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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., (© The Author(s) 2022. Published by Oxford University Press on behalf of the International Epidemiological Association.)

Vaccine development and implementation decisions need to be guided by accurate and robust burden of disease data. We developed an innovative systematic framework outlining the properties of such data that are needed to advance vaccine development and evaluation, and prioritize research and surveillance activities. We focus on 4 objectives-advocacy, regulatory oversight and licensure, policy and post-licensure evaluation, and post-licensure financing-and identify key stakeholders and specific requirements for burden of disease data aligned with each objective. We apply this framework to group A Streptococcus, a pathogen with an underrecognized global burden, and give specific examples pertinent to 8 clinical endpoints. This dynamic framework can be adapted for any disease with a vaccine in development and can be updated as vaccine candidates progress through clinical trials. This framework will also help with research and innovation priority setting of the Immunization Agenda 2030 (IA2030) and accelerate development of future vaccines., Competing Interests: Potential conflicts of interest. H. C. M. has received funding from Merck, Sharp and Dohme under the Merck Investigator Studies Program (not related to the work presented in this article). D. C. K. reports an unpaid volunteer leadership or fiduciary role on the WHO Product Development for Vaccines Advisory Committee, Leducq Foundation Scientific Advisory Board, and SAVAC Executive Committee. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Infectious Diseases Society of America.)

Background: Children with chronic medical conditions are at higher risk of invasive pneumococcal disease (IPD), but little is known about the effectiveness of the primary course of pneumococcal conjugate vaccine (PCV) in these children., Methods: A cohort born in 2001-2004 from two Australian states and identified as medically at-risk (MAR) of IPD either using ICD-coded hospitalizations (with conditions of interest identified by 6 months of age) or linked perinatal data (for prematurity) were followed to age 5 years for notified IPD by serotype. We categorized fully vaccinated children as either receiving PCV dose 3 by <12 months of age or ≥1 PCV dose at ≥12 months of age. Cox proportional hazard modeling was used to estimate hazard ratios (HRs), adjusted for confounders, and vaccine effectiveness (VE) was estimated as (1-HR) × 100., Results: A total of 9220 children with MAR conditions had 53 episodes of IPD (43 vaccine-type); 4457 (48.3%) were unvaccinated and 4246 (46.1%) were fully vaccinated, with 1371 (32.3%) receiving dose 3 by 12 months and 2875 (67.7%) having ≥1 dose at ≥12 months. Estimated VE in fully vaccinated children was 85.9% (95% CI: 33.9-97.0) against vaccine-type IPD and 71.5% (95% CI: 26.6-88.9) against all-cause IPD., Conclusion: This is the first population-based study evaluating the effectiveness of PCV in children with MAR conditions using record linkage. Our study provides evidence that the VE for vaccine-type and all-cause IPD in MAR children in Australia is high and not statistically different from previously reported estimates for the general population. This method can be replicated in other countries to evaluate VE in MAR children., (© The Author(s) 2022. Published by Oxford University Press on behalf of The Journal of the Pediatric Infectious Diseases Society.)

Background: Influenza is the most common vaccine-preventable disease in Australia, causing significant morbidity and mortality. We assessed the burden of influenza across all ages in terms of influenza-associated mortality and hospitalizations using national mortality, hospital-discharge and influenza surveillance data., Methods: Influenza-associated excess respiratory mortality and hospitalization rates from 2007 to 2015 were estimated using generalized additive models with a proxy of influenza activity based on syndromic and laboratory surveillance data. Estimates were made for each age group and year., Results: The estimated mean annual influenza-associated excess respiratory mortality was 2.6 per 100 000 population [95% confidence interval (CI): 1.8, 3.4 per 100 000 population]. The excess annual respiratory hospitalization rate was 57.4 per 100 000 population (95% CI: 32.5, 82.2 per 100 000 population). The highest mortality rates were observed among those aged ≥75 years (35.11 per 100 000 population; 95% CI: 19.93, 50.29 per 100 000 population) and hospitalization rates were also highest among older adults aged ≥75 years (302.95 per 100 000 population; 95% CI: 144.71, 461.19 per 100 000 population), as well as children aged <6 months (164.02 per 100 000 population; 95% CI: -34.84, 362.88 per 100 000 population). Annual variation was apparent, ranging from 1.0 to 3.9 per 100 000 population for mortality and 24.2 to 94.28 per 100 000 population for hospitalizations. Influenza A contributed to almost 80% of the average excess respiratory hospitalizations and 60% of the average excess respiratory deaths., Conclusions: Influenza causes considerable burden to all Australians. Expected variation was observed among age groups, years and influenza type, with the greatest burden falling to older adults and young children. Understanding the current burden is useful for understanding the potential impact of mitigation strategies, such as vaccination., (© The Author(s) 2021; all rights reserved. Published by Oxford University Press on behalf of the International Epidemiological Association.)

Public health measures targeting coronavirus disease 2019 have potential to impact transmission of other respiratory viruses. We found 98.0% and 99.4% reductions in respiratory syncytial virus and influenza detections, respectively, in Western Australian children through winter 2020 despite schools reopening. Border closures have likely been important in limiting external introductions., (© The Author(s) 2020. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Background: Significant progress has been made towards an effective respiratory syncytial virus (RSV) vaccine. Age-stratified estimates of RSV burden are urgently needed for vaccine implementation. Current estimates are limited to small cohorts or clinical coding data only. We present estimates of laboratory-confirmed RSV across multiple severity levels., Methods: We linked laboratory, perinatal, and hospital data of 469 589 children born in Western Australia in 1996-2012. Respiratory syncytial virus tests and detections were classified into community, emergency department (ED), and hospital levels to estimate infection rates. Clinical diagnoses given to children with RSV infection presenting to ED or hospitalized were identified., Results: In 2000-2012, 10% (n = 45 699) of children were tested for RSV and 16% (n = 11 461) of these tested positive. Respiratory syncytial virus was detected in community, ED (both 0.3 per 1000 child-years), and hospital (2.4 per 1000 child-years) settings. Respiratory syncytial virus-confirmed rates were highest among children aged <3 months (31 per 1000 child-years). At least one third of children with RSV infection presenting to ED were diagnosed as other infection, other respiratory, or other (eg, agranulocytosis)., Conclusions: Respiratory syncytial virus is pervasive across multiple severity levels and diagnoses. Vaccines targeting children <3 months must be prioritized. Given that most children are never tested, estimating the under-ascertainment of RSV infection is imperative., (© The Author(s) 2020. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Background: Pneumococcal conjugate vaccine (PCV) was included in Australia's National Immunisation Program for all children from 2005. We assessed the impact of PCV on all-cause and pathogen-specific pneumonia hospitalizations in Western Australian (WA) children aged ≤16 years., Methods: All hospitalizations with pneumonia-related International Statistical Classification of Diseases and Related Health Problems, Tenth Revision, Australian Modification diagnosis codes occurring in WA-born children (1996-2012) were linked to pathology records. Age-specific incidence rate ratios and temporal trends for all-cause and pathogen-specific pneumonia hospitalizations were calculated before and after PCV introduction., Results: Among 469589 births, there were 15175 pneumonia-related hospitalizations. Hospitalization rates were 6.7 (95% confidence interval, 6.4-6.9) times higher in Aboriginal than in non-Aboriginal children. Following PCV introduction, all-cause pneumonia hospitalizations showed significant declines across all age groups. A pathogen was identified in 2785 of 6693 (41.6%) pneumonia hospitalizations that linked to a pathology record. Respiratory syncytial virus (RSV) was most frequently identified, with RSV-associated pneumonia hospitalization rates of 89.6/100000 child-years in Aboriginal and 26.6/100000 child-years in non-Aboriginal children. The most common bacterial pathogen was Streptococcus pneumoniae in Aboriginal children (32.9/100000 child-years) and Mycoplasma pneumoniae in non-Aboriginal children (8.4/100000 child-years). Viral pneumonia rates declined in all children following PCV introduction, with the greatest declines seen in non-Aboriginal children; declines in bacterial pneumonia were observed in non-Aboriginal children., Conclusions: Based on our ecological analyses, PCV seems to have had an impact on hospitalizations for pneumonia, suggesting that the pneumococcus is likely to play a role in both bacterial and viral pneumonia. Respiratory viruses remain an important pathogen in childhood pneumonia. Vaccines targeting respiratory viruses are needed to combat the residual burden of childhood pneumonia.

Background: Children with acute respiratory tract infection (ARTI) frequently exhibit virus-virus codetection, yet the clinical significance of ARTI remains contentious. Using data from a prospective cohort of children with influenza-like illness, we examined the virology of ARTI and determined the clinical impact of virus-virus codetection., Methods: Children aged 6 to 59 months who presented to a tertiary pediatric hospital between influenza seasons 2008 and 2012 with fever and acute respiratory symptoms were enrolled, and nasal samples were collected. Respiratory viruses were identified by culture and polymerase chain reaction. We compared demographics, presenting symptoms, and clinical outcomes of children with a single-virus infection and those in whom 2 or more viruses were detected (virus-virus codetection). We used logistic regression models and estimated marginal means to calculate the adjusted odds ratios and probabilities of symptom presentation, prescription of antibiotics, and hospitalization., Results: Of 2356 children, a virus was detected in 1630 (69.2%) of them; rhinovirus (40.8%), influenza (29.5%), and respiratory syncytial virus (26.4%) were detected most commonly. Two or more viruses were detected in 25% of these children. After we adjusted for demographic factors, children with virus-virus codetection had greater odds of presenting with cough (adjusted odds ratio [aOR], 1.9; 95% confidence interval [CI], 1.2-3.1) and rhinorrhea (aOR, 1.8; 95% CI, 1.1-2.9) than those with a single-virus infection, although both symptoms were common. Children with influenza and respiratory syncytial virus combined had the highest probability of hospitalization (55%; 95% CI, 35%-73%), which was significantly greater than for those with influenza infection alone (22%; 95% CI, 16%-29%)., Conclusions: Overall, virus-virus codetection has limited impact on clinical severity among children with influenza-like illness. However, infection with specific pathogen pairs might be associated with more severe outcomes. Routine diagnostics to identify specific viruses should be restricted to common pathogens., (© The Author 2016. Published by Oxford University Press on behalf of the Pediatric Infectious Diseases Society. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Background: Although antenatal influenza vaccination is an important public health intervention for preventing serious infection in pregnant women and newborns, reported vaccine coverage is often <50%. Concern for the safety to the fetus is a commonly cited reason for vaccine hesitancy and refusal. The incidence of stillbirth following pandemic vaccination has been previously studied; however, no population-based study has evaluated the incidence of stillbirth following seasonal trivalent influenza vaccination., Methods: We used probabilistic linking of perinatal and maternal vaccination records to establish a cohort of 58 008 births occurring between April 2012 and December 2013. Stillbirth was defined as birth ≥20 weeks' gestation with an Apgar score of zero at 1 and 5 minutes following delivery. Cox regression models adjusted for maternal smoking, Indigenous status, and propensity for vaccination were used to calculate adjusted hazard ratios (aHRs) in vaccinated and unvaccinated mothers., Results: A total of 5076 (8.8%) pregnant women received trivalent influenza vaccine and 377 stillbirths occurred. There were 5.0 and 3.0 stillbirths per 100 000 pregnancy-days among unvaccinated and vaccinated women, respectively. After adjustment, stillbirth was 51% less likely among vaccinated vs unvaccinated mothers (aHR, 0.49; 95% confidence interval [CI], .29-.84). The largest relative reduction in stillbirths was observed for births occurring just after influenza season (aHR, 0.33; 95% CI, .12-.88)., Conclusions: Mothers who received seasonal TIV during pregnancy were significantly less likely to experience stillbirth compared with unvaccinated mothers. These results support the safety of seasonal influenza immunization during pregnancy and suggest a protective effect., (© The Author 2016. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail journals.permissions@oup.com.)

Influenza and pertussis are major causes of pediatric morbidity. We measured the accuracy of their International Classification of Diseases (ICD-10-AM) diagnosis codes using linked population-based laboratory and hospital data in 245,249 children. Influenza diagnosis codes had high specificity (98.6%) and modest positive predictive value (PPV; 84.1%) and sensitivity (86.1%, 95% CI: 83.4%-88.6%) for a laboratory-confirmed episode. For pertussis diagnosis codes, PPV (86.8%) and specificity (98.9%) were high, but sensitivity was poor (27.8%, 95% CI: 23.5%-32.4%). Measures varied according to age, remoteness, Aboriginality, severity, and detection method. Both laboratory and hospitalization data are needed to accurately determine the burden of pediatric influenza and pertussis., (© The Author 2013. Published by Oxford University Press on behalf of the Pediatric Infectious Diseases Society. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

BACKGROUND. In 2001, Australia introduced a unique 7-valent pneumococcal conjugate vaccine (7vPCV) 2-, 4-, and 6-month schedule with a 23-valent pneumococcal polysaccharide vaccine (23vPPV) booster for Aboriginal children, and in 2005, 7vPCV alone in a 2-, 4-, and 6-month schedule for non-Aboriginal children. Aboriginal adults are offered 23vPPV but coverage is poor. We investigated trends in invasive pneumococcal disease (IPD) in Western Australia (WA). METHODS. Enhanced IPD surveillance has been ongoing since 1996. We calculated IPD incidence rates for Aboriginal and non-Aboriginal Australians before and after introduction of 7vPCV. RESULTS. A total of 1792 cases occurred during the period 1997-2007; the IPD incidence rate was 47 cases per 100,000 population per year among Aboriginal people and 7 cases per 100,000 population per year in non-Aboriginal people. After introduction of 7vPCV, IPD rates among Aboriginal children decreased by 46% for those <2 years of age and by 40% for those 2-4 years of age; rates decreased by 64% and 51% in equivalent age groups for non-Aboriginal children. IPD rates decreased by >30% in non-Aboriginal people 50 years of age but increased among Aboriginal adults (eg, from 59.1 to 109.6 cases per 100,000 population per year among those 30-49 years of age). Although IPD due to 7vPCV serotypes decreased in all age groups, IPD incidence due to non-7vPCV serotypes increased, and it almost doubled among Aboriginal adults 30-49 years of age (from 48.3 to 97.0 cases per 100,000 population per year). Among non-Aboriginal children, 37% of IPD is now due to serotype 19A. CONCLUSIONS. IPD incidence rates have decreased markedly among children and non-Aboriginal adults with a 3-dose infant 7vPCV schedule. However, IPD due to non-7vPCV serotypes has increased and is of particular concern among young Aboriginal adults, for whom an intensive 23vPPV campaign is needed. An immunization register covering all age groups should be established.