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Summary Background In October, 2012, Fiji introduced routine infant immunisation with a ten-valent pneumococcal conjugate vaccine (PCV10) using three primary doses and no booster dose (3 + 0 schedule). Data are scarce for the effect of PCV in the Asia and Pacific region. We aimed to evaluate the effect of PCV10 on pneumonia hospital admissions in children younger than 5 years and adults aged 55 years and older in Fiji, 5 years after vaccine introduction. Methods We did a time-series analysis assessing changes in pneumonia hospital admissions at three public tertiary hospitals in Fiji. Four pneumonia outcomes were evaluated: all-cause pneumonia, severe or very severe pneumonia, hypoxic pneumonia, and radiological pneumonia. Participants aged younger than 2 months, 2–23 months, 24–59 months, and 55 years and older were included. Data were extracted from the national hospital admission database according to International Classification of Diseases-tenth revision codes J10·0-18·9, J21, and J22 for all-cause pneumonia. Medical records and chest radiographs were reviewed for the main tertiary hospital to reclassify hospital admissions in children aged younger than 2 years as severe or very severe, hypoxic, or radiological pneumonia as per WHO definitions. Time-series analyses were done using the synthetic control method and multiple imputation to adjust for changes in hospital usage and missing data. Findings Between Jan 1, 2007, and Dec 31, 2017, the ratio of observed cases to expected cases for all-cause pneumonia was 0·92 (95% CI 0·70–1·36) for children aged younger than 2 months, 0·86 (0·74–1·00) for children aged 2–23 months, 0·74 (0·62–0·87) for children aged 24–59 months, and 1·90 (1·53–2·31) in adults aged 55 years and older, 5 years after PCV10 introduction. These findings indicate a reduction in all-cause pneumonia among children aged 24–59 months and an increase in adults aged 55 years and older, but no change among children aged younger than 2 months. Among children aged 2–23 months, we observed declines of 21% (95% CI 5–35) for severe or very severe pneumonia, 46% (33–56) for hypoxic pneumonia, and 25% (9–38) for radiological pneumonia. Mortality reduced by 39% (95% CI 5–62) for all-cause pneumonia, bronchiolitis, and asthma admissions in children aged 2–23 months. Interpretation The introduction of PCV10 was associated with a decrease in pneumonia hospital admissions in children aged 2–59 months. This is the first study in a middle-income country in the Asia and Pacific region to show the effect of PCV on pneumonia, filling gaps in the literature on the effects of PCV10 and 3 + 0 schedules. These data support decision making on PCV introduction for other low-income and middle-income countries in the region. Funding Department of Foreign Affairs and Trade of the Australian Government.

Background Currently there are trials in Africa and Asia investigating whether prophylactic azithromycin during pregnancy reduces infection-related neonatal morbidity and mortality. We undertook a systematic review and meta-analysis to determine the effect of azithromycin during pregnancy on perinatal and neonatal outcomes. Methods We identified articles between January 1990 and 13th June 2021 by searching five electronic databases. Randomised control trials (RCTs) that included pregnant women administered azithromycin alone or in combination with other medications, and that reported outcomes of low birthweight (LBW), prematurity, stillbirth, and neonatal deaths, infections, and admissions, were eligible. Fixed effects meta-analyses were used for primary analysis. Quality appraisal was performed using Cochrane's Risk of Bias 2 tool. This review was registered with PROSPERO, CRD42019127099. Findings The search generated 5777 studies, of which 14 studies were included involving 17,594 participants. Most studies investigated azithromycin as Intermittent Preventive Treatment in Pregnancy (IPTp) for malaria. More than 50% of the studies had low risk of bias for all outcomes, except for LBW and neonatal admissions. Fixed-effects meta-analyses found that azithromycin reduced the risk of LBW (seven studies, Pooled RR 0·79; 95% CI 0·68-0·93; I2 = 0·00%), and prematurity compared to controls (eight studies, Pooled RR 0·87; 95% CI 0·78-0·98; I2 = 23·28%). There was no strong evidence of any effect on neonatal mortality, infections and admissions. There was an increase in stillbirth but the 95% CI crossed the null value (seven studies, Pooled RR 1·39; 95% CI 0·94 – 2.07; I2=0·00%). However this review was limited by differences in the types of intervention and study populations, and inconsistency in outcome reporting between studies. Interpretation Prophylactic azithromycin during pregnancy reduces LBW and prematurity. However, as azithromycin has been investigated as part of IPTp, it is unclear whether it would improve perinatal and neonatal outcomes in non-malaria endemic settings. The potential harm on stillbirth rates needs further investigation. Funding None

Background Pneumococcal disease is preceded by carriage of pneumococci. We describe factors associated with pneumococcal nasopharyngeal carriage in Fiji, using data from annual (2012-2015) cross-sectional surveys, pre- and post-introduction of ten-valent pneumococcal conjugate vaccine (PCV10). Methods Infants (5-8 weeks), toddlers (12-23 months), children (2-6 years), and their caregivers participated. Pneumococci were detected using lytA qPCR, with molecular serotyping by microarray. We used logistic regression to determine predictors of carriage and density. Results There were 8,109 participants. Pneumococcal carriage was associated with: years post-PCV10 introduction (global P2 children Conclusions Introduction of PCV10 reduced the odds of overall and PCV10 pneumococcal carriage in Fiji. ITaukei ethnicity was positively associated with carriage after adjustment for PCV10. Key messages PCV10 introduction was associated with reduced odds of overall and PCV10 pneumococcal carriage in Fiji. Despite high and similar PCV10 coverage rates, iTaukei ethnicity is positively associated with pneumococcal carriage, compared with Fijian of Indian Descent populations.

Highlights • Pneumococcal carriage rates and the frequency of physical contact differed by ethnicity. • Contact with older children and toddlers was positively associated with vaccine-type carriage. • Unvaccinated older children may become a vaccine-type carriage reservoir post-PCV10. • Ethnic differences in social contact did not explain ethnic differences in carriage. • Pneumococcal density was not associated with ethnicity, contact, or PCV10 status., Background Pneumococcal carriage is a prerequisite for pneumococcal disease. Little is known about whether social contact frequency and intensity are associated with pneumococcal carriage. In Fiji, indigenous iTaukei have higher prevalence of pneumococcal carriage compared with Fijians of Indian Descent (FID). We hypothesised that contact differences may contribute to ethnic differences in pneumococcal carriage prevalence and density. Methods In 2015, young infants (5–8 weeks), toddlers (12–23 months), children (2–6 years), and caregivers from Suva and surrounding areas, participated in a cross-sectional survey (n = 2014), three years post pneumococcal conjugate vaccine introduction. Demographic and contact data, and nasopharyngeal swabs were collected. Pneumococci were detected, and quantified using quantitative real-time PCR, with molecular serotyping by microarray. Associations between ethnicity, contact, and pneumococcal carriage and density were estimated using multivariable generalised estimating equation regression models. Results iTaukei participants had larger household sizes, higher pneumococcal carriage rates, more contacts, and more frequent contacts of longer duration, compared with FID. The odds of vaccine-type carriage increased by 28% (95% CI 8–53%) P

To quantify the impact of the change in definition of severe pneumonia on documented pneumonia burden.We reviewed existing data acquired during observational hospitalized pneumonia studies, before the introduction of the pneumococcal conjugate vaccine, in infants aged 2-23 months from Fiji, Gambia, Lao People's Democratic Republic, Malawi, Mongolia and Viet Nam. We used clinical data to calculate the percentage of all-cause pneumonia hospitalizations with severe pneumonia, and with primary end-point consolidation, according to both the 2005 or 2013 World Health Organization (WHO) definitions. Where population data were available, we also calculated the incidence of severe pneumonia hospitalizations according to the different definitions.At six of the seven sites, the percentages of all-cause pneumonia hospitalizations due to severe pneumonia were significantly less (The revision of WHO's definition of severe pneumonia affects pneumonia epidemiology, and hence the interpretation of any pneumonia intervention impact evaluation.Quantifier l'impact de la modification de la définition de pneumonie sévère sur le fardeau documenté de la pneumonie.Nous avons examiné les données existantes obtenues dans le cadre d'études d'observation de la pneumonie hospitalière, avant l'introduction du vaccin antipneumococcique conjugué, chez des nourrissons âgés de 2 à 23 mois aux Fidji, en Gambie, au Malawi, en Mongolie, en République démocratique populaire lao et au Viet Nam. Nous avons utilisé des données cliniques pour calculer le pourcentage d'hospitalisations pour une pneumonie toutes causes confondues avec une pneumonie sévère, et avec une consolidation des critères d'évaluation primaire, selon les définitions de l'Organisation mondiale de la Santé (OMS) de 2005 et 2013. Lorsque des données démographiques étaient disponibles, nous avons également calculé l'incidence des hospitalisations pour une pneumonie sévère selon les différentes définitions.Dans six des sept sites, les pourcentages d'hospitalisations pour une pneumonie toutes causes confondues en raison d'une pneumonie sévère étaient nettement plus faibles (La révision de la définition de l'OMS de la pneumonie sévère affecte l'épidémiologie de la pneumonie et, par conséquent, l'interprétation de toute évaluation de l'impact d'une intervention contre la pneumonie.Cuantificar el impacto del cambio en la definición de neumonía grave sobre la carga de neumonía documentada.Se revisaron los datos existentes adquiridos durante los estudios observacionales de neumonía hospitalizada, antes de la introducción de la vacuna antineumocócica conjugada, en lactantes de 2 a 23 meses de edad procedentes de Fiji, Gambia, Malawi, Mongolia, la República Democrática Popular Lao y Vietnam. Se utilizaron datos clínicos para calcular el porcentaje de hospitalizaciones por neumonía de cualquier causa con neumonía grave, y con consolidación del punto final primario, de acuerdo con las definiciones de la Organización Mundial de la Salud (OMS) de 2005 o 2013. Cuando se dispuso de datos demográficos, también se calculó la incidencia de las hospitalizaciones por neumonía grave de acuerdo con las diferentes definiciones.En seis de los siete sitios, los porcentajes de hospitalizaciones por neumonía de cualquier causa con neumonía grave fueron significativamente menores (p0,001) según la definición de la OMS de 2013 en comparación con la de 2005. Sin embargo, el porcentaje de hospitalizaciones por neumonía grave, según las dos definiciones de neumonía grave, con consolidación del punto final primario varió poco dentro de cada sitio. La incidencia anual de hospitalizaciones por neumonía grave por cada 100.000 lactantes fue significativamente menor (total p0,001) según la definición de 2013 en comparación con la de 2005 y osciló entre una diferencia de −301,0 (intervalo de confianza, IC, del 95 %: −405,2 a −196,8) en Fiji y −3242,6 (IC del 95 %: −3695,2 a −2789,9) en Gambia.La revisión de la definición de neumonía grave de la OMS afecta a la epidemiología de la neumonía y, por tanto, a la interpretación de cualquier evaluación del impacto de una intervención para la neumonía.الغرض قياس تأثير التغيير في تعريف الالتهاب الرئوي الشديد على عبء الالتهاب الرئوي الموثق. الطريقة لقد قمنا باستعراض البيانات التي تم الحصول عليها أثناء دراسات الالتهاب الرئوي في المستشفيات تحت الملاحظة، قبل طرح لقاح المكورات الرئوية، في الرضع الذين تتراوح أعمارهم بين 2 و3 أشهر من فيجي، وغامبيا، وجمهورية لاو الديمقراطية الشعبية، وملاوي، ومنغوليا، وفييت نام. واستخدمنا البيانات السريرية لحساب النسبة المئوية لعلاج حالات الإصابة بالالتهاب الرئوي الشديد بالمستشفيات مع كل الأسباب، ومع توحيد نقطة النهاية الأولية، وفقا لكل من تعريفات منظمة الصحة العالمية (WHO) عامي 2005 أو 2013. وحيثما كانت البيانات السكانية متاحة، قمنا أيضاً بحساب معدل العلاج بالمستشفى لحالات الالتهاب الرئوي الشديد وفقاً للتعريفات المختلفة.في ستة من المواقع السبعة، كانت النسب المئوية لحالات العلاج بالمستشفيات نتيجة الإصابة بالالتهاب الرئوي الشديد بالمستشفيات مع كل الأسباب أقل بشكل ملموس (نسبة الاحتمال0.001) وفقًا لتعريف منظمة الصحة العالمية لعام 2013 مقارنةً بتعريف عام 2005. إلا أن النسبة المئوية لحالات علاج الالتهاب الرئوي الشديد بالمستشفيات، وفقا لتعريفي الالتهاب الرئوي الشديد، مع توحيد نقطة النهاية الأولية، تباينت قليلا داخل كل موقع. كان المعدل السنوي لحالات العلاج بالمستشفيات نتيجة الإصابة بالالتهاب الرئوي الشديد من كل الأسباب أقل بشكل ملموس (نسبة الاحتمال0.001) وفقًا لتعريف عام 2013 مقارنةً بتعريف عام 2005، يتراوح من اختلاف قدره -301.0 (فاصل الثقة 95%: 405.2- إلى 196.8-) في فيجي إلى 3242.6- (فاصل الثقة 95‏%: 3695.2- إلى 2789.9-) في غامبيا.إن مراجعة تعريف منظمة الصحة العالمية (WHO) للالتهاب الرئوي الشديد يؤثر على الانتشار الوبائي الالتهاب الرئوي، ومن ثم يؤثر على تحليل أي تقييم لتأثير التدخل العلاجي للالتهاب الرئوي.旨在量化重症肺炎定义的变化对已记录肺炎负担的影响。.我们回顾了斐济、冈比亚、老挝人民民主共和国、马拉维、蒙古和越南六国在引入肺炎球菌结合疫苗之前，2–23 个月大的婴儿在住院肺炎的观察性研究中获得的现有数据。根据 2005 年和 2013 年世界卫生组织的定义，我们使用临床数据计算了重症肺炎和主要终点巩固的全因肺炎住院患者的百分比。基于可获得的人口数据，我们还根据不同定义计算了重症肺炎住院治疗的发病率。.根据 2013 年与 2005 年世界卫生组织的定义对比结果，发现 6 个地点（共 7 个）中因重症肺炎而住院的全因肺炎患者百分比显著下降（世卫组织对重症肺炎定义的修订会影响肺炎流行病学，从而对任何肺炎干预评估的解释造成影响。.Количественная оценка воздействия изменений в определении тяжелой формы пневмонии на документированное бремя заболевания.Авторы изучили имеющиеся данные, собранные во время обсервационных исследований пневмонии у госпитализированных больных до начала использования пневмококковой конъюгированной вакцины у детей в возрасте от 2 до 23 месяцев из Вьетнама, Гамбии, Лаосской Народно-Демократической Республики, Малави, Монголии и Фиджи. Клинические данные использовались для расчета процентной доли госпитализации пациентов с тяжелой формой пневмонии, независимо от ее причины, с консолидацией по основной конечной точке в соответствии с двумя разными определениями ВОЗ: от 2005 года и от 2013 года. При наличии популяционных данных авторы также рассчитывали частоту госпитализации пациентов с тяжелой формой пневмонии в соответствии с этими двумя определениями.В шести из семи исследованных стран доля госпитализации пациентов с тяжелой формой пневмонии, независимо от причины заболевания, была значительно ниже (Пересмотр определений ВОЗ для тяжелой формы пневмонии влияет на эпидемиологию заболевания и, следовательно, на интерпретацию оценки воздействия любого вмешательства, связанного с этим заболеванием.

The introduction of the rotavirus vaccine, Rotarix, into the Fiji National Immunisation Program in 2012 has reduced the burden of rotavirus disease and hospitalisations in children less than 5 years of age. The aim of this study was to describe the pattern of rotavirus genotype diversity from 2005 to 2018, to investigate changes following the introduction of the rotavirus vaccine in Fiji. Faecal samples from children less than 5 years with acute diarrhoea between 2005 to 2018 were analysed at the WHO Rotavirus Regional Reference Laboratory at the Murdoch Children’s Research Institute, Melbourne, Australia, and positive samples were serotyped by EIA (2005–2006) or genotyped by heminested RT-PCR (2007 onwards). We observed a transient increase in the zoonotic strain equine-like G3P[8] in the initial period following vaccine introduction. G1P[8] and G2P[4], dominant genotypes prior to vaccine introduction, have not been detected since 2015 and 2014, respectively. A decrease in rotavirus genotypes G2P[8], G3P[6], G8P[8] and G9P[8] was also observed following vaccine introduction. Monitoring the rotavirus genotypes that cause diarrhoeal disease in children in Fiji is important to ensure that the rotavirus vaccine will continue to be protective and to enable early detection of new vaccine escape strains if this occurs.

Background: In 2012, Fiji introduced the 10-valent pneumococcal conjugate vaccine (PCV10). We assessed the impact of PCV10 on invasive pneumococcal disease (IPD), probable bacterial or pneumococcal meningitis (PBPM), meningitis and sepsis 3-5 years post-introduction. Methods: Laboratory-confirmed IPD and PBPM cases were extracted from national laboratory records. ICD-10-AM coded all-cause meningitis and sepsis cases were extracted from national hospitalisation records. Incidence rate ratios were used to compare outcomes pre/post-PCV10, stratified by age groups: 1-23m, 2-4y, 5-9y, 10-19y, 20-54y, ≥55y. To account for different detection and serotyping methods in the pre-and post-PCV10 period, a Bayesian inference model estimated serotype-specific changes in IPD, using pneumococcal carriage and surveillance data. Findings: There were 423 IPD, 1,029 PBPM, 1,391 all-cause meningitis and 7,611 all-cause sepsis cases. Five years post-PCV10 introduction, IPD declined by 60% (95%CI: 37%, 76%) in children 1-23m months old, and in age groups 2-4y, 5-9y, 10-19y although confidence intervals spanned zero. PBPM declined by 36% (95%CI: 21%, 48%) among children 1-23 months old, and in all other age groups, although some confidence intervals spanned zero. Among children

Background: In 2012, Fiji became the first independent Pacific island country to introduce rotavirus vaccine. We describe the impact of rotavirus vaccine on all-cause diarrhoea admissions in all ages, and rotavirus diarrhoea in children

Human papillomavirus (HPV) vaccines are safe and effective in preventing HPV infection and cervical precancers. Neutralizing antibodies are thought to be the primary mechanism of protection for HPV vaccines, although the exact level required for protection has not been identified. Three common serological assays used in clinical trials to measure HPV antibodies are HPV pseudovirion-based neutralization assay (PBNA), competitive or total Luminex immunoassays (cLIA or LIA) and VLP-based enzyme linked immunosorbent assays (ELISA). While PBNA is the gold-standard for measuring neutralizing antibodies (NAb), it is labor intensive. Luminex immunoassay and VLP-ELISA are rapid and high throughput, but their reagents and equipment can be difficult to source. Nevertheless, data generated from these assays generally correlate well with PBNA. Here, we described a simplified high-throughput PsV-based ELISA for HPV antibody measurement, to circumvent some of the limitations of existing assays. Using this assay, we were able to differentiate HPV-specific IgG and IgM, and found a strong correlation between HPV-specific IgG and NAb levels, as previously determined by PBNA. This assay platform is simpler and less time-consuming than PBNA. In addition, the materials can be readily produced and obtained commercially. This assay can be used as an alternative method to measure HPV antibodies.

Background Cholera poses a public health and economic threat to Zanzibar. Detailed epidemiologic analyses are needed to inform a multisectoral cholera elimination plan currently under development. Methods We collated passive surveillance data from 1997 to 2017 and calculated the outbreak-specific and cumulative incidence of suspected cholera per shehia (neighborhood). We explored the variability in shehia-specific relative cholera risk and explored the predictive power of targeting intervention at shehias based on historical incidence. Using flexible regression models, we estimated cholera’s seasonality and the relationship between rainfall and cholera transmission. Results From 1997 and 2017, 11921 suspected cholera cases were reported across 87% of Zanzibar’s shehias, representing an average incidence rate of 4.4 per 10000/year. The geographic distribution of cases across outbreaks was variable, although a number of high-burden areas were identified. Outbreaks were highly seasonal with 2 high-risk periods corresponding to the annual rainy seasons. Conclusions Shehia-targeted interventions should be complemented with island-wide cholera prevention activities given the spatial variability in cholera risk from outbreak to outbreak. In-depth risk factor analyses should be conducted in the high-burden shehias. The seasonal nature of cholera provides annual windows of opportunity for cholera preparedness activities.

Objectives Post-licensure studies to evaluate vaccine impact are an important component of introducing new vaccines. Such studies often rely on routinely collected data but the limitations to these data must be understood. To validate administrative data for use in 10-valent pneumococcal conjugate and rotavirus vaccine impact evaluations we have audited the two electronic database capturing hospital admissions in Fiji for completeness and consistency. Methods Hospital admission data for one week per year between 2007–2011 and 2014–2015 was collected from ward registers for selected hospitals. Ward registers were defined as the reference standard and compared to data captured in electronic databases. Data quality was assessed for completeness of admissions data (percentage of admissions in the electronic database, expressed as sensitivity), consistency of complete reporting (determined by identifying variables associated to complete reporting), and completeness of coding (percentage of admissions in the electronic database with an assigned ICD-10-AM code). Results Over all hospitals and years, the sensitivity for completeness of admission data was 83% (95% CI: 81.3, 84.6). Consistency of complete reporting varied and was highest at tertiary hospitals using the electronic database (sensitivity: 89.1%, 95% CI: 87.4, 90.7). The overall completeness of coding at tertiary hospitals was 90.8% (95% CI: 90.5, 91.1) with annual and hospital variation. Conclusion The administrative data in the electronic databases in Fiji are of reasonable quality for the vaccine impact evaluation. This quantification of the missing data can be used to adjust the vaccine impact estimates.

This study describes predictors of pneumococcal nasopharyngeal carriage and density in Fiji. We used data from four annual (2012-2015) cross-sectional surveys, pre- and post-introduction of ten-valent pneumococcal conjugate vaccine (PCV10) in October 2012. Infants (5-8 weeks), toddlers (12-23 months), children (2-6 years), and their caregivers participated. Pneumococci were detected and quantified using lytA qPCR, with molecular serotyping by microarray. Logistic and quantile regression were used to determine predictors of pneumococcal carriage and density, respectively. There were 8,109 participants. Pneumococcal carriage was negatively associated with years post-PCV10 introduction (global P

The duration of cross-neutralising antibody responses (cross-NAb) following HPV immunisation is unknown. We compared cross-NAb responses in cohort of girls who were either unimmunised or had received immunisation with one, two or three doses of 4vHPV (Gardasil&reg, Merck Inc.) six years earlier, before and one month after a booster dose of 2vHPV (Cervarix&reg, GSK). NAb to potentially cross-reactive HPV genotypes 31, 33, 45, 52 and 58 were measured using a HPV pseudovirion-based neutralisation assay. Girls who had previously received at least one dose of 4vHPV had significantly higher NAb titres for HPV31 when compared with unimmunised girls, whereas no difference in NAb titre was observed for four other genotypes (33, 45, 52 and 58). Following a single further immunisation with 2vHPV, NAb titres to each of the five tested HPV genotypes were comparable for girls who previously received one, two or three doses of 4vHPV, and were significantly higher than for previously unimmunised girls. Immunisation with one, two or three doses of 4vHPV induced NAb to HPV31 that persisted for six years, but there was no persistence of NAb to HPV33, 45, 52 or 58. Our results suggest that one or two doses of 4vHPV may provide long-term protection against HPV31.

Key Points Question Is pneumococcal nasopharyngeal carriage associated with mode of delivery in Fijian infants aged 5 to 8 weeks? Findings In this cross-sectional study, pneumococcal nasopharyngeal carriage prevalence, density, and serotype range were higher in infants delivered vaginally vs cesarean delivery. After adjustment, vaginal delivery was positively associated with pneumococcal nasopharyngeal carriage. Meaning These findings may be owing to differential exposure to the vaginal microbiota during delivery and the association of intrapartum antibiotics with the infant microbiome, and raises the hypothesis of vertical transmission., Importance Pneumococcal nasopharyngeal carriage is a prerequisite for pneumococcal disease. The main transmission route is from toddlers, who commonly carry pneumococci. However, neonatal pneumococcal disease case reports suggest that vertical pneumococcal transmission may also occur. Objective To describe and compare pneumococcal nasopharyngeal carriage and density by infant mode of delivery in young Fijian infants. Design, Setting, and Participants Annual cross-sectional surveys were performed in Suva, Fiji, before the introduction of 10-valent pneumococcal conjugate vaccine (PCV10), from September 14 to December 20, 2012, and after PCV10 was introduced, from July 11 to November 19, 2013; July 15 to December 9, 2014; and August 13 to November 19, 2015. Caregivers of 2006 infants aged 5 to 8 weeks participated in the surveys. Statistical analysis was performed from May 24, 2018, to August 12, 2019. Exposures Caregivers provided data on infant mode of delivery and demographics via interviewer-led survey. Main Outcomes and Measures Pneumococci in swab samples were detected and quantified by lytA quantitative polymerase chain reaction with molecular serotyping by microarray. Pneumococci were categorized as PCV10 or non-PCV10 serotypes. Results Of the 2006 infants (976 girls and 1030 boys; mean [SD] age, 6.1 [0.02] weeks]), 1742 (86.8%) were born vaginally and 264 were born by cesarean delivery. Infants delivered vaginally, compared with those born by cesarean delivery, had a higher prevalence of overall pneumococcal nasopharyngeal carriage (470 of 1722 [27.3%; 95% CI, 25.2%-29.4%] vs 47 of 260 [18.1%; 95% CI, 13.6%-23.3%]; P = .002), PCV10 carriage (113 of 1698 [6.7%; 95% CI, 5.5%-7.9%] vs 8 of 256 [3.1%; 95% CI, 1.4%-6.1%]; P = .03), and non-PCV10 carriage (355 of 1698 [20.9%; 95% CI, 19.0%-22.9%] vs 38 of 256 [14.8%; 95% CI, 10.7%-19.8%]; P = .02), and had higher median densities of overall pneumococci (4.9 log10 genome equivalents [GE]/mL [interquartile range, 4.8-5.0 log10 GE/mL] vs 4.5 log10 GE/mL [interquartile range, 4.1-4.6 log10 GE/mL]; P = .01) and non-PCV10 pneumococci (4.9 log10 GE/mL [interquartile range, 4.7-5.0 log10 GE/mL] vs 4.4 log10 GE/mL [interquartile range, 4.0-4.7 log10 GE/mL]; P = .01). Vaginal delivery was associated with overall (adjusted odds ratio, 1.57 [95% CI, 1.10-2.23]; P = .01) and non-PCV10 (adjusted odds ratio, 1.49 [95% CI, 1.01-2.20]; P = .04]) pneumococcal nasopharyngeal carriage. Vaginal delivery was not associated with PCV10 carriage (adjusted odds ratio, 1.67 [95% CI, 0.80-3.51]; P = .17). After adjustment, vaginal delivery was not associated with density. Conclusions and Relevance Pneumococcal nasopharyngeal carriage prevalence and density were higher in infants delivered vaginally compared with those delivered by cesarean birth. After adjustment, vaginal delivery was associated with pneumococcal carriage. Differences in carriage by mode of delivery may be due to differential exposure to the vaginal microbiota during delivery and the effect of intrapartum antibiotics during cesarean delivery on the infant microbiome. Our findings also raise the hypothesis that vertical transmission may contribute to pneumococcal acquisition., This cross-sectional study uses surveys to describe and compare pneumococcal nasopharyngeal carriage and density by vaginal vs cesarean delivery in young Fijian infants.

BACKGROUND: Diphtheria is a vaccine-preventable disease. When vaccination coverage and population immunity are low, outbreaks can occur. We investigated a diphtheria outbreak in Lao People’s Democratic Republic that occurred during 2012–2013 and highlighted challenges in immunization services delivery to children in the country. METHODS: We reviewed diphtheria surveillance data from April 1, 2012–May 31, 2013. A diphtheria case was defined as a respiratory illness consisting of pharyngitis, tonsillitis, or laryngitis, and an adherent tonsillar or nasopharyngeal pseudomembrane. To identify potential risk factors for diphtheria, we conducted a retrospective case-control study with two aged-matched neighborhood controls per case-patient in Houaphan Province, using bivariate analysis to calculate matched odds ratio (mOR) with 95% confidence intervals (CI). Reasons for non-vaccination among unvaccinated persons were assessed. RESULTS: Sixty-two clinical cases of diphtheria and 12 diphtheria-related deaths were reported in seven of 17 provinces. Among case-patients, 43 (69%) were

Summary: Background: The indirect effects of pneumococcal conjugate vaccines (PCVs) are mediated through reductions in carriage of vaccine serotypes. Data on PCVs in Asia and the Pacific are scarce. Fiji introduced the ten-valent PCV (PCV10) in 2012, with a schedule consisting of three priming doses at 6, 10, and 14 weeks of age and no booster dose (3 + 0 schedule) without catch-up. We investigated the effects of PCV10 introduction using cross-sectional nasopharyngeal carriage surveys. Methods: We did four annual carriage surveys (one pre-PCV10 and three post-PCV10) in the greater Suva area in Fiji, during 2012–15, of 5–8-week-old infants, 12–23-month-old children, 2–6-year-old children, and their caregivers (total of 8109 participants). Eligible participants were of appropriate age, had axillary temperature lower than 37°C, and had lived in the community for at least 3 consecutive months. We used purposive quota sampling to ensure a proper representation of the Fiji population. Pneumococci were detected by real-time quantitative PCR, and molecular serotyping was done with microarray. Findings: 3 years after PCV10 introduction, vaccine-serotype carriage prevalence declined, with adjusted prevalences (2015 vs 2012) of 0·56 (95% CI 0·34–0·93) in 5–8-week-old infants, 0·34 (0·23–0·49) in 12–23-month-olds, 0·47 (0·34–0·66) in 2–6-year-olds, and 0·43 (0·13–1·42) in caregivers. Reductions in PCV10 serotype carriage were evident in both main ethnic groups in Fiji; however, carriage of non-PCV10 serotypes increased in Indigenous Fijian infants and children. Density of PCV10 serotypes and non-PCV10 serotypes was lower in PCV10-vaccinated children aged 12–23 months than in PCV10-unvaccinated children of the same age group (PCV10 serotypes −0·56 [95% CI −0·98 to −0·15], p=0·0077; non-PCV10 serotypes −0·29 [–0·57 to −0·02], p=0·0334). Interpretation: Direct and indirect effects on pneumococcal carriage post-PCV10 are likely to result in reductions in pneumococcal disease, including in infants too young to be vaccinated. Serotype replacement in carriage in Fijian children, particularly Indigenous children, warrants further monitoring. Observed changes in pneumococcal density might be temporal rather than vaccine related. Funding: Department of Foreign Affairs and Trade of the Australian Government through the Fiji Health Sector Support Program; Victorian Government's Operational Infrastructure Support Program; Bill & Melinda Gates Foundation.

In 2012, Fiji introduced rotavirus vaccine (Rotarix, GSK) into the national immunisation schedule. We describe the intussusception epidemiology prior to rotavirus vaccine, temporal association of intussusception cases to administration of rotavirus vaccine, and estimate the additional number of intussusception cases that may be associated with rotavirus vaccine. A retrospective review of intussusception cases for children aged

Background This study examined the cellular immunity of 0, 1, 2, and 3 doses of Gardasil vaccine (4vHPV) in girls after 6 years and their responses to a subsequent dose of Cervarix vaccine (2vHPV). Methods A subset of girls (n = 59) who previously received 0, 1, 2, or 3 doses of 4vHPV 6 years earlier were randomly selected from a cohort study of Fijian girls (age 15–19 years). Blood was collected before and 28 days after a dose of 2vHPV. The HPV16- and HPV18-specific cellular immune response was determined by IFNγ-ELISPOT and by measurement of cytokines in peripheral blood mononuclear cell supernatants. Results Six years after 4vHPV vaccination, HPV18-specific responses were significantly lower in the 1- (1D) or 2-dose (2D) recipients compared with 3-dose recipients (2D: IFNγ-ELISPOT: P = .008; cytokines, IFNγ: P = .002; IL-2: P = .022; TNFα: P = .016; IL-10: P = .018; 1D: IL-2: P = .031; IL-10: P = .014). These differences were no longer significant post-2vHPV. No significant differences in HPV16 responses (except IL-2, P < .05) were observed between the 2- or 1-dose recipients and 3-dose recipients. Conclusions These data suggest that cellular immunity following reduced-dose schedules was detectable after 6 years, although the responses were variable between HPV types and dosage groups. The clinical significance of this is unknown. Further studies on the impact of reduced dose schedules are needed, particularly in high–disease burden settings.

Summary Oral cholera vaccination could be deployed in a diverse range of situations from cholera-endemic areas and locations of humanitarian crises, but no clear consensus exists. The supply of licensed, WHO-prequalified cholera vaccines is not sufficient to meet endemic and epidemic needs worldwide and so prioritisation is needed. We have developed a scenario approach to systematically classify situations in which oral cholera vaccination might be useful. Our scenario approach distinguishes between five types of cholera epidemiology based on experiences from around the world and provides evidence that we hope will spur the development of detailed guidelines on how and where oral cholera vaccines could, and should, be most rationally deployed.

The replacement of “presumptive treatment for malaria” by “test before treat” strategies for the management of febrile illness is raising awareness of the importance of knowing more about the causes of illness in children who are suspected to have malaria but return a negative parasitological test. The most common cause of non-malarial febrile illness (NMFI) in African children is respiratory tract infection. Whilst the bacterial causes of NMFI are well known, the increasing use of sensitive techniques such as polymerase chain reaction (PCR) tests is revealing large numbers of viruses that are potential respiratory pathogens. However, many of these organisms are commonly present in the respiratory tract of healthy children so causality and risk factors for pneumonia remain poorly understood. Infection with a combination of viral and bacterial pathogens is increasingly recognised as important in the pathogenesis of pneumonia. Similarly, blood stream infections with organisms typically grown by aerobic culture are well known but a growing number of organisms that can be identified only by PCR, viral culture, or serology are now recognised to be common pathogens in African children. The high mortality of hospitalised children on the first or second day of admission suggests that, unless results are rapidly available, diagnostic tests to identify specific causes of illness will still be of limited use in guiding the potentially life saving decisions relating to initial treatment of children admitted to district hospitals in Africa with severe febrile illness and a negative test for malaria. Malaria control and the introduction of vaccines against Haemophilus influenzae type b and pneumococcal disease are contributing to improved child survival in Africa. However, increased parasitological testing for malaria is associated with increased use of antibiotics to which resistance is already high.

As part of the World Health Organization Invasive Bacterial-Vaccine Preventable Diseases (IB-VPD) surveillance in Suva, Fiji, cerebrospinal fluid (CSF) samples from suspected meningitis patients of all ages were examined by traditional methods (culture, Gram stain, and latex agglutination for bacterial antigen) and qPCR for Streptococcus pneumoniae, Neisseria meningitidis, and Haemophilus influenzae. Of 266 samples tested, pathogens were identified in 47 (17.7%). S. pneumoniae was the most common pathogen detected (n = 17) followed by N. meningitidis (n = 13). The use of qPCR significantly increased detection of IB-VPD pathogens (P = 0.0001): of 35 samples that were qPCR positive for S. pneumoniae, N. meningitidis, and H. influenzae, only 10 were culture positive. This was particularly relevant for N. meningitidis, as only 1/13 cases was culture positive. Molecular serotyping by microarray was used to determine pneumococcal serotypes from 9 of 16 (56%) of samples using DNA directly extracted from CSF specimens. Results indicate that qPCR significantly increases detection of S. pneumoniae, N. meningitidis, and H. influenzae in CSF, and that application of molecular diagnostics is a feasible way to enhance local and global surveillance for IB-VPD.

The duration of antibody response following reduced human papillomavirus (HPV) vaccine doses has not been determined. We compared the antibody responses in girls previously vaccinated with zero, 1, 2, or 3 doses of quadrivalent HPV vaccine (4vHPV; Gardasil, Merck) 6 years previously.A prospective cohort study was undertaken in 200 Fijian girls 15-19 years of age. Approximately equal numbers of girls from 2 main ethnic groups (Fijians of Indian descent [FID] and Indigenous Fijians [iTaukei]) in Fiji were recruited for each dosage groups. Blood was drawn before and 28 days following a single dose of bivalent HPV vaccine (2vHPV; Cervarix, GlaxoSmithKline). We measured neutralizing antibodies (NAb) against HPV-6, -11, -16, and -18 using the pseudovirion-based neutralization assay.After 6 years (before a dose of 2vHPV was given), the geometric mean NAb titers for all 4 HPV types were not statistically different between 2-dose (2D) and 3-dose (3D) recipients: HPV-6 (3D: 2216 [95% confidence interval {CI},1695-2896]; 2D: 1476 [95% CI, 1019-2137]; P = .07), HPV-11 (3D: 4431 [95% CI, 3396-5783]; 2D: 2951 [95% CI, 1984-4390]; P = .09), HPV-16 (3D: 3373 [95% CI, 2511-4530]; 2D: 3275 [95% CI, 2452-4373]; P = .89); HPV-18 (3D: 628 [95% CI: 445-888]; 2D: 606 [95% CI, 462-862]; P = .89), and were higher in FID than iTaukei girls. Although 1-dose recipients had significantly lower NAb titers than 2-/3-dose recipients, their NAb titers were 5- to 30-fold higher than unvaccinated girls. Post-2vHPV NAb titers against HPV-16 and -18 were not statistically different between girls who received 1, 2, or 3 doses of 4vHPV previously.Two doses of 4vHPV provide similar NAb titers as 3 doses for 6 years, although the clinical significance is unknown. A single dose of 4vHPV elicits antibodies that persisted for at least 6 years, and induced immune memory, suggesting possible protection against HPV vaccine types after a single dose of 4vHPV.

Summary Background Zanzibar, in east Africa, has been severely and repeatedly affected by cholera since 1978. We assessed the effectiveness of oral cholera vaccination in high-risk populations in the archipelago to estimate the indirect (herd) protection conferred by the vaccine and direct vaccine effectiveness. Methods We offered two doses of a killed whole-cell B-subunit cholera vaccine to individuals aged 2 years and older in six rural and urban sites. To estimate vaccine direct protection, we compared the incidence of cholera between recipients and non-recipients using generalised estimating equations with the log link function while controlling for potential confounding variables. To estimate indirect effects, we used a geographic information systems approach and assessed the association between neighbourhood-level vaccine coverage and the risk for cholera in the non-vaccinated residents of that neighbourhood, after controlling for potential confounding variables. This study is registered with ClinicalTrials.gov, number NCT00709410. Findings Of 48 178 individuals eligible to receive the vaccine, 23 921 (50%) received two doses. Between February, 2009, and May, 2010, there was an outbreak of cholera, enabling us to assess vaccine effectiveness. The vaccine conferred 79% (95% CI 47–92) direct protection against cholera in participants who received two doses. Indirect (herd) protection was shown by a decrease in the risk for cholera of non-vaccinated residents within a household's neighbourhood as the vaccine coverage in that neighbourhood increased. Interpretation Our findings suggest that the oral cholera vaccine offers both direct and indirect (herd) protection in a sub-Saharan African setting. Mass oral cholera immunisation campaigns have the potential to provide not only protection for vaccinated individuals but also for the unvaccinated members of the community and should be strongly considered for wider use. Because this is an internationally-licensed vaccine, we could not undertake a randomised placebo-controlled trial, but the absence of vaccine effectiveness against non-cholera diarrhoea indicates that the noted protection against cholera could not be explained by bias. Funding Bill & Melinda Gates Foundation, Swedish International Development Cooperation Agency, and the South Korean Government.

Background. The duration of antibody response following reduced human papillomavirus (HPV) vaccine doses has not been determined. We compared the antibody responses in girls previously vaccinated with zero, 1, 2, or 3 doses of quadrivalent HPV vaccine (4vHPV; Gardasil, Merck) 6 years previously. Methods. A prospective cohort study was undertaken in 200 Fijian girls 15-19 years of age. Approximately equal numbers of girls from 2 main ethnic groups (Fijians of Indian descent [FID] and Indigenous Fijians [iTaukei]) in Fiji were recruited for each dosage groups. Blood was drawn before and 28 days following a single dose of bivalent HPV vaccine (2vHPV; Cervarix, GlaxoSmithKline). We measured neutralizing antibodies (NAb) against HPV-6, -11, -16, and -18 using the pseudovirion-based neutralization assay. Results. After 6 years (before a dose of 2vHPV was given), the geometric mean NAb titers for all 4 HPV types were not statistically different between 2-dose (2D) and 3-dose (3D) recipients: HPV-6 (3D: 2216 [95% confidence interval {CI},1695-2896]; 2D: 1476 [95% CI, 1019-2137]; P = .07), HPV-11 (3D: 4431 [95% CI, 3396-5783]; 2D: 2951 [95% CI, 1984-4390]; P = .09), HPV-16 (3D: 3373 [95% CI, 2511-4530]; 2D: 3275 [95% CI, 2452-4373]; P = .89); HPV-18 (3D: 628 [95% CI: 445-888]; 2D: 606 [95% CI, 462-862]; P = .89), and were higher in FID than iTaukei girls. Although 1-dose recipients had significantly lower NAb titers than 2-/3-dose recipients, their NAb titers were 5- to 30-fold higher than unvaccinated girls. Post-2vHPV NAb titers against HPV-16 and -18 were not statistically different between girls who received 1, 2, or 3 doses of 4vHPV previously. Conclusions. Two doses of 4vHPV provide similar NAb titers as 3 doses for 6 years, although the clinical significance is unknown. A single dose of 4vHPV elicits antibodies that persisted for at least 6 years, and induced immune memory, suggesting possible protection against HPV vaccine types after a single dose of 4vHPV.

BackgroundThe gold standard for the diagnosis of cholera is stool culture, but this requires laboratory facilities and takes at least 24 hours. A rapid diagnostic test (RDT) that can be used by minimally trained staff at treatment centers could potentially improve the reporting and management of cholera outbreaks.MethodsWe evaluated the Crystal VC™ RDT under field conditions in Zanzibar in 2009. Patients presenting to treatment centers with watery diarrhea provided a stool sample for rapid diagnostic testing. Results were compared to stool culture performed in a reference laboratory. We assessed the overall performance of the RDT and evaluated whether previous intake of antibiotics, intravenous fluids, location of testing, and skill level of the technician affected the RDT results.ResultsWe included stool samples from 624 patients. Compared to culture, the overall sensitivity of the RDT was 93.1% (95%CI: 88.7 to 96.2%), specificity was 49.2% (95%CI: 44.3 to 54.1%), the positive predictive value was 47.0% (95%CI: 42.1 to 52.0%) and the negative predictive value was 93.6% (95%CI: 89.6 to 96.5%). The overall false positivity rate was 50.8% (213/419); fieldworkers frequently misread very faint test lines as positive.ConclusionThe observed sensitivity of the Crystal VC RDT evaluated was similar compared to earlier versions, while specificity was poorer. The current version of the RDT could potentially be used as a screening tool in the field. Because of the high proportion of false positive results when field workers test stool specimens, positive results will need to be confirmed with stool culture.

Introduction Mass vaccinations are a main strategy in the deployment of oral cholera vaccines. Campaigns avoid giving vaccine to pregnant women because of the absence of safety data of the killed whole-cell oral cholera (rBS-WC) vaccine. Balancing this concern is the known higher risk of cholera and of complications of pregnancy should cholera occur in these women, as well as the lack of expected adverse events from a killed oral bacterial vaccine. Methodology/Principal Findings From January to February 2009, a mass rBS-WC vaccination campaign of persons over two years of age was conducted in an urban and a rural area (population 51,151) in Zanzibar. Pregnant women were advised not to participate in the campaign. More than nine months after the last dose of the vaccine was administered, we visited all women between 15 and 50 years of age living in the study area. The outcome of pregnancies that were inadvertently exposed to at least one oral cholera vaccine dose and those that were not exposed was evaluated. 13,736 (94%) of the target women in the study site were interviewed. 1,151 (79%) of the 1,453 deliveries in 2009 occurred during the period when foetal exposure to the vaccine could have occurred. 955 (83%) out of these 1,151 mothers had not been vaccinated; the remaining 196 (17%) mothers had received at least one dose of the oral cholera vaccine. There were no statistically significant differences in the odds ratios for birth outcomes among the exposed and unexposed pregnancies. Conclusions/Significance We found no statistically significant evidence of a harmful effect of gestational exposure to the rBS-WC vaccine. These findings, along with the absence of a rational basis for expecting a risk from this killed oral bacterial vaccine, are reassuring but the study had insufficient power to detect infrequent events. Trial Registration ClinicalTrials.gov NCT00709410, Author Summary Pregnant women are more vulnerable to complications of cholera than other people. It would be helpful to include pregnant women in vaccination campaigns against cholera but pregnant women and their unborn children are highly vulnerable to the potential adverse effects of biological products such as vaccines. The safety of oral cholera vaccines in pregnant women has up to now not been evaluated. During a large mass cholera vaccination campaign in Zanzibar in 2009, women were advised not to participate if they thought they may be pregnant. The large majority (955 or 83%) of women residing in the study area who were to be pregnant during the 9 months following the vaccinations did not participate in the campaign. The remaining 196 (17%) women received the vaccine. A comparison between vaccine exposed and unexposed pregnancies did not reveal any significant differences in outcome between the two groups. The small number of miscarriages, infant deaths and ill infants was similarly distributed between the two groups. These findings are reassuring but continued monitoring of this vaccine when given during pregnancy is recommended.

Global cholera incidence is increasing, particularly in sub-Saharan Africa. We examined the impact of climate and ocean environmental variability on cholera outbreaks, and developed a forecasting model for outbreaks in Zanzibar. Routine cholera surveillance reports between 1997 and 2006 were correlated with remotely and locally sensed environmental data. A seasonal autoregressive integrated moving average (SARIMA) model determined the impact of climate and environmental variability on cholera. The SARIMA model shows temporal clustering of cholera. A 1°C increase in temperature at 4 months lag resulted in a 2-fold increase of cholera cases, and an increase of 200 mm of rainfall at 2 months lag resulted in a 1.6-fold increase of cholera cases. Temperature and rainfall interaction yielded a significantly positive association (P < 0.04) with cholera at a 1-month lag. These results may be applied to forecast cholera outbreaks, and guide public health resources in controlling cholera in Zanzibar.

Introduction The outbreak of cholera in Zimbabwe intensified interest in the control and prevention of cholera. While there is agreement that safe water, sanitation, and personal hygiene are ideal for the long term control of cholera, there is controversy about the role of newer approaches such as oral cholera vaccines (OCVs). In October 2009 the Strategic Advisory Group of Experts advised the World Health Organization to consider reactive vaccination campaigns in response to large cholera outbreaks. To evaluate the potential benefit of this pivotal change in WHO policy, we used existing data from cholera outbreaks to simulate the number of cholera cases preventable by reactive mass vaccination. Methods Datasets of cholera outbreaks from three sites with varying cholera endemicity—Zimbabwe, Kolkata (India), and Zanzibar (Tanzania)—were analysed to estimate the number of cholera cases preventable under differing response times, vaccine coverage, and vaccine doses. Findings The large cholera outbreak in Zimbabwe started in mid August 2008 and by July 2009, 98,591 cholera cases had been reported with 4,288 deaths attributed to cholera. If a rapid response had taken place and half of the population had been vaccinated once the first 400 cases had occurred, as many as 34,900 (40%) cholera cases and 1,695 deaths (40%) could have been prevented. In the sites with endemic cholera, Kolkata and Zanzibar, a significant number of cases could have been prevented but the impact would have been less dramatic. A brisk response is required for outbreaks with the majority of cases occurring during the early weeks. Even a delayed response can save a substantial number of cases and deaths in long, drawn-out outbreaks. If circumstances prevent a rapid response there are good reasons to roll out cholera mass vaccination campaigns well into the outbreak. Once a substantial proportion of a population is vaccinated, outbreaks in subsequent years may be reduced if not prevented. A single dose vaccine would be of advantage in short, small outbreaks. Conclusions We show that reactive vaccine use can prevent cholera cases and is a rational response to cholera outbreaks in endemic and non-endemic settings. In large and long outbreaks a reactive vaccination with a two-dose vaccine can prevent a substantial proportion of cases. To make mass vaccination campaigns successful, it would be essential to agree when to implement reactive vaccination campaigns and to have a dynamic and determined response team that is familiar with the logistic challenges on standby. Most importantly, the decision makers in donor and recipient countries have to be convinced of the benefit of reactive cholera vaccinations., Author Summary Cholera outbreaks have had catastrophic impact on societies for centuries. Despite more than half a century of advocacy for safe water, sanitation and hygiene, approximately 100,000 cholera cases and 5,000 deaths were reported in Zimbabwe between August 2008 and by July 2009. Safe and effective oral cholera vaccines have been licensed and used by affluent tourists for more than a decade to prevent cholera. We asked whether oral cholera vaccines could be used to protect high risk populations at a time of cholera. We calculated how many cholera cases could have been prevented if mass cholera vaccinations would have been implemented in reaction to past cholera outbreaks. We estimate that determined, well organized mass vaccination campaigns could have prevented 34,900 (40%) cholera cases and 1,695 deaths (40%) in Zimbabwe. In the sites with endemic cholera, Kolkata and Zanzibar, a significant number of cases could have been prevented but the impact would have been less dramatic. The barriers which currently prevent the implementation of mass vaccinations, including but not only the cost to purchase the vaccine, seem insurmountable. A concerted effort of donors and key decision makers will be needed to offer better protection to populations at risk.

The replacement of “presumptive treatment for malaria” by “test before treat” strategies for the management of febrile illness is raising awareness of the importance of knowing more about the causes of illness in children who are suspected to have malaria but return a negative parasitological test. The most common cause of non-malarial febrile illness (NMFI) in African children is respiratory tract infection. Whilst the bacterial causes of NMFI are well known, the increasing use of sensitive techniques such as polymerase chain reaction (PCR) tests is revealing large numbers of viruses that are potential respiratory pathogens. However, many of these organisms are commonly present in the respiratory tract of healthy children so causality and risk factors for pneumonia remain poorly understood. Infection with a combination of viral and bacterial pathogens is increasingly recognised as important in the pathogenesis of pneumonia. Similarly, blood stream infections with organisms typically grown by aerobic culture are well known but a growing number of organisms that can be identified only by PCR, viral culture, or serology are now recognised to be common pathogens in African children. The high mortality of hospitalised children on the first or second day of admission suggests that, unless results are rapidly available, diagnostic tests to identify specific causes of illness will still be of limited use in guiding the potentially life‑saving decisions relating to initial treatment of children admitted to district hospitals in Africa with severe febrile illness and a negative test for malaria. Malaria control and the introduction of vaccines against Haemophilus influenzae type b and pneumococcal disease are contributing to improved child survival in Africa. However, increased parasitological testing for malaria is associated with increased use of antibiotics to which resistance is already high.