RESUMO
Understanding the burden and risk factors of dengue virus (DENV) infection in Puerto Rico is important for the prevention of dengue in local, traveler and military populations. Using sera from the Department of Defense Serum Repository, we estimated the prevalence and predictors of DENV seropositivity in those who had served in Puerto Rico, stratified by birth or prior residence ("birth/residence") in dengue-endemic versus non-endemic regions. We selected sera collected in early 2015 from 500 U.S. military members, a time-point also permitting detection of early cryptic Zika virus (ZIKV) circulation. 87.2% were born or resided in a DENV-endemic area before their military service in Puerto Rico. A high-throughput, flow-cytometry-based neutralization assay was employed to screen sera for ZIKV and DENV neutralizing antibodies, and confirmatory testing was done by plaque-reduction neutralization test (PRNT). We identified one Puerto Rico resident who seroconverted to ZIKV by June 2015, suggesting cryptic ZIKV circulation in Puerto Rico at least 4 months before the first reported cases. A further six PRNT-positive presumptive ZIKV infections which were resolved as DENV infections only by the use of paired sera. We noted 66.8% of the total study sample was DENV seropositive by early 2015. Logistic regression analysis indicated that birth/residence in a dengue non-endemic region (before military service in Puerto Rico) was associated with a lower odds of DENV exposure by January-June 2015 (aOR = 0.28, p = 0.001). Among those with birth/residence in a non-endemic country, we noted moderate evidence to support increase in odds of DENV exposure for each year of military service in Puerto Rico (aOR = 1.58, p = 0.06), but no association with age. In those with birth/residence in dengue-endemic regions (before military service in Puerto Rico), we noted that age (aOR = 1.04, p = 0.02), rather than duration of Puerto Rico service, was associated with dengue seropositivity, suggesting earlier lifetime DENV exposure. Our findings provide insights into the burden and predictors of DENV infection in local, traveler and military populations in Puerto Rico. Our study also highlights substantial PRNT ZIKV false-positivity when paired sera are not available, even during periods of very low ZIKV prevalence.
Assuntos
Dengue/epidemiologia , Militares , Infecção por Zika virus/epidemiologia , Adulto , Anticorpos Neutralizantes/sangue , Vírus da Dengue/imunologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Prevalência , Porto Rico/epidemiologia , Características de Residência , Fatores de Risco , Estudos Soroepidemiológicos , Estados Unidos , Zika virus/imunologiaRESUMO
Dengue viruses (DENV) pose a significant and increasing threat to human health across broad regions of the globe. Currently, prevention, control, and treatment strategies are limited. Promising interventions are on the horizon, including multiple vaccine candidates under development and a renewed and innovative focus on controlling the vector, Aedes aegypti. However, significant gaps persist in our understanding of the similarities and differences in DENV epidemiology across regions of potential implementation and evaluation. In this manuscript, we highlight and compare findings from two analogous cluster-based studies for DENV transmission and pathogenesis conducted in Thailand and Ecuador to identify key features and questions for further pursuit. Despite a remarkably similar incidence of DENV infection among enrolled neighborhood contacts at the two sites, we note a higher occurrence of secondary infection and severe illness in Thailand compared to Ecuador. A higher force of infection in Thailand, defined as the incidence of infection among susceptible individuals, is suggested by the higher number of captured Aedes mosquitoes per household, the increasing proportion of asymptomatic infections with advancing age, and the high proportion of infections identified as secondary-type infections by serology. These observations should be confirmed in long-term, parallel prospective cohort studies conducted across regions, which would advantageously permit characterization of baseline immune status (susceptibility) and contemporaneous assessment of risks and risk factors for dengue illness.
Assuntos
Vírus da Dengue , Dengue , Animais , Dengue/epidemiologia , Equador/epidemiologia , Humanos , Mosquitos Vetores , Estudos Prospectivos , Tailândia/epidemiologiaRESUMO
Four formulations of an investigational tetravalent dengue purified inactivated vaccine, administered as two doses one month (M) apart, were previously shown to be immunogenic and well-tolerated up to M13 of the phase I study NCT01702857. Here, we report results of the follow-up from M14 to year (Y) 3. One hundred healthy Puerto Rican adults, predominantly dengue virus (DENV)-primed, were randomized 1:1:1:1:1 to receive placebo or vaccine formulations: 1 µg/serotype/dose adjuvanted with aluminum, AS01E or AS03B, or aluminum-adjuvanted 4 µg/serotype/dose. No serious adverse events occurred. Two medically-attended potential immune-mediated disease cases, vaccination unrelated, were reported (groups 1 µg+Alum and 1 µg+AS03B). Of 14 instances of suspected dengue, none were laboratory confirmed. Geometric mean neutralizing antibody titers against DENV 1-4 waned from M14, but remained above pre-vaccination levels for DENV 1-3, with the highest values for group 1 µg+AS03B: 1220.1, 920.5, 819.4, and 940.5 (Y2), and 1329.3, 1169.2, 1219.8, and 718.9 (Y3). All formulations appeared to be safe and immunogenic during the 3-year follow-up.
Assuntos
Vacinas contra Dengue/uso terapêutico , Vírus da Dengue/imunologia , Dengue/prevenção & controle , Adulto , Anticorpos Neutralizantes/imunologia , Anticorpos Antivirais/imunologia , Vacinas contra Dengue/administração & dosagem , Vacinas contra Dengue/efeitos adversos , Vacinas contra Dengue/imunologia , Feminino , Seguimentos , Humanos , Masculino , Porto RicoRESUMO
BACKGROUND: In recent years, Ecuador and other South American countries have experienced an increase in arboviral diseases. A rise in dengue infections was followed by introductions of chikungunya and Zika, two viruses never before seen in many of these areas. Furthermore, the latest socioeconomic and political instability in Venezuela and the mass migration of its population into the neighboring countries has given rise to concerns of infectious disease spillover and escalation of arboviral spread in the region. RESULTS: We performed phylogeographic analyses of dengue (DENV) and chikungunya (CHIKV) virus genomes sampled from a surveillance site in Ecuador in 2014-2015, along with genomes from the surrounding countries. Our results revealed at least two introductions of DENV, in 2011 and late 2013, that initially originated from Venezuela and/or Colombia. The introductions were subsequent to increases in the influx of Venezuelan and Colombian citizens into Ecuador, which in 2013 were 343% and 214% higher than in 2009, respectively. However, we show that Venezuela has historically been an important source of DENV dispersal in this region, even before the massive exodus of its population, suggesting already established paths of viral distribution. Like DENV, CHIKV was introduced into Ecuador at multiple time points in 2013-2014, but unlike DENV, these introductions were associated with the Caribbean. Our findings indicated no direct CHIKV connection between Ecuador, Colombia, and Venezuela as of 2015, suggesting that CHIKV was, at this point, not following the paths of DENV spread. CONCLUSION: Our results reveal that Ecuador is vulnerable to arbovirus import from many geographic locations, emphasizing the need of continued surveillance and more diversified prevention strategies. Importantly, increase in human movement along established paths of viral dissemination, combined with regional outbreaks and epidemics, may facilitate viral spread and lead to novel virus introductions. Thus, strengthening infectious disease surveillance and control along migration routes and improving access to healthcare for the vulnerable populations is of utmost importance.
Assuntos
Febre de Chikungunya/epidemiologia , Vírus Chikungunya/classificação , Vírus Chikungunya/genética , Vírus da Dengue/classificação , Vírus da Dengue/genética , Dengue/epidemiologia , Emigração e Imigração/estatística & dados numéricos , Febre de Chikungunya/transmissão , Febre de Chikungunya/virologia , Vírus Chikungunya/isolamento & purificação , Colômbia/epidemiologia , Dengue/transmissão , Dengue/virologia , Vírus da Dengue/isolamento & purificação , Surtos de Doenças , Equador/epidemiologia , Emigração e Imigração/tendências , Genoma Viral , Genótipo , Humanos , Mutação de Sentido Incorreto/fisiologia , Fenótipo , Filogeografia , Análise de Sequência de DNA , América do Sul/epidemiologia , Venezuela/epidemiologia , Zika virus/isolamento & purificação , Infecção por Zika virus/epidemiologia , Infecção por Zika virus/transmissão , Infecção por Zika virus/virologiaRESUMO
Three phase II randomized trials evaluated the safety/immunogenicity of two formulations of live-attenuated tetravalent dengue virus (TDEN) vaccine in dengue-endemic (Puerto Rico, Thailand) and non-endemic (US) regions (NCT00350337/NCT00370682/NCT00468858). We describe cell-mediated immune (CMI) responses; safety and humoral responses were reported previously. Participants received two doses of vaccine or control (placebo or the precursor live-attenuated TDEN vaccine) 6 months apart. Selected US participants received a booster 5-12 months post-dose 2. Evaluated subsets of the per-protocol cohorts included 75 primarily dengue virus (DENV)-unprimed US adults, 69 primarily flavivirus-primed Thai adults, and 100 DENV-primed or DENV-unprimed Puerto Rican adults/adolescents/children. T-cell responses were quantified using intracellular cytokine staining (ICS; DENV-infected cell-lysate or DENV-1/DENV-2 peptide-pool stimulation) or IFN-γ ELISPOT (DENV-2 peptide-pool stimulation). Memory B-cell responses were quantified using B-cell ELISPOT. Across populations and age strata, DENV serotype-specific CD4+ T-cell responses were slightly to moderately increased (medians ≤0.18% [ICS]), DENV-2-biased, and variable for both formulations. Responses in unprimed subjects were primarily detected post-dose 1. Response magnitudes in primed subjects were similar between doses. Multifunctional CD8+ T-cell responses were detected after peptide-pool stimulation. T-cell responses were mostly directed to DENV nonstructural proteins 3 and 5. Memory B-cell responses were tetravalent, of low-to-moderate magnitudes (medians ≤0.25%), and mainly observed post-dose 2 in unprimed subjects and post-dose 1 in primed subjects. A third dose did not boost CMI responses. In conclusion, both formulations of the live-attenuated TDEN vaccine candidate were poorly to moderately immunogenic with respect to B-cell and T-cell responses, irrespective of the priming status of the participants. Abbreviation ATP: according-to-protocol; ICS: Intracellular Cytokine Staining; NS3: Nonstructural protein 3; ELISPOT: Enzyme-Linked ImmunoSpot; JEV: Japanese encephalitis virus; PBMC: peripheral blood mononuclear cells.
Assuntos
Vacinas contra Dengue/imunologia , Dengue/prevenção & controle , Imunidade Celular , Adolescente , Adulto , Anticorpos Antivirais/sangue , Criança , Pré-Escolar , Estudos de Coortes , Vírus da Dengue , Doenças Endêmicas , Feminino , Humanos , Memória Imunológica , Lactente , Masculino , Pessoa de Meia-Idade , Porto Rico , Tailândia , Vacinas Atenuadas/imunologia , Adulto JovemRESUMO
Here, we report the findings from the first 2 years (2014-2015) of an arbovirus surveillance study conducted in Machala, Ecuador, a dengue-endemic region. Patients with suspected dengue virus (DENV) infections (index cases, N = 324) were referred from five Ministry of Health clinical sites. A subset of DENV-positive index cases (N = 44) were selected, and individuals from the index household and four neighboring homes within 200 m were recruited (N = 400). Individuals who entered the study, other than the index cases, are referred to as associates. In 2014, 70.9% of index cases and 35.6% of associates had acute or recent DENV infections. In 2015, 28.3% of index cases and 12.8% of associates had acute or recent DENV infections. For every DENV infection captured by passive surveillance, we detected an additional three acute or recent DENV infections in associates. Of associates with acute DENV infections, 68% reported dengue-like symptoms, with the highest prevalence of symptomatic acute infections in children aged less than 10 years. The first chikungunya virus (CHIKV) infections were detected on epidemiological week 12 in 2015; 43.1% of index cases and 3.5% of associates had acute CHIKV infections. No Zika virus infections were detected. Phylogenetic analyses of isolates of DENV from 2014 revealed genetic relatedness and shared ancestry of DENV1, DENV2, and DENV4 genomes from Ecuador with those from Venezuela and Colombia, indicating the presence of viral flow between Ecuador and surrounding countries. Enhanced surveillance studies, such as this, provide high-resolution data on symptomatic and inapparent infections across the population.
Assuntos
Febre de Chikungunya/epidemiologia , Febre de Chikungunya/virologia , Dengue/epidemiologia , Dengue/virologia , Adolescente , Adulto , Idoso , Vírus Chikungunya/genética , Criança , Pré-Escolar , Vírus da Dengue/genética , Equador/epidemiologia , Feminino , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Filogenia , Vigilância da População , Prevalência , Adulto JovemRESUMO
The safety and immunogenicity of four adjuvanted formulations of an investigational tetravalent dengue purified inactivated vaccine (DPIV) were evaluated in a predominantly dengue-primed population in Puerto Rico. In this placebo-controlled, randomized, observer-blind, phase I trial, 100 healthy adults were randomized 1:1:1:1:1 to receive DPIV at Day (D)0 and D28 (1 µg per dengue virus [DENV] type 1-4 adjuvanted with either alum, AS01E or AS03B, or 4 µg per DENV type adjuvanted with alum) or saline placebo. Functional antibody responses were assessed using a microneutralization assay at D56, Month (M)7, and M13. All DPIV formulations were well tolerated and no safety signals were identified through M13. The M13 according-to-protocol (ATP) immunogenicity cohort included 83 participants. The ATP analysis of immunogenicity was performed only on the 78 subjects seropositive for ≥ 1 DENV type at baseline: 69 tetravalent, three trivalent, two bivalent, and four monovalent. In all DPIV groups, geometric mean antibody titers (GMTs) increased from D0 to D56 and waned modestly through M13, while remaining well above prevaccination levels. The 4 µg + alum and the AS01E- and AS03B-adjuvanted formulations were highly immunogenic, with M13-neutralizing antibody GMTs against all four DENV types above 1,000. M13/D0 GMT ratios were highest in the 1 µg + AS03B group (ranging 3.2-3.7 depending on the DENV type). These results encourage continued clinical development of DPIV (ClinicalTrials.gov: NCT01702857).
Assuntos
Vacinas contra Dengue/administração & dosagem , Vacinas contra Dengue/imunologia , Dengue/prevenção & controle , Adjuvantes Imunológicos , Adolescente , Adulto , Anticorpos Neutralizantes/sangue , Anticorpos Antivirais/sangue , Dengue/epidemiologia , Vacinas contra Dengue/efeitos adversos , Relação Dose-Resposta Imunológica , Feminino , Humanos , Masculino , Porto Rico/epidemiologia , Vacinas Atenuadas/administração & dosagem , Vacinas Atenuadas/efeitos adversos , Vacinas Atenuadas/imunologia , Vacinas de Produtos Inativados/administração & dosagem , Vacinas de Produtos Inativados/efeitos adversos , Vacinas de Produtos Inativados/imunologia , Adulto JovemRESUMO
AbstractDengue virus infections have adversely impacted U.S. military operations since the Spanish-American War. The erosion of mission capabilities and lost duty days are underestimated. Appreciating the incidence and prevalence of dengue infections in U.S. military personnel is important to inform disease prevention strategies. Banked pre- and post-deployment serum samples from 1,000 U.S. military personnel with a single deployment to a dengue-endemic region were tested using a screening microneutralization assay to detect anti-dengue-virus-neutralizing antibodies. A total of 76 (7.6%) post-deployment samples were positive and 15 of the pre-deployment samples were negative. These figures represent an infection incidence of 1.5% and total of 17.6 seroconversions per 10,000 deployment months. These data represent a deploying military population with a relatively high background rate of dengue seropositivity, a low level of infection during deployment compared with background infection rates in the local populations, and the potential for worsening clinical attack rates with increased frequency of deployment. Additional studies are required to more clearly elucidate the dengue infection and disease risk in U.S. military personnel.
Assuntos
Anticorpos Antivirais/sangue , Vírus da Dengue/imunologia , Dengue/epidemiologia , Doenças Endêmicas , Militares , Adulto , África/epidemiologia , Sudeste Asiático/epidemiologia , Bancos de Sangue , América Central/epidemiologia , Dengue/sangue , Dengue/virologia , Vírus da Dengue/isolamento & purificação , Feminino , Humanos , Soros Imunes/química , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Estudos Soroepidemiológicos , Viagem , Estados Unidos/epidemiologiaRESUMO
The genus Bartonella contains >40 species, and an increasing number of these Bartonella species are being implicated in human disease. One such pathogen is Bartonella ancashensis, which was isolated in blood samples from 2 patients living in Caraz, Peru, during a clinical trial of treatment for bartonellosis. Three B. ancashensis strains were analyzed by using whole-genome restriction mapping and high-throughput pyrosequencing. Genome-wide comparative analysis of Bartonella species showed that B. ancashensis has features seen in modern and ancient lineages of Bartonella species and is more related to B. bacilliformis. The divergence between B. ancashensis and B. bacilliformis is much greater than what is seen between known Bartonella genetic lineages. In addition, B. ancashensis contains type IV secretion system proteins, which are not present in B. bacilliformis. Whole-genome analysis indicates that B. ancashensis might represent a distinct Bartonella lineage phylogenetically related to B. bacilliformis.
Assuntos
Infecções por Bartonella/microbiologia , Bartonella/genética , Genoma Bacteriano , Adolescente , Adulto , Bartonella/classificação , Infecções por Bartonella/epidemiologia , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Peru/epidemiologia , Filogenia , Adulto JovemRESUMO
Zika virus (ZIKV) is responsible for a major ongoing epidemic in the Americas and has been causally associated with fetal microcephaly. The development of a safe and effective ZIKV vaccine is therefore an urgent global health priority. Here we demonstrate that three different vaccine platforms protect against ZIKV challenge in rhesus monkeys. A purified inactivated virus vaccine induced ZIKV-specific neutralizing antibodies and completely protected monkeys against ZIKV strains from both Brazil and Puerto Rico. Purified immunoglobulin from vaccinated monkeys also conferred passive protection in adoptive transfer studies. A plasmid DNA vaccine and a single-shot recombinant rhesus adenovirus serotype 52 vector vaccine, both expressing ZIKV premembrane and envelope, also elicited neutralizing antibodies and completely protected monkeys against ZIKV challenge. These data support the rapid clinical development of ZIKV vaccines for humans.