Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the novel coronavirus that causes coronavirus disease 2019 (COVID-19), has caused substantial morbidity and mortality. Operation Warp ...Speed aims to accelerate the development of a safe and effective vaccine by early 2021. Multiple vaccine candidates with reassuring safety and efficacy profiles have advanced to phase 3 clinical trials in adults. The purpose of this review is to describe the burden of COVID-19 in children, to update pediatricians about adult COVID-19 vaccine clinical trials, to discuss the importance of COVID-19 vaccine trials in children and to instill confidence in the established vaccine development and licensure processes.
Children of all ages are at risk for SARS-CoV-2 infection and severe disease manifestations. Children are also susceptible to downstream effects of COVID-19, including social isolation and interruption in education. Developing a pediatric COVID-19 vaccine could prevent disease, mitigate downstream effects and enable children to re-engage in their world.
Children could benefit both directly and indirectly from vaccination. In light of the safety and immunogenicity results from recent adult COVID-19 vaccine clinical trials, children should have the opportunity to be included in clinical trials in parallel to ongoing adult phase 3 clinical trials in a manner that is careful, methodical and transparent.
Currently, the United States has the largest number of reported coronavirus disease 2019 (COVID-19) cases and deaths globally. Using a geographically diverse surveillance network, we describe risk ...factors for severe outcomes among adults hospitalized with COVID-19.
We analyzed data from 2491 adults hospitalized with laboratory-confirmed COVID-19 between 1 March-2 May 2020, as identified through the Coronavirus Disease 2019-Associated Hospitalization Surveillance Network, which comprises 154 acute-care hospitals in 74 counties in 13 states. We used multivariable analyses to assess associations between age, sex, race and ethnicity, and underlying conditions with intensive care unit (ICU) admission and in-hospital mortality.
The data show that 92% of patients had ≥1 underlying condition; 32% required ICU admission; 19% required invasive mechanical ventilation; and 17% died. Independent factors associated with ICU admission included ages 50-64, 65-74, 75-84, and ≥85 years versus 18-39 years (adjusted risk ratios aRRs, 1.53, 1.65, 1.84, and 1.43, respectively); male sex (aRR, 1.34); obesity (aRR, 1.31); immunosuppression (aRR, 1.29); and diabetes (aRR, 1.13). Independent factors associated with in-hospital mortality included ages 50-64, 65-74, 75-84, and ≥ 85 years versus 18-39 years (aRRs, 3.11, 5.77, 7.67, and 10.98, respectively); male sex (aRR, 1.30); immunosuppression (aRR, 1.39); renal disease (aRR, 1.33); chronic lung disease (aRR 1.31); cardiovascular disease (aRR, 1.28); neurologic disorders (aRR, 1.25); and diabetes (aRR, 1.19).
In-hospital mortality increased markedly with increasing age. Aggressive implementation of prevention strategies, including social distancing and rigorous hand hygiene, may benefit the population as a whole, as well as those at highest risk for COVID-19-related complications.
Summary Rotavirus causes gastroenteritis in almost all children by 5 years of age. Immunity to rotavirus is incomplete, with potential for recurrent infections occurring throughout life. Live ...rotavirus vaccines have been developed for the protection of children from severe wildtype rotavirus infections. Transmission of vaccine virus strains from vaccinated children to unvaccinated contacts harbours the potential for herd immunity, but also the risk of vaccine-derived disease in immunocompromised contacts. A review of rotavirus vaccine prelicensure studies shows that viral shedding and transmission were higher with the old tetravalent rhesus rotavirus vaccine than with the current human attenuated monovalent rotavirus vaccine and the pentavalent bovine-human reassortant vaccine. Immunocompromised contacts should be advised to avoid contact with stool from the immunised child if possible, particularly after the first vaccine dose for at least 14 days. Since the risk of vaccine transmission and subsequent vaccine-derived disease with the current vaccines is much less than the risk of wildtype rotavirus disease in immunocompromised contacts, vaccination should be encouraged.
Background The effects of pre-existing endemic human coronavirus (HCoV) immunity on SARS-CoV-2 serologic and clinical responses are incompletely understood. Objectives We sought to determine the ...effects of prior exposure to HCoV Betacoronavirus HKU1 spike protein on serologic responses to SARS-CoV-2 spike protein after intramuscular administration in mice. We also sought to understand the baseline seroprevalence of HKU1 spike antibodies in healthy children and to measure their correlation with SARS-CoV-2 binding and neutralizing antibodies in children hospitalized with acute coronavirus disease 2019 (COVID-19) or multisystem inflammatory syndrome (MIS-C). Methods Groups of 5 mice were injected intramuscularly with two doses of alum-adjuvanted HKU1 spike followed by SARS-CoV-2 spike; or the reciprocal regimen of SARS-Cov-2 spike followed by HKU1 spike. Sera collected 21 days following each injection was analyzed for IgG antibodies to HKU1 spike, SARS-CoV-2 spike, and SARS-CoV-2 neutralization. Sera from children hospitalized with acute COVID-19, MIS-C or healthy controls (n = 14 per group) were analyzed for these same antibodies. Results Mice primed with SARS-CoV-2 spike and boosted with HKU1 spike developed high titers of SARS-CoV-2 binding and neutralizing antibodies; however, mice primed with HKU1 spike and boosted with SARS-CoV-2 spike were unable to mount neutralizing antibodies to SARS-CoV-2. HKU1 spike antibodies were detected in all children with acute COVID-19, MIS-C, and healthy controls. Although children with MIS-C had significantly higher HKU1 spike titers than healthy children (GMT 37239 vs. 7551, P = 0.012), these titers correlated positively with both SARS-CoV-2 binding (r = 0.7577, P<0.001) and neutralizing (r = 0.6201, P = 0.001) antibodies. Conclusions Prior murine exposure to HKU1 spike protein completely impeded the development of neutralizing antibodies to SARS-CoV-2, consistent with original antigenic sin. In contrast, the presence of HKU1 spike IgG antibodies in children with acute COVID-19 or MIS-C was not associated with diminished neutralizing antibody responses to SARS-CoV-2.
Abstract
While adult clinical trials of coronavirus disease 2019 (COVID-19) vaccines have moved quickly into phase 3 clinical trials, clinical trials have not started in children in the United ...States. The direct COVID-19 impact upon children is greater than that observed for a number of other pathogens for which we now have effective pediatric vaccines. Additionally, the role of children in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) transmission has clearly been underappreciated. Carefully conducted phase 2 clinical trials can adequately address potential COVID-19 vaccine safety concerns. Delaying phase 2 vaccine clinical trials in children will delay our recovery from COVID-19 and unnecessarily prolong its impact upon children’s education, health, and emotional well-being, and equitable access to opportunities for development and social success. Given the potential direct and indirect benefits of pediatric vaccination, implementation of phase 2 clinical trials for COVID-19 vaccines should begin now.
While COVID-19 vaccines have moved quickly into adult Phase 3 clinical trials, clinical trials have not started in children in the US. Given potential direct and indirect benefits, implementation of pediatric COVID-19 Phase II vaccine clinical trials should begin now.
Most reverse transcription PCR protocols for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) include 2-3 targets for detection. We developed a triplex, real-time reverse transcription ...PCR for SARS-CoV-2 that maintained clinical performance compared with singleplex assays. This protocol could streamline detection and decrease reagent use during current high SARS-CoV-2 testing demands.
Central to modern neuroscientific theories of human intelligence is the notion that general intelligence depends on a primary brain region or network, engaging spatially localized (rather than ...global) neural representations. Recent findings in network neuroscience, however, challenge this assumption, providing evidence that general intelligence may depend on system‐wide network mechanisms, suggesting that local representations are necessary but not sufficient to account for the neural architecture of human intelligence. Despite the importance of this key theoretical distinction, prior research has not systematically investigated the role of local versus global neural representations in predicting general intelligence. We conducted a large‐scale connectome‐based predictive modeling study (N = 297), administering resting‐state fMRI and a comprehensive cognitive battery to evaluate the efficacy of modern neuroscientific theories of human intelligence, including spatially localized theories (Lateral Prefrontal Cortex Theory, Parieto‐Frontal Integration Theory, and Multiple Demand Theory) and recent global accounts (Process Overlap Theory and Network Neuroscience Theory). The results of our study demonstrate that general intelligence can be predicted by local functional connectivity profiles but is most robustly explained by global profiles of whole‐brain connectivity. Our findings further suggest that the improved efficacy of global theories is not reducible to a greater strength or number of connections, but instead results from considering both strong and weak connections that provide the basis for intelligence (as predicted by the Network Neuroscience Theory). Our results highlight the importance of considering local neural representations in the context of a global information‐processing architecture, suggesting future directions for theory‐driven research on system‐wide network mechanisms underlying general intelligence.
Recent evidence in network neuroscience indicates that general intelligence may depend on system‐wide network mechanisms, suggesting that the spatially localized predictions of standard theories may be necessary but not sufficient to account for the neural architecture of intelligence. To investigate this key theoretical issue, we directly compared the predictions of local versus global theories within a connectome‐based predictive modeling framework, demonstrating that general intelligence can be predicted by local functional connectivity profiles but is most accurately explained by global profiles of whole‐brain connectivity.
While the role of children in the transmission of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) remains to be defined, children likely play an important role based on our knowledge of ...other respiratory viruses. Children are more likely to be asymptomatic or have milder symptoms and less likely to present for healthcare and be tested for SARS-CoV-2. Thus, our current estimates are likely under-representative of the true burden of SARS-CoV-2 in children. Given the potential direct benefit of a SARS-CoV-2 vaccine in children and the substantial indirect benefit through community protection, or "herd immunity," we argue that planning and implementation of SARS-CoV-2 vaccines should include children. Furthermore, community protection occurred after widespread implementation of prior childhood vaccines against Streptococcus pneumoniae, rubella, and rotavirus. We detail considerations for vaccine clinical trials, potential barriers to the implementation of widespread vaccination and argue why children would be an ideal target population for vaccination.
Respiratory syncytial virus (RSV) is a major cause of respiratory tract infections in infants, young children, and older or immunocompromised adults. Although aerosolized ribavirin was licensed for ...RSV treatment on the basis of data demonstrating a reduced need for supplemental oxygen, ribavirin use is limited because of issues with efficacy, safety, and cost. Currently, the treatment of RSV is primarily supportive. New antiviral treatments for RSV are in the early stages of development, but it will be years until any of these may be licensed by the US Food and Drug Administration (FDA). Palivizumab, an RSV monoclonal antibody immunoprophylaxis (IP), has demonstrated effectiveness in disease prevention and is the only licensed IP for RSV disease in specific high-risk pediatric populations. Although its efficacy is well established, some challenges that may interfere with its clinical use include cost, need for monthly injections, and changing policy for use by the American Academy of Pediatrics (AAP). Preventing RSV disease would be possible through RSV vaccine development (e.g., live-attenuated, vector-based subunit, or particle-based). Alternatively, new long-acting monoclonal antibodies have demonstrated promising results in early clinical trials. Despite scientific advances, until new agents become available, palivizumab should continue to be used to reduce RSV disease burden in high-risk patients for whom it is indicated.
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