One versus two doses of ivermectin-based mass drug administration for the control of scabies: A cluster randomised non-inferiority trial.

BACKGROUND: Mass drug administration (MDA) based on two doses of ivermectin, one week apart, substantially reduces prevalence of both scabies and impetigo. The Regimens of Ivermectin for Scabies Elimination (RISE) trial assessed whether one-dose ivermectin-based MDA would be as effective. METHODS: RISE was a cluster-randomised trial in Solomon Islands. We assigned 20 villages in a 1:1 ratio to one- or two-dose ivermectin-based MDA. We planned to test whether the impact of one dose on scabies prevalence at 12 and 24 months was non-inferior to two, at a 5% non-inferiority margin. RESULTS: We deferred endpoint assessment to 21 months due to COVID-19. We enrolled 5239 participants in 20 villages at baseline and 3369 at 21 months from an estimated population of 5500. At baseline scabies prevalence was similar in the two arms (one-dose 17·2%; two-dose 13·2%). At 21 months, there was no reduction in scabies prevalence (one-dose 18·7%; two-dose 13·4%), and the confidence interval around the difference included values substantially greater than 5%. There was however a reduction in prevalence among those who had been present at the baseline assessment (one-dose 15·9%; two-dose 10·8%). Additionally, we found a reduction in both scabies severity and impetigo prevalence in both arms, to a similar degree. CONCLUSIONS: There was no indication of an overall decline in scabies prevalence in either arm. The reduction in scabies prevalence in those present at baseline suggests that the unexpectedly high influx of people into the trial villages, likely related to the COVID-19 pandemic, may have compromised the effectiveness of the MDA. Despite the lack of effect there are important lessons to be learnt from this trial about conducting MDA for scabies in high prevalence settings. TRIAL REGISTRATION: Registered with Australian New Zealand Clinical Trials Registry ACTRN12618001086257.

Paediatric admissions with SARS-CoV-2 during the Delta and Omicron waves: an Australian single-centre retrospective study.

BACKGROUND: The clinical course of Australian children admitted to hospital with COVID-19 infection is not well understood, particularly over the Omicron period. METHODS: This study describes paediatric admissions to a single tertiary paediatric institution through the Delta and Omicron variant waves. All children admitted from 1 June 2021 to 30 September 2022 with a diagnosis of COVID-19 infection were included for analysis. RESULTS: 117 patients were admitted during the Delta wave compared with 737 during the Omicron wave. The median length of stay was 3.3 days (IQR 1.7-6.75.1) during Delta, compared with 2.1 days (IQR 1.1-4.53.4) during Omicron (p<0.01). 83 patients (9.7%) required intensive care unit (ICU) admission, a greater proportion during Delta (20, 17.1%) than Omicron (63, 8.6%, p<0.01). Patients admitted to the ICU were less likely to have received a dose of COVID-19 vaccination prior to admission than patients admitted to the ward (8, 24.2% vs 154, 45.8%, p=0.028). CONCLUSION: The Omicron wave resulted in an absolute increase in the number of children compared with Delta, but cases had lower severity, demonstrated by shorter length of stay and a smaller proportion of patients requiring intensive care. This is consistent with US and UK data describing a similar pattern.

Comparison of antibody responses to SARS-CoV-2 variants in Australian children.

There is limited understanding of antibody responses in children across different SARS-CoV-2 variants. As part of an ongoing household cohort study, we assessed the antibody response among unvaccinated children infected with Wuhan, Delta, or Omicron variants, as well as vaccinated children with breakthrough Omicron infection, using a SARS-CoV-2 S1-specific IgG assay and surrogate virus neutralization test (% inhibition). Most children infected with Delta (100%, 35/35) or Omicron (81.3%, 13/16) variants seroconverted by one month following infection. In contrast, 37.5% (21/56) children infected with Wuhan seroconverted, as previously reported. However, Omicron-infected children (geometric mean concentration 46.4 binding antibody units/ml; % inhibition = 16.3%) mounted a significantly lower antibody response than Delta (435.5 binding antibody untis/mL, % inhibition = 76.9%) or Wuhan (359.0 binding antibody units/mL, % inhibition = 74.0%). Vaccinated children with breakthrough Omicron infection mounted the highest antibody response (2856 binding antibody units/mL, % inhibition = 96.5%). Our findings suggest that despite a high seropositivity rate, Omicron infection in children results in lower antibody levels and function compared with Wuhan or Delta infection or with vaccinated children with breakthrough Omicron infection. Our data have important implications for public health measures and vaccination strategies to protect children.

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.

Secondary Antibiotic Prophylaxis for Latent Rheumatic Heart Disease.

BACKGROUND: Rheumatic heart disease affects more than 40.5 million people worldwide and results in 306,000 deaths annually. Echocardiographic screening detects rheumatic heart disease at an early, latent stage. Whether secondary antibiotic prophylaxis is effective in preventing progression of latent rheumatic heart disease is unknown. METHODS: We conducted a randomized, controlled trial of secondary antibiotic prophylaxis in Ugandan children and adolescents 5 to 17 years of age with latent rheumatic heart disease. Participants were randomly assigned to receive either injections of penicillin G benzathine (also known as benzathine benzylpenicillin) every 4 weeks for 2 years or no prophylaxis. All the participants underwent echocardiography at baseline and at 2 years after randomization. Changes from baseline were adjudicated by a panel whose members were unaware of the trial-group assignments. The primary outcome was echocardiographic progression of latent rheumatic heart disease at 2 years. RESULTS: Among 102,200 children and adolescents who had screening echocardiograms, 3327 were initially assessed as having latent rheumatic heart disease, and 926 of the 3327 subsequently received a definitive diagnosis on the basis of confirmatory echocardiography and were determined to be eligible for the trial. Consent or assent for participation was provided for 916 persons, and all underwent randomization; 818 participants were included in the modified intention-to-treat analysis, and 799 (97.7%) completed the trial. A total of 3 participants (0.8%) in the prophylaxis group had echocardiographic progression at 2 years, as compared with 33 (8.2%) in the control group (risk difference, -7.5 percentage points; 95% confidence interval, -10.2 to -4.7; P<0.001). Two participants in the prophylaxis group had serious adverse events that were attributable to receipt of prophylaxis, including one episode of a mild anaphylactic reaction (representing <0.1% of all administered doses of prophylaxis). CONCLUSIONS: Among children and adolescents 5 to 17 years of age with latent rheumatic heart disease, secondary antibiotic prophylaxis reduced the risk of disease progression at 2 years. Further research is needed before the implementation of population-level screening can be recommended. (Funded by the Thrasher Research Fund and others; GOAL ClinicalTrials.gov number, NCT03346525.).

Innovative vaccine approaches-a Keystone Symposia report.

The rapid development of COVID-19 vaccines was the result of decades of research to establish flexible vaccine platforms and understand pathogens with pandemic potential, as well as several novel changes to the vaccine discovery and development processes that partnered industry and governments. And while vaccines offer the potential to drastically improve global health, low-and-middle-income countries around the world often experience reduced access to vaccines and reduced vaccine efficacy. Addressing these issues will require novel vaccine approaches and platforms, deeper insight how vaccines mediate protection, and innovative trial designs and models. On June 28-30, 2021, experts in vaccine research, development, manufacturing, and deployment met virtually for the Keystone eSymposium "Innovative Vaccine Approaches" to discuss advances in vaccine research and development.

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.

Characteristics and outcomes of SARS-CoV-2 infection in Victorian children at a tertiary paediatric hospital.

AIM: Victoria experienced two 'waves' of COVID-19 between March and September 2020 and more cases than any other jurisdiction in Australia. Although world-wide reports of COVID-19 reflect that children are less likely to experience severe disease compared with adults, hospitalisations and deaths have been reported. We report testing and outcomes of children with SARS-CoV-2 infection presenting to a tertiary paediatric hospital in Melbourne. METHODS: We conducted a prospective cohort study at The Royal Children's Hospital (RCH), including all children and adolescents (aged 0-18 years) who presented and were tested for SARS-CoV-2 over a 6-month period, between 21 March 2020, up to the 21 September 2020. Detailed epidemiological and clinical data were recorded. RESULTS: A total of 19 708 tests for SARS-CoV-2 were performed in 14 419 patients. One hundred and eighty patients tested positive for SARS-CoV-2 (1.2%). 110 (61%) were symptomatic, 60 (33%) were asymptomatic and 10 (6%) were pre-symptomatic. Close contacts of a positive case were associated with a higher risk of a testing positive for SARS-CoV-2 (120/2027 (6%) vs. 60/14589 (0.4%), RD 5.5 (95% CI 4.5 to 6.5), P < 0.001). Eighteen (10%) SARS-CoV-2-positive patients were admitted to hospital with one patient requiring intensive care. All patients recovered fully with no deaths. CONCLUSION: In Victorian children presenting to a tertiary hospital, SARS-CoV-2 infection caused predominantly mild or asymptomatic infection, with most children not requiring hospitalisation.

Persistence of SARS-CoV-2-Specific IgG in Children 6 Months After Infection, Australia.

The duration of the humoral immune response in children infected with severe acute respiratory syndrome coronavirus 2 is unknown. We detected specific IgG 6 months after infection in children who were asymptomatic or had mild symptoms of coronavirus disease. These findings will inform vaccination strategies and other prevention measures.

Innate cell profiles during the acute and convalescent phase of SARS-CoV-2 infection in children.

Children have mild severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) confirmed disease (COVID-19) compared to adults and the immunological mechanisms underlying this difference remain unclear. Here, we report acute and convalescent innate immune responses in 48 children and 70 adults infected with, or exposed to, SARS-CoV-2. We find clinically mild SARS-CoV-2 infection in children is characterised by reduced circulating subsets of monocytes (classical, intermediate, non-classical), dendritic cells and natural killer cells during the acute phase. In contrast, SARS-CoV-2-infected adults show reduced proportions of non-classical monocytes only. We also observe increased proportions of CD63+ activated neutrophils during the acute phase to SARS-CoV-2 in infected children. Children and adults exposed to SARS-CoV-2 but negative on PCR testing display increased proportions of low-density neutrophils that we observe up to 7 weeks post exposure. This study characterises the innate immune response during SARS-CoV-2 infection and household exposure in children.

SARS-CoV-2 testing and outcomes in the first 30 days after the first case of COVID-19 at an Australian children's hospital.

OBJECTIVE: International studies describing COVID-19 in children have shown low proportions of paediatric cases and generally a mild clinical course. We aimed to present early data on children tested for SARS-CoV-2 at a large Australian tertiary children's hospital according to the state health department guidelines, which varied over time. METHODS: We conducted a retrospective cohort study at The Royal Children's Hospital, Melbourne, Australia. It included all paediatric patients (aged 0-18 years) who presented to the ED or the Respiratory Infection Clinic (RIC) and were tested for SARS-CoV-2. The 30-day study period commenced after the first confirmed positive case was detected at the hospital on 21 March 2020, until 19 April 2020. We recorded epidemiological and clinical data. RESULTS: There were 433 patients in whom SARS-CoV-2 testing was performed in ED (331 [76%]) or RIC (102 [24%]). There were four (0.9%) who had positive SARS-CoV-2 detected, none of whom were admitted to hospital or developed severe disease. Of these SARS-CoV-2 positive patients, 1/4 (25%) had a comorbidity, which was asthma. Of the SARS-CoV-2 negative patients, 196/429 (46%) had comorbidities. Risk factors for COVID-19 were identified in 4/4 SARS-CoV-2 positive patients and 47/429 (11%) SARS-CoV-2 negative patients. CONCLUSION: Our study identified a very low rate of SARS-CoV-2 positive cases in children presenting to a tertiary ED or RIC, none of whom were admitted to hospital. A high proportion of patients who were SARS-CoV-2 negative had comorbidities.