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1.
N Engl J Med ; 386(11): 1046-1057, 2022 03 17.
Artigo em Inglês | MEDLINE | ID: mdl-35081293

RESUMO

BACKGROUND: Although the three vaccines against coronavirus disease 2019 (Covid-19) that have received emergency use authorization in the United States are highly effective, breakthrough infections are occurring. Data are needed on the serial use of homologous boosters (same as the primary vaccine) and heterologous boosters (different from the primary vaccine) in fully vaccinated recipients. METHODS: In this phase 1-2, open-label clinical trial conducted at 10 sites in the United States, adults who had completed a Covid-19 vaccine regimen at least 12 weeks earlier and had no reported history of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection received a booster injection with one of three vaccines: mRNA-1273 (Moderna) at a dose of 100 µg, Ad26.COV2.S (Johnson & Johnson-Janssen) at a dose of 5×1010 virus particles, or BNT162b2 (Pfizer-BioNTech) at a dose of 30 µg. The primary end points were safety, reactogenicity, and humoral immunogenicity on trial days 15 and 29. RESULTS: Of the 458 participants who were enrolled in the trial, 154 received mRNA-1273, 150 received Ad26.COV2.S, and 153 received BNT162b2 as booster vaccines; 1 participant did not receive the assigned vaccine. Reactogenicity was similar to that reported for the primary series. More than half the recipients reported having injection-site pain, malaise, headache, or myalgia. For all combinations, antibody neutralizing titers against a SARS-CoV-2 D614G pseudovirus increased by a factor of 4 to 73, and binding titers increased by a factor of 5 to 55. Homologous boosters increased neutralizing antibody titers by a factor of 4 to 20, whereas heterologous boosters increased titers by a factor of 6 to 73. Spike-specific T-cell responses increased in all but the homologous Ad26.COV2.S-boosted subgroup. CD8+ T-cell levels were more durable in the Ad26.COV2.S-primed recipients, and heterologous boosting with the Ad26.COV2.S vaccine substantially increased spike-specific CD8+ T cells in the mRNA vaccine recipients. CONCLUSIONS: Homologous and heterologous booster vaccines had an acceptable safety profile and were immunogenic in adults who had completed a primary Covid-19 vaccine regimen at least 12 weeks earlier. (Funded by the National Institute of Allergy and Infectious Diseases; DMID 21-0012 ClinicalTrials.gov number, NCT04889209.).


Assuntos
Vacina de mRNA-1273 contra 2019-nCoV/imunologia , Ad26COVS1/imunologia , Anticorpos Neutralizantes/sangue , Anticorpos Antivirais/sangue , Vacina BNT162/imunologia , Vacinas contra COVID-19/imunologia , Imunogenicidade da Vacina , Adulto , Idoso , Idoso de 80 Anos ou mais , Vacinas contra COVID-19/efeitos adversos , Feminino , Humanos , Imunização Secundária/efeitos adversos , Injeções Intramusculares/efeitos adversos , Masculino , Pessoa de Meia-Idade , SARS-CoV-2/imunologia , Glicoproteína da Espícula de Coronavírus/imunologia , Linfócitos T/imunologia
3.
Clin Infect Dis ; 77(4): 560-564, 2023 08 22.
Artigo em Inglês | MEDLINE | ID: mdl-37036397

RESUMO

In a randomized clinical trial, we compare early neutralizing antibody responses after boosting with bivalent severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) messenger RNA (mRNA) vaccines based on either BA.1 or BA.4/BA.5 Omicron spike protein combined with wild-type spike. Responses against SARS-CoV-2 variants exhibited the greatest reduction in titers against currently circulating Omicron subvariants for both bivalent vaccines.


Assuntos
COVID-19 , Humanos , COVID-19/prevenção & controle , SARS-CoV-2/genética , Anticorpos Neutralizantes , Vacinas Combinadas , Anticorpos Antivirais
4.
N Engl J Med ; 383(20): 1920-1931, 2020 11 12.
Artigo em Inglês | MEDLINE | ID: mdl-32663912

RESUMO

BACKGROUND: The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged in late 2019 and spread globally, prompting an international effort to accelerate development of a vaccine. The candidate vaccine mRNA-1273 encodes the stabilized prefusion SARS-CoV-2 spike protein. METHODS: We conducted a phase 1, dose-escalation, open-label trial including 45 healthy adults, 18 to 55 years of age, who received two vaccinations, 28 days apart, with mRNA-1273 in a dose of 25 µg, 100 µg, or 250 µg. There were 15 participants in each dose group. RESULTS: After the first vaccination, antibody responses were higher with higher dose (day 29 enzyme-linked immunosorbent assay anti-S-2P antibody geometric mean titer [GMT], 40,227 in the 25-µg group, 109,209 in the 100-µg group, and 213,526 in the 250-µg group). After the second vaccination, the titers increased (day 57 GMT, 299,751, 782,719, and 1,192,154, respectively). After the second vaccination, serum-neutralizing activity was detected by two methods in all participants evaluated, with values generally similar to those in the upper half of the distribution of a panel of control convalescent serum specimens. Solicited adverse events that occurred in more than half the participants included fatigue, chills, headache, myalgia, and pain at the injection site. Systemic adverse events were more common after the second vaccination, particularly with the highest dose, and three participants (21%) in the 250-µg dose group reported one or more severe adverse events. CONCLUSIONS: The mRNA-1273 vaccine induced anti-SARS-CoV-2 immune responses in all participants, and no trial-limiting safety concerns were identified. These findings support further development of this vaccine. (Funded by the National Institute of Allergy and Infectious Diseases and others; mRNA-1273 ClinicalTrials.gov number, NCT04283461).


Assuntos
Infecções por Coronavirus/prevenção & controle , Pandemias/prevenção & controle , Pneumonia Viral/prevenção & controle , RNA Mensageiro/imunologia , Glicoproteína da Espícula de Coronavírus/imunologia , Vacinas Virais/uso terapêutico , Vacina de mRNA-1273 contra 2019-nCoV , Adulto , Anticorpos Neutralizantes/sangue , Anticorpos Antivirais/sangue , Formação de Anticorpos , Betacoronavirus , COVID-19 , Vacinas contra COVID-19 , Feminino , Humanos , Imunização Secundária , Masculino , SARS-CoV-2 , Linfócitos T/imunologia , Vacinas Virais/efeitos adversos , Adulto Jovem
5.
N Engl J Med ; 383(25): 2427-2438, 2020 12 17.
Artigo em Inglês | MEDLINE | ID: mdl-32991794

RESUMO

BACKGROUND: Testing of vaccine candidates to prevent infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in an older population is important, since increased incidences of illness and death from coronavirus disease 2019 (Covid-19) have been associated with an older age. METHODS: We conducted a phase 1, dose-escalation, open-label trial of a messenger RNA vaccine, mRNA-1273, which encodes the stabilized prefusion SARS-CoV-2 spike protein (S-2P) in healthy adults. The trial was expanded to include 40 older adults, who were stratified according to age (56 to 70 years or ≥71 years). All the participants were assigned sequentially to receive two doses of either 25 µg or 100 µg of vaccine administered 28 days apart. RESULTS: Solicited adverse events were predominantly mild or moderate in severity and most frequently included fatigue, chills, headache, myalgia, and pain at the injection site. Such adverse events were dose-dependent and were more common after the second immunization. Binding-antibody responses increased rapidly after the first immunization. By day 57, among the participants who received the 25-µg dose, the anti-S-2P geometric mean titer (GMT) was 323,945 among those between the ages of 56 and 70 years and 1,128,391 among those who were 71 years of age or older; among the participants who received the 100-µg dose, the GMT in the two age subgroups was 1,183,066 and 3,638,522, respectively. After the second immunization, serum neutralizing activity was detected in all the participants by multiple methods. Binding- and neutralizing-antibody responses appeared to be similar to those previously reported among vaccine recipients between the ages of 18 and 55 years and were above the median of a panel of controls who had donated convalescent serum. The vaccine elicited a strong CD4 cytokine response involving type 1 helper T cells. CONCLUSIONS: In this small study involving older adults, adverse events associated with the mRNA-1273 vaccine were mainly mild or moderate. The 100-µg dose induced higher binding- and neutralizing-antibody titers than the 25-µg dose, which supports the use of the 100-µg dose in a phase 3 vaccine trial. (Funded by the National Institute of Allergy and Infectious Diseases and others; mRNA-1273 Study ClinicalTrials.gov number, NCT04283461.).


Assuntos
Vacinas contra COVID-19/efeitos adversos , Vacinas contra COVID-19/imunologia , COVID-19/prevenção & controle , SARS-CoV-2/imunologia , Vacina de mRNA-1273 contra 2019-nCoV , Idoso , Anticorpos Neutralizantes/sangue , Anticorpos Antivirais/sangue , COVID-19/imunologia , Vacinas contra COVID-19/administração & dosagem , Relação Dose-Resposta a Droga , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Testes de Neutralização , Glicoproteína da Espícula de Coronavírus , Linfócitos T/fisiologia
6.
N Engl J Med ; 383(19): 1813-1826, 2020 11 05.
Artigo em Inglês | MEDLINE | ID: mdl-32445440

RESUMO

BACKGROUND: Although several therapeutic agents have been evaluated for the treatment of coronavirus disease 2019 (Covid-19), no antiviral agents have yet been shown to be efficacious. METHODS: We conducted a double-blind, randomized, placebo-controlled trial of intravenous remdesivir in adults who were hospitalized with Covid-19 and had evidence of lower respiratory tract infection. Patients were randomly assigned to receive either remdesivir (200 mg loading dose on day 1, followed by 100 mg daily for up to 9 additional days) or placebo for up to 10 days. The primary outcome was the time to recovery, defined by either discharge from the hospital or hospitalization for infection-control purposes only. RESULTS: A total of 1062 patients underwent randomization (with 541 assigned to remdesivir and 521 to placebo). Those who received remdesivir had a median recovery time of 10 days (95% confidence interval [CI], 9 to 11), as compared with 15 days (95% CI, 13 to 18) among those who received placebo (rate ratio for recovery, 1.29; 95% CI, 1.12 to 1.49; P<0.001, by a log-rank test). In an analysis that used a proportional-odds model with an eight-category ordinal scale, the patients who received remdesivir were found to be more likely than those who received placebo to have clinical improvement at day 15 (odds ratio, 1.5; 95% CI, 1.2 to 1.9, after adjustment for actual disease severity). The Kaplan-Meier estimates of mortality were 6.7% with remdesivir and 11.9% with placebo by day 15 and 11.4% with remdesivir and 15.2% with placebo by day 29 (hazard ratio, 0.73; 95% CI, 0.52 to 1.03). Serious adverse events were reported in 131 of the 532 patients who received remdesivir (24.6%) and in 163 of the 516 patients who received placebo (31.6%). CONCLUSIONS: Our data show that remdesivir was superior to placebo in shortening the time to recovery in adults who were hospitalized with Covid-19 and had evidence of lower respiratory tract infection. (Funded by the National Institute of Allergy and Infectious Diseases and others; ACTT-1 ClinicalTrials.gov number, NCT04280705.).


Assuntos
Monofosfato de Adenosina/análogos & derivados , Alanina/análogos & derivados , Antivirais/uso terapêutico , Infecções por Coronavirus/tratamento farmacológico , Pneumonia Viral/tratamento farmacológico , Monofosfato de Adenosina/administração & dosagem , Monofosfato de Adenosina/efeitos adversos , Monofosfato de Adenosina/uso terapêutico , Administração Intravenosa , Adulto , Idoso , Alanina/administração & dosagem , Alanina/efeitos adversos , Alanina/uso terapêutico , Antivirais/administração & dosagem , Antivirais/efeitos adversos , Betacoronavirus , COVID-19 , Infecções por Coronavirus/mortalidade , Infecções por Coronavirus/terapia , Método Duplo-Cego , Oxigenação por Membrana Extracorpórea , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Oxigenoterapia , Pandemias , Pneumonia Viral/mortalidade , Pneumonia Viral/terapia , Respiração Artificial , SARS-CoV-2 , Fatores de Tempo , Adulto Jovem , Tratamento Farmacológico da COVID-19
8.
Curr Opin Crit Care ; 27(5): 487-492, 2021 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-34353998

RESUMO

PURPOSE OF REVIEW: COVID-19 represents an unprecedented public health crisis caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The antiviral remdesivir is one component of treating COVID-19. Unfortunately, the trials evaluating remdesivir have reported mixed results, leading to uncertainty on when to use remdesivir. This review discusses the trials evaluating the efficacy of remdesivir for COVID-19 and other supporting data to help inform the role of remdesivir in patients with COVID-19. RECENT FINDINGS: Since the start of the pandemic, there have been four randomized trials of remdesivir in treating patients hospitalized with COVID-19. More recently, extensive observational studies have provided supportive data. SUMMARY: The majority of trials evaluating remdesivir suggest that remdesivir is effective in the treatment of patients hospitalized with COVID-19. Although there may be a benefit in some subgroups more than others, there is insufficient data to make definitive statements about benefits or lack of benefits in particular groups. Remdesivir has demonstrated clinical benefits such as decreased time in the hospital, lower progression to mechanical ventilation, and decreased utilization of other hospital resources; it is unclear if it reduces mortality, but one randomized controlled trial suggested possible survival benefits. Based on the data available, remdesivir has been approved (or authorized for early use) in 48 countries.


Assuntos
Tratamento Farmacológico da COVID-19 , Monofosfato de Adenosina/análogos & derivados , Alanina/análogos & derivados , Antivirais/uso terapêutico , Humanos , SARS-CoV-2
9.
BMC Infect Dis ; 21(1): 881, 2021 Aug 28.
Artigo em Inglês | MEDLINE | ID: mdl-34454432

RESUMO

BACKGROUND: The introduction of Zika and chikungunya to dengue hyperendemic regions increased interest in better understanding characteristics of these infections. We conducted a cohort study in Mexico to evaluate the natural history of Zika infection. We describe here the frequency of Zika, chikungunya and dengue virus infections immediately after Zika introduction in Mexico, and baseline characteristics of participants for each type of infection. METHODS: Prospective, observational cohort evaluating the natural history of Zika virus infection in the Mexico-Guatemala border area. Patients with fever, rash or both, meeting the modified criteria of PAHO for probable Zika cases were enrolled (June 2016-July 2018) and followed-up for 6 months. We collected data on sociodemographic, environmental exposure, clinical and laboratory characteristics. Diagnosis was established based on viral RNA identification in serum and urine samples using RT-PCR for Zika, chikungunya, and dengue. We describe the baseline sociodemographic and environmental exposure characteristics of participants according to diagnosis, and the frequency of these infections over a two-year period immediately after Zika introduction in Mexico. RESULTS: We enrolled 427 participants. Most patients (n = 307, 65.7%) had an acute illness episode with no identified pathogen (UIE), 37 (8%) Zika, 82 (17.6%) dengue, and 1 (0.2%) chikungunya. In 2016 Zika predominated, declined in 2017 and disappeared in 2018; while dengue increased after 2017. Patients with dengue were more likely to be men, younger, and with lower education than those with Zika and UIE. They also reported closer contact with water sources, and with other people diagnosed with dengue. Participants with Zika reported sexual exposure more frequently than people with dengue and UIE. Zika was more likely to be identified in urine while dengue was more likely found in blood in the first seven days of symptoms; but PCR results for both were similar at day 7-14 after symptom onset. CONCLUSIONS: During the first 2 years of Zika introduction to this dengue hyper-endemic region, frequency of Zika peaked and fell over a two-year period; while dengue progressively increased with a predominance in 2018. Different epidemiologic patterns between Zika, dengue and UIE were observed. Trial registration Clinical.Trials.gov (NCT02831699).


Assuntos
Febre de Chikungunya , Vírus da Dengue , Dengue , Infecção por Zika virus , Zika virus , Febre de Chikungunya/epidemiologia , Estudos de Coortes , Dengue/epidemiologia , Vírus da Dengue/genética , Feminino , Humanos , Masculino , México/epidemiologia , Estudos Prospectivos , Infecção por Zika virus/epidemiologia
10.
Clin Infect Dis ; 70(11): 2317-2324, 2020 05 23.
Artigo em Inglês | MEDLINE | ID: mdl-31541242

RESUMO

BACKGROUND: Duration of viral shedding is a determinant of infectivity and transmissibility, but few data exist about oseltamivir's ability to alter viral shedding. METHODS: From January 2012 through October 2017, a randomized, double-blinded multicenter clinical trial was conducted in adults aged 18-64 years at 42 sites in Thailand, the United States, and Argentina. Participants with influenza A or B and without risk factors for complications of influenza were screened for the study. Eligible participants were randomized to receive oseltamivir 75 mg or placebo twice daily for 5 days. The primary endpoint was the percentage of participants with virus detectable by polymerase chain reaction in nasopharyngeal swab at day 3. RESULTS: Of 716 adults screened for the study, 558 were randomized, and 501 were confirmed to have influenza. Forty-six participants in the pilot study were excluded, and 449 of the 455 participants in the population for the primary analysis had day 3 viral shedding results. Ninety-nine (45.0%) of 220 participants in the oseltamivir arm had virus detected at day 3 compared with 131 (57.2%) of 229 participants in the placebo arm (absolute difference of -12.2% [-21.4%, -3.0%], P =; .010). The median time to alleviation of symptoms was 79.0 hours for the oseltamivir arm and 84.0 hours for the placebo arm (P =; .34) in those with confirmed influenza infection. CONCLUSIONS: Oseltamivir decreased viral shedding in this low-risk population. However, in the population enrolled in this study, it did not significantly decrease the time to resolution of clinical symptoms. CLINICAL TRIALS REGISTRATION: NCT01314911.


Assuntos
Antivirais , Influenza Humana , Adolescente , Adulto , Antivirais/uso terapêutico , Argentina/epidemiologia , Método Duplo-Cego , Humanos , Influenza Humana/tratamento farmacológico , Pessoa de Meia-Idade , Oseltamivir/uso terapêutico , Projetos Piloto , Tailândia , Resultado do Tratamento , Adulto Jovem
11.
N Engl J Med ; 376(4): 330-341, 2017 01 26.
Artigo em Inglês | MEDLINE | ID: mdl-25830322

RESUMO

BACKGROUND: The worst Ebola virus disease (EVD) outbreak in history has resulted in more than 28,000 cases and 11,000 deaths. We present the final results of two phase 1 trials of an attenuated, replication-competent, recombinant vesicular stomatitis virus (rVSV)-based vaccine candidate designed to prevent EVD. METHODS: We conducted two phase 1, placebo-controlled, double-blind, dose-escalation trials of an rVSV-based vaccine candidate expressing the glycoprotein of a Zaire strain of Ebola virus (ZEBOV). A total of 39 adults at each site (78 participants in all) were consecutively enrolled into groups of 13. At each site, volunteers received one of three doses of the rVSV-ZEBOV vaccine (3 million plaque-forming units [PFU], 20 million PFU, or 100 million PFU) or placebo. Volunteers at one of the sites received a second dose at day 28. Safety and immunogenicity were assessed. RESULTS: The most common adverse events were injection-site pain, fatigue, myalgia, and headache. Transient rVSV viremia was noted in all the vaccine recipients after dose 1. The rates of adverse events and viremia were lower after the second dose than after the first dose. By day 28, all the vaccine recipients had seroconversion as assessed by an enzyme-linked immunosorbent assay (ELISA) against the glycoprotein of the ZEBOV-Kikwit strain. At day 28, geometric mean titers of antibodies against ZEBOV glycoprotein were higher in the groups that received 20 million PFU or 100 million PFU than in the group that received 3 million PFU, as assessed by ELISA and by pseudovirion neutralization assay. A second dose at 28 days after dose 1 significantly increased antibody titers at day 56, but the effect was diminished at 6 months. CONCLUSIONS: This Ebola vaccine candidate elicited anti-Ebola antibody responses. After vaccination, rVSV viremia occurred frequently but was transient. These results support further evaluation of the vaccine dose of 20 million PFU for preexposure prophylaxis and suggest that a second dose may boost antibody responses. (Funded by the National Institutes of Health and others; rVSV∆G-ZEBOV-GP ClinicalTrials.gov numbers, NCT02269423 and NCT02280408 .).


Assuntos
Vacinas contra Ebola/imunologia , Ebolavirus/imunologia , Doença pelo Vírus Ebola/prevenção & controle , Adulto , Anticorpos Antivirais/sangue , Método Duplo-Cego , Vacinas contra Ebola/administração & dosagem , Vacinas contra Ebola/efeitos adversos , Ebolavirus/genética , Ebolavirus/isolamento & purificação , Ensaio de Imunoadsorção Enzimática , Feminino , Doença pelo Vírus Ebola/imunologia , Humanos , Masculino , Pessoa de Meia-Idade , Proteínas Recombinantes , Soroconversão , Vacinas Atenuadas/imunologia , Vírus da Estomatite Vesicular Indiana , Proteínas do Envelope Viral/isolamento & purificação , Viremia
13.
Clin Infect Dis ; 69(11): 1903-1911, 2019 11 13.
Artigo em Inglês | MEDLINE | ID: mdl-30753384

RESUMO

BACKGROUND: Effective therapeutics for respiratory viruses are needed. Early data suggest that nitazoxanide (NTZ) may be beneficial for treating acute respiratory viral illness. METHODS: From March 2014 through March 2017, a double-blind, placebo-controlled trial was conducted in 260 participants ≥1 year old hospitalized with influenza-like illness at 6 hospitals in Mexico. Participants were randomized 1:1 to NTZ (age ≥12 years, 600 mg twice daily; age 4-11 years and 1-3 years, 200 or 100 mg twice daily, respectively) or placebo for 5 days in addition to standard of care. The primary endpoint was time from first dose to hospital discharge. Influenza reverse-transcription polymerase chain reaction and Respifinder 22 multiplex test were used for virus detection. RESULTS: Of 260 participants enrolled, 257 were randomized and took at least 1 dose of study treatment (intention-to-treat population): 130 in the NTZ group and 127 in the placebo group. The Kaplan-Meier estimate of the median duration of hospitalization was 6.5 (interquartile range [IQR], 4.0-9.0) days in the NTZ group vs 7.0 (IQR, 4.0-9.0) days in the placebo group (P = .56). Duration of hospitalization between the 2 treatments was similar in children (P = .29) and adults (P = .62), influenza A and B (P = .32), and other respiratory viruses. Seven (5.4%) and 6 (4.7%) participants in the NTZ and placebo groups, respectively, reported serious adverse events. CONCLUSIONS: Treatment with NTZ did not reduce the duration of hospital stay in severe influenza-like illness. Further analyses based on age and evaluations by virus did not reveal any subgroups that appeared to benefit from NTZ. CLINICAL TRIALS REGISTRATION: NCT02057757.


Assuntos
Antivirais/uso terapêutico , Síndrome Respiratória Aguda Grave/tratamento farmacológico , Tiazóis/uso terapêutico , Adolescente , Adulto , Idoso , Antivirais/efeitos adversos , Criança , Pré-Escolar , Método Duplo-Cego , Feminino , Hospitalização , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Nitrocompostos , Oseltamivir/efeitos adversos , Oseltamivir/uso terapêutico , Síndrome Respiratória Aguda Grave/virologia , Tiazóis/efeitos adversos , Resultado do Tratamento , Adulto Jovem , Zanamivir/efeitos adversos , Zanamivir/uso terapêutico
17.
Curr Opin Infect Dis ; 31(6): 527-534, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30299360

RESUMO

PURPOSE OF REVIEW: This review summarizes past and ongoing efforts for using polyclonal and monoclonal antibodies for the treatment of influenza, and is focused on products that have entered clinical trials. RECENT FINDINGS: At least three polyclonal and eight monoclonal antibody products have been tested in clinical trials for the treatment of influenza. Considered across the two classes of therapeutics, these products appear to be safe and well tolerated. However, the efficacy results have been mixed and inconclusive. To date, no products have consistently shown superiority to currently available antivirals. SUMMARY: No products within these two classes have been licensed, and several products appear to have stopped further clinical development. There are several ongoing studies that are anticipated to be completed or reported in the next 1-2 years which will be critical for understanding the value of polyclonal and monoclonal antibodies in the treatment of influenza.


Assuntos
Anticorpos Monoclonais/uso terapêutico , Anticorpos Antivirais/uso terapêutico , Antivirais/uso terapêutico , Influenza Humana/tratamento farmacológico , Humanos , Imunoglobulinas Intravenosas
18.
Br J Clin Pharmacol ; 84(1): 25-34, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-28929521

RESUMO

AIMS: The aims of the present study were to assess the safety, tolerability and pharmacokinetics of radavirsen following single ascending doses and multiple doses given as intravenous infusions in healthy adults. METHODS: A phase I safety and pharmacokinetic study of radavirsen was performed in healthy volunteers. The study was divided into two parts. The first was a single-ascending-dose study of five cohorts of eight subjects each, randomized 6:2 to receive single intravenous doses of radavirsen ranging from 0.5 mg kg-1 to 8 mg kg-1 or placebo. The second was a multiple-dose study of 16 subjects randomized 12:4 to receive 8 mg kg-1 or placebo once daily for 5 days. RESULTS: A total of 66 subjects were screened, and 56 subjects were dosed between 2013 and 2015. At least one adverse event occurred in 31/42 (74%) who received radavirsen, and 13/14 (93%) receiving placebo. The most common adverse events were headache and proteinuria, and were similar in incidence and severity among those receiving radavirsen or placebo. Single-dose pharmacokinetics demonstrated relatively linear and dose-proportional increases in maximal concentration and in area under the concentration-time curve from zero to 24 h (AUC0-24 ). At 8 mg kg-1 in the multiple-dose cohort, the day 4 geometric mean AUC0-24 was 57.9 µg*h ml-1 . CONCLUSION: Single infusions of radavirsen up to 8 mg kg-1 , and multi-dosing at 8 mg kg-1 once daily for 5 days, appear to be safe and well tolerated in healthy subjects. The multi-dose day 4 AUC0-24 in the present study was comparable with that associated with protection from viral infection in a preclinical ferret influenza model. Further evaluation of radavirsen for the treatment of influenza infections is warranted.


Assuntos
Antivirais/farmacologia , Influenza Humana/tratamento farmacológico , Morfolinos/farmacologia , Oligonucleotídeos Antissenso/farmacologia , Adulto , Antivirais/uso terapêutico , Método Duplo-Cego , Esquema de Medicação , Feminino , Cefaleia/induzido quimicamente , Cefaleia/epidemiologia , Voluntários Saudáveis , Humanos , Incidência , Vírus da Influenza A/genética , Influenza Humana/virologia , Infusões Intravenosas , Masculino , Pessoa de Meia-Idade , Morfolinos/genética , Morfolinos/uso terapêutico , Oligonucleotídeos Antissenso/genética , Oligonucleotídeos Antissenso/uso terapêutico , Placebos , Biossíntese de Proteínas/genética , Proteinúria/induzido quimicamente , Proteinúria/epidemiologia , Proteínas da Matriz Viral/genética , Adulto Jovem
19.
JCI Insight ; 8(14)2023 07 24.
Artigo em Inglês | MEDLINE | ID: mdl-37289541

RESUMO

BACKGROUNDAntibody-based therapies for respiratory viruses are of increasing importance. The INSIGHT 006 trial administered anti-influenza hyperimmune intravenous immunoglobulin (Flu-IVIG) to patients hospitalized with influenza. Flu-IVIG treatment improved outcomes in patients with influenza B but showed no benefit for influenza A.METHODSTo probe potential mechanisms of Flu-IVIG utility, sera collected from patients hospitalized with influenza A or B viruses (IAV or IBV) were analyzed for antibody isotype/subclass and Fcγ receptor (FcγR) binding by ELISA, bead-based multiplex, and NK cell activation assays.RESULTSInfluenza-specific FcγR-binding antibodies were elevated in Flu-IVIG-infused IBV- and IAV-infected patients. In IBV-infected participants (n = 62), increased IgG3 and FcγR binding were associated with more favorable outcomes. Flu-IVIG therapy also improved the odds of a more favorable outcome in patients with low levels of anti-IBV Fc-functional antibody. Higher FcγR-binding antibody was associated with less favorable outcomes in IAV-infected patients (n = 50), and Flu-IVIG worsened the odds of a favorable outcome in participants with low levels of anti-IAV Fc-functional antibody.CONCLUSIONThese detailed serological analyses provide insights into antibody features and mechanisms required for a successful humoral response against influenza, suggesting that IBV-specific, but not IAV-specific, antibodies with Fc-mediated functions may assist in improving influenza outcome. This work will inform development of improved influenza immunotherapies.TRIAL REGISTRATIONClinicalTrials.gov NCT02287467.FUNDINGFunding for this research was provided by subcontract 13XS134 under Leidos Biomedical Research Prime Contract HHSN261200800001E and HHSN261201500003I, NCI/NIAID.


Assuntos
Vírus da Influenza A , Influenza Humana , Humanos , Imunoglobulinas Intravenosas/uso terapêutico , Receptores de IgG , Imunoglobulina G
20.
Open Forum Infect Dis ; 10(5): ofad205, 2023 May.
Artigo em Inglês | MEDLINE | ID: mdl-37206623

RESUMO

We performed a secondary analysis of the National Institutes of Health-sponsored Adaptive COVID-19 Treatment Trial (ACTT-2) randomized controlled trial and found that baricitinib was associated with a 50% reduction in secondary infections after controlling for baseline and postrandomization patient characteristics. This finding provides a novel mechanism of benefit for baricitinib and supports the safety profile of this immunomodulator for the treatment of coronavirus disease 2019.

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