials reported statistically significant results, these being Simberkoff (increased mortality), Riley (decreased mortality), Austrian (increased all-cause pneumonia), Gaillet (decreased all-cause pneumonia) and Smit (decreased all-cause pneumonia).
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3.2. Meta-analysis
Fig. 1. Flow diagram of trial identification, based on the QUOROM statement [19]. Asterisk denotes Medline, Embase, Cochrane controlled trials register.
Firstly, we considered trials carried out in industrialised countries (Table 3, which includes all trials). We found a non-significant increase for overall mortality, all-cause pneumonia and pneumococcal pneumonia, for those immunised. For bacteraemia, we found a non-significant reduction. The findings were altered very slightly when lower quality studies were excluded (Table 4, trials with a score of ≥3), and the statistically significant heterogeneity for all-cause pneumonia disappeared. In the trials whose participants fulfilled the JCVI ‘high risk’ criteria we found non-significant adverse effects for overall mortality, pneumococcal and all-cause pneumonia. A non-significant protective effect was found for bacteraemia. The estimates are not greatly affected when the one lower quality study is excluded, Klastersky et al. [20]. This study had a Jadad score of 2. In trials involving unselected elderly populations, the estimates for overall mortality, and pneumococcal pneumonia showed no significant change. We found a non-significant increase in all-cause pneumonia, and a reduction in bacteraemia. Confining the analysis to higher quality studies did not materially alter the estimates other than for pneumococcal pneumonia where a non-significant reduction (0.81, 95%
Table 1 Details of reports included in review Study
Participants, principal exclusions, length of follow-up (FU)
Industrialised countries, high risk Klastersky et al. [20] Bronchial carcinoma, FU unclear Simberkoff et al. [21] Chronic renal, hepatic, cardiac, pulmonary disease, alcoholism, diabetes. Excluded asplenia, recent hospitalisation, previous vaccination, haematological malignancy, FU 2.9 years Davis et al. [22] COPD; excluded asthma, neoplasms, renal or hepatic impairment, sickle cell disease, FU 2 years Leech et al. [23] COPD; excluded other lung disease, previous vaccination, FU 2 years Industrialised countries, older age Koivula et al. [24] Elderly, community, FU 3 years Honkanen et al. [25] Elderly, community, excluded terminally ill, FU 3 years Industrialised countries, other Austriana [26] Health plan members age >45, FU 2 years Austriana [26] Psychiatric in-patients, FU 3 years Gaillet et al. [27] Retirement home residents, geriatric in-patients. Excluded co-morbidities, terminal illness, immunodeficiency, FU 2 years Ortqvist et al. [28] Patients over 50 with previous pneumonia. Excluded immunosuppression, low compliance, FU 4 years Less industrialised countries Austrian et al.a [29] Novice gold miners, Riley et al. [30] Subsistence farmers, Smit et al.a [31] Novice gold miners, Smit et al.a [31] Novice gold miners, a
Multiple trials presented in single report.
FU FU FU FU
2 3 2 2
years years years years
Intervention/control
Quality score (maximum = 5)
17 valent/placebo 14 valent/placebo
2 4
14 valent/placebo
4
14 valent plus influenza/placebo plus influenza
3
14 valent plus influenza/influenza alone 23 valent plus influenza/influenza alone
4 2
12 valent/placebo 12 valent/placebo 14 valent/no placebo
4 4 2
23 valent/placebo
4
6 or 13 valent/meningococcal vaccine/placebo 14 valent/placebo 6 valent/meningococcal vaccine/placebo 12 valent/meningococcal vaccine/placebo
2 3 3 3
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Table 3 Effectiveness of pneumococcal vaccine: comparison of outcomes, all studies Grouping
No. of studies
No. of participants
Relative risk, fixed effects model, 95% confidence interval
Relative risk, random effects model, 95% confidence interval
Chi-square (d.f.) P-value
Industrialised Mortality Pneumonia, all cause Pneumonia, pneumococcal Bacteraemia
8 9 5 6
22760 49685 32854 29641
1.07 1.06 1.06 0.53
[0.97, [0.97, [0.82, [0.22,
1.18] 1.17] 1.37] 1.29]
Same 1.03 [0.86, 1.25] 1.06 [0.82, 1.38] 0.53 [0.20, 1.43]
5.3 22.7 3.4 3.6
High risk Mortality Pneumonia, all cause Pneumonia, pneumococcal Bacteraemia
3 3 2 1
2646 2646 2401 47
1.20 1.17 1.07 0.81
[1.00, [0.86, [0.58, [0.05,
1.42] 1.60] 1.97] 12.16]
1.15 [0.87, 1.52] 1.13 [0.79, 1.62] 0.91 [0.33, 2.53] Same
2.4 (2) 0.30 2.6 (2) 0.31 1.7 (1) 0.19 –
Elderly Mortality Pneumonia, all cause Pneumonia, pneumococcal Bacteraemia
1 2 2 1
2837 29762 29762 26925
0.99 1.15 1.02 0.37
[0.80, [0.95, [0.75, [0.07,
1.22] 1.40] 1.40] 1.91]
Same Same 1.01 [0.69, 1.49] Same
– 0 (1) 0.95 1.46 (1) 0.23 –
Less industrialised Mortality Pneumonia, all cause Pneumonia, pneumococcal Bacteraemia
1 3 – 1
11958 10067 – 5383
0.79 [0.63, 0.99] 0.67 [0.52, 0.87] – 0.14 [0.02, 1.14]
Same Same – Same
– 0.27 (2) 0.87 – –
(7) (8) (4) (5)
0.62 0.00 0.49 0.61
Table 4 Effectiveness of pneumococcal vaccine: comparison of outcomes, studies with Jadad score ≥3 Grouping
No. of studies
No. of participants
Relative risk, fixed effects model, 95% confidence interval
Relative risk, random effects model, 95% confidence interval
Chi-square (d.f.) P-value
Industrialised Mortality Pneumonia, all cause Pneumonia, pneumococcal Bacteraemia
7 7 3 3
21074 21074 5882 983
1.07 1.09 1.02 0.70
1.21] 1.21] 1.43] 2.45]
1.08 [0.96, 1.21] 1.10 [0.99, 1.22] Same 0.92 [0.13, 6.48]
5.3 (6) 0.49 5.4 (6) 0.52 1.6 (2) 0.45 2.97 (2) 0.23
High risk Mortality Pneumonia, all cause Pneumonia, pneumococcal Bacteraemia
3 3 1 –
2646 2646 2354 –
1.20 [1.00, 1.42] 1.17 [0.86, 1.60] 1.27 [0.65, 2.49] –
1.15 [0.87, 1.52] 1.13 [0.79, 1.62] Same –
2.4 (2) 0.30 2.6 (2) 0.31 – –
Elderly Mortality Pneumonia, all cause Pneumonia, pneumococcal Bacteraemia
1 1 1 –
2837 2837 2837 –
0.99 [0.80, 1.22] 1.14 [0.83, 1.57] 0.81 [0.49, 1.33] –
Same Same Same –
– – – –
[0.95, [0.98, [0.73, [0.20,
Less industrialised results are the same as in Table 3.
CI 0.49, 1.33), was found. Excluding the weaker studies removed the bacteraemia estimate. Examining the trials set in less industrialised countries, we found that all-cause pneumonia was the only outcome that could be combined. We found a statistically significant protective effect, a result which was unchanged when lower quality studies were excluded. From a single trial, we found statistically significant protective effects against mortality and a reduction in bacteraemia. The numbers needed to treat
to prevent an adverse outcome based on these estimates are 69 for all-cause pneumonia and 169 for overall mortality.
4. Discussion In this study, we aimed to answer two questions: whether there was evidence that pneumococcal vaccine is similarly effective in industrialised and non-industrialised popu-
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lations, and whether it is effective in those groups for whom it is recommended by UK and US health departments. The results for non-industrialised populations show significant protective effects for all-cause pneumonia and mortality. However, we failed to demonstrate any protective effect of pneumococcal vaccine on three of four relevant clinical outcomes (the exception being bacteraemia) in industrialised populations. Of the trials where participants met UK criteria for high risk, vaccines experienced non-significant increases in adverse events, particularly for mortality and all-cause pneumonia, but with a reduction in bacteraemia. In the unselected elderly, we did not identify benefit for any outcome other than bacteraemia. It is important to note that the very small numbers and wide confidence intervals make it difficult to draw any firm conclusions from the results for bacteraemia. 4.1. Trials The decision to exclude the trials from the 1940s [32,33] was taken because an early vaccine was used, and the sero-epidemiology of pneumococcal disease may also have changed since that time [34]. Since conducting this review, we have identified one further trial initially published in conference proceedings, conducted in Uganda with HIV positive participants [35,36]. This trial found no benefit from vaccination and will be discussed further in Section 4.4. Although data from the trial by Austrian et al. [29] could not be included due to unclear outcome measures, its results are consistent with the other included trials in non-industrialised populations. 4.2. Outcomes In restricting outcomes to those of direct clinical relevance, we aimed to evaluate the overall impact of vaccination on patients and health services. For this reason, we did not consider that serotype-specific outcomes were necessarily helpful. The outcome ‘respiratory deaths’ was considered for inclusion, but we decided that the lack of a common definition and the unreliability of cause of death entered on death certificates would compromise the validity of any results. We also carefully scrutinised the diagnostic criteria for pneumococcal pneumonia, and excluded data on this outcome in studies where it was likely that unreliable criteria were used, or commensal pneumococci might be detected, e.g. nasopharyngeal aspirates. Bacteraemia was included as it is a marker of severe infection. We did not obtain patient specific data from trials because of time constraints. Neither did we have the time or resources to pursue access to all trial data which had been originally obtained, but not published. In addition, we did not address questions of vaccine safety or unwanted effects, but it is generally accepted that the vaccine is safe and this aspect has been widely tested.
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4.3. Variation in effect We find that the disparate results of these trials can be explained by effect modifiers, i.e. variations in the host, agent and environment which are important in determining the effectiveness of pneumococcal vaccine in routine practice. For example, the biological activity of the vaccine will depend upon host immune response and on the probability of exposure to the relevant pathogen. In the studies in less industrialised countries, the host populations were relatively young and fit, and would be expected to have an optimal immune response to the vaccine. This contrasts with studies in industrialised countries, where those with serious underlying illness and elderly persons may have sub-optimal response to the vaccine [37]. A higher proportion of pneumonias may be due to pneumococcal infection in a closed, overcrowded environment, where carriage rates of specific serotypes may be high, in contrast to sporadic cases in more affluent circumstances where there are also more competing causes of illness. Weisholtz et al. [38] have demonstrated in work on the 14 valent vaccine that there is a variable risk of infection with non-vaccine serotypes: in order of decreasing risk, those who are immunosuppressed, those with co-morbidity and those with neither. In addition, the sero-epidemiology of pneumococcal infection is different between industrialised and less industrialised countries [34,39], with different serotypes exhibiting different pathogenic properties. These aspects underline the importance of taking into account clinical heterogeneity in meta-analysis [40–42]. It may be argued that, because of the rarity of clinical outcomes in developed countries, this analysis lacks adequate power to detect a convincing protective effect. However, our approach takes into account absolute rather than relative risk reduction, and considers clinical rather than surrogate outcome measures. If demonstrable health gain for clinical outcomes such as pneumonia and mortality cannot be detected in trials to date, this implies that the numbers needed to treat to prevent any adverse outcomes will be high. Although this is often the case with vaccines, unlike other cases, there is no additional herd immunity effect. Where health commissioners have to prioritise interventions according to effectiveness, efficiency, need and ability to benefit, an expensive vaccination campaign may not be the best use of money if the benefits are uncertain or very marginal. We have demonstrated non-significant increases in important clinical outcomes, bringing into question the exact relation between a reduction in bacteraemia, and hospital admissions or mortality. 4.4. Comparison with other work This meta-analysis is consistent with the previous work of Fine et al. [10], who found no benefit for older patients and those who satisfy JCVI criteria. Their conclusion that vaccination protected from pneumococcal pneumonia in
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‘low risk’ adults was based predominantly on the early studies in non-industrialised countries. It is compatible with the findings of Hutchison et al. [11], although our focus on clinically relevant outcomes and the addition of more recent trials brings us to a different view. A report in Bandolier [35] briefly examined a review with different inclusion criteria (exclusion of quasi-randomised trials, inclusion of trials from the 1940s), but the conclusions concur with ours regarding the lack of demonstration of vaccine effectiveness in industrialised countries. The recent trial in Ugandans with HIV was included [36]. This study found a significant increase in all-cause pneumonia in vaccine recipients, and reinforces our view that clinical heterogeneity in study populations is an important consideration. Non-randomised trials [43] have also produced negative results for clinically important outcomes such as pneumonia, but policy recommendations for use of the vaccine in the west have relied heavily on observational studies, which have not supported effectiveness in the immunosuppressed [8,9]. Retrospective studies are potentially subject to selection bias, e.g. there is evidence of social and racial variation in risk of infection, the highest risk in the poor and in ethnic minorities [12]. McBean et al. demonstrated that elderly Medicare beneficiaries in the US who were white were almost twice as likely to have been immunised than if they were black [7]. We suggest that it is likely that this variation may also exist in younger adults, reflecting socio-economic status and access to medical care. Case-control or cohort studies may not have been able to match adequately for these confounders from variables such as site of hospitalisation [9,44]. Indirect cohort studies have used the distribution of vaccine and non-vaccine serotypes to infer protection from vaccination [8]. This approach requires that risks of infection with such serotypes are evenly distributed between vaccines and non-vaccines. Serotypes may not be evenly distributed in different social circumstances [34,39] or at different ages [34], and neither is vaccination [7]. It is possible that bias may be introduced using this method. 4.5. Policy implications Our finding that the benefit derived from vaccination may depend upon patient characteristics and baseline risk is similar to the case of cholesterol lowering and coronary heart disease [45]. Indeed, the principal reason for conducting trials in the past in non-industrialised populations was that the incidence of pneumococcal disease was unusually high, as was the proportion of deaths from pneumococcal disease. Resources are wasted if treatments are given to patients who are unlikely to benefit [46]. We would welcome a more consistent approach to the interpretation of available evidence by policymakers.
5. Conclusion Our results show that the beneficial effects of pneumococcal polysaccharide vaccine may be dependent on host characteristics, and on the underlying epidemiology of infection in the target population. We suggest that rigorous evidence for widespread vaccination in the susceptible populations for which the vaccine is recommended in the UK and US is lacking. Conjugate or species wide pneumococcal vaccines hold greater promise for prevention of pneumococcal infection.
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[30] Riley ID, Andrews M, Howard R, Tarr PI, Pfeiffer M, Challands P, et al. Immunisation with a polyvalent pneumococcal vaccine. Lancet 1977;25:1338–41. [31] Smit P, Oberholzer D, Hayden-Smith S, Koornhof HJ, Hilleman RL. Protective efficacy of pneumococcal polysaccharide vaccines. JAMA 1977;238:2613–6. [32] MacLeod CM, Hodges RG, Heidelberger M, et al. Prevention of pneumococcal pneumonia by immunisation with specific capsular polysaccharides. J Exp Med 1945;82:445–65. [33] Kaufman P. Pneumonia in old age: active immunisation against pneumonia with pneumococcus polysaccharides: results of a 6-year study. Arch Int Med 1947;79:518–31. [34] Scott JAG, Hall AJ, Dagan R, et al. Serogroup-specific epidemiology of Streptococcus pneumoniae: associations with age, sex and geography in 7000 episodes of invasive disease. Clin Infect Dis 1996;22:973–81. [35] Anon. Are pneumococcal vaccines effective? Bandolier February 2000;72–4 (http://www.jr2.ox.ac.uk/bandolier/band72/672-4.html). [36] French N, Nakiyingi J, Carpenter LM, et al. 23-Valent pneumococcal polysaccharide vaccine in HIV-1-infected Ugandan adults: double-blind, randomised and placebo-controlled trial. Lancet 2000;355:2106–11. [37] Rubins JB, Puri AKG, Loch J, et al. Magnitude, duration, quality, and function of pneumococcal vaccine responses in elderly adults. J Infect Dis 1998;178:431–40. [38] Weisholtz SJ, Hartman BJ, Roberts RB. Effect of underlying disease and age on pneumococcal serotype distribution. Am J Med 1983;75:199–205. [39] Sniadack DH, Schwartz B, Lipman H, et al. Potential interventions for the prevention of childhood pneumonia: geographic and temporal differences in serotype and serogroup distribution of sterile site pneumococcal isolates from children-implications for vaccine strategies. Pediatr Infect Dis J 1995;14:503–10. [40] Naylor CD. Meta-analysis and the meta-epidemiology of clinical research. BMJ 1997;315:917–9. [41] Lau J, Ioannidis JPA, Schmid HC. Summing up evidence: one answer is not always enough. Lancet 1998;351:123–7. [42] Smeeth L, Haines A, Ebrahim S. Numbers needed to treat derived from meta-analysis—sometimes informative, usually misleading. BMJ 1999;318:1548–51. [43] Bentley DW, Ha K, Mamot K, et al. Pneumococcal vaccine in the institutionalised elderly: design of a non-randomised trial and preliminary results. Rev Infect Dis 1981;3:S71–81. [44] Nichol KL, Baken L, Wuorenma J, Nelson A. The health and economic benefits associated with pneumococcal vaccination of elderly persons with chronic lung disease. Arch Int Med 1999;159:2437–42. [45] Smith GD, Song F, Sheldon TA. Cholesterol lowering and risk of mortality: the importance of considering initial level of risk. BMJ 1993;306:1367–73. [46] Vijan S, Kent DM, Hayward RA. Are randomised controlled trials sufficient evidence to guide clinical practice in type II (noninsulin-dependent) diabetes mellitus? Diabetologia 2000;43: 125–30.
Review
Pneumococcal polysaccharide vaccine: a systematic review of clinical effectiveness in adults Lorna Watson a,∗ , Brenda J. Wilson b , Norman Waugh c a
c
Department of Public Health Medicine, Grampian Health Board, Aberdeen, UK b Department of Public Health, University of Aberdeen, Aberdeen, UK Wessex Institute for Health Research and Development, University of Southampton, Southampton, UK Received 19 June 2001; received in revised form 28 January 2002; accepted 5 February 2002
Abstract Pneumococcal polysaccharide vaccine is recommended in western countries for individuals at high risk of pneumococcal illness. We undertook a systematic review of randomised controlled trials of pneumococcal vaccine in adults, to determine the effects on clinical outcomes. Results: In industrialised populations, no benefit was detected for outcomes other than pneumococcal bacteraemia, and this did not reach statistical significance. In non-industrial populations, clear benefit was demonstrated for mortality and all-cause pneumonia. Conclusion: Benefit from pneumococcal vaccination depends on the baseline risk of infection and characteristics of a given population. Evidence from randomised trials for widespread adult vaccination in industrial countries is lacking. © 2002 Elsevier Science Ltd. All rights reserved. Keywords: Vaccination; Pneumococcal; Review
1. Introduction Pneumococcal illness remains a serious public health problem around the world despite medical advances [1]. It is a major cause of pneumonia, meningitis and septicaemia, as well as less serious infections, in developed and developing populations, and mortality remains high. The most vulnerable groups are the very young, the very old and those with predisposing co-morbidities, including immunosuppression and chronic organ dysfunction [2]. The pneumococcal polysaccharide vaccine has been licensed for twenty years in the US and UK. The vaccine contains 23 of the commoner serotypes of pneumococcal infection, covering around 90% of invasive infections. Its overall efficacy is quoted as ‘probably 60–70%’ in preventing pneumococcal pneumonia, but less in the presence of immunosuppression or in children under 2 years [3]. The US Advisory Committee on Immunisation Practices (ACIP) recommend use of pneumococcal polysaccharide vaccine in ∗ Corresponding author. Present address: Public Health Medicine, Information and Statistics Division, Trinity Park House, South Trinity Road, Edinburgh EH5 3SQ, Scotland, UK. Tel.: +44-131-552-6255; fax: +44-131-551-1392. E-mail address: [email protected] (L. Watson).
people over 65, as well as persons at high risk of pneumococcal infection due to co-morbidity [4,5]. In the UK, vaccination is recommended for patients with chronic organ dysfunction and immunosuppression [3]. Around 8% of the UK population fulfils this definition. Immunisation rates in adults in the UK have been low, but have increased in the past few years [6]. Much of the evidence for the efficacy of the vaccine has been derived from ecological and observational studies [7–9]. Meta-analyses have produced inconsistent recommendations: Fine and colleagues failed to find definitive evidence of vaccine efficacy in ‘high risk’ groups [10], but Hutchison et al. [11] concluded that the vaccine was efficacious against the specific serotypes included in the preparation, with no evidence of poorer efficacy in immunocompromised subjects. This conflicting evidence led us to re-examine the evidence of effectiveness of the vaccine by conducting an updated systematic review and meta-analysis, with a focus firstly on those groups in which vaccination is recommended in UK and US guidance, and secondly on endpoints which are clinically relevant, rather than proxy indicators. We also wished to examine whether differences in the epidemiology of pneumococcal infection in industrialised and less industrialised countries appeared to affect vaccine effectiveness [12–14].
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2. Methods
2.3. Data extraction and quality assessment
2.1. Identification of relevant trials
Two observers independently extracted data and methodological details from the unmasked published reports [16] and a third checked data from a sample of reports. Each report was scored by two reviewers using Jadad’s system [17], in which one point is allocated for each of randomisation, blinding, and description of withdrawals, and an additional point added for each of well described methods of randomisation and blinding. Points were subtracted for clearly inadequate randomisation or blinding. The maximum possible score was five points, and we took studies scoring <3 to be to be of low methodological quality. Any disagreements were resolved by discussion.
We carried out a literature search using the following electronic databases: Medline 1966 to March 1999; Embase 1980 to March 1999; the Cochrane Controlled Trials Register; CINAHL; the Inter-Dec database; ASSIA; Grey Literature databases; SIGLE. Internet sources were also accessed, including Medscape, the Centers for Disease Control, dotPharmacy, WebDoctor, InPharma. Medline searches were updated in May 2000. For Medline searches we used the medical subject headings “pneumococcal infection”, “immunisation” and “bacterial vaccines”, as part of a standard search based on that developed by the Cochrane Collaboration [15]. Animal studies were excluded and there was no language restriction. Citations of relevant articles were reviewed. Bibliographies of publications such as HMSO Immunisation against Infectious Disease 1996 [3] and medical reference textbooks were also searched. The Science Citation Index was used to trace any articles quoting a previous meta-analysis. We approached the vaccine manufacturers, Pasteur– Merieux and Lederle, for any unpublished data that might be relevant. We contacted the authors of trials published in the last few years and asked if they were aware of further studies. We approached experts, including epidemiologists from the Scottish Centre for Environment and Environmental Health, medical officers in the UK Department of Health, and members of the Joint Committee on Vaccines and Immunisation, for contacts or knowledge of further trials.
2.4. Grouping of studies Studies were grouped first for comparison between subjects from industrialised and non-industrialised populations. For studies set in industrialised countries, two further groups were examined: (a) persons with chronic organ dysfunction or immunosuppression (the JCVI definition of “high risk”) [6] and (b) all persons over 65 years (the ACIP definition of “older age”) [8]. We performed a sensitivity analysis, comparing the findings from all studies with those confined to studies with a quality score of ≥3. 2.5. Statistical methods Calculations were done with Revman 4.0.4 software [18], and results were expressed as relative risks using both random effects and fixed effects models. Statistical heterogeneity was tested with the Chi-square test.
2.2. Inclusion criteria 3. Results We included in the review studies which fulfilled the following criteria:
3.1. Studies identified
(a) Participants had to be adults. (b) Participants had to be randomised to an intervention group which received the vaccine or a control group which did not. We did not include newer conjugate vaccines, which are not generally available, nor trials of a prototype vaccine in the 1940s, as it was likely to be significantly different in composition from modern vaccines. (c) The outcome measures had to be clinically relevant, e.g. death, bacteraemia or other invasive infection of a normally sterile body site. We accepted all-cause pneumonia as defined by combinations of clinical and radiographic changes. We did not accept pneumococcal pneumonia if the diagnosis relied significantly on potentially unreliable tests such as naso-pharyngeal aspirates. (d) Data on outcomes of interest had to be reported in numerical format, including numerator and denominator data.
We identified 16 studies, presented in 12 published reports, which satisfied the inclusion criteria; one report was identified from citations alone (Fig. 1). Table 1 summarises the characteristics of the studies included. Clinical outcomes for which meaningful data were reported from more than one study were: all-cause pneumonia, pneumococcal pneumonia, pneumococcal bacteraemia, and overall mortality. These are summarised in Table 2. The three trials carried out by Austrian et al. [29] were not reported fully, and no definition of their category “putative pneumococcal pneumonia” was given. Although these trials had positive results for other outcomes, we could not include them in this meta-analysis. Very few individual trials reported statistically significant results, these being Simberkoff (increased mortality), Riley (decreased mortality), Austrian (increased all-cause pneumonia), Gaillet (decreased all-cause pneumonia) and Smit (decreased all-cause pneumonia).
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3.2. Meta-analysis
Fig. 1. Flow diagram of trial identification, based on the QUOROM statement [19]. Asterisk denotes Medline, Embase, Cochrane controlled trials register.
Firstly, we considered trials carried out in industrialised countries (Table 3, which includes all trials). We found a non-significant increase for overall mortality, all-cause pneumonia and pneumococcal pneumonia, for those immunised. For bacteraemia, we found a non-significant reduction. The findings were altered very slightly when lower quality studies were excluded (Table 4, trials with a score of ≥3), and the statistically significant heterogeneity for all-cause pneumonia disappeared. In the trials whose participants fulfilled the JCVI ‘high risk’ criteria we found non-significant adverse effects for overall mortality, pneumococcal and all-cause pneumonia. A non-significant protective effect was found for bacteraemia. The estimates are not greatly affected when the one lower quality study is excluded, Klastersky et al. [20]. This study had a Jadad score of 2. In trials involving unselected elderly populations, the estimates for overall mortality, and pneumococcal pneumonia showed no significant change. We found a non-significant increase in all-cause pneumonia, and a reduction in bacteraemia. Confining the analysis to higher quality studies did not materially alter the estimates other than for pneumococcal pneumonia where a non-significant reduction (0.81, 95%
Table 1 Details of reports included in review Study
Participants, principal exclusions, length of follow-up (FU)
Industrialised countries, high risk Klastersky et al. [20] Bronchial carcinoma, FU unclear Simberkoff et al. [21] Chronic renal, hepatic, cardiac, pulmonary disease, alcoholism, diabetes. Excluded asplenia, recent hospitalisation, previous vaccination, haematological malignancy, FU 2.9 years Davis et al. [22] COPD; excluded asthma, neoplasms, renal or hepatic impairment, sickle cell disease, FU 2 years Leech et al. [23] COPD; excluded other lung disease, previous vaccination, FU 2 years Industrialised countries, older age Koivula et al. [24] Elderly, community, FU 3 years Honkanen et al. [25] Elderly, community, excluded terminally ill, FU 3 years Industrialised countries, other Austriana [26] Health plan members age >45, FU 2 years Austriana [26] Psychiatric in-patients, FU 3 years Gaillet et al. [27] Retirement home residents, geriatric in-patients. Excluded co-morbidities, terminal illness, immunodeficiency, FU 2 years Ortqvist et al. [28] Patients over 50 with previous pneumonia. Excluded immunosuppression, low compliance, FU 4 years Less industrialised countries Austrian et al.a [29] Novice gold miners, Riley et al. [30] Subsistence farmers, Smit et al.a [31] Novice gold miners, Smit et al.a [31] Novice gold miners, a
Multiple trials presented in single report.
FU FU FU FU
2 3 2 2
years years years years
Intervention/control
Quality score (maximum = 5)
17 valent/placebo 14 valent/placebo
2 4
14 valent/placebo
4
14 valent plus influenza/placebo plus influenza
3
14 valent plus influenza/influenza alone 23 valent plus influenza/influenza alone
4 2
12 valent/placebo 12 valent/placebo 14 valent/no placebo
4 4 2
23 valent/placebo
4
6 or 13 valent/meningococcal vaccine/placebo 14 valent/placebo 6 valent/meningococcal vaccine/placebo 12 valent/meningococcal vaccine/placebo
2 3 3 3
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Table 3 Effectiveness of pneumococcal vaccine: comparison of outcomes, all studies Grouping
No. of studies
No. of participants
Relative risk, fixed effects model, 95% confidence interval
Relative risk, random effects model, 95% confidence interval
Chi-square (d.f.) P-value
Industrialised Mortality Pneumonia, all cause Pneumonia, pneumococcal Bacteraemia
8 9 5 6
22760 49685 32854 29641
1.07 1.06 1.06 0.53
[0.97, [0.97, [0.82, [0.22,
1.18] 1.17] 1.37] 1.29]
Same 1.03 [0.86, 1.25] 1.06 [0.82, 1.38] 0.53 [0.20, 1.43]
5.3 22.7 3.4 3.6
High risk Mortality Pneumonia, all cause Pneumonia, pneumococcal Bacteraemia
3 3 2 1
2646 2646 2401 47
1.20 1.17 1.07 0.81
[1.00, [0.86, [0.58, [0.05,
1.42] 1.60] 1.97] 12.16]
1.15 [0.87, 1.52] 1.13 [0.79, 1.62] 0.91 [0.33, 2.53] Same
2.4 (2) 0.30 2.6 (2) 0.31 1.7 (1) 0.19 –
Elderly Mortality Pneumonia, all cause Pneumonia, pneumococcal Bacteraemia
1 2 2 1
2837 29762 29762 26925
0.99 1.15 1.02 0.37
[0.80, [0.95, [0.75, [0.07,
1.22] 1.40] 1.40] 1.91]
Same Same 1.01 [0.69, 1.49] Same
– 0 (1) 0.95 1.46 (1) 0.23 –
Less industrialised Mortality Pneumonia, all cause Pneumonia, pneumococcal Bacteraemia
1 3 – 1
11958 10067 – 5383
0.79 [0.63, 0.99] 0.67 [0.52, 0.87] – 0.14 [0.02, 1.14]
Same Same – Same
– 0.27 (2) 0.87 – –
(7) (8) (4) (5)
0.62 0.00 0.49 0.61
Table 4 Effectiveness of pneumococcal vaccine: comparison of outcomes, studies with Jadad score ≥3 Grouping
No. of studies
No. of participants
Relative risk, fixed effects model, 95% confidence interval
Relative risk, random effects model, 95% confidence interval
Chi-square (d.f.) P-value
Industrialised Mortality Pneumonia, all cause Pneumonia, pneumococcal Bacteraemia
7 7 3 3
21074 21074 5882 983
1.07 1.09 1.02 0.70
1.21] 1.21] 1.43] 2.45]
1.08 [0.96, 1.21] 1.10 [0.99, 1.22] Same 0.92 [0.13, 6.48]
5.3 (6) 0.49 5.4 (6) 0.52 1.6 (2) 0.45 2.97 (2) 0.23
High risk Mortality Pneumonia, all cause Pneumonia, pneumococcal Bacteraemia
3 3 1 –
2646 2646 2354 –
1.20 [1.00, 1.42] 1.17 [0.86, 1.60] 1.27 [0.65, 2.49] –
1.15 [0.87, 1.52] 1.13 [0.79, 1.62] Same –
2.4 (2) 0.30 2.6 (2) 0.31 – –
Elderly Mortality Pneumonia, all cause Pneumonia, pneumococcal Bacteraemia
1 1 1 –
2837 2837 2837 –
0.99 [0.80, 1.22] 1.14 [0.83, 1.57] 0.81 [0.49, 1.33] –
Same Same Same –
– – – –
[0.95, [0.98, [0.73, [0.20,
Less industrialised results are the same as in Table 3.
CI 0.49, 1.33), was found. Excluding the weaker studies removed the bacteraemia estimate. Examining the trials set in less industrialised countries, we found that all-cause pneumonia was the only outcome that could be combined. We found a statistically significant protective effect, a result which was unchanged when lower quality studies were excluded. From a single trial, we found statistically significant protective effects against mortality and a reduction in bacteraemia. The numbers needed to treat
to prevent an adverse outcome based on these estimates are 69 for all-cause pneumonia and 169 for overall mortality.
4. Discussion In this study, we aimed to answer two questions: whether there was evidence that pneumococcal vaccine is similarly effective in industrialised and non-industrialised popu-
L. Watson et al. / Vaccine 20 (2002) 2166–2173
lations, and whether it is effective in those groups for whom it is recommended by UK and US health departments. The results for non-industrialised populations show significant protective effects for all-cause pneumonia and mortality. However, we failed to demonstrate any protective effect of pneumococcal vaccine on three of four relevant clinical outcomes (the exception being bacteraemia) in industrialised populations. Of the trials where participants met UK criteria for high risk, vaccines experienced non-significant increases in adverse events, particularly for mortality and all-cause pneumonia, but with a reduction in bacteraemia. In the unselected elderly, we did not identify benefit for any outcome other than bacteraemia. It is important to note that the very small numbers and wide confidence intervals make it difficult to draw any firm conclusions from the results for bacteraemia. 4.1. Trials The decision to exclude the trials from the 1940s [32,33] was taken because an early vaccine was used, and the sero-epidemiology of pneumococcal disease may also have changed since that time [34]. Since conducting this review, we have identified one further trial initially published in conference proceedings, conducted in Uganda with HIV positive participants [35,36]. This trial found no benefit from vaccination and will be discussed further in Section 4.4. Although data from the trial by Austrian et al. [29] could not be included due to unclear outcome measures, its results are consistent with the other included trials in non-industrialised populations. 4.2. Outcomes In restricting outcomes to those of direct clinical relevance, we aimed to evaluate the overall impact of vaccination on patients and health services. For this reason, we did not consider that serotype-specific outcomes were necessarily helpful. The outcome ‘respiratory deaths’ was considered for inclusion, but we decided that the lack of a common definition and the unreliability of cause of death entered on death certificates would compromise the validity of any results. We also carefully scrutinised the diagnostic criteria for pneumococcal pneumonia, and excluded data on this outcome in studies where it was likely that unreliable criteria were used, or commensal pneumococci might be detected, e.g. nasopharyngeal aspirates. Bacteraemia was included as it is a marker of severe infection. We did not obtain patient specific data from trials because of time constraints. Neither did we have the time or resources to pursue access to all trial data which had been originally obtained, but not published. In addition, we did not address questions of vaccine safety or unwanted effects, but it is generally accepted that the vaccine is safe and this aspect has been widely tested.
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4.3. Variation in effect We find that the disparate results of these trials can be explained by effect modifiers, i.e. variations in the host, agent and environment which are important in determining the effectiveness of pneumococcal vaccine in routine practice. For example, the biological activity of the vaccine will depend upon host immune response and on the probability of exposure to the relevant pathogen. In the studies in less industrialised countries, the host populations were relatively young and fit, and would be expected to have an optimal immune response to the vaccine. This contrasts with studies in industrialised countries, where those with serious underlying illness and elderly persons may have sub-optimal response to the vaccine [37]. A higher proportion of pneumonias may be due to pneumococcal infection in a closed, overcrowded environment, where carriage rates of specific serotypes may be high, in contrast to sporadic cases in more affluent circumstances where there are also more competing causes of illness. Weisholtz et al. [38] have demonstrated in work on the 14 valent vaccine that there is a variable risk of infection with non-vaccine serotypes: in order of decreasing risk, those who are immunosuppressed, those with co-morbidity and those with neither. In addition, the sero-epidemiology of pneumococcal infection is different between industrialised and less industrialised countries [34,39], with different serotypes exhibiting different pathogenic properties. These aspects underline the importance of taking into account clinical heterogeneity in meta-analysis [40–42]. It may be argued that, because of the rarity of clinical outcomes in developed countries, this analysis lacks adequate power to detect a convincing protective effect. However, our approach takes into account absolute rather than relative risk reduction, and considers clinical rather than surrogate outcome measures. If demonstrable health gain for clinical outcomes such as pneumonia and mortality cannot be detected in trials to date, this implies that the numbers needed to treat to prevent any adverse outcomes will be high. Although this is often the case with vaccines, unlike other cases, there is no additional herd immunity effect. Where health commissioners have to prioritise interventions according to effectiveness, efficiency, need and ability to benefit, an expensive vaccination campaign may not be the best use of money if the benefits are uncertain or very marginal. We have demonstrated non-significant increases in important clinical outcomes, bringing into question the exact relation between a reduction in bacteraemia, and hospital admissions or mortality. 4.4. Comparison with other work This meta-analysis is consistent with the previous work of Fine et al. [10], who found no benefit for older patients and those who satisfy JCVI criteria. Their conclusion that vaccination protected from pneumococcal pneumonia in
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‘low risk’ adults was based predominantly on the early studies in non-industrialised countries. It is compatible with the findings of Hutchison et al. [11], although our focus on clinically relevant outcomes and the addition of more recent trials brings us to a different view. A report in Bandolier [35] briefly examined a review with different inclusion criteria (exclusion of quasi-randomised trials, inclusion of trials from the 1940s), but the conclusions concur with ours regarding the lack of demonstration of vaccine effectiveness in industrialised countries. The recent trial in Ugandans with HIV was included [36]. This study found a significant increase in all-cause pneumonia in vaccine recipients, and reinforces our view that clinical heterogeneity in study populations is an important consideration. Non-randomised trials [43] have also produced negative results for clinically important outcomes such as pneumonia, but policy recommendations for use of the vaccine in the west have relied heavily on observational studies, which have not supported effectiveness in the immunosuppressed [8,9]. Retrospective studies are potentially subject to selection bias, e.g. there is evidence of social and racial variation in risk of infection, the highest risk in the poor and in ethnic minorities [12]. McBean et al. demonstrated that elderly Medicare beneficiaries in the US who were white were almost twice as likely to have been immunised than if they were black [7]. We suggest that it is likely that this variation may also exist in younger adults, reflecting socio-economic status and access to medical care. Case-control or cohort studies may not have been able to match adequately for these confounders from variables such as site of hospitalisation [9,44]. Indirect cohort studies have used the distribution of vaccine and non-vaccine serotypes to infer protection from vaccination [8]. This approach requires that risks of infection with such serotypes are evenly distributed between vaccines and non-vaccines. Serotypes may not be evenly distributed in different social circumstances [34,39] or at different ages [34], and neither is vaccination [7]. It is possible that bias may be introduced using this method. 4.5. Policy implications Our finding that the benefit derived from vaccination may depend upon patient characteristics and baseline risk is similar to the case of cholesterol lowering and coronary heart disease [45]. Indeed, the principal reason for conducting trials in the past in non-industrialised populations was that the incidence of pneumococcal disease was unusually high, as was the proportion of deaths from pneumococcal disease. Resources are wasted if treatments are given to patients who are unlikely to benefit [46]. We would welcome a more consistent approach to the interpretation of available evidence by policymakers.
5. Conclusion Our results show that the beneficial effects of pneumococcal polysaccharide vaccine may be dependent on host characteristics, and on the underlying epidemiology of infection in the target population. We suggest that rigorous evidence for widespread vaccination in the susceptible populations for which the vaccine is recommended in the UK and US is lacking. Conjugate or species wide pneumococcal vaccines hold greater promise for prevention of pneumococcal infection.
Acknowledgements The authors would like to thank Dr. Fred Soper for initiating the project, Carole Clark and Lynda Bain for help with literature searching (Grampian Health Board) and Jill Mollison (Department Public Health, University of Aberdeen) for statistical advice. Beverley Balkau of INSERM helped with translation of the French study. This work was initially undertaken as a thesis for the M.Sc. in Health Services and Public Health Research at the University of Aberdeen, awarded in 1999 and funded by Grampian Health Board. References [1] Ostroff SM. Continuing challenge of pneumococcal disease. Lancet 1999;353:1201–2. [2] Obaro SK, Monteil MA, Henderson DC. The pneumococcal problem. BMJ 1996;312:1521–5. [3] Department of Health. Immunisation against Infectious Disease. London: HMSO, 1996. [4] Fedson D, Henrichsen J, Makela PH, Austrian R. WHO recommendations on pneumococcal vaccination. Immunisation of elderly people with polyvalent pneumococcal vaccine. Infection 1989;17:437–41. [5] Prevention of pneumococcal disease: recommendations of the Advisory Committee on Immunisation Practices (ACIP). MMWR 1997;(RR-08):1–24. [6] McDonald P, Friedman EHI, Banks A, Anderson R, Carman V. Pneumococcal vaccine campaign based in general practice. BMJ 1997;314:1094–8. [7] McBean AM, Babish JD, Prihoda R. The utilisation of pneumococcal polysaccharide vaccine among elderly Medicare beneficiaries, 1985 through 1988. Arch Int Med 1991;151:2009–16. [8] Butler JC, Breiman RF, Campbell JF, Lipman HB, Broome CV, Facklam RR. Pneumococcal polysaccharide vaccine efficacy: an evaluation of current recommendations. JAMA 1993;270:1826–31. [9] Shapiro ED, Berg AT, Austrian R, et al. The protective efficacy of polyvalent pneumococcal polysaccharide vaccine. N Eng J Med 1991;325:1453–60. [10] Fine MJ, Smith MA, Carson CA, Meffe F, Sankey SS, Weissfeld LA, et al. Efficacy of pneumococcal vaccination in adults: a meta-analysis of randomised controlled trials. Arch Int Med 1994;154:2666–77. [11] Hutchison BG, Oxman AD, Shannon HS, Lloyd S, Altmayer CA, Thomas K. Clinical effectiveness of pneumococcal vaccine. Can Fam Phys 1999;45:2381–93. [12] Pastor P, Medley F, Murphy TV. Invasive pneumococcal disease surveillance in Dallas County, Texas: results from population-based surveillance in 1995. Clin Infect Dis 1998;26:590–5.
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