Immunogenicity, reactogenicity, and IgE-mediated immune responses of a mixed whole-cell and acellular pertussis vaccine schedule in Australian infants: A randomised, double-blind, noninferiority trial.

BACKGROUND: In many countries, infant vaccination with acellular pertussis (aP) vaccines has replaced use of more reactogenic whole-cell pertussis (wP) vaccines. Based on immunological and epidemiological evidence, we hypothesised that substituting the first aP dose in the routine vaccination schedule with wP vaccine might protect against IgE-mediated food allergy. We aimed to compare reactogenicity, immunogenicity, and IgE-mediated responses of a mixed wP/aP primary schedule versus the standard aP-only schedule. METHODS AND FINDINGS: OPTIMUM is a Bayesian, 2-stage, double-blind, randomised trial. In stage one, infants were assigned (1:1) to either a first dose of a pentavalent wP combination vaccine (DTwP-Hib-HepB, Pentabio PT Bio Farma, Indonesia) or a hexavalent aP vaccine (DTaP-Hib-HepB-IPV, Infanrix hexa, GlaxoSmithKline, Australia) at approximately 6 weeks old. Subsequently, all infants received the hexavalent aP vaccine at 4 and 6 months old as well as an aP vaccine at 18 months old (DTaP-IPV, Infanrix-IPV, GlaxoSmithKline, Australia). Stage two is ongoing and follows the above randomisation strategy and vaccination schedule. Ahead of ascertainment of the primary clinical outcome of allergist-confirmed IgE-mediated food allergy by 12 months old, here we present the results of secondary immunogenicity, reactogenicity, tetanus toxoid IgE-mediated immune responses, and parental acceptability endpoints. Serum IgG responses to diphtheria, tetanus, and pertussis antigens were measured using a multiplex fluorescent bead-based immunoassay; total and specific IgE were measured in plasma by means of the ImmunoCAP assay (Thermo Fisher Scientific). The immunogenicity of the mixed schedule was defined as being noninferior to that of the aP-only schedule using a noninferiority margin of 2/3 on the ratio of the geometric mean concentrations (GMR) of pertussis toxin (PT)-IgG 1 month after the 6-month aP. Solicited adverse reactions were summarised by study arm and included all children who received the first dose of either wP or aP. Parental acceptance was assessed using a 5-point Likert scale. The primary analyses were based on intention-to-treat (ITT); secondary per-protocol (PP) analyses were also performed. The trial is registered with ANZCTR (ACTRN12617000065392p). Between March 7, 2018 and January 13, 2020, 150 infants were randomised (75 per arm). PT-IgG responses of the mixed schedule were noninferior to the aP-only schedule at approximately 1 month after the 6-month aP dose [GMR = 0·98, 95% credible interval (0·77 to 1·26); probability (GMR > 2/3) > 0·99; ITT analysis]. At 7 months old, the posterior median probability of quantitation for tetanus toxoid IgE was 0·22 (95% credible interval 0·12 to 0·34) in both the mixed schedule group and in the aP-only group. Despite exclusions, the results were consistent in the PP analysis. At 6 weeks old, irritability was the most common systemic solicited reaction reported in wP (65 [88%] of 74) versus aP (59 [82%] of 72) vaccinees. At the same age, severe systemic reactions were reported among 14 (19%) of 74 infants after wP and 8 (11%) of 72 infants after aP. There were 7 SAEs among 5 participants within the first 6 months of follow-up; on blinded assessment, none were deemed to be related to the study vaccines. Parental acceptance of mixed and aP-only schedules was high (71 [97%] of 73 versus 69 [96%] of 72 would agree to have the same schedule again). CONCLUSIONS: Compared to the aP-only schedule, the mixed schedule evoked noninferior PT-IgG responses, was associated with more severe reactions, but was well accepted by parents. Tetanus toxoid IgE responses did not differ across the study groups. TRIAL REGISTRATION: Trial registered at the Australian and New Zealand Clinical 207 Trial Registry (ACTRN12617000065392p).

Concurrent warming and browning eliminate cold-water fish habitat in many temperate lakes.

Cold-water species in temperate lakes face two simultaneous climate-driven ecosystem changes: warming and browning of their waters. Browning refers to reduced transparency arising from increased dissolved organic carbon (DOC), which absorbs solar energy near the surface. It is unclear whether the net effect is mitigation or amplification of climate warming impacts on suitable oxythermal habitat (<20 °C, >5 mgO/L) for cold-loving species because browning expands the vertical distribution of both cool water and oxygen depletion. We analyzed long-term trends and high-frequency sensor data from browning lakes in New York's Adirondack region to assess the contemporary status of summertime habitat for lacustrine brook trout. Across two decades, surface temperatures increased twice as fast and bottom dissolved oxygen declined >180% faster than average trends for temperate lakes. We identify four lake categories based on oxythermal habitat metrics: constrained, squeezed, overheated, and buffered. In most of our study lakes, trout face either seasonal loss (7 of 15) or dramatic restriction (12 to 21% of the water column; 5 of 15) of suitable habitat. These sobering statistics reflect rapid upward expansion of oxygen depletion in lakes with moderate or high DOC relative to compression of heat penetration. Only in very clear lakes has browning potentially mitigated climate warming. Applying our findings to extensive survey data suggests that decades of browning have reduced oxythermal refugia in most Adirondack lakes. We conclude that joint warming and browning may preclude self-sustaining cold-water fisheries in many temperate lakes; hence, oxythermal categorization is essential to guide triage strategies and management interventions.

Species trait diversity sustains multiple dietary nutrients supplied by freshwater fisheries.

Species, through their traits, influence how ecosystems simultaneously sustain multiple functions. However, it is unclear how trait diversity sustains the multiple contributions biodiversity makes to people. Freshwater fisheries nourish hundreds of millions of people globally, but overharvesting and river fragmentation are increasingly affecting catches. We analyse how loss of nutritional trait diversity in consumed fish portfolios affects the simultaneous provisioning of six essential dietary nutrients using household data from the Amazon and Tonlé Sap, two of Earth's most productive and diverse freshwater fisheries. We find that fish portfolios with high trait diversity meet higher thresholds of required daily intakes for a greater variety of nutrients with less fish biomass. This beneficial biodiversity effect is driven by low redundancy in species nutrient content profiles. Our findings imply that sustaining the dietary contributions fish make to people given declining biodiversity could require more biomass and ultimately exacerbate fishing pressure in already-stressed ecosystems.

Environmental footprints of farmed chicken and salmon bridge the land and sea.

Food production, particularly of fed animals, is a leading cause of environmental degradation globally.1,2 Understanding where and how much environmental pressure different fed animal products exert is critical to designing effective food policies that promote sustainability.3 Here, we assess and compare the environmental footprint of farming industrial broiler chickens and farmed salmonids (salmon, marine trout, and Arctic char) to identify opportunities to reduce environmental pressures. We map cumulative environmental pressures (greenhouse gas emissions, nutrient pollution, freshwater use, and spatial disturbance), with particular focus on dynamics across the land and sea. We found that farming broiler chickens disturbs 9 times more area than farming salmon (∼924,000 vs. ∼103,500 km2) but yields 55 times greater production. The footprints of both sectors are extensive, but 95% of cumulative pressures are concentrated into <5% of total area. Surprisingly, the location of these pressures is similar (85.5% spatial overlap between chicken and salmon pressures), primarily due to shared feed ingredients. Environmental pressures from feed ingredients account for >78% and >69% of cumulative pressures of broiler chicken and farmed salmon production, respectively, and could represent a key leverage point to reduce environmental footprints. The environmental efficiency (cumulative pressures per tonne of production) also differs geographically, with areas of high efficiency revealing further potential to promote sustainability. The propagation of environmental pressures across the land and sea underscores the importance of integrating food policies across realms and sectors to advance food system sustainability.

Extensive global wetland loss over the past three centuries.

Wetlands have long been drained for human use, thereby strongly affecting greenhouse gas fluxes, flood control, nutrient cycling and biodiversity1,2. Nevertheless, the global extent of natural wetland loss remains remarkably uncertain3. Here, we reconstruct the spatial distribution and timing of wetland loss through conversion to seven human land uses between 1700 and 2020, by combining national and subnational records of drainage and conversion with land-use maps and simulated wetland extents. We estimate that 3.4 million km2 (confidence interval 2.9-3.8) of inland wetlands have been lost since 1700, primarily for conversion to croplands. This net loss of 21% (confidence interval 16-23%) of global wetland area is lower than that suggested previously by extrapolations of data disproportionately from high-loss regions. Wetland loss has been concentrated in Europe, the United States and China, and rapidly expanded during the mid-twentieth century. Our reconstruction elucidates the timing and land-use drivers of global wetland losses, providing an improved historical baseline to guide assessment of wetland loss impact on Earth system processes, conservation planning to protect remaining wetlands and prioritization of sites for wetland restoration4.

Mapping the planet's critical natural assets.

Sustaining the organisms, ecosystems and processes that underpin human wellbeing is necessary to achieve sustainable development. Here we define critical natural assets as the natural and semi-natural ecosystems that provide 90% of the total current magnitude of 14 types of nature's contributions to people (NCP), and we map the global locations of these critical natural assets at 2 km resolution. Critical natural assets for maintaining local-scale NCP (12 of the 14 NCP) account for 30% of total global land area and 24% of national territorial waters, while 44% of land area is required to also maintain two global-scale NCP (carbon storage and moisture recycling). These areas overlap substantially with cultural diversity (areas containing 96% of global languages) and biodiversity (covering area requirements for 73% of birds and 66% of mammals). At least 87% of the world's population live in the areas benefitting from critical natural assets for local-scale NCP, while only 16% live on the lands containing these assets. Many of the NCP mapped here are left out of international agreements focused on conserving species or mitigating climate change, yet this analysis shows that explicitly prioritizing critical natural assets and the NCP they provide could simultaneously advance development, climate and conservation goals.

Estimating the excess burden of pertussis disease in Australia within the first year of life, that might have been prevented through timely vaccination.

BACKGROUND: Previous Australian studies have shown that delayed vaccination with each of the three primary doses of diphtheria-tetanus-pertussis-containing vaccines (DTP) is up to 50 % in certain subpopulations. We estimated the excess burden of pertussis that might have been prevented if (i) all primary doses and (ii) each dose was given on time. METHODS: Perinatal, immunization, pertussis notification and death data were probabilistically linked for 1 412 984 infants born in two Australian states in 2000-12. A DTP dose administered >15 days after the recommended age was considered delayed. We used Poisson regression models to compare pertussis notification rates to 1-year of age in infants with ≥1 dose delayed (Aim 1) or any individual dose delayed (Aim 2) versus a propensity weighted counterfactual on-time cohort. RESULTS: Of all infants, 42% had ≥1 delayed DTP dose. We estimated that between 39 to 365 days of age, 85 (95% CI: 61-109) cases per 100 000 infants, could have been prevented if all infants with ≥1 delayed dose had received their three doses within the on-time window. Risk of pertussis was higher in the delayed versus the on-time cohort, so crude rates overestimated the excess burden (110 cases per 100 000 infants (95% CI: 95-125)). The estimated dose-specific excess burden per 100 000 infants was 132 for DTP1, 50 for DTP2 and 19 for DTP3. CONCLUSIONS: We provide robust evidence that improved DTP vaccine timeliness, especially for the first dose, substantially reduces the burden of infant pertussis. Our methodology, using a potential outcomes framework, is applicable to other settings.

Can preserved museum specimens be used to reconstruct fish mercury burden and sources through time?

To evaluate the utility of preserved fishes for reconstructing historical and spatial patterns of mercury (Hg) exposure, we experimentally tested the stability of Hg concentrations and Hg stable isotope ratios under standard museum practices of specimen preservation. We found that loss of unidentified constituents during preservation increased Hg concentrations in fish muscle. Low-Hg fish reared in the laboratory were susceptible to exogenous contamination with inorganic mercury (iHg) when preservative fluids were intentionally spiked or iHg leached passively from contaminated wild fishes in the same container. This contamination impacted Hg isotope values of total Hg, but the conservative nature of methylmercury allows us to quantitatively correct for iHg contamination. Our findings validate the potential to use fishes from the world's museums to generate spatiotemporal baselines for the Minamata Convention on Mercury, but we recommend a set of precautions to maximize inference strength. Selecting the largest specimens of a target species helps dilute any iHg contamination. Specimens should be drawn from lots that were not comingled with fishes from other collections to minimize risk of iHg transfer among fish with different contamination histories. Finally, focusing on low-lipid species will enhance the comparability of Hg concentrations between historical and contemporary collections.

Body size has primacy over stoichiometric variables in nutrient excretion by a tropical stream fish community.

Ecological Stoichiometry (ES) and the Metabolic Theory of Ecology (MTE) are the main theories used to explain consumers' nutrient recycling. ES posits that imbalances between an animal's body and its diet stoichiometry determine its nutrient excretion rates, whereas the MTE predicts that excretion reflects metabolic activity arising from body size and temperature. We measured nitrogen, phosphorus and N:P excretion, body N:P stoichiometry, body size, and temperature for 12 fish species from a Brazilian stream. We fitted competing models reflecting different combinations of ES (body N:P, armor classification, diet group) and MTE (body size, temperature) variables. Only body size predicted P excretion rates, while N excretion was predicted by body size and time of day. N:P excretion was not explained by any variable. There was no interspecific difference in size-scaling coefficients neither for N nor for P. Fitted size scaling coefficients were lower than the MTE prediction of 0.75 for N (0.58), and for P (0.56). We conclude that differences in nutrient excretion among species within a shared environment primarily reflect contrasts in metabolic rates arising from body size, rather than disparities between consumer and resource stoichiometry. Our findings support the MTE as the primary framework for predicting nutrient excretion rates.

Stream and ocean hydrodynamics mediate partial migration strategies in an amphidromous Hawaiian goby.

Partial migration strategies, in which some individuals migrate but others do not, are widely observed in populations of migratory animals. Such patterns could arise via variation in migratory behaviors made by individual animals, via genetic variation in migratory predisposition, or simply by variation in migration opportunities mediated by environmental conditions. Here we use spatiotemporal variation in partial migration across populations of an amphidromous Hawaiian goby to test whether stream or ocean conditions favor completing its life cycle entirely within freshwater streams rather than undergoing an oceanic larval migration. Across 35 watersheds, microchemical analysis of otoliths revealed that most adult Awaous stamineus were freshwater residents (62% of n = 316 in 2009, 83% of n = 274 in 2011), but we found considerable variation among watersheds. We then tested the hypothesis that the prevalence of freshwater residency increases with the stability of stream flows and decreases with the availability of dispersal pathways arising from ocean hydrodynamics. We found that streams with low variation of daily discharge were home to a higher incidence of freshwater residents in each survey year. The magnitude of the shift in freshwater residency between survey years was positively associated with predicted interannual variability in the success of larval settlement in streams on each island based on passive drift in ocean currents. We built on these findings by developing a theoretical model of goby life history to further evaluate whether mediation of migration outcomes by stream and ocean hydrodynamics could be sufficient to explain the range of partial migration frequency observed across populations. The model illustrates that the proportion of larvae entering the ocean and differential survival of freshwater-resident versus ocean-going larvae are plausible mechanisms for range-wide shifts in migration strategies. Thus, we propose that hydrologic variation in both ocean and stream environments contributes to spatiotemporal variation in the prevalence of migration phenotypes in A. stamineus. Our empirical and theoretical results suggest that the capacity for partial migration could enhance the persistence of metapopulations of diadromous fish when confronted with variable ocean and stream conditions.

How accurately does the Australian Immunisation Register identify children overdue for vaccine doses? A national cross-sectional study.

Abstract: The accuracy of data recorded in the Australian Immunisation Register (AIR) is important for assessment of population-level vaccine coverage but has not been assessed nationally since 2001. We undertook a cross-sectional study in five states in 2017 using standard criteria to validate AIR records classified as three months overdue for any vaccine at 12, 24 and 48 months. Of 2,000 records selected for audit, 905 were assessable, of which 124 (14%) were misclassified as overdue (errors). Among 563 general practice (GP) records, 91 (16.1%) were errors. Compared with Victoria (1/99; 1%), errors were significantly higher in Western Australia (11/106; 10.4%), Queensland (13/104; 12.5%), South Australia (23/110; 20.9%) and New South Wales (43/144; 29.9%); p < 0.01 for all. Among 165 council and community health centre providers, the overall error rate (17; 10.3%) was non-significantly lower than for GP providers, with an odds ratio (OR) of 0.6 and a 95% confidence interval (95% CI) of 0.3-1.1, and did not differ between states. Records were transmitted to the AIR by paper-based methods in 13 cases, with significantly higher error rates (7/13; 54%) than for practice management software (77/630; 12.2%); OR 9.8 (95% CI 2.8-36.4) or the AIR secure site (23/87; 26.4%); OR 2.6 (95% CI 1.4-4.5). Accuracy is increasingly important, with mandatory reporting to the AIR for all National Immunisation Program vaccines from July 2021, and best achieved by uniform use of practice management software.

Reducing adverse impacts of Amazon hydropower expansion.

Proposed hydropower dams at more than 350 sites throughout the Amazon require strategic evaluation of trade-offs between the numerous ecosystem services provided by Earth's largest and most biodiverse river basin. These services are spatially variable, hence collective impacts of newly built dams depend strongly on their configuration. We use multiobjective optimization to identify portfolios of sites that simultaneously minimize impacts on river flow, river connectivity, sediment transport, fish diversity, and greenhouse gas emissions while achieving energy production goals. We find that uncoordinated, dam-by-dam hydropower expansion has resulted in forgone ecosystem service benefits. Minimizing further damage from hydropower development requires considering diverse environmental impacts across the entire basin, as well as cooperation among Amazonian nations. Our findings offer a transferable model for the evaluation of hydropower expansion in transboundary basins.

Australian vaccine preventable disease epidemiological review series: Pertussis, 2013-2018.

INTRODUCTION: Significant recent changes in Australian pertussis immunisation policy include the progressive introduction of funded pertussis immunisation programs for pregnant women, from late 2014 to mid-2015 at jurisdictional level and then under the National Immunisation Program from July 2018, and reintroduction of the 18-month booster dose in 2016. This study analyses pertussis notification, hospitalisation, and mortality data from 2013 to 2018 in the context of trends since 1995. METHODS: This study used data from the National Notifiable Diseases Surveillance System, the National Hospital Morbidity Database, and the Australian Coordinating Registry, for descriptive analysis of pertussis notifications, hospitalisations and deaths in Australia by Aboriginal and Torres Strait Islander (Indigenous) status from 2013 to 2018, examining trends between 1995 and 2012 at both the national and jurisdictional level. Incidence rate ratios (IRR) were utilised to compare pertussis incidence in infants aged < 2 months and 6-11 months for each year from the 2015-2018 (post-maternal-vaccination) period against the 2010-2013 (pre-maternal-vaccination) period. RESULTS AND DISCUSSION: Annual national all-age incidence of pertussis notifications between 2013 and 2018 was 63.6 per 100,000 population, 40% less than between 2006 and 2012. Between 2016 and 2018, infants aged < 2 months had the lowest notification rates of age groups < 5 years old, with the highest notification rates in pre-adolescents aged 9-11 years. Compared with the baseline period (2010-2013), the IRR for infants aged < 2 months decreased in each year during the post-maternal-vaccination period from 0.4 (95% confidence interval [95% CI]: 0.3-0.5) in 2015 to 0.1 (95% CI: 0.1-0.2) in 2018. For infants aged 6-11 months, the IRR was 0.9 (95% CI: 0.8-1.0) in 2015, 1.1 (95% CI: 1.0-1.2) in 2016 and declined to 0.7 (95% CI: 0.6-0.8) in 2017 and 2018. Notification and hospitalisation rates in Indigenous children were 3-8 times as high as rates in non-Indigenous children across all age groups < 5 years old. CONCLUSION: Pertussis remains the second most frequently notified vaccine preventable disease in Australia, after influenza, but dramatic decreases in incidence have been observed in infants too young to receive any doses of pertussis-containing vaccine.

Pertussis Disease and Antenatal Vaccine Effectiveness in Australian Children.

BACKGROUND: Population-level studies of severe pertussis extending beyond infancy are sparse, and none in the context of antenatal vaccination. We compared hospitalized pertussis cases from birth to 15 years of age before and after introduction of antenatal immunization. METHODS: Active surveillance of laboratory-confirmed pertussis hospitalizations in a national network of pediatric hospitals in Australia January 2012 to June 2019. Impact of maternal vaccination was assessed by vaccine effectiveness (VE) in cases and test-negative controls with <2 months of age and by before-after comparison of age distribution of cases. Among cases eligible for one or more vaccine doses, we examined proportions age-appropriately immunized and with comorbidities by age group. RESULTS: Among 419 eligible cases, the proportion <2 months of age significantly decreased from 33.1% in 2012 to 2014 compared with 19.6% in 2016 to 2019 when mothers of only 4 of 17 (23.5%) cases <2 months of age had received antenatal vaccination. VE was estimated to be 84.3% (95% CI, 26.1-96.7). Across all years (2012-2019), of 55 cases 4-11 months of age, 21 (38%) had ≥2 vaccine doses, whereas among 155 cases ≥12 months of age, 122 (85.2%) had ≥3 vaccine doses. Prevalence of comorbidities (primarily cardiorespiratory) increased from 5 (2.1%) <6 months of age to 36 (24.2%) ≥12 months of age (P < 0.001), with 6/16 (38%) cases ≥12 months of age who required intensive care having comorbidities. CONCLUSIONS: Below the age of 12 months, prevention of severe pertussis will be maximized by high maternal antenatal vaccine uptake and timeliness of infant vaccine doses. Despite full immunization, we found children ≥12 months of age accounted for 27% of hospitalizations <15 years, with 24% having comorbities, suggesting new vaccine strategies, such as additional doses or more immunogenic vaccines, require evaluation.

Genomic and environmental influences on resilience in a cold-water fish near the edge of its range.

Small, isolated populations present a challenge for conservation. The dueling effects of selection and drift in a limited pool of genetic diversity make the responses of small populations to environmental perturbations erratic and difficult to predict. This is particularly true at the edge of a species range, where populations often persist at the limits of their environmental tolerances. Populations of cisco, Coregonus artedi, in inland lakes have experienced numerous extirpations along the southern edge of their range in recent decades, which are thought to result from environmental degradation and loss of cold, well-oxygenated habitat as lakes warm. Yet, cisco extirpations do not show a clear latitudinal pattern, suggesting that local environmental factors and potentially local adaptation may influence resilience. Here, we used genomic tools to investigate the nature of this pattern of resilience. We used restriction site-associated DNA capture (Rapture) sequencing to survey genomic diversity and differentiation in southern inland lake cisco populations and compared the frequency of deleterious mutations that potentially influence fitness across lakes. We also examined haplotype diversity in a region of the major histocompatibility complex involved in stress and immune system response. We correlated these metrics to spatial and environmental factors including latitude, lake size, and measures of oxythermal habitat and found significant relationships between genetic metrics and broad and local factors. High levels of genetic differentiation among populations were punctuated by a phylogeographic break and residual patterns of isolation-by-distance. Although the prevalence of deleterious mutations and inbreeding coefficients was significantly correlated with latitude, neutral and non-neutral genetic diversity were most strongly correlated with lake surface area. Notably, differences among lakes in the availability of estimated oxythermal habitat left no clear population genomic signature. Our results shed light on the complex dynamics influencing these isolated populations and provide valuable information for their conservation.

SARS-CoV-2 Vaccines: Where Are We Now?

The best and safest way to control the coronavirus disease 2019 (COVID-19) pandemic is by using vaccination to generate widespread immunity. The urgent need to develop safe and effective COVID-19 vaccines was met with unprecedented speed and action from the global community. There are now 289 vaccines in the development pipeline. More remarkably, there are 20 publicly available vaccines, and more than 3.3 billion doses of COVID-19 vaccines have been administered across 180 countries. This is just the beginning of our fight against the pandemic. Even at the current vaccination rate, it could take years to vaccinate the world's population; many high-income countries are focusing on their needs, whereas the poorer nations are waiting for vaccines. There is still much that we do not understand about immunity to this new disease, and we will have to contend with the emerging variants. In this commentary, we describe the current status of COVID-19 vaccine development and provide insights into how the development and approvals happened so quickly. We discuss the clinical trial data that led to rapid emergency use authorization and the many challenges of global rollout. We also comment on some of the key unanswered questions and future directions for COVID-19 vaccine development and deployment.

Levels of pneumococcal conjugate vaccine coverage and indirect protection against invasive pneumococcal disease and pneumonia hospitalisations in Australia: An observational study.

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 misclassification of children (based on residential address at birth only), and unmeasured confounders. CONCLUSIONS: In this study, we observed substantial indirect protection at lower levels of PCV coverage than previously described-challenging assumptions that high levels of PCV coverage (i.e., greater than 90%) are required. Understanding the association between PCV coverage and indirect protection is a priority since the control of vaccine-type pneumococcal disease is a prerequisite for reducing the number of PCV doses (from 3 to 2). Reduced dose schedules have the potential to substantially reduce program costs while maintaining vaccine impact.