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BACKGROUND: There is limited empiric evidence on the coverage of pneumococcal conjugate vaccines (PCVs) required to generate substantial indirect protection. We investigate the association between population PCV coverage and indirect protection against invasive pneumococcal disease (IPD) and pneumonia hospitalisations among undervaccinated Australian children. METHODS AND FINDINGS: Birth and vaccination records, IPD notifications, and hospitalisations were individually linked for children aged <5 years, born between 2001 and 2012 in 2 Australian states (New South Wales and Western Australia; 1.37 million children). Using Poisson regression models, we examined the association between PCV coverage, in small geographical units, and the incidence of (1) 7-valent PCV (PCV7)-type IPD; (2) all-cause pneumonia; and (3) pneumococcal and lobar pneumonia hospitalisation in undervaccinated children. Undervaccinated children received <2 doses of PCV at <12 months of age and no doses at ≥12 months of age. Potential confounding variables were selected for adjustment a priori with the assistance of a directed acyclic graph. There were strong inverse associations between PCV coverage and the incidence of PCV7-type IPD (adjusted incidence rate ratio [aIRR] 0.967, 95% confidence interval [CI] 0.958 to 0.975, p-value < 0.001), and pneumonia hospitalisations (all-cause pneumonia: aIRR 0.991 95% CI 0.990 to 0.994, p-value < 0.001) among undervaccinated children. Subgroup analyses for children <4 months old, urban, rural, and Indigenous populations showed similar trends, although effects were smaller for rural and Indigenous populations. Approximately 50% coverage of PCV7 among children <5 years of age was estimated to prevent up to 72.5% (95% CI 51.6 to 84.4) of PCV7-type IPD among undervaccinated children, while 90% coverage was estimated to prevent 95.2% (95% CI 89.4 to 97.8). The main limitations of this study include the potential for differential loss to follow-up, geographical misc

River ecosystems receive and process vast quantities of terrestrial organic carbon, the fate of which depends strongly on microbial activity. Variation in and controls of processing rates, however, are poorly characterized at the global scale. In response, we used a peer-sourced research network and a highly standardized carbon processing assay to conduct a global-scale field experiment in greater than 1000 river and riparian sites. We found that Earth’s biomes have distinct carbon processing signatures. Slow processing is evident across latitudes, whereas rapid rates are restricted to lower latitudes. Both the mean rate and variability decline with latitude, suggesting temperature constraints toward the poles and greater roles for other environmental drivers (e.g., nutrient loading) toward the equator. These results and data set the stage for unprecedented “next-generation biomonitoring” by establishing baselines to help quantify environmental impacts to the functioning of ecosystems at a global scale.

Background: Most studies use indirect cohort or case-control methods to estimate vaccine effectiveness (VE) of 7- and 13-valent pneumococcal conjugate vaccines (PCV7 and PCV13) against invasive pneumococcal disease (IPD). Neither method can measure the benefit vaccination programs afford the unvaccinated and many studies were unable to estimate dose-specific VE. We linked Australia's national immunisation register with health data from two states to calculate IPD incidence by vaccination status and VE for a 3 + 0 PCV schedule (doses at 2, 4, 6 months, no booster) among a cohort of 1.4 million births. Methods: Births records for 2001–2012 were probabilistically linked to IPD notifications, hospitalisations, deaths, and vaccination history (available until December 2013). IPD rates in vaccinated and unvaccinated children <2 years old were compared using Cox proportional hazards models (adjusting for potential confounders), with VE = (1 − adjusted hazard ratio) × 100. Separate models were performed for all-cause, PCV7, PCV13 and PCV13-non-PCV7 serotype-specific IPD, and for Aboriginal and non-Aboriginal children. Results: Following introduction of universal PCV7 in 2005, rates of PCV7 serotype and all-cause IPD in unvaccinated children declined 89.5% and 61.4%, respectively, to be similar to rates in vaccinated children. Among non-Aboriginal children, VEs for 3 doses were 94.2% (95%CI: 81.9–98.1) for PCV7 serotype-specific IPD, 85.6% (95%CI: 60.5–94.8) for PCV13-non-PCV7 serotype-specific IPD and 80.1% (95%CI: 59.4–90.3) for all-cause IPD. There were no statistically significant differences between the VEs for 3 doses and for 1 or 2 doses against PCV13 and PCV13-non-PCV7 serotype-specific IPD, or between Aboriginal and non-Aboriginal children. Conclusion: Our population-based cohort study demonstrates that >90% coverage in the first year of a universal 3 + 0 PCV program provided high population-level protection, predominantly attributable to strong herd effects. The si

Background: The World Health Organization has targeted rubella virus for elimination regionally. Australia was one of the first countries to implement a nationally funded rubella immunisation program, in 1971, and conducts regular national rubella serosurveillance studies. We aimed to estimate the seroprevalence of rubella-specific IgG antibody in the Australian population by age and sex in 2012–2013, to compare the results with three previous serosurveys conducted in 1996–1999, 2002 and 2007 and to estimate the effective reproduction numbers (Rn). Methods: This study used 2729 serum and plasma specimens, randomly selected from a specimen bank collected in 2012–2013 across Australia. Age groups included in the sample ranged from 1 to 49 years. Sera were tested for rubella-specific IgG-antibody using the Enzygnost anti-rubella IgG enzyme immunoassay and classified as positive, negative or equivocal according to rubella-specific IgG concentrations of >7 IU/ml, <3 IU/ml and 3–7 IU/ml, respectively. Results: The overall proportions seropositive, seronegative and equivocal for rubella-specific IgG were 92.1% (95% CI, 91.0–93.2), 6.7% (95% CI, 5.7–7.7) and 1.2% (95% CI, 0.8–1.6), respectively. The proportion of males seropositive was significantly lower than females in the 30–34 (83.1% vs. 96.8%, p = 0.003), 35–39 (86.1% vs. 96.3%, p = 0.02) and 40–44 (86.1% vs. 95.7%, p = 0.03) year age groups. Rn for rubella in 2012–2013 was estimated to be 0.33 (95% CI 0.28–0.39). Discussion: The 2012–2013 national serosurvey showed levels of rubella-specific IgG seropositivity in the Australian population are relatively high with no evidence of decrease compared to previous serosurveys conducted in 1996–1999, 2002 and 2007. The lower proportion of seropositive males aged 30–44 years likely reflects the initial immunisation program targeting females only. To our knowledge this study represents the longest period of serosurveillance following introduction of a nationally funded rubella

Background: Australia is one of only a few countries with a long-standing and consistent serosurveillance program. We conducted a national serosurvey in 2012–2013 to estimate population seroprevalence of measles-specific IgG and the effective reproduction number, R, and compare the results with the three previous serosurveys (1996–1999, 2002 and 2007) to examine trends following a decade of sustained measles control. Methods: 2729 residual sera from 1 to 49 year olds were tested using the Enzygnost anti-measles IgG enzyme immunoassay (EIA). All sera in the equivocal range by EIA on re-testing and a random sample of low positive and negative sera were later tested by a microneutralisation assay. R was calculated from weighted estimates of the proportion seronegative by age using a previously developed contact matrix. Results: In the 2012–13 serosurvey, anti-measles IgG seropositivity for 1–49 year olds was 80.8% (95% CI: 79.4–82.3%) and 8.9% (95% CI: 7.8–10.0%) had equivocal antibody levels. The increasing proportion of seronegative and equivocal individuals in age groups 10–39 years continued a trend seen in previous serosurveys. There was also an increase in equivocal results among 2–4 and 5–9 year old children, >90% of whom were recently vaccinated. R increased from 0.57 in 1999 to above the epidemic threshold of 1 in 2012–13 (R = 1.7). All 20 EIA negative sera, 238/241 (98.8%) equivocal sera, and 89/92 (96.7%) low positive sera had a titre <10 (negative) in the measles microneutralisation assay. Conclusions: A number of countries with sustained measles control have now demonstrated that measles-specific IgG antibodies decline with time since vaccination. As there is good epidemiologic evidence of population-level protection, the implications of declining measles-specific IgG antibody levels for maintaining measles elimination are unclear. Novel studies to determine correlates of protection against measles transmission and disease in the post-elimination era are n

INTRODUCTION: Several countries have developed national immunisation registers, but only the Nordic countries have linked their registers to other health data in order to comprehensively evaluate the `real world' effectiveness of vaccines. Nordic countries can link datasets deterministically using the national person identifier, but most countries, including Australia, don't have such an identifier to enable this type of linkage. OBJECTIVES: To describe the process for assembling a linked study cohort that will enable the conduct of population-based studies related to immunisation and immunisation policy. METHODS: National death and immunisation databases along with state health data (notifications of vaccine preventable diseases, perinatal data, hospital admissions and emergency department presentations) up until December 2013 were probabilistically linked (using demographic details) for children born between 1996 and 2012 in two states: Western Australia and New South Wales (42% of Australia's population, combined). RESULTS: After exclusions there were 1.95 million children in the study cohort (live born children with both a birth and perinatal record which represents 97.5% of all live births in the state perinatal data collections - our source population) and 18.0 million person years of follow up (mean: 9.2 years per child). The characteristics of children in the cohort were generally similar to those only included in state perinatal databases and outcome measures were in keeping with expected figures from unlinked data sources. However, the lack of a dynamic national population register meant immigrants could not be included. CONCLUSIONS: We have been able to develop a similarly comprehensive system to the Nordic countries based on probabilistic linkage methods. Our experience should provide encouragement to other countries with national immunisation registers looking to establish similar systems.

Introduction: Vaccine coverage data are typically collected through vaccine registers and retrospective surveys. alternatively, crosssectional serosurveys enable direct estimation of vaccine coverage from antibody prevalence by exploiting correlated seropositivity for multiantigen vaccines. Here, we extend previous methods by accounting for temporal antibody decline in estimating vaccine coverage for measles-mumps-rubella vaccine using serial serosurvey data. Methods: We introduce a Markovian cohort model of antibody waning and boosting applied to dichotomous seropositivity data for measles, mumps, and rubella. Simulation studies are used to test model identifiability and to explore bias induced by previous methods that ignore waning. the cohort model is then fitted to three australian serosurveys, entailing estimates of vaccine coverage from routine and catch-up vaccination as well as waning rates for each antigen. Results: the simulation results show that the cohort model is identifiable and qualitatively captures the decline in seropositivity observed in older children. When fitted to all three australian surveys, the estimated seroconversion and waning parameters are similar to estimates based on recent meta-analyses, whereas the coverage estimates appear consistent with previous australian survey-based estimates. Discussion: We show that previous methods of estimating coverage from serological data can be improved by fitting a cohort model with waning and boosting processes to serial serosurvey data, furthermore yielding estimates of more parameters of interest such as rates of waning. in settings where serial serosurvey data is available, our method could be duplicated or applied to related questions such as coverage in routine two-dose schedules or from other combination vaccines.

Objectives: To measure the acute burden of and to identify risk factors associated with notified Q fever in older adults in New South Wales. Design, settings and participants: A prospective cohort of adults aged 45 years and over (the 45 and Up Study) recruited during 2006e2009 and followed using linked Q fever notifications, hospital records and death records during 2006e2012. Main outcome measures: Incident cases ofQfever, based on a linkedQfever notification; proportion of cases with a Q fever-coded hospitalisation. Results: A total of 266906 participants were followed up for 1 254650 person-years (mean, 4.7 ± 1.0 years per person). In our study population, the incidence of notified Q fever during follow-up was 3.6 (95% CI, 2.7e4.8) per 100000 person-years. After adjustments, age (≥65years v 45e54years: hazard ratio [HR], 0.39; 95% CI, 0.16e0.96), sex (women v men: HR, 0.48; 95% CI, 0.26e0.88), and area and type of residence (P<0.001 for trend) remained significantly associated with Q fever. Compared with those living in an inner regional area but not on a farm, the risk of notified Q fever was highest for those living on a farm in outer regional or remote areas (HR, 11.98; 95% CI, 5.47e26.21), followed by those living on a farm in inner regional areas (HR, 4.95; 95% CI, 1.79e13.65). Of notified Q fever cases, 15 of 39 (38%) had been hospitalised with a diagnosis consistent with Q fever. Conclusions: Adults living on a farm in outer regional and remote areas are at a substantially greater risk of contracting Q fever. This suggests that, as well as targeting specific occupational groups for vaccination, there would be benefits in increasing public awareness of Q fever and vaccination among those living on and near farms in outer regional and remote areas of Australia.

Introduction: Australia has achieved measles elimination as announced in March 2014 by the WHO Western Pacific Regional Committee, based on several lines of evidence. However, despite strong national evidence for elimination, there remains substantial regional variation in vaccine coverage, has resulted in recent outbreaks and potential for increased frequency in the future. Methods: In this study, we apply a multiple cohort model of measles immunity, stratified by age and local geographic area to predict trends in the measles reproduction number R. In addition, we use branching process models of outbreak risks to predict state-level probabilities of the occurrence of measles outbreaks over the next 20 years. Results: Our results suggest increasing risks of large measles outbreaks over this period, in particular in the states of Queensland and New South Wales. In addition, there is wide variation in predicted R values by smaller geographic areas, although uncertainty in age-specific immunity limits the precision of our results. Discussion: Our predictions align with observed outbreaks in Australian states and suggest our approach to determining future outbreak risks could be applied more widely in elimination or near-elimination settings.

In Australia, varicella vaccine was universally funded in late 2005 as a single dose at 18 months. A school-based catch-up programme for children aged 10-13 years without a history of infection or vaccination was funded until 2015, when those eligible for universal infant vaccination would have reached the age of high school entry. This study projects the impact of discontinuing catch-up vaccination on varicella and zoster incidence and morbidity using a transmission dynamic model, in comparison with alternative policy options, including two-dose strategies. At current vaccine coverage (83% at 2 years and 90% at 5 years), ceasing the adolescent catch-up programme in 2015 was projected to increase varicella-Associated morbidity between 2035 and 2050 by 39%. Although two-dose infant programmes had the lowest estimated varicella morbidity, the incremental benefit from the second dose fell by 70% if first dose coverage increased from 83% to 95% by age 24 months. Overall zoster morbidity was predicted to rise after vaccination, but differences between strategies were small. Our results suggest that feasibility of one-dose coverage approaching 95% is an important consideration in estimating incremental benefit from a second dose of varicella vaccine.

Background: Elderly people do not mount strong immune responses to vaccines. We compared 23-valent capsular polysaccharide (23vPPV) alone versus 7-valent conjugate (PCV7) vaccine followed by 23vPPV 6 months later in hospitalized elderly. Methods: Participants were randomized to receive 23vPPV or PCV7-23vPPV. Antibodies against serotypes 3, 4, 6A, 6B, 9V, 14, 18C, 19A, 19F, 23F were measured by enzyme-linked immunosorbent (ELISA) and opsonophagocytic (OPA) assays at baseline, 6 months and 12 months. Results: Of 312 recruited, between 40% and 72% of subjects had undetectable OPA titres at baseline. After one dose, PCV7 recipients had significantly higher responses to serotypes 9V (both assays) and 23F (OPA only), and 23vPPV recipients had significantly higher responses to serotype 3 (ELISA), 19F and 19A (OPA only). In subjects with undetectable OPA titres at baseline, a proportionately greater rise in OPA titre (P<0.01) was seen for all serotypes after both vaccines. The GMT ratio of OPA was significantly higher at 12 months in the PCV7-23vPPV group for serotypes 6A, 9V, 18C and 23F. OPA titre levels for these serotypes increased moderately after 6 months, whereas immunity waned in the 23vPPV only arm. Conclusion: We did not show overwhelming benefit of one vaccine over the other. Low baseline immunity does not preclude a robust immune response, reiterating the importance of vaccinating the frail elderly. A schedule of PCV7-23vPPV prevents waning of antibody, suggesting that both vaccines could be useful in the elderly. Follow up studies are needed to determine persistence of immunity. Trial Registration: The Australian Clinical Trials Registry ACTRN12607000387426 © 2014 MacIntyre et al.

Background:Vaccine-serotype (VT) invasive pneumococcal disease (IPD) rates declined substantially following introduction of 7-valent pneumococcal conjugate vaccine (PCV7) into national immunization programs. Increases in non-vaccine-serotype (NVT) IPD rates occurred in some sites, presumably representing serotype replacement. We used a standardized approach to describe serotype-specific IPD changes among multiple sites after PCV7 introduction.Methods and Findings:Of 32 IPD surveillance datasets received, we identified 21 eligible databases with rate data ≥2 years before and ≥1 year after PCV7 introduction. Expected annual rates of IPD absent PCV7 introduction were estimated by extrapolation using either Poisson regression modeling of pre-PCV7 rates or averaging pre-PCV7 rates. To estimate whether changes in rates had occurred following PCV7 introduction, we calculated site specific rate ratios by dividing observed by expected IPD rates for each post-PCV7 year. We calculated summary rate ratios (RRs) using random effects meta-analysis. For children <5 years old, overall IPD decreased by year 1 post-PCV7 (RR 0·55, 95% CI 0·46-0·65) and remained relatively stable through year 7 (RR 0·49, 95% CI 0·35-0·68). Point estimates for VT IPD decreased annually through year 7 (RR 0·03, 95% CI 0·01-0·10), while NVT IPD increased (year 7 RR 2·81, 95% CI 2·12-3·71). Among adults, decreases in overall IPD also occurred but were smaller and more variable by site than among children. At year 7 after introduction, significant reductions were observed (18-49 year-olds [RR 0·52, 95% CI 0·29-0·91], 50-64 year-olds [RR 0·84, 95% CI 0·77-0·93], and ≥65 year-olds [RR 0·74, 95% CI 0·58-0·95]).Conclusions:Consistent and significant decreases in both overall and VT IPD in children occurred quickly and were sustained for 7 years after PCV7 introduction, supporting use of PCVs. Increases in NVT IPD occurred in most sites, with variable magnitude. These findings may not represent the experience in

Background. High, or increasing, rates of invasive Haemophilus influenzae (Hi) type a disease have been reported from North American native children from circumpolar regions, raising the question of serotype replacement being driven by vaccination against Hi type b (Hib). Indigenous Australians from remote areas had high rates of invasive Hib disease in the past, comparable to those in North American Indigenous populations. Objective. Evaluate incidence rates of invasive Hi (overall and by serotype) in Indigenous Australian children over time. Design. Descriptive study of Hi incidence rates by serotype, in the Northern Territory (NT) and South Australia (SA) from 2001 to 2011. Comparison of NT data with a study that was conducted in the NT in 1985-1988, before Hib vaccine was introduced. Results. The average annual rate of invasive Hi type a (Hia) disease in Indigenous children aged <5 years was 11/100,000 population. Although the incidence of Hi infection in Indigenous children in 2001-2003 was lower than during 2004-2011, this may be due to changes in surveillance. No other trend over time in individual serotypes or total invasive Hi disease, in Indigenous or non-Indigenous people, was identified. Compared to 1985-1988, rates in 2001-2011 were lower in all serotype groupings, by 98% for Hib, 75% for Hia, 79% for other serotypes and 67% for non-typeable Hi. Conclusions. There is no evidence of increases in invasive disease due to Hia, other specific non-b types, or non-typeable Hi in Australian Indigenous children. These data suggest that the increase in Hia some time after the introduction of Hib vaccine, as seen in the North American Arctic Region, is not common to all populations with high pre-vaccine rates of invasive Hib disease. However, small case numbers and the lack of molecular subtyping and PCR confirmation of pre-vaccine results complicate comparisons with North American epidemiology. © 2013 Robert I. Menzies et al.