Replication and Excretion of the Live Attenuated Tetravalent Dengue Vaccine CYD-TDV in a Flavivirus-Naive Adult Population: Assessment of Vaccine Viremia and Virus Shedding.

Background: We assessed replication and excretion of the live attenuated tetravalent dengue vaccine (CYD-TDV) into biological fluids following vaccination in dengue-naive adults in Australia. Methods: Vaccinal viremia/shedding was assessed in a subset of participants enrolled in a lot-to-lot consistency study; 95 participants received 3 subcutaneous doses of CYD-TDV from phase 2/3 lots of the vaccine, and 8 received placebo; doses were administered 6 months apart. Quantitative reverse-transcription polymerase chain reaction (qR-PCR) analysis was used to initially detect the yellow fever virus (YFV) core protein gene in the backbone of CYD-TDV in serum, saliva and urine, followed by serotype-specific qRT-PCR analysis of samples positive for YFV by qRT-PCR (lower limit of detection, 5.16 GEq/mL). Results: YFV viremia was detected by qRT-PCR in 69.5% of participants (66 of 95) who received CYD-TDV, mainly 6-14 days after injection 1. The serotypes detected were serotype 4 (in 68.2% of participants [45 of 95]), serotype 3 (in 19.7% [13 of 95]), and serotype 1 (in 12.1% [8 of 95]); serotype 2 was not detected. None of the placebo recipients had vaccinal viremia/shedding. No participants had detectable viral shedding into saliva at levels above the lower limit of quantitation. Two participants had low-level viral shedding (serotype 3) in urine (5.47 and 5.77 GEq/mL). None of the participants with viremia or shedding experienced concomitant fever. Conclusions: Low-level vaccinal viremia may occur following vaccination with CYD-TDV, but this is not associated with any symptom or adverse event. Clinical Trials Registration: NCT01134263.

Cross-reacting antibodies against the pandemic (H1N1) 2009 influenza virus in older Australians.

OBJECTIVE: To assess background pre-pandemic cross-reacting antibodies to the pandemic (H1N1) 2009 virus in older populations in Australia. DESIGN, SETTING AND PARTICIPANTS: Data were opportunistically generated from three cross-sectional pre-pandemic studies involving people aged 60 years or older: a 3-year (2006-2008) study of influenza outbreaks in aged care facilities (ACFs) in Sydney; an investigation of a respiratory virus outbreak in an ACF in rural New South Wales in June 2009; and a non-influenza serosurvey undertaken in NSW in 2007 and 2008. MAIN OUTCOME MEASURE: Prevalence of pandemic (H1N1) 2009 haemagglutination inhibition (HAI) antibody titres ≥ 1:40 (putative protective level) in pre-pandemic sera. RESULTS: In total, 259 serum samples from individuals aged 60 years or older (range, 60-101 years) were tested. More than half of the individuals tested were women (151/259; 58.3%). About a third of individuals (37.5%) had cross-reacting HAI antibody titres ≥ 1:40. The prevalence of cross-reacting antibodies was highest in the oldest age groups (≥ 85 years), with more than 60% of these people having HAI antibody titres ≥ 1:40. The proportion of subjects with HAI antibody titres ≥ 1:40 decreased significantly and successively in younger groups to only 12% of those aged 60-64 years. CONCLUSIONS: Our study suggests a pre-existing influenza A antibody reserve in most of the oldest group of people that was cross-reactive to the new pandemic (H1N1) 2009 virus; this is likely to be lifelong and to have provided them with clinical protection against the first wave of the pandemic. Pandemic influenza control measures need to focus more on younger adults naive to the pandemic virus and at increased risk of severe disease.

Facemask against viral respiratory infections among Hajj pilgrims: A challenging cluster-randomized trial.

BACKGROUND: In this large-scale cluster-randomized controlled trial (cRCT) we sought to assess the effectiveness of facemasks against viral respiratory infections. METHODS AND RESULTS: Over three consecutive Hajj seasons (2013, 2014, 2015) pilgrims' tents in Makkah were allocated to 'facemask' or 'no facemask' group. Fifty facemasks were offered to participants in intervention tents, to be worn over four days, and none were offered to participants in control tents. All participants recorded facemask use and respiratory symptoms in health diaries. Nasal swabs were collected from the symptomatic for virus detection by reverse transcription polymerase chain reaction. Clinical symptoms and laboratory results were analyzed by 'intention- to-treat' and 'per-protocol'. A total of 7687 adult participants from 318 tents were randomized: 3864 from 149 tents to the intervention group, and 3823 from 169 tents to the control group. Participants were aged 18 to 95 (median 34, mean 37) years, with a male to female ratio of 1:1.2. Overall, respiratory viruses were detected in 277 of 650 (43%) nasal/pharyngeal swabs collected from symptomatic pilgrims. Common viruses were rhinovirus (35.1%), influenza (4.5%) and parainfluenza (1.7%). In the intervention arm, respectively 954 (24.7%) and 1842 (47.7%) participants used facemasks daily and intermittently, while in the control arm, respectively 546 (14.3%) and 1334 (34.9%) used facemasks daily and intermittently. By intention-to-treat analysis, facemask use did not seem to be effective against laboratory-confirmed viral respiratory infections (odds ratio [OR], 1.4; 95% confidence interval [CI], 0.9 to 2.1, p = 0.18) nor against clinical respiratory infection (OR, 1.1; 95% CI, 0.9 to 1.4, p = 0.40). Similarly, in a per-protocol analysis, facemask use did not seem to be effective against laboratory-confirmed viral respiratory infections (OR 1.2, 95% CI 0.9-1.7, p = 0.26) nor against clinical respiratory infection (OR 1.3, 95% CI 1.0-1.8, p = 0.06). CONCLUSION: This trial was unable to provide conclusive evidence on facemask efficacy against viral respiratory infections most likely due to poor adherence to protocol.

Planning for pandemic influenza surveillance in NSW.

Early detection of a novel strain (genotype) of influenza virus in the NSW population is the key to controlling a pandemic. If this occurs, ongoing surveillance will help determine the epidemiology and risk factors of the virus as well as its impact on essential services. Important components of surveillance preparedness in NSW include: border surveillance; hospital-based screening for suspected cases; protocols for efficient transport and testing of viral specimens; flexible, robust electronic tools for rapid surveillance data collection; management and reporting; and creation of surveillance surge capacity.

Lot-to-lot consistency of a tetravalent dengue vaccine in healthy adults in Australia: a randomised study.

BACKGROUND: The recombinant yellow fever-17D-dengue virus, live, attenuated, tetravalent dengue vaccine (CYD-TDV) has undergone extensive clinical trials. Here safety and consistency of immunogenicity of phase III manufacturing lots of CYD-TDV were evaluated and compared with a phase II lot and placebo in a dengue-naïve population. METHODS: Healthy 18-60 year-olds were randomly assigned in a 3:3:3:3:1 ratio to receive three subcutaneous doses of either CYD-TDV from any one of three phase III lots or a phase II lot, or placebo, respectively in a 0, 6, 12 month dosing schedule. Neutralising antibody geometric mean titres (PRNT50 GMTs) for each of the four dengue serotypes were compared in sera collected 28 days after the third vaccination-equivalence among lots was demonstrated if the lower and upper limits of the two-sided 95% CIs of the GMT ratio were ≥0.5 and ≤2.0, respectively. RESULTS: 712 participants received vaccine or placebo and 614 (86%) completed the study; 17 (2.4%) participants withdrew after adverse events. Equivalence of phase III lots was demonstrated for 11 of 12 pairwise comparisons. One of three comparisons for serotype 2 was not statistically equivalent. GMTs for serotype 2 in phase III lots were close to each other (65.9, 44.1 and 58.1, respectively). CONCLUSIONS: Phase III lots can be produced in a consistent manner with predictable immune response and acceptable safety profile similar to previously characterised phase II lots. The phase III lots may be considered as not clinically different as statistical equivalence was shown for serotypes 1, 3 and 4 across the phase III lots. For serotype 2, although equivalence was not shown between two lots, the GMTs observed in the phase III lots were consistently higher than those for the phase II lot. As such, in our view, biological equivalence for all serotypes was demonstrated.

Epidemiology of respiratory viral infections in children enrolled in a study of influenza vaccine effectiveness.

BACKGROUND: Influenza-like illness (ILI) confers a high annual morbidity in young children. We report the epidemiology of ILIs in children who participated in an influenza vaccine effectiveness study during the 2010 Southern Hemisphere influenza season in Sydney, Australia. METHODS: Children aged 0·5-3 years were prospectively recruited from child care centres (CCCs). We classified them as fully vaccinated, partially vaccinated and unvaccinated according to their receipt of unadjuvanted vaccines containing influenza A (H1N1)pdm09. For 13 weeks commencing 30 July 2010, parents reported when their children developed an ILI (fever ≥37·8°C/feverishness plus ≥1 respiratory symptom) and collected nose and/or throat swabs for multiplex respiratory virus polymerase chain reaction (PCR) testing. Health impacts were assessed by telephone interview at enrolment and two weeks after each ILI. RESULTS: There were 124 ILIs reported in 105 of 381 enrolled children. Swabs were taken in 117 ILIs: 175 viruses were identified from 103 swabs. Adeno- and rhinoviruses were most frequently identified; 44% of swabs yielded multiple viruses. No virus was associated with more severe symptoms, although rhinovirus-related ILIs lasted longer. Nose swabs had a higher virus detection rate than throat swabs. Influenza-vaccinated children were 1·6 times (P = 0·001) more likely than unvaccinated children to have a non-influenza ILI. CONCLUSION: Adeno- and rhinoviruses were the most common viruses causing ILI. Swabs taken by parents are an effective method for sample collection. Influenza-like illness was more common in children vaccinated against influenza in this observational study, but prior health-seeking behaviour may have contributed to this difference.

Treating and preventing influenza in aged care facilities: a cluster randomised controlled trial.

BACKGROUND: Influenza is an important cause of morbidity and mortality for frail older people. Whilst the antiviral drug oseltamivir (a neuraminidase inhibitor) is approved for treatment and prophylaxis of influenza during outbreaks, there have been no trials comparing treatment only (T) versus treatment and prophylaxis (T&P) in Aged Care Facilities (ACFs). Our objective was to compare a policy of T versus T&P for influenza outbreaks in ACFs. METHODS AND FINDINGS: We performed a cluster randomised controlled trial in 16 ACFs, that followed a policy of either "T"-oseltamivir treatment (75 mg twice a day for 5 days)-or "T&P"-treatment and prophylaxis (75 mg once a day for 10 days) for influenza outbreaks over three years, in addition to enhanced surveillance. The primary outcome measure was the attack rate of influenza. Secondary outcomes measures were deaths, hospitalisation, pneumonia and adverse events. Laboratory testing was performed to identify the viral cause of influenza-like illness (ILI) outbreaks. The study period 30 June 2006 to 23 December 2008 included three southern hemisphere winters. During that time, influenza was confirmed as the cause of nine of the 23 ILI outbreaks that occurred amongst the 16 ACFs. The policy of T&P resulted in a significant reduction in the influenza attack rate amongst residents: 93/255 (36%) in residents in T facilities versus 91/397 (23%) in T&P facilities (p=0.002). We observed a non-significant reduction in staff: 46/216 (21%) in T facilities versus 47/350 (13%) in T&P facilities (p=0.5). There was a significant reduction in mean duration of outbreaks (T=24 days, T&P=11 days, p=0.04). Deaths, hospitalisations and pneumonia were non-significantly reduced in the T&P allocated facilities. Drug adverse events were common but tolerated. CONCLUSION: Our trial lacked power but these results provide some support for a policy of "treatment and prophylaxis" with oseltamivir in controlling influenza outbreaks in ACFs. TRIAL REGISTRATION: [corrected] Australian Clinical Trials Registry ACTRN12606000278538.

Perinatal transmission of hepatitis B virus: an Australian experience.

OBJECTIVE: To determine the rate of perinatal hepatitis B virus (HBV) transmission in an Australian setting and to identify maternal virological factors associated with highest risk of transmission. DESIGN, PARTICIPANTS AND SETTING: A prospective, observational study of perinatal transmission of HBV. Participants were pregnant women attending Sydney South West Area Health Service antenatal clinics who tested positive for hepatitis B surface antigen (HBsAg), and their babies. All babies were routinely offered hepatitis B immunoglobulin (HBIG) and HBV vaccination. Babies positive for HBsAg at 9-month follow-up underwent further virological testing, including HBV DNA sequencing. The study was conducted between August 2002 and May 2008. MAIN OUTCOME MEASURES: HBV DNA levels and demographic characteristics of HBsAg-positive pregnant women; proportion of their infants with active HBV infection at 9-month follow-up; maternal characteristics affecting transmission rate; HBV DNA sequencing of infected infants and their mothers. RESULTS: Of 313 HBsAg-positive pregnant women, 213 (68%) were HBV DNA-positive and 92 (29%) were positive for hepatitis B "e" antigen (HBeAg); 138 babies born to HBV DNA-positive mothers were tested for HBV infection (HBsAg positivity) at about 9 months of age. Four cases of transmission were identified. All four mothers had very high HBV DNA levels (> 10(8) copies/mL) and were HBeAg-positive. Three of the four infants were infected with wild-type HBV strains, with identical maternal/infant isolates. The fourth mother-infant pair had an S gene variant, HBV D144E, which has been previously reported in association with vaccine/HBIG escape. (Unfortunately, HBIG was inadvertently omitted from the immunisation schedule of this infant.) Transmission rates were 4/138 (3%) from HBV DNA-positive mothers overall, 4/61 (7%) from HBeAg-positive mothers, and 4/47 (9%) from mothers with very high HBV DNA levels. No transmission was seen in 91 babies of mothers with HBV DNA levels < 10(8) copies/mL. CONCLUSION: In this cohort, HBV perinatal transmission was restricted to HBeAg-positive mothers with very high viral loads.

Methaemoglobinaemia following ingestion of a commonly available food additive.

Five cases of methaemoglobinaemia after ingestion of sodium nitrite occurred in two clusters in Sydney in 2006. All cases were unintentional poisonings following use in cooking of an imported compound sold as a food additive. In all cases, methaemoglobinaemia was recognised early and treated promptly, with all patients making a full recovery. These cases highlight the importance of accurate food labelling and surveillance of imported goods.

A novel hepatitis B vaccination regimen for adolescents: two doses 12 months apart.

BACKGROUND: Two- and three-dose hepatitis B vaccinations for adolescents are usually administered using dosing schedules of 6 months duration. This does not suit all circumstances. A 12-month schedule would be useful in schools and settings where only annual vaccination is the most practical option. AIM: To examine the efficacy of a 12-month dosing interval for two-dose hepatitis B vaccination of adolescents. SUBJECTS: Four hundred and fifty-eight healthy first-year high school (Year 7) students. VACCINATION REGIMEN: Engerix-B (GlaxoSmithKline Biologicals) 20 micro g: two doses, 12 months apart. SERUM COLLECTION: #1, same day as first vaccine dose given; #2, >1 month after second vaccine dose. RESULTS: Of the 458 children: 15 did not provide serum #1, 17 had prior vaccination, 2 had prior infection, 18 moved, 7 failed to provide serum #2, 12 withdrew (only 1 cited vaccine adverse reactions as the reason). Three hundred and eighty-seven (210 males, 177 females) aged 11.8-14.2 years (mean: 12.9+/-0.42 years) at entry completed both injections 321-381 days (mean: 359+/-10.7 days) apart and supplied serum #2, 30-57 days (mean: 41+/-5.6 days) after the second vaccine dose.Anti-HBs responses: 379 of the 387 subjects (97.9%; 95% CI: 95.9-99.1%) achieved anti-HBs > or =10 mIU/ml (range 10-170,460 mIU/ml, geometric mean concentration (GMC) 4155 mIU/ml-95% CI of mean: 3381-5106 mIU/ml). Sex was the only determinant of anti-HBs concentration (206 males: GMC 3073 mIU/ml-95% CI: 2285-4134 mIU/ml; 173 females: GMC 5944 mIU/ml-95% CI: 4508-7851 mIU/ml; P=0.001). CONCLUSION: A high seroprotection rate and GMC were achieved using two 20 micro g doses of Engerix-B administered 12 months apart. These results are similar to those achieved by others using 6-month three- and two-dose regimens in adolescents.