Publications by authors named "Peter McIntyre"

380 Publications

Marine Bile Natural Products as Agonists of the TGR5 Receptor.

J Nat Prod 2021 Apr 27. Epub 2021 Apr 27.

School of Health and Biomedical Sciences, RMIT University, Bundoora, Victoria 3083, Australia.

Agonism of the G protein-coupled bile acid receptor "Takeda G-protein receptor 5" (TGR5) aids in attenuating cholesterol accumulation due to atherosclerotic progression. Although mammalian bile compounds can activate TGR5, they are generally weak agonists, and more effective compounds need to be identified. In this study, two marine bile compounds (5β-scymnol and its sulfate) were compared with mammalian bile compounds deoxycholic acid (DCA) and ursodeoxycholic acid (UDCA) using an model of TGR5 agonism. The response profiles of human embryonic kidney 293 cells (HEK293) transfected to overexpress TGR5 (HEK293-TGR5) and incubated with subcytotoxic concentrations of test compounds were compared to nontransfected HEK293 control cells using the specific calcium-binding fluorophore Fura-2AM to measure intracellular calcium [Ca] release. Scymnol and scymnol sulfate caused a sustained increase in [Ca] within TGR5 cells only, which was abolished by a specific inhibitor for G protein (UBO-QIC). Sustained increases in [Ca] were seen in both cell types with DCA exposure; this was unaffected by UBO-QIC, indicating that TGR5 activation was not involved. Exposure to UDCA did not alter [Ca], suggesting a lack of TGR5 bioactivity. These findings demonstrated that both scymnol and scymnol sulfate are novel agonists of TGR5 receptors, showing therapeutic potential for treating atherosclerosis.
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http://dx.doi.org/10.1021/acs.jnatprod.0c01327DOI Listing
April 2021

Serotonin-induced vascular permeability is mediated by transient receptor potential vanilloid 4 in the airways and upper gastrointestinal tract of mice.

Lab Invest 2021 Apr 15. Epub 2021 Apr 15.

School of Medical Sciences and Health Innovations Research Institute, RMIT University, Bundoora, VIC, Australia.

Endothelial and epithelial cells form physical barriers that modulate the exchange of fluid and molecules. The integrity of these barriers can be influenced by signaling through G protein-coupled receptors (GPCRs) and ion channels. Serotonin (5-HT) is an important vasoactive mediator of tissue edema and inflammation. However, the mechanisms that drive 5-HT-induced plasma extravasation are poorly defined. The Transient Receptor Potential Vanilloid 4 (TRPV4) ion channel is an established enhancer of signaling by GPCRs that promote inflammation and endothelial barrier disruption. Here, we investigated the role of TRPV4 in 5-HT-induced plasma extravasation using pharmacological and genetic approaches. Activation of either TRPV4 or 5-HT receptors promoted significant plasma extravasation in the airway and upper gastrointestinal tract of mice. 5-HT-mediated extravasation was significantly reduced by pharmacological inhibition of the 5-HT receptor subtype, or with antagonism or deletion of TRPV4, consistent with functional interaction between 5-HT receptors and TRPV4. Inhibition of receptors for the neuropeptides substance P (SP) or calcitonin gene-related peptide (CGRP) diminished 5-HT-induced plasma extravasation. Supporting studies assessing treatment of HUVEC with 5-HT, CGRP, or SP was associated with ERK phosphorylation. Exposure to the TRPV4 activator GSK1016790A, but not 5-HT, increased intracellular Ca in these cells. However, 5-HT pre-treatment enhanced GSK1016790A-mediated Ca signaling, consistent with sensitization of TRPV4. The functional interaction was further characterized in HEK293 cells expressing 5-HT to reveal that TRPV4 enhances the duration of 5-HT-evoked Ca signaling through a PLA and PKC-dependent mechanism. In summary, this study demonstrates that TRPV4 contributes to 5-HT-induced plasma extravasation in the airways and upper GI tract, with evidence supporting a mechanism of action involving SP and CGRP release.
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http://dx.doi.org/10.1038/s41374-021-00593-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8047529PMC
April 2021

Immunisation Coverage Annual Report 2018.

Commun Dis Intell (2018) 2021 03 31;45. Epub 2021 Mar 31.

National Centre for Immunisation Research and Surveillance.

Abstract: Australian Immunisation Register data have been analysed for children aged < 5 years, focusing on changes in coverage at key milestone ages (12, 24 and 60 months) between 2017 and 2018, while also documenting longer term trends. Fully vaccinated coverage increased at the 12- and 60-months milestones to 93.9% and 94.0%, respectively, but, in the context of additional antigens required, decreased to 90.1% at 24 months. Following the move to a two-dose rotavirus vaccine schedule across Australia from mid-2017, rotavirus vaccine coverage increased from 86.8% to 90.9%. In 2018, most jurisdictions funded influenza vaccine for non-Indigenous children aged 6 months to < 5 years; the National Immunisation Program has funded influenza vaccine for Aboriginal and Torres Strait Islander children and medically at-risk children since 2015 and 2010, respectively. Recorded influenza vaccine coverage in Aboriginal and Torres Strait Islander children doubled from 14.9% to 31.4%, and increased fivefold in non-Indigenous children from 5.0% to 25.9% in 2018. The timeliness of fully vaccinated coverage was also examined at earlier milestones (3 months after due date of last scheduled vaccine) of 9, 15, 21 and 51 months, by area of residence. For all children, coverage among those living in the least advantaged residential area quintile was 3-4% lower than that for those in the most advantaged quintile at the 9-, 15- and 21-month milestones. Importantly, although Aboriginal and Torres Strait Islander children had lower coverage for the second dose of measles-mumps-rubella vaccine at 24 months (91.8% versus 93.1% for non-Indigenous), coverage increased to 98.5% at 60 months; coverage was also high in non-Indigenous children at 96.2%, above the 95% target critical to measles control. These data demonstrate continuing improvements in immunisation coverage and suggest potential new coverage targets for earlier protection in the first two years of life.
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http://dx.doi.org/10.33321/cdi.2020.45.17DOI Listing
March 2021

Otitis media outcomes of a combined 10-valent pneumococcal Haemophilus influenzae protein D conjugate vaccine and 13-valent pneumococcal conjugate vaccine schedule at 1-2-4-6 months: PREVIX_COMBO, a 3-arm randomised controlled trial.

BMC Pediatr 2021 Mar 8;21(1):117. Epub 2021 Mar 8.

Child Health Division, Menzies School of Heath Research, Casuarina, Northern Territory, Australia.

Background: Aboriginal children living in Australian remote communities are at high risk of early and persistent otitis media, hearing loss, and social disadvantage. Streptococcus pneumoniae and non-typeable Haemophilus influenzae (NTHi) are the primary pathogens. We compared otitis media outcomes in infants randomised to either a combination of Synflorix™ (PHiD-CV10, with protein D of NTHi) and Prevenar13™ (PCV13, with 3, 6A, and 19A), with recommended schedules for each vaccine alone. We previously reported superior broader overall immunogenicity of the combination schedule at 7 months, and early superiority of PHiD-CV10 compared to PCV13 at 4 months.

Methods: In an open-label superiority trial, we randomised (1:1:1) Aboriginal infants at 28 to 38 days of age, to either Prevenar13™ (P) at 2-4-6 months (_PPP), Synflorix™ (S) at 2-4-6 months (_SSS), or Synflorix™ at 1-2-4 months plus Prevenar13™ at 6 months (SSSP). Ears were assessed using tympanometry at 1 and 2 months, combined with otoscopy at 4, 6, and 7 months. A worst ear diagnosis was made for each child visit according to a severity hierarchy of normal, otitis media with effusion (OME), acute otitis media without perforation (AOMwoP), AOM with perforation (AOMwiP), and chronic suppurative otitis media (CSOM).

Results: Between September 2011 and September 2017, 425 infants were allocated to _PPP(143), _SSS(141) or SSSP(141). Ear assessments were successful in 96% scheduled visits. At 7 months prevalence of any OM was 91, 86, and 90% in the _PPP, _SSS, and SSSP groups, respectively. There were no significant differences in prevalence of any form of otitis media between vaccine groups at any age. Combined group prevalence of any OM was 43, 57, 82, 87, and 89% at 1, 2, 4, 6, and 7 months of age, respectively. Of 388 infants with ear assessments at 4, 6 and 7 months, 277 (71.4%) had OM that met criteria for specialist referral; rAOM, pOME, or CSOM.

Conclusions: Despite superior broader overall immunogenicity of the combination schedule at 7 months, and early superiority of PHiD-CV10 compared to PCV13 at 4 months, there were no significant differences in prevalence of otitis media nor healthy ears throughout the first months of life.

Trial Registration: ACTRN12610000544077 registered 06/07/2010 and ClinicalTrials.gov NCT01174849 registered 04/08/2010.
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http://dx.doi.org/10.1186/s12887-021-02552-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7938290PMC
March 2021

Interchangeability, immunogenicity and safety of a combined 10-valent pneumococcal protein D conjugate vaccine (Synflorix) and 13-valent-PCV (Prevenar13) schedule at 1-2-4-6 months: PREVIX_COMBO, a 3-arm randomised controlled trial.

Vaccine X 2021 Apr 15;7:100086. Epub 2021 Feb 15.

Child Health Division, Menzies School of Heath Research, PO Box 41096, Casuarina, Australia.

Background: Aboriginal children living in remote communities are at high risk of early and persistent otitis media. and non-typeable (NTHi) are primary pathogens. Vaccines with potential to prevent early OM have not been evaluated in this population. We compared immunogenicity (ELISA and opsonophagocytic activity) of a combination of Synflorix™ (PHiD-CV10, 10 serotypes and protein D of NTHi) and Prevenar13™ (PCV13, 10 serotypes plus 3, 6A, and 19A), with recommended schedules.

Methods: This open-label superiority trial randomised (1:1:1) Aboriginal infants at 28 to 38 days of age, to PCV13 (P) at 2-4-6 months (_PPP), PHiD-CV10 (S) at 2-4-6 months (_SSS), or PHiD-CV10 at 1-2-4 plus PCV13 at -6 months (SSSP). Primary outcomes (blinded) were immunogenicity against PCV13-only serotypes 3, 6A, 19A, and PHiD-CV10-only protein D at 7 months. Secondary outcomes include immunogenicity against all serotypes at 2, 4 and 7 months.

Findings: Between 2011 and 2017, 425 infants were allocated to _PPP(143), _SSS(141) or SSSP(1 4 1). An intention to treat approach including all available data was used. The SSSP group had superior immunogenicity against serotypes 3, 6A, and 19A compared to _SSS (OPA GMT ratios 8.1 to 59.5, p < 0.001), and against protein D compared to _PPP (GMC ratio 11.9 (95%CI 9.7 to 14.6)). Immune responses to protein D and 3, 6A, and 19A in SSSP were not significantly lower (i.e. no harm) than either _SSS or _PPP. For ten common serotypes responses at 2, 4 and 7 months were superior for SSSP (following 1-, 2-, and 4- doses) than _SSS and _PPP (following 0-, 1-, and 3- doses). At 4 months, _SSS was superior to _PPP. Reactogenicity and hospitalisations were rare and unrelated to the intervention.

Interpretation: From two months, the 1-2-4-6-month combined schedule (SSSP) was safe and significantly more immunogenic than 2-4-6-month schedules. The earlier responses may be beneficial in high-risk populations.
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http://dx.doi.org/10.1016/j.jvacx.2021.100086DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7930582PMC
April 2021

COVID-19 vaccines - are we there yet?

Aust Prescr 2021 Feb 17;44(1):19-25. Epub 2020 Dec 17.

National Centre for Immunisation Research and Surveillance (NCIRS).

The novel coronavirus SARS-CoV-2, the cause of the COVID-19 pandemic, is a highly infectious human respiratory pathogen to which the global population had no prior immunity. The virus will likely continue to cause significant morbidity until there is a broadly effective vaccine As of mid-December 2020, more than 200 COVID-19 vaccine candidates are in development and 11 have entered phase III clinical trials globally. All generate immunity to the viral spike glycoprotein Three vaccine candidates have agreements for procurement and use in Australia if efficacy and safety requirements are met - one protein-based vaccine, one vaccine using a simian-derived adenovirus vector and one messenger RNA vaccine. The latter two vaccines have published interim analyses and efficacy results of their phase III trials. The messenger RNA vaccine is being rolled out in the UK, USA and Canada Significant uncertainties remain. How well will some of those at highest risk of severe disease (such as older people aged >75 years and those with immunocompromising conditions) be protected by a vaccine, and for how long? Also, to what extent will vaccination protect against infection? This will determine the degree of indirect 'herd' protection needed through broad vaccine coverage of younger age groups.
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http://dx.doi.org/10.18773/austprescr.2020.084DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7900269PMC
February 2021

Estimating pneumococcal vaccine coverage among Australian Indigenous children and children with medically at-risk conditions using record linkage.

Vaccine 2021 Mar 20;39(12):1727-1735. Epub 2021 Feb 20.

School of Population Health, Faculty of Medicine, University of New South Wales, Sydney, NSW, Australia; The University of Sydney Northern Clinical School, Women and Babies Research, St Leonards, NSW, Australia; Northern Sydney Local Health District, Kolling Institute, St Leonards, NSW, Australia; National Centre for Immunisation Research and Surveillance, Westmead, NSW, Australia.

Background: Risk-based recommendations are common for pneumococcal vaccines but little is known about their uptake. In Australia, pneumococcal conjugate vaccine (PCV) was funded only for Aboriginal or Torres Strait Islander (Indigenous) children and those with underlying medical conditions in 2001, and then there were different booster dose recommendations depending on risk after the introduction of universal PCV vaccination in 2005.

Methods: We measured coverage of PCV dose 3 and additional PCV and 23-valent pneumococcal polysaccharide vaccine (PPV23) doses by risk group among children born in July 2001-December 2012 in two Australian states using linked immunisation and hospitalisation data (available until December 2013). We ascertained medical risk conditions using hospitalisation diagnosis codes and Indigenous status using an established algorithm, comparing coverage for children born pre (2001-2004) and post (2005-2012) universal PCV funding.

Results: Among 1.3 million children, 63,897 (4.9%) were Indigenous and 32,934 (2.5%) had at least one medically at-risk condition identified by age 6 months. For births in 2001-2004, coverage for PCV dose 3 by 1 year of age was 37% for Indigenous, 15% for medically at-risk and 11% in other children, increasing to 83%, 91% and 92%, respectively for births in 2005-2012. In children with medically at-risk conditions, PCV dose 4 coverage by 2 years was 1% for 2001-2004 births, increasing to 9% for 2005-2012 births, with PPV23 coverage by 6 years 3% in both cohorts. Among eligible Indigenous children, PPV23 coverage by 3 years was 45% for 2001-2004 births and 51% for 2005-2012 births.

Conclusions: Coverage with additional recommended booster doses was very low among children with medical conditions, and only modest among Indigenous children. If additional PCV doses are recommended for some risk groups, especially in the context of routine schedules with reduced doses (e.g. 2 + 1 and 1 + 1), measures to improve implementation will be required.
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http://dx.doi.org/10.1016/j.vaccine.2021.02.015DOI Listing
March 2021

Vaccines for older adults.

BMJ 2021 02 22;372:n188. Epub 2021 Feb 22.

Departments of Pediatrics and Medicine, University of Colorado School of Medicine Anschutz Medical Campus, Aurora, Colorado, USA.

The proportion of the global population aged 65 and older is rapidly increasing. Infections in this age group, most recently with SARS-CoV-2, cause substantial morbidity and mortality. Major improvements have been made in vaccines for older people, either through the addition of novel adjuvants-as in the new recombinant zoster vaccine and an adjuvanted influenza vaccine-or by increasing antigen concentration, as in influenza vaccines. In this article we review improvements in immunization for the three most important vaccine preventable diseases of aging. The recombinant zoster vaccine has an efficacy of 90% that is minimally affected by the age of the person being vaccinated and persists for more than four years. Increasing antigen dose or inclusion of adjuvant has improved the immunogenicity of influenza vaccines in older adults, although the relative effectiveness of the enhanced influenza vaccines and the durability of the immune response are the focus of ongoing clinical trials. Conjugate and polysaccharide pneumococcal vaccines have similar efficacy against invasive pneumococcal disease and pneumococcal pneumonia caused by vaccine serotypes in older adults. Their relative value varies by setting, depending on the prevalence of vaccine serotypes, largely related to conjugate vaccine coverage in children. Improved efficacy will increase public confidence and uptake of these vaccines. Co-administration of these vaccines is feasible and important for maximal uptake in older people. Development of new vaccine platforms has accelerated following the arrival of SARS-CoV-2, and will likely result in new vaccines against other pathogens in the future.
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http://dx.doi.org/10.1136/bmj.n188DOI Listing
February 2021

Depth-discrete metagenomics reveals the roles of microbes in biogeochemical cycling in the tropical freshwater Lake Tanganyika.

ISME J 2021 Feb 9. Epub 2021 Feb 9.

Department of Bacteriology, University of Wisconsin-Madison, Madison, WI, USA.

Lake Tanganyika (LT) is the largest tropical freshwater lake, and the largest body of anoxic freshwater on Earth's surface. LT's mixed oxygenated surface waters float atop a permanently anoxic layer and host rich animal biodiversity. However, little is known about microorganisms inhabiting LT's 1470 meter deep water column and their contributions to nutrient cycling, which affect ecosystem-level function and productivity. Here, we applied genome-resolved metagenomics and environmental analyses to link specific taxa to key biogeochemical processes across a vertical depth gradient in LT. We reconstructed 523 unique metagenome-assembled genomes (MAGs) from 34 bacterial and archaeal phyla, including many rarely observed in freshwater lakes. We identified sharp contrasts in community composition and metabolic potential with an abundance of typical freshwater taxa in oxygenated mixed upper layers, and Archaea and uncultured Candidate Phyla in deep anoxic waters. Genomic capacity for nitrogen and sulfur cycling was abundant in MAGs recovered from anoxic waters, highlighting microbial contributions to the productive surface layers via recycling of upwelled nutrients, and greenhouse gases such as nitrous oxide. Overall, our study provides a blueprint for incorporation of aquatic microbial genomics in the representation of tropical freshwater lakes, especially in the context of ongoing climate change, which is predicted to bring increased stratification and anoxia to freshwater lakes.
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http://dx.doi.org/10.1038/s41396-021-00898-xDOI Listing
February 2021

Assessing the impact of the 13 valent pneumococcal vaccine on childhood empyema in Australia.

Thorax 2021 Jan 27. Epub 2021 Jan 27.

Department of Respiratory Medicine, Sydney Children's Hospital Randwick, Randwick, New South Wales, Australia.

Background: Empyema is a serious complication of pneumonia frequently caused by (SP). We assessed the impact of the 13-valent pneumococcal conjugate vaccine (13vPCV) on childhood pneumonia and empyema after inclusion in the Australian National Immunisation Program.

Methods: For bacterial pneumonia and empyema hospitalisations, we ascertained incidence rates (IRs) using the National Hospital Morbidity Database International Statistical Classification of Disease discharge codes and relevant population denominators, and calculated incidence rate ratios (IRR) comparing the 13vPCV period (June 2012-May 2017) with the 7vPCV period (June 2007-May 2011). Blood and pleural fluid (PF) cultures and PF PCR of 401 children with empyema from 11 Australian hospitals during the 13vPCV period were compared with our previous study in the 7vPCV period.

Findings: Across 7vPCV and 13vPCV periods, IRs per million children (95% CIs) were 1605 (1588 to 1621) and 1272 (1259 to 1285) for bacterial pneumonia, and 14.23 (12.67 to 15.79) and 17.89 (16.37 to 19.42) for empyema hospitalisations. IRRs were 0.79 (0.78 to 0.80) for bacterial pneumonia and 1.25 (1.09 to 1.44) for empyema. Of 161 empyema cases with SP serotypes, 147 (91.3%) were vaccine types. ST3 accounted for 76.4% of identified serotypes in the 13vPCV period, more than double than the 7vPCV period (p<0.001); ST19A decreased from 36.4% to 12.4%. No cases of ST1 empyema were identified in the 13vPCV period versus 14.5% in the 7vPCV period.

Interpretation: 13vPCV resulted in a significant reduction in all-cause hospitalisations for bacterial pneumonia but empyema hospitalisations significantly increased, with emergence of pneumococcal ST3 as the dominant serotype in empyema.

Trial Registration Number: Australian and New Zealand Clinical Trial Registry ACTRN 12614000354684.
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http://dx.doi.org/10.1136/thoraxjnl-2020-216032DOI Listing
January 2021

A network of grassroots reserves protects tropical river fish diversity.

Nature 2020 12 25;588(7839):631-635. Epub 2020 Nov 25.

Center for Limnology, University of Wisconsin-Madison, Madison, WI, USA.

Intensive fisheries have reduced fish biodiversity and abundance in aquatic ecosystems worldwide. 'No-take' marine reserves have become a cornerstone of marine ecosystem-based fisheries management, and their benefits for adjacent fisheries are maximized when reserve design fosters synergies among nearby reserves. The applicability of this marine reserve network paradigm to riverine biodiversity and inland fisheries remains largely untested. Here we show that reserves created by 23 separate communities in Thailand's Salween basin have markedly increased fish richness, density, and biomass relative to adjacent areas. Moreover, key correlates of the success of protected areas in marine ecosystems-particularly reserve size and enforcement-predict differences in ecological benefits among riverine reserves. Occupying a central position in the network confers additional gains, underscoring the importance of connectivity within dendritic river systems. The emergence of network-based benefits is remarkable given that these reserves are young (less than 25 years old) and arose without formal coordination. Freshwater ecosystems are under-represented among the world's protected areas, and our findings suggest that networks of small, community-based reserves offer a generalizable model for protecting biodiversity and augmenting fisheries as the world's rivers face unprecedented pressures.
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http://dx.doi.org/10.1038/s41586-020-2944-yDOI Listing
December 2020

GenBank's reliability is uncertain for biodiversity researchers seeking species-level assignment for eDNA.

Proc Natl Acad Sci U S A 2020 12 24;117(51):32211-32212. Epub 2020 Nov 24.

Department of Natural Resources, Cornell University, Ithaca, NY 14853.

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http://dx.doi.org/10.1073/pnas.2007421117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7768753PMC
December 2020

Outsized nutrient contributions from small tributaries to a Great Lake.

Proc Natl Acad Sci U S A 2020 11 26;117(45):28175-28182. Epub 2020 Oct 26.

Center for Limnology, University of Wisconsin-Madison, Madison, WI 53706.

Excessive nitrogen (N) and phosphorus (P) loading is one of the greatest threats to aquatic ecosystems in the Anthropocene, causing eutrophication of rivers, lakes, and marine coastlines worldwide. For lakes across the United States, eutrophication is driven largely by nonpoint nutrient sources from tributaries that drain surrounding watersheds. Decades of monitoring and regulatory efforts have paid little attention to small tributaries of large water bodies, despite their ubiquity and potential local importance. We used a snapshot of nutrient inputs from nearly all tributaries of Lake Michigan-the world's fifth largest freshwater lake by volume-to determine how land cover and dams alter nutrient inputs across watershed sizes. Loads, concentrations, stoichiometry (N:P), and bioavailability (percentage dissolved inorganic nutrients) varied by orders of magnitude among tributaries, creating a mosaic of coastal nutrient inputs. The 6 largest of 235 tributaries accounted for ∼70% of the daily N and P delivered to Lake Michigan. However, small tributaries exhibited nutrient loads that were high for their size and biased toward dissolved inorganic forms. Higher bioavailability of nutrients from small watersheds suggests greater potential to fuel algal blooms in coastal areas, especially given the likelihood that their plumes become trapped and then overlap in the nearshore zone. Our findings reveal an underappreciated role that small streams may play in driving coastal eutrophication in large water bodies. Although they represent only a modest proportion of lake-wide loads, expanding nutrient management efforts to address smaller watersheds could reduce the ecological impacts of nutrient loading on valuable nearshore ecosystems.
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http://dx.doi.org/10.1073/pnas.2001376117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7668162PMC
November 2020

Australia needs a vaccine injury compensation scheme: Upcoming COVID-19 vaccines make its introduction urgent.

Aust J Gen Pract 2020 09 9;49. Epub 2020 Sep 9.

PhD, FRACP, Professorial Fellow, National Centre for Immunisation Research and Surveillance (NCIRS), NSW; Professor, Faculty of Medicine and Health, The University of Sydney Children@s Hospital Westmead, NSW.

There is a strong public health ethical justification to introduce a vaccine injury compensation scheme in Australia, and it needs to be in place before widespread use of COVID-19 vaccines.
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http://dx.doi.org/10.31128/AJGP-COVID-36DOI Listing
September 2020

Comparing mortalities of the first wave of coronavirus disease 2019 (COVID-19) and of the 1918-19 winter pandemic influenza wave in the USA.

Int J Epidemiol 2021 01;49(6):2089-2091

Department of Women's and Children's Health, University of Otago, Dunedin, New Zealand.

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http://dx.doi.org/10.1093/ije/dyaa186DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7543530PMC
January 2021

Polio - The old foe and new challenges: An update for clinicians.

J Paediatr Child Health 2020 Oct 9;56(10):1527-1532. Epub 2020 Sep 9.

Sydney Medical School, University of Sydney, Sydney, New South Wales, Australia.

The Global Polio Eradication Initiative since 1988 has seen the impact of poliovirus decline from frequent global epidemics in the early 1900s to being now only endemic in two countries today. Global vaccination programmes and surveillance for the disease have resulted in the landmark eradication of two of the three poliovirus strains in the last 5 years. Australia continues to contribute to global surveillance efforts for the disease via the Australian Paediatric Surveillance Unit and the Paediatric Active Enhanced Disease Surveillance Network, which aim to detect cases of acute flaccid paralysis in children, the key clinical feature of poliomyelitis. Today, in the era of the polio 'endgame', there is growing recognition of non-polio enteroviruses causing paralytic diseases that are polio-like, particularly in children, with an increased need for awareness and vigilance by paediatric clinicians.
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http://dx.doi.org/10.1111/jpc.15140DOI Listing
October 2020

Australian mumps serosurvey 2012-2013: any cause for concern?

Commun Dis Intell (2018) 2020 Aug 17;44. Epub 2020 Aug 17.

National Centre for Immunisation Research and Surveillance, Children's Hospital at Westmead, Sydney, Australia.

Objectives: To determine population-level immunity to mumps in Australia.

Methods: We tested randomly selected specimens from people aged 1-49 years using the Enzygnost anti-parotitis IgG enzyme immunoassay from an opportunistically collected serum bank in 2012-2013. Weighted estimates of the proportion seropositive and equivocal for mumps-specific IgG antibody were determined by age group and compared with two previous national serosurveys conducted in 2007-2008 and 1997-1998.

Results: Overall, 82.1% (95% CI 80.6-83.5%) of 2,729 specimens were positive or equivocal for mumps-specific IgG antibodies (71.1% positive [95% CI 69.4-72.9%]; 10.9% equivocal [95% CI 9.8-12.2%]). The proportion positive or equivocal was higher in 2012-2013 (82.1%) than in 2007-2008 (75.5%) and 1997-1998 (72.5%), but varied by age. The proportion positive or equivocal in 2012-2013 was above 80% for all age groups older than 1 year except for 30-34 year olds, corresponding to the 1978-1982 birth cohort previously identified as most likely to have missed out on a second MMR vaccine dose.

Conclusion: Seropositivity to mumps in 2012-2013 was well-maintained compared with previous serosurveys. Low mumps notifications over this period in Australia suggest an absence of community-based transmission of mumps infection in the general population, but recent outbreaks among Aboriginal adolescents and young adults in close-contact settings, despite high 2-dose MMR coverage, suggest that seroprotection may be insufficient in other similar settings in Australia.Seropositivity to mumps in 2012-2013 was well-maintained compared with previous serosurveys. Low mumps notifications over this period in Australia suggest an absence of community-based transmission of mumps infection in the general population, but recent outbreaks among Aboriginal adolescents and young adults in close-contact settings, despite high 2-dose MMR coverage, suggest that seroprotection may be insufficient in other similar settings in Australia.
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http://dx.doi.org/10.33321/cdi.2020.44.67DOI Listing
August 2020

Structural genomic variation leads to genetic differentiation in Lake Tanganyika's sardines.

Mol Ecol 2020 09 9;29(17):3277-3298. Epub 2020 Aug 9.

Department of Botany and Program in Ecology, University of Wyoming, Laramie, WY, USA.

Identifying patterns in genetic structure and the genetic basis of ecological adaptation is a core goal of evolutionary biology and can inform the management and conservation of species that are vulnerable to population declines exacerbated by climate change. We used reduced-representation genomic sequencing methods to gain a better understanding of genetic structure among and within populations of Lake Tanganyika's two sardine species, Limnothrissa miodon and Stolothrissa tanganicae. Samples of these ecologically and economically important species were collected across the length of Lake Tanganyika, as well as from nearby Lake Kivu, where L. miodon was introduced in 1959. Our results reveal differentiation within both S. tanganicae and L. miodon that is not explained by geography. Instead, this genetic differentiation is due to the presence of large sex-specific regions in the genomes of both species, but involving different polymorphic sites in each species. Our results therefore indicate rapidly evolving XY sex determination in the two species. Additionally, we found evidence of a large chromosomal rearrangement in L. miodon, creating two homokaryotypes and one heterokaryotype. We found all karyotypes throughout Lake Tanganyika, but the frequencies vary along a north-south gradient and differ substantially in the introduced Lake Kivu population. We do not find evidence for significant isolation by distance, even over the hundreds of kilometres covered by our sampling, but we do find shallow population structure.
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http://dx.doi.org/10.1111/mec.15559DOI Listing
September 2020

Active surveillance of acute paediatric hospitalisations demonstrates the impact of vaccination programmes and informs vaccine policy in Canada and Australia.

Euro Surveill 2020 06;25(25)

The IMPACT and PAEDS investigators are acknowledged at the end of this article.

Sentinel surveillance of acute hospitalisations in response to infectious disease emergencies such as the 2009 influenza A(H1N1)pdm09 pandemic is well described, but recognition of its potential to supplement routine public health surveillance and provide scalability for emergency responses has been limited. We summarise the achievements of two national paediatric hospital surveillance networks relevant to vaccine programmes and emerging infectious diseases in Canada (Canadian Immunization Monitoring Program Active; IMPACT from 1991) and Australia (Paediatric Active Enhanced Disease Surveillance; PAEDS from 2007) and discuss opportunities and challenges in applying their model to other contexts. Both networks were established to enhance capacity to measure vaccine preventable disease burden, vaccine programme impact, and safety, with their scope occasionally being increased with emerging infectious diseases' surveillance. Their active surveillance has increased data accuracy and utility for syndromic conditions (e.g. encephalitis), pathogen-specific diseases (e.g. pertussis, rotavirus, influenza), and adverse events following immunisation (e.g. febrile seizure), enabled correlation of biological specimens with clinical context and supported responses to emerging infections (e.g. pandemic influenza, parechovirus, COVID-19). The demonstrated long-term value of continuous, rather than incident-related, operation of these networks in strengthening routine surveillance, bridging research gaps, and providing scalable public health response, supports their applicability to other countries.
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http://dx.doi.org/10.2807/1560-7917.ES.2020.25.25.1900562DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7331140PMC
June 2020

Pertussis vaccination and allergic illness in Australian children.

Pediatr Allergy Immunol 2020 10 20;31(7):857-861. Epub 2020 Jul 20.

Woolcock Institute of Medical Research, The University of Sydney, Sydney, NSW, Australia.

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http://dx.doi.org/10.1111/pai.13300DOI Listing
October 2020

10-Valent pneumococcal non-typeable protein D conjugate vaccine (PHiD-CV10) versus 13-valent pneumococcal conjugate vaccine (PCV13) as a booster dose to broaden and strengthen protection from otitis media (PREVIX_BOOST) in Australian Aboriginal children: study protocol for a randomised controlled trial.

BMJ Open 2020 05 24;10(5):e033511. Epub 2020 May 24.

Child Health Division, Menzies School of Health Research and Charles Darwin University, Darwin, Northern Territory, Australia

Introduction: and non-typeable (NTHi) are major otitis media pathogens that densely co-colonise the nasopharynx and infect the middle ear of Australian Aboriginal infants from very early in life. Our co-primary hypotheses are that at 18 months of age infants receiving 10-valent pneumococcal protein D conjugate vaccine (PHiD-CV10) compared with those receiving 13-valent pneumococcal conjugate vaccine (PCV13) as a booster at 12 months of age will have higher antibody levels to protein D and that infants receiving PCV13 will have higher antibody levels to PCV13-only serotypes 3, 6A and 19A.

Methods And Analyses: Our randomised controlled trial will enrol 270 Aboriginal children at 12 months of age to a booster dose of either PHiD-CV10 or PCV13. Children who completed the three-dose primary course schedules of PHiD-CV10 at 2, 4, 6 months of age; PCV13 at 2, 4, 6 months of age; or a combination schedule of PHiD-CV10 at 1, 2, 4 months of age plus PCV13 at 6 months of age are eligible. The co-primary assessor-blinded outcomes when the infants are 18 months of age are as follows: (a) IgG geometric mean concentration (GMC) and proportion with IgG ≥100 EU/mL for protein D, and (b) IgG GMC and the proportion with IgG ≥0.35 µg/mL for pneumococcal serotypes 3, 6A and 19A. Secondary immunogenicity comparisons of six primary and booster dose schedules of 10 shared serotypes at 18 months of age, nasopharyngeal carriage, all forms of otitis media, hearing loss and developmental milestones at 18, 24, 30 and 36 months of age will be reported.

Ethics And Dissemination: Ethics committees of NT Department of Health, Menzies, WA Department of Health and WA Aboriginal Health approved the study. Results will be presented to communities, at conferences and published in peer-reviewed journals.

Trial Registration Number: NCT01735084.
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http://dx.doi.org/10.1136/bmjopen-2019-033511DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7252982PMC
May 2020

CRISP3 expression drives prostate cancer invasion and progression.

Endocr Relat Cancer 2020 07;27(7):415-430

Department of Anatomy and Developmental Biology, Monash University, Clayton, Victoria, Australia.

Identifying the factors stimulating prostate cancer cells migration and invasion has the potential to bring new therapeutic targets to the clinic. Cysteine-rich secretory protein 3 (CRISP3) is one of the most highly upregulated proteins during the transition of a healthy human prostatic epithelium to prostate cancer. Here we show using a genetically engineered mouse model of prostate cancer that CRISP3 production greatly facilitates disease progression from carcinoma in situ to invasive prostate cancer in vivo. This interpretation was confirmed using both human and mouse prostate cancer cell lines, which showed that exposure to CRISP3 enhanced cell motility and invasion. Further, using mass spectrometry, we show that CRISP3 induces changes in abundance of a subset of cell-cell adhesion proteins, including LASP1 and TJP1 both in vivo and in vitro. Collectively, these data identify CRISP3 as being pro-tumorigenic in the prostate and validate it as a potential target for therapeutic intervention.
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http://dx.doi.org/10.1530/ERC-20-0092DOI Listing
July 2020

The transient receptor potential vanilloid 4 (TRPV4) ion channel mediates protease activated receptor 1 (PAR1)-induced vascular hyperpermeability.

Lab Invest 2020 08 27;100(8):1057-1067. Epub 2020 Apr 27.

School of Medical Sciences and Health Innovations Research Institute, RMIT University, Bundoora, VIC, 3083, Australia.

Endothelial barrier disruption is a hallmark of tissue injury, edema, and inflammation. Vascular endothelial cells express the G protein-coupled receptor (GPCR) protease acctivated receptor 1 (PAR1) and the ion channel transient receptor potential vanilloid 4 (TRPV4), and these signaling proteins are known to respond to inflammatory conditions and promote edema through remodeling of cell-cell junctions and modulation of endothelial barriers. It has previously been established that signaling initiated by the related protease activated receptor 2 (PAR2) is enhanced by TRPV4 in sensory neurons and that this functional interaction plays a critical role in the development of neurogenic inflammation and nociception. Here, we investigated the PAR1-TRPV4 axis, to determine if TRPV4 plays a similar role in the control of edema mediated by thrombin-induced signaling. Using Evans Blue permeation and retention as an indication of increased vascular permeability in vivo, we showed that TRPV4 contributes to PAR1-induced vascular hyperpermeability in the airways and upper gastrointestinal tract of mice. TRPV4 contributes to sustained PAR1-induced Ca signaling in recombinant cell systems and to PAR1-dependent endothelial junction remodeling in vitro. This study supports the role of GPCR-TRP channel functional interactions in inflammatory-associated changes to vascular function and indicates that TRPV4 is a signaling effector for multiple PAR family members.
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http://dx.doi.org/10.1038/s41374-020-0430-7DOI Listing
August 2020

High healthcare resource utilisation due to pertussis in Australian adults aged 65 years and over.

Vaccine 2020 04 24;38(19):3553-3559. Epub 2020 Mar 24.

School of Public Health and Community Medicine, University of New South Wales, Sydney, NSW, Australia.

Background: In the context of co-morbid illness and increasing age, data on excess morbidity from pertussis in older adults is crucial for immunisation policy but has been largely limited to case-series.

Methods: We designed a matched case-control study nested within a population-based cohort of 267,153 adults aged ≥45 years in New South Wales, Australia (The 45 and Up Study cohort). Excess hospital bed days, emergency department (ED) admissions, general practitioner (GP) visits, and prescriptions were estimated using negative binomial regression models. An additional self-controlled analysis was also conducted to validate the main models, and to evaluate results for those with either asthma or a body mass index (BMI)≥30 compared to those without these risk factors.

Results: Based on 524 pairs of PCR-confirmed pertussis cases and matched controls, we estimated an excess healthcare utilisation per case of 2.5 prescriptions (95% CI: 0.2-4.7), of which 1.1 (95% CI: 0.5-2.2) were antibiotics, 2.3 GP visits (95% CI: 2.0-2.6), and 0.1 ED admissions (95% CI: 0.1-0.2). Compared to those 45-64 years, cases ≥65 years had a significantly greater excess for all prescriptions (1.1 vs 4.7/case), antibiotic prescriptions (0.1 vs 2.2/case), and ED admissions (0.1 vs 0.2/case), but no significant excess of respiratory-related hospital bed days. An additional self-controlled analysis confirmed that cases with either asthma or BMI≥30 had higher overall healthcare utilisation but this was not associated with pertussis infection.

Conclusion: We found a substantial excess outpatient healthcare burden among adults aged 65 years and over with PCR-confirmed pertussis, supporting further evaluation of preventive measures.
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http://dx.doi.org/10.1016/j.vaccine.2020.03.021DOI Listing
April 2020

Acute flaccid myelitis - has it gone unrecognised in Australian children?

Commun Dis Intell (2018) 2020 Mar 16;44. Epub 2020 Mar 16.

Discipline of Child and Adolescent Health, University of Sydney, NSW; The Children's Hospital at Westmead, NSW.

We have identified a previously unrecognised cluster of a newly recognised condition - acute flaccid myelitis (AFM) - among acute flaccid paralysis (AFP) cases identified by the Australian Paediatric Active Enhanced Disease Surveillance Network (PAEDS) 2007-2017. In the 12 months before and after detection of enterovirus D68 (EV-D68) from a single AFP case in April 2016, 24 of 97 notified cases of AFP were found to be clinically compatible with AFM; of these 24 cases, ten, clustered in early 2016, met magnetic resonance imaging (MRI) criteria for AFM. Detection of emerging enteroviruses requires collection of respiratory, cerebrospinal fluid and stool specimens, and should be routine practice for all AFP cases.
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http://dx.doi.org/10.33321/cdi.2020.44.22DOI Listing
March 2020

Australian vaccine preventable disease epidemiological review series: invasive Haemophilus influenzae type b disease, 2000-2017.

Commun Dis Intell (2018) 2020 Feb 17;44. Epub 2020 Feb 17.

National Centre for Immunisation Research and Surveillance, Westmead, New South Wales, Australia; The University of Sydney, New South Wales, Australia.

Introduction: Invasive type b (Hib) disease is rare in Australia following vaccine introduction in 1993. Two deaths in vaccinated children in 2017, and the Hib booster dose moving from age 12 months to 18 months in 2018, prompted this review.

Methods: Hib Case Surveillance Scheme 2000-2017 data were used to calculate incidence, incidence rate ratios (IRR) and vaccine failure (VF) trends. We used denominators from the Australian Immunisation Register to calculate incidence in immunised and unimmunised children.

Results: All-age national invasive Hib disease incidence halved from 0.13 per 100,000 population in 2000 to 0.06 in 2017. Of 345 cases notified in 2000-2017, 153 were born post-2000, with 51 (33%) Aboriginal and Torres Strait Islander (Indigenous), and compared with non-Indigenous children IRR was 8.34 (95% CI: 5.83-11.79), with no evidence of decrease. Overall case fatality rate was 12.4% (19/153); 6 cases had underlying medical conditions. The overall incidence of invasive Hib disease was over 8 times higher (16.6 per 100,000) in children with no recorded doses than in children with ≥1 vaccine dose (1.9 per 100,000). VF criteria were met in 65/145 (45%) cases aged >8 weeks, of whom 7 (11%) were immunocompromised and 6 (9%) died, with no evidence of VF increase over time.

Conclusion: Overall, invasive Hib disease incidence declined by 55% from 2000 to 2017, but marked disparity persists between Indigenous and non-Indigenous children. Following moving the fourth dose from 12 to 18 months in 2018, monitoring of 3-dose VFs will be important, especially in Indigenous children.
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http://dx.doi.org/10.33321/cdi.2020.44.11DOI Listing
February 2020

Ecosystem responses to channel restoration decline with stream size in urban river networks.

Ecol Appl 2020 07 23;30(5):e02107. Epub 2020 Mar 23.

Center for Limnology, University of Wisconsin-Madison, Madison, Wisconsin, 53706, USA.

Urban streams are often severely impaired due to channelization, high loads of nutrients and contaminants, and altered land cover in the watershed. Physical restoration of stream channels is widely used to offset the effects of urbanization on streams, with the goal of improving ecosystem structure and function. However, these efforts are rarely guided by strategic analysis of the factors that mediate the responsiveness of stream ecosystems to restoration. Given that ecological gradients from headwater streams to mainstem rivers are ubiquitous, we posited that location within a river network could mediate the benefits of channel restoration. We studied existing stream restorations in Milwaukee, Wisconsin, to determine (1) whether restorations improve ecosystem function (e.g., nutrient uptake, whole-stream metabolism) and (2) how ecosystem responses vary by position in the urban river network. We quantified a suite of physicochemical and biological metrics in six pairs of contiguous restored and concrete channel reaches, spanning gradients in baseflow discharge (19-196 L/s) and river network position (i.e., headwater to mainstem). Hydrology differed dramatically between the restored and concrete reaches; water velocity was reduced 2- to 13-fold while water residence time was 50-5,000% greater in adjacent restored reaches. Restored reaches had shorter nutrient uptake lengths for ammonium, nitrate, and phosphate, as well as higher whole-stream metabolism. Furthermore, the majority of reaches were autotrophic (i.e., gross primary production > ecosystem respiration), which is not common in stream ecosystems. The difference in ecosystem functioning between restored and unrestored reaches was generally largest in headwaters and declined to equivalence in mainstem restorations. Our results suggest that headwater sites offer higher return on investment compared to larger downstream channels, where ecosystem responsiveness is low. If this pattern proves to be general, the scaling of ecosystem responses with river size could be integrated into planning guidelines for urban stream restorations to enhance the societal and ecological benefits of these expensive interventions.
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http://dx.doi.org/10.1002/eap.2107DOI Listing
July 2020

Challenges in Valuing Vaccine Prevention of Severe Early-Infant Infections.

Authors:
Peter McIntyre

Clin Infect Dis 2020 11;71(8):1988-1989

Department of Women's and Children's Health, Dunedin School of Medicine, University of Otago, Dunedin, New Zealand.

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http://dx.doi.org/10.1093/cid/ciaa170DOI Listing
November 2020

Lower immunity to poliomyelitis viruses in Australian young adults not eligible for inactivated polio vaccine.

Vaccine 2020 03 7;38(11):2572-2577. Epub 2020 Feb 7.

National Centre for Immunisation Research and Surveillance, Children's Hospital at Westmead, Sydney, Australia.

There are limited long-term data on seroprevalence of neutralising antibody (nAb) to the three poliovirus serotypes following the switch from oral polio vaccine (OPV) to inactivated polio vaccine (IPV). In Australia, combination vaccines containing IPV replaced OPV in late 2005. Using serum and plasma specimens collected during 2012 and 2013, we compared prevalence of nAb to poliovirus type 1 (PV1), type 2 (PV2) and type 3 (PV3) in birth cohorts with differing IPV and OPV eligibility from an Australian population-based sample. In the total sample of 1673 persons aged 12 months to 99 years, 85% had nAb against PV1, 83% PV2 and 67% PV3. In the cohort 12 to <18 years (eligible for 4 OPV doses, last dose 8-14 years prior), a significantly lower proportion had nAb than in the 7 to <12 year cohort (eligible for 3 OPV doses and an IPV booster, last dose 3-8 years prior) for all poliovirus types: [PV1: 87.1% vs. 95.9% (P = 0.01), PV2: 80.4% vs. 92.9% (P = 0.003) and PV3: 38.1% vs. 84.0% (P < 0.0001)]. These data suggest individual-level immunity may be better maintained when an OPV primary schedule is boosted by IPV, and support inclusion of an IPV booster in travel recommendations for young adults who previously received only OPV.
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http://dx.doi.org/10.1016/j.vaccine.2020.01.080DOI Listing
March 2020

Whole-Cell Pertussis Vaccination and Decreased Risk of IgE-Mediated Food Allergy: A Nested Case-Control Study.

J Allergy Clin Immunol Pract 2020 06 28;8(6):2004-2014. Epub 2019 Dec 28.

Wesfarmers Centre of Vaccines & Infectious Diseases, Telethon Kids Institute, Nedlands, WA, Australia; School of Public Health, Curtin University, Bentley, WA, Australia. Electronic address:

Background: Rates of food allergy have increased markedly in Australia and other high- income countries in recent years. On the basis of ecological observations, and the known immunologic characteristics of whole-cell pertussis (wP) compared with acellular pertussis (aP) vaccines, we hypothesized that wP vaccination in infancy protects against the development of food allergy.

Objective: To determine whether infants who receive wP in infancy were less likely to develop IgE-mediated food allergy than those who received aP.

Methods: Retrospective cohort-nested case-control study of Australian children born in the period 1997 to 1999, the period of transition from using wP-containing to aP-containing vaccines. Children diagnosed with IgE-mediated food allergy were individually matched to 10 controls by date of birth, socioeconomic decile, and jurisdiction of birth. The odds ratio of vaccination with wP versus aP among cases and matched controls was calculated using conditional logistic regression.

Results: The odds ratio of receiving the first dose as wP (rather than aP) among cases of food allergy compared with controls was 0.77 (95% CI, 0.62-0.95). The results of secondary analyses (any dose as wP vs aP-only, and wP-only vs aP-only) were broadly similar.

Conclusions: Australian infants who received wP vaccines were less likely to be diagnosed with food allergy in childhood than contemporaneous children who received aP vaccines. If a protective effect is confirmed in a randomized controlled trial, wP or mixed wP and aP vaccination schedules could form part of an effective strategy for combating the rise in food allergies.
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http://dx.doi.org/10.1016/j.jaip.2019.12.020DOI Listing
June 2020