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1.
J Infect Dis ; 2019 Oct 04.
Artigo em Inglês | MEDLINE | ID: mdl-31581292

RESUMO

BACKGROUND: Multiple factors influence the HIV antibody response produced during natural infection, leading to responses that can vary in specificity, strength, and breadth. METHODS: People who inject drugs identified as recently infected with HIV (n=23) were analyzed for clustering of their viral sequences (genetic distance <2%). Longitudinal antibody responses were identified for neutralizing antibody (Nab) potential, and differences in antibody subclass, specificity, and Fc receptor ligation using pseudovirus entry and multiplexed Fc array assays, respectively. Responses were analyzed for differences between subject groups defined by similarity in the sequence of the infecting virus. RESULTS: Viral sequences from infected individuals were grouped into three distinct clusters with seven unclustered individuals. Subjects in cluster one generally had lower antibody response magnitudes with the exception of antibodies targeting the V1/V2 region. Subjects in clusters two and three typically had higher antibody response magnitudes, with the Fv specificity of cluster two favoring gp140 recognition. NAb responses were significantly different between clusters for 3/18 pseudoviruses examined (p<0.05), but there were no differences in overall NAb breadth (p=0.62). DISCUSSION: These data demonstrate that individuals infected with similar viral strains can generate partially similar antibody responses, but these do not drastically differ from individuals infected with relatively unrelated strains.

2.
Clin Infect Dis ; 2019 Sep 18.
Artigo em Inglês | MEDLINE | ID: mdl-31532827

RESUMO

INTRODUCTION: After scaleup of antiretroviral therapy (ART), routine annual viral load monitoring has been adopted by most countries, but reduced frequency of viral load monitoring may offer cost savings in resource limited settings. We investigated if viral load monitoring frequency could be reduced while maintaining detection of treatment failure. METHODS: The Rakai Health Sciences Program performed routine, biannual viral load monitoring on 2,489 HIV infected persons (age 15+). Based on these data, we built a two-stage simulation model to compare different viral load monitoring schemes. We fit Weibull regression models for time to viral load above 1000 copies/ml (treatment failure), and simulated data for 10,000 individuals over 5 years to compare five monitoring schemes to the current viral load testing every six months and testing every 12 months. RESULTS: Among seven monitoring schemes tested, monitoring every six months for all subjects had the fewest months of undetected failure but also had the highest number of viral load tests. Adaptive schemes using previous viral load measurements to inform future monitoring significantly decreased the number of viral load tests without markedly increasing the number of months of undetected failure. The best adaptive monitoring scheme resulted in a 67% reduction in viral load measurements, while increasing the months of undetected failure by <20%. CONCLUSIONS: Adaptive viral load monitoring based on previous viral load measurements may be optimal for maintaining patient care while reducing costs, allowing more patients to be treated and monitored. Future empirical studies to evaluate differentiated monitoring are warranted.

3.
Clin Infect Dis ; 2019 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-31504347

RESUMO

BACKGROUND: Patients with HIV and low CD4 counts starting antiretroviral therapy (ART) are at high risk for immune reconstitution inflammatory syndrome (IRIS) and death. METHODS: To investigate the clinical impact of IRIS in adults with HIV and CD4 counts below 100 cells/µL starting ART, we designed an international, prospective, observational study in United States, Thailand, and Kenya. An independent review committee adjudicated IRIS events. We used Cox models to investigate associations between baseline biomarkers, IRIS, immune recovery at week 48, and death by week 48. RESULTS: We enrolled 506 participants, 39.3% of whom were women. Median age was 37 years (IQR 31-45) and CD4 T cell count was 29 cells/µL (IQR 11-56). Within 6 months of ART initiation, 97 (19.2%) participants developed IRIS and 31 (6.5%) died. Participants with lower hemoglobin at study start were at higher risk of IRIS (HR 1.2, p=0.004). IRIS was independently associated with increased risk of death even after adjustment for known risk factors (HR 3.2, P=0.031). In addition, being female (P=0.004), having lower BMI (P=0.003), higher WBC (P=0.005) and higher D-dimer levels (P=0.044) were also significantly associated with increased risk of death. Decision tree analysis identified hemoglobin less than 8.5 g/dL as highly predictive of IRIS and CRP>106 µg/ml and BMI < 15.6 kg/m2 as predictive of death . CONCLUSIONS: For patients with HIV and severe immunosuppression who are initiating ART, baseline low BMI and hemoglobin, and high CRP and D-dimer may be clinically useful predictors of IRIS and death risk.

4.
Science ; 365(6452): 505-509, 2019 08 02.
Artigo em Inglês | MEDLINE | ID: mdl-31371616

RESUMO

Technologies that define the atomic-level structure of neutralization-sensitive epitopes on viral surface proteins are transforming vaccinology and guiding new vaccine development approaches. Previously, iterative rounds of protein engineering were performed to preserve the prefusion conformation of the respiratory syncytial virus (RSV) fusion (F) glycoprotein, resulting in a stabilized subunit vaccine candidate (DS-Cav1), which showed promising results in mice and macaques. Here, phase I human immunogenicity data reveal a more than 10-fold boost in neutralizing activity in serum from antibodies targeting prefusion-specific surfaces of RSV F. These findings represent a clinical proof of concept for structure-based vaccine design, suggest that development of a successful RSV vaccine will be feasible, and portend an era of precision vaccinology.

5.
Sci Transl Med ; 11(499)2019 07 03.
Artigo em Inglês | MEDLINE | ID: mdl-31270270

RESUMO

Public health emergencies, such as an Ebola disease outbreak, provide a complex and challenging environment for the evaluation of candidate vaccines. Here, we outline the need for flexible and responsive vaccine trial designs to be used in public health emergencies, and we summarize recommendations for their use in this setting.

6.
Cell ; 178(3): 567-584.e19, 2019 Jul 25.
Artigo em Inglês | MEDLINE | ID: mdl-31348886

RESUMO

The vaccine-mediated elicitation of antibodies (Abs) capable of neutralizing diverse HIV-1 strains has been a long-standing goal. To understand how broadly neutralizing antibodies (bNAbs) can be elicited, we identified, characterized, and tracked five neutralizing Ab lineages targeting the HIV-1-fusion peptide (FP) in vaccinated macaques over time. Genetic and structural analyses revealed two of these lineages to belong to a reproducible class capable of neutralizing up to 59% of 208 diverse viral strains. B cell analysis indicated each of the five lineages to have been initiated and expanded by FP-carrier priming, with envelope (Env)-trimer boosts inducing cross-reactive neutralization. These Abs had binding-energy hotspots focused on FP, whereas several FP-directed Abs induced by immunization with Env trimer-only were less FP-focused and less broadly neutralizing. Priming with a conserved subregion, such as FP, can thus induce Abs with binding-energy hotspots coincident with the target subregion and capable of broad neutralization.

7.
Lancet HIV ; 6(7): e475-e482, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31078451

RESUMO

Despite the recent success of antiretrovirals for HIV prevention, additional, more effective, or more acceptable biomedical interventions will ultimately be needed to end the HIV epidemic. Designing clinical trials to evaluate the efficacy of new products that reduce HIV infection risk is challenging because of the existence of highly effective interventions to prevent HIV. However, the implementation of these interventions is uneven, and the fact that multiple HIV prevention efficacy trials are currently evaluating new products means the field confronts uncertainty in the emerging standard of prevention. In this Viewpoint, we take stock of the current state of HIV prevention, and subsequently discuss the key challenges in designing future trials to evaluate the next generation of HIV prevention products. We also highlight gaps in the knowledge base that need to be addressed to advance the design of research. Future trials are tenable, even in the context of existing and effective interventions, and should involve careful statistical approaches and multidisciplinary collaborative design.

8.
Lancet ; 393(10174): 889-898, 2019 03 02.
Artigo em Inglês | MEDLINE | ID: mdl-30686586

RESUMO

BACKGROUND: mAb114 is a single monoclonal antibody that targets the receptor-binding domain of Ebola virus glycoprotein, which prevents mortality in rhesus macaques treated after lethal challenge with Zaire ebolavirus. Here we present expedited data from VRC 608, a phase 1 study to evaluate mAb114 safety, tolerability, pharmacokinetics, and immunogenicity. METHODS: In this phase 1, dose-escalation study (VRC 608), conducted at the US National Institutes of Health (NIH) Clinical Center (Bethesda, MD, USA), healthy adults aged 18-60 years were sequentially enrolled into three mAb114 dose groups of 5 mg/kg, 25 mg/kg, and 50 mg/kg. The drug was given to participants intravenously over 30 min, and participants were followed for 24 weeks. Participants were only enrolled into increased dosing groups after interim safety assessments. Our primary endpoints were safety and tolerability, with pharmacokinetic and anti-drug antibody assessments as secondary endpoints. We assessed safety and tolerability in all participants who received study drug by monitoring clinical laboratory data and self-report and direct clinician assessment of prespecified infusion-site symptoms 3 days after infusion and systemic symptoms 7 days after infusion. Unsolicited adverse events were recorded for 28 days. Pharmacokinetic and anti-drug antibody assessments were completed in participants with at least 56 days of data. This trial is registered with ClinicalTrials.gov, number NCT03478891, and is active but no longer recruiting. FINDINGS: Between May 16, and Sept 27, 2018, 19 eligible individuals were enrolled. One (5%) participant was not infused because intravenous access was not adequate. Of 18 (95%) remaining participants, three (17%) were assigned to the 5 mg/kg group, five (28%) to the 25 mg/kg group, and ten (55%) to the 50 mg/kg group, each of whom received a single infusion of mAb114 at their assigned dose. All infusions were well tolerated and completed over 30-37 min with no infusion reactions or rate adjustments. All participants who received the study drug completed the safety assessment of local and systemic reactogenicity. No participants reported infusion-site symptoms. Systemic symptoms were all mild and present only in four (22%) of 18 participants across all dosing groups. No unsolicited adverse events occurred related to mAb114 and one serious adverse event occurred that was unrelated to mAb114. mAb114 has linear pharmacokinetics and a half-life of 24·2 days (standard error of measurement 0·2) with no evidence of anti-drug antibody development. INTERPRETATION: mAb114 was well tolerated, showed linear pharmacokinetics, and was easily and rapidly infused, making it an attractive and deployable option for treatment in outbreak settings. FUNDING: Vaccine Research Center, US National Institute of Allergy and Infectious Diseases, and NIH.


Assuntos
Anticorpos Monoclonais/imunologia , Anticorpos Monoclonais/farmacocinética , Vacinas contra Ebola/imunologia , Ebolavirus/imunologia , Doença pelo Vírus Ebola/imunologia , Fatores Imunológicos/imunologia , Fatores Imunológicos/farmacocinética , Proteínas Virais/imunologia , Administração Intravenosa , Adulto , Animais , Anticorpos Monoclonais/administração & dosagem , Relação Dose-Resposta a Droga , Vacinas contra Ebola/administração & dosagem , Feminino , Doença pelo Vírus Ebola/prevenção & controle , Humanos , Fatores Imunológicos/administração & dosagem , Macaca mulatta , Masculino , Pessoa de Meia-Idade , Adulto Jovem
9.
Artigo em Inglês | MEDLINE | ID: mdl-30170123

RESUMO

BACKGROUND: Caspase activation and recruitment domain 11 (CARD11) encodes a scaffold protein in lymphocytes that links antigen receptor engagement with downstream signaling to nuclear factor κB, c-Jun N-terminal kinase, and mechanistic target of rapamycin complex 1. Germline CARD11 mutations cause several distinct primary immune disorders in human subjects, including severe combined immune deficiency (biallelic null mutations), B-cell expansion with nuclear factor κB and T-cell anergy (heterozygous, gain-of-function mutations), and severe atopic disease (loss-of-function, heterozygous, dominant interfering mutations), which has focused attention on CARD11 mutations discovered by using whole-exome sequencing. OBJECTIVES: We sought to determine the molecular actions of an extended allelic series of CARD11 and to characterize the expanding range of clinical phenotypes associated with heterozygous CARD11 loss-of-function alleles. METHODS: Cell transfections and primary T-cell assays were used to evaluate signaling and function of CARD11 variants. RESULTS: Here we report on an expanded cohort of patients harboring novel heterozygous CARD11 mutations that extend beyond atopy to include other immunologic phenotypes not previously associated with CARD11 mutations. In addition to (and sometimes excluding) severe atopy, heterozygous missense and indel mutations in CARD11 presented with immunologic phenotypes similar to those observed in signal transducer and activator of transcription 3 loss of function, dedicator of cytokinesis 8 deficiency, common variable immunodeficiency, neutropenia, and immune dysregulation, polyendocrinopathy, enteropathy, X-linked-like syndrome. Pathogenic variants exhibited dominant negative activity and were largely confined to the CARD or coiled-coil domains of the CARD11 protein. CONCLUSION: These results illuminate a broader phenotypic spectrum associated with CARD11 mutations in human subjects and underscore the need for functional studies to demonstrate that rare gene variants encountered in expected and unexpected phenotypes must nonetheless be validated for pathogenic activity.

10.
PLoS Pathog ; 14(8): e1007246, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30142226

RESUMO

Chronic activation of the immune system in HIV infection is one of the strongest predictors of morbidity and mortality. As such, approaches that reduce immune activation have received considerable interest. Previously, we demonstrated that administration of a type I interferon receptor antagonist (IFN-1ant) during acute SIV infection of rhesus macaques results in increased virus replication and accelerated disease progression. Here, we administered a long half-life PASylated IFN-1ant to ART-treated and ART-naïve macaques during chronic SIV infection and measured expression of interferon stimulated genes (ISG) by RNA sequencing, plasma viremia, plasma cytokines, T cell activation and exhaustion as well as cell-associated virus in CD4 T cell subsets sorted from peripheral blood and lymph nodes. Our study shows that IFN-1ant administration in both ART-suppressed and ART-untreated chronically SIV-infected animals successfully results in reduction of IFN-I-mediated inflammation as defined by reduced expression of ISGs but had no effect on plasma levels of IL-1ß, IL-1ra, IL-6 and IL-8. Unlike in acute SIV infection, we observed no significant increase in plasma viremia up to 25 weeks after IFN-1ant administration or up to 15 weeks after ART interruption. Likewise, cell-associated virus measured by SIV gag DNA copies was similar between IFN-1ant and placebo groups. In addition, evaluation of T cell activation and exhaustion by surface expression of CD38, HLA-DR, Ki67, LAG-3, PD-1 and TIGIT, as well as transcriptome analysis showed no effect of IFN-I blockade. Thus, our data show that blocking IFN-I signaling during chronic SIV infection suppresses IFN-I-related inflammatory pathways without increasing virus replication, and thus may constitute a safe therapeutic intervention in chronic HIV infection.

11.
Immunity ; 49(2): 301-311.e5, 2018 Aug 21.
Artigo em Inglês | MEDLINE | ID: mdl-30076101

RESUMO

An important class of HIV-1 broadly neutralizing antibodies, termed the VRC01 class, targets the conserved CD4-binding site (CD4bs) of the envelope glycoprotein (Env). An engineered Env outer domain (OD) eOD-GT8 60-mer nanoparticle has been developed as a priming immunogen for eliciting VRC01-class precursors and is planned for clinical trials. However, a substantial portion of eOD-GT8-elicited antibodies target non-CD4bs epitopes, potentially limiting its efficacy. We introduced N-linked glycans into non-CD4bs surfaces of eOD-GT8 to mask irrelevant epitopes and evaluated these mutants in a mouse model that expressed diverse immunoglobulin heavy chains containing human IGHV1-2∗02, the germline VRC01 VH segment. Compared to the parental eOD-GT8, a mutant with five added glycans stimulated significantly higher proportions of CD4bs-specific serum responses and CD4bs-specific immunoglobulin G+ B cells including VRC01-class precursors. These results demonstrate that glycan masking can limit elicitation of off-target antibodies and focus immune responses to the CD4bs, a major target of HIV-1 vaccine design.

13.
Stat Med ; 37(7): 1047-1058, 2018 Mar 30.
Artigo em Inglês | MEDLINE | ID: mdl-29280170

RESUMO

Testing the equality of 2 proportions for a control group versus a treatment group is a well-researched statistical problem. In some settings, there may be strong historical data that allow one to reliably expect that the control proportion is one, or nearly so. While one-sample tests or comparisons to historical controls could be used, neither can rigorously control the type I error rate in the event the true control rate changes. In this work, we propose an unconditional exact test that exploits the historical information while controlling the type I error rate. We sequentially construct a rejection region by first maximizing the rejection region in the space where all controls have an event, subject to the constraint that our type I error rate does not exceed α for any true event rate; then with any remaining α we maximize the additional rejection region in the space where one control avoids the event, and so on. When the true control event rate is one, our test is the most powerful nonrandomized test for all points in the alternative space. When the true control event rate is nearly one, we demonstrate that our test has equal or higher mean power, averaging over the alternative space, than a variety of well-known tests. For the comparison of 4 controls and 4 treated subjects, our proposed test has higher power than all comparator tests. We demonstrate the properties of our proposed test by simulation and use our method to design a malaria vaccine trial.

14.
N Engl J Med ; 377(15): 1438-1447, 2017 10 12.
Artigo em Inglês | MEDLINE | ID: mdl-29020589

RESUMO

BACKGROUND: The safety and efficacy of vaccines to prevent Ebola virus disease (EVD) were unknown when the incidence of EVD was peaking in Liberia. METHODS: We initiated a randomized, placebo-controlled, phase 3 trial of the chimpanzee adenovirus 3 vaccine (ChAd3-EBO-Z) and the recombinant vesicular stomatitis virus vaccine (rVSV∆G-ZEBOV-GP) in Liberia. A phase 2 subtrial was embedded to evaluate safety and immunogenicity. Because the incidence of EVD declined in Liberia, the phase 2 component was expanded and the phase 3 component was eliminated. RESULTS: A total of 1500 adults underwent randomization and were followed for 12 months. The median age of the participants was 30 years; 36.6% of the participants were women. During the week after the administration of vaccine or placebo, adverse events occurred significantly more often with the active vaccines than with placebo; these events included injection-site reactions (in 28.5% of the patients in the ChAd3-EBO-Z group and 30.9% of those in the rVSV∆G-ZEBOV-GP group, as compared with 6.8% of those in the placebo group), headache (in 25.1% and 31.9%, vs. 16.9%), muscle pain (in 22.3% and 26.9%, vs. 13.3%), feverishness (in 23.9% and 30.5%, vs. 9.0%), and fatigue (in 14.0% and 15.4%, vs. 8.8%) (P<0.001 for all comparisons); these differences were not seen at 1 month. Serious adverse events within 12 months after injection were seen in 40 participants (8.0%) in the ChAd3-EBO-Z group, in 47 (9.4%) in the rVSV∆G-ZEBOV-GP group, and in 59 (11.8%) in the placebo group. By 1 month, an antibody response developed in 70.8% of the participants in the ChAd3-EBO-Z group and in 83.7% of those in the rVSV∆G-ZEBOV-GP group, as compared with 2.8% of those in the placebo group (P<0.001 for both comparisons). At 12 months, antibody responses in participants in the ChAd3-EBO-Z group (63.5%) and in those in the rVSV∆G-ZEBOV-GP group (79.5%) remained significantly greater than in those in the placebo group (6.8%, P<0.001 for both comparisons). CONCLUSIONS: A randomized, placebo-controlled phase 2 trial of two vaccines that was rapidly initiated and completed in Liberia showed the capability of conducting rigorous research during an outbreak. By 1 month after vaccination, the vaccines had elicited immune responses that were largely maintained through 12 months. (Funded by the National Institutes of Allergy and Infectious Diseases and the Liberian Ministry of Health; PREVAIL I ClinicalTrials.gov number, NCT02344407 .).


Assuntos
Vacinas contra Ebola/efeitos adversos , Vacinas contra Ebola/imunologia , Ebolavirus/imunologia , Doença pelo Vírus Ebola/prevenção & controle , Adenoviridae , Adulto , Animais , Surtos de Doenças , Método Duplo-Cego , Feminino , Febre/etiologia , Soropositividade para HIV/complicações , Cefaleia/etiologia , Doença pelo Vírus Ebola/complicações , Doença pelo Vírus Ebola/imunologia , Humanos , Injeções Intramusculares/efeitos adversos , Libéria , Masculino , Mialgia/etiologia , Pan troglodytes , RNA Viral/sangue , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Vesiculovirus
15.
Curr Top Microbiol Immunol ; 411: 229-261, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28918539

RESUMO

The Ebola virus disease outbreak that began in Western Africa in December 2013 was unprecedented in both scope and spread, and the global response was slower and less coherent than was optimal given the scale and pace of the epidemic. Past experience with limited localized outbreaks, lack of licensed medical countermeasures, reluctance by first responders to direct scarce resources to clinical research, community resistance to outside interventions, and lack of local infrastructure were among the factors delaying clinical research during the outbreak. Despite these hurdles, the global health community succeeded in accelerating Ebola virus vaccine development, in a 5-month interval initiating phase I trials in humans in September 2014 and initiating phase II/III trails in February 2015. Each of the three Ebola virus disease-affected countries, Sierra Leone, Guinea, and Liberia, conducted a phase II/III Ebola virus vaccine trial. Only one of these trials evaluating recombinant vesicular stomatitis virus expressing Ebola virus glycoprotein demonstrated vaccine efficacy using an innovative mobile ring vaccination trial design based on a ring vaccination strategy responsible for eradicating smallpox that reached areas of new outbreaks. Thoughtful and intensive community engagement in each country enabled the critical community partnership and acceptance of the phase II/III in each country. Due to the delayed clinical trial initiation, relative to the epidemiologic peak of the outbreak in the three countries, vaccine interventions may or may not have played a major role in bringing the epidemic under control. Having demonstrated that clinical trials can be performed during a large outbreak, the global research community can now build on the experience to implement trials more rapidly and efficiently in future outbreaks. Incorporating clinical research needs into planning for future health emergencies and understanding what kind of trial designs is needed for reliable results in an epidemic of limited duration should improve global response to future infectious disease outbreaks.

16.
Clin Infect Dis ; 65(8): 1308-1315, 2017 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-28535179

RESUMO

Background: Human immunodeficiency virus type 1 (HIV-1) persists in latently infected resting CD4+ T cells (rCD4 cells), posing a major barrier to curing HIV-1 infection. Previous studies have quantified this pool of latently infected cells in Americans; however, no study has quantified this reservoir in sub-Saharan Africans, who make up the largest population of HIV-1-infected individuals globally. Methods: Peripheral blood was collected from 70 virally suppressed HIV-1-infected individuals from Rakai District, Uganda, who had initiated antiretroviral therapy (ART) during chronic infection. The quantitative viral outgrowth assay was used to determine frequency of latently infected rCD4 cells containing replication-competent virus. Multivariate regression was used to identify correlates of reservoir size and to compare reservoir size between this Ugandan cohort and a previously studied cohort of individuals from Baltimore, Maryland. Results: The median frequency of latently infected rCD4 cells in this Ugandan cohort was 0.36 infectious units per million cells (IUPM; 95% confidence interval, 0.26-0.55 IUPM), 3-fold lower than the frequency observed in the Baltimore cohort (1.08 IUPM; .72-1.49 IUPM; P < .001). Reservoir size in Ugandans was correlated positively with set-point viral load and negatively with duration of viral suppression. Conclusions: Virally suppressed Ugandans had a 3-fold lower frequency of rCD4 cells latently infected with replication-competent HIV-1, compared with previous observations in a cohort of American patients, also treated with ART during chronic infection. The biological mechanism driving the observed smaller reservoir in Ugandans is of interest and may be of significance to HIV-1 eradication efforts.


Assuntos
Linfócitos T CD4-Positivos/virologia , Infecções por HIV/epidemiologia , Infecções por HIV/virologia , HIV-1 , Adulto , Fármacos Anti-HIV/uso terapêutico , Estudos de Coortes , Feminino , Infecções por HIV/tratamento farmacológico , HIV-1/patogenicidade , HIV-1/fisiologia , Humanos , Masculino , Pessoa de Meia-Idade , RNA Viral/sangue , Uganda/epidemiologia , Carga Viral , Latência Viral
17.
Clin Nucl Med ; 42(5): 329-334, 2017 May.
Artigo em Inglês | MEDLINE | ID: mdl-28288041

RESUMO

BACKGROUND: While PET using F-FDG is most commonly used for imaging malignant tumors, vaccination is known to cause transient inflammation of lymph nodes inducing positive findings on F-FDG PET scans. The pattern, magnitude, and duration of lymph node activation following vaccination have not been clearly defined. Furthermore, the addition of adjuvants to vaccines can further enhance the immune response. The presented study was designed to define lymph node activation following administration of the Food and Drug Administration-licensed human papillomavirus vaccines, Cervarix and Gardasil, which contain similar antigens with different adjuvants. METHODS: Twenty-seven women aged 18 to 25 years were randomized to receive either Cervarix or Gardasil in the clinical trial VRC 900. Fifteen subjects participated in the PET/CT portion of the trial and received scans of lymph node activation at prevaccination and "1 week" (8-14 days) and "1 month" (23-36 days) after the first or third vaccination. RESULTS: PET/CT scans revealed that all vaccine recipients had ipsilateral axillary lymph node activity. Three of 4 Cervarix recipients also showed contralateral lymph node activity 1 month after the first vaccination. For both Cervarix and Gardasil, the SUV activity resolved over time, with activity extended up to day 37 after the first and third vaccinations. CONCLUSIONS: Following intramuscular vaccination, there were no major differences between duration of uptake and intensity of SUV between Cervarix and Gardasil recipients in ipsilateral axillary lymph nodes. Contralateral node activation was detected up to 1 month after the first vaccination in Cervarix recipients only, possibly reflecting differences in vaccine adjuvant formulation.


Assuntos
Vacina Quadrivalente Recombinante contra HPV tipos 6, 11, 16, 18/imunologia , Linfonodos/diagnóstico por imagem , Linfonodos/metabolismo , Vacinas contra Papillomavirus/imunologia , Tomografia Computadorizada com Tomografia por Emissão de Pósitrons , Adolescente , Adulto , Feminino , Humanos , Papillomaviridae , Vacinação , Adulto Jovem
18.
Proc Natl Acad Sci U S A ; 114(10): 2711-2716, 2017 03 07.
Artigo em Inglês | MEDLINE | ID: mdl-28223498

RESUMO

A live-attenuated malaria vaccine, Plasmodium falciparum sporozoite vaccine (PfSPZ Vaccine), confers sterile protection against controlled human malaria infection (CHMI) with Plasmodium falciparum (Pf) parasites homologous to the vaccine strain up to 14 mo after final vaccination. No injectable malaria vaccine has demonstrated long-term protection against CHMI using Pf parasites heterologous to the vaccine strain. Here, we conducted an open-label trial with PfSPZ Vaccine at a dose of 9.0 × 105 PfSPZ administered i.v. three times at 8-wk intervals to 15 malaria-naive adults. After CHMI with homologous Pf parasites 19 wk after final immunization, nine (64%) of 14 (95% CI, 35-87%) vaccinated volunteers remained without parasitemia compared with none of six nonvaccinated controls (P = 0.012). Of the nine nonparasitemic subjects, six underwent repeat CHMI with heterologous Pf7G8 parasites 33 wk after final immunization. Five (83%) of six (95% CI, 36-99%) remained without parasitemia compared with none of six nonvaccinated controls. PfSPZ-specific T-cell and antibody responses were detected in all vaccine recipients. Cytokine production by T cells from vaccinated subjects after in vitro stimulation with homologous (NF54) or heterologous (7G8) PfSPZ were highly correlated. Interestingly, PfSPZ-specific T-cell responses in the blood peaked after the first immunization and were not enhanced by subsequent immunizations. Collectively, these data suggest durable protection against homologous and heterologous Pf parasites can be achieved with PfSPZ Vaccine. Ongoing studies will determine whether protective efficacy can be enhanced by additional alterations in the vaccine dose and number of immunizations.


Assuntos
Vacinas Antimaláricas/administração & dosagem , Malária Falciparum/prevenção & controle , Plasmodium falciparum/efeitos dos fármacos , Vacinas Atenuadas/administração & dosagem , Adolescente , Adulto , Feminino , Voluntários Saudáveis , Humanos , Vacinas Antimaláricas/efeitos adversos , Vacinas Antimaláricas/imunologia , Malária Falciparum/imunologia , Malária Falciparum/parasitologia , Masculino , Pessoa de Meia-Idade , Plasmodium falciparum/patogenicidade , Esporozoítos/imunologia , Esporozoítos/patogenicidade , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologia , Linfócitos T/parasitologia , Vacinas Atenuadas/efeitos adversos , Vacinas Atenuadas/imunologia
19.
J Infect Dis ; 215(4): 547-553, 2017 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-28003349

RESUMO

Recent studies have suggested that Ebola virus (EBOV) ribonucleic acid (RNA) potentially present in the semen of a large number of survivors of Ebola virus disease (EVD) in Western Africa may contribute to sexual transmission of EVD and generate new clusters of cases in regions previously declared EVD-free. These findings drive the immediate need for a reliable, rapid, user-friendly assay for detection of EBOV RNA in semen that is deployable to multiple sites across Western Africa. In this study, we optimized the Xpert EBOV assay for semen samples by adding dithiothreitol. Compared to the assays currently in use in Liberia (including Ebola Zaire Target 1, major groove binder real-time-polymerase chain reaction assays, and original Xpert EBOV assay), the modified Xpert EBOV assay demonstrated greater sensitivity than the comparator assays. Thus, the modified Xpert EBOV assay is optimal for large-scale monitoring of EBOV RNA persistence in male survivors.


Assuntos
Ebolavirus/isolamento & purificação , Doença pelo Vírus Ebola/diagnóstico , RNA Viral/isolamento & purificação , Reação em Cadeia da Polimerase em Tempo Real/métodos , Sêmen/virologia , República Democrática do Congo , Doença pelo Vírus Ebola/sangue , Humanos , Libéria , Limite de Detecção , Masculino , Projetos Piloto , RNA Viral/sangue , Sensibilidade e Especificidade , Sobreviventes
20.
PLoS One ; 11(11): e0166393, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27846256

RESUMO

BACKGROUND: VRC 012 was a Phase I study of a prototype recombinant adenoviral-vector serotype-35 (rAd35) HIV vaccine, the precursor to two recently published clinical trials, HVTN 077 and 083. On the basis of prior evaluation of multiclade rAd5 HIV vaccines, Envelope A (EnvA) was selected as the standard antigen for a series of prototype HIV vaccines to compare various vaccine platforms. In addition, prior studies of rAd5-vectored vaccines suggested pre-existing human immunity may be a confounding factor in vaccine efficacy. rAd35 is less seroprevalent across human populations and was chosen for testing alone and in combination with a rAd5-EnvA vaccine in the present two-part phase I study. METHODS: First, five subjects each received a single injection of 109, 1010, or 1011 particle units (PU) of rAd35-EnvA in an open-label, dose-escalation study. Next, 20 Ad5/Ad35-seronegative subjects were randomized to blinded, heterologous prime-boost schedules combining rAd5-EnvA and rAd35-EnvA with a three month interval. rAd35-EnvA was given at 1010 or 1011 PU to ten subjects each; all rAd5-EnvA injections were 1010 PU. EnvA-specific immunogenicity was assessed four weeks post-injection. Solicited reactogenicity and clinical safety were followed after each injection. RESULTS: Vaccinations were well tolerated at all dosages. Antibody responses measured by ELISA were detected at 4 weeks in 30% and 50% of subjects after single doses of 1010 or 1011 PU rAd35, respectively, and in 89% after a single rAd5-EnvA 1010 PU injection. EnvA-specific IFN-γ ELISpot responses were detected at four weeks in 0%, 70%, and 50% of subjects after the respective rAd35-EnvA dosages compared to 89% of subjects after rAd5. T cell responses were higher after a single rAd5-EnvA 1010 PU injection than after a single rAd35-EnvA 1010 PU injection, and humoral responses were low after a single dose of either vector. Of those completing the vaccine schedule, 100% of rAd5-EnvA recipients and 90% of rAd35-EnvA recipients had both T cell and humoral responses after boosting with the heterologous vector. ELISpot response magnitude was similar in both regimens and comparable to a single dose of rAd5. A trend toward more robust CD8 T cell responses using rAd5-EnvA prime and rAd35-EnvA boost was observed. Humoral response magnitude was also similar after either heterologous regimen, but was several fold higher than after a single dose of rAd5. Adverse events (AEs) related to study vaccines were in general mild and limited to one episode of hematuria, Grade two. Activated partial thromboplastin time (aPTT) AEs were consistent with an in vitro effect on the laboratory assay for aPTT due to a transient induction of anti-phospholipid antibody, a phenomenon that has been reported in other adenoviral vector vaccine trials. CONCLUSIONS: Limitations of the rAd vaccine vectors, including the complex interactions among pre-existing adenoviral immunity and vaccine-induced immune responses, have prompted investigators to include less seroprevalent vectors such as rAd35-EnvA in prime-boost regimens. The rAd35-EnvA vaccine described here was well tolerated and immunogenic. While it effectively primed and boosted antibody responses when given in a reciprocal prime-boost regimen with rAd5-EnvA using a three-month interval, it did not significantly improve the frequency or magnitude of T cell responses above a single dose of rAd5. The humoral and cellular immunogenicity data reported here may inform future vaccine and study design. TRIAL REGISTRATION: ClinicalTrials.gov NCT00479999.


Assuntos
Vacinas contra a AIDS/administração & dosagem , Anticorpos Antivirais/imunologia , Infecções por HIV/genética , Infecções por HIV/prevenção & controle , Produtos do Gene env do Vírus da Imunodeficiência Humana/imunologia , Vacinas contra a AIDS/genética , Adenoviridae/genética , Adolescente , Adulto , Formação de Anticorpos/imunologia , Feminino , Vetores Genéticos , Infecções por HIV/imunologia , Infecções por HIV/virologia , HIV-1/efeitos dos fármacos , HIV-1/imunologia , HIV-1/patogenicidade , Humanos , Imunização Secundária , Masculino , Pessoa de Meia-Idade , Vacinas de DNA/administração & dosagem , Vacinas de DNA/genética , Vacinas de DNA/imunologia , Adulto Jovem , Produtos do Gene env do Vírus da Imunodeficiência Humana/administração & dosagem , Produtos do Gene env do Vírus da Imunodeficiência Humana/genética
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