Margaret Danchin

Intussusception following rotavirus vaccine administration: Post-marketing surveillance in the National Immunization Program in Australia

INTRODUCTION In Australia, post-marketing surveillance for intussusception following vaccination commenced with funding of RotaTeq(®) and Rotarix(®) vaccines under the National Immunization Program (NIP) in July 2007. METHODS Two active surveillance mechanisms (hospital-based case ascertainment and monthly reports from paediatricians) identified intussusception cases between 1st July 2007 and 31st December 2008 in four states. Linkage to vaccination records identified cases occurring within 1-7 and 1-21 days of rotavirus vaccination. Expected cases within the post-vaccination windows were calculated by applying rates of intussusception from national hospitalisation data over 6 years (mid-2000 to mid-2006), by age and state, to numbers vaccinated (by dose) according to the Australian Childhood Immunization Register. RESULTS Combining exposure windows associated with all doses of rotavirus vaccine from 1 to 9 months of age, there was no evidence of an increased risk of intussusception following vaccination for either vaccine. However, in infants 1 to <3 months of age, there was suggestive evidence of excess intussusception cases 1-7 and 1-21 days following dose 1 (1-7 days: RotaTeq(®) relative risk (RR)=5.3, 95% confidence interval [CI] 1.1,15.4; Rotarix(®) RR 3.5, 95% CI 0.7,10.1; 1-21 days: RotaTeq(®) RR 3.5, 95% CI 1.3, 7.6; Rotarix(®)RR 1.5, 95% CI 0.4, 3.9). There was no evidence that clinical outcome of intussusception occurring within 21 days of rotavirus vaccination differed from that in cases occurring later post-vaccination. CONCLUSION Although we found no overall increase in intussusception following receipt of rotavirus vaccine, there was some evidence of an elevated risk following the first dose of both vaccines. Larger population-based studies using linked databases are required to provide more definitive evidence.

Group A streptococcal infections in children

Abstract:  The group A streptococcus causes the widest range of disease in humans of all bacterial pathogens. Group A streptococcal diseases are more common in children than adults with diseases ranging from pharyngitis and impetigo to invasive infections and the post‐streptococcal sequelae – acute rheumatic fever and acute post‐streptococcal glomerulonephritis. The global burden of severe group A streptococcal disease is concentrated largely in developing countries and Indigenous populations such as Aboriginal Australians. Control of group A streptococcal disease is poor in these settings and the need for a vaccine has been argued. With an ever‐increasing understanding of the group A streptococcus at a molecular level, new and sophisticated vaccines are currently in human trials and the next decade holds exciting prospects for curbing group A streptococcal diseases.

Strain Prevalence, Rather than Innate Virulence Potential, Is the Major Factor Responsible for an Increase in Serious Group A Streptococcus Infections

BACKGROUND It is postulated that the surge in incidence and severity of group A streptococcus (GAS) infections since the 1980s is due to the emergence of strains of GAS with increased virulence. We used active, population-based surveillance of invasive GAS disease, serologically confirmed pharyngitis, and carriage to determine whether particular strains were associated with invasive disease. METHODS Two hundred twenty GAS isolates were collected--78 invasive, 34 pharyngitis, and 108 carriage. Isolates were characterized using emm typing, random amplification of polymorphic DNA (RAPD) profiling, and superantigen genotyping. RESULTS emm1, emm12, and emm28 predominated in invasive disease and accounted for 30.8%, 12.8%, and 12.8% of all isolates, respectively. emm1, emm75, emm28, and emm4 were the most frequently isolated emm types in pharyngitis, and emm12 and emm1 predominated in carriage. emm12 was significantly associated with carriage rather than disease. There were no other significant associations between emm type and disease or carriage. There were no associations between any RAPD profile or superantigen genotype and invasive disease, pharyngitis, or carriage. One RAPD profile accounted for most cases of necrotizing fasciitis, which suggests that this strain might have particular features promoting connective-tissue infection. CONCLUSIONS These data suggest that the emergence of GAS strains with increased virulence is not the main factor responsible for the surge in GAS-related infections. The prevalence of particular emm types, RAPD profiles, or superantigen genes in invasive disease may simply indicate widespread transmission of these strains in the population, rather than a particular ability to cause disease.

Burden of Acute Sore Throat and Group A Streptococcal Pharyngitis in School-aged Children and Their Families in Australia

OBJECTIVE. The objective of this study was to determine the incidence, transmission, carriage, and risk factors for group A streptococcal pharyngitis in school-aged children and their families. METHODS. A 16-month, prospective, family-based cohort study was undertaken from August 2001 through December 2002 in Melbourne, Australia. A total of 202 families (853 people) with at least 1 child aged 3 to 12 years were randomly selected from 3 primary care practices across suburban Melbourne to collect surveillance data for acute group A streptococcal pharyngitis, including serology for index and secondary cases and intermittent carriage data. Cohort retention was 97% for 16 months. RESULTS. The incidence of acute sore throat, group A streptococcal swab–positive pharyngitis, and serologically confirmed group A streptococcal pharyngitis was 33, 13, and 8 per 100 child-years, respectively, for school-aged children (5–12 years) and 60, 20, and 15 per 100 family-years, respectively. Sore throat was less common in adults than children, but adults with sore throat were as likely as children to have group A streptococcal culture–positive or serologically proven pharyngitis. In families who had a primary case, 43% had at least 1 secondary case, and in family members who were at risk, 13% contracted a secondary case. The spring, summer, and winter carriage rates for children were 13%, 8%, and 16%, respectively, and for adults the rate was 2% across all seasons. CONCLUSIONS. Group A streptococcal pharyngitis is still common, and the peak incidence occurs in school-aged children. However, the incidence in adults is higher than expected, and the number of secondary cases in families may be an important factor when considering the potential benefits of treatment.

Safety and immunogenicity of RV3-BB human neonatal rotavirus vaccine administered at birth or in infancy: a randomised, double-blind, placebo-controlled trial

BACKGROUND Despite the success of rotavirus vaccines, suboptimal vaccine efficacy in regions with a high burden of disease continues to present a challenge to worldwide implementation. A birth dose strategy with a vaccine developed from an asymptomatic neonatal rotavirus strain has the potential to address this challenge and provide protection from severe rotavirus disease from birth. METHODS This phase 2a randomised, double-blind, three-arm, placebo-controlled safety and immunogenicity trial was undertaken at a single centre in New Zealand between Jan 13, 2012, and April 17, 2014. Healthy, full-term (≥36 weeks gestation) babies, who weighed at least 2500 g, and were 0-5 days old at the time of randomisation were randomly assigned (1:1:1; computer-generated; telephone central allocation) according to a concealed block randomisation schedule to oral RV3-BB vaccine with the first dose given at 0-5 days after birth (neonatal schedule), to vaccine with the first dose given at about 8 weeks after birth (infant schedule), or to placebo. The primary endpoint was cumulative vaccine take (serum immune response or stool shedding of vaccine virus after any dose) after three doses. The immunogenicity analysis included all randomised participants with available outcome data. This trial is registered with the Australian New Zealand Clinical Trials Registry, ACTRN12611001212943. FINDINGS 95 eligible participants were randomised, of whom 89 were included in the primary analysis. A cumulative vaccine take was detected in 27 (90%) of 30 participants in the neonatal schedule group after three doses of RV3-BB vaccine compared with four (13%) of 32 participants in the placebo group (difference in proportions 0·78, 95% CI 0·55-0·88; p<0·0001). 25 (93%) of 27 participants in the infant schedule group had a cumulative vaccine take after three doses compared with eight (25%) of 32 participants in the placebo group (difference in proportions 0·68, 0·44-0·81; p<0·0001). A serum IgA response was detected in 19 (63%) of 30 participants and 20 (74%) of 27 participants, and stool shedding of RV3-BB was detected in 21 (70%) of 30 participants and 21 (78%) of 27 participants in the neonatal and infant schedule groups, respectively. The frequency of solicited and unsolicited adverse events was similar across the treatment groups. RV3-BB vaccine was not associated with an increased frequency of fever or gastrointestinal symptoms compared with placebo. INTERPRETATION RV3-BB vaccine was immunogenic and well tolerated when given as a three-dose neonatal or infant schedule. A birth dose strategy of RV3-BB vaccine has the potential to improve the effectiveness and implementation of rotavirus vaccines. FUNDING Australian National Health and Medical Research Council, the New Zealand Health Research Council, and the Murdoch Childrens Research Institute.

Defeating rotavirus? The global recommendation for rotavirus vaccination.

Drs. Margaret Danchin and Julie Bines write that the global recommendation for rotavirus vaccination marks a major step toward reducing the contribution of rotavirus to child mortality. However, 86...

Detection of group a streptococcal pharyngitis by quantitative PCR

BackgroundGroup A streptococcus (GAS) is the most common bacterial cause of sore throat. School-age children bear the highest burden of GAS pharyngitis. Accurate diagnosis is difficult: the majority of sore throats are viral in origin, culture-based identification of GAS requires 24–48 hours, and up to 15% of children are asymptomatic throat carriers of GAS. The aim of this study was to develop a quantitative polymerase chain reaction (qPCR) assay for detecting GAS pharyngitis and assess its suitability for clinical diagnosis.MethodsPharyngeal swabs were collected from children aged 3–18 years (n = 91) and adults (n = 36) located in the Melbourne area who presented with sore throat. Six candidate PCR assays were screened using a panel of reference isolates, and two of these assays, targeting speB and spy1258, were developed into qPCR assays. The qPCR assays were compared to standard culture-based methods for their ability to detect GAS pharyngitis. GAS isolates from culture positive swabs underwent emm-typing. Clinical data were used to calculate McIsaac scores as an indicator of disease severity.ResultsTwenty-four of the 127 samples (18.9%) were culture-positive for GAS, and all were in children (26%). The speB qPCR had 100% sensitivity and 100% specificity compared with gold-standard culture, whereas the spy1258 qPCR had 87% sensitivity and 100% specificity. Nine different emm types were found, of which emm 89, 3, and 28 were most common. Bacterial load as measured by qPCR correlated with culture load. There were no associations between symptom severity as indicated by McIsaac scores and GAS bacterial load.ConclusionsThe speB qPCR displayed high sensitivity and specificity and may be a useful tool for GAS pharyngitis diagnosis and research.

Rotavirus Specific Maternal Antibodies and Immune Response to RV3-BB Neonatal Rotavirus Vaccine in New Zealand.

ABSTRACT Background: Maternal antibodies, acquired passively via placenta and/or breast milk, may contribute to the reduced efficacy of oral rotavirus vaccines observed in children in developing countries. This study aimed to investigate the effect of rotavirus specific maternal antibodies on the serum IgA response or stool excretion of vaccine virus after any dose of an oral rotavirus vaccine, RV3-BB, in parallel to a Phase IIa clinical trial conducted at Dunedin Hospital, New Zealand. At the time of the study rotavirus vaccines had not been introduced in New Zealand and the burden of rotavirus disease was evident. Methods: Rotavirus specific IgG and serum neutralizing antibody (SNA) levels in cord blood and IgA levels in colostrum and breast milk samples collected ∼4 weeks, ∼20 weeks and ∼28 weeks after birth were measured. Infants were randomized to receive the first dose of vaccine at 0–5 d (neonatal schedule) or 8 weeks (infant schedule). Breast feeding was with-held for 30 minutes before and after vaccine administration. The relationship between rotavirus specific IgG and SNA levels in cord blood and IgA in colostrum and breast milk at the time of first active dose of RV3-BB vaccine and level of IgA response and stool excretion after 3 doses of vaccine was assessed using linear and logistic regression. Results: Forty infants received 3 doses of RV3-BB rotavirus vaccine and were included in the analysis of the neonatal and infant groups. Rotavirus specific IgA in colostrum (neonatal schedule group) and breast milk at 4 weeks (infant schedule group) was identified in 14/21 (67%) and 14/17 (82%) of infants respectively. There was little evidence of an association between IgA in colostrum or breast milk IgA at 4 weeks, or between cord IgG or SNA level, and IgA response or stool excretion after 3 doses of RV3-BB, or after one dose (neonatal schedule) (all p>0.05). Conclusions: The level of IgA in colostrum or breast milk and level of placental IgG and SNA did not impact on the serum IgA response or stool excretion following 3 doses of RV3-BB Rotavirus Vaccine administered using either a neonatal or infant schedule in New Zealand infants.

Clinical research potential in Victorian hospitals: the Victorian clinician researcher needs analysis survey

The 2012 McKeon Review highlighted the role of clinician researchers in patient based research and the need to foster this capacity. While anecdotal evidence suggests that clinician researchers are under threat and underfunded, Australian data on barriers and enablers of clinician‐led research are scant.

Managing simple food allergy in community settings: A pilot study investigating a new model of care.

The prevalence of food allergy in Australia has increased, paralleled by an increase in waiting time to access tertiary paediatric allergy care. We aimed to test whether a new model of care, based on serum specific IgE testing, was feasible and acceptable to Australian families.