RESUMO
Several severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines are being deployed, but the global need greatly exceeds the supply, and different formulations might be required for specific populations. Here we report Day 42 interim safety and immunogenicity data from an observer-blinded, dose escalation, randomized controlled study of a virus-like particle vaccine candidate produced in plants that displays the SARS-CoV-2 spike glycoprotein (CoVLP: NCT04450004 ). The co-primary outcomes were the short-term tolerability/safety and immunogenicity of CoVLP formulations assessed by neutralizing antibody (NAb) and cellular responses. Secondary outcomes in this ongoing study include safety and immunogenicity assessments up to 12 months after vaccination. Adults (18-55 years, n = 180) were randomized at two sites in Quebec, Canada, to receive two intramuscular doses of CoVLP (3.75 µg, 7.5 µg, and 15 µg) 21 d apart, alone or adjuvanted with AS03 or CpG1018. All formulations were well tolerated, and adverse events after vaccination were generally mild to moderate, transient and highest in the adjuvanted groups. There was no CoVLP dose effect on serum NAbs, but titers increased significantly with both adjuvants. After the second dose, NAbs in the CoVLP + AS03 groups were more than tenfold higher than titers in Coronavirus 2019 convalescent sera. Both spike protein-specific interferon-γ and interleukin-4 cellular responses were also induced. This pre-specified interim analysis supports further evaluation of the CoVLP vaccine candidate.
Assuntos
Vacinas contra COVID-19/administração & dosagem , COVID-19/prevenção & controle , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/prevenção & controle , Vacinas de Partículas Semelhantes a Vírus/administração & dosagem , Adolescente , Adulto , Anticorpos Neutralizantes/sangue , Anticorpos Antivirais/sangue , COVID-19/genética , COVID-19/imunologia , COVID-19/terapia , COVID-19/virologia , Vacinas contra COVID-19/efeitos adversos , Canadá , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/imunologia , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/virologia , Feminino , Humanos , Imunização Passiva , Imunogenicidade da Vacina , Masculino , Pessoa de Meia-Idade , SARS-CoV-2/efeitos dos fármacos , SARS-CoV-2/patogenicidade , Glicoproteína da Espícula de Coronavírus , Vacinas de Partículas Semelhantes a Vírus/efeitos adversos , Adulto Jovem , Soroterapia para COVID-19RESUMO
PURPOSE: The prognosis for patients with recurrent or metastatic head and neck squamous cell carcinoma (R/M HNSCC) is poor, and only a minority of patients benefit from checkpoint immunotherapy. Talimogene laherparepvec (T-VEC), an oncolytic immunotherapy approved for advanced melanoma, in combination with pembrolizumab may yield enhanced antitumor activity over either agent alone. PATIENTS AND METHODS: This was a phase Ib/III, multicenter trial testing intratumoral T-VEC combined with intravenous pembrolizumab in R/M HNSCC refractory to platinum-based chemotherapy. For phase Ib, primary endpoint was incidence of dose-limiting toxicity (DLT). Key secondary endpoints included objective response rate and progression-free survival per irRECIST, overall survival, and safety. RESULTS: Thirty-six patients were enrolled into the phase Ib study. The data cut-off date was August 28, 2018. Median follow-up was 5.8 months (range, 0.3-24.2). One DLT of T-VEC-related fatal arterial hemorrhage was reported. Twenty (55.6%) and 21 (58.3%) patients experienced adverse events (AE) related to T-VEC and pembrolizumab, respectively. Besides the DLT, there were no treatment-related fatal AEs. A confirmed partial response was observed in 5 (13.9%) patients. Ten (27.8%) patients were unevaluable for response due to early death. Median PFS and OS were 3.0 months [95% confidence interval (Cl), 2.0-5.8] and 5.8 months (95% Cl, 2.9-11.4), respectively. CONCLUSIONS: The combination of T-VEC and pembrolizumab demonstrated a tolerable safety profile in R/M HNSCC. The efficacy with the combination was similar to that with pembrolizumab monotherapy in historical HNSCC studies. Phase III part of this study was not further pursued (ClinicalTrials.gov Identifier: NCT02626000).
Assuntos
Anticorpos Monoclonais Humanizados/administração & dosagem , Produtos Biológicos/administração & dosagem , Recidiva Local de Neoplasia/tratamento farmacológico , Terapia Viral Oncolítica , Carcinoma de Células Escamosas de Cabeça e Pescoço/tratamento farmacológico , Adulto , Idoso , Anticorpos Monoclonais Humanizados/efeitos adversos , Produtos Biológicos/efeitos adversos , Terapia Combinada , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/classificação , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/patologia , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/virologia , Feminino , Herpesvirus Humano 1 , Humanos , Imunoterapia , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Recidiva Local de Neoplasia/patologia , Recidiva Local de Neoplasia/virologia , Intervalo Livre de Progressão , Carcinoma de Células Escamosas de Cabeça e Pescoço/patologia , Carcinoma de Células Escamosas de Cabeça e Pescoço/virologiaAssuntos
Antagonistas de Receptores de Angiotensina/efeitos adversos , Inibidores da Enzima Conversora de Angiotensina/efeitos adversos , Betacoronavirus/efeitos dos fármacos , Doenças Cardiovasculares/tratamento farmacológico , Infecções por Coronavirus/complicações , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/virologia , Pneumonia Viral/complicações , COVID-19 , Infecções por Coronavirus/virologia , Humanos , Pandemias , Pneumonia Viral/virologia , SARS-CoV-2Assuntos
Antineoplásicos/efeitos adversos , Betacoronavirus , Infecções por Coronavirus/complicações , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/virologia , Neoplasias Pulmonares/tratamento farmacológico , Pneumonia Viral/complicações , COVID-19 , Infecções por Coronavirus/virologia , Humanos , Neoplasias Pulmonares/virologia , Pandemias , Pneumonia Viral/virologia , SARS-CoV-2RESUMO
BACKGROUND: The novel coronavirus disease 2019 (COVID-19) is an ongoing pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). There is limited information on the safety of drugs used for the treatment of COVID-19. OBJECTIVE: Objective of this study is to describe the pattern of stimulated spontaneous adverse drug reaction (ADR) reports received from healthcare professionals for SARS-CoV-2 positive patients in Ghana and lessons learnt particularly for low- and middle-income countries. METHODS: This is a study of individual case safety reports (ICSRs) received from healthcare professionals between 1st April 2020 to 31st July 2020 in SARS-CoV-2 positive patients in Ghana. The ICSRs were retrieved from the SafetyWatch System and descriptive statistics used to describe the ADRs by System Organ Classification and Preferred Term. RESULTS: Information was received from 40 COVID-19 Treatment Centres across the country with 9 centres submitting a total of 53 ICSRs containing 101 ADRs; approximately two ADRs per ICSR. Females accounted for 29(54.7%) of the ICSRs and males 24(45.3%). Newly reported ADRs of interest were one report each of tremor for doxycycline; scrotal pain, dyspnoea, gait disturbances and dysgeusia for chloroquine; and dry throat, hyperhidrosis, restlessness and micturition frequency increased for hydroxychloroquine. A strong spontaneous system with the availability of focal persons at the Treatment Centres played a key role in reporting ADRs during the pandemic. CONCLUSION: This is the first experience with spontaneous reporting during COVID-19 pandemic in Ghana. The profile of most of the ADRs reported appears consistent with what is expected from the summary of product characteristics. A study with a larger sample size with well-defined denominator in future studies is paramount in determining the relative risk of these medications in SARS-CoV-2 positive patients. FUNDING: None declared.
Assuntos
Sistemas de Notificação de Reações Adversas a Medicamentos/estatística & dados numéricos , Tratamento Farmacológico da COVID-19 , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/epidemiologia , SARS-CoV-2 , Adulto , Idoso , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/virologia , Feminino , Gana/epidemiologia , Humanos , Masculino , Pessoa de Meia-Idade , Estudos ProspectivosRESUMO
Adverse drug reactions (ADRs) are a significant source of patient morbidity and mortality and represent a major burden to health care systems and drug development. Up to 50% of such reactions are preventable. Although many ADRs can be predicted based on the on-target pharmacologic activity, ADRs arising from drug interactions with off-target receptors are recognized. Off-target ADRs include the immune-mediated ADRs (IM-ADRs) and pharmacologic drug effects. In this review, we discuss what is known about the immunogenetics and pathogenesis of IM-ADRs and the hypothesized role of heterologous immunity in the development of IM-ADRs.
Assuntos
Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/imunologia , Antígenos HLA/genética , Linfócitos T/imunologia , Viroses/genética , Antígenos Virais/imunologia , Autoantígenos/imunologia , Reações Cruzadas , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/genética , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/virologia , Frequência do Gene , Predisposição Genética para Doença , Genótipo , Humanos , Memória Imunológica , Polimorfismo Genético , Risco , Viroses/imunologia , Viroses/virologiaRESUMO
BACKGROUND: The introduction of antiretroviral therapy (ART) has resulted in significant mortality reduction and improvement in the quality of life. However, this has come at a cost of increased drug toxicity. The objective of this study was to assess the patterns and predictors of ART toxicity in adult HIV patients in Ethiopia. METHODS: This is a prospective cohort study conducted at seven teaching hospitals between September 2009 and December 2013 involving 3921 HIV patients on ART. Adverse drug reactions (ADR) due to ART were identified based on clinical assessment and/or laboratory parameters. Multivariable random effects Poisson regression analysis was used to identify factors independently associated with toxicity. RESULT: ADR due to ART drugs was reported in 867 (22.1 %) of the participants; 374 (9.5%) had severe forms. About 87% of reported toxicities were limited to three organ systems - the skin, nervous system and blood. The overall incidence of ADR was 9 per 100 person years. About a third of toxicities occurred during the first six months after ART initiation with the incidence rate of 22.4 per 100 person years. Concomitant anti-tuberculosis treatment was the strongest independent predictor of toxicity. CONCLUSION: ADR was found to be highly prevalent in HIV patients on ART at tertiary hospitals in Ethiopia. Most of these conditions occurred early after ART initiation and in those with concomitant anti-tuberculosis treatment. Thus, routine monitoring of patients on ART should be strengthened with particular emphasis in the first 6 months. Strategies should also be devised to replace older and more toxic agents with newer and safer drugs available.
Assuntos
Fármacos Anti-HIV/efeitos adversos , Terapia Antirretroviral de Alta Atividade/efeitos adversos , Infecções por HIV/tratamento farmacológico , Adulto , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/epidemiologia , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/virologia , Métodos Epidemiológicos , Etiópia/epidemiologia , Feminino , Hospitais de Ensino/estatística & dados numéricos , Humanos , MasculinoRESUMO
The lymphotropic herpesviruses, cytomegalovirus (CMV), Epstein-Barr virus (EBV), and human herpesvirus 6B (HHV-6B) can reactivate and cause disease in organ transplant recipients; the contributions of HHV-6A and HHV-7 to disease are less certain. Less is known about their pathogenic roles in children undergoing treatment for malignancies. Children with newly diagnosed cancer were followed for 24 months. Clinical information and blood samples were collected during routine visits and during acute visits for fever or possible viral infections. Lymphotropic herpesvirus DNA in blood was measured by polymerase chain reaction (PCR). Although HHV-6B DNA was detected at least once in about half of the patients; the other viruses were seldom detected. There was no association between HHV-6B detection and individual acute clinical events, however, HHV-6B detection was more common in children who experienced more frequent acute clinical events. In children being treated for various malignancies, HHV-6B detection was common, but was not associated with individual events of acute illness. Thus, if HHV-6B is not assessed longitudinally, clinical events may be misattributed to the virus. The elevated frequency of detection of HHV-6B in sicker children is consistent with prior reports of its detection during apparently unrelated acute clinical events. J. Med. Virol. 88:1427-1437, 2016. © 2016 Wiley Periodicals, Inc.
Assuntos
Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/virologia , Herpesvirus Humano 6/isolamento & purificação , Neoplasias/complicações , Neoplasias/tratamento farmacológico , Infecções por Roseolovirus/virologia , Doença Aguda , Adolescente , Adulto , Criança , Pré-Escolar , Estudos de Coortes , DNA Viral/sangue , Tratamento Farmacológico , Feminino , Herpesvirus Humano 6/genética , Herpesvirus Humano 7/genética , Herpesvirus Humano 7/isolamento & purificação , Humanos , Lactente , Estudos Longitudinais , Masculino , Neoplasias/virologia , Reação em Cadeia da Polimerase , Infecções por Roseolovirus/diagnóstico , Infecções por Roseolovirus/etiologia , Carga Viral , Adulto JovemRESUMO
BACKGROUND & OBJECTIVES: Japanese encephalitis (JE) caused by mosquito-borne Flavivirus is one of the leading causes of viral encephalitis in Asia. Control strategies include vector control and human vaccination. Due to lack of immunization programmes in endemic regions, there are still high mortality and morbidity. A live-attenuated SA 14-14-2 JE vaccine (LAJEV) has been licensed and used in Asian countries, including India. We report the assessment of immunogenicity and safety of the vaccine in adults during the first mass adult vaccination campaign carried out in Assam, India. METHODS: One thousand and seventy five adults (aged ≥15 yr) who received LAJEV were monitored for adverse events following immunization for one year. The safety assessment of vaccinated population was evaluated till 28 days and at 6 and 12 months. Blood samples collected from the enrolled participants were tested by plaque reduction neutralization test (PRNT 50 ) to assess the neutralizing antibody titres (NATs) before vaccination and 28 days, six and 12 months post-vaccination (PV). RESULTS: Among the 1075 vaccinated individuals, four reported minor adverse effects from 30 min to 28 days PV. Based on the pre-vaccination NAT, the study participants were categorized as seronegative, moderately seropositive and strongly seropositive. Nearly 85.5 per cent of JE seronegative participants seroconverted by 28 days PV. The geometric mean titre (GMT) in all the three groups increased by 28 days and decreased by six and 12 months PV. Nearly 60 per cent of the moderately positive individuals exhibited four-fold rise in GMT, 28 days PV. Almost 95.5 per cent of the participants in the study population remained seroprotected at the end of 12 months PV. INTERPRETATION & CONCLUSIONS: This study on immunogenicity and safety of LAJEV in adults showed that a single dose of the live-attenuated vaccine was safe and induced protective immunity to both JE seronegative and naturally seropositive adults. Further study is required to find out long term protective efficacy of this vaccine.
Assuntos
Encefalite Japonesa/tratamento farmacológico , Vacinas contra Encefalite Japonesa/imunologia , Vacinas Atenuadas/imunologia , Adulto , Anticorpos Neutralizantes/efeitos adversos , Anticorpos Neutralizantes/imunologia , Anticorpos Neutralizantes/uso terapêutico , Anticorpos Antivirais/efeitos adversos , Anticorpos Antivirais/imunologia , Anticorpos Antivirais/uso terapêutico , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/epidemiologia , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/imunologia , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/virologia , Encefalite Japonesa/imunologia , Encefalite Japonesa/virologia , Feminino , Humanos , Imunização/efeitos adversos , Índia , Vacinas contra Encefalite Japonesa/efeitos adversos , Vacinas contra Encefalite Japonesa/uso terapêutico , Masculino , Pessoa de Meia-Idade , Vacinas Atenuadas/efeitos adversos , Vacinas Atenuadas/uso terapêuticoAssuntos
Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/virologia , Eosinofilia/etiologia , Hepatite/etiologia , Miocardite/etiologia , Infecções por Roseolovirus/complicações , Adulto , Anti-Infecciosos/efeitos adversos , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/patologia , Eosinofilia/patologia , Feminino , Herpesvirus Humano 6 , Humanos , Masculino , Minociclina/efeitos adversos , Infecções por Roseolovirus/patologia , Sulfassalazina/efeitos adversosAssuntos
Vírus JC/efeitos dos fármacos , Leucoencefalopatia Multifocal Progressiva/induzido quimicamente , Ácido Micofenólico/análogos & derivados , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/virologia , Humanos , Imunossupressores/efeitos adversos , Leucoencefalopatia Multifocal Progressiva/virologia , Ácido Micofenólico/efeitos adversosRESUMO
BACKGROUND AND OBJECTIVES: Producers of plasma derivatives continuously improve the viral safety of their products by, for example, introducing additional virus-reducing steps into the manufacturing process. Here we present virus-elimination studies undertaken for a number of steps employed in a new manufacturing process for liquid intravenous immunoglobulin (Nanogam) that comprises two specific virus-reducing steps: a 15-nm filtration step combined with pepsin treatment at pH 4.4 (pH 4.4/15NF); and solvent-detergent (SD) treatment. The manufacturing process also includes precipitation of Cohn fraction III and viral neutralization, which contribute to the total virus-reducing capacity of the manufacturing process. In addition, the mechanism and robustness of the virus-reducing steps were studied. MATERIALS AND METHODS: Selected process steps were studied with spiking experiments using a range of lipid enveloped (LE) and non-lipid-enveloped (NLE) viruses. The LE viruses used were bovine viral diarrhoea virus (BVDV), human immunodeficiency virus (HIV) and pseudorabies virus (PRV); the NLE viruses used were parvovirus B19 (B19), canine parvovirus (CPV) and encephalomyocarditis virus (EMC). After spiking, samples were collected and tested for residual infectivity, and the reduction factors were calculated. For B19, however, removal of B19 DNA was measured, not residual infectivity. To reveal the contribution of viral neutralization, bovine parvovirus (BPV) and hepatitis A virus (HAV) were used. RESULTS: For the pH 4.4/15NF step, complete reduction (> 6 log(10)) was demonstrated for all viruses, including B19, but not for CPV (> 3.4 but < or = 4.2 log(10)). Robustness studies of the pH 4.4/15NF step with CPV showed that pH was the dominant process parameter. SD treatment for 10 min resulted in complete inactivation (> 6 log(10)) of all LE viruses tested. Precipitation of Cohn fraction III resulted in the significant removal (3-4 log(10)) of both LE and NLE viruses. Virus-neutralization assays of final product revealed significant reduction (> or = 3 log(10)) of both BPV and HAV. CONCLUSIONS: The manufacturing process of Nanogam comprises two effective steps for the reduction of LE viruses and one for NLE viruses. In addition, the precipitation of Cohn fraction III and the presence of neutralizing antibodies contribute to the total virus-reducing capacity of Nanogam. The overall virus-reducing capacity was > 15 log(10) for LE viruses. For the NLE viruses B19, CPV and EMC, the overall virus-reducing capacities were > 10, > 7 and > 9 log(10), respectively. Including the contribution of immune neutralization, the overall virus-reducing capacity for B19 and HAV is estimated to be > 10 log(10).