Terry Nolan

Comparison of the Immunogenicity and Reactogenicity of a Prophylactic Quadrivalent Human Papillomavirus (Types 6, 11, 16, and 18) L1 Virus-Like Particle Vaccine in Male and Female Adolescents and Young Adult Women

OBJECTIVE. Prophylactic vaccination of 16- to 23-year-old females with a quadrivalent human papillomavirus (types 6, 11, 16, 18) L1 virus-like particle vaccine has been shown to prevent type-specific human papillomavirus infection and associated clinical disease. We conducted a noninferiority immunogenicity study to bridge the efficacy findings in young women to preadolescent and adolescent girls and boys, who represent a primary target for human papillomavirus vaccination. METHODS. We enrolled 506 girls and 510 boys (10–15 years of age) and 513 females (16–23 years of age). Participants were vaccinated on day 1, at month 2, and at month 6, and serology testing was performed on day 1 and at months 3 and 7 on blinded samples. Neutralizing antibody concentrations were determined using type-specific immunoassays and summarized as geometric mean titers and seroconversion rates. Vaccine tolerability also was assessed. RESULTS. By month 7, seroconversion rates were ≥99% for all 4 human papillomavirus types in each group. By month 7, compared with women, anti–human papilloma virus geometric mean titers in girls or boys were noninferior and were 1.7- to 2.7-fold higher. Most (>97%) injection-site adverse events were mild to moderate in intensity. Significantly more boys (13.8%) and girls (12.8%) than women (7.3%) reported fevers ≥37.8°C within 5 days of vaccination. Most (96.4%) fevers were mild (<39°C). CONCLUSIONS. Noninferior immunogenic responses to all 4 human papillomavirus types in the quadrivalent vaccine permit the bridging of efficacy data that were generated in young women to girls. The results in boys lend support for the implementation of gender-neutral human papillomavirus vaccination programs. This vaccine generally was well tolerated.

Twelve year outcomes following bacterial meningitis: further evidence for persisting effects

AIM To determine whether intellectual and cognitive impairments observed seven years following early childhood bacterial meningitis persist into adolescence. METHODS Blinded neuropsychological, auditory, and behaviour assessments were conducted in 109 (69%) subjects from an original cohort of 158 children, seven and 12 years after their meningitis, and in 96 controls. RESULTS Meningitis subjects remained at greater risk than controls for any disability (odds ratio OR 4.7, confidence interval 2.2 to 9.6). Those with acute neurological complications had more sequelae than children with uncomplicated meningitis or controls (47% v 30%v 11.5% respectively; p < 0.001). Differences in intellectual, academic, and high level cognitive function between subjects and controls were maintained at the seven and 12 year assessments. In contrast, lower order skills improved, while behaviour scores deteriorated significantly (p = 0.033). CONCLUSIONS Many of the deficits identified at the seven year follow up persist 12 years after an episode of bacterial meningitis. Key messages Bacterial meningitis in children is associated with substantial excess risk of intellectual, cognitive, and auditory impairment that persists into adolescence Continuing developmental problems of higher order language, organisation, problem solving, and central auditory function may increase learning and behavioural difficulties The risk of these adverse outcomes is greatest in, but not confined to, those who experienced acute neurological complications at the time of their illness Families, schoolteachers, and health professionals have an important role in identifying and/or helping those with learning and behavioural difficulties

Immunogenicity of a Monovalent 2009 Influenza A(H1N1) Vaccine in Infants and Children: A Randomized Trial

CONTEXT In the ongoing influenza pandemic, a safe and effective vaccine against 2009 influenza A(H1N1) is needed for infants and children. OBJECTIVE To assess the immunogenicity and safety of a 2009 influenza A(H1N1) vaccine in children. DESIGN, SETTING, AND PARTICIPANTS Randomized, observer-blind, age-stratified, parallel group study assessing 2 doses of an inactivated, split-virus 2009 influenza A(H1N1) vaccine in 370 healthy infants and children aged 6 months to less than 9 years living in Australia. INTERVENTION Intramuscular injection of 15 microg or 30 microg of hemagglutinin antigen dose of monovalent, unadjuvanted 2009 influenza A(H1N1) vaccine in a 2-dose regimen, administered 21 days apart. MAIN OUTCOME MEASURES Hemagglutination inhibition assay to estimate the proportion of participants with antibody titers of 1:40 or greater, seroconversion, or a significant antibody titer increase, and factor increase in geometric mean titer. Assessments of solicited adverse events during 7 days and unsolicited adverse events for 21 days after each vaccination. RESULTS Following the first dose of vaccine, antibody titers of 1:40 or greater were observed in 161 of 174 infants and children in the 15-microg group (92.5%; 95% confidence interval [CI], 87.6%-95.6%) and in 168 of 172 infants and children in the 30-microg group (97.7%; 95% CI, 94.2%-99.1%). Corresponding seroconversion rates were 86.8% (95% CI, 80.9%-91.0%) and 94.2% (95% CI, 89.6%-96.8%), and factor increases in geometric mean titer were 13.6 (95% CI, 11.8-15.6) and 18.3 (95% CI, 15.7-21.4). All participants demonstrated antibody titers of 1:40 or greater after the second vaccine dose. Immune responses were robust regardless of age, baseline serostatus, or seasonal influenza vaccination status. The majority of adverse events were mild to moderate in severity. CONCLUSION One 15-microg dose of vaccine was immunogenic in infants and children starting at 6 months of age and vaccine-associated reactions were mild to moderate in severity. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00940108.

Systematic review of rheumatic heart disease prevalence in children in developing countries: The role of environmental factors

Objectives:  To consider the worldwide prevalence of rheumatic heart disease in children in developing countries using surveys with uniform methodologies, and to consider the effect of environmental factors including socio‐economic status, overcrowding, urbanization, nutrition and access to medical services on the distribution of rheumatic heart disease in developing countries.

Community‐Based Study of Mortality in Children with Epilepsy

Summary: Summary: We used the records of a statewide pediatric mortality surveillance system to determine mortality rates and causes of death in children with epilepsy. Of the 1,095 children aged 1–14 years who died in the state of Victoria during the study period 1985–1989,93 had a history of epilepsy. Six children (6%) had primary epilepsy, and 87 (94%) had secondary epilepsy. Death was (a) directly attributable to epilepsy in 20 (22%), including 11 with sudden unexplained death, (b) not directly attributable to epilepsy in 59 (63%), and (c) of undetermined cause in 14 (15%). No classifiable death occurred as a direct result of status epilepticus. The average annual mortality rates for children with epilepsy were (a) death from all causes, 30.6 in 10,000 [95% confidence interval (CI) 19.7, 47.51, and (b) death attributable to epilepsy, 6.6 in 10,000 (95% CI 3.7, 11.8). Relative to the all‐cause mortality rate in children without epilepsy, the all‐cause mortality rate ratios were (a) all children with epilepsy, 13.2 (95% CI 8.5, 20.7); (b) primary epilepsy, 1.1 (95% CI 0.5, 2.6); and (c) secondary epilepsy, 49.7 (95% CI 31.7, 77.9). The mortality rate ratios for secondary epilepsy relative to primary epilepsy were (a) death from all causes, 43.5 (95% CI 19.0, 99.5); and (b) death attributable to epilepsy, 9.0 (95% CI 3.3, 24.8). Epilepsy appeared on the death certificate of only 11 of 20 (55%) children whose deaths were attributable to epilepsy. We conclude that (a) there was an increased risk of death during childhood in children with epilepsy; (b) the risk of death was greatest for children with secondary epilepsy; (c) potentially preventable, epilepsy‐related deaths occurred in children with primary epilepsy; (d) sudden unexplained death accounted for at least 12% of deaths; and (e) death certification was deficient with respect to recording of epilepsy.

Impact of baseline covariates on the immunogenicity of a quadrivalent (types 6, 11, 16, and 18) human papillomavirus virus-like-particle vaccine.

BACKGROUND The quadrivalent (types 6, 11, 16, and 18) human papillomavirus (HPV) L1 virus-like-particle vaccine was 95%-100% effective in preventing cervical and genital disease related to HPV-6, -11, -16, and -18. Vaccine efficacy is thought to be mediated by humoral immunity. Here, we analyze the effect of the baseline characteristics of subjects on vaccine-induced immune responses. METHODS Immunogenicity data from 12,343 subjects 9-26 years old randomized to quadrivalent HPV vaccine or placebo in phase 2/3 studies were analyzed. Covariates examined were day 1 HPV serostatus, age, race/ethnicity, region of residence, lactation status, hormonal contraceptive usage, smoking status, Pap test diagnosis, immunosuppressant or anti-inflammatory agent use, and number of sex partners. Anti-HPV responses were summarized as serum anti-HPV-6, -11, -16, or -18 geometric mean titers 1 month after dose 3. RESULTS Age at vaccination initiation was inversely proportional to the vaccine-induced anti-HPV response. Vaccination of subpopulations of subjects who were seropositive at day 1 to a vaccine HPV type resulted in more robust anti-HPV responses to that type, compared with those in subjects who were seronegative at baseline. Anti-HPV responses were comparable among the remaining demographic subgroups. CONCLUSIONS The immunogenicity of quadrivalent HPV vaccine was comparable among subjects with differing baseline characteristics. These data support vaccination with quadrivalent HPV vaccine across a broad range of baseline subject characteristics.

Walking to school and traffic exposure in Australian children

Abstract: Daily patterns of pedestrian activity in young children have important health implications, primarily because of the risk of road traffic injury, but also because they may reflect the commencement of exercise habits with long–term consequences. A cross–sectional survey in two Australian cities, Melbourne and Perth, aimed to collect, by parent self–administered questionnaire, population–based data on modes of travel, numbers of street crossings (both accompanied and unaccompanied by an adult), and sociode–mographic factors for six– and nine–year–old children. Results indicate that 35 per cent (95 per cent confidence interval (CI) 31 to 39 per cent) and 31 per cent (CI 28 to 34 per cent) walk to school in Melbourne and Perth respectively, while over 60 per cent are driven to school by car, with very small proportions riding bicycles or taking public transport. A higher level of walking was associated with lower levels of several indicators of socioeconomic status. Logistic regression analysis showed that the strongest predictor of walking activity was school type (government versus independent), and after adjusting for this, lesser car ownership, non–English–speaking background and lower occupational category were associated with walking to school, while a different set of predictors–age, sex and maternal education–was associated with the unaccompanied crossing of streets. There was litde difference in overall walking levels between boys and girls, but boys were significandy more likely to cross streets unaccompanied (adjusted odds ratio 1.41, CI 1.14 to 1.72), providing a partial explanation of documented sex differences in injury rates.

A random cluster survey and a convenience sample give comparable estimates of immunity to vaccine preventable diseases in children of school age in Victoria, Australia.

We compared estimates of the age-specific population immunity to measles, mumps, rubella, hepatitis B and varicella zoster viruses in Victorian school children obtained by a national sero-survey, using a convenience sample of residual sera from diagnostic laboratories throughout Australia, with those from a three-stage random cluster survey. When grouped according to school age (primary or secondary school) there was no significant difference in the estimates of immunity to measles, mumps, hepatitis B or varicella. Compared with the convenience sample, the random cluster survey estimated higher immunity to rubella in samples from both primary (98.7% versus 93.6%, P = 0.002) and secondary school students (98.4% versus 93.2%, P = 0.03). Despite some limitations, this study suggests that the collection of a convenience sample of sera from diagnostic laboratories is an appropriate sampling strategy to provide population immunity data that will inform Australias current and future immunisation policies.

Phase I and II randomised trials of the safety and immunogenicity of a prototype adjuvanted inactivated split-virus influenza A (H5N1) vaccine in healthy adults.

OBJECTIVE The primary objective was to evaluate the safety and immunogenicity of a prototype inactivated, split-virus H5N1 (avian influenza A) vaccine. A secondary objective was to assess the cross-reactivity of immune responses to two variant clade 2 H5N1 strains. METHODS In two randomised, dose comparison, parallel assignment, multicentre trials conducted in Australia, healthy adult volunteers received two doses of 7.5 microg or 15 microg H5 haemagglutinin (HA) vaccine+/-AlPO4 adjuvant (phase I trial; N=400) or two doses of 30 microg or 45 microg H5 HA with AlPO4 adjuvant (phase II trial; N=400). Revaccination with a booster dose was offered 6 months after dose 2 (phase I trial only). Main outcome measures were the change in immunogenicity at each follow-up visit from baseline, measured using HA inhibition (HI) and virus microneutralisation (MN) assays, and the frequency and nature of adverse events (AEs). Computer generated tables were used to randomly allocate treatments; participants and investigators were blinded to treatment allocation. FINDINGS All formulations were well-tolerated; no unexpected serious adverse events were reported. Two doses of 30 microg or 45 microg H5 HA adjuvanted formulations elicited the highest immune responses, with considerable MN antibody (>or=1:20) persistence up to 6 months post-vaccination. The 7.5 and 15 microg formulations (+/-adjuvant) were less immunogenic than the higher dose formulations; HI and MN antibody titres decreased to near pre-vaccination levels at 6 months but were restored to post-dose 2 levels after the booster dose. Immune responses in the phase I trial demonstrated modest levels of cross-protective MN antibodies against two currently circulating, distinct clade 2 H5N1 strains. INTERPRETATION Two doses of prototype 30 microg or 45 microg aluminium-adjuvanted, clade 1 H5N1 vaccines were immunogenic and well-tolerated with considerable 6-month antibody persistence. The prototype H5N1 vaccine also elicited modest levels of cross-protective MN antibodies against variant clade 2 H5N1 strains [ClinicalTrials.gov identifiers: NCT00136331, NCT00320346; FUNDING CSL Limited, Australia].

Safety and immunogenicity of a prototype adjuvanted inactivated split-virus influenza A (H5N1) vaccine in infants and children

OBJECTIVE Highly pathogenic avian influenza A virus (H5N1) is a leading candidate for the next influenza pandemic, and infants and children may play an important role in transmission in a pandemic. Our objective was to evaluate the safety and immunogenicity of a prototype inactivated, aluminium adjuvanted, split-virus, clade 1 H5N1 vaccine (A/Vietnam/1194/2004/NIBRG-14) in infants and children aged > or =6 months to < 9 years. METHODS Healthy infants and children (N=150) received two doses of 30 microg or 45 microg H5 HA with AlPO4 adjuvant 21 days apart. Serum samples were collected for virus microneutralisation (MN) and haemagglutination inhibition (HI) assays on Days 0, 21, and 42. Six-month antibody persistence following second vaccine dose was assessed by MN, and cross-reactive HI antibodies to a clade 2 variant strain (INDO5/RG2) were evaluated at Day 42. FINDINGS Both formulations were well-tolerated. Two doses of 30 microg or 45 microg H5 HA formulations elicited strong immune responses by both MN (98-99% > or =1:20) and HI assays (95-100% > or =1:32), with 80-87% of children having MN antibody persistence (> or =1:20) up to 6 months post-vaccination. Additionally, robust cross-clade HI antibody responses were elicited following two doses. INTERPRETATION Two doses of prototype 30 microg or 45 microg aluminium-adjuvanted, H5N1 vaccines were highly immunogenic and well-tolerated, with considerable antibody persistence 6 months after the primary vaccination course. Additional cross-clade HI antibody responses and an acceptable safety and tolerability profile support the use of the either candidate vaccine formulations in infants and children in the event of a pandemic.