RESUMO
BACKGROUND: Recent reports have described the contribution of adult respiratory syncytial virus (RSV) infections to the use of advanced healthcare resources and death. METHODS: Data regarding patients aged ≥18 years admitted to any of Maryland's 50 acute-care hospitals were evaluated over 12 consecutive years (2001-2013). We examined RSV and influenza (flu) surveillance data from the US National Respiratory and Enteric Virus Surveillance System and the Centers for Disease Control and Prevention and used this information to define RSV and flu outbreak periods in the Maryland area. Outbreak periods consisted of consecutive individual weeks during which at least 10% of RSV and/or flu diagnostic tests were positive. We examined relationships of RSV and flu outbreaks to occurrence of 4 advanced medical outcomes (hospitalization, intensive care unit admission, intubated mechanical ventilation, and death) due to medically attended acute respiratory illness (MAARI). RESULTS: Occurrences of all 4 MAARI-related hospital advanced medical outcomes were consistently greater for all adult ages during RSV, flu, and combined RSV-flu outbreak periods compared to nonoutbreak periods and tended to be greatest in adults aged ≥65 years during combined RSV-flu outbreak periods. Rate ratios for all 4 MAARI-related advanced medical outcomes ranged from 1.04 to 1.38 during the RSV, flu, or combined RSV-flu outbreaks compared to the nonoutbreak periods, with all 95% lower confidence limits >1. CONCLUSIONS: Both RSV and flu outbreaks were associated with surges in MAARI-related advanced medical outcomes (hospitalization, intensive care unit admission, intubated mechanical ventilation, and death) for adults of all ages.
Assuntos
Influenza Humana , Infecções por Vírus Respiratório Sincicial , Vírus Sincicial Respiratório Humano , Adulto , Surtos de Doenças , Hospitalização , Humanos , Influenza Humana/epidemiologia , Maryland/epidemiologia , Infecções por Vírus Respiratório Sincicial/epidemiologiaRESUMO
Clinical Trials Registration: ClinicalTrials.gov [NCT02378753] and Pan African Clinical Trials Registry [PACTR201502001037220].
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Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/epidemiologia , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/patologia , Vacinas contra Ebola/administração & dosagem , Vacinas contra Ebola/efeitos adversos , Epidemias , Doença pelo Vírus Ebola/epidemiologia , Doença pelo Vírus Ebola/prevenção & controle , Adolescente , Adulto , Idoso , Feminino , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Serra Leoa/epidemiologia , Vacinas Sintéticas/administração & dosagem , Vacinas Sintéticas/efeitos adversos , Adulto JovemRESUMO
Clinical Trials Registration: ClinicalTrials.gov [NCT02378753] and Pan African Clinical Trials Registry [PACTR201502001037220].
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Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/epidemiologia , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/patologia , Vacinas contra Ebola/administração & dosagem , Vacinas contra Ebola/efeitos adversos , Epidemias , Doença pelo Vírus Ebola/epidemiologia , Doença pelo Vírus Ebola/prevenção & controle , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Serra Leoa/epidemiologia , Análise de Sobrevida , Vacinas Sintéticas/administração & dosagem , Vacinas Sintéticas/efeitos adversos , Adulto JovemRESUMO
BACKGROUND: Universal vaccination of children 6 to 59 months of age with trivalent inactivated influenza vaccine has recently been recommended by U.S. advisory bodies. To evaluate alternative vaccine approaches, we compared the safety and efficacy of intranasally administered live attenuated influenza vaccine with those of inactivated vaccine in infants and young children. METHODS: Children 6 to 59 months of age, without a recent episode of wheezing illness or severe asthma, were randomly assigned in a 1:1 ratio to receive either cold-adapted trivalent live attenuated influenza vaccine (a refrigeration-stable formulation of live attenuated intranasally administered influenza vaccine) or trivalent inactivated vaccine in a double-blind manner. Influenza-like illness was monitored with cultures throughout the 2004-2005 influenza season. RESULTS: Safety data were available for 8352 children, and 7852 children completed the study according to the protocol. There were 54.9% fewer cases of cultured-confirmed influenza in the group that received live attenuated vaccine than in the group that received inactivated vaccine (153 vs. 338 cases, P<0.001). The superior efficacy of live attenuated vaccine, as compared with inactivated vaccine, was observed for both antigenically well-matched and drifted viruses. Among previously unvaccinated children, wheezing within 42 days after the administration of dose 1 was more common with live attenuated vaccine than with inactivated vaccine, primarily among children 6 to 11 months of age; in this age group, 12 more episodes of wheezing were noted within 42 days after receipt of dose 1 among recipients of live attenuated vaccine (3.8%) than among recipients of inactivated vaccine (2.1%, P=0.076). Rates of hospitalization for any cause during the 180 days after vaccination were higher among the recipients of live attenuated vaccine who were 6 to 11 months of age (6.1%) than among the recipients of inactivated vaccine in this age group (2.6%, P=0.002). CONCLUSIONS: Among young children, live attenuated vaccine had significantly better efficacy than inactivated vaccine. An evaluation of the risks and benefits indicates that live attenuated vaccine should be a highly effective, safe vaccine for children 12 to 59 months of age who do not have a history of asthma or wheezing. (ClinicalTrials.gov number, NCT00128167 [ClinicalTrials.gov].).
Assuntos
Vacinas contra Influenza , Influenza Humana/prevenção & controle , Pré-Escolar , Feminino , Seguimentos , Hospitalização/estatística & dados numéricos , Humanos , Lactente , Vacinas contra Influenza/efeitos adversos , Influenza Humana/epidemiologia , Estimativa de Kaplan-Meier , Masculino , Sons Respiratórios , Resultado do Tratamento , Vacinas Atenuadas/efeitos adversosRESUMO
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.
RESUMO
BACKGROUND: Reliable availability of influenza vaccine before October could enable the vaccination of many children who might not otherwise be vaccinated. METHODS: Available data for children were analyzed to describe protection provided by live attenuated influenza vaccine (LAIV) for greater than 5 months postvaccination. RESULTS: Four studies conducted in children aged 6 months to 18 years were identified. Culture-confirmed efficacy against A/H1N1 and A/H3N2 strains at 9-12 months postvaccination was 77% [95% confidence interval (CI): 53-89%] to 100% (95% CI: 68-100%) and through a second influenza season without revaccination was 56% (95% CI: 31-73%) and 57% (95% CI: 6-82%), respectively. Against B strains, 1 study demonstrated 86% (95% CI: 59-95%) efficacy at 5-7 months. Another study demonstrated 27% (95% CI: -62% to 67%) efficacy at 9-12 months compared with 74% (95% CI: 39-89%) at 1 to <5 months during a period of antigenic drift for circulating B strains. A third study estimated 50% (95% CI: -49% to 83%) efficacy against influenza B strains through a second season without revaccination. CONCLUSIONS: In children, live attenuated influenza vaccine provided sustained protection against influenza illness caused by antigenically similar strains. Efficacy at 1 to <5 months postvaccination was comparable to that at 9-12 months for A/H1N1 and A/H3N2 strains and at 5-7 months for B strains. Meaningful efficacy was seen through a second season without revaccination, although at a lower level than during the first 12 months postvaccination.
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Vírus da Influenza A/classificação , Vírus da Influenza A/efeitos dos fármacos , Vírus da Influenza B/efeitos dos fármacos , Vacinas contra Influenza/administração & dosagem , Influenza Humana/prevenção & controle , Adolescente , Criança , Pré-Escolar , Método Duplo-Cego , Humanos , Lactente , Vírus da Influenza A Subtipo H1N1/efeitos dos fármacos , Vírus da Influenza A Subtipo H3N2/efeitos dos fármacos , Influenza Humana/imunologia , Influenza Humana/virologia , Ensaios Clínicos Controlados Aleatórios como Assunto , Fatores de Tempo , Resultado do Tratamento , VacinaçãoRESUMO
Live attenuated influenza vaccine (LAIV) offers a novel approach to influenza vaccination and is approved for healthy individuals 5 to 49 years of age. In placebo-controlled studies in children, LAIV was 73 to 93 percent efficacious, and protection lasted more than 12 months. In head-to-head studies in children, LAIV demonstrated a 35 to 53 percent reduction in influenza attack rates compared with injectable influenza vaccine (TIV) for matched strains. Compared with TIV, LAIV has demonstrated broader serum antibody responses, particularly against mismatched influenza A. The most common adverse events are runny nose and nasal congestion. Increased rates of asthma events were observed in young children. Additional large-scale safety and efficacy studies in young children, including a formal risk-benefit assessment, are ongoing. The results of these analyses will guide potential future use in young children.
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Imunização/métodos , Vírus da Influenza A/imunologia , Vacinas contra Influenza/administração & dosagem , Influenza Humana/prevenção & controle , Administração Intranasal , Anticorpos Antivirais/sangue , Criança , Pré-Escolar , Ensaios Clínicos como Assunto , Humanos , Vacinas contra Influenza/efeitos adversos , Influenza Humana/imunologia , Influenza Humana/virologia , Vacinas Atenuadas/administração & dosagem , Vacinas Atenuadas/efeitos adversosRESUMO
BACKGROUND: Osteonecrosis has been reported to occur occasionally among HIV-infected patients. The diagnosis of symptomatic osteonecrosis of the hip in two of the authors' patients, together with reports from community physicians, raised a concern that the prevalence of osteonecrosis is increasing. OBJECTIVE: To determine the prevalence of osteonecrosis of the hip in asymptomatic HIV-infected patients and to identify potential risk factors associated with osteonecrosis. DESIGN: Survey and comparison study. SETTING: The Clinical Center of the U.S. National Institutes of Health. PARTICIPANTS: 339 asymptomatic HIV-infected adults (of 364 asked to participate) and 118 age- and sex-matched HIV-negative volunteers enrolled between 1 June and 15 December 1999. MEASUREMENTS: Osteonecrosis of the hip, as documented by magnetic resonance imaging. Data from clinic records and a patient questionnaire administered before magnetic resonance imaging were used in an analysis of risk factors. A subset of patients was evaluated for hypercoagulable state. RESULTS: Fifteen (4.4% [95% CI, 2.5% to 7.2%]) of 339 HIV-infected participants had osteonecrosis lesions on magnetic resonance imaging, and no HIV-negative participants had similar lesions. Among HIV-infected participants, osteonecrosis occurred more frequently in those who used systemic corticosteroids, lipid-lowering agents, or testosterone; those who exercised routinely by bodybuilding; and those who had detectable levels of anticardiolipin antibodies. CONCLUSIONS: Patients infected with HIV have an unexpectedly high occurrence of osteonecrosis of the hip. Although screening asymptomatic patients is not warranted, HIV-infected patients with persistent groin or hip pain should be evaluated for this debilitating complication.
Assuntos
Infecções por HIV/complicações , Quadril/patologia , Osteonecrose/complicações , Feminino , Humanos , Imageamento por Ressonância Magnética , Masculino , Análise por Pareamento , Osteonecrose/epidemiologia , Osteonecrose/patologia , Exame Físico , Prevalência , Fatores de Risco , Inquéritos e QuestionáriosRESUMO
The effect of etanercept, a soluble p75 tumor necrosis factor (TNF) receptor:Fc fusion protein (Enbrel; Immunex, Seattle, WA) on plasma cytokines was evaluated in 11 HIV-infected subjects receiving highly active antiretroviral therapy (HAART) for 28 weeks with or without subcutaneous or intravenous recombinant human interleukin 2 (rhIL-2). Plasma IL-6 and C-reactive protein (CRP) levels increased after rhIL-2 treatment. Etanercept pretreatment attenuated these increases. Median plasma IL-6 levels were 20.29 pg/ml 4 days after rhIL-2 and 7.87 pg/ml 4 days after etanercept and rhIL-2 (p = 0.22); median CRP levels were 78.73 and 46.16 microg/ml, respectively (p = 0.03). An effect on TNF bioactivity could not be assessed as all measurements were below limits of detection. No significant changes were seen in temperature or plasma levels of IL-4, IL-10, IL-12, interferon gamma, or HIV-1 RNA levels. All subjects had undetectable or low-level HIV-1 RNA levels before etanercept dosing. One subject died; however, her death was thought to be unrelated to etanercept. Pretreatment with etanercept may blunt activation of IL-6 and CRP expression induced by rhIL-2. The safety and utility of etanercept in HIV-infected persons should be explored further.
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Infecções por HIV/metabolismo , Imunoglobulina G/farmacologia , Interleucina-2/antagonistas & inibidores , Interleucina-6/sangue , Fator de Necrose Tumoral alfa/metabolismo , Terapia Antirretroviral de Alta Atividade , Proteína C-Reativa/metabolismo , Interações Medicamentosas , Etanercepte , Infecções por HIV/sangue , Infecções por HIV/tratamento farmacológico , Humanos , Fatores Imunológicos/farmacologia , Interleucina-2/uso terapêutico , Receptores do Fator de Necrose Tumoral , Proteínas Recombinantes/antagonistas & inibidores , Proteínas Recombinantes/uso terapêuticoRESUMO
BACKGROUND: Influenza infections can cause severe respiratory disease in high risk persons such as those with asthma, but immunization rates for high risk groups remain suboptimal. An investigational influenza virus vaccine, trivalent, types A and B, live, cold-adapted (CAIV-T) administered by intranasal spray was shown previously to be effective in healthy adults and healthy children. PURPOSE: To assess the safety and tolerability of CAIV-T in subjects 9 years of age and older with moderate to severe asthma. METHODS: In this randomized, double blind, placebo-controlled study, spirometry was performed twice before vaccination to establish a baseline forced expiratory volume at 1 s (FEV1) and once 2 to 5 days thereafter. The primary outcome index was the percent change in percent predicted FEV1 before and after vaccination. Peak flows, clinical asthma symptom scores and nighttime awakening scores were measured daily from 7 days pre- to 28 days postvaccination. RESULTS: The primary outcome index (percentage change in percent predicted FEV1) was not different between the two groups (0.2% vs. 0.4% for the treatment and placebo groups, respectively; P = 0.78). Secondary outcomes did not differ between the two groups; these included the number of subjects with a decrease in FEV1 > or =15% from baseline, reductions in peak flows > or =15%, > or =30% or > or =2 sd below baseline, use of beta-adrenergic rescue medications, asthma exacerbations and clinical asthma symptom scores before and after vaccination. The same proportion of subjects in each group experienced postvaccination symptoms within 10 days (92% and 91%, respectively; P = 1.0). No serious adverse event occurred. CONCLUSION: CAIV-T was generally safe and well-tolerated in children and adolescents with moderate to severe asthma.
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Asma/complicações , Vacinas contra Influenza/imunologia , Administração Intranasal , Adolescente , Criança , Temperatura Baixa , Método Duplo-Cego , Feminino , Humanos , Vacinas contra Influenza/administração & dosagem , Vacinas contra Influenza/efeitos adversos , Masculino , Placebos , Testes de Função Respiratória , Fatores de RiscoRESUMO
BACKGROUND: Hemagglutination inhibition (HAI) assay is the standard method for evaluating inactivated influenza vaccines, but no standard assay has been established for evaluating live attenuated influenza vaccines (LAIV). LAIV containing A/Beijing/262/95(H1N1) induced low serum HAI antibody responses to the antigenic variant, A/New Caledonia/20/99(H1N1) in a serologic study but provided protection against the A/New Caledonia-like viruses in a community study. Neutralization and HAI assays were compared by measuring H1N1 cross-reactive antibody responses to the LAIV in children. METHODS: Sera were collected from 50 children 1-8 years of age before vaccination and 4-6 weeks after each dose of the LAIV. Antibody titers to the 3 vaccine viruses were measured by the HAI assay, whereas antibody titers against the H1N1 vaccine virus (A/Beijing/262/95) and 2 H1N1 antigenic variants (A/Shenzhen/227/95 and A/New Caledonia/20/99) were measured by the HAI and neutralization assays. RESULTS: Initially seronegative participants were more likely to develop HAI seroconversion responses to the 3 vaccine viruses than the baseline seropositive participants (77% versus 14% for H1N1, 100% versus 20% for H3N2, 100% versus 19% for B, P < 0.01, Fisher's exact test). For the H1N1 cross-reactive antibody responses, seroconversion rates measured by the neutralization assay were significantly higher than those measured by the HAI assay (95% versus 78%, P = 0.0485 for A/Beijing/262/95; 75% versus 24%, P < 0.0001 for A/Shenzhen/227/95; 51% versus 5%, P < 0.0001 for A/New Caledonia/20/99). CONCLUSIONS: The neutralization assay was more sensitive than the HAI assay for measuring H1N1 antibody responses after vaccination of children with the LAIV and may provide a better correlate of clinical protection provided by the LAIV.
Assuntos
Anticorpos Antivirais/análise , Vacinas contra Influenza/imunologia , Influenza Humana/imunologia , Vacinação , Formação de Anticorpos/imunologia , Criança , Pré-Escolar , Estudos de Coortes , Intervalos de Confiança , Feminino , Seguimentos , Testes de Inibição da Hemaglutinação , Humanos , Esquemas de Imunização , Vacinas contra Influenza/administração & dosagem , Influenza Humana/prevenção & controle , Masculino , Probabilidade , Vacinas Atenuadas/administração & dosagem , Vacinas Atenuadas/imunologiaRESUMO
In a large comparative study in 2004-2005, children aged 6-59 months vaccinated with live attenuated influenza vaccine (LAIV) experienced 55% fewer cases of culture-confirmed influenza illness compared with trivalent inactivated influenza vaccine (TIV) recipients. To better understand the characteristics of the breakthrough influenza illnesses, we analyzed the HA1 genetic sequence for all available samples and examined disease severity by strain and treatment group. All 48 A/H1N1 viruses were well-matched to the vaccine, whereas all 276 A/H3N2 viruses and 349 (96%) influenza B viruses were mismatched to the vaccine. The incidence of fever or lower respiratory illness did not differ by strain; however, LAIV recipients had less febrile disease and fewer lower respiratory illnesses than TIV recipients. Viruses of each influenza B lineage caused more illnesses than A/H1N1 viruses; strategies to enhance protection against multiple influenza B lineages should be pursued.
Assuntos
Vírus da Influenza A Subtipo H1N1/genética , Vírus da Influenza A Subtipo H3N2/genética , Vírus da Influenza B/genética , Vacinas contra Influenza/administração & dosagem , Influenza Humana/epidemiologia , Pré-Escolar , Humanos , Incidência , Lactente , Vírus da Influenza A Subtipo H1N1/classificação , Vírus da Influenza A Subtipo H3N2/classificação , Vírus da Influenza B/classificação , Filogenia , RNA Viral/genética , Análise de Sequência de RNA , Vacinas Atenuadas/administração & dosagem , Vacinas de Produtos Inativados/administração & dosagemRESUMO
Live attenuated influenza vaccine (LAIV) provides a useful tool to rapidly immunize populations in the developing world to prevent influenza outbreaks. In this noninferiority trial conducted in Asia and South America, where oral poliovirus vaccine (OPV) is still used, 2503 children aged 6 to <36 months with three polio immunizations were randomized to receive LAIV+OPV, placebo+OPV, or LAIV only. Immune responses in children receiving concomitant LAIV+OPV were noninferior to those observed in recipients of either vaccine alone. Response rates for different poliovirus types were similar in recipients of LAIV+OPV and placebo+OPV. Response rates to all influenza strains were similar in LAIV+OPV and LAIV-only recipients. Concomitant OPV and LAIV were safely administered to young children.
Assuntos
Vacinas contra Influenza/administração & dosagem , Influenza Humana/prevenção & controle , Poliomielite/prevenção & controle , Vacina Antipólio Oral/administração & dosagem , Anticorpos Antivirais/sangue , Pré-Escolar , Feminino , Humanos , Esquemas de Imunização , Lactente , Vacinas contra Influenza/efeitos adversos , Vacinas contra Influenza/imunologia , Masculino , Vacina Antipólio Oral/efeitos adversos , Vacina Antipólio Oral/imunologia , Vacinas Atenuadas/administração & dosagem , Vacinas Atenuadas/efeitos adversos , Vacinas Atenuadas/imunologiaRESUMO
BACKGROUND: Live attenuated influenza vaccine (LAIV) is indicated for influenza prevention in persons 2-49 years of age. This study describes the incidence and duration of vaccine virus shedding and serum immune responses after receipt of LAIV. METHODS: A single open-label dose of trivalent LAIV was administered intranasally to 344 subjects in 3 age cohorts: 5-8, 9-17, and 18-49 years of age. Shedding was determined by culture of nasal swabs (on days 1-7, daily; days 9-25, every other day; and day 28). Immunogenicity was measured as serum strain-specific hemagglutinin inhibition (HAI) titers (days 0, 28). RESULTS: Among subjects aged 5-8 years, 9-17 years, and 18-49 years, 44%, 27%, and 17% of subjects, respectively, shed vaccine virus after vaccination, and the mean number of positive samples per subject was 2.2, 1.8, and 1.5, respectively. Shedding occurred on days 1-11 postvaccination. Shedding incidence peaked on day 2, and maximum observed titers were highest on days 2-3 (<5, <4, and <3 log(10)TCID(50)/mL, respectively, by age group). Despite positive cultures, all titers were <1 log(10)TCID(50)/mL after days 10, 6, and 6, respectively, by age group. Shedding incidence was inversely correlated to age and baseline serum HAI titer. The seroresponse rate (4-fold rise in HAI) to at least 1 strain was 59% (68%, 64%, and 47%, respectively, by age group), and strain-specific rates were higher in baseline seronegative/serosusceptible subjects. Reactogenicity, most commonly runny nose, headache, and sore throat, was not associated with shedding or seroresponse. CONCLUSIONS: This is the first study to comprehensively evaluate nasal shedding of LAIV in individuals 5-49 years of age. Shedding was generally of short duration and at low titers. Study findings support the current recommendation of the Advisory Committee on Immunization Practices that LAIV recipients should only avoid contact with severely immunosuppressed persons (e.g., hematopoietic stem cell transplant recipients) for 7 days after vaccination.
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Vírus da Influenza A/imunologia , Vírus da Influenza A/fisiologia , Vírus da Influenza B/imunologia , Vírus da Influenza B/fisiologia , Vacinas contra Influenza/imunologia , Influenza Humana/prevenção & controle , Vacinas Atenuadas/imunologia , Eliminação de Partículas Virais , Adolescente , Adulto , Fatores Etários , Anticorpos Antivirais/sangue , Criança , Pré-Escolar , Demografia , Feminino , Humanos , Vírus da Influenza A/isolamento & purificação , Vírus da Influenza B/isolamento & purificação , Vacinas contra Influenza/administração & dosagem , Vacinas contra Influenza/efeitos adversos , Masculino , Pessoa de Meia-Idade , Fatores de Tempo , Vacinação , Vacinas Atenuadas/administração & dosagem , Vacinas Atenuadas/efeitos adversosRESUMO
MEDI-534 is a bivalent live attenuated vaccine candidate against human respiratory syncytial virus (hRSV) and human parainfluenza virus type 3 (hPIV3) that was previously shown to be immunogenic and to protect rodents and African green monkeys from wild-type (wt) hRSV challenge. We performed further preclinical evaluations to address the safety of MEDI-534 prior to human testing. MEDI-534 did not predispose rodents to enhanced RSV disease following wt-RSV challenge, and the tissue tropism of the chimeric virus was confined to the respiratory tract. Representative clinical trial material did not produce toxicity in rats. In adults, MEDI-534 was highly restricted in replication, did not boost RSV and PIV3 antibody titers, and produced no medically significant vaccine-related adverse events thereby warranting further evaluation in pediatric populations.
Assuntos
Vacinas contra Parainfluenza , Vírus da Parainfluenza 3 Humana/imunologia , Infecções por Vírus Respiratório Sincicial/prevenção & controle , Vacinas contra Vírus Sincicial Respiratório , Infecções por Respirovirus/prevenção & controle , Vacinas Atenuadas , Adolescente , Adulto , Animais , Chlorocebus aethiops , Cricetinae , Modelos Animais de Doenças , Método Duplo-Cego , Feminino , Vetores Genéticos , Humanos , Masculino , Vacinas contra Parainfluenza/administração & dosagem , Vacinas contra Parainfluenza/genética , Vacinas contra Parainfluenza/imunologia , Vírus da Parainfluenza 3 Humana/genética , Ratos , Ratos Sprague-Dawley , Infecções por Vírus Respiratório Sincicial/imunologia , Infecções por Vírus Respiratório Sincicial/virologia , Vacinas contra Vírus Sincicial Respiratório/administração & dosagem , Vacinas contra Vírus Sincicial Respiratório/efeitos adversos , Vacinas contra Vírus Sincicial Respiratório/imunologia , Vírus Sincicial Respiratório Humano/imunologia , Infecções por Respirovirus/imunologia , Infecções por Respirovirus/virologia , Sigmodontinae , Resultado do Tratamento , Vacinas Atenuadas/administração & dosagem , Vacinas Atenuadas/efeitos adversos , Vacinas Atenuadas/imunologia , Células Vero , Adulto JovemRESUMO
The frozen version of live attenuated influenza vaccine (LAIV; FluMist) was compared with a newly licensed, refrigerated formulation, the cold-adapted influenza vaccine, trivalent (CAIV-T), for their immunogenicity, safety, and tolerability in healthy subjects 5 to 49 years of age. Eligible subjects were randomized 1:1 to receive CAIV-T or frozen LAIV. Subjects 5 to 8 years of age received two doses of vaccine 46 to 60 days apart; subjects 9 to 49 years of age received one dose of vaccine. Equivalent immunogenicities were defined as serum hemagglutination inhibition (HAI) geometric mean titer (GMT) ratios >0.5 and <2.0 for each of the three vaccine-specific strains. A total of 376 subjects 5 to 8 years of age and 566 subjects 9 to 49 years of age were evaluable. Postvaccination HAI GMT ratios were equivalent for CAIV-T and LAIV. The GMT ratios of CAIV-T/LAIV for the H1N1, H3N2, and B strains were 1.24, 1.02, and 1.00, respectively, for the 5- to 8-year-old age group and 1.14, 1.12, and 0.96, respectively, for the 9- to 49-year-old age group. Seroresponse/seroconversion rates (fourfold or greater rise) were similar in both age groups for each of the three vaccine strains. Within 28 days, the most frequent reactogenicity event in the CAIV-T and LAIV groups was runny nose/nasal congestion, which occurred at higher rates after dose 1 (44% and 42%, respectively) than after dose 2 (41% and 29%, respectively) in the 5- to 8-year-old group. Otherwise, the rates of adverse events (AEs) were similar between the treatment groups and the two age cohorts, with no serious AEs related to the study vaccines. The immunogenicities, reactogenicity events, and AEs were comparable for refrigerated CAIV-T and frozen LAIV.
Assuntos
Vacinas contra Influenza/imunologia , Vacinas Atenuadas/imunologia , Adolescente , Adulto , Criança , Pré-Escolar , Temperatura Baixa , Método Duplo-Cego , Feminino , Congelamento , Testes de Inibição da Hemaglutinação , Humanos , Esquemas de Imunização , Vacinas contra Influenza/administração & dosagem , Vacinas contra Influenza/efeitos adversos , Masculino , Pessoa de Meia-Idade , Vacinação/efeitos adversos , Vacinação/métodos , Vacinas Atenuadas/administração & dosagem , Vacinas Atenuadas/efeitos adversosRESUMO
Respiratory syncytial virus (RSV) and parainfluenza virus type 3 (PIV3) are two leading causes of lower respiratory illness (LRI) in infants. Many efforts have been directed to develop vaccines against these two viruses. Licensure of new vaccines includes three phases of clinical trials to evaluate safety, immunogenicity, and efficacy. To design an efficacy trial, age-specific incidence rates of suitable clinical endpoints need to be available. In this review, historical data are summarized to estimate the age-specific rates of acute respiratory illness (ARI), LRI, and hospitalization caused by RSV and PIV3 among US children <5 years of age. Nation-wide data are available for hospitalization but not ARI and LRI. Age-specific rates of RSV and PIV3-related ARI or LRI can vary 9-fold or 5-fold, respectively, in different studies conducted in different populations using different clinical and laboratory definitions. The annual medical burden for RSV and PIV3 in children <5 was estimated respectively to be about 4.19 and 3.24 million cases of medically-attended ARI, 2.1 and 1.08 million cases of LRI, and 113 and 29 thousand cases of hospitalization, respectively. The impact of three important variables including age at vaccination, clinical endpoints, and laboratory diagnosis in designing efficacy trials is discussed. A RSV vaccine which is safe and effective in the first six months of life is optimal to reduce the severe disease burden of LRI and hospitalization, however, interference of maternal antibody may reduce vaccine efficacy in this age group. LRI occurs more frequently than hospitalization and may be the most feasible clinical endpoint for designing efficacy trials. Since age-specific rates of RSV and PIV3-related LRI can vary significantly in different populations, collecting age-specific LRI rates in phase 1 and 2 trials to further understand this variability appears warranted.
Assuntos
Vacinas contra Parainfluenza/economia , Vírus da Parainfluenza 3 Humana , Infecções por Vírus Respiratório Sincicial/economia , Vacinas contra Vírus Sincicial Respiratório/economia , Vírus Sincicial Respiratório Humano , Infecções por Respirovirus/economia , Fatores Etários , Criança , Ensaios Clínicos como Assunto , Efeitos Psicossociais da Doença , Hospitalização , Humanos , Vacinas contra Parainfluenza/uso terapêutico , Projetos de Pesquisa , Infecções por Vírus Respiratório Sincicial/epidemiologia , Infecções por Vírus Respiratório Sincicial/prevenção & controle , Vacinas contra Vírus Sincicial Respiratório/uso terapêutico , Infecções por Respirovirus/epidemiologia , Infecções por Respirovirus/prevenção & controle , Estados Unidos/epidemiologiaRESUMO
BACKGROUND: A phase 2 trial was conducted to assess in young infants the safety, tolerability, infectivity, and immunogenicity of multiple doses of an intranasal vaccine using bovine parainfluenza virus type 3 (bPIV3). METHODS: One hundred ninety-two healthy 2-month-old infants were randomized 1 : 1 : 1 to receive 1x10(5) median tissue culture infective dose (TCID(50)) bPIV3 vaccine, 1x10(6) TCID(50) bPIV3 vaccine, or placebo at 2, 4, 6, and 12-15 months of age. Safety information was collected by use of diary sheets and telephone interviews. Nasal wash and serum specimens were collected for assessment of infectivity and immunogenicity. RESULTS: The safety profiles of both dosages of bPIV3 were similar to that of placebo, with the exception of fever with temperature of >/=38.1 degrees C after dose 2 only, occurring in 34% of the 1x10(5) TCID(50) group, 35% of the 1x10(6) TCID(50) group, and 12% of the placebo group (P<.01). No vaccine-related serious adverse events were reported. The cumulative vaccine infectivity (isolation of bPIV3 and/or bPIV3 seroconversion) after dose 3 was similar in the 2 vaccine groups (87% in the 1x10(5) TCID(50) group and 77% in the 1x10(6) TCID(50) group) (P=.46). Seroconversion rates after dose 3, assessed by means of hemagglutination inhibition assay, after adjustment for decrease in maternal antibody titers, were 67% in the 1x10(5) TCID(50) group, 57% in the 1x10(6) TCID(50) group, and 12% in the placebo group (P<.01). Isolation of bPIV3 was common after dose 1, dose 2, or dose 3, but only 1 of 51 participants in the vaccine groups had bPIV3 isolated after dose 4. CONCLUSIONS: Multiple doses of bPIV3 vaccine were well tolerated and immunogenic in young infants.
Assuntos
Anticorpos Antivirais/sangue , Vacinas contra Parainfluenza/efeitos adversos , Vacinas contra Parainfluenza/imunologia , Vírus da Parainfluenza 3 Bovina/imunologia , Vírus da Parainfluenza 3 Humana/imunologia , Infecções por Respirovirus/prevenção & controle , Administração Intranasal , Testes de Inibição da Hemaglutinação , Humanos , Lactente , Líquido da Lavagem Nasal/imunologia , Líquido da Lavagem Nasal/virologia , Vacinas contra Parainfluenza/administração & dosagem , Estados UnidosRESUMO
Data supporting the use of the live attenuated influenza vaccine (LAIV) in children and adults is reviewed, and the development and characteristics of the vaccine are summarized. The vaccine is highly effective and well tolerated in children and adults from 5 to 49 years of age. Correlates of immune protection include serum hemagglutination-inhibition antibody and secretory immunoglobulin A. Efficacy against antigenically well-matched epidemic influenza strains was high at 92%. In 1 year, despite a significant antigenic change in the epidemic influenza virus that did not match the vaccine, LAIV conferred 86% protection against culture-confirmed illness in children. In the future it is expected that additional studies will support a broadening of the age range for use with the LAIV to prevent influenza in children and adults.
Assuntos
Vírus da Influenza A/imunologia , Vírus da Influenza B/imunologia , Vacinas contra Influenza/imunologia , Influenza Humana/prevenção & controle , Administração Intranasal , Adolescente , Adulto , Fatores Etários , Criança , Pré-Escolar , Humanos , Imunidade Inata , Vacinas contra Influenza/administração & dosagem , Influenza Humana/imunologia , Influenza Humana/transmissão , Pessoa de Meia-Idade , Ensaios Clínicos Controlados Aleatórios como Assunto , Vacinas Atenuadas/administração & dosagem , Vacinas Atenuadas/imunologiaRESUMO
This study was designed to compare the safety and immunogenicity of a trivalent live-attenuated, cold-adapted influenza vaccine (CAIV-T) blended and filled at two different manufacturing facilities (Medeva and Aviron-PA). The vaccines contained approximately 10(7) TCID(50) (median tissue culture infectious dose) of each of the three recommended 1997-1998 influenza vaccine components, A/Shenzhen/227/95 (H1N1) (A/Bayern/7/95 (H1N1)-like strain), A/Wuhan/359/95 (H3N2), and B/Ann Arbor/1/94 (B/Beijing/184/93-like strain). Two hundred and twenty-five healthy Australian children aged 12-42 months were enrolled and randomized in a 3:2 ratio to receive CAIV-T blended and filled either at Medeva or at Aviron-PA. Two doses of CAIV-T were given 4-6 weeks apart as an intranasal spray. Three blood specimens were collected (immediately before doses one and two, and 28 +/- 5 days following dose two) for measuring hemagglutination inhibition (HAI) antibody responses. Adverse events occurring within 10 days and serious adverse events occurring within 42 days were collected. Serum HAI antibody levels were measured against the three vaccine strains. Equivalent immunogenicity between the two vaccine groups was pre-specified as: (1) within 20% difference in seroconversion rates (HAI titers > or =4-fold rise); and (2) within 4-fold difference in the 90% confidence interval of geometric mean titer ratio. Among 10 pre-specified adverse events, only vomiting had significantly different incidence rates in the two vaccine groups following dose one (3% versus 13%, P = 0.01) but the difference disappeared following dose two (4% versus 4%). Differences in seroconversion rates following dose two between the two vaccine groups in pre-vaccination seronegative children were all <20% for the three vaccine strains (16% for H1N1, 0% for H3N2, and 0% for B). The results indicate that CAIV-T blended and filled in the two facilities had equivalent profiles of safety and immunogenicity.