Author
Thomas C. Luke
Other affiliations: Silver Spring Networks, Henry M. Jackson Foundation for the Advancement of Military Medicine, Bureau of Medicine and Surgery ...read more
Bio: Thomas C. Luke is an academic researcher from Naval Medical Research Center. The author has contributed to research in topics: Antibody & Virus. The author has an hindex of 17, co-authored 35 publications receiving 2860 citations. Previous affiliations of Thomas C. Luke include Silver Spring Networks & Henry M. Jackson Foundation for the Advancement of Military Medicine.
Topics: Antibody, Virus, Hyperimmunization, Medicine, Neutralization
Papers
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TL;DR: These results expand published findings demonstrating that immunization by exposure to thousands of mosquitoes carrying radiation-attenuated Pf sporozoites is safe and well tolerated and elicits strain-transcendent protective immunity that persists for at least 42 weeks.
Abstract: During 1989-1999, 11 volunteers were immunized by the bites of 1001-2927 irradiated mosquitoes harboring infectious sporozoites of Plasmodium falciparum (Pf) strain NF54 or clone 3D7/NF54. Ten volunteers were first challenged by the bites of Pf-infected mosquitoes 2-9 weeks after the last immunization, and all were protected. A volunteer challenged 10 weeks after the last immunization was not protected. Five previously protected volunteers were rechallenged 23-42 weeks after a secondary immunization, and 4 were protected. Two volunteers were protected when rechallenged with a heterologous Pf strain (7G8). In total, there was protection in 24 of 26 challenges. These results expand published findings demonstrating that immunization by exposure to thousands of mosquitoes carrying radiation-attenuated Pf sporozoites is safe and well tolerated and elicits strain-transcendent protective immunity that persists for at least 42 weeks.
722 citations
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TL;DR: A review of 8 controlled studies published in English-language medical literature between 1918 to 1925 found that transfusion with influenza-convalescent human blood products may have reduced ri... as discussed by the authors.
Abstract: This review of 8 controlled studies published in English-language medical literature between 1918 to 1925 found that transfusion with influenza-convalescent human blood products may have reduced ri...
515 citations
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TL;DR: To assess the potential treatment efficacy of convalescent plasma in reducing mortality in current patients with H5N1 influenza, a review of studies from the Spanish influenza era that used influenza-convalescent human blood products to treat patients with Spanish influenza complicated by pneumonia was conducted.
Abstract: Background: Studies from the Spanish influenza era reported that transfusion of influenza-convalescent human blood products reduced mortality in patients with influenza complicated by pneumonia. Treatments for H5N1 influenza are unsatisfactory, and convalescent human plasma containing H5N1 antibodies could be an effective therapy during outbreaks and pandemics. Purpose: To determine whether transfusion with influenza-convalescent human blood products reduced the risk for death in patients with Spanish influenza pneumonia. Data Sources: Manual search of English-language journals from 1918 to 1925. Citations from retrieved studies were also searched. Study Selection: Published English-language studies that had at least 10 patients in the treatment group, used convalescent blood products to treat Spanish influenza pneumonia in a hospital setting, and reported on a control or comparison group. Data Extraction: Two investigators independently extracted data on study characteristics, outcomes, adverse events, and quality. Data Synthesis: Eight relevant studies involving 1703 patients were found. Treated patients, who were often selected because of more severe illness, were compared with untreated controls with influenza pneumonia in the same hospital or ward. The overall crude case-fatality rate was 16% (54 of 336) among treated patients and 37% (452 of 1219) among controls. The range of absolute risk differences in mortality between the treatment and control groups was 8% to 26% (pooled risk difference, 21% [95% Cl, 15% to 27%]). The overall crude case-fatality rate was 19% (28 of 148) among patients who received early treatment (after <4 days of pneumonia complications) and 59% (49 of 83) among patients who received late treatment (after ≥4 days of pneumonia complications). The range of absolute risk differences in mortality between the early treatment group and the late treatment group was 26% to 50% (pooled risk difference, 41 % [Cl, 29% to 54%]). Adverse effects included chill reactions and possible exacerbations of symptoms in a few patients. Limitations: Studies were few and had many methodologic limitations. No study was a blinded, randomized, or placebo-controlled trial. Some pertinent studies may have been missed. Conclusions: Patients with Spanish influenza pneumonia who received influenza-convalescent human blood products may have experienced a clinically important reduction in the risk for death. Convalescent human H5N1 plasma could be an effective, timely, and widely available treatment that should be studied in clinical trials.
402 citations
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TL;DR: By producing a vaccine for travelers, Sanaria will provide the infrastructure, regulatory foundation and funds necessary to speed licensure, manufacturing and deployment of the vaccine for the infants and children who need it most.
Abstract: SUMMARY Annually, malaria causes >300 million clinical cases and 1 million
deaths, is responsible for the loss of >1% of gross domestic product (GDP)
in Africa and is a serious concern for travelers. An effective vaccine could
have a dramatic impact on the disease. For 20 years, scientists have tried to
develop modern, recombinant `subunit9 malaria vaccines. This has been
difficult. In fact, there is only one recombinant protein vaccine on the
market for any disease, and no vaccines based on synthetic peptides,
recombinant viruses, recombinant bacteria or DNA plasmids. Most vaccines are
based on attenuated or inactivated whole pathogens or material derived
directly from the infectious agent. It is in that context that our recent
report summarizing the protection of humans with attenuated Plasmodium
falciparum ( Pf ) sporozoites produced at four different sites
over 25 years is important. In studies utilizing live mosquitoes as the
vaccine delivery mechanism, there was complete protection against malaria in
93% of volunteers (13/14) and 94% of challenges (33/35). Sanaria9s goal is to
develop and commercialize a non-replicating, metabolically active Pf
sporozoite vaccine. Three practical questions must be addressed before manufacturing for
clinical trials: (1) can one administer the vaccine by a route that is
clinically practical; (2) can one produce adequate quantities of sporozoites;
and (3) can sporozoites be produced with the physical characteristics that
meet the regulatory, potency and safety requirements of regulatory
authorities? Once these questions have been answered, Sanaria will demonstrate
that the vaccine protects >90% of human recipients against experimental
challenge with Pf sporozoites, can be produced with an efficiency
that makes it economically feasible, and protects >90% of African infants
and children from infection, and thus from severe morbidity and mortality. By
producing a vaccine for travelers, Sanaria will provide the infrastructure,
regulatory foundation and funds necessary to speed licensure, manufacturing
and deployment of the vaccine for the infants and children who need it
most.
250 citations
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TL;DR: Efficacy testing will be challenging because of the small pool of donors with sufficiently high antibody titers.
Abstract: We explored the feasibility of collecting convalescent plasma for passive immunotherapy of Middle East respiratory syndrome coronavirus (MERS-CoV) infection by using ELISA to screen serum samples from 443 potential plasma donors: 196 patients with suspected or laboratory-confirmed MERS-CoV infection, 230 healthcare workers, and 17 household contacts exposed to MERS-CoV. ELISA-reactive samples were further tested by indirect fluorescent antibody and microneutralization assays. Of the 443 tested samples, 12 (2.7%) had a reactive ELISA result, and 9 of the 12 had reactive indirect fluorescent antibody and microneutralization assay titers. Undertaking clinical trials of convalescent plasma for passive immunotherapy of MERS-CoV infection may be feasible, but such trials would be challenging because of the small pool of potential donors with sufficiently high antibody titers. Alternative strategies to identify convalescent plasma donors with adequate antibody titers should be explored, including the sampling of serum from patients with more severe disease and sampling at earlier points during illness.
198 citations
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TL;DR: The interaction of SARS-CoV-2 with the immune system and the subsequent contribution of dysfunctional immune responses to disease progression is described and the implications of these approaches for potential therapeutic interventions that target viral infection and/or immunoregulation are highlighted.
Abstract: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of the ongoing coronavirus disease 2019 (COVID-19) pandemic. Alongside investigations into the virology of SARS-CoV-2, understanding the fundamental physiological and immunological processes underlying the clinical manifestations of COVID-19 is vital for the identification and rational design of effective therapies. Here, we provide an overview of the pathophysiology of SARS-CoV-2 infection. We describe the interaction of SARS-CoV-2 with the immune system and the subsequent contribution of dysfunctional immune responses to disease progression. From nascent reports describing SARS-CoV-2, we make inferences on the basis of the parallel pathophysiological and immunological features of the other human coronaviruses targeting the lower respiratory tract - severe acute respiratory syndrome coronavirus (SARS-CoV) and Middle East respiratory syndrome coronavirus (MERS-CoV). Finally, we highlight the implications of these approaches for potential therapeutic interventions that target viral infection and/or immunoregulation.
3,236 citations
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TL;DR: The emergence of Middle East respiratory syndrome coronavirus (MERS-CoV) in 2012 marked the second introduction of a highly pathogenic coronav virus into the human population in the twenty-first century, and the current state of development of measures to combat emerging coronaviruses is discussed.
Abstract: The emergence of Middle East respiratory syndrome coronavirus (MERS-CoV) in 2012 marked the second introduction of a highly pathogenic coronavirus into the human population in the twenty-first century. The continuing introductions of MERS-CoV from dromedary camels, the subsequent travel-related viral spread, the unprecedented nosocomial outbreaks and the high case-fatality rates highlight the need for prophylactic and therapeutic measures. Scientific advancements since the 2002-2003 severe acute respiratory syndrome coronavirus (SARS-CoV) pandemic allowed for rapid progress in our understanding of the epidemiology and pathogenesis of MERS-CoV and the development of therapeutics. In this Review, we detail our present understanding of the transmission and pathogenesis of SARS-CoV and MERS-CoV, and discuss the current state of development of measures to combat emerging coronaviruses.
2,794 citations
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TL;DR: The COVID-19 pandemic represents the greatest global public health crisis of this generation and, potentially, since the pandemic influenza outbreak of 1918 and both the need and capability to produce high-quality evidence even in the middle of a pandemic.
Abstract: Importance The pandemic of coronavirus disease 2019 (COVID-19) caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) presents an unprecedented challenge to identify effective drugs for prevention and treatment. Given the rapid pace of scientific discovery and clinical data generated by the large number of people rapidly infected by SARS-CoV-2, clinicians need accurate evidence regarding effective medical treatments for this infection. Observations No proven effective therapies for this virus currently exist. The rapidly expanding knowledge regarding SARS-CoV-2 virology provides a significant number of potential drug targets. The most promising therapy is remdesivir. Remdesivir has potent in vitro activity against SARS-CoV-2, but it is not US Food and Drug Administration approved and currently is being tested in ongoing randomized trials. Oseltamivir has not been shown to have efficacy, and corticosteroids are currently not recommended. Current clinical evidence does not support stopping angiotensin-converting enzyme inhibitors or angiotensin receptor blockers in patients with COVID-19. Conclusions and Relevance The COVID-19 pandemic represents the greatest global public health crisis of this generation and, potentially, since the pandemic influenza outbreak of 1918. The speed and volume of clinical trials launched to investigate potential therapies for COVID-19 highlight both the need and capability to produce high-quality evidence even in the middle of a pandemic. No therapies have been shown effective to date.
2,143 citations
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McMaster University1, Copenhagen University Hospital2, King Saud bin Abdulaziz University for Health Sciences3, Albert Einstein College of Medicine4, University of Toronto5, Brown University6, Rhode Island Hospital7, Utrecht University8, Oklahoma State University Center for Health Sciences9, NewYork–Presbyterian Hospital10, Peking Union Medical College Hospital11, Sunnybrook Health Sciences Centre12, Humanitas University13, University of Ulsan14, National Institutes of Health15, Imperial College London16, United Arab Emirates University17, Population Health Research Institute18, St George’s University Hospitals NHS Foundation Trust19, Emory University Hospital20, University at Buffalo21, Baylor College of Medicine22, University of Milano-Bicocca23, King Abdulaziz Medical City24, King Saud Medical City25, Royal North Shore Hospital26, The George Institute for Global Health27, University of Virginia28, University of Washington29
TL;DR: The Surviving Sepsis Campaign CO VID-19 panel issued several recommendations to help support healthcare workers caring for critically ill ICU patients with COVID-19, and will provide new recommendations in further releases of these guidelines.
Abstract: The novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the cause of a rapidly spreading illness, Coronavirus Disease 2019 (COVID-19), affecting thousands of people around the world. Urgent guidance for clinicians caring for the sickest of these patients is needed.
We formed a panel of 36 experts from 12 countries. All panel members completed the World Health Organization conflict of interest disclosure form. The panel proposed 53 questions that are relevant to the management of COVID-19 in the ICU. We searched the literature for direct and indirect evidence on the management of COVID-19 in critically ill patients in the ICU. We identified relevant and recent systematic reviews on most questions relating to supportive care. We assessed the certainty in the evidence using the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach, then generated recommendations based on the balance between benefit and harm, resource and cost implications, equity, and feasibility. Recommendations were either strong or weak, or in the form of best practice recommendations.
The Surviving Sepsis Campaign COVID-19 panel issued 54 statements, of which 4 are best practice statements, 9 are strong recommendations, and 35 are weak recommendations. No recommendation was provided for 6 questions. The topics were: (1) infection control, (2) laboratory diagnosis and specimens, (3) hemodynamic support, (4) ventilatory support, and (5) COVID-19 therapy.
The Surviving Sepsis Campaign COVID-19 panel issued several recommendations to help support healthcare workers caring for critically ill ICU patients with COVID-19. When available, we will provide new recommendations in further releases of these guidelines.
1,762 citations
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TL;DR: CP therapy was well tolerated and could potentially improve the clinical outcomes through neutralizing viremia in severe COVID-19 cases and the optimal dose and time point, as well as the clinical benefit of CP therapy, needs further investigation in larger well-controlled trials.
Abstract: Currently, there are no approved specific antiviral agents for novel coronavirus disease 2019 (COVID-19). In this study, 10 severe patients confirmed by real-time viral RNA test were enrolled prospectively. One dose of 200 mL of convalescent plasma (CP) derived from recently recovered donors with the neutralizing antibody titers above 1:640 was transfused to the patients as an addition to maximal supportive care and antiviral agents. The primary endpoint was the safety of CP transfusion. The second endpoints were the improvement of clinical symptoms and laboratory parameters within 3 d after CP transfusion. The median time from onset of illness to CP transfusion was 16.5 d. After CP transfusion, the level of neutralizing antibody increased rapidly up to 1:640 in five cases, while that of the other four cases maintained at a high level (1:640). The clinical symptoms were significantly improved along with increase of oxyhemoglobin saturation within 3 d. Several parameters tended to improve as compared to pretransfusion, including increased lymphocyte counts (0.65 × 109/L vs. 0.76 × 109/L) and decreased C-reactive protein (55.98 mg/L vs. 18.13 mg/L). Radiological examinations showed varying degrees of absorption of lung lesions within 7 d. The viral load was undetectable after transfusion in seven patients who had previous viremia. No severe adverse effects were observed. This study showed CP therapy was well tolerated and could potentially improve the clinical outcomes through neutralizing viremia in severe COVID-19 cases. The optimal dose and time point, as well as the clinical benefit of CP therapy, needs further investigation in larger well-controlled trials.
1,645 citations