Acceptability of an asymptomatic COVID-19 screening program for schools in Victoria, Australia: a qualitative study with caregivers from priority populations.

BACKGROUND: An asymptomatic COVID-19 rapid antigen testing (RAT) screening program was implemented in Victorian schools in January 2022, to support keeping schools open throughout the pandemic. This study explored compliance with the program among caregivers from priority populations in Victorian mainstream and specialist schools. METHODS: We conducted semi-structured interviews between 7-31 March 2022 with caregivers of school-aged children participating in the RAT program in Victoria. Participants were asked about awareness, acceptability, compliance, frequency, and barriers to testing. Recordings were transcribed and deductively analysed using a framework approach. RESULTS: Fifty caregivers participated. They expressed confusion about the 'recommended' program, assuming it was mandatory. Caregivers wanted notification from schools of positive cases to increase motivation for compliance. Culturally and linguistically diverse (CALD) families were compliant; however, in-language resources were limited. Aboriginal or Torres Strait Islander (Koori) families tested less regularly and received information from their community rather than school. Caregivers of children living with disabilities reported behavioural challenges to testing, resulting in distress or non-compliance, and received non-specific information for their children. CONCLUSIONS: To increase engagement with future surveillance programs, caregivers need clarity about optionality, conducting tests, reporting results, and timely notification of cases. Requirements unique to each priority population include: accurate in-language information for CALD caregivers, community-led communication for Koori caregivers, tailored information, less testing, and flexibility for caregivers of children living with a disability. Keeping schools open and having tailored strategies to ensure equitable access for priority populations are essential for future pandemic management.

Immunogenicity, safety, and reactogenicity of a half- versus full-dose BNT162b2 (Pfizer-BioNTech) booster following a two-dose ChAdOx1 nCoV-19, BBIBP-CorV, or Gam-COVID-Vac priming schedule in Mongolia: a randomised, controlled, non-inferiority trial.

Background: COVID-19 vaccine booster doses restore vaccine effectiveness lost from waning immunity and emerging variants. Fractional dosing may improve COVID-19 booster acceptability and uptake and will reduce the per-dose cost of COVID-19 booster programmes. We sought to quantify the immunogenicity, reactogenicity, and safety of a half-dose BNT162b2 (Pfizer-BioNTech) booster relative to the standard formulation. Methods: This randomised, controlled, non-inferiority trial recruited adults in Mongolia primed with a two-dose homologous ChAdOx1 nCov-19 (Oxford-AstraZeneca, n = 129 participants), BBIBP-CorV (Sinopharm (Beijing), n = 399), or Gam-COVID-Vac (Gamaleya, n = 70) schedule. Participants were randomised (1:1) to receive a 15 µg (half-dose) or 30 µg (full-dose) BNT162b2 booster. Participants and study staff assessing reactogenicity were blinded up to day 28. Co-primary endpoints were Wuhan-Hu-1 anti-spike S1 IgG seroresponse 28 days post-boosting and reactogenicity within 7 days of boosting. The non-inferiority margin for the absolute difference in seroresponse was -10%. Differences in seroresponse were estimated from logistic regression with marginal standardisation. Geometric mean ratios of IgG were also estimated. ClinicalTrials.gov Identifier: NCT05265065. Findings: Between May 27th and September 30th, 2022, 601 participants were randomized to full-dose BNT162b2 (n = 300) or half-dose (n = 301). 598 were included in safety analyses, and 587 in immunological analyses. The frequency of grade 3-4 reactions was similar between arms (half-dose: 4/299 [1.3%]; full-dose: 6/299 [2.0%]). Across all severity grades, half-dose recipients reported fewer local and systemic reactions (60% versus 72% and 25% versus 32%, respectively). Seroresponse was 84.7% (250/295) and 86.6% (253/292) in the half-dose and full-dose arms, respectively (Difference: -2.8%; 95% CI -7.7, 2.1). Geometric mean IgG titres were similar in those receiving full and half-dose boosters for the ChAdOx1 and BBIBP-CorV primed groups, but lower in the half-dose arm in Gam-COVID-Vac-primed participants (GMR: 0.71; 95% CI 0.54, 0.93). Interpretation: Half-dose BNT162b2 boosting elicited an immune response that was non-inferior to a full-dose, with fewer reactions, in adults primed with ChAdOx1 nCov-19 or BBIBP-CorV. Half-dose boosting may not be suitable in adults primed with Gam-COVID-Vac. Half-dose BNT162b2 boosting may be considered in populations primed with ChAdOx1 nCov-19 or BBIBP-CorV. Funding: Coalition for Epidemic Preparedness Innovations (CEPI).

Neonatal rotavirus vaccine (RV3-BB) immunogenicity and safety in a neonatal and infant administration schedule in Malawi: a randomised, double-blind, four-arm parallel group dose-ranging study.

BACKGROUND: Rotavirus vaccines reduce rotavirus-related deaths and hospitalisations but are less effective in high child mortality countries. The human RV3-BB neonatal G3P[6] rotavirus vaccine administered in a neonatal schedule was efficacious in reducing severe rotavirus gastroenteritis in Indonesia but had not yet been evaluated in African infants. METHODS: We did a phase 2, randomised, double-blind, parallel group dose-ranging study of three doses of oral RV3-BB rotavirus vaccine in infants in three primary health centres in Blantyre, Malawi. Healthy infants less than 6 days of age with a birthweight 2·5 to 4·0 kg were randomly assigned (1:1:1:1) into one of four treatment groups: neonatal vaccine group, which included high-titre (1·0 × 107 focus-forming unit [FFU] per mL), mid-titre (3·0 × 106 FFU per mL), or low-titre (1·0 × 106 FFU per mL); and infant vaccine group, which included high-titre (1·0 × 107 FFU per mL) using a computer generated code (block size of four), stratified by birth (singleton vs multiple). Neonates received their three doses at 0-5 days to 10 weeks and infants at 6-14 weeks. Investigators, participant families, and laboratory staff were masked to group allocation. Anti-rotavirus IgA seroconversion and vaccine take (IgA seroconversion and stool shedding) were evaluated. Safety was assessed in all participants who received at least one dose of vaccine or placebo. The primary outcome was the cumulative IgA seroconversion 4 weeks after three doses of RV3-BB in the neonatal schedule in the high-titre, mid-titre, and low-titre groups in the per protocol population, with its 95% CI. With the high-titre group as the active control group, we did a non-inferiority analysis of the proportion of participants with IgA seroconversion in the mid-titre and low-titre groups, using a non-inferiority margin of less than 20%. This trial is registered at ClinicalTrials.gov (NCT03483116). FINDINGS: Between Sept 17, 2018, and Jan 27, 2020, 711 participants recruited were randomly assigned into four treatment groups (neonatal schedule high titre n=178, mid titre n=179, low titre n=175, or infant schedule high titre n=179). In the neonatal schedule, cumulative IgA seroconversion 4 weeks after three doses of RV3-BB was observed in 79 (57%) of 139 participants in the high-titre group, 80 (57%) of 141 participants in the mid-titre group, and 57 (41%) of 138 participants in the low-titre group and at 18 weeks in 100 (72%) of 139 participants in the high-titre group, 96 (67%) of 143 participants in the mid-titre group, and 86 (62%) of 138 of participants in the low-titre. No difference in cumulative IgA seroconversion 4 weeks after three doses of RV3-BB was observed between high-titre and mid-titre groups in the neonatal schedule (difference in response rate 0·001 [95%CI -0·115 to 0·117]), fulfilling the criteria for non-inferiority. In the infant schedule group 82 (59%) of 139 participants had a cumulative IgA seroconversion 4 weeks after three doses of RV3-BB at 18 weeks. Cumulative vaccine take was detected in 483 (85%) of 565 participants at 18 weeks. Three doses of RV3-BB were well tolerated with no difference in adverse events among treatment groups: 67 (39%) of 170 participants had at least one adverse event in the high titre group, 68 (40%) of 172 participants had at least one adverse event in the mid titre group, and 69 (41%) of 169 participants had at least one adverse event in the low titre group. INTERPRETATION: RV3-BB was well tolerated and immunogenic when co-administered with Expanded Programme on Immunisation vaccines in a neonatal or infant schedule. A lower titre (mid-titre) vaccine generated similar IgA seroconversion to the high-titre vaccine presenting an opportunity to enhance manufacturing capacity and reduce costs. Neonatal administration of the RV3-BB vaccine has the potential to improve protection against rotavirus disease in children in a high-child mortality country in Africa. FUNDING: Bill & Melinda Gates Foundation, Australian Tropical Medicine Commercialisation Grant.

Human Neonatal Rotavirus Vaccine (RV3-BB) to Target Rotavirus from Birth.

BACKGROUND: A strategy of administering a neonatal rotavirus vaccine at birth to target early prevention of rotavirus gastroenteritis may address some of the barriers to global implementation of a rotavirus vaccine. METHODS: We conducted a randomized, double-blind, placebo-controlled trial in Indonesia to evaluate the efficacy of an oral human neonatal rotavirus vaccine (RV3-BB) in preventing rotavirus gastroenteritis. Healthy newborns received three doses of RV3-BB, administered according to a neonatal schedule (0 to 5 days, 8 weeks, and 14 weeks of age) or an infant schedule (8 weeks, 14 weeks, and 18 weeks of age), or placebo. The primary analysis was conducted in the per-protocol population, which included only participants who received all four doses of vaccine or placebo within the visit windows, with secondary analyses performed in the intention-to-treat population, which included all participants who underwent randomization. RESULTS: Among the 1513 participants in the per-protocol population, severe rotavirus gastroenteritis occurred up to the age of 18 months in 5.6% of the participants in the placebo group (28 of 504 babies), in 1.4% in the neonatal-schedule vaccine group (7 of 498), and in 2.7% in the infant-schedule vaccine group (14 of 511). This resulted in a vaccine efficacy of 75% (95% confidence interval [CI], 44 to 91) in the neonatal-schedule group (P<0.001), 51% (95% CI, 7 to 76) in the infant-schedule group (P=0.03), and 63% (95% CI, 34 to 80) in the neonatal-schedule and infant-schedule groups combined (combined vaccine group) (P<0.001). Similar results were observed in the intention-to-treat analysis (1649 participants); the vaccine efficacy was 68% (95% CI, 35 to 86) in the neonatal-schedule group (P=0.001), 52% (95% CI, 11 to 76) in the infant-schedule group (P=0.02), and 60% (95% CI, 31 to 76) in the combined vaccine group (P<0.001). Vaccine response, as evidenced by serum immune response or shedding of RV3-BB in the stool, occurred in 78 of 83 participants (94%) in the neonatal-schedule group and in 83 of 84 participants (99%) in the infant-schedule group. The incidence of adverse events was similar across the groups. No episodes of intussusception occurred within the 21-day risk period after administration of any dose of vaccine or placebo, and one episode of intussusception occurred 114 days after the third dose of vaccine in the infant-schedule group. CONCLUSIONS: RV3-BB was efficacious in preventing severe rotavirus gastroenteritis when administered according to a neonatal or an infant schedule in Indonesia. (Funded by the Bill and Melinda Gates Foundation and others; Australian New Zealand Clinical Trials Registry number, ACTRN12612001282875 .).

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.

Recurrent intussusception in infants.

AIM: Clinical features to identify infants at increased risk of recurrence after a primary episode of intussusception (IS) are poorly defined. METHODS: Prospective study of the clinical presentation, treatment and outcome in infants <2 years presenting with acute IS to the National Hospital of Pediatrics, Hanoi, over a 14-month period (1 November 2002 to 31 December 2003). A retrospective review of medical records was performed to verify complete patient ascertainment. RESULTS: Five hundred ninety-eight children were recruited, including 513 (86%) with a primary episode only and 53 (9%) with ≥1 recurrent episodes. Another 32 (5%) infants presented with recurrent IS, but the primary episode of IS occurred outside the study period. Estimated recurrence risk at 6 months following a primary episode was 14%. A pathological lead point was rare in primary (n= 1) and recurrent IS (n= 1). Most infants were successfully treated with enema reduction. CONCLUSIONS: This study describes the natural history of recurrent IS in infants and may assist in interpreting data from post-marketing surveillance following introduction of rotavirus vaccines.

Accuracy of ultrasonography for the diagnosis of intussusception in infants in Vietnam.

BACKGROUND: Intussusception (IS) is the most common cause of acute bowel obstruction in infants and young children. Ultrasonography is being increasingly used as the primary investigation for the diagnosis of IS and to guide air or hydrostatic enema reduction. However the accuracy of ultrasonography outside tertiary care settings in developed countries has not been assessed, particularly in Asia where the incidence of IS based on sonographic diagnosis has been reported as the highest in the world. OBJECTIVE: The aim of this study was to evaluate the accuracy of ultrasonography in the diagnosis of acute IS in infants less than 2 years of age in a paediatric hospital in Vietnam. MATERIALS AND METHODS: A prospective study was conducted at the National Hospital for Paediatrics, Hanoi, Vietnam, over a 14-month period recruiting patients <2 years of age with IS. Abdominal ultrasonography was performed on each patient and the accuracy of the diagnosis was evaluated against the final diagnosis provided by air enema and/or surgery. RESULTS: A total of 640 infants <2 years of age presented with clinical symptoms and signs of IS. The diagnosis was confirmed in 533 patients via air enema or surgery. Abdominal ultrasonography was 97.5% (466/478) sensitive and 99% (106/107) specific in the detection of IS. CONCLUSION: Ultrasonography is an accurate, safe and valuable clinical tool in the diagnosis of IS. The use of ultrasonography as a primary investigation for patients with suspected IS prevents unnecessary radiological or surgical procedures being performed, and reduces radiation exposure while maintaining a high level of diagnostic accuracy. These results validate the use of ultrasonography for the diagnosis of IS in a developing country setting.

Risk factors for intussusception in infants in Vietnam and Australia: adenovirus implicated, but not rotavirus.

OBJECTIVE: This study aimed to investigate risk factors for the development of intussusception in infants in a developing country with a suspected high incidence and in a developed country with a low incidence. STUDY DESIGN: A prospective case-control study of infants <2 years of age with idiopathic intussusception confirmed by air enema or surgery was conducted at the National Hospital of Paediatrics (NHP), Vietnam (n = 533) and the Royal Children's Hospital (RCH), Australia (n = 51). Diagnosis was validated in a subset (84% NHP; 67% RCH) by an independent blinded radiologist. Risk factor assessment was performed using a standardized questionnaire. Stool specimens were assayed for bacterial, viral, and parasitic agents. RESULTS: The incidence of intussusception in Vietnam was 302/100,000 in infants <1 year of age (95% CI: 258-352), substantially higher than in Australia (71/100,000). A strong association with adenovirus infection was observed at both sites (cases positive at NHP: 34%, OR 8.2; cases positive at RCH: 40%, OR 44). No association was identified between intussusception and rotavirus, other enteric pathogens, oral polio vaccine, feeding practices, or living conditions. CONCLUSIONS: The incidence of intussusception in infants was markedly higher in Vietnam than in Australia. A strong association between adenovirus infection and intussusception was identified at both sites suggesting that adenovirus may play a role in the etiology of intussusception.

Validation of clinical case definition of acute intussusception in infants in Viet Nam and Australia.

OBJECTIVE: To test the sensitivity and specificity of a clinical case definition of acute intussusception in infants to assist health-care workers in settings where diagnostic facilities are not available. METHODS: Prospective studies were conducted at a major paediatric hospital in Viet Nam (the National Hospital of Pediatrics, Hanoi) from November 2002 to December 2003 and in Australia (the Royal Children's Hospital, Melbourne) from March 2002 to March 2004 using a clinical case definition of intussusception. Diagnosis of intussusception was confirmed by air enema or surgery and validated in a subset of participants by an independent clinician who was blinded to the participant's status. Sensitivity of the definition was evaluated in 584 infants aged<2 years with suspected intussusception (533 infants in Hanoi; 51 in Melbourne). Specificity was evaluated in 638 infants aged<2 years presenting with clinical features consistent with intussusception but for whom another diagnosis was established (234 infants in Hanoi; 404 in Melbourne). FINDINGS: In both locations the definition used was sensitive (96% sensitivity in Hanoi; 98% in Melbourne) and specific (95% specificity in Hanoi; 87% in Melbourne) for intussusception among infants with sufficient data to allow classification (449/533 in Hanoi; 50/51 in Melbourne). Reanalysis of patients with missing data suggests that modifying minor criteria would increase the applicability of the definition while maintaining good sensitivity (96-97%) and specificity (83-89%). CONCLUSION: The clinical case definition was sensitive and specific for the diagnosis of acute intussusception in infants in both a developing country and a developed country but minor modifications would enable it to be used more widely.

Intussusception: trends in clinical presentation and management.

BACKGROUND: The association of a rotavirus vaccine and intussusception has renewed interest in understanding the incidence, clinical presentation and outcome of intussusception. METHODS: A retrospective chart review of all patients diagnosed with intussusception at Royal Children's Hospital, Melbourne over a 6.5-year period (1 January 1995-30 June 2001) was conducted using patients identified by a medical record database (ICD-9-CM code 560.0 1993-1997; ICD-10-CM code 56.1 1998-2001). Patient profile, clinical presentation, diagnosis methods, treatment and outcome were analyzed and compared to data previously reported on children with intussusception at the same hospital during 1962-1968. RESULTS: The hospitalization rate for primary idiopathic intussusception increased marginally from 0.19 to 0.27 per 1000 live births during the period 1962-1968 to 1995-2001. Most patients (80%) were <12 months of age (median age 7 months, range 2-72 months). The combination of abdominal pain, lethargy and vomiting was reported in 78% of infants. Air enema confirmed the diagnosis of intussusception in 186 of 191 cases (97%) and air reduction was successful in most cases (82%). Factors associated with increased risk of intestinal resection included abdominal distension (32%), bowel obstruction on abdominal X-ray (27%) and hypovolemic shock (40%). No mortality was observed in the present study. CONCLUSIONS: Over the past 40 years at Royal Children's Hospital, Melbourne the hospitalization rate due to primary idiopathic intussusception has marginally increased from 0.19 to 0.27 per 1000 live births. Diagnosis and treatment using air enema has been highly successful, resulting in a reduction in patients requiring surgery and reduced hospital stays.

Changing epidemiology of intussusception in Australia.

OBJECTIVES: Oral rotavirus vaccines are expected to become available in Australia within the next 2 years. In light of evidence for an association between a rotavirus vaccine and intussusception, it is important to define the baseline epidemiology of intussusception in Australia and establish a system for intussusception surveillance in the immediate post-licensure period. This study reports on incidence and epidemiology of intussusception in Australia. METHODS: Data were obtained from the Australian Institute of Health and Welfare on all patients with a discharge diagnosis of intussusception from public and private hospitals in each state and territory of Australia from 1994 to 2000. We examined age at presentation, sex, month and year of presentation, indigenous status and clinical outcomes. The incidence of intussusception was calculated and annual trends examined. Surveillance data on rotavirus gastroenteritis hospitalizations over the same time period were also obtained to compare seasonal patterns. RESULTS: From 1994 to 2000, a 39% reduction in intussusception incidence in infants aged <1 year was observed in Australia (13.1/10,000 to 8.1/10,000; P < 0.001). The incidence of intussusception was lower in indigenous infants (3.3/10,000 <1 year) compared to non-indigenous infants (10.4/10,000 <1 year; P < 0.001). There was no association between the seasonality of rotavirus infection and intussusception. Only one of 12 deaths due to intussusception was reported in an infant <1 year. CONCLUSIONS: This study documents the epidemiology of intussusception in Australia from 1994 to 2000 and provides important baseline information for future rotavirus vaccines. A lower risk of intussusception was identified in indigenous compared to non-indigenous infants.

Clinical case definition for the diagnosis of acute intussusception.

OBJECTIVE: Because of the reported association between intussusception and a rotavirus vaccine, future clinical trials of rotavirus vaccines will need to include intussusception surveillance in the evaluation of vaccine safety. The aim of this study is to develop and validate a clinical case definition for the diagnosis of acute intussusception. METHODS: A clinical case definition for the diagnosis of acute intussusception was developed by analysis of an extensive literature review that defined the clinical presentation of intussusception in 70 developed and developing countries. The clinical case definition was then assessed for sensitivity and specificity using a retrospective chart review of hospital admissions. Sensitivity of the clinical case definition was assessed in children diagnosed with intussusception over a 6.5-year period. Specificity was assessed in patients aged <2 years admitted with bowel obstruction and in patients aged <19 years presenting with symptoms that may occur in intussusception. RESULTS: The clinical case definition accurately identified 185 of 191 assessable cases as "probable" intussusception and six cases as "possible" intussusception (sensitivity, 97%). No case of radiologic or surgically proven intussusception failed to be identified by the clinical case definition. The specificity of the definition in correctly identifying patients who did not have intussusception ranged from 87% to 91%. CONCLUSIONS: The clinical case definition for intussusception may assist in the prompt identification of patients with intussusception and may provide an important tool for the future trials of enteric vaccines.

Influence of diet complexity on intestinal adaptation following massive small bowel resection in a preclinical model.

AIMS: To investigate the effect of dietary complexity on intestinal adaptation using a preclinical model. METHODS: Four-week-old piglets underwent a 75% proximal small bowel resection or transection operation (control). Post-operatively, animals received either pig chow (n = 15), polymeric formula (n = 9), polymeric formula plus fiber (n = 6), or elemental formula (n = 7). RESULTS: The weight gain of all groups was reduced compared with controls that were fed the same diet. Animals that had a resection, which were fed elemental formula, had significantly reduced weight gain compared with the other groups (4.7 4.2 vs 30.7 7.1 kg chow and 11.5 1.3 kg polymeric formula). Villus height was increased in the jejunum, ileum and terminal ileum of resected animals compared with controls in animals fed with pig chow, polymeric formula and elemental formula. The animals that had a resection had a significant reduction in the transepithelial conductance (10.4 5.5 vs 25.4 6.5 mS/cm2) and 51Chromium-EDTA flux (2.8 1.9 vs 4.8 4.9 microL/h per cm2) compared with the controls. CONCLUSIONS: A complex diet was found to be superior to an elemental diet in terms of the morphological and functional features of adaptation following massive small bowel resection.