Effectiveness of 7-valent pneumococcal conjugate vaccine against radiologically diagnosed pneumonia in indigenous infants in Australia

139Bull World Health Organ 2010;88:139–146 | doi:10.2471/BLT.09.068239 Effectiveness of 7-valent pneumococcal conjugate vaccine against radiologically diagnosed pneumonia in indigenous infants in Australia KF O’Grady,a JB Carlin,b AB Chang,c PJ Torzillo,d TM Nolan,e A Ruben f & RM Andrewsa Objective To evaluate the effectiveness of the 7-valent pneumococcal conjugate vaccine (PCV7) in preventing pneumonia, diagnosed radiologically according to World Health Organization (WHO) criteria, among indigenous infants in the Northern Territory of Australia. Methods We conducted a historical cohort study of consecutive indigenous birth cohorts between 1 April 1998 and 28 February 2005. Children were followed up to 18 months of age. The PCV7 programme commenced on 1 June 2001. All chest X-rays taken within 3 days of any hospitalization were assessed. The primary endpoint was a first episode of WHO-defined pneumonia requiring hospitalization. Cox proportional hazards models were used to compare disease incidence. Findings There were 526 pneumonia events among 10 600 children – an incidence of 3.3 per 1000 child-months; 183 episodes (34.8%) occurred before 5 months of age and 247 (47.0%) by 7 months. Of the children studied, 27% had received 3 doses of vaccine by 7 months of age. Hazard ratios for endpoint pneumonia were 1.01 for 1 versus 0 doses; 1.03 for 2 versus 0 doses; and 0.84 for 3 versus 0 doses. Conclusion There was limited evidence that PCV7 reduced the incidence of radiologically confirmed pneumonia among Northern Territory indigenous infants, although there was a non-significant trend towards an effect after receipt of the third dose. These findings might be explained by lack of timely vaccination and/or occurrence of disease at an early age. Additionally, the relative contribution of vaccine-type pneumococcus to severe pneumonia in a setting where multiple other pathogens are prevalent may differ with respect to other settings where vaccine efficacy has been clearly established. Une traduction en français de ce résumé figure à la fin de l’article. Al final del artículo se facilita una traducción al español. .ةلاقلما هذهل لماكلا صنلا ةياهن في ةصلاخلا هذهل ةيبرعلا ةمجترلا a Menzies School of Health Research, Charles Darwin University, PO Box 41096, Casuarina, NT, 0811, Australia. b Clinical Epidemiology and Biostatistics Unit, Murdoch Childrens Research Institute, Parkville, Vic., Australia. c Queensland Children’s Medical Research Institute, Royal Children’s Hospital, Brisbane, Qld, Australia. d Department of Respiratory Medicine, Royal Prince Alfred Hospital, Camperdown, NSW, Australia e School of Population Health, University of Melbourne, Carlton, Vic., Australia. f Northern Territory Clinical School, Flinders University, Casuarina, NT, Australia. Correspondence to KF O’Grady (e-mail: kogrady@menzies.edu.au). (Submitted: 2 June 2009 – Revised version received: 3 August 2009 – Accepted: 10 August 2009 – Published online: 8 December 2009 ) Introduction Australian indigenous children suffer from extremely high rates of pneumonia and acute respiratory illness,1–3 and determining the potential for reducing disease burden with pneumococcal conjugate vaccines is therefore seen as a major health priority.4 In June 2001, the 7-valent pneumococcal conjugate vaccine (PCV7) was included in the Australian National Immunisation Program as part of a publicly funded course of primary vaccination at 2, 4 and 6 months of age, with a booster dose of the 23-valent polysaccharide pneu- mococcal vaccine at 18 months, for all indigenous infants born on or after 1 April 2001. Catch-up campaigns were conducted in August 2001, targeting indigenous children aged up to 2 years in the northern region and up to 5 years in the central region of the Northern Territory. Although antibiotic use in the community was high and the consequent yield of blood cultures at the time of hospi- talization was poor, data from a central Australian study that used multiple diagnostic methods (culture and pneumolysin assays) had suggested that approximately 30% of hospitalized pneumonia cases were pneumococcal.5 PCV7 covered ap- proximately 56% of pneumococcal serotypes causing invasive disease in indigenous children6 and 60% of pneumococcal serotypes carried in the nasopharynx (K Hare, Menzies School of Health Research, Darwin, personal communication, 2009) although the contribution of these serotypes to nonbacterae- mic pneumonia was unknown. Assumptions based on these data suggested that a PCV7 uptake of at least 80% offered the potential for a 17% reduction of hospitalized pneumonia cases, an effect consistent with data from the pivotal trial of the vaccine in Californian children.7 The aim of this study was to estimate the effectiveness of PCV7 in preventing radiologically diagnosed pneumonia as defined by the World Health Organization (WHO)8 among Northern Territory indigenous infants aged up to 18 months. The WHO case definition was chosen as it was the only one that could be standardized and systematically applied to the available data. For brevity, the term “pneumonia” will be used to refer to radiologically confirmed cases in the remainder of this paper. Methods Design We conducted a historical cohort study of consecutive North- ern Territory indigenous birth cohorts over an 8-year period. 140 Bull World Health Organ 2010;88:139–146 | doi:10.2471/BLT.09.068239 Research Vaccination of Australian indigenous infants against pneumococcus KF O’Grady et al. Birth cohorts were constructed from two population-based health datasets – Northern Territory Immunisation Reg- ister data for the Northern Territory and Northern Territory hospital discharge data. The study was approved by the Human Research Ethics Committee of the Northern Territory Department of Health & Family Services and the Men- zies School of Health Research (approval ID #05/49). Setting Of the Northern Territory’s 200 000 residents, 29% identify themselves as indigenous. Approximately 1500 births occur in this population per year. There are five public hospitals in the North- ern Territory and one private hospital; the latter is rarely used by indigenous persons. Health care is readily available in the Northern Territory. Indigenous infants present on average to primary health centres in remote areas at least once every two weeks in the first year of life.9 All Northern Territory indig- enous children requiring hospitalization are admitted to one of the five public hospitals. Out-of-hospital deaths are rare in the Northern Territory. Mobil- ity is predominantly limited to within regions in the Territory; interstate mi- gration is infrequent. All persons born in or who receive services at any public health care facility in the Northern Territory are allocated a unique health record number. This number is used for all subsequent epi- sodes of medical care in the Territory, and it is the basis for registration on the Northern Territory Immunisation Register – a population-based register to which all vaccine providers report routinely. Children not born in a public hospital are added to the immunization register either through compulsory registration on the Northern Territory midwives’ data collection system or at the time of their first immunization encounter or first presentation for health care. Population studied Children were included if they were born between 1 April 1998 and 28 February 2005 and were resident in the Northern Territory at the time they were enrolled. Children were excluded if they died during the perinatal period (0–29 days of age) or while hospitalized if the admission date had been in the perinatal period, or if they had a first episode of pneumonia in the perinatal period. Outcomes All chest X-rays taken within the first 3 days of any admission for any diag- nosis were obtained from all Northern Territory hospital radiology depart- ments. Films were read independently by two general paediatricians or pae- diatric respiratory specialists blinded to all demographic, clinical and vac- cination history data. Where readings were discordant, the films were read by a panel of paediatric radiologists simi- larly blinded to subject data and to the reason for discordance. All readers had achieved ³ 80% agreement with the WHO training films before the start of the study, and inter-observer agree- ment during the study was ³ 90%. The primary endpoint was a first episode of pneumonia (for consistency with clinical trials of the vaccine). Data on clinical presentation and laboratory investigations were not available for this study. For children in whom more than one chest X-ray was taken, any positive film classified the episode as a pneumonia event. Person–time under observation commenced at 29 days of age (to ex- clude perinatal conditions) and ceased at the earliest of the following: date of admission for the first episode of pneumonia requiring hospitalization (failure date); 31 March 2005; date of death; date on which a child reached 18 months of age; or date on which a child received the 23-valent polysaccharide pneumococcal vaccine (to reduce con- founding of PCV7 effects). Follow-up time was censored at 31 March 2005. As a result, not all children were fol- lowed until 18 months of age, particu- larly those in the last birth cohort. Vaccination status Vaccination status was assigned accord- ing to Northern Territory immuniza- tion register records of PCV7 vaccina- tion. As vaccination status varied with time, person–time was split and anal- ysed by intervals of 0 doses of PCV7, 1 dose, 2 doses and 3 or more doses. To allow sufficient time for an adequate immune response, a dose was not con- sidered to have been received until 14 days after actual administration. Covariates Data available on the children in the study were limited to demographic information, vaccination history and hospitalization data; only age, sex and region of residence could be included as covariates in the analyses. Age was considered a time-varying covariate categorized into 3-month age groups (0 to < 3 months, 3 to < 6 months, 6 to < 9 months, 9 to < 12 months, 12 to < 15 months, 15 to < 18 months). To assess the potential for differ- ential vaccination of children with key co-morbidities known to be associated with the risk of pneumonia (gastro- enteritis, anaemia and/or malnutri- tion), we assessed the differences in vaccination status between hospital- ized children with and without these conditions. To account for opportunity for exposure to 3 doses of vaccine, this analysis was conducted only for chil- dren born on or after 1 April 2001 who were 7 months of age or older at the time of admission. Sample size This study was nested within a larger burden of pneumonia study conducted in the Northern Territory over the same time period.3 On the basis of data from central Australia 5 and tak- ing into account differences in the invasive pneumococcal disease burden between Northern Territory regions,6 we assumed an incidence of 70 cases per 1000 population per year across the Territory as a whole. If 80% cover- age is assumed (on the basis of routine childhood immunization data), 3 birth cohort years before and after the vac- cine would provide 80% power (a = 0.05) to detect a 20% reduction in pneumonia incidence. Statistical analyses Crude incidence rates were calculated by dividing number of cases by person– time at risk and are presented in units per 1000 child–months with cor- responding 95% confidence inter- vals (CIs). Cox proportional hazards models with time-varying covariates10 were used to evaluate the association between receipt of PCV7 (categorized as 0, 1, 2 or 3 doses) and the time 141Bull World Health Organ 2010;88:139–146 | doi:10.2471/BLT.09.068239 Research Vaccination of Australian indigenous infants against pneumococcusKF O’Grady et al. to first pneumonia event. Vaccine ef- fectiveness (VE) was calculated from the estimated hazard ratio (HR) for 1, 2 and 3 doses compared to zero [VE = (1−HR) × 100]. Potential predictors evaluated in the models were age, sex, birth cohort and region of residence. Schoenfeld residual tests were used to evaluate the proportional hazards assumption for each covariate.10 Likelihood ratio tests were used to assess covariate effects and potential interactions.11 Data were ana- lysed using Stata SE v9.1 (StataCorp, College Station, Texas, United States of America). The primary analysis evaluated the association between vaccination and pneumonia in children born on or after 1 April 1998; children born before 1 April 2001 were included as historical controls. Secondary analyses were performed including only chil- dren born on or after 1 April 2001 and with the observation period com- mencing at 5 months, by which time children should have received 2 doses of vaccine. Results A total of 10 600 children were in- cluded in the final analysis. There was no evidence of a change in all- cause hospitalization rates over time (average incidence: 66.0 per 1000 child–months, 95% CI: 64.1–68.0) or the chest X-ray rate per 1000 hospital- izations. A total of 8488 chest X-rays were taken within 3 days of admission in 6775 episodes of care. Chest X-rays were considered of inadequate quality for endpoint diagnosis in 984 (14.5%) episodes. In this analysis, these episodes were considered negative for the study endpoint. There were 526 first episodes of pneumonia – an overall incidence of 3.3 per 1000 child–months (95% CI: 3.1–3.6). Although the data were sug- gestive of a declining incidence over time (Fig. 1), there was insufficient statistical evidence to exclude chance as the basis for the observed change (likeli- hood ratio test for trend c²: 9.98; P = 0.13). This may be due to insufficient follow-up time in the final birth cohort and an increase in incidence in the April 2002–March 2003 cohort. There was little evidence for any patterns in incidence within birth co- Fig. 1. Incidencea of a first episode of WHO-defined consolidated pneumonia, by birth cohort, among NT-resident Australian indigenous children aged 29 days to 18 monthsb, 1998–2005 0In ci de nc e ra te / 10 00 c hi ld -m on th s 6.0 Birth cohort Apr 98– Mar 99 Apr 99– Mar 00 Apr 00– Mar 01 Apr 01– Mar 02 Apr 02– Mar 03 Apr 03– Mar 04 Apr 04– Mar 05 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 95% CI NT, Northern Territory; WHO, World Health Organization. a Cases per 1000 child–months. b Mean person–time at risk in the last birth cohort was 5.5 months compared to 16.4 months in other cohorts. horts by vaccination status (Table 1), although incidence appeared to be declining in both vaccinated and non- vaccinated children between cohorts. The mean age at first episode was 8.1 months; 183 episodes (34.8%) occurred before 5 months of age, 247 (47.0%) by 7 months, and 402 (76.4%) by 12 months. There was no difference in mean ages at the time of first episode by birth cohort. Incidence rates per 1000 child–months were highest in the two youngest age groups (Table 2). Completeness of PCV7 vaccina- tion among children in the study population aged 5 and 7 months by 31 March 2005 was poor: 38.1% (2365 infants) had received 2 doses by 5 months of age, and only 27.0% (1743 infants) had received 3 doses by 7 months. Coverage of 3 doses in- creased to 74% by 12 months of age and 82% by 18 months. Age-adjusted hazard ratios for pneumonia comparing time vaccinated to time unvaccinated are presented in Table 3. There was limited evidence to support an effect of the vaccine in Northern Territory indigenous children for any dose level or cohort group anal- ysed, although the evidence strengthened somewhat after the receipt of 3 doses in children beyond 5 months of age. There was no evidence to support a difference in vaccination status by pres- ence or absence of key co-morbidities (gastroenteritis, anaemia and/or malnu- trition) in children hospitalized for any cause (data not shown). Discussion To our knowledge, this is the first post- licensure field evaluation of PCV7 effectiveness in preventing a first epi- sode of WHO-defined radiologically confirmed pneumonia in infants and the only study that has evaluated the effect of successive doses of the vaccine as children progress in age up to 18 months. It is also the first study that has measured the incidence of a first episode of WHO-defined radiologi- cally confirmed pneumonia in an entire population from 29 days of age with detailed analyses of pneumonia risk by small time intervals. While point estimates suggested a reduction in dis- ease incidence in both vaccinated and unvaccinated children over time and a trend towards a vaccine effectiveness of between 16% and 24% following the third dose, we were unable to exclude chance as the basis of our findings. Vaccine efficacy estimates of 25– 37% have been reported in randomized controlled trials of the 7- and 9-valent vaccines in California, South Africa, the Gambia and the Philippines.12–15 An ecological study in the United States re- ported a 39% decline (95% CI: 22–52) in hospitalized cases with a discharge diagnosis of pneumonia among children less than 2 years of age.16,17 Nelson et al. reported a decline of 40% (incidence rate ratio, IRR 0.60; 95% CI: 0.35–1.04) in cases with a discharge diagnosis of pneumonia among hospitalized children aged less than 1 year, with no evidence 142 Bull World Health Organ 2010;88:139–146 | doi:10.2471/BLT.09.068239 Research Vaccination of Australian indigenous infants against pneumococcus KF O’Grady et al. of an effect in older children.17 However, the WHO definition was not used in the latter two studies and their findings therefore cannot be readily compared to ours. Possible explanations for the dif- ferences between our results and those reported in the clinical trials include: chance variation (our 95% CI allows the possibility of moderately substantial benefit after 3 doses), differences in case ascertainment methods, differences in vaccine schedules and serotype cover- age, the possibility that the seven Strep- tococcus pneumoniae vaccine serotypes are not responsible for the majority of severe pneumonia in these children and/or serotype replacement. The latter may be of particular relevance given that while nasopharyngeal carriage of the serotypes targeted by the PCV7 has declined dramatically since its in- troduction in the Northern Territory, overall carriage of all serotypes remains unchanged.18 Similarly, rates of pneu- monia due to respiratory syncytial virus and influenza virus in this population are high.5,19,20 While there are no data on its contribution to lower respiratory infection in these children, carriage of non-encapsulated Haemophilus influ- enzae is as high as 100% by 120 days of age.21 Data from studies published since this study was conducted suggest that the WHO definition substantially un- derestimates the vaccine-preventable proportion of pneumonia cases and that additional clinical data such as cross-reactive protein values may be im- portant,22–24 although the latter may be population-dependent. In a subanalysis of data from the phase III clinical trial of the 9-valent pneumococcal conjugate vaccine in the Gambia, cross-reactive protein values did not improve esti- mates of vaccine efficacy or vaccine- attributable reduction in incidence.25 We did not have access to clinical data, however, and it is possible that the vac- cine has prevented clinical illness not measured in our study. The early age at which the first episode of pneumonia occurs in this population is an important finding. Half of the cases in our study occurred before 7 months of age and one quarter before 3 months of age. These data are consistent with the known early colo- nization by respiratory pathogens (e.g. Moraxella catarrhalis, H. influenzae and S. pneumoniae) in these children.26,27 It is clear that an effective vaccine would need to be given earlier to Australian indigenous children in order to achieve any substantial effect at the population level. In older children aged 6 months or more, timeliness of vaccination is Table 1. Incidence of WHO-defined consolidated pneumonia, by birth cohort and number of vaccine doses received, among NT-resident Australian indigenous children aged 29 days to 18 months, 1998–2005 Cohort Total Apr 98– Mar 99 Apr 99– Mar 00 Apr 00– Mar 01 Apr 01– Mar 02 Apr 02– Mar 03 Apr 03– Mar 04 Apr 04– Mar 05 0 doses Cases 89 84 58 22 21 13 4 291 Child–months 22 514.3 24 312.7 18 779.7 6 571.7 4 915.9 4 129.7 2 288.0 83 512.0 Incidencea (95% CI) 3.95 (3.21– 4.87) 3.46 (2.79– 4.28) 3.09 (2.39– 3.99) 3.35 (2.20– 5.08) 4.27 (2.79– 6.55) 3.15 (1.83– 5.42) 1.75 (0.66– 4.66) 3.48 (3.10– 3.91) 1 dose Cases NA 0 8 28 15 17 7 75 Child–months NA 65.9 3 047.2 4 653.3 4 658.5 4 444.5 2 211.4 19 080.8 Incidencea (95% CI) NA 0 2.63 (1.31– 5.25) 6.02 (4.15– 8.71) 3.22 (1.94– 5.34) 3.82 (2.38– 6.15) 3.17 (1.51– 6.64) 3.93 (3.13– 4.93) 2 doses Cases NA 0 12 11 23 13 3 62 Child–months NA 1.6 2 918.3 4 653.4 4 630.7 4 232.8 1 386.0 17 822.7 Incidencea (95% CI) NA 0 4.11 (2.34– 7.24) 2.36 (1.31– 4.27) 4.97 (3.30– 7.47) 3.07 (1.78– 5.29) 2.16 (0.69– 6.71) 3.47 (2.71– 4.46) 3 doses Cases NA NA 1 25 37 32 3 98 Child-months NA NA 883.9 11 713.9 12 401.8 11 134.9 1 176.1 37 310.6 Incidencea (95% CI) NA NA 1.13 (0.16– 8.03) 2.13 (1.44– 3.16) 2.98 (2.16– 4.12) 2.87 (2.03– 4.06) 2.55 (0.82– 7.90) 2.63 (2.15– 3.20) Total Cases 89 84 79 86 96 75 17 526 Child-months 22 514.3 24 380.2 25 629.0 27 592.2 26 607.0 23 941.9 7 061.5 15 7726.1 Incidencea (95% CI) 3.95 (3.21– 4.87) 3.46 (2.78– 4.27) 3.08 (2.47– 3.84) 3.12 (2.52– 3.85) 3.61 (2.95– 4.41) 3.13 (2.50– 3.93) 2.41 (1.49– 3.87) 3.33 (3.06– 3.63) CI, confidence interval; NT, Northern Territory; WHO, World Health Organization. a Cases per 1000 child–months. 143Bull World Health Organ 2010;88:139–146 | doi:10.2471/BLT.09.068239 Research Vaccination of Australian indigenous infants against pneumococcusKF O’Grady et al. Table 2. Incidence of WHO-defined consolidated pneumonia, by age group, among NT-resident Australian indigenous children aged 29 days to 18 months, 1998–2005 Age group No. children Cases Child–months Incidencea (95% CI) 29 days to < 3 months 10 600 128 30 596.2 4.18 (3.52–4.97) 3 to < 6 months 10 102 112 29 210.2 3.83 (3.19–4.61) 6 to < 9 months 9 668 95 27 921.7 3.40 (2.78–4.16) 9 to < 12 months 9 225 80 26 625.1 3.00 (2.41–3.74) 12 to < 15 months 8 766 74 25 186.2 2.93 (2.34–3.69) 15 to < 18 months 8 275 37 18 186.6 2.03 (1.47–2.81) Totalb 10 600 526 157 726.1 3.33 (3.06–3.63) CI, confidence interval; NT, Northern Territory; WHO, World Health Organization. a Cases per 1000 child–months. b Row represents the total number of children who contributed time to the study, and the total number of cases and overall incidence rate, irrespective of age. Table 3. Age-adjusted hazard rate ratios for WHO-defined consolidated pneumonia in vaccinated and unvaccinated NT indigenous infants aged 29 days to 18 months, by number of vaccine doses and analysis time period Time period and cohort 0 doses 1 dose 2 doses 3 doses Cases (child– months) Cases (child– months) HRR 95% CI Cases (child– months) HRR 95% CI Cases (child– months) HRR 95% CI Children born 1 Apr 2001 – 28 Feb 2005, from 29 days of age 61 (17 909) 68 (15 972) 1.02 0.69–1.49 50 (14 907) 1.10 0.72–1.67 97 (36 438) 0.97 0.65–1.47 Children born 1 Apr 1998 – 28 Feb 2005, from 29 days of age 295 (83 623) 76 (19 085) 1.01 0.78–1.32 62 (17 827) 1.03 0.72–1.47 98 (37 322) 0.84 0.60–1.17 All children, from 5 months of agea 155 (49 362) 21 (7 709) 0.83 0.52–1.32 45 (12 697) 1.37 0.81–2.32 97 (37 165) 0.76 0.53–1.09 CI, confidence interval; HRR, hazard rate ratio; NT, Northern Territory ; WHO, World Health Organization. a Excludes 183 children who were censored before reaching 5 months of age. likely to be critical. While coverage reached over 85% by 18 months of age,28 fewer than 40% of eligible chil- dren had received 3 doses of the vaccine by 7 months of age. The necessity of 3 doses in infancy is suggested by this study’s data: while not statistically sig- nificant, the data indicated a reduction in incidence of 24% (95% CI: −9–47) after the third dose in children aged 5 months and older. The major strength of this study is that we reviewed every hospitalization and every chest X-ray for every indig- enous infant in the Northern Territory during the study period. The same per- son collected and processed all X-rays, and the person analysing the data was not involved in the reading of X-rays. The X-ray readers were not aware of the subject’s demographic, clinical and vac- cination history. The study design and analysis methods allowed an assessment of pneumonia as children aged over small time intervals and accounted for the potential variations in risk over time. We were able to commence measure- ment of person–time at risk at the same time for all individuals (29 days). In populations with rapid acquisition and nasopharyngeal colonization of respira- tory pathogens early in life, as occurs in the Northern Territory indigenous population,26 variations in the age at which children enter a study may lead to differences in risk profiles between these children. This would be critical in studies without randomization of children to different groups. Account- ing for the risk of infection and subse- quent disease early in life is critical to the formulation of policies concerning vaccine schedules and number of doses required by specific ages. We were able to exclude infants who had suffered a first episode of WHO-defined consolidated pneumo- nia in the perinatal period and who were therefore likely to have a different risk profile from those who had sur- vived this period without contracting pneumonia. Importantly, as individual consent was not required for entry into the study, we were able to include every Northern Territory child. A major issue in clinical trials and other studies that enrol individuals is accounting for po- tentially important differences between those who do and do not consent to participate. Similarly, generally only healthy children are eligible for inclu- sion in clinical trials. Uncertainty about the accuracy of the person–time denominator is a limi- tation. However, increasing vaccination coverage as children aged suggested that children were continuing to present to Northern Territory health services throughout infancy. The predominant reasons for censoring in this study were subjects reaching 18 months of age and the study reaching its end date of 31 March 2005. Both of these are ad- ministrative censoring points and the bias to the study is less important given that this type of censoring is largely independent of the characteristics of the individuals under observation.29 However, the considerably shorter person–time available in the analysis 144 Bull World Health Organ 2010;88:139–146 | doi:10.2471/BLT.09.068239 Research Vaccination of Australian indigenous infants against pneumococcus KF O’Grady et al. Résumé Efficacité du vaccin antipneumococcique conjugué heptavalent contre la pneumonie diagnostiquée par examen radiologique chez les nourrissons indigènes en Australie Objectif Évaluer l’efficacité du vaccin antipneumococcique conjugué heptavalent (PCV7) dans la prévention de la pneumonie diagnostiquée par examen radiologique selon les critères de l’Organisation mondiale de la Santé (OMS) chez les nourrissons indigènes du Territoire du Nord en Australie. Méthodes Nous avons mené une étude historique sur des cohortes de naissances dans la population indigène consécutives, nées entre le 1er avril 1998 et le 28 février 2005. Les enfants ont été suivis jusqu’à l’âge de 18 mois. Le programme PCV7 a débuté le 1er juin 2001. Toutes les radiographies thoraciques réalisées dans les 3 jours suivant une hospitalisation quelconque ont été évaluées. Le principal critère de jugement était l’existence d’un premier épisode de pneumonie selon la définition de l’OMS ayant nécessité une hospitalisation. Nous avons fait appel à des modèles de Cox à risques proportionnels pour comparer les incidences de cette maladie. Résultats Nous avons relevé 526 cas de pneumonie parmi 10600 enfants - soit une incidence de 3,3 cas pour 1000 enfants- mois ; 183 épisodes (34,8 %) sont intervenus avant l’âge de 5 mois et 247 (47,0 %) à 7 mois. Parmi les enfants étudiés, 27 % avaient reçu 3 doses de vaccin à l’âge de 7 mois. Les rapports de risques pour le critère de jugement pneumonie valaient 1,01 pour la comparaison 1 dose de vaccin contre 0 dose ; 1,03 pour la comparaison 2 doses contre 0 dose ; et 0,84 pour la comparaison 3 doses contre 0 dose. Conclusion Les preuves d’une réduction par le vaccin PCV7 de l’incidence de la pneumonie diagnostiquée par examen radiologique chez les nourrissons indigènes du territoire du Nord étaient limitées, malgré la présence d’une tendance non significative à la manifestation d’un effet après l’administration de la troisième dose. Ces résultats peuvent s’expliquer par la fréquence des retards dans la vaccination et/ou par l’apparition de la maladie à un âge précoce. De plus, la contribution des germes pneumococcus de type vaccinal à la pneumonie sévère dans un contexte où l’on rencontre de nombreux autres agents pathogènes peut être différente de leur contribution dans une situation où l’efficacité du vaccin a été clairement établie. for the last birth cohort may have lim- ited the study’s ability to detect vaccine effects. This is of particular relevance to interpreting the trend observed over time, as it is impossible to determine whether the decline in rates observed in the last year was sustained or was just a yearly variation in the incidence of disease. Moreover, declines appeared to be occurring independent of vac- cination status. This underscores the need for ongoing surveillance of severe pneumonia in the Northern Territory population. The lack of information on poten- tially confounding factors – particu- larly known risk factors such as prema- turity, low birth weight, co-morbidities and exposure to household and to- bacco smoke 30 – necessitates a cau- tious approach to the interpretation of vaccine effectiveness in this study. Differences in these factors between vaccinated and unvaccinated children could have confounded the vaccine effectiveness. However, for these fac- tors to explain our findings, vaccinated children would need to be at higher risk of exposure. Our data do suggest that vaccination status did not differ between hospitalized children with and without the other major causes of paediatric morbidity in the Northern Territory (gastroenteritis, malnutrition and anaemia). A final limitation is the potential lack of power in this study to dem- onstrate an effect. Baseline disease incidence was calculated on estimates derived from a study that did not use the WHO definition for radiologically confirmed pneumonia because it was not available at the time.5 Because of our use of the WHO definition and our decision to evaluate only the first episode, disease incidence in this population was considerably lower than anticipated. Additional analyses evaluating repeated episodes of WHO- defined radiologically diagnosed pneu- monia and all-cause acute lower respira- tory infection and pneumonia requiring hospitalization have been performed for children from 5 to 23 months of age and have not changed our findings substantially.31 We were unable to demonstrate definitively that PCV7 had an effect in preventing a first episode of radiologi- cally diagnosed pneumonia in a setting characterized by high rates occurring very early in infancy with delays in de- livery of the primary vaccination series. This study highlights the importance of immunization timeliness to extrapo- lating the results of vaccine efficacy established in randomized controlled trials relative to vaccine effectiveness at the population level with vaccine delivery under routine field conditions. Optimizing the timeliness of vaccina- tion in the Northern Territory infant population is a priority public health measure. Ongoing surveillance and further studies are required to evaluate whether the trend observed in the final year of the study was maintained. ■ Acknowledgements The authors would like to thank the following people for their invaluable contribution to this work: Debbie Taylor-Thomson, Paul Bauert, Peter Morris, Gavin Wheaton, Grant Mack- enzie, John De Campo, Margaret De Campo and Jane Benson of the study team; Vicki Krause, Christine Selvey, Linda Graham and Charles Roberts of the Centre for Disease Control, North- ern Territory Department of Health and Families; Suzanna Vidmar of the Murdoch Childrens Research Institute; and Kim Mulholland, Tilman Ruff and Thomas Cherian, expert advisors. Funding: Funding for this study was provided by Wyeth Vaccines. K O’Grady was supported by a National Health & Medical Research Council Post- Graduate Training Scholarship in indigenous Health and by the Austra- lian Academy of Science’s Douglas and Lola Douglas Scholarship in Medical Research. The sponsors of this study had no role in the design, implementa- tion, analysis, interpretation or report- ing of the work. Competing interests: None declared. 145Bull World Health Organ 2010;88:139–146 | doi:10.2471/BLT.09.068239 Research Vaccination of Australian indigenous infants against pneumococcusKF O’Grady et al. Resumen Eficacia de la vacuna antineumocócica conjugada heptavalente contra la neumonía diagnosticada radiológicamente en lactantes indígenas en Australia Objetivo Determinar la eficacia de la vacuna antineumocócica conjugada heptavalente (PCV7) en la prevención de la neumonía diagnosticada radiológicamente de acuerdo con los criterios de la Organización Mundial de la Salud (OMS) entre lactantes indígenas del Territorio Septentrional de Australia. Métodos Realizamos un estudio de cohorte histórica con cohortes de nacimiento de indígenas consecutivas entre el 1 de abril de 1998 y el 28 de febrero 2005. Los niños fueron sometidos a seguimiento hasta los 18 meses de edad. El programa de administración de PCV7 comenzó el 1 de junio de 2001. Se estudiaron todas las radiografías de tórax realizadas dentro de los tres primeros días de hospitalización. La variable de evaluación principal fue un primer episodio de neumonía acorde con la definición de la OMS que requiriese hospitalización. Para comparar la incidencia de la enfermedad se usaron modelos de riesgos proporcionales de Cox. Resultados Se registraron 526 eventos de neumonía entre 10 600 niños, lo que supone una incidencia de 3,3 por 1000 niños-mes; 183 episodios (34,8%) se produjeron antes de los 5 meses de edad, y 247 (47,0%) antes de los 7 meses. De los niños estudiados, un 27% habían recibido 3 dosis de vacuna antes de los 7 meses de edad. Los cocientes de riesgos instantáneos para la neumonía como variable de evaluación fueron de 1,01 para 1 frente a 0 dosis; 1,03 para 2 frente a 0 dosis; y 0,84 para 3 frente a 0 dosis. Conclusión Los datos obtenidos no parecen respaldar la idea de que la PCV7 reduzca la incidencia de neumonía confirmada radiológicamente entre los lactantes indígenas del Territorio Septentrional, pese a que se detecta una tendencia, no significativa, a la manifestación de un efecto después de la tercera dosis. Estos resultados podrían explicarse suponiendo que la vacunación no se hizo en su debido momento y/o la enfermedad apareció a una edad temprana. Además, la contribución relativa del neumococo del tipo vacunal a la neumonía grave en un entorno donde concurren con frecuencia muchos otros agentes patógenos puede diferir respecto a otros entornos en que la eficacia de la vacuna ha quedado claramente demostrada. صخلم ايلاترسا في ينيلصلأا لافطلأا ينب ًايعاعش صخشلما يوئرلا باهتللاا في ةيوئرلا تاروكملل داضلما نراقتلما ءوفاكتلا يعابسلا حاقللا ةيلاعف داضلما نراقتلما ءوفاكتلا يعابسلا حاقللا ةيلاعف ىدم مييقت :فدهلا اقفو ًايعاعش صخشلما ،يوئرلا باهتللاا نم ةياقولا في ةيوئرلا تاروكملل ةيلماشلا ضيارلأا في ينيلصلأا لافطلأا ينب كلذو ةيلماعلا ةحصلا ةمظنم يرياعلم .ايلاترسلا ةعباتتلما ةيبارتلأا تادلاولا لوح ةيبارتأ ةيخيرات ةسارد تيرجأ :ةقيرطلا ريابرف/طابش 28 ىتحو 1998 ليربإ/ناسين 1 نم ةترفلا في ينيلصلأا ناكسلل أدب دقو .رمعلا نم ًارهش 18 مهغولب ىتح لافطلأا ةعباتم تتمو ،2005 لوأ في ةيوئرلا تاروكملل داضلما نراقتلما ءوفاكتلا يعابسلا حاقللا جمانرب ةذوخألما ةيردصلا ةيعاعشلا روصلا عيمج مييقت متو .2001 هينوي/ناريزح ةيلولأا ةياهنلا ةطقن تناكو .تايفشتسلما في زاجتحلاا نم مايأ ةثلاث للاخ ةيلماعلا ةحصلا ةمظنم تاددحلم اقفو يوئرلا باهتللاا نم لىولأا ةبئانلا يه Cox سكوك جذانم تمدختسا ماك .ىفشتسلما في زاجتحلاا بلطتت يتلاو .ضرلما تاعوقو ةنراقلم كلذو ةيبسنلا رطاخلما سايقل – لفط 10600 ينب يوئرلا باهتللاا نم ةلاح 526 كانه تناك :تادوجولما ةبئان 183 تثدحو ؛رهشلا في لفط 1000 لكل 3.3 تاعوقولا ةبسن تغلب لولحب )%47.0( ةبئان 247 و ،رمعلا نم سماخلا رهشلا لبق )%34.8( %27 ناك ،ةساردلل اوعضخ نيذلا لافطلأا ينب نمو .رمعلا نم عباسلا رهشلا امأ .رمعلا نم عباسلا رهشلا مهغولبب حاقللا نم تاعرج ثلاث اوقلت دق مهنم ةعرج لكل 1.01 تناكف يوئرلا باهتللاا نم ةيئاهنلا ةطقنلل رطاخلما ةبسن ،تاعرجلا نم رفص لباقم ينتعرج لكل 1.03 و ،تاعرجلا نم رفص لباقم .تاعرجلا نم رفص لباقم تاعرج ثلاث لكل 0.84و نراقتلما ءوفاكتلا يعابسلا حاقللا نأ لىع ةدودحم تانيب كانه :جاتنتسلاا ريوصتلاب دكؤلما يوئرلا باهتللاا ثودح نم دحي ةيوئرلا تاروكملل داضلما نم مغرلاب ،ايلاترسلأ ةيلماشلا ضيارلأا في ينيلصلأا لافطلأا ينب يعاعشلا ةثلاثلا ةعرجلا يقلت دعب حاقللا يرثأت لوح ًايئاصحإ هب دتعي لا هاجتا دوجو بسانلما تقولا في حيقلتلا ءارجإ مدع لىإ جئاتنلا هذه ىزعت نأ نكيمو .هنم داضلما حاقلل يعونلا يرثأتلا نأ لىع ةولاع اذه .ركبم رمع في ضرلما ثودح وأ شرتنتت يتلا نكاملأا في ميخولا يوئرلا باهتللال ةبسنلاب ةيوئرلا تاروكملل ثيح ىرخلأا نكاملأا في هنع فلتخي دق ىرخلأا تاضرملما نم ديدعلا اهيف .ةحضاو ةروصب اهيف حاقللا ةيلاعف تدكأت References 1. 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