Exploring the infectious contribution to intussusception causality using the effects of COVID-19 lockdowns in Australia: An ecological study.

INTRODUCTION: Intussusception is the primary cause of acute bowel obstruction in infants. The majority of cases under 2 years of age are classed as idiopathic with viral infection implicated as one of the causes. COVID-19 public health measures led to significant decreases in communicable disease prevalence. During these times, reductions in intussusception frequency were reported - reductions greater than would be expected with our previous understanding of its infectious aetiology. METHODS: We conducted a retrospective, multi-state, ecological study over a twelve-year period. Monthly case numbers of ICD-10-AM K56.1 'Intussusception' coded admissions were acquired from state-wide admissions datasets from New South Wales (NSW), Victoria and Queensland, representing 77.62% of the eligible Australian population. These counts within differing jurisdictional lockdowns were compared to non-lockdown periods in order to investigate a correlation between intussusception frequency and lockdown periods. RESULTS: We found a negative association between intussusception frequency and lockdown periods in both eligible states. The largest reductions were seen in the under 2 year age groups with Victoria experiencing a 62.7% reduction (Rate ratio (RR) = 0.37, p < 0.0001) and NSW a 40.1% reduction (RR = 0.599, p = 0.006) during lockdown times. Controls for variations in lockdown restrictions between both regional and metropolitan areas also showed expected decreases. CONCLUSION: Our ecological study demonstrates significant decreases in the frequency of paediatric intussusception admissions during the COVID-19 lockdown periods. The unexpected magnitude of the reductions suggests that the true proportion of infectious disease-caused idiopathic intussusception is greatly underestimated.

Vaccine Take of RV3-BB Rotavirus Vaccine Observed in Indonesian Infants Regardless of HBGA Status.

BACKGROUND: Histo-blood group antigen (HBGA) status may affect vaccine efficacy due to rotavirus strains binding to HBGAs in a P genotype-dependent manner. This study aimed to determine if HBGA status affected vaccine take of the G3P[6] neonatal vaccine RV3-BB. METHODS: DNA was extracted from stool samples collected in a subset (n = 164) of the RV3-BB phase IIb trial in Indonesian infants. FUT2 and FUT3 genes were amplified and sequenced, with any single-nucleotide polymorphisms analyzed to infer Lewis and secretor status. Measures of positive cumulative vaccine take were defined as serum immune response (immunoglobulin A or serum-neutralizing antibody) and/or stool excretion of RV3-BB virus. Participants were stratified by HBGA status and measures of vaccine take. RESULTS: In 147 of 164 participants, Lewis and secretor phenotype were determined. Positive vaccine take was recorded for 144 (97.9%) of 147 participants with the combined phenotype determined. Cumulative vaccine take was not significantly associated with secretor status (relative risk, 1.00 [95% CI, .94-1.06]; P = .97) or Lewis phenotype (relative risk, 1.03 [95% CI, .94-1.14]; P = .33), nor was a difference observed when analyzed by each component of vaccine take. CONCLUSIONS: The RV3-BB vaccine produced positive cumulative vaccine take, irrespective of HBGA status in Indonesian infants.

Rotavirus genotypes in children under five years hospitalized with diarrhea in low and middle-income countries: Results from the WHO-coordinated Global Rotavirus Surveillance Network.

Rotavirus is the most common pathogen causing pediatric diarrhea and an important cause of morbidity and mortality in low- and middle-income countries. Previous evidence suggests that the introduction of rotavirus vaccines in national immunization schedules resulted in dramatic declines in disease burden but may also be changing the rotavirus genetic landscape and driving the emergence of new genotypes. We report genotype data of more than 16,000 rotavirus isolates from 40 countries participating in the Global Rotavirus Surveillance Network. Data from a convenience sample of children under five years of age hospitalized with acute watery diarrhea who tested positive for rotavirus were included. Country results were weighted by their estimated rotavirus disease burden to estimate regional genotype distributions. Globally, the most frequent genotypes identified after weighting were G1P[8] (31%), G1P[6] (8%) and G3P[8] (8%). Genotypes varied across WHO Regions and between countries that had and had not introduced rotavirus vaccine. G1P[8] was less frequent among African (36 vs 20%) and European (33 vs 8%) countries that had introduced rotavirus vaccines as compared to countries that had not introduced. Our results describe differences in the distribution of the most common rotavirus genotypes in children with diarrhea in low- and middle-income countries. G1P[8] was less frequent in countries that had introduced the rotavirus vaccine while different strains are emerging or re-emerging in different regions.

Histo-blood group antigen profile of Australian Aboriginal children and seropositivity following oral rotavirus vaccination.

BACKGROUND: Histo-blood group antigens (HBGAs) may influence immune responses to rotavirus vaccination. METHODS: HBGA phenotyping was determined by detection of antigens A, B, H and Lewis a and b in saliva using enzyme-linked immunosorbent assay. Secretor status was confirmed by lectin antigen assay if A, B and H antigens were negative or borderline (OD ± 0.1 of threshold of detection). PCR-RFLP analysis was used to identify the FUT2 'G428A' mutation in a subset. Rotavirus seropositivity was defined as serum anti-rotavirus IgA ≥ 20 AU/mL. RESULTS: Of 156 children, 119 (76 %) were secretors, 129 (83 %) were Lewis antigen positive, and 105 (67 %) were rotavirus IgA seropositive. Eighty-seven of 119 (73 %) secretors were rotavirus seropositive, versus 4/9 (44 %) weak secretors and 13/27 (48 %) non-secretors. CONCLUSIONS: Most Australian Aboriginal children were secretor and Lewis antigen positive. Non-secretor children were less likely to be seropositive to rotavirus antibodies following vaccination, but this phenotype was less common. HBGA status is unlikely to fully explain underperformance of rotavirus vaccines among Australian Aboriginal children.

Review of the health impact of the oral rotavirus vaccine program in children under 5 years in Australia: 2006 - 2021.

Oral rotavirus vaccines were incorporated into the National Immunisation Program (NIP) for all Australian infants in July 2007. Initially each of the eight jurisdictions implemented Rotarix or RotaTeq rotavirus vaccine, however from July 2017 all states and territories have administered Rotarix only. This review evaluates the health impact of the oral rotavirus vaccine program for Australian children less than 5 years old over the first 15 years of the rotavirus vaccine program, observing long-term changes in rotavirus-related health care attendances, public health notifications, and vaccine effectiveness and safety data for both Rotarix and RotaTeq rotavirus vaccines. We searched Medline for studies published between January 2006 and May 2022 using the search terms 'rotavirus', 'rotavirus vaccine' and 'Australia'. Of 491 items identified, 76 items - 36 peer-reviewed articles and 40 reports - were included in the review. We found evidence that the introduction of the oral rotavirus vaccine program in Australia was associated with a prompt reduction in rotavirus-coded and all-cause gastroenteritis hospitalisations of vaccine-eligible children. In the context of less complete coverage, reduced vaccine timeliness and lower vaccine effectiveness, a less substantial and inconsistent reduction in severe rotavirus disease was observed among Aboriginal and Torres Strait Islander children, particularly those living in rural and remote northern Australia. Additional studies report no evidence for the emergence of non-vaccine serotypes and/ or replacement serotypes in Australia during the vaccine era. While the health impact for young children and consequent cost-savings of the oral rotavirus vaccine program have been high, it is important to find strategies to improve rotavirus vaccine impact for Aboriginal and Torres Strait Islander populations to ensure health benefits for all Australian children.

Australian Rotavirus Surveillance Program: Annual Report, 2021.

Abstract: This report from the Australian Rotavirus Surveillance Program describes the circulating rotavirus genotypes identified in children and adults during the period 1 January to 31 December 2021. During this period, 521 faecal specimens had been referred for rotavirus G- and P- genotype analysis, of which 474 were confirmed as rotavirus positive. Of these, 336/474 were wildtype rotavirus strains and 138/474 were identified as vaccine-like. Of the 336 wildtype samples, 87.5% (n = 294/336) were identified as G8P[8], and were detected in five of the six jurisdictions that provided samples for the reporting period. Two rotavirus outbreaks, located in the Northern Territory and Western Australia, were also attributed to G8P[8]. As with the 2020 reporting period, a low number of stool samples were received for this reporting period as a result of the COVID-19 pandemic. However, an unexpectedly high proportion of samples with unusual genotypes were identified which were potentially zoonotic in nature, including feline G3, P[9], bovine-like G8, P[14], and porcine-like G4, G6, P[1], and P[6]. Ongoing rotavirus surveillance is crucial to identify changes in genotypic patterns and to provide diagnostic laboratories with quality assurance by reporting incidences of wildtype, vaccine-like, or false positive rotavirus results.

Model-based estimation of the impact on rotavirus disease of RV3-BB vaccine administered in a neonatal or infant schedule.

Rotavirus infection is a common cause of severe diarrheal disease and a major cause of deaths and hospitalizations among young children. Incidence of rotavirus has declined globally with increasing vaccine coverage. However, it remains a significant cause of morbidity and mortality in low-income countries where vaccine access is limited and efficacy is lower. The oral human neonatal vaccine RV3-BB can be safely administered earlier than other vaccines, and recent trials in Indonesia have demonstrated high efficacy. In this study, we use a stochastic individual-based model of rotavirus transmission and disease to estimate the anticipated population-level impact of RV3-BB following delivery according to either an infant (2, 4, 6 months) and neonatal (0, 2, 4 months) schedule. Using our model, which incorporated an age- and household-structured population and estimates of vaccine efficacy derived from trial data, we found both delivery schedules to be effective at reducing infection and disease. We estimated 95-96% reductions in infection and disease in children under 12 months of age when vaccine coverage is 85%. We also estimate high levels of indirect protection from vaccination, including 78% reductions in infection in adults over 17 years of age. Even for lower vaccine coverage of 55%, we estimate reductions of 84% in infection and disease in children under 12 months of age. While open questions remain about the drivers of observed lower efficacy in low-income settings, our model suggests RV3-BB could be effective at reducing infection and preventing disease in young infants at the population level.

The feasibility of SARS-CoV-2 surveillance using wastewater and environmental sampling in Indonesia.

BACKGROUND: Wastewater-based epidemiology (WBE) surveillance as an early warning system (EWS) for monitoring community transmission of SARS-CoV-2 in low- and middle-income country (LMIC) settings, where diagnostic testing capacity is limited, needs further exploration. We explored the feasibility to conduct a WBE surveillance in Indonesia, one of the global epicenters of the COVID-19 pandemic in the middle of 2021, with the fourth largest population in the world where sewer and non-sewered sewage systems are implemented. The feasibility and resource capacity to collect samples on a weekly or fortnightly basis with grab and/or passive sampling methods, as well as to conduct qualitative and quantitative identification of SARS-CoV-2 ribonucleic acid (RNA) using real-time RT-PCR (RT-qPCR) testing of environmental samples were explored. MATERIALS AND METHODS: We initiated a routine surveillance of wastewater and environmental sampling at three predetermined districts in Special Region of Yogyakarta Province. Water samples were collected from central and community wastewater treatment plants (WWTPs), including manholes flowing to the central WWTP, and additional soil samples were collected for the near source tracking (NST) locations (i.e., public spaces where people congregate). RESULTS: We began collecting samples in the Delta wave of the COVID-19 pandemic in Indonesia in July 2021. From a 10-week period, 54% (296/544) of wastewater and environmental samples were positive for SARS-CoV-2 RNA. The sample positivity rate decreased in proportion with the reported incidence of COVID-19 clinical cases in the community. The highest positivity rate of 77% in week 1, was obtained for samples collected in July 2021 and decreased to 25% in week 10 by the end of September 2021. CONCLUSION: A WBE surveillance system for SARS-CoV-2 in Indonesia is feasible to monitor the community burden of infections. Future studies testing the potential of WBE and EWS for signaling early outbreaks of SARS-CoV-2 transmissions in this setting are required.

Virology and immune dynamics reveal high household transmission of ancestral SARS-CoV-2 strain.

BACKGROUND: Household studies are crucial for understanding the transmission of SARS-CoV-2 infection, which may be underestimated from PCR testing of respiratory samples alone. We aim to combine the assessment of household mitigation measures; nasopharyngeal, saliva, and stool PCR testing; along with mucosal and systemic SARS-CoV-2-specific antibodies, to comprehensively characterize SARS-CoV-2 infection and transmission in households. METHODS: Between March and September 2020, we obtained samples from 92 participants in 26 households in Melbourne, Australia, in a 4-week period following the onset of infection with ancestral SARS-CoV-2 variants. RESULTS: The secondary attack rate was 36% (24/66) when using nasopharyngeal swab (NPS) PCR positivity alone. However, when respiratory and nonrespiratory samples were combined with antibody responses in blood and saliva, the secondary attack rate was 76% (50/66). SARS-CoV-2 viral load of the index case and household isolation measures were key factors that determine secondary transmission. In 27% (7/26) of households, all family members tested positive by NPS for SARS-CoV-2 and were characterized by lower respiratory Ct values than low transmission families (Median 22.62 vs. 32.91; IQR 17.06-28.67 vs. 30.37-34.24). High transmission families were associated with enhanced plasma antibody responses to multiple SARS-CoV-2 antigens and the presence of neutralizing antibodies. Three distinguishing saliva SARS-CoV-2 antibody features were identified according to age (IgA1 to Spike 1, IgA1 to nucleocapsid protein (NP)), suggesting that adults and children generate distinct mucosal antibody responses during the acute phase of infection. CONCLUSION: Utilizing respiratory and nonrespiratory PCR testing, along with the measurement of SARS-CoV-2-specific local and systemic antibodies, provides a more accurate assessment of infection within households and highlights some of the immunological differences in response between children and adults.

Timeliness of routine childhood vaccinations in Indonesian infants in the first year of life.

BACKGROUND: Vaccines have proven to be one of the most effective strategies to control infectious diseases and contributed to childhood survival. While high vaccine coverages provide individual's and herd immunity, age-appropriate vaccination or vaccine timeliness is important for maximum vaccine's protection, but often not evaluated. We aimed to describe the timeliness of childhood vaccination for Indonesian infants and identify risk factors associated with delayed vaccination. METHODS: This study was a sub-study of the Indonesian Pneumonia and Vitamin D status (IPAD) study, a community-based cohort study to investigate pneumonia incidence in two districts in Yogyakarta province, Indonesia. Socio-demographic data were obtained from structured interviews and vaccine status was obtained from maternal and child health records. Timely vaccination was defined if the vaccine was received between four days or less before and within 28 days after the recommended age of vaccination. RESULTS: 359 (85%) out of 422 IPAD participants and their immunisation records were included. Between December 2015 and December 2017, vaccination coverage was high and ranged from 96.1% (Measles) to 100% (DTP-HepB-Hib 1). However, two thirds (67%, 242/359) of all participants had received either early or late vaccines, with dose 2 IPV (40%, 143/356), dose 3 IPV (56%, 196/349) and dose 3 DTP-HepB-Hib (29%, 103/354) most delayed, and only 1% received early doses. The main risk factors for untimely vaccination were if the infant was born in a private practice versus in a public health facility (AOR 1.90; 95% CI: 1.18-3.07) and rural residence (AOR 1.84; 95% CI: 1.15-2.94). CONCLUSIONS: Despite high vaccine coverage for Indonesian infants (>95%), two thirds (67%) of infants had untimely vaccinations, with dose 3 IPV (56%) the most delayed. Future strategies should focus on coordination between government, health care providers, and carers to ensure timely access and vaccination of infants to ensure adherence to vaccination schedules.

Comparison of Seroconversion in Children and Adults With Mild COVID-19.

Importance: The immune response in children with SARS-CoV-2 infection is not well understood. Objective: To compare seroconversion in nonhospitalized children and adults with mild SARS-CoV-2 infection and identify factors that are associated with seroconversion. Design, Setting, and Participants: This household cohort study of SARS-CoV-2 infection collected weekly nasopharyngeal and throat swabs and blood samples during the acute (median, 7 days for children and 12 days for adults [IQR, 4-13] days) and convalescent (median, 41 [IQR, 31-49] days) periods after polymerase chain reaction (PCR) diagnosis for analysis. Participants were recruited at The Royal Children's Hospital, Melbourne, Australia, from May 10 to October 28, 2020. Participants included patients who had a SARS-CoV-2-positive nasopharyngeal or oropharyngeal swab specimen using PCR analysis. Main Outcomes and Measures: SARS-CoV-2 immunoglobulin G (IgG) and cellular (T cell and B cell) responses in children and adults. Seroconversion was defined by seropositivity in all 3 (an in-house enzyme-linked immunosorbent assay [ELISA] and 2 commercial assays: a SARS-CoV-2 S1/S2 IgG assay and a SARS-CoV-2 antibody ELISA) serological assays. Results: Among 108 participants with SARS-CoV-2-positive PCR findings, 57 were children (35 boys [61.4%]; median age, 4 [IQR, 2-10] years) and 51 were adults (28 women [54.9%]; median age, 37 [IQR, 34-45] years). Using the 3 established serological assays, a lower proportion of children had seroconversion to IgG compared with adults (20 of 54 [37.0%] vs 32 of 42 [76.2%]; P < .001). This result was not associated with viral load, which was similar in children and adults (mean [SD] cycle threshold [Ct] value, 28.58 [6.83] vs 24.14 [8.47]; P = .09). In addition, age and sex were not associated with seroconversion within children (median age, 4 [IQR, 2-14] years for both seropositive and seronegative groups; seroconversion by sex, 10 of 21 girls [47.6%] vs 10 of 33 boys [30.3%]) or adults (median ages, 37 years for seropositive and 40 years for seronegative adults [IQR, 34-39 years]; seroconversion by sex, 18 of 24 women [75.0%] vs 14 of 18 men [77.8%]) (P > .05 for all comparisons between seronegative and seropositive groups). Symptomatic adults had 3-fold higher SARS-CoV-2 IgG levels than asymptomatic adults (median, 227.5 [IQR, 133.7-521.6] vs 75.3 [IQR, 36.9-113.6] IU/mL), whereas no differences were observed in children regardless of symptoms. Moreover, differences in cellular immune responses were observed in adults compared with children with seroconversion. Conclusions and Relevance: The findings of this cohort study suggest that among patients with mild COVID-19, children may be less likely to have seroconversion than adults despite similar viral loads. This finding has implications for future protection after SARS-CoV-2 infection in children and for interpretation of serosurveys that involve children. Further research to understand why seroconversion and development of symptoms are potentially less likely in children after SARS-CoV-2 infection and to compare vaccine responses may be of clinical and scientific importance.

Leveraging Beneficial Off-Target Effects of Live-Attenuated Rotavirus Vaccines.

Following the introduction of live-attenuated rotavirus vaccines in many countries, a notable reduction in deaths and hospitalisations associated with diarrhoea in children <5 years of age has been reported. There is growing evidence to suggest that live-attenuated vaccines also provide protection against other infections beyond the vaccine-targeted pathogens. These so called off-target effects of vaccination have been associated with the tuberculosis vaccine Bacille Calmette Guérin (BCG), measles, oral polio and recently salmonella vaccines, and are thought to be mediated by modified innate and possibly adaptive immunity. Indeed, rotavirus vaccines have been reported to provide greater than expected reductions in acute gastroenteritis caused by other enteropathogens, that have mostly been attributed to herd protection and prior underestimation of rotavirus disease. Whether rotavirus vaccines also alter the immune system to reduce non targeted gastrointestinal infections has not been studied directly. Here we review the current understanding of the mechanisms underlying off-target effects of vaccines and propose a mechanism by which the live-attenuated neonatal rotavirus vaccine, RV3-BB, could promote protection beyond the targeted pathogen. Finally, we consider how vaccine developers may leverage these properties to improve health outcomes in children, particularly those in low-income countries where disease burden and mortality is disproportionately high relative to developed countries.

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.

Direct and indirect costs of acute diarrhea in children under five years of age in Indonesia: Health facilities and community survey.

BACKGROUND: Diarrhea remains a major cause of child morbidity and mortality in low- and middle-income countries. Reliable data on the economic burden of diarrhea is required to support the selection of appropriate health intervention programs. This study aimed to estimate the costs of acute diarrhea in children under five years of age in Indonesia, a large middle-income country with a substantial diarrheal burden. METHODS: Direct medical cost data were extracted retrospectively for 1050 children under five years of age with acute diarrhea receiving inpatient care across 45 health facilities in seven Indonesian provinces during 2017-2020. Direct medical costs for children treated in outpatient settings were estimated by collecting unit costs associated with standard diarrhea case management in children. A structured interview of 240 caregivers of inpatients was also conducted retrospectively to estimate direct non-medical costs as well as indirect costs from caregiver income loss. RESULTS: The weighted average direct medical cost for treatment of acute diarrhea as an inpatient and outpatient across health facility types was US$99.8 (SD±$56.8)(35% room costs, 29% professional fees, 26% medication costs, 10% diagnostic costs) and US$7.6 (SD±$4.3) (34% diagnostic costs, 28% medication costs, 27% professional fees, 10% registration fees), respectively. The average direct non-medical household cost for an acute diarrheal admission was US$4.90 and the indirect cost was US$9.90. CONCLUSION: There is a significant economic burden associated with acute diarrhea in children in Indonesia. This study, based on a wide variety of health care settings and geographical regions, provides data to inform the economic evaluation of rotavirus vaccines and other diarrheal prevention programs. FUNDING: This work was supported by a research grant from the Murdoch Children's Research Institute (MCRI) and PATH; and the Indonesian Technical Advisory Group on Immunization (ITAGI).

Rotavirus Disease and Genotype Diversity in Older Children and Adults in Australia.

BACKGROUND: Rotavirus is a major cause of gastroenteritis in children <5 years of age. The disease burden in older children, adults, and the elderly is underappreciated. This study describes rotavirus disease and genotypic diversity in the Australian population comprising children ≥5 years of age and adults. METHODS: Rotavirus positive fecal samples were collected from laboratories Australia-wide participating in the Australian Rotavirus Surveillance Program between 2010 and 2018. Rotavirus samples were genotyped using a heminested multiplex reverse-transcription polymerase chain reaction. Notification data from the National Notifiable Diseases Surveillance System were also analyzed. RESULTS: Rotavirus disease was highest in children aged 5-9 years and adults ≥85 years. G2P[4] was the dominant genotype in the population ≥5 years of age. Genotype distribution fluctuated annually and genotypic diversity varied among different age groups. Geographical differences in genotype distribution were observed based on the rotavirus vaccine administered to infants <1 year of age. CONCLUSIONS: This study revealed a substantial burden of rotavirus disease in the population ≥5 years of age, particularly in children 5-9 years and the elderly. This study highlights the continued need for rotavirus surveillance across the population, despite the implementation of efficacious vaccines.

Modeling the long-term 2-8 °C stability profiles of a live, rotavirus vaccine candidate (RV3-BB) in various liquid formulations via extrapolations of real-time and accelerated stability data.

To accelerate the formulation development of live-virus vaccine (LVV) candidates, more rapid approaches to rank-order formulations and estimate their real-time storage stability losses are needed. In this case-study, we utilize new and previously described stability data of a live, rotavirus vaccine candidate (RV3-BB) in three different liquid formulations to model and compare predicted vs. experimental RV3-BB stability profiles. Linear-regression extrapolations of limited real-time (2-8 °C) stability data and Arrhenius modeling of accelerated (15, 25, 37 °C) stability data provided predictions of RV3-BB real-time stability profiles (2-8 °C, 24 months). Good correlations of modeled versus experimental stability data to rank-order the RV3-BB formulations were achieved by employing (1) a high-throughput RT-qPCR assay to measure viral titers, (2) additional assay replicates and stability time-points, and (3) a -80 °C control for each formulation to benchmark results at each stability time-point and temperature. Instead of accumulating two-year, 2-8 °C storage stability data, the same rank-ordering of the three RV3-BB formulations could have been achieved by modeling 37°, 25°, 15° (and 2-8 °C) stability data over 1, 3 and 12 months, respectively. The results of this case-study are discussed in the context of accelerating LVV formulation development by expeditiously identifying stable formulations, estimating their shelf-lives, and determining vaccine vial monitoring (VVM) designations.

Aetiology and incidence of diarrhoea requiring hospitalisation in children under 5 years of age in 28 low-income and middle-income countries: findings from the Global Pediatric Diarrhea Surveillance network.

INTRODUCTION: Diarrhoea remains a leading cause of child morbidity and mortality. Systematically collected and analysed data on the aetiology of hospitalised diarrhoea in low-income and middle-income countries are needed to prioritise interventions. METHODS: We established the Global Pediatric Diarrhea Surveillance network, in which children under 5 years hospitalised with diarrhoea were enrolled at 33 sentinel surveillance hospitals in 28 low-income and middle-income countries. Randomly selected stool specimens were tested by quantitative PCR for 16 causes of diarrhoea. We estimated pathogen-specific attributable burdens of diarrhoeal hospitalisations and deaths. We incorporated country-level incidence to estimate the number of pathogen-specific deaths on a global scale. RESULTS: During 2017-2018, 29 502 diarrhoea hospitalisations were enrolled, of which 5465 were randomly selected and tested. Rotavirus was the leading cause of diarrhoea requiring hospitalisation (attributable fraction (AF) 33.3%; 95% CI 27.7 to 40.3), followed by Shigella (9.7%; 95% CI 7.7 to 11.6), norovirus (6.5%; 95% CI 5.4 to 7.6) and adenovirus 40/41 (5.5%; 95% CI 4.4 to 6.7). Rotavirus was the leading cause of hospitalised diarrhoea in all regions except the Americas, where the leading aetiologies were Shigella (19.2%; 95% CI 11.4 to 28.1) and norovirus (22.2%; 95% CI 17.5 to 27.9) in Central and South America, respectively. The proportion of hospitalisations attributable to rotavirus was approximately 50% lower in sites that had introduced rotavirus vaccine (AF 20.8%; 95% CI 18.0 to 24.1) compared with sites that had not (42.1%; 95% CI 33.2 to 53.4). Globally, we estimated 208 009 annual rotavirus-attributable deaths (95% CI 169 561 to 259 216), 62 853 Shigella-attributable deaths (95% CI 48 656 to 78 805), 36 922 adenovirus 40/41-attributable deaths (95% CI 28 469 to 46 672) and 35 914 norovirus-attributable deaths (95% CI 27 258 to 46 516). CONCLUSIONS: Despite the substantial impact of rotavirus vaccine introduction, rotavirus remained the leading cause of paediatric diarrhoea hospitalisations. Improving the efficacy and coverage of rotavirus vaccination and prioritising interventions against Shigella, norovirus and adenovirus could further reduce diarrhoea morbidity and mortality.

Children and Adults in a Household Cohort Study Have Robust Longitudinal Immune Responses Following SARS-CoV-2 Infection or Exposure.

Children have reduced severity of COVID-19 compared to adults and typically have mild or asymptomatic disease. The immunological mechanisms underlying these age-related differences in clinical outcomes remain unexplained. Here, we quantify 23 immune cell populations in 141 samples from children and adults with mild COVID-19 and their PCR-negative close household contacts at acute and convalescent time points. Children with COVID-19 displayed marked reductions in myeloid cells during infection, most prominent in children under the age of five. Recovery from infection in both children and adults was characterised by the generation of CD8 TCM and CD4 TCM up to 9 weeks post infection. SARS-CoV-2-exposed close contacts also had immunological changes over time despite no evidence of confirmed SARS-CoV-2 infection on PCR testing. This included an increase in low-density neutrophils during convalescence in both exposed children and adults, as well as increases in CD8 TCM and CD4 TCM in exposed adults. In comparison to children with other common respiratory viral infections, those with COVID-19 had a greater change in innate and T cell-mediated immune responses over time. These findings provide new mechanistic insights into the immune response during and after recovery from COVID-19 in both children and adults.

Australian Rotavirus Surveillance Program: Annual Report, 2020.

ABSTRACT: This report from the Australian Rotavirus Surveillance Network describes the circulating rotavirus genotypes identified in children and adults during the period 1 January - 31 December 2020. During this period, 229 faecal specimens were referred for rotavirus G- and P- genotype analysis, including 189 samples that were confirmed as rotavirus positive. Of these, 98/189 were wildtype rotavirus strains and 86/189 were identified as vaccine-like. A further five samples could not be determined as wildtype or vaccine-like due to poor sequence reads. Genotype analysis of the 98 wildtype rotavirus samples from both children and adults demonstrated that G3P[8] was the dominant genotype identified for the third consecutive year, identified in 27.6% of samples, followed by G2P[4] in 20.4% of samples. Forty-six percent of rotavirus positive samples received were identified as vaccine-like, highlighting the need to add caution in interpreting rotavirus positive results in children aged 0-8 months. This surveillance period was significantly impacted by the coronavirus disease 2019 ( COVID-19 ) pandemic. The reduction in rotavirus notifications reflected reduced healthcare-seeking behaviour and a decrease in community spread, with 'community lockdowns', school and day-care centre closure and improved compliance with hand hygiene. Fewer stool samples were collected throughout Australia during this period. There was a reluctance to store samples at collaborating laboratories and uncertainties regarding the safety and feasibility of the transport of samples to the central laboratory during the closure of state and territory borders. Systems have now been adapted to manage and send biological samples safely and confidently. Ongoing rotavirus surveillance is crucial to identify changes in genotypic patterns and to provide diagnostic laboratories quality assurance by reporting incidences of wildtype, vaccine-like, or false positive rotavirus results.