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1.
Arch Gynecol Obstet ; 308(1): 73-78, 2023 07.
Artigo em Inglês | MEDLINE | ID: mdl-35831759

RESUMO

PURPOSE: To evaluate how women of child-bearing age perceive the use of remote fetal ECG monitoring technologies. Telemedicine has advanced to the forefront of healthcare delivery, including maternal-fetal medicine. Smart wearable electrocardiogram (ECG) devices can enable pregnant women to monitor their health and that of their fetuses. Such technology would be a logical extension of the telemedicine ecosystem. METHODS: We conducted an observational cross-sectional study via online surveying in the United States. Study participants were recruited using the SurveyMonkey Audience Polling system and responded virtually. In all, the sample consisted of 507 women, aged 18-45 from 45 states, who are expecting to become pregnant in the next five years. Women were asked to identify their willingness to use a wearable ECG device the size of a patch-sized large band-aid on their abdomen. Ten binary or multiple-choice questions were used to gauge population interest and related demographics toward the usage of a wearable ECG device. RESULTS: Of the 507 participants, 461 (91%) women expressed an acceptance of wearable ECG technology throughout the pregnancy as a mechanism for increased frequency of monitoring of maternal and fetal health outside the hospital. 395 (78%) women demonstrated a willingness to wear devices day and night or at least during sleep and 213 (42%) of the women would spend up to $200 on such a device. CONCLUSION: Even though conducted prior to the COVID-19 pandemic, this study clearly indicates a high degree of readiness of prospective pregnant women for telemedicine with continuous health monitoring of the mother-fetus dyad.


Assuntos
COVID-19 , Dispositivos Eletrônicos Vestíveis , Feminino , Gravidez , Humanos , Estados Unidos , Masculino , Estudos Transversais , Ecossistema , Pandemias , Estudos Prospectivos
2.
Lancet Infect Dis ; 21(2): 252-262, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-32946836

RESUMO

BACKGROUND: In the absence of a licensed vaccine, Clostridioides (formerly Clostridium) difficile infection represents a substantial health burden. The aim of this study was to evaluate the efficacy, immunogenicity, and safety of a toxoid vaccine candidate. METHODS: We did a phase 3 multicentre, observer-blind, randomised, controlled trial at 326 hospitals, clinics, and clinical research centres in 27 countries in the USA, Canada, Latin America, Europe, and the Asia-Pacific region. We included adults aged 50 years or older who were considered to be at an increased risk of C difficile infection because they had previously had two hospital stays (each ≥24 h in duration) and had received systemic antibiotics in the previous 12 months (risk stratum 1), or because they were anticipating being admitted to hospital for 72 h or more for elective surgery within 60 days of enrolment (risk stratum 2). Eligible participants were stratified by geographical region and the two risk strata, and randomly assigned (2:1), with a fixed block size of three, to receive either a C difficile toxoid vaccine candidate, containing toxoids A and B (C difficile vaccine candidate group), or a placebo vaccine (placebo group). Participants, investigators, and personnel responsible for collecting safety data and analysing blood and stool samples were masked to group assignment. Personnel responsible for study product preparation and administration were not masked to group assignment. One dose (0·5 mL) of C difficile vaccine candidate or placebo vaccine was administered intramuscularly on days 0, 7, and 30. The primary outcome was the efficacy of the vaccine in preventing symptomatic C difficile infection, defined as having three or more loose stools in a period of 24 h or less, loose stools for 24 h or more, and a PCR-positive test for C difficile toxin B in a loose stool sample, within 3 years after the final vaccine dose. The primary outcome was measured in the modified intention-to-treat population (ie, all participants who received at least one injection of the assigned vaccine). The safety of the vaccine was assessed in the safety analysis set (ie, all participants who had received at least one injection, analysed according to the product received). This study is registered with WHO/ICTRP, number U111-1127-7162, and ClinicalTrials.gov, number NCT01887912, and has been terminated. FINDINGS: Between July 30, 2013, and Nov 17, 2017, we enrolled and randomly assigned 9302 participants to the C difficile vaccine candidate group (n=6201) or to the placebo group (n=3101). 6173 (99·5%) participants in the C difficile vaccine candidate group and 3085 (99·5%) participants in the placebo group received at least one dose of the vaccine. The study was terminated after the first planned interim analysis because of futility. In the C difficile vaccine candidate group, 34 C difficile infections were reported over 11 697·2 person-years at risk (0·29 infections per 100 person-years [95% CI 0·20-0·41]) compared with 16 C difficile infections over 5789·4 person-years at risk in the placebo group (0·28 infections per 100 person-years [0·16-0·45]), indicating a vaccine efficacy of -5·2% (95% CI -104·1 to 43·5). In the C difficile vaccine candidate group, 2847 (46·6%) of 6113 participants reported an adverse event within 30 days of injection compared with 1282 (41·9%) of 3057 participants in the placebo group. The proportion of participants who had an adverse event leading to study discontinuation was 4·8% in both groups (296 participants in the C difficile vaccine candidate group and 146 participants in the placebo group). 1662 (27·2%) participants in the C difficile vaccine candidate group reported at least one serious adverse event compared with 851 (27·8%) participants in the placebo group. INTERPRETATION: In adults at risk for C difficile infection, a bivalent C difficile toxoid vaccine did not prevent C difficile infection. Since the C difficile vaccine candidate met the criteria for futility, the study was terminated and clinical development of this vaccine candidate was stopped. FUNDING: Sanofi Pasteur.


Assuntos
Vacinas Bacterianas/imunologia , Clostridioides difficile , Infecções por Clostridium/prevenção & controle , Idoso , Idoso de 80 Anos ou mais , Vacinas Bacterianas/efeitos adversos , Feminino , Humanos , Esquemas de Imunização , Masculino , Pessoa de Meia-Idade
4.
J Virol ; 93(3)2019 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-30429340

RESUMO

As part of the continuing effort to develop an effective HIV vaccine, we generated a poxviral vaccine vector (previously described) designed to improve on the results of the RV144 phase III clinical trial. The construct, NYVAC-KC, is a replication-competent, attenuated recombinant of the vaccinia virus strain NYVAC. NYVAC is a vector that has been used in many previous clinical studies but is replication deficient. Here, we report a side-by-side comparison of replication-restricted NYVAC and replication-competent NYVAC-KC in a nonhuman primate study, which utilized a prime-boost regimen similar to that of RV144. NYVAC-C and NYVAC-C-KC express the HIV-1 antigens gp140, and Gag/Gag-Pol-Nef-derived virus-like particles (VLPs) from clade C and were used as the prime, with recombinant virus plus envelope protein used as the boost. In nearly every T and B cell immune assay against HIV-1, including neutralization and antibody binding, NYVAC-C-KC induced a greater immune response than NYVAC-C, indicating that replication competence in a poxvirus may improve upon the modestly successful regimen used in the RV144 clinical trial.IMPORTANCE Though the RV144 phase III clinical trial showed promise that an effective vaccine against HIV-1 is possible, a successful vaccine will require improvement over the vaccine candidate (ALVAC) used in the RV144 study. With that goal in mind, we have tested in nonhuman primates an attenuated but replication-competent vector, NYVAC-KC, in direct comparison to its parental vector, NYVAC, which is replication restricted in human cells, similar to the ALVAC vector used in RV144. We have utilized a prime-boost regimen for administration of the vaccine candidate that is similar to the one used in the RV144 study. The results of this study indicate that a replication-competent poxvirus vector may improve upon the effectiveness of the RV144 clinical trial vaccine candidate.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Antígenos HIV/imunologia , Infecções por HIV/imunologia , HIV-1/imunologia , Vacinas Virais/administração & dosagem , Replicação Viral , Produtos do Gene env do Vírus da Imunodeficiência Humana/imunologia , Animais , Anticorpos Neutralizantes/sangue , Anticorpos Anti-HIV/sangue , Infecções por HIV/prevenção & controle , Infecções por HIV/virologia , Humanos , Macaca mulatta , Masculino , Vacinação , Vaccinia virus/imunologia , Vacinas Virais/imunologia
5.
Commun Biol ; 1: 174, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30374464

RESUMO

While the incidence of esophageal adenocarcinoma (EAC) has risen drastically in Western countries over the last 40 years, a similar trend has not been observed for EAC in China. Here, we analyzed mutational spectrum, copy number alterations, and structural variants from whole-genome sequencing of 10 Chinese EAC tumor samples and their matched normal samples, and compared them to previously reported EAC tumor specimens from Western countries. The mutational burden in Chinese EAC was significantly lower than that found in EAC from Western countries. The hallmark A>C mutational signature observed at high frequency in EAC from Western countries, which has been linked to acid reflux, is completely absent in Chinese samples. Furthermore, none of the Chinese samples showed evidence of chromothripsis and genome doubling that are often found in EAC from Western countries. In summary, Chinese EAC tumor samples had distinct genomic profiles and signatures, suggesting that EAC in Chinese individuals may arise from a different etiological pathway.

6.
PLoS One ; 13(9): e0202925, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30208068

RESUMO

BACKGROUND: Helicobacter pylori infection increases risk for gastric cancer. Geographic variation in gastric cancer risk has been attributed to variation in carriage and type of the H. pylori oncogene cagA. Colonization density may also influence disease and cagA has been associated with higher shedding in stool. However, the relationship between H. pylori load in the stool and in the stomach is not clear. METHODS: To investigate possible differences in H. pylori load in the stomach and shedding in stool, H. pylori load and cagA genotype were assessed using droplet digital PCR assays on gastric mucosa and stool samples from 49 urea breath test-positive individuals, including 25 gastric cancer and 24 non-cancer subjects at Henan Cancer Hospital, Henan, China. RESULTS: Quantitation of H. pylori DNA indicated similar gastric loads among cancer and non-cancer cases, but the gastric cancer group had a median H. pylori load in the stool that was six times higher than that of the non-cancer subjects. While the cagA gene was uniformly present among study subjects, only 70% had the East Asian cagA allele, which was significantly associated with gastric cancer (Fisher's Exact Test, p = 0.03). CONCLUSION: H. pylori persists in a subset of gastric cancer cases and thus may contribute to cancer progression. In this East Asian population with a high prevalence of the cagA gene, the East Asian allele could still provide a marker for gastric cancer risk. IMPACT: This study contributes to our understanding of H. pylori dynamics in the context of pathological changes.


Assuntos
Alelos , Antígenos de Bactérias/genética , Proteínas de Bactérias/genética , Fezes/microbiologia , Helicobacter pylori/genética , Helicobacter pylori/fisiologia , Hospitais , Neoplasias Gástricas/microbiologia , Adulto , Idoso , Sequência de Aminoácidos , Antígenos de Bactérias/química , Proteínas de Bactérias/química , China , Feminino , Humanos , Masculino , Pessoa de Meia-Idade
7.
J Clin Microbiol ; 56(9)2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-29925646

RESUMO

Chronic infection with Helicobacter pylori causes peptic ulcers and stomach cancer in a subset of infected individuals. While standard eradication therapy includes multiple antibiotics, treatment failure due to resistance is an increasing clinical problem. Accurate assessment of H. pylori antimicrobial resistance has been limited by slow growth and sampling of few isolates per subject. We established a method to simultaneously quantify H. pylori clarithromycin-resistant (mutant) and -susceptible (wild-type) 23S rRNA gene alleles in both stomach and stool samples using droplet digital PCR (ddPCR). In 49 subjects, we assessed the performance of these assays alongside clarithromycin MIC testing of up to 16 H. pylori isolates per subject and included both cancer (25 subjects) and noncancer (24 subjects) cases. Gastric ddPCR and H. pylori culture showed agreement with urea breath test (UBT) detection of infection in 94% and 88% of subjects, respectively, while stool ddPCR showed agreement with UBT in 92% of subjects. Based on MIC testing of 43 culture-positive cases, 20 subjects had only susceptible isolates, 14 had a mix of susceptible and resistant isolates, and 9 had only resistant isolates. ddPCR of gastric samples indicated that 21 subjects had only wild-type alleles, 13 had a mixed genotype, and 9 had only mutant alleles. Stool ddPCR detected mutant alleles in four subjects for which mutant alleles were not detected by stomach ddPCR, and no resistant isolates were cultured. Our results indicate that ddPCR detects H. pylori clarithromycin resistance-associated genotypes, especially in the context of heteroresistance.


Assuntos
Antibacterianos/farmacologia , Claritromicina/farmacologia , Farmacorresistência Bacteriana/genética , Infecções por Helicobacter/microbiologia , Helicobacter pylori/isolamento & purificação , Reação em Cadeia da Polimerase , Adulto , Idoso , Farmacorresistência Bacteriana/efeitos dos fármacos , Fezes/microbiologia , Feminino , Mucosa Gástrica/microbiologia , Variação Genética , Genótipo , Infecções por Helicobacter/diagnóstico , Helicobacter pylori/efeitos dos fármacos , Helicobacter pylori/genética , Humanos , Masculino , Testes de Sensibilidade Microbiana , Pessoa de Meia-Idade , RNA Ribossômico 23S/genética
8.
Tuberculosis (Edinb) ; 109: 61-68, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29559122

RESUMO

Current diagnostic tests for Mycobacterium tuberculosis (MTB) infection have low prognostic specificity for identifying individuals who will develop tuberculosis (TB) disease, making mass preventive therapy strategies targeting all MTB-infected individuals impractical in high-burden TB countries. Here we discuss general considerations for a risk-targeted test-and-treat strategy based on a highly specific transcriptomic biomarker that can identify individuals who are most likely to progress to active TB disease as well as individuals with TB disease who have not yet presented for medical care. Such risk-targeted strategies may offer a rapid, ethical and cost-effective path towards decreasing the burden of TB disease and interrupting transmission and would also be critical to achieving TB elimination in countries nearing elimination. We also discuss design considerations for a Correlate of Risk Targeted Intervention Study (CORTIS), which could provide proof-of-concept for the strategy. One such study in South Africa is currently enrolling 1500 high-risk and 1700 low-risk individuals, as defined by biomarker status, and is randomizing high-risk participants to TB preventive therapy or standard of care treatment. All participants are monitored for progression to active TB with primary objectives to assess efficacy of the treatment and performance of the biomarker.


Assuntos
Antituberculosos/uso terapêutico , Técnicas Bacteriológicas , Perfilação da Expressão Gênica , Mycobacterium tuberculosis/isolamento & purificação , Medicina de Precisão/métodos , RNA Mensageiro/genética , Transcriptoma , Tuberculose/prevenção & controle , Tomada de Decisão Clínica , Progressão da Doença , Marcadores Genéticos , Predisposição Genética para Doença , Humanos , Fenótipo , Valor Preditivo dos Testes , Estudo de Prova de Conceito , RNA Mensageiro/sangue , Ensaios Clínicos Controlados Aleatórios como Assunto , África do Sul , Tuberculose/genética , Tuberculose/microbiologia , Tuberculose/transmissão
9.
J Immunol ; 199(4): 1476-1489, 2017 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-28687661

RESUMO

In this study, we used a systems vaccinology approach to identify temporal changes in immune response signatures to the yellow fever (YF)-17D vaccine, with the aim of comprehensively characterizing immune responses associated with protective immunity. We conducted a cohort study in which 21 healthy subjects in China were administered one dose of the YF-17D vaccine; PBMCs were collected at 0 h and then at 4 h and days 1, 2, 3, 5, 7, 14, 28, 84, and 168 postvaccination, and analyzed by transcriptional profiling and immunological assays. At 4 h postvaccination, genes associated with innate cell differentiation and cytokine pathways were dramatically downregulated, whereas receptor genes were upregulated, compared with their baseline levels at 0 h. Immune response pathways were primarily upregulated on days 5 and 7, accompanied by the upregulation of the transcriptional factors JUP, STAT1, and EIF2AK2. We also observed robust activation of innate immunity within 2 d postvaccination and a durable adaptive response, as assessed by transcriptional profiling. Coexpression network analysis indicated that lysosome activity and lymphocyte proliferation were associated with dendritic cell (DC) and CD4+ T cell responses; FGL2, NFAM1, CCR1, and TNFSF13B were involved in these associations. Moreover, individuals who were baseline-seropositive for Abs against another flavivirus exhibited significantly impaired DC, NK cell, and T cell function in response to YF-17D vaccination. Overall, our findings indicate that YF-17D vaccination induces a prompt innate immune response and DC activation, a robust Ag-specific T cell response, and a persistent B cell/memory B cell response.


Assuntos
Imunidade Adaptativa/genética , Perfilação da Expressão Gênica , Imunidade Inata/genética , Vacina contra Febre Amarela/imunologia , Adulto , Anticorpos Antivirais/sangue , Linfócitos B/imunologia , Linfócitos T CD4-Positivos/imunologia , Estudos de Coortes , Citocinas/genética , Citocinas/imunologia , Células Dendríticas/imunologia , Desmoplaquinas/genética , Desmoplaquinas/imunologia , Feminino , Regulação da Expressão Gênica , Humanos , Memória Imunológica , Leucócitos Mononucleares/imunologia , Ativação Linfocitária , Masculino , Biologia de Sistemas/métodos , Vacinação , Febre Amarela/prevenção & controle , Vacina contra Febre Amarela/administração & dosagem , gama Catenina
10.
J Virol ; 91(9)2017 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-28202751

RESUMO

We compared the HIV-1-specific immune responses generated by targeting HIV-1 envelope protein (Env gp140) to either CD40 or LOX-1, two endocytic receptors on dendritic cells (DCs), in rhesus macaques primed with a poxvirus vector (NYVAC-KC) expressing Env gp140. The DC-targeting vaccines, humanized recombinant monoclonal antibodies fused to Env gp140, were administered as a boost with poly-ICLC adjuvant either alone or coadministered with the NYVAC-KC vector. All the DC-targeting vaccine administrations with poly-ICLC increased the low-level serum anti-Env IgG responses elicited by NYVAC-KC priming significantly more (up to a P value of 0.01) than in a group without poly-ICLC. The responses were robust and cross-reactive and contained antibodies specific to multiple epitopes within gp140, including the C1, C2, V1, V2, and V3, C4, C5, and gp41 immunodominant regions. The DC-targeting vaccines also elicited modest serum Env-specific IgA responses. All groups gave serum neutralization activity limited to tier 1 viruses and antibody-dependent cytotoxicity responses (ADCC) after DC-targeting boosts. Furthermore, CD4+ and CD8+ T cell responses specific to multiple Env epitopes were strongly boosted by the DC-targeting vaccines plus poly-ICLC. Together, these results indicate that prime-boost immunization via NYVAC-KC and either anti-CD40.Env gp140/poly-ICLC or anti-LOX-1.Env gp140/poly-ICLC induced balanced antibody and T cell responses against HIV-1 Env. Coadministration of NYVAC-KC with the DC-targeting vaccines increased T cell responses but had minimal effects on antibody responses except for suppressing serum IgA responses. Overall, targeting Env to CD40 gave more robust T cell and serum antibody responses with broader epitope representation and greater durability than with LOX-1.IMPORTANCE An effective vaccine to prevent HIV-1 infection does not yet exist. An approach to elicit strong protective antibody development is to direct virus protein antigens specifically to dendritic cells, which are now known to be the key cell type for controlling immunity. In this study, we have tested in nonhuman primates two prototype vaccines engineered to direct the HIV-1 coat protein Env to dendritic cells. These vaccines bind to either CD40 or LOX-1, two dendritic cell surface receptors with different functions and tissue distributions. We tested the vaccines described above in combination with attenuated virus vectors that express Env. Both vaccines, but especially that delivered via CD40, raised robust immunity against HIV-1 as measured by monitoring potentially protective antibody and T cell responses in the blood. The safety and efficacy of the CD40-targeted vaccine justify further development for future human clinical trials.


Assuntos
Vacinas contra a AIDS/imunologia , Linfócitos T CD4-Positivos/imunologia , Antígenos CD40/imunologia , Linfócitos T CD8-Positivos/imunologia , Anticorpos Anti-HIV/imunologia , HIV-1/imunologia , Receptores Depuradores Classe E/imunologia , Produtos do Gene env do Vírus da Imunodeficiência Humana/imunologia , Vacinas contra a AIDS/genética , Animais , Anticorpos Neutralizantes/imunologia , Células CHO , Carboximetilcelulose Sódica/análogos & derivados , Cricetulus , Células Dendríticas/imunologia , Imunoglobulina A/imunologia , Imunoglobulina G/imunologia , Macaca mulatta , Masculino , Poli I-C/imunologia , Polilisina/análogos & derivados , Polilisina/imunologia , Vacinação
11.
Biometrics ; 73(1): 283-293, 2017 03.
Artigo em Inglês | MEDLINE | ID: mdl-27378138

RESUMO

Many diseases arise due to exposure to one of multiple possible pathogens. We consider the situation in which disease counts are available over time from a study region, along with a measure of clinical disease severity, for example, mild or severe. In addition, we suppose a subset of the cases are lab tested in order to determine the pathogen responsible for disease. In such a context, we focus interest on modeling the probabilities of disease incidence given pathogen type. The time course of these probabilities is of great interest as is the association with time-varying covariates such as meteorological variables. In this set up, a natural Bayesian approach would be based on imputation of the unsampled pathogen information using Markov Chain Monte Carlo but this is computationally challenging. We describe a practical approach to inference that is easy to implement. We use an empirical Bayes procedure in a first step to estimate summary statistics. We then treat these summary statistics as the observed data and develop a Bayesian generalized additive model. We analyze data on hand, foot, and mouth disease (HFMD) in China in which there are two pathogens of primary interest, enterovirus 71 (EV71) and Coxackie A16 (CA16). We find that both EV71 and CA16 are associated with temperature, relative humidity, and wind speed, with reasonably similar functional forms for both pathogens. The important issue of confounding by time is modeled using a penalized B-spline model with a random effects representation. The level of smoothing is addressed by a careful choice of the prior on the tuning variance.


Assuntos
Biometria/métodos , Interpretação Estatística de Dados , Modelos Biológicos , Probabilidade , Teorema de Bayes , China/epidemiologia , Enterovirus , Enterovirus Humano D , Doença de Mão, Pé e Boca/epidemiologia , Doença de Mão, Pé e Boca/virologia , Humanos , Incidência , Fatores de Tempo
12.
Lancet ; 388(10040): 158-69, 2016 Jul 09.
Artigo em Inglês | MEDLINE | ID: mdl-27212429

RESUMO

BACKGROUND: Replacement of the trivalent oral poliovirus vaccine (tOPV) with bivalent types 1 and 3 oral poliovirus vaccine (bOPV) and global introduction of inactivated poliovirus vaccine (IPV) are major steps in the polio endgame strategy. In this study, we assessed humoral and intestinal immunity in Latin American infants after three doses of bOPV combined with zero, one, or two doses of IPV. METHODS: This open-label randomised controlled multicentre trial was part of a larger study. 6-week-old full-term infants due for their first polio vaccinations, who were healthy on physical examination, with no obvious medical conditions and no known chronic medical disorders, were enrolled from four investigational sites in Colombia, Dominican Republic, Guatemala, and Panama. The infants were randomly assigned by permuted block randomisation (through the use of a computer-generated list, block size 36) to nine groups, of which five will be discussed in this report. These five groups were randomly assigned 1:1:1:1 to four permutations of schedule: groups 1 and 2 (control groups) received bOPV at 6, 10, and 14 weeks; group 3 (also a control group, which did not count as a permutation) received tOPV at 6, 10, and 14 weeks; group 4 received bOPV plus one dose of IPV at 14 weeks; and group 5 received bOPV plus two doses of IPV at 14 and 36 weeks. Infants in all groups were challenged with monovalent type 2 vaccine (mOPV2) at 18 weeks (groups 1, 3, and 4) or 40 weeks (groups 2 and 5). The primary objective was to assess the superiority of bOPV-IPV schedules over bOPV alone, as assessed by the primary endpoints of humoral immunity (neutralising antibodies-ie, seroconversion) to all three serotypes and intestinal immunity (faecal viral shedding post-challenge) to serotype 2, analysed in the per-protocol population. Serious and medically important adverse events were monitored for up to 6 months after the study vaccination. This study is registered with ClinicalTrials.gov, number NCT01831050, and has been completed. FINDINGS: Between May 20, 2013, and Aug 15, 2013, 940 eligible infants were enrolled and randomly assigned to the five treatment groups (210 to group 1, 210 to group 2, 100 to group 3, 210 to group 4, and 210 to group 5). One infant in group 1 was not vaccinated because their parents withdrew consent after enrolment and randomisation, so 939 infants actually received the vaccinations. Three doses of bOPV or tOPV elicited type 1 and 3 seroconversion rates of at least 97·7%. Type 2 seroconversion occurred in 19 of 198 infants (9·6%, 95% CI 6·2-14·5) in the bOPV-only groups, 86 of 88 (97·7%, 92·1-99·4) in the tOPV-only group (p<0·0001 vs bOPV-only), and 156 of 194 (80·4%, 74·3-85·4) infants in the bOPV-one dose of IPV group (p<0·0001 vs bOPV-only). A further 20 of 193 (10%) infants in the latter group seroconverted 1 week after mOPV2 challenge, resulting in around 98% of infants being seropositive against type 2. After a bOPV-two IPV schedule, all 193 infants (100%, 98·0-100; p<0·0001 vs bOPV-only) seroconverted to type 2. IPV induced small but significant decreases in a composite serotype 2 viral shedding index after mOPV2 challenge. 21 serious adverse events were reported in 20 patients during the study, including two that were judged to be possibly related to the vaccines. Most of the serious adverse events (18 [86%] of 21) and 24 (80%) of the 30 important medical events reported were infections and infestations. No deaths occurred during the study. INTERPRETATION: bOPV provided humoral protection similar to tOPV against polio serotypes 1 and 3. After one or two IPV doses in addition to bOPV, 80% and 100% of infants seroconverted, respectively, and the vaccination induced a degree of intestinal immunity against type 2 poliovirus. FUNDING: Bill & Melinda Gates Foundation.


Assuntos
Anticorpos Neutralizantes/imunologia , Imunidade Humoral/imunologia , Imunidade nas Mucosas/imunologia , Mucosa Intestinal/imunologia , Poliomielite/prevenção & controle , Vacina Antipólio de Vírus Inativado/uso terapêutico , Vacina Antipólio Oral/uso terapêutico , Eliminação de Partículas Virais/imunologia , Colômbia , República Dominicana , Quimioterapia Combinada , Fezes/virologia , Feminino , Guatemala , Humanos , Esquemas de Imunização , Lactente , América Latina , Masculino , Panamá , Poliomielite/imunologia , Soroconversão , Método Simples-Cego
13.
PLoS One ; 11(4): e0153484, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27077384

RESUMO

Improved antigenicity against HIV-1 envelope (Env) protein is needed to elicit vaccine-induced protective immunity in humans. Here we describe the first tests in non-human primates (NHPs) of Env gp140 protein fused to a humanized anti-LOX-1 recombinant antibody for delivering Env directly to LOX-1-bearing antigen presenting cells, especially dendritic cells (DC). LOX-1, or 1ectin-like oxidized low-density lipoprotein (LDL) receptor-1, is expressed on various antigen presenting cells and endothelial cells, and is involved in promoting humoral immune responses. The anti-LOX-1 Env gp140 fusion protein was tested for priming immune responses and boosting responses in animals primed with replication competent NYVAC-KC Env gp140 vaccinia virus. Anti-LOX-1 Env gp140 vaccination elicited robust cellular and humoral responses when used for either priming or boosting immunity. Co-administration with Poly ICLC, a TLR3 agonist, was superior to GLA, a TLR4 agonist. Both CD4+ and CD8+ Env-specific T cell responses were elicited by anti-LOX-1 Env gp140, but in particular the CD4+ T cells were multifunctional and directed to multiple epitopes. Serum IgG and IgA antibody responses induced by anti-LOX-1 Env gp140 against various gp140 domains were cross-reactive across HIV-1 clades; however, the sera neutralized only HIV-1 bearing sequences most similar to the clade C 96ZM651 Env gp140 carried by the anti-LOX-1 vehicle. These data, as well as the safety of this protein vaccine, justify further exploration of this DC-targeting vaccine approach for protective immunity against HIV-1.


Assuntos
HIV-1/imunologia , Receptores Depuradores Classe E/imunologia , Produtos do Gene env do Vírus da Imunodeficiência Humana/imunologia , Vacinas contra a AIDS/imunologia , Animais , Anticorpos Monoclonais Humanizados/imunologia , Anticorpos Antivirais/imunologia , Especificidade de Anticorpos , Humanos , Macaca mulatta , Masculino , Camundongos , Proteínas Recombinantes de Fusão/imunologia , Linfócitos T/imunologia
14.
PLoS One ; 11(4): e0152952, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27124598

RESUMO

INTRODUCTION: Initial evaluation of a candidate vaccine against HIV includes an assessment of the vaccine's ability to generate immune responses. However, the dynamics of vaccine-induced immune responses are unclear. We hypothesized that the IFN-γ producing cytotoxic CD8+ (CD8+ IFN-γ+) T cell responses could be predicted by early IL-2 producing CD4+ (CD4+ IL-2+) helper T cell responses, and we evaluated this hypothesis using data from a phase I/II prophylactic HIV vaccine trial. The objective was to assess the dynamics and correlations between CD4+ IL-2+ T cell and CD8+ IFN-γ+ T cell responses after vaccination with a recombinant adenoviral serotype 5 (rAd5) HIV vaccine. METHODS: We analyzed data from the HVTN 068 HIV vaccine trial, which evaluated the immunogenicity of two different strategies for prime and boost vaccination (rAd5-rAd5 vaccine versus DNA-rAd5) in 66 healthy volunteers. Spearman correlations between immunogenicity markers across time-points were calculated. CD8+ IFN-γ+ T cell response in the rAd5-rAd5 arm was modeled as a function of CD4+ IL-2+ T cell response and time using mixed effects regression models. RESULTS: Moderate to high correlations (r = 0.48-0.76) were observed in the rAd5-rAd5 arm between the CD4+ IL-2+ T cell response at week 2 and later CD8+ IFN-γ+ T cell responses (weeks 2-52). Regression models confirmed this relationship with a significant association between the two markers: for a 1.0% increase in CD4+ IL-2+ T cells at week 2 post-prime, a 0.3% increase in CD8+ IFN-γ+ T cell responses across subsequent time points, including post-boost time points, was observed (p<0.01). CONCLUSION: These results suggest an early and leading role of CD4+ T cells in the cellular response to the rAd5-rAd5 vaccine and in particular the stimulation of cytotoxic CD8+ T cell responses. These results could inform better timing of CD4+ T cell measurements in future clinical trials.


Assuntos
Vacinas contra a AIDS/imunologia , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Infecções por HIV/imunologia , HIV-1/imunologia , Adenoviridae/imunologia , Adolescente , Adulto , Anticorpos Antivirais/imunologia , DNA Recombinante/imunologia , Vetores Genéticos/imunologia , Humanos , Imunização Secundária/métodos , Interferon gama/imunologia , Interleucina-2/imunologia , Pessoa de Meia-Idade , Vacinação/métodos , Vacinas de DNA/imunologia , Adulto Jovem
15.
Stat Med ; 35(11): 1848-65, 2016 May 20.
Artigo em Inglês | MEDLINE | ID: mdl-26530705

RESUMO

In recent years, the availability of infectious disease counts in time and space has increased, and consequently, there has been renewed interest in model formulation for such data. In this paper, we describe a model that was motivated by the need to analyze hand, foot, and mouth disease surveillance data in China. The data are aggregated by geographical areas and by week, with the aims of the analysis being to gain insight into the space-time dynamics and to make short-term predictions, which will aid in the implementation of public health campaigns in those areas with a large predicted disease burden. The model we develop decomposes disease-risk into marginal spatial and temporal components and a space-time interaction piece. The latter is the crucial element, and we use a tensor product spline model with a Markov random field prior on the coefficients of the basis functions. The model can be formulated as a Gaussian Markov random field and so fast computation can be carried out using the integrated nested Laplace approximation approach. A simulation study shows that the model can pick up complex space-time structure and our analysis of hand, foot, and mouth disease data in the central north region of China provides new insights into the dynamics of the disease.


Assuntos
Teorema de Bayes , Doença de Mão, Pé e Boca/epidemiologia , Criança , China/epidemiologia , Simulação por Computador , Surtos de Doenças , Feminino , Humanos , Masculino , Cadeias de Markov , Distribuição de Poisson , Vigilância da População , Fatores de Risco
16.
Nat Med ; 21(10): 1139-41, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-26322580

RESUMO

Given the variation in the HIV-1 viral load (VL) set point across subjects, as opposed to a fairly stable VL over time within an infected individual, it is important to identify the characteristics of the host and virus that affect VL set point. Although recently infected individuals with multiple phylogenetically linked HIV-1 founder variants represent a minority of HIV-1 infections, we found--n two different cohorts--hat more diverse HIV-1 populations in early infection were associated with significantly higher VL 1 year after HIV-1 diagnosis.


Assuntos
Efeito Fundador , Infecções por HIV/genética , HIV-1/isolamento & purificação , Carga Viral , Infecções por HIV/virologia , Humanos
17.
Hum Genomics ; 9: 22, 2015 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-26374103

RESUMO

BACKGROUND: Esophageal adenocarcinoma (EA) is among the leading causes of cancer mortality, especially in developed countries. A high level of somatic copy number alterations (CNAs) accumulates over the decades in the progression from Barrett's esophagus, the precursor lesion, to EA. Accurate identification of somatic CNAs is essential to understand cancer development. Many studies have been conducted for the detection of CNA in EA using microarrays. Next-generation sequencing (NGS) technologies are believed to have advantages in sensitivity and accuracy to detect CNA, yet no NGS-based CNA detection in EA has been reported. RESULTS: In this study, we analyzed whole-exome (WES) and whole-genome sequencing (WGS) data for detecting CNA from a published large-scale genomic study of EA. Two specific comparisons were conducted. First, the recurrent CNAs based on WGS and WES data from 145 EA samples were compared to those found in five previous microarray-based studies. We found that the majority of the previously identified regions were also detected in this study. Interestingly, some novel amplifications and deletions were discovered using the NGS data. In particular, SKI and PRKCZ detected in a deletion region are involved in transforming growth factor-ß pathway, suggesting the potential utility of novel biomarkers for EA. Second, we compared CNAs detected in WGS and WES data from the same 15 EA samples. No large-scale CNA was identified statistically more frequently by WES or WGS, while more focal-scale CNAs were detected by WGS than by WES. CONCLUSIONS: Our results suggest that NGS can replace microarrays to detect CNA in EA. WGS is superior to WES in that it can offer finer resolution for the detection, though if the interest is on recurrent CNAs, WES can be preferable to WGS for its cost-effectiveness.


Assuntos
Adenocarcinoma/genética , Variações do Número de Cópias de DNA/genética , Neoplasias Esofágicas/genética , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Adenocarcinoma/patologia , Esôfago de Barrett/genética , Esôfago de Barrett/patologia , Neoplasias Esofágicas/patologia , Exoma/genética , Genoma Humano , Humanos , Proteínas de Neoplasias/genética
18.
Lancet Infect Dis ; 15(11): 1273-82, 2015 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-26318714

RESUMO

BACKGROUND: Bivalent oral poliovirus vaccine (bOPV; types 1 and 3) is expected to replace trivalent OPV (tOPV) globally by April, 2016, preceded by the introduction of at least one dose of inactivated poliovirus vaccine (IPV) in routine immunisation programmes to eliminate vaccine-associated or vaccine-derived poliomyelitis from serotype 2 poliovirus. Because data are needed on sequential IPV-bOPV schedules, we assessed the immunogenicity of two different IPV-bOPV schedules compared with an all-IPV schedule in infants. METHODS: We did a randomised, controlled, open-label, non-inferiority trial with healthy, full-term (>2·5 kg birthweight) infants aged 8 weeks (± 7 days) at six well-child clinics in Santiago, Chile. We used supplied lists to randomly assign infants (1:1:1) to receive three polio vaccinations (IPV by injection or bOPV as oral drops) at age 8, 16, and 24 weeks in one of three sequential schedules: IPV-bOPV-bOPV, IPV-IPV-bOPV, or IPV-IPV-IPV. We did the randomisation with blocks of 12 stratified by study site. All analyses were done in a masked manner. Co-primary outcomes were non-inferiority of the bOPV-containing schedules compared with the all-IPV schedule for seroconversion (within a 10% margin) and antibody titres (within two-thirds log2 titres) to poliovirus serotypes 1 and 3 at age 28 weeks, analysed in the per-protocol population. Secondary outcomes were seroconversion and titres to serotype 2 and faecal shedding for 4 weeks after a monovalent OPV type 2 challenge at age 28 weeks. Safety analyses were done in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, number NCT01841671, and is closed to new participants. FINDINGS: Between April 25 and August 1, 2013, we assigned 570 infants to treatment: 190 to IPV-bOPV-bOPV, 192 to IPV-IPV-bOPV, and 188 to IPV-IPV-IPV. 564 (99%) were vaccinated and included in the intention-to-treat cohort, and 537 (94%) in the per-protocol analyses. In the IPV-bOPV-bOPV, IPV-IPV-bOPV, and IPV-IPV-IPV groups, respectively, the proportions of children with seroconversion to type 1 poliovirus were 166 (98·8%) of 168, 95% CI 95·8-99·7; 178 (100%), 97·9-100·0; and 175 (100%), 97·9-100·0. Proportions with seroconvsion to type 3 poliovirus were 163 (98·2%) of 166, 94·8-99·4; 177 (100%), 97·9-100·0, and 172 (98·9%) of 174, 95·9-99·7. Non-inferiority was thus shown for the bOPV-containing schedules compared with the all-IPV schedule, with no significant differences between groups. In the IPV-bOPV-bOPV, IPV-IPV-bOPV, and IPV-IPV-IPV groups, respectively, the proportions of children with seroprotective antibody titres to type 1 poliovirus were 168 (98·8%) of 170, 95% CI 95·8-99·7; 181 (100%), 97·9-100·0; and 177 (100%), 97·9-100·0. Proportions to type 3 poliovirus were 166 (98·2%) of 169, 94·9-99·4; 180 (100%), 97·9-100·0; and 174 (98·9%) of 176, 96·0-99·7. Non-inferiority comparisons could not be done for this outcome because median titres for the groups receiving OPV were greater than the assay's upper limit of detection (log2 titres >10·5). The proportions of children seroconverting to type 2 poliovirus in the IPV-bOPV-bOPV, IPV-IPV-bOPV, and IPV-IPV-IPV groups, respectively, were 130 (77·4%) of 168, 95% CI 70·5-83·0; 169 (96·0%) of 176, 92·0-98·0; and 175 (100%), 97·8-100. IPV-bOPV schedules resulted in almost a 0·3 log reduction of type 2 faecal shedding compared with the IPV-only schedule. No participants died during the trial; 81 serious adverse events were reported, of which one was thought to be possibly vaccine-related (intestinal intussusception). INTERPRETATION: Seroconversion rates against polioviruses types 1 and 3 were non-inferior in sequential schedules containing IPV and bOPV, compared with an all-IPV schedule, and proportions of infants with protective antibodies were high after all three schedules. One or two doses of bOPV after IPV boosted intestinal immunity for poliovirus type 2, suggesting possible cross protection. Additionally, there was evidence of humoral priming for type 2 from one dose of IPV. Our findings could give policy makers flexibility when choosing a vaccination schedule, especially when trying to eliminate vaccine-associated and vaccine-derived poliomyelitis. FUNDING: Bill & Melinda Gates Foundation.


Assuntos
Esquemas de Imunização , Poliomielite/prevenção & controle , Vacina Antipólio de Vírus Inativado/administração & dosagem , Vacina Antipólio de Vírus Inativado/imunologia , Vacina Antipólio Oral/administração & dosagem , Vacina Antipólio Oral/imunologia , Vacinação/métodos , Anticorpos Antivirais/sangue , Chile , Fezes/virologia , Feminino , Voluntários Saudáveis , Humanos , Lactente , Masculino , Vacina Antipólio de Vírus Inativado/efeitos adversos , Vacina Antipólio Oral/efeitos adversos , Resultado do Tratamento , Eliminação de Partículas Virais
19.
J Virol ; 89(16): 8525-39, 2015 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-26041302

RESUMO

UNLABELLED: We compared the HIV-1-specific cellular and humoral immune responses elicited in rhesus macaques immunized with two poxvirus vectors (NYVAC and ALVAC) expressing the same HIV-1 antigens from clade C, Env gp140 as a trimeric cell-released protein and a Gag-Pol-Nef polyprotein as Gag-induced virus-like particles (VLPs) (referred to as NYVAC-C and ALVAC-C). The immunization protocol consisted of two doses of the corresponding poxvirus vector plus two doses of a combination of the poxvirus vector and a purified HIV-1 gp120 protein from clade C. This immunogenicity profile was also compared to that elicited by vaccine regimens consisting of two doses of the ALVAC vector expressing HIV-1 antigens from clades B/E (ALVAC-vCP1521) plus two doses of a combination of ALVAC-vCP1521 and HIV-1 gp120 protein from clades B/E (similar to the RV144 trial regimen) or clade C. The results showed that immunization of macaques with NYVAC-C stimulated at different times more potent HIV-1-specific CD4(+) T-cell responses and induced a trend toward higher-magnitude HIV-1-specific CD8(+) T-cell immune responses than did ALVAC-C. Furthermore, NYVAC-C induced a trend toward higher levels of binding IgG antibodies against clade C HIV-1 gp140, gp120, or murine leukemia virus (MuLV) gp70-scaffolded V1/V2 and toward best cross-clade-binding IgG responses against HIV-1 gp140 from clades A, B, and group M consensus, than did ALVAC-C. Of the linear binding IgG responses, most were directed against the V3 loop in all immunization groups. Additionally, NYVAC-C and ALVAC-C also induced similar levels of HIV-1-neutralizing antibodies and antibody-dependent cellular cytotoxicity (ADCC) responses. Interestingly, binding IgA antibody levels against HIV-1 gp120 or MuLV gp70-scaffolded V1/V2 were absent or very low in all immunization groups. Overall, these results provide a comprehensive survey of the immunogenicity of NYVAC versus ALVAC expressing HIV-1 antigens in nonhuman primates and indicate that NYVAC may represent an alternative candidate to ALVAC in the development of a future HIV-1 vaccine. IMPORTANCE: The finding of a safe and effective HIV/AIDS vaccine immunogen is one of the main research priorities. Here, we generated two poxvirus-based HIV vaccine candidates (NYVAC and ALVAC vectors) expressing the same clade C HIV-1 antigens in separate vectors, and we analyzed in nonhuman primates their immunogenicity profiles. The results showed that immunization with NYVAC-C induced a trend toward higher HIV-1-specific cellular and humoral immune responses than did ALVAC-C, indicating that this new NYVAC vector could be a novel optimized HIV/AIDS vaccine candidate for human clinical trials.


Assuntos
Vacinas contra a AIDS/imunologia , Produtos do Gene env/metabolismo , Vetores Genéticos/imunologia , Infecções por HIV/prevenção & controle , Vacinas Sintéticas/imunologia , Vacinas Virais/imunologia , Animais , Anticorpos Neutralizantes , Embrião de Galinha , Anticorpos Anti-HIV , Antígenos HIV/metabolismo , Macaca mulatta , Poxviridae/genética , Regiões Promotoras Genéticas/genética , Ensaio de Placa Viral
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