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Coronavirus disease 2019 (COVID-19) epidemiology and product landscapes have changed considerably since onset of the pandemic. Safe and effective vaccines and therapeutics are available, but the continual emergence of severe acute respiratory syndrome coronavirus 2 variants introduce limitations in our ability to prevent and treat disease. Project NextGen is a collaboration between the Biomedical Advanced Research and Development Authority, part of the Administration for Strategic Preparedness and Response, and the National Institute of Allergy and Infectious Diseases, part of the National Institutes of Health, that is leveraging public-private partnerships to address gaps in the nation's COVID-19 vaccine and therapeutic capabilities. Targeted investments will advance promising next-generation candidates through the most difficult phases of clinical development to encourage further private sector interest for later stage development and commercial availability. New commercial vaccines and therapeutics that are more durable and effective across variants will improve our fight against COVID-19 and transform our response to future threats.
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Vacinas contra COVID-19 , COVID-19 , Parcerias Público-Privadas , SARS-CoV-2 , Humanos , COVID-19/prevenção & controle , COVID-19/epidemiologia , SARS-CoV-2/imunologia , Estados Unidos , Desenvolvimento de Vacinas , Tratamento Farmacológico da COVID-19 , Antivirais/uso terapêutico , Desenvolvimento de Medicamentos/tendências , Pandemias/prevenção & controleRESUMO
Effective antivirals provide crucial benefits during the early phase of an influenza pandemic, when vaccines are still being developed and manufactured. Currently, two classes of viral protein-targeting drugs, neuraminidase inhibitors and polymerase inhibitors, are approved for influenza treatment and post-exposure prophylaxis. Resistance to both classes has been documented, highlighting the need to develop novel antiviral options that may include both viral and host-targeted inhibitors. Such efforts will form the basis of management of seasonal influenza infections and of strategic planning for future influenza pandemics. This review focuses on the two classes of approved antivirals, their drawbacks, and ongoing work to characterize novel agents or combination therapy approaches to address these shortcomings. The importance of these topics in the ongoing process of influenza pandemic planning is also discussed.
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Antivirais , Influenza Humana , Humanos , Antivirais/farmacologia , Antivirais/uso terapêutico , Farmacorresistência Viral , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/uso terapêutico , Influenza Humana/tratamento farmacológico , Influenza Humana/epidemiologia , Influenza Humana/prevenção & controle , Neuraminidase/antagonistas & inibidores , Oseltamivir/farmacologia , Pandemias/prevenção & controleRESUMO
Host-directed therapeutics targeting immune dysregulation are considered the most promising approach to address the unmet clinical need for acute lung injury (ALI)/acute respiratory distress syndrome (ARDS) related to coronavirus disease 2019 (COVID-19). To better understand the current clinical study landscape and gaps in treating hospitalized patients with severe or critical COVID-19, we identified COVID-19 trials developing host-directed therapies registered at ClinicalTrials.gov and discussed the factors contributing to the success vs failure of these studies. We have learned, instead of the one-size-fits-all approach, future clinical trials evaluating a targeted immunomodulatory agent in heterogeneous patients with ALI/ARDS due to COVID-19 or other infectious diseases can use immune-based biomarkers in addition to clinical and demographic characteristics to improve patient stratification and inform clinical decision-making. Identifying distinct patient subgroups based on immune profiles across the disease trajectory, regardless of the causative pathogen, may accelerate evaluating host-directed therapeutics in trials of ALI/ARDS and related conditions (eg, sepsis).
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BACKGROUND: Since 1999, the US Food and Drug Administration approved neuraminidase and endonuclease inhibitors to treat uncomplicated outpatient influenza but not severe hospitalized influenza. After the 2009 pandemic, several influenza hospital-based clinical therapeutic trials were unsuccessful, possibly due to certain study factors. Therefore, in 2014, the US Health and Human Services agencies formed a Working Group (WG) to address related clinical challenges. METHODS: Starting in 2014, the WG obtained retrospective data from failed hospital-based influenza therapeutic trials and nontherapeutic hospital-based influenza studies. These data allowed the WG to identify factors that might improve hospital-based therapeutic trials. These included primary clinical endpoints, increased clinical site enrollment, and appropriate baseline enrollment criteria. RESULTS: During 2018, the WG received retrospective data from a National Institutes of Health hospital-based influenza therapeutic trial that demonstrated time to resolution of respiratory status, which was not a satisfactory primary endpoint. The WG statisticians examined these data and believed that ordinal outcomes might be a more powerful primary endpoint. Johns Hopkins' researchers provided WG data from an emergency-department (ED) triage study to identify patients with confirmed influenza using molecular testing. During the 2013-2014 influenza season, 4 EDs identified 1074 influenza-patients, which suggested that triage testing should increase enrollment by hospital-based clinical trial sites. In 2017, the WG received data from Northwestern Memorial Hospital researchers regarding 703 influenza inpatients over 5 seasons. The WG applied National Early Warning Score (NEWS) at patient baseline to identify appropriate criteria to enroll patients into hospital-based therapeutic trials. CONCLUSIONS: Data received by the WG indicated that hospital-based influenza therapeutic trials could use ordinal outcome analyses, ED triage to identify influenza patients, and NEWS for enrollment criteria.
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Background: For most classes of drugs, rapid development of therapeutics to treat emerging infections is challenged by the timelines needed to identify compounds with the desired efficacy, safety, and pharmacokinetic profiles. Fully human monoclonal antibodies (mAbs) provide an attractive method to overcome many of these hurdles to rapidly produce therapeutics for emerging diseases. Methods: In this study, we deployed a platform to generate, test, and develop fully human antibodies to Zaire ebolavirus. We obtained specific anti-Ebola virus (EBOV) antibodies by immunizing VelocImmune mice that use human immunoglobulin variable regions in their humoral responses. Results: Of the antibody clones isolated, 3 were selected as best at neutralizing EBOV and triggering FcγRIIIa. Binding studies and negative-stain electron microscopy revealed that the 3 selected antibodies bind to non-overlapping epitopes, including a potentially new protective epitope not targeted by other antibody-based treatments. When combined, a single dose of a cocktail of the 3 antibodies protected nonhuman primates (NHPs) from EBOV disease even after disease symptoms were apparent. Conclusions: This antibody cocktail provides complementary mechanisms of actions, incorporates novel specificities, and demonstrates high-level postexposure protection from lethal EBOV disease in NHPs. It is now undergoing testing in normal healthy volunteers in preparation for potential use in future Ebola epidemics.
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Anticorpos Monoclonais/uso terapêutico , Anticorpos Neutralizantes/uso terapêutico , Anticorpos Antivirais/uso terapêutico , Doença pelo Vírus Ebola/tratamento farmacológico , Animais , Anticorpos Monoclonais/isolamento & purificação , Glicoproteínas/imunologia , Cobaias , Células HEK293 , Humanos , Macaca mulatta , Masculino , CamundongosRESUMO
It has been suggested that enhanced perceptual processing underlies some of the social difficulties associated with autism spectrum disorder (ASD). While a variety of visual tasks have been reported in which individuals with ASD outperform neurotypical individuals in control groups, the precise origin of such effects within the visual pathway remains unclear. It has recently been established that visual acuity is intact yet unremarkable in ASD. This suggests that the earliest levels of retinal processing are an unlikely candidate as the source of differences. The next potential levels for divergent visual processing are those involved in processing simple aspects of visual stimuli, such as orientation and spatial frequency, considered to be functions of early visual cortex. Here we focused on the basic processing of orientation. In three experiments, we assessed three basic aspects of orientation processing-discrimination, veridical perception, and detection-in participants with ASD in comparison to age-, gender-, and IQ-matched adults without ASD. Each experiment allowed for both qualitative and quantitative comparisons between the two groups. These provided a dense array of data indicating that participants with ASD perceive orientation of low-level stimuli in a qualitatively (as well as quantitatively) similar manner to participants without ASD in control groups, with no evidence of superior processing in detection, precision, or accuracy aspects of orientation perception. These results suggest that the source for altered perceptual abilities should be sought elsewhere, possibly in specific subgroups of people with ASD, other aspects of low-level vision such as spatial frequency, or subsequent levels of visual processing.
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Transtorno do Espectro Autista/fisiopatologia , Orientação , Córtex Visual/fisiopatologia , Percepção Visual/fisiologia , Adulto , Transtornos Globais do Desenvolvimento Infantil/fisiopatologia , Feminino , Humanos , Masculino , Baixa Visão/fisiopatologia , Acuidade Visual , Vias Visuais/fisiopatologia , Adulto JovemRESUMO
Visual-spatial strengths observed among people with autism spectrum disorder (ASD) may be associated with increased efficiency of selective attention mechanisms such as visual search. In a series of studies, researchers examined the visual search of targets that share features with distractors in a visual array and concluded that people with ASD showed enhanced performance on visual search tasks. However, methodological limitations, the small sample sizes, and the lack of developmental analysis have tempered the interpretations of these results. In this study, we specifically addressed age-related changes in visual search. We examined conjunctive visual search in groups of children with (n = 34) and without ASD (n = 35) at 7-9 years of age when visual search performance is beginning to improve, and later, at 10-12 years, when performance has improved. The results were consistent with previous developmental findings; 10- to 12-year-old children were significantly faster visual searchers than their 7- to 9-year-old counterparts. However, we found no evidence of enhanced search performance among the children with ASD at either the younger or older ages. More research is needed to understand the development of visual search in both children with and without ASD.
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Atenção , Transtornos Globais do Desenvolvimento Infantil/diagnóstico , Reconhecimento Visual de Modelos , Fatores Etários , Criança , Percepção de Cores , Estudos Transversais , Aprendizagem por Discriminação , Feminino , Humanos , Masculino , Tempo de ReaçãoRESUMO
BACKGROUND: The measurement of head circumference (HC) is widely used in clinical and research settings as a proxy of neural growth. Although it could aid data collection, no studies have explored either the reliability of adult self-measurements or parental measurements of young children. This study therefore aimed to examine whether adult self and parental measurement of HC constitute reliable data. FINDINGS: A total of 57 adults (32 male) were asked to measure their HC twice following written instructions (adult self-measurement). These measures were compared to those of a researcher independently measuring the same participant's HC twice. Additionally, mothers of 25 children (17 male) were also asked to measure their child's HC (parental measure), and again this was compared to researcher measurements of the child's HC. The intraclass correlation coefficient between adult self- and researcher measurement was 0.84 and between parent and researcher measurement was 0.99. The technical error of measurement was also acceptable, within the range of a skilled anthropometrist. CONCLUSIONS: The high degree of agreement between researcher and adult self-measurement/parental measurement of HC demonstrates that these different assessors produce similarly reliable and reproducible data. This suggests adult self- and parental measurements can reliably be used for data collection to enable valid large-scale developmental and clinical studies of HC.
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The Autism Spectrum Quotient (AQ) is widely used to measure autism spectrum disorder (ASD) symptoms and screen for ASD. It is readily available free of charge online and is easily accessible to practitioners, researchers and individuals who suspect that they may have an ASD. Thus, the AQ is a potentially useful, widely accessible tool for ASD screening. The objective of this study was to examine the convergent validity of the AQ using a well-established, published screening measure of autism: the Social Responsiveness Scale (SRS). Twenty-three high-functioning participants (aged 8-19) with ASD were administered both measures. Results indicated a significant correlation between the SRS and AQ ratings, providing evidence for convergent validity of the AQ with the SRS.
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Transtornos Globais do Desenvolvimento Infantil/diagnóstico , Transtornos Globais do Desenvolvimento Infantil/psicologia , Relações Interpessoais , Comportamento Social , Adolescente , Criança , Feminino , Humanos , Masculino , Escalas de Graduação Psiquiátrica , Psicometria , Inquéritos e Questionários , Adulto JovemRESUMO
Single-dose nevirapine (NVP) is quite effective in preventing transmission of the human immunodeficiency virus (HIV) from mother to child; however, many women develop resistance to NVP in this setting. Comparing outcomes of clinical studies reveals an increased amount of resistance in subtype C relative to that in other subtypes. This study investigates how nonnucleoside reverse transcriptase inhibitor (NNRTI) drug resistance mutations of subtype C affect replication capacity. The 103N, 106A, 106M, 181C, 188C, 188L, and 190A drug resistance mutations were placed in a reverse transcriptase (RT) that matches the consensus subtype C sequence as well as the HXB2 RT, as a subtype B reference. The replicative fitness of each mutant was compared with that of the wild type in a head-to-head competition assay. The 106A mutant of subtype C would not grow in the competition assay, making it the weakest virus tested. The effect of the 106M mutation was weaker than those of the 181C and 188C mutations in the consensus C RT, but in subtype B, this difference was not seen. To see if the 106A mutation in a different subtype C background would have a different replicative profile, the same NNRTI resistance mutations were added to the MJ4 RT, a reference subtype C molecular clone. In the context of MJ4 RT, the 106A mutant was not the only mutant that showed poor replicative fitness; the 106M, 188C, and 190A mutants also failed to replicate. These results suggest that NNRTIs may be a cost-effective alternative for salvage therapy if deleterious mutations are present in a subtype C setting.
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HIV/efeitos dos fármacos , HIV/genética , Inibidores da Transcriptase Reversa/farmacologia , Linhagem Celular , Farmacorresistência Viral/genética , Humanos , Mutagênese , Mutação , Reação em Cadeia da Polimerase , Replicação Viral/efeitos dos fármacos , Replicação Viral/genéticaRESUMO
In order to understand the impact of zidovudine resistance and thymidine analog mutations (TAMs) on subtype C human immunodeficiency virus type 1, we created mutants in subtype C reverse transcriptase (RT). The subtype B RT was placed in a subtype C backbone to act as a control. Mutants and wild-type (WT) virus were competed in a head-to-head competition assay to determine how different clones grew in the same culture. Different viruses were distinguished by sequence tags in nef and a quantitative-PCR assay. The 67N and 70R accessory mutations gave an advantage over the WT in subtype C, but these mutations in subtype B had replication capacities similar to that of the WT. Of the triple mutants examined, the TAM-1 types, 41L210W215Y, were the most fit in both subtypes, but only in subtype C was the replication capacity the same as that of the WT. The TAM-2 mutants, 67N70R215F, had the slowest replication in both clones. The mixed TAM pathway mutant, 67N70R215Y, in subtype C had a significant advantage over the TAM-2 mutant, but this was not seen in subtype B. When the WT viruses were competed with each other, the subtype B RT had enhanced replication relative to subtype C. The increased capacities of the 67N and 70R mutations may indicate that there will be greater transmitted resistance and persistence in a subtype C setting than what is known for subtype B.