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Macartney K.K.,National Center for Immunization Research and Surveillance | Macartney K.K.,University of Sydney | Macartney K.K.,Childrens Hospital Westmead | Gidding H.F.,National Center for Immunization Research and Surveillance | And 33 more authors.
Vaccine | Year: 2015

BACKGROUND: Febrile seizures (FS) are common in childhood with incidence peaking in the second year of life when measles and varicella-containing vaccines are administered. This study aimed to examine the vaccine-attributable risk of FS following separate administration of MMR and monovalent varicella vaccines (VV) prior to a planned change to MMRV as the second dose of measles-containing vaccine at 18 months of age. METHODS: All FS cases in children aged <5 years from 1st January 2012 to 30th April 2013 were identified from emergency department (ED) and inpatient databases at five Australian tertiary paediatric hospitals participating in PAEDS (Paediatric Active Enhanced Disease Surveillance). Immunization records were obtained from the Australian Childhood Immunization Register (ACIR). The relative incidence (RI) of FS following MMR dose 1 (MMR1) and VV in children aged 11-23 months was determined using the self-controlled case series (SCCS) method and used to calculate attributable risk. RESULTS: There were 2013 FS episodes in 1761 children. The peak age at FS was 18 months. The risk of FS was significantly increased 5-12 days post receipt of MMR1 at 12 months (RI=1.9 [95% CI: 1.3-2.9]), but not after VV at 18 months (RI=0.6 [95% CI: 0.3-1.2]. The estimated excess annual number of FS post MMR1 was 24 per 100,000 vaccinated children aged 11-23 months (95% CI=7-49 cases per 100,000) or 1 per 4167 doses. CONCLUSIONS: Our study detected the expected increased FS risk post MMR1 vaccine at 12 months, but monovalent varicella vaccine at age 18 months was not associated with increased risk of FS. This provides baseline data to assess the risk of FS post MMRV, introduced in Australia as the second dose of measles-containing vaccine at 18 months of age in July 2013. © 2014 Elsevier Ltd. All rights reserved.


Mulholland E.K.,Murdoch Childrens Research Institute | Mulholland E.K.,London School of Hygiene and Tropical Medicine | Torzillo P.J.,Prince Alfred Hospital | Torzillo P.J.,University of Sydney | And 7 more authors.
BMJ Open | Year: 2015

Introduction: Otitis media (OM) starts within weeks of birth in almost all Indigenous infants living in remote areas of the Northern Territory (NT). OM and associated hearing loss persist from infancy throughout childhood and often into adulthood. Educational and social opportunities are greatly compromised. Pneumococcus and non-typeable Haemophilus influenzae (NTHi) are major OM pathogens that densely colonise the nasopharynx and infect the middle ear from very early in life. Our hypothesis is that compared to current single vaccine schedules, a combination of vaccines starting at 1 month of age, may provide earlier, broadened protection. Methods and analyses: This randomised outcome assessor, blinded controlled trial will recruit 425 infants between 28 and 38 days of age and randomly allocate them (1:1:1) to one of three pneumococcal conjugate vaccine (PCV) schedules: Synflorix at 2, 4, 6 months of age, Prevenar13 at 2, 4 and 6 months of age, or an investigational schedule of Synflorix at 1, 2 and 4 months plus Prevenar13 at 6 months of age. The blinded primary outcomes at 7 months of age are immunogenicity of specific vaccine antigens (geometric mean concentration (GMC) and proportion of participants with above threshold GMC of 0.35 μg/L). Secondary outcomes at all timepoints are additional immunogenicity measures and proportion of participants with nasopharyngeal carriage of vaccine-type pneumococci and NTHi, and any OM, including any tympanic membrane perforation. Parental interviews will provide data on common risk factors for OM. Ethics and dissemination: Ethical approval has been obtained from NT Department of Health and Menzies HREC (EC00153), Central Australian HREC (EC00155) and West Australian Aboriginal Health Ethics Committee (WAAHEC-377-12/2011). Final trial results, data analyses, interpretation and conclusions will be presented in appropriate written and oral formats to parents and guardians, participating communities, local, national and international conferences, and published in peer-reviewed open access journals. © 2015, BMJ Publishing Group. All rights reserved.


Marshall H.S.,University of Adelaide | McIntyref P.,Childrens Hospital | McIntyref P.,National Center for Immunization Research and Surveillance | McIntyref P.,University of Sydney | And 18 more authors.
Pediatric Infectious Disease Journal | Year: 2013

Background: Varicella in children, although usually mild, can cause hospitalization and rarely death. This study examined patterns of hospitalized children with varicella, and associated varicella genotypes, in 4 tertiary children's hospitals throughout Australia before and after varicella vaccine was introduced. Methods: We obtained coded data on discharge diagnoses from each hospital before (1999 to 2001) and after (2007 to 2010) varicella vaccine introduction in 2005, adding active surveillance to capture clinical features, complications and immunization history in the latter period. Varicella vesicles were swabbed, and genotyping of varicella strains was performed by real-time polymerase chain reaction amplification. Results: Overall, a 68% reduction in coded hospitalizations (varicella, 73.2% [P< 0.001]; zoster, 40% [P = 0.002]) occurred post-vaccine introduction. Of children with detailed clinical data (97 varicella and 18 zoster cases), 46 (40%) were immunocompromised. Only 6 of 32 (19%) age-eligible immunocompetent children were immunized. Complications, most commonly secondary skin infections (n = 25) and neurologic conditions (n = 14), occurred in 44% of children. There were no deaths; but 3 immunocompetent unimmunized children had severe multiple complications requiring intensive care. All strains genotyped were "wild-type" varicella, with Clade 1 (European origin) predominating. Conclusions: After the introduction of varicella vaccine, coverage of greater than 80% at 2 years of age was achieved, with varicella hospitalizations reduced by almost 70%. Of hospitalized children age-eligible for varicella vaccine, 80% were unimmunized, including all cases requiring intensive care. Copyright © 2013 by Lippincott Williams & Wilkins.


PubMed | National Center for Immunization Research and Surveillance, Murdoch Childrens Research Institute, University of Western Australia, National Aboriginal Community Controlled Health Organisation and 5 more.
Type: Comparative Study | Journal: BMJ open | Year: 2015

Otitis media (OM) starts within weeks of birth in almost all Indigenous infants living in remote areas of the Northern Territory (NT). OM and associated hearing loss persist from infancy throughout childhood and often into adulthood. Educational and social opportunities are greatly compromised. Pneumococcus and non-typeable Haemophilus influenzae (NTHi) are major OM pathogens that densely colonise the nasopharynx and infect the middle ear from very early in life. Our hypothesis is that compared to current single vaccine schedules, a combination of vaccines starting at 1month of age, may provide earlier, broadened protection.This randomised outcome assessor, blinded controlled trial will recruit 425 infants between 28 and 38days of age and randomly allocate them (1:1:1) to one of three pneumococcal conjugate vaccine (PCV) schedules: Synflorix at 2, 4, 6months of age, Prevenar13 at 2, 4 and 6months of age, or an investigational schedule of Synflorix at 1, 2 and 4months plus Prevenar13 at 6months of age. The blinded primary outcomes at 7months of age are immunogenicity of specific vaccine antigens (geometric mean concentration (GMC) and proportion of participants with above threshold GMC of 0.35g/L). Secondary outcomes at all timepoints are additional immunogenicity measures and proportion of participants with nasopharyngeal carriage of vaccine-type pneumococci and NTHi, and any OM, including any tympanic membrane perforation. Parental interviews will provide data on common risk factors for OM.Ethical approval has been obtained from NT Department of Health and Menzies HREC (EC00153), Central Australian HREC (EC00155) and West Australian Aboriginal Health Ethics Committee (WAAHEC- 377-12/2011). Final trial results, data analyses, interpretation and conclusions will be presented in appropriate written and oral formats to parents and guardians, participating communities, local, national and international conferences, and published in peer-reviewed open access journals.ACTRN12610000544077 and NCT01174849.


Marshall H.,University of Adelaide | McMillan M.,University of Adelaide | Macartney K.,Sydney Medical School | Macartney K.,The Childrens Hospital at Westmead | And 2 more authors.
Human Vaccines and Immunotherapeutics | Year: 2016

Maternal immunization has the potential to reduce the burden of infectious diseases in the pregnant woman and her infant. Many countries now recommend immunization against influenza at any stage of pregnancy and against pertussis in the third trimester. Despite evidence of the safety and effectiveness of these vaccines when administered during pregnancy, uptake generally remains low for influenza and moderate for pertussis vaccine. Enhancing confidence in both immunization providers and pregnant women by increasing the evidence-base for the safety and effectiveness of vaccines during pregnancy, improving communication and access by incorporating immunization into standard models of antenatal care are likely to improve uptake. Developing a framework for implementation of vaccines for pregnant women which is cognizant of local and national cultural, epidemiological, behavioral and societal factors will enable a smooth transition and high uptake for new vaccines currently in development for pregnant women. © 2016 Taylor & Francis.


Buttery J.P.,Murdoch Childrens Research Institute | Buttery J.P.,Monash University | Lambert S.B.,University of Melbourne | Grimwood K.,University of Melbourne | And 9 more authors.
Pediatric Infectious Disease Journal | Year: 2011

Introduction: Rotavirus vaccines were introduced into the funded Australian National Immunization Program (NIP) in July 2007. Due to purchasing arrangements, individual states and territories chose either a 2-dose RV1 (Rotarix, GSK) regimen or 3-dose RV5 (Rotateq, Merck/CSL) regimen. This allowed comparison of both vaccines in similar populations with high infant vaccination coverage. Methods: Admission and rotavirus identification data from the major pediatric hospitals in 3 states (2 using RV5, 1 RV1), together with state-based hospitalization and vaccination data from Queensland (RV5) were analyzed for the years before, and up to 30 months following rotavirus vaccine introduction. Emergency encounters and short-stay unit admissions for gastroenteritis are also described. Results: Rotavirus vaccine coverage in Australia is high, with 87% of infants receiving at least 1 dose. Hospital admissions for both rotavirus gastroenteritis and nonrotavirus-coded gastroenteritis were reduced following vaccine introduction in all states, not only for the age group eligible for NIP rotavirus vaccination, but also for children born prior. RV5 vaccine efficacy in Queensland has been estimated at 89.3%. Marked reductions in acute gastroenteritis emergency presentations and short-stay unit admissions have also been observed. Conclusions: Early evidence from the NIP in Australia has demonstrated high rotavirus coverage with both RV1 and RV5. The introduction of both vaccines has been associated with a marked reduction in gastroenteritis admissions, supportive of both direct vaccine protection, as well as with indirect herd protection. © 2010 by Lippincott Williams & Wilkins.


Liyanage S.S.,University of New South Wales | Rahman B.,University of New South Wales | Gao Z.,University of New South Wales | Zheng Y.,U.S. Center for Disease Control and Prevention | And 8 more authors.
BMJ Open | Year: 2013

Objectives: We aimed to conduct a meta-analysis of human papillomavirus (HPV) as a risk factor for oesophageal squamous cell carcinoma (OSCC) in China, using all eligible studies published in the English and Chinese language literature. Design: The random effect model was used to analyse the pooled OR. The I2 and Q tests were included in the subgroup analyses. Setting: Literature searches of databases including MEDLINE, PUBMED, EMBASE and Chinese National Knowledge Infrastructure (CNKI) and other available resources were performed to retrieve studies investigating OSCC tissue from Chinese participants for the presence of HPV DNA. Primary outcome measure: A collective analysis of OSCC cases and control specimens was carried out from 15 case-control studies (6 in the English language and 9 in the Chinese language) for HPV prevalence. Results: Of a total of 1177 OSCC and 1648 oesophageal control samples, 55% (642/1177) of cancer specimens and 27% (445/1648) of control samples were positive for HPV DNA. A positive strong association between HPV DNA and OSCC was observed among the included studies, with a pooled OR of 3.69 (95% CI 2.74 to 4.96). Heterogeneity and publication bias were not observed in the analysis. Subgroup analyses of the included studies also supported the measure of association of causal links between HPV and OSCC. Conclusions: This meta-analysis provides the strongest evidence until now of an association between HPV and OSCC in the Chinese population. China has a high burden of OSCC, making this an important research finding. A strength and new contribution of this study is combining data from the English and Chinese language literature to analyse all studies conducted in China. These findings may inform the population level use of prophylactic HPV vaccination to reduce the burden of OSCC in China.


MacIntyre C.R.,University of New South Wales | MacIntyre C.R.,National Center for Immunization Research and Surveillance | Ridda I.,University of New South Wales | Gao Z.,University of New South Wales | And 6 more authors.
PLoS ONE | Year: 2014

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


PubMed | National Center for Immunization Research and Surveillance, University of Sydney, University of New South Wales and Pfizer
Type: Journal Article | Journal: PloS one | Year: 2014

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


PubMed | Murdoch Childrens Research Institute, University of Sydney, The Childrens Hospital at Westmead, National Center for Immunization Research and Surveillance and Royal Childrens Hospital
Type: Journal Article | Journal: Pediatrics | Year: 2016

We aimed to describe the clinical features and outcome of human parechovirus (HPeV) encephalitis cases identified by the Australian Childhood Encephalitis (ACE) study.Infants with suspected encephalitis were prospectively identified in 5 hospitals through the (ACE) study. Cases of confirmed HPeV infection had comprehensive demographic, clinical, laboratory, imaging, and outcome at discharge data reviewed by an expert panel and were categorized by using predetermined case definitions. Twelve months after discharge, neurodevelopment was assessed by using the Ages and Stages Questionnaire (ASQ).We identified thirteen cases of suspected encephalitis with HPeV infection between May 2013 and December 2014. Nine infants had confirmed encephalitis; median age was 13 days, including a twin pair. All had HPeV detected in cerebrospinal fluid with absent pleocytosis. Most were girls (7), admitted to ICU (8), and had seizures (8). Many were born preterm (5). Seven patients had white matter diffusion restriction on MRI; 3 with normal cranial ultrasounds. At discharge, 3 of 9 were assessed to have sequelae; however, at 12 months follow-up, by using the ASQ, 5 of 8 infants showed neurodevelopmental sequelae: 3 severe (2 cerebral palsy, 1 central visual impairment). A further 2 showed concern in gross motor development.Children with HPeV encephalitis were predominantly young, female infants with seizures and diffusion restriction on MRI. Cranial ultrasound is inadequately sensitive. HPeV encephalitis is associated with neurodevelopmental sequelae despite reassuring short-term outcomes. Given the absent cerebrospinal fluid pleocytosis and need for specific testing, HPeV could be missed as a cause of neonatal encephalopathy and subsequent cerebral palsy.

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