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1.
J Infect Dis ; 219(11): 1786-1798, 2019 May 05.
Artigo em Inglês | MEDLINE | ID: mdl-30566602

RESUMO

BACKGROUND: Adjuvant System 03 (AS03) markedly enhances responses to influenza A/H5N1 vaccines, but the mechanisms of this enhancement are incompletely understood. METHODS: Using ribonucleic acid sequencing on peripheral blood mononuclear cells (PBMCs) from AS03-adjuvanted and unadjuvanted inactivated H5N1 vaccine recipients, we identified differentially expressed genes, enriched pathways, and genes that correlated with serologic responses. We compared bulk PBMC findings with our previously published assessments of flow-sorted immune cell types. RESULTS: AS03-adjuvanted vaccine induced the strongest differential signals on day 1 postvaccination, activating multiple innate immune pathways including interferon and JAK-STAT signaling, Fcγ receptor (FcγR)-mediated phagocytosis, and antigen processing and presentation. Changes in signal transduction and immunoglobulin genes predicted peak hemagglutinin inhibition (HAI) titers. Compared with individual immune cell types, activated PBMC genes and pathways were most similar to innate immune cells. However, several pathways were unique to PBMCs, and several pathways identified in individual cell types were absent in PBMCs. CONCLUSIONS: Transcriptomic analysis of PBMCs after AS03-adjuvanted H5N1 vaccination revealed early activation of innate immune signaling, including a 5- to 8-fold upregulation of FcγR1A/1B/1C genes. Several early gene responses were correlated with HAI titer, indicating links with the adaptive immune response. Although PBMCs and cell-specific results shared key innate immune signals, unique signals were identified by both approaches.

2.
J Virol ; 91(23)2017 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-28931680

RESUMO

Herpes simplex virus 1 (HSV-1) and HSV-2 are large, double-stranded DNA viruses that cause lifelong persistent infections characterized by periods of quiescence and recurrent disease. How HSV evolves within an infected individual experiencing multiple episodes of recurrent disease over time is not known. We determined the genome sequences of viruses isolated from two subjects in the Herpevac Trial for Women who experienced primary HSV-2 genital disease and compared them with sequences of viruses isolated from the subsequent fifth or sixth episode of recurrent disease in the same individuals. Each of the HSV-2 genome sequences was initially obtained using next-generation sequencing and completed with Sanger sequencing. Polymorphisms over the entire genomes were mapped, and amino acid variants resulting from nonsynonymous changes were analyzed based on the secondary and tertiary structures of a previously crystallized protein. A phylogenetic reconstruction was used to assess relationships among the four HSV-2 samples, other North American sequences, and reference sequences. Little genetic drift was detected in viruses shed by the same subjects following repeated reactivation events, suggesting strong selective pressure on the viral genome to maintain sequence fidelity during reactivations from its latent state within an individual host. Our results also demonstrate that some primary HSV-2 isolates from North America more closely resemble the HG52 laboratory strain from Scotland than the low-passage-number clinical isolate SD90e from South Africa or laboratory strain 333. Thus, one of the sequences reported here would be a logical choice as a reference strain for inclusion in future studies of North American HSV-2 isolates.IMPORTANCE The extent to which the HSV-2 genome evolves during multiple episodes of reactivation from its latent state within an infected individual is not known. We used next-generation sequencing techniques to determine whole-genome sequences of four viral samples from two subjects in the Herpevac Trial. The sequence of each subject's well-documented primary isolate was compared with the sequence of the isolate from their fifth or sixth episode of recurrent disease. Only 19 genetic polymorphisms unique to the primary or recurrent isolate were identified, 10 in subject A and 9 in subject B. These observations indicate remarkable genetic conservation between primary and recurrent episodes of HSV-2 infection and imply that strong selection pressures exist to maintain the fidelity of the viral genome during repeated reactivations from its latent state. The genome conservation observed also has implications for the potential success of a therapeutic vaccine.


Assuntos
Evolução Molecular , Genoma Viral , Herpes Genital/virologia , Herpesvirus Humano 2/genética , Ensaios Clínicos como Assunto , DNA Viral/genética , Feminino , Deriva Genética , Herpesvirus Humano 2/isolamento & purificação , Herpesvirus Humano 2/fisiologia , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Mutação INDEL , América do Norte , Filogenia , Polimorfismo Genético , Recidiva , Escócia , Análise de Sequência de DNA , África do Sul , Ativação Viral , Eliminação de Partículas Virais
3.
Vaccine ; 35(36): 4730-4737, 2017 08 24.
Artigo em Inglês | MEDLINE | ID: mdl-28750854

RESUMO

BACKGROUND: Tularemia is caused by Francisella tularensis, a gram-negative bacterium that has been weaponized as an aerosol. For protection of personnel conducting biodefense research, the United States Army required clinical evaluation of a new lot of tularemia live vaccine strain manufactured in accordance with Current Good Manufacturing Practices. METHODS: A phase 2 randomized clinical trial compared the new lot (DVC-LVS) to the existing vaccine that has been in use for decades (USAMRIID-LVS). The vaccines were delivered by scarification to 228 participants. Safety, reactogenicity, take and/or antibody levels were assessed on days 0, 1, 2, 8, 14, 28, 56, and 180. PRINCIPAL RESULTS: Both vaccines were safe and had acceptable reactogenicity profiles during six months of follow-up. There were no serious or grade 3 and 4 laboratory adverse events. Moderate systemic reactogenicity (mostly headache or feeling tired) was reported by ∼23% of participants receiving either vaccine. Injection site reactogenicity was mostly mild itchiness and pain. The frequencies of vaccine take skin reactions were 73% (95% CI, 64, 81) for DVC-LVS and 80% (95% CI, 71, 87) for USAMRIID-LVS. The 90% CI for the difference in proportions was -6.9% (-16.4, 2.6). The rates of seroconversion measured by microagglutination assay on days 28 or 56 were 94% (95% CI, 88, 98; n=98/104) for DVC-LVS and 94% (95% CI, 87, 97; n=103/110) for USAMRIID-LVS (p=1.00). Day 14 sera revealed more rapid seroconversion for DVC-LVS relative to USAMRIID-LVS: 82% (95% CI, 73, 89) versus 55% (95% CI, 45, 65), respectively (p<0.0001). MAJOR CONCLUSIONS: The DVC-LVS vaccine had similar safety, reactogenicity, take and antibody responses compared to the older USAMRIID vaccine, and was superior for early (day 14) antibody production. Vaccination take was not a sensitive surrogate for seroconversion in a multi-center study where personnel at five research clinics performed assessments. ClinicalTrials.gov identifier NCT01150695.


Assuntos
Anticorpos Antibacterianos/sangue , Vacinas Bacterianas/efeitos adversos , Vacinas Bacterianas/imunologia , Francisella tularensis/imunologia , Tularemia/prevenção & controle , Adolescente , Adulto , Testes de Aglutinação , Vacinas Bacterianas/administração & dosagem , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Soroconversão , Tularemia/imunologia , Vacinação , Vacinas Atenuadas/administração & dosagem , Vacinas Atenuadas/efeitos adversos , Vacinas Atenuadas/imunologia , Adulto Jovem
4.
Proteomics ; 17(12)2017 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-28508465

RESUMO

Adjuvants enhance immunity elicited by vaccines through mechanisms that are poorly understood. Using a systems biology approach, we investigated temporal protein expression changes in five primary human immune cell populations: neutrophils, monocytes, natural killer cells, T cells, and B cells after administration of either an Adjuvant System 03 adjuvanted or unadjuvanted split-virus H5N1 influenza vaccine. Monocytes demonstrated the strongest differential signal between vaccine groups. On day 3 post-vaccination, several antigen presentation-related pathways, including MHC class I-mediated antigen processing and presentation, were enriched in monocytes and neutrophils and expression of HLA class I proteins was increased in the Adjuvant System 03 group. We identified several protein families whose proteomic responses predicted seroprotective antibody responses (>1:40 hemagglutination inhibition titer), including inflammation and oxidative stress proteins at day 1 as well as immunoproteasome subunit (PSME1 and PSME2) and HLA class I proteins at day 3 in monocytes. While comparison between temporal proteomic and transcriptomic results showed little overlap overall, enrichment of the MHC class I antigen processing and presentation pathway in monocytes and neutrophils was confirmed by both approaches.


Assuntos
Apresentação do Antígeno , Virus da Influenza A Subtipo H5N1/imunologia , Vacinas contra Influenza/uso terapêutico , Proteoma/metabolismo , Adjuvantes Imunológicos , Linfócitos B/citologia , Linfócitos B/imunologia , Linfócitos B/metabolismo , Células Cultivadas , Humanos , Influenza Humana/imunologia , Influenza Humana/prevenção & controle , Células Matadoras Naturais/citologia , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/metabolismo , Monócitos/citologia , Monócitos/imunologia , Monócitos/metabolismo , Neutrófilos/citologia , Neutrófilos/imunologia , Neutrófilos/metabolismo , Mapas de Interação de Proteínas , Proteômica , Linfócitos T/citologia , Linfócitos T/imunologia , Linfócitos T/metabolismo
5.
Vaccine ; 35(13): 1675-1682, 2017 03 23.
Artigo em Inglês | MEDLINE | ID: mdl-28256358

RESUMO

INTRODUCTION: To guide the use of modified vaccinia Ankara (MVA) vaccine in response to a release of smallpox virus, the immunogenicity and safety of shorter vaccination intervals, and administration by jet injector (JI), were compared to the standard schedule of administration on Days 1 and 29 by syringe and needle (S&N). METHODS: Healthy adults 18-40years of age were randomly assigned to receive MVA vaccine subcutaneously by S&N on Days 1 and 29 (standard), Days 1 and 15, or Days 1 and 22, or to receive the vaccine subcutaneously by JI on Days 1 and 29. Blood was collected at four time points after the second vaccination for plaque reduction neutralization test (PRNT) (primary endpoint) and ELISA (secondary endpoint) antibody assays. For each subject, the peak PRNT (or ELISA) titer was defined by the highest PRNT (or ELISA) titer among all available measurements post second vaccination. Non-inferiority of a non-standard arm compared to the standard arm was met if the upper limit of the 98.33% confidence interval of the difference in the mean log2 peak titers between the standard and non-standard arm was less than 1. RESULTS: Non-inferiority of the PRNT antibody response was not established for any of the three non-standard study arms. Non-inferiority of the ELISA antibody response was established for the Day 1 and 22 compressed schedule and for administration by JI. Solicited local reactions, such as redness and swelling, tended to be more commonly reported with JI administration. Four post-vaccination hypersensitivity reactions were observed. CONCLUSIONS: Evaluations of the primary endpoint of PRNT antibody responses do not support alternative strategies of administering MVA vaccine by S&N on compressed schedules or administration by JI on the standard schedule. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01827371.


Assuntos
Portadores de Fármacos , Esquemas de Imunização , Vacina Antivariólica/efeitos adversos , Vacina Antivariólica/imunologia , Vírus Vaccinia/imunologia , Adolescente , Adulto , Anticorpos Neutralizantes/sangue , Anticorpos Antivirais/sangue , Ensaio de Imunoadsorção Enzimática , Estudos de Equivalência como Asunto , Feminino , Voluntários Saudáveis , Humanos , Injeções Subcutâneas , Masculino , Testes de Neutralização , Vacina Antivariólica/administração & dosagem , Ensaio de Placa Viral , Adulto Jovem
6.
PLoS One ; 12(1): e0167488, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28099485

RESUMO

BACKGROUND: Vaccine development for influenza A/H5N1 is an important public health priority, but H5N1 vaccines are less immunogenic than seasonal influenza vaccines. Adjuvant System 03 (AS03) markedly enhances immune responses to H5N1 vaccine antigens, but the underlying molecular mechanisms are incompletely understood. OBJECTIVE AND METHODS: We compared the safety (primary endpoint), immunogenicity (secondary), gene expression (tertiary) and cytokine responses (exploratory) between AS03-adjuvanted and unadjuvanted inactivated split-virus H5N1 influenza vaccines. In a double-blinded clinical trial, we randomized twenty adults aged 18-49 to receive two doses of either AS03-adjuvanted (n = 10) or unadjuvanted (n = 10) H5N1 vaccine 28 days apart. We used a systems biology approach to characterize and correlate changes in serum cytokines, antibody titers, and gene expression levels in six immune cell types at 1, 3, 7, and 28 days after the first vaccination. RESULTS: Both vaccines were well-tolerated. Nine of 10 subjects in the adjuvanted group and 0/10 in the unadjuvanted group exhibited seroprotection (hemagglutination inhibition antibody titer > 1:40) at day 56. Within 24 hours of AS03-adjuvanted vaccination, increased serum levels of IL-6 and IP-10 were noted. Interferon signaling and antigen processing and presentation-related gene responses were induced in dendritic cells, monocytes, and neutrophils. Upregulation of MHC class II antigen presentation-related genes was seen in neutrophils. Three days after AS03-adjuvanted vaccine, upregulation of genes involved in cell cycle and division was detected in NK cells and correlated with serum levels of IP-10. Early upregulation of interferon signaling-related genes was also found to predict seroprotection 56 days after first vaccination. CONCLUSIONS: Using this cell-based systems approach, novel mechanisms of action for AS03-adjuvanted pandemic influenza vaccination were observed. TRIAL REGISTRATION: ClinicalTrials.gov NCT01573312.


Assuntos
Adjuvantes Imunológicos/uso terapêutico , Virus da Influenza A Subtipo H5N1/imunologia , Vacinas contra Influenza/imunologia , Influenza Humana/prevenção & controle , Biologia de Sistemas/métodos , Adolescente , Adulto , Anticorpos Antivirais/sangue , Formação de Anticorpos/imunologia , Apresentação do Antígeno/genética , Apresentação do Antígeno/imunologia , Quimiocina CXCL10/sangue , Células Dendríticas/imunologia , Método Duplo-Cego , Feminino , Testes de Inibição da Hemaglutinação , Humanos , Influenza Humana/imunologia , Interleucina-6/sangue , Células Matadoras Naturais/imunologia , Masculino , Pessoa de Meia-Idade , Monócitos/imunologia , Neutrófilos/imunologia , Vacinação , Adulto Jovem
7.
F1000Res ; 6: 2162, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-30026912

RESUMO

RNA-Seq is increasingly being used to measure human RNA expression on a genome-wide scale. Expression profiles can be interrogated to identify and functionally characterize treatment-responsive genes. Ultimately, such controlled studies promise to reveal insights into molecular mechanisms of treatment effects, identify biomarkers, and realize personalized medicine. RNA-Seq Reports (RSEQREP) is a new open-source cloud-enabled framework that allows users to execute start-to-end gene-level RNA-Seq analysis on a preconfigured RSEQREP Amazon Virtual Machine Image (AMI) hosted by AWS or on their own Ubuntu Linux machine via a Docker container or installation script. The framework works with unstranded, stranded, and paired-end sequence FASTQ files stored locally, on Amazon Simple Storage Service (S3), or at the Sequence Read Archive (SRA). RSEQREP automatically executes a series of customizable steps including reference alignment, CRAM compression, reference alignment QC, data normalization, multivariate data visualization, identification of differentially expressed genes, heatmaps, co-expressed gene clusters, enriched pathways, and a series of custom visualizations. The framework outputs a file collection that includes a dynamically generated PDF report using R, knitr, and LaTeX, as well as publication-ready table and figure files. A user-friendly configuration file handles sample metadata entry, processing, analysis, and reporting options. The configuration supports time series RNA-Seq experimental designs with at least one pre- and one post-treatment sample for each subject, as well as multiple treatment groups and specimen types. All RSEQREP analyses components are built using open-source R code and R/Bioconductor packages allowing for further customization. As a use case, we provide RSEQREP results for a trivalent influenza vaccine (TIV) RNA-Seq study that collected 1 pre-TIV and 10 post-TIV vaccination samples (days 1-10) for 5 subjects and two specimen types (peripheral blood mononuclear cells and B-cells).

8.
J Infect Dis ; 214(7): 1020-9, 2016 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-27443611

RESUMO

BACKGROUND: Influenza A(H5N1) virus and other avian influenza virus strains represent major pandemic threats. Like all influenza A virus strains, A(H5N1) viruses evolve rapidly. Innovative immunization strategies are needed to induce cross-protective immunity. METHODS: Subjects primed with clade 1 H5 antigen, with or without adjuvant, and H5-naive individuals were boosted with clade 2 H5 antigen. The impact of priming on T cells capable of both proliferation and cytokine production after antigen restimulation was assessed. RESULTS: Subjects previously vaccinated with clade 1 H5 antigen developed significantly enhanced clade 2 H5 cross-reactive T cell responses detectable 6 months after vaccination with clade 2 H5 antigen. Priming dose (15 µg vs 45 or 90 µg) had no effect on magnitude of heterotypic H5 T cell responses. In contrast, age at priming negatively modulated both the magnitude and duration of heterotypic H5 T cell responses. Elderly subjects developed significantly less heterotypic H5 T cell boosting, predominantly for T cells capable of cytokine production. Adjuvant had a positive albeit weaker effect than age. The magnitude of CD4(+) interferon-γ producing T cells correlated with H5 antibody responses. CONCLUSIONS: H5 heterotypic priming prior to onset of an A(H5N1) pandemic may increase magnitude and duration of immunity against a newly drifted pandemic H5 virus.


Assuntos
Glicoproteínas de Hemaglutininação de Vírus da Influenza/imunologia , Imunidade Heteróloga , Vacinas contra Influenza/imunologia , Influenza Humana/prevenção & controle , Linfócitos T/imunologia , Vacinação/métodos , Adulto , Idoso , Idoso de 80 Anos ou mais , Proliferação de Células , Citocinas/metabolismo , Método Duplo-Cego , Feminino , Glicoproteínas de Hemaglutininação de Vírus da Influenza/administração & dosagem , Humanos , Vacinas contra Influenza/administração & dosagem , Masculino , Pessoa de Meia-Idade , Adulto Jovem
9.
Vaccine ; 34(4): 547-554, 2016 Jan 20.
Artigo em Inglês | MEDLINE | ID: mdl-26657997

RESUMO

PURPOSE: The study aims were to determine whether inactivated influenza A/H5N1 vaccine administration elicited cell mediated immune (CMI) responses and the impact of adjuvant, vaccine dose and subject age on these responses. METHODS: Adults who were previously primed with either adjuvanted or unadjuvanted, inactivated, A/H5N1/Vietnam/1203/2004 (Clade 1) vaccine or unprimed (received placebo) in previous vaccine studies were randomized to receive one (primed) or two (unprimed) 15- or 90-mcg doses of inactivated, A/H5N1/Indonesia/05/05 (Clade 2) vaccine. Peripheral blood mononuclear cells (PBMCs) were collected and analyzed from a subset of vaccinees to assess CMI responses using IFN-γ and granzyme B ELISPOT assays. Cytokine measurements were performed on PBMC supernatants after stimulation with H5N1 virus. RESULTS: PBMCs were available from 177 participants; 88 and 89 received 15-mcg and 90-mcg of unadjuvanted clade 2 vaccine, respectively. Following H5N1 clade 1 stimulation, IFN-γ but not granzyme B normalized spot-forming cell numbers had statistically significant increased numbers at each of the post-vaccination timepoints compared to baseline in pooled analyses of all vaccine doses and age groups. Clade 2 stimulation resulted in statistically significant increased numbers of IFN-γ cells only 180 days following the last vaccination. Responses were similar among younger and older study participants, as were responses among those primed with alum-adjuvanted or non-adjuvanted clade 1 H5N1 vaccines. The dosage of clade 2 vaccine did not impact CMI responses among primed subjects, but responses were statistically significantly greater in unprimed recipients of the 90-mcg dosage compared to unprimed recipients of the 15-mcg dosage. IFN-γ levels in the supernatants of stimulated PBMC were strongly correlated with IFN-γ ELISPOT results. CONCLUSION: CMI responses occur in adults administered influenza A/H5N1 inactivated influenza vaccine.


Assuntos
Imunidade Celular , Imunização Secundária , Vacinas contra Influenza/administração & dosagem , Vacinas contra Influenza/uso terapêutico , Influenza Humana/prevenção & controle , Adjuvantes Imunológicos/administração & dosagem , Adulto , Fatores Etários , Idoso , Citocinas/imunologia , Feminino , Granzimas/imunologia , Humanos , Virus da Influenza A Subtipo H5N1 , Interferon gama/imunologia , Leucócitos Mononucleares/imunologia , Masculino , Pessoa de Meia-Idade , Vacinas de Produtos Inativados/administração & dosagem , Vacinas de Produtos Inativados/uso terapêutico , Adulto Jovem
10.
Vaccine ; 33(39): 5225-34, 2015 Sep 22.
Artigo em Inglês | MEDLINE | ID: mdl-26143613

RESUMO

BACKGROUND: Modified vaccinia Ankara (MVA) is being developed as a safer smallpox vaccine and is being placed in the US Strategic National Stockpile (SNS) as a liquid formulation for subcutaneous (SC) administration at a dose of 1×10(8) TCID50 in a volume of 0.5mL. This study compared the safety and immunogenicity of the standard formulation, dose and route with both a more stable, lyophilized formulation and with an antigen-sparing intradermal (ID) route of administration. METHODS: 524 subjects were randomized to receive either a full dose of Lyophilized-SC, a full dose of Liquid-SC or 20% (2×10(7) TCID50 in 0.1mL) of a full dose Liquid-ID MVA on Days 0 and 28. Safety and immunogenicity were followed through 180 days post second vaccination. RESULTS: Among the 3 groups, the proportion of subjects with moderate/severe functional local reactions was significantly different (P=0.0013) between the Lyophilized-SC group (30.3%), the Liquid-SC group (13.8%) and Liquid-ID group (22.0%) only after first vaccination; and for moderate/severe measured erythema and/or induration after any vaccination (P=0.0001) between the Lyophilized-SC group (58.2%), the Liquid-SC group (58.1%) and the Liquid-ID group (94.8%) and the reactions lasted longer in the Liquid-ID group. In the ID Group, 36.1% of subjects had mild injection site skin discoloration lasting ≥6 months. After second vaccination Day (42-208), geometric mean of peak neutralization titers were 87.8, 49.5 and 59.5 for the Lyophilized-SC, Liquid-SC and Liquid-ID groups, respectively, and the maximum number of responders based on peak titer in each group was 142/145 (97.9%), 142/149 (95.3%) and 138/146 (94.5%), respectively. At 180 days after the second vaccination, geometric mean neutralization titers declined to 11.7, 10.2 and 10.4 with only 54.3%, 39.2% and 35.2% of subjects remaining seropositive for the Lyophilized-SC, Liquid-SC and Liquid-ID groups, respectively. Both the Lyophilized-SC and Liquid-ID groups were considered non-inferior (primary objective) to the Liquid-SC group. CONCLUSIONS: Transitioning to a lyophilized formulation, which has a longer shelf life, will not negatively impact immunogenicity. In a situation where insufficient vaccine is available, ID vaccination could be used, increasing the number of available doses of vaccine in the SNS 5-fold (i.e., from 20 million to 100 million doses).


Assuntos
Anticorpos Neutralizantes/sangue , Anticorpos Antivirais/sangue , Vacina Antivariólica/administração & dosagem , Vacina Antivariólica/imunologia , Adolescente , Adulto , Química Farmacêutica , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/epidemiologia , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/patologia , Feminino , Humanos , Injeções Intradérmicas , Injeções Subcutâneas , Masculino , Vacina Antivariólica/efeitos adversos , Adulto Jovem
11.
Vaccine ; 32(47): 6284-93, 2014 Oct 29.
Artigo em Inglês | MEDLINE | ID: mdl-25239484

RESUMO

BACKGROUND: Strategies to implement post exposure prophylaxis (PEP) in case of an anthrax bioterror event are needed. To increase the number of doses of vaccine available we evaluated reducing the amount of vaccine administered at each of the vaccinations, and reducing the number of doses administered. METHODS: Healthy male and non-pregnant female subjects between the ages of 18 and 65 were enrolled and randomized 1:1:1:1 to one of four study arms to receive 0.5 mL (standard dose) of vaccine subcutaneously (SQ) at: (A) days 0, 14; (B) days 0 and 28; (C) days 0, 14, and 28; or (D) 0.25 mL at days 0, 14, and 28. A booster was provided on day 180. Safety was assessed after each dose. Blood was obtained on days 0, 7, 14, 21, 28, 35, 42, 49, 56, 63, 70, 84, 100, 180, and 201 and both Toxin Neutralizing antibody and anti-PA IgG antibody measured. RESULTS: Almost all subjects developed some local reactions with 46-64% reported to be of moderate severity and 3.3% severe during the primary series. Vaccine groups that included a day 14 dose induced a ≥ 4 fold antibody rise in more subjects on days 21, 28, and 35 than the arm without a day 14 dose. However, schedules with a full day 28 dose induced higher peak levels of antibody that persisted longer. The half dose regimen did not induce antibody as well as the full dose study arms. CONCLUSION: Depending on the extent of the outbreak, effectiveness of antibiotics and availability of vaccine, the full dose 0, 28 or 0, 14, 28 schedules may have advantages.


Assuntos
Vacinas contra Antraz/administração & dosagem , Antraz/prevenção & controle , Profilaxia Pós-Exposição , Adolescente , Adulto , Idoso , Vacinas contra Antraz/efeitos adversos , Vacinas contra Antraz/uso terapêutico , Anticorpos Antibacterianos/sangue , Anticorpos Neutralizantes/sangue , Feminino , Humanos , Esquemas de Imunização , Imunização Secundária , Imunoglobulina G/sangue , Masculino , Pessoa de Meia-Idade , Adulto Jovem
12.
JAMA ; 311(17): 1760-9, 2014 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-24794369

RESUMO

IMPORTANCE: Maternal immunization with tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis (Tdap) vaccine could prevent infant pertussis. OBJECTIVE: To evaluate the safety and immunogenicity of Tdap immunization during pregnancy and its effect on infant responses to diphtheria and tetanus toxoids and acellular pertussis (DTaP) vaccine. DESIGN, SETTING, AND PARTICIPANTS: Phase 1-2, randomized, double-blind, placebo-controlled, clinical trial conducted from 2008 to 2012. Forty-eight pregnant women aged 18 to 45 years received Tdap (n = 33) or placebo (n = 15) at 30 to 32 weeks' gestation, with crossover immunization postpartum. INTERVENTIONS: Tdap vaccination at 30 to 32 weeks' gestation or postpartum. MAIN OUTCOMES AND MEASURES: Primary outcomes were maternal and infant adverse events, pertussis illness, and infant growth and development until age 13 months. Secondary outcomes were antibody concentrations in pregnant women before and 4 weeks after Tdap immunization or placebo, at delivery and 2 months' postpartum, and in infants at birth, at 2 months, and after the third and fourth doses of DTaP. RESULTS: No Tdap-associated serious adverse events occurred in women or infants. Injection site reactions after Tdap immunization were reported in 26 (78.8% [95% CI, 61.1%-91.0%]) and 12 (80% [95% CI, 51.9%-95.7%]) pregnant and postpartum women, respectively (P > .99). Systemic symptoms were reported in 12 (36.4% [ 95% CI, 20.4%-54.9%]) and 11 (73.3% [95% CI, 44.9%-92.2%]) pregnant and postpartum women, respectively (P = .03). Growth and development were similar in both infant groups. No cases of pertussis occurred. Significantly higher concentrations of pertussis antibodies were measured at delivery in women who received Tdap during pregnancy vs postpartum (eg, pertussis toxin antibodies: 51.0 EU/mL [95% CI, 37.1-70.1] and 9.1 EU/mL [95% CI, 4.6-17.8], respectively; P < .001) and in their infants at birth (68.8 EU/mL [95% CI, 52.1-90.8] and 14.0 EU/mL [95% CI, 7.3-26.9], respectively; P < .001) and at age 2 months (20.6 EU/mL [95% CI, 14.4-29.6] and 5.3 EU/mL [95% CI, 3.0-9.4], respectively; P < .001). Antibody responses in infants born to women receiving Tdap during pregnancy were not different following the fourth dose of DTaP. CONCLUSIONS AND RELEVANCE: This preliminary assessment did not find an increased risk of adverse events among women who received Tdap vaccine during pregnancy or their infants. For secondary outcomes, maternal immunization with Tdap resulted in high concentrations of pertussis antibodies in infants during the first 2 months of life and did not substantially alter infant responses to DTaP. Further research is needed to provide definitive evidence of the safety and efficacy of Tdap immunization during pregnancy. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00707148.


Assuntos
Vacina contra Difteria, Tétano e Coqueluche/imunologia , Vacinas contra Difteria, Tétano e Coqueluche Acelular/imunologia , Recém-Nascido/imunologia , Coqueluche/prevenção & controle , Adolescente , Adulto , Formação de Anticorpos , Desenvolvimento Infantil , Vacina contra Difteria, Tétano e Coqueluche/administração & dosagem , Vacina contra Difteria, Tétano e Coqueluche/efeitos adversos , Vacinas contra Difteria, Tétano e Coqueluche Acelular/administração & dosagem , Método Duplo-Cego , Feminino , Humanos , Imunização , Lactente , Período Pós-Parto , Gravidez , Terceiro Trimestre da Gravidez , Coqueluche/imunologia , Adulto Jovem
13.
Vaccine ; 32(23): 2732-9, 2014 May 13.
Artigo em Inglês | MEDLINE | ID: mdl-24607004

RESUMO

INTRODUCTION: Reintroduction of Variola major as an agent of bioterrorism remains a concern. Time to seroconversion and plaque reduction neutralizing antibody titers (PRNT) of 1 or 2 standard doses (SD) were compared to a single high dose (HD) of modified vaccinia Ankara (MVA). METHODS: Ninety subjects were randomized 1:1 to receive 1 HD or 2 SD of MVA subcutaneously on Days 0 and 28 in a placebo-controlled trial. Serum was collected for PRNT and ELISA. Subjects were followed for safety for the entire study. RESULTS: The HD was well-tolerated. Using Bavarian Nordic's ELISA, subjects in both groups achieved seroconversion by Study Day 15 (HD) and Day 28 (SD). Before second vaccination, the hazard rate of seroconverting for the HD group was 1.7 times the SD group with a median time for seroconversion of 14 days for both groups. The peak titer of one HD vaccine was superior to one dose of SD vaccine but inferior to the peak titer after the second dose of the SD vaccination regimen. Using Saint Louis University's PRNT, peak titers were 95.8 and 65.2 for the HD and SD groups, respectively, prior to second vaccination. Non-inferiority of the SD group was not established. The proportions of positives were 93.3% (42/45) and 82.2% (37/45) for the HD and SD groups, respectively. The peak titer after two standard doses was superior to that of the HD. CONCLUSIONS: HD MVA was safe and well-tolerated. While the hazard rate for seroconverting was significantly higher in the HD group before second dose, the effect was small as the median time to seroconversion was identical. When comparing PRNT, non-inferiority of one SD was not established and the peak titers were low for both groups. The HD peak response was inferior to the standard two-dose regimen response based on ELISA and PRNT.


Assuntos
Anticorpos Antivirais/sangue , Vacina Antivariólica/administração & dosagem , Varíola/prevenção & controle , Adolescente , Adulto , Anticorpos Neutralizantes/sangue , Feminino , Humanos , Masculino , Testes de Neutralização , Vacina Antivariólica/efeitos adversos , Vacina Antivariólica/imunologia , Ensaio de Placa Viral , Adulto Jovem
14.
PLoS One ; 8(12): e81862, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-24349140

RESUMO

Understanding the microbial content of the air has important scientific, health, and economic implications. While studies have primarily characterized the taxonomic content of air samples by sequencing the 16S or 18S ribosomal RNA gene, direct analysis of the genomic content of airborne microorganisms has not been possible due to the extremely low density of biological material in airborne environments. We developed sampling and amplification methods to enable adequate DNA recovery to allow metagenomic profiling of air samples collected from indoor and outdoor environments. Air samples were collected from a large urban building, a medical center, a house, and a pier. Analyses of metagenomic data generated from these samples reveal airborne communities with a high degree of diversity and different genera abundance profiles. The identities of many of the taxonomic groups and protein families also allows for the identification of the likely sources of the sampled airborne bacteria.


Assuntos
Microbiologia do Ar , Bactérias/genética , DNA Bacteriano/genética , Técnicas de Amplificação de Ácido Nucleico , Filogenia , RNA Ribossômico 16S/genética , Bactérias/classificação , Biodiversidade , DNA Bacteriano/classificação , Monitoramento Ambiental , Genes de RNAr , Metagenômica , Análise de Componente Principal , RNA Ribossômico 16S/classificação
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