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The COVID-19 pandemic has had a staggering impact on social, economic, and public health systems worldwide. Vaccine development and mobilization against SARS-CoV-2 (the etiologic agent of COVID-19) has been rapid. However, novel strategies are still necessary to slow the pandemic, and this includes new approaches to vaccine development and/or delivery that will improve vaccination compliance and demonstrate efficacy against emerging variants. Here, we report on the immunogenicity and efficacy of a SARS-CoV-2 vaccine comprising stabilized, pre-fusion spike protein trimers displayed on a ferritin nanoparticle (SpFN) adjuvanted with either conventional aluminum hydroxide or the Army Liposomal Formulation QS-21 (ALFQ) in a cynomolgus macaque COVID-19 model. Vaccination resulted in robust cell-mediated and humoral responses and a significant reduction in lung lesions following SARS-CoV-2 infection. The strength of the immune response suggests that dose sparing through reduced or single dosing in primates may be possible with this vaccine. Overall, the data support further evaluation of SpFN as a SARS-CoV-2 protein-based vaccine candidate with attention to fractional dosing and schedule optimization.
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Cricothyrotomy is an invasive airway used in "cannot intubate, cannot ventilate" events and can be taught using simulation. A mobile cricothyrotomy simulation for 66 anesthesia providers included an initial cricothyrotomy attempt (pretest), education, practice and feedback, and a second cricothyrotomy attempt (posttest). Provider confidence, skills, and procedure time were measured. Comparison of the posttest to the pretest showed significant improvement in: (a) provider confidence scores (Z = 7.01, P < .001), (b) technical skills (Global Rating Scale for Cricothyrotomy: Z = 7.05, P <.001; Checklist for Cricothyrotomy Performance: Z = 7.07, P < .001), and (c) procedure time (Z = 2.68, P = .007). The mobile cricothyrotomy simulation significantly improved anesthesia providers' confidence, cricothyrotomy skills, and procedure time.
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Anestesia , Anestesiología , Anestesiología/educación , HumanosRESUMEN
Disease associated with Nipah virus infection causes a devastating and often fatal spectrum of syndromes predominated by both respiratory and neurologic conditions. Additionally, neurologic sequelae may manifest months to years later after virus exposure or apparent recovery. In the two decades since this disease emerged, much work has been completed in an attempt to understand the pathogenesis and facilitate development of medical countermeasures. Here we provide detailed organ system-specific pathologic findings following exposure of four African green monkeys to 2.41×105 pfu of the Malaysian strain of Nipah virus. Our results further substantiate the African green monkey as a model of human Nipah virus disease, by demonstrating both the respiratory and neurologic components of disease. Additionally, we demonstrate that a chronic phase of disease exists in this model, that may provide an important opportunity to study the enigmatic late onset and relapse encephalitis as it is described in human disease.
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Encefalitis Viral/patología , Infecciones por Henipavirus/patología , Enfermedades Pulmonares/virología , Virus Nipah/patogenicidad , Animales , Chlorocebus aethiops , Modelos Animales de Enfermedad , Enfermedades Pulmonares/patología , Malasia , Masculino , Virus Nipah/clasificaciónRESUMEN
A proprietary antimicrobial feed additive comprised of essential oils, medium-chain fatty acids, and a toxin-adsorbing mineral showed promising bacteriostatic and bactericidal effects in vitro. This study investigated the impacts of supplementing this blend on growth, gut microbiome, and enteric disease resilience in weaned pigs experimentally challenged with an enterotoxigenic Escherichia coli (ETEC). Thirty-six weanling pigs (6.88â ±â 0.30 kg body weight) blocked by weight and gender were assigned to one of three dietary treatments: control or dietary supplementation with 0.25% or 0.50% of the antimicrobial blend. This study lasted 28 d with 7 d before and 21 d after the first ETEC inoculation (day 0). All pigs were orally inoculated with 1010 CFU F18â +â ETEC/3-mL dose for 3 consecutive days. Growth performance data and diarrhea scores were recorded throughout the experiment. Fecal samples collected on days -7, 0, 7, and 21 post first inoculation (PI), and ileal digesta and mucosal tissue collected on day 21 PI were further analyzed for gut microbiome using 16S rRNA sequencing. All data, except for frequency of diarrhea and gut microbiome, were analyzed by ANOVA using the PROC MIXED of SAS. The chi-square test was used for analyzing frequency of diarrhea. Gut microbiome data were analyzed using QIIME2 and visualized using the R program. Dietary supplementation of 0.25% or 0.5% of the antimicrobial blend increased (Pâ <â 0.05) feed efficiency on days 14 to 21 PI of ETEC and reduced (Pâ <â 0.05) frequency of diarrhea during the study. Compared with the control group, adding 0.5% dietary antimicrobial blend increased (Pâ <â 0.05) relative abundance of Firmicutes but reduced (Pâ <â 0.05) Bacteroidetes and Proteobacteria in feces on day 7 PI. Pigs that received the antimicrobial blend also had higher (Pâ <â 0.05) relative abundance of Lactobacillaceae, but lower (Pâ <â 0.05) relative abundance of Enterobacteriaceae in feces on day 7 PI than pigs in control. In conclusion, supplementation of this antimicrobial blend at 0.5% reduced incidence of severe diarrhea in weaned pigs challenged with F18 ETEC and enhanced feed efficiency of weaned pigs at the last week of the experiment. Supplementation of this antimicrobial blend also modified the microbiota diversity in feces and ileal mucosa of weaned pigs.
This experiment aims to investigate an antimicrobial blend consisting of essential oils, medium-chain fatty acids, and a toxin-adsorbing mineral on diarrhea, growth performance, and gut microbiome of newly weaned pigs experimentally infected with a pathogenic Escherichia coli (F18 E. coli). A total of 36 weaned pigs were randomly allotted to one of three dietary treatments: (1) a complex control diet that met the nutrient requirement of weaned pigs; (2) supplementing 0.25% of the antimicrobial blend; and (3) 0.50% of the antimicrobial blend. The experiment lasted 28 d with 7 d adaptation and 21 d after the first F18 E. coli inoculation. Results of this experiment demonstrate that supplementation of this antimicrobial blend enhanced disease resistance of weaned pigs, as indicated by reduced frequency of diarrhea during the entire experimental period. An improved feed efficiency was also observed in pigs supplemented with antimicrobial blend at the last week of the experiment. In addition, feces collected on day 7 post-E. coli inoculation contained relatively more Lactobacillaceae but less Enterobacteriaceae when pigs were supplemented with this antimicrobial blend. In conclusion, supplementation of antimicrobial blend could reduce diarrhea of E. coli-infected pigs and modify fecal microbiome of weaned pigs during the peak of E. coli infection.
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Escherichia coli Enterotoxigénica , Infecciones por Escherichia coli , Microbioma Gastrointestinal , Aceites Volátiles , Enfermedades de los Porcinos , Alimentación Animal/análisis , Animales , Diarrea/veterinaria , Dieta/veterinaria , Infecciones por Escherichia coli/veterinaria , Ácidos Grasos , Minerales , Aceites Volátiles/farmacología , ARN Ribosómico 16S , Porcinos , DesteteRESUMEN
Ebola virus disease (EVD) is a serious global health concern because case fatality rates are approximately 50% due to recent widespread outbreaks in Africa. Well-defined nonhuman primate (NHP) models for different routes of Ebola virus exposure are needed to test the efficacy of candidate countermeasures. In this natural history study, four rhesus macaques were challenged via aerosol with a target titer of 1000 plaque-forming units per milliliter of Ebola virus. The course of disease was split into the following stages for descriptive purposes: subclinical, clinical, and decompensated. During the subclinical stage, high levels of venous partial pressure of carbon dioxide led to respiratory acidemia in three of four of the NHPs, and all developed lymphopenia. During the clinical stage, all animals had fever, viremia, and respiratory alkalosis. The decompensatory stage involved coagulopathy, cytokine storm, and liver and renal injury. These events were followed by hypotension, elevated lactate, metabolic acidemia, shock and mortality similar to historic intramuscular challenge studies. Viral loads in the lungs of aerosol-exposed animals were not distinctly different compared to previous intramuscularly challenged studies. Differences in the aerosol model, compared to intramuscular model, include an extended subclinical stage, shortened clinical stage, and general decompensated stage. Therefore, the shortened timeframe for clinical detection of the aerosol-induced disease can impair timely therapeutic administration. In summary, this nonhuman primate model of aerosol-induced EVD characterizes early disease markers and additional details to enable countermeasure development.
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Modelos Animales de Enfermedad , Ebolavirus/patogenicidad , Fiebre Hemorrágica Ebola/etiología , Aerosoles , Animales , Femenino , Fiebre Hemorrágica Ebola/inmunología , Fiebre Hemorrágica Ebola/patología , Fiebre Hemorrágica Ebola/virología , Macaca mulatta , Masculino , ARN Viral/sangre , Carga ViralRESUMEN
Ebola virus remains a significant public health concern due to high morbidity and mortality rates during recurrent outbreaks in endemic areas. Therefore, the development of countermeasures against Ebola virus remains a high priority, and requires the availability of appropriate animal models for efficacy evaluations. The most commonly used nonhuman primate models for efficacy evaluations against Ebola virus utilize the intramuscular or aerosol route of exposure. Although clinical disease signs are similar to human cases, disease progression in these models is much more rapid, and this can pose significant hurdles for countermeasure evaluations. The objective of the present study was to evaluate the Ebola virus disease course that arises after cynomolgus macaques are exposed to Ebola virus by a mucosal route (the intranasal route). Two different doses (10 pfu and 100 pfu) and delivery methodologies (drop-wise and mucosal atomization device) were evaluated on this study. Differences in clinical disease between dose and delivery groups were not noted. However, a delayed disease course was identified for approximately half of the animals on study, and this delayed disease was dose and administration method independent. Therefore, it appears that mucosal exposure with Ebola virus results in a disease course in cynomolgus macaques that more accurately replicates that which is documented for human cases. In summary, the data presented support the need for further development of this model as a possible alternative to parenteral and small-particle aerosol models for the study of human Ebola virus disease and for countermeasure evaluations.
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Modelos Animales de Enfermedad , Fiebre Hemorrágica Ebola/etiología , Administración Intranasal , Amilasas/metabolismo , Animales , Progresión de la Enfermedad , Femenino , Fiebre Hemorrágica Ebola/inmunología , Fiebre Hemorrágica Ebola/patología , Fiebre Hemorrágica Ebola/virología , Macaca fascicularis , Masculino , ARN Viral/sangreRESUMEN
Background and Objectives: Early warning of bacterial and viral infection, prior to the development of overt clinical symptoms, allows not only for improved patient care and outcomes but also enables faster implementation of public health measures (patient isolation and contact tracing). Our primary objectives in this effort are 3-fold. First, we seek to determine the upper limits of early warning detection through physiological measurements. Second, we investigate whether the detected physiological response is specific to the pathogen. Third, we explore the feasibility of extending early warning detection with wearable devices. Research Methods: For the first objective, we developed a supervised random forest algorithm to detect pathogen exposure in the asymptomatic period prior to overt symptoms (fever). We used high-resolution physiological telemetry data (aortic blood pressure, intrathoracic pressure, electrocardiograms, and core temperature) from non-human primate animal models exposed to two viral pathogens: Ebola and Marburg (N = 20). Second, to determine reusability across different pathogens, we evaluated our algorithm against three independent physiological datasets from non-human primate models (N = 13) exposed to three different pathogens: Lassa and Nipah viruses and Y. pestis. For the third objective, we evaluated performance degradation when the algorithm was restricted to features derived from electrocardiogram (ECG) waveforms to emulate data from a non-invasive wearable device. Results: First, our cross-validated random forest classifier provides a mean early warning of 51 ± 12 h, with an area under the receiver-operating characteristic curve (AUC) of 0.93 ± 0.01. Second, our algorithm achieved comparable performance when applied to datasets from different pathogen exposures - a mean early warning of 51 ± 14 h and AUC of 0.95 ± 0.01. Last, with a degraded feature set derived solely from ECG, we observed minimal degradation - a mean early warning of 46 ± 14 h and AUC of 0.91 ± 0.001. Conclusion: Under controlled experimental conditions, physiological measurements can provide over 2 days of early warning with high AUC. Deviations in physiological signals following exposure to a pathogen are due to the underlying host's immunological response and are not specific to the pathogen. Pre-symptomatic detection is strong even when features are limited to ECG-derivatives, suggesting that this approach may translate to non-invasive wearable devices.
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Filoviruses (Family Filoviridae genera Ebolavirus and Marburgvirus) are negative-stranded RNA viruses that cause severe health effects in humans and non-human primates, including death. Except in outbreak settings, vaccines and other medical countermeasures against Ebola virus (EBOV) will require testing under the FDA Animal Rule. Multiple vaccine candidates have been evaluated using cynomolgus monkeys (CM) exposed to EBOV Kikwit strain. To the best of our knowledge, however, animal model development data supporting the use of CM in vaccine research have not been submitted to the FDA. This study describes a large CM database (122 CM, 62 female and 60 male, age 2 to 9 years) and demonstrates the consistency of the CM model through time to death models and descriptive statistics. CMs were exposed to EBOV doses of 0.1 to 100,000 PFU in 33 studies conducted at three Animal Biosafety Level 4 facilities, by three exposure routes. Time to death was modeled using Cox proportional hazards models with a frailty term that incorporated study-to-study variability. Despite significant differences attributed to exposure variables, all CMs exposed to the 100 to 1,000 pfu doses commonly used in vaccine studies died or met euthanasia criteria within 21 days of exposure, median 7 days, 93% between 5 and 12 days of exposure. Moderate clinical signs were observed 4 to 5 days after exposure and preceded death or euthanasia by approximately one day. Viremia was detected within a few days of infection. Hematology indices were indicative of viremia and the propensity for hemorrhage with progression of Ebola viremia. Changes associated with coagulation parameters and platelets were consistent with coagulation disruption. Changes in leukocyte profiles were indicative of an acute inflammatory response. Increased liver enzymes were observed shortly after exposure. Taken together, these factors suggest that the cynomolgus monkey is a reliable animal model for human disease.
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Ebolavirus/fisiología , Fiebre Hemorrágica Ebola , Animales , Modelos Animales de Enfermedad , Brotes de Enfermedades , Femenino , Macaca fascicularis , Masculino , Reproducibilidad de los Resultados , Carga ViralRESUMEN
Airborne transmission is predicted to be a prevalent route of human exposure with SARS-CoV-2. Aside from African green monkeys, nonhuman primate models that replicate airborne transmission of SARS-CoV-2 have not been investigated. A comparative evaluation of COVID-19 in African green monkeys, rhesus macaques, and cynomolgus macaques following airborne exposure to SARS-CoV-2 was performed to determine critical disease parameters associated with disease progression, and establish correlations between primate and human COVID-19. Respiratory abnormalities and viral shedding were noted for all animals, indicating successful infection. Cynomolgus macaques developed fever, and thrombocytopenia was measured for African green monkeys and rhesus macaques. Type II pneumocyte hyperplasia and alveolar fibrosis were more frequently observed in lung tissue from cynomolgus macaques and African green monkeys. The data indicate that, in addition to African green monkeys, macaques can be successfully infected by airborne SARS-CoV-2, providing viable macaque natural transmission models for medical countermeasure evaluation.
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COVID-19/fisiopatología , Modelos Animales de Enfermedad , Macaca mulatta , SARS-CoV-2/fisiología , Animales , COVID-19/patología , COVID-19/transmisión , Chlorocebus aethiops , Transmisión de Enfermedad Infecciosa , Femenino , Pulmón/patología , Macaca fascicularis , Masculino , Esparcimiento de VirusRESUMEN
OBJECTIVE: This study aimed to assess the effectiveness of team sports on alleviating depression, anxiety, perceived stress, and poor sleep quality in college students. Participants: Undergraduates (n = 291) from a major public university in China. Methods: A 12-week quasi-experimental study was conducted. Students were enrolled in team sports classes (n = 138, experimental group) and aerobic dance classes (n = 153, comparison group). Data was collected via questionnaires at pre and post-test. Results: Results indicated significant improvement in depression and sleep quality for college students over time (p < .05). Depression levels decreased significantly more for team sports group (p < .05) compared to aerobic dance group. Results showed no significant differences in anxiety or perceived stress between the two groups over time (p > .05). Conclusions: Team sports may help reduce depression and poor sleep quality in college students. However, physical activity alone may not help improve anxiety and perceived stress.
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Depresión , Deportes de Equipo , Ansiedad/terapia , Depresión/terapia , Humanos , Sueño , Estrés Psicológico/terapia , Estudiantes , UniversidadesRESUMEN
Nipah virus (NiV) is an emerging zoonotic paramyxovirus that causes highly lethal henipavirus encephalitis in humans. Survivors develop various neurologic sequelae, including late-onset and relapsing encephalitis, several months up to several years following initial infection. However, the underlying pathology and disease mechanisms of persistent neurologic complications remain unknown. Here, we demonstrate persistent NiV infection in the brains of grivets that survived experimental exposure to NiV. Encephalitis affected the entire brains, with the majority of NiV detected in the neurons and microglia of the brainstems, cerebral cortices, and cerebella. We identified the vascular endothelium in the brain as an initial target of NiV infection during the acute phase of disease, indicating a primary path of entry for NiV into the brain. Notably, we were unable to detect NiV anywhere else except the brains in the examined survivors. Our findings indicate that late-onset and relapsing encephalitis of NiV in human survivors may be due to viral persistence in the brain and shed light on the pathogenesis of chronic henipavirus encephalitis.
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Encéfalo/virología , Enfermedades Transmisibles Emergentes/patología , Infecciones por Henipavirus/patología , Virus Nipah/aislamiento & purificación , Zoonosis/patología , Animales , Encéfalo/irrigación sanguínea , Encéfalo/patología , Chlorocebus aethiops , Enfermedad Crónica , Enfermedades Transmisibles Emergentes/mortalidad , Enfermedades Transmisibles Emergentes/virología , Modelos Animales de Enfermedad , Endotelio Vascular/patología , Endotelio Vascular/virología , Infecciones por Henipavirus/mortalidad , Infecciones por Henipavirus/virología , Humanos , Masculino , Virus Nipah/patogenicidad , Recurrencia , Sobrevivientes , Zoonosis/mortalidad , Zoonosis/virologíaRESUMEN
Angola variant (MARV/Ang) has replaced Mt. Elgon variant Musoke isolate (MARV/MtE-Mus) as the consensus standard variant for Marburg virus research and is regarded as causing a more aggressive phenotype of disease in animal models; however, there is a dearth of published evidence supporting the higher virulence of MARV/Ang. In this retrospective study, we used data pooled from eight separate studies in nonhuman primates experimentally exposed with either 1000 pfu intramuscular (IM) MARV/Ang or MARV/MtE-Mus between 2012 and 2017 at the United States Army Medical Research Institute of Infectious Diseases (USAMRIID). Multivariable Cox proportional hazards regression was used to evaluate the association of variant type with time to death, the development of anorexia, rash, viremia, and 10 select clinical laboratory values. A total of 47 cynomolgus monkeys were included, of which 18 were exposed to MARV/Ang in three separate studies and 29 to MARV/MtE-Mus in five studies. Following universally fatal Marburg virus exposure, compared to MARV/MtE-Mus, MARV/Ang was associated with an increased risk of death (HR = 22.10; 95% CI: 7.08, 68.93), rash (HR = 5.87; 95% CI: 2.76, 12.51) and loss of appetite (HR = 35.10; 95% CI: 7.60, 162.18). Our data demonstrate an increased virulence of MARV/Ang compared to MARV/MtE-Mus variant in the 1000 pfu IM cynomolgus macaque model.
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Macaca , Enfermedad del Virus de Marburg/patología , Marburgvirus/patogenicidad , Animales , Modelos Animales de Enfermedad , Inyecciones Intramusculares , Estudios Retrospectivos , Análisis de Supervivencia , Estados Unidos , VirulenciaRESUMEN
Rift Valley fever virus (RVFV) is an important mosquito-borne veterinary and human pathogen that has caused large outbreaks of severe disease throughout Africa and the Arabian Peninsula. Currently, no licensed vaccine or therapeutics exists to treat this potentially deadly disease. The explosive nature of RVFV outbreaks and the severe consequences of its accidental or intentional introduction into RVFV-free areas provide the impetus for the development of novel vaccine candidates for use in both livestock and humans. Rationally designed vaccine candidates using reverse genetics have been used to develop deletion mutants of two known RVFV virulence factors, the NSs and NSm genes. These recombinant viruses were demonstrated to be protective and immunogenic in rats, mice, and sheep, without producing clinical illness in these animals. Here, we expand upon those findings and evaluate the single deletion mutant (ΔNSs rRVFV) and double deletion mutant (ΔNSs-ΔNSm rRVFV) vaccine candidates in the common marmoset (Callithrix jacchus), a non-human primate (NHP) model resembling severe human RVF disease. We demonstrate that both the ΔNSs and ΔNSs-ΔNSm rRVFV vaccine candidates were found to be safe and immunogenic in the current study. The vaccinated animals received a single dose of vaccine that led to the development of a robust antibody response. No vaccine-induced adverse reactions, signs of clinical illness or infectious virus were detected in the vaccinated marmosets. All vaccinated animals that were subsequently challenged with RVFV were protected against viremia and liver disease. In summary, our results provide the basis for further development of the ΔNSs and ΔNSs-ΔNSm rRVFV as safe and effective human RVFV vaccines for this significant public health threat.
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Fiebre del Valle del Rift/prevención & control , Virus de la Fiebre del Valle del Rift/inmunología , Vacunas Virales/inmunología , Animales , Anticuerpos Antivirales/inmunología , Callithrix/inmunología , Callithrix/virología , Modelos Animales de Enfermedad , Evaluación Preclínica de Medicamentos , Humanos , Fiebre del Valle del Rift/inmunología , Fiebre del Valle del Rift/virología , Virus de la Fiebre del Valle del Rift/genética , Eliminación de Secuencia , Vacunación , Vacunas Atenuadas/administración & dosificación , Vacunas Atenuadas/genética , Vacunas Atenuadas/inmunología , Proteínas no Estructurales Virales/administración & dosificación , Proteínas no Estructurales Virales/genética , Proteínas no Estructurales Virales/inmunología , Vacunas Virales/administración & dosificación , Vacunas Virales/genéticaRESUMEN
From 2006 to 2007, an active surveillance program for human monkeypox (MPX) in the Democratic Republic of the Congo identified 151 cases of coinfection with monkeypox virus and varicella zoster virus from 1158 suspected cases of human MPX (13%). Using clinical and socio-demographic data collected with standardized instruments by trained, local nurse supervisors, we examined a variety of hypotheses to explain the unexpectedly high proportion of coinfections among the sample, including the hypothesis that the two viruses occur independently. The probabilities of disease incidence and selection necessary to yield the observed sample proportion of coinfections under an assumption of independence are plausible given what is known and assumed about human MPX incidence. Cases of human MPX are expected to be underreported, and more coinfections are expected with improved surveillance.
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Varicela/epidemiología , Monitoreo Epidemiológico , Herpesvirus Humano 3/aislamiento & purificación , Monkeypox virus/aislamiento & purificación , Mpox/epidemiología , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Animales , Niño , Preescolar , Coinfección , República Democrática del Congo/epidemiología , Femenino , Humanos , Incidencia , Lactante , Recién Nacido , Masculino , Persona de Mediana Edad , Prevalencia , Adulto JovenRESUMEN
Ebola virus disease is a serious illness of humans and nonhuman primates (NHPs). Direct contact has been shown to be the primary source of Ebola (EBOV) transmission. We used a high-volume air sampler to determine whether EBOV could be detected during 3 independent studies with EBOV-challenged NHPs. Viral RNA was recovered during days 9 and 10 of Study I and days 7 and 8 of Study III. Viral RNA levels were below limits of detection during all other collections. The results demonstrate that the biosafety level 4 (BSL-4) suit protects workers from aerosols in a BSL-4 environment using proper engineering and administrative controls.
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Microbiología del Aire , Transmisión de Enfermedad Infecciosa , Ebolavirus/aislamiento & purificación , ARN Viral/aislamiento & purificación , Aerosoles/análisis , Animales , Modelos Animales de Enfermedad , Fiebre Hemorrágica Ebola/virología , Humanos , Límite de Detección , Macaca fascicularis/virología , Macaca mulatta/virologíaRESUMEN
Marburg virus infection in humans causes a hemorrhagic disease with a high case fatality rate. Countermeasure development requires the use of well-characterized animal models that mimic human disease. To further characterize the cynomolgus macaque model of MARV/Angola, two independent dose response studies were performed using the intramuscular or aerosol routes of exposure. All animals succumbed at the lowest target dose; therefore, a dose effect could not be determined. For intramuscular-exposed animals, 100 PFU was the first target dose that was not significantly different than higher target doses in terms of time to disposition, clinical pathology, and histopathology. Although a significant difference was not observed between aerosol-exposed animals in the 10 PFU and 100 PFU target dose groups, 100 PFU was determined to be the lowest target dose that could be consistently obtained and accurately titrated in aerosol studies.
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Aerosoles/administración & dosificación , Enfermedad del Virus de Marburg/virología , Marburgvirus/fisiología , Animales , Inyecciones Intramusculares , Estimación de Kaplan-Meier , Macaca fascicularis , Enfermedad del Virus de Marburg/sangre , ARN Viral/sangre , TemperaturaRESUMEN
The U.S. Department of Defense vaccinates personnel deployed to high-risk areas with the vaccinia virus (VACV)-based smallpox vaccine. Autoinoculations and secondary and tertiary transmissions due to VACV shedding from the vaccination site continue to occur despite education of vaccinees on the risks of such infections. The objectives of this study were to investigate, in naïve smallpox vaccinees, (a) whether the vaccination site can remain contagious after the scab separates and (b) whether the application of povidone iodine ointment (PIO) to the vaccination site inactivates VACV without affecting the immune response. These objectives were tested in 60 individuals scheduled to receive smallpox vaccine. Thirty individuals (control) did not receive PIO; 30 subjects (treatment) received PIO starting on post-vaccination day 7. Counter to current dogma, this study showed that VACV continues to shed from the vaccination site after the scab separates. Overall viral shedding levels in the PIO group were significantly lower than those in the control group (p=0.0045), and PIO significantly reduced the duration of viral shedding (median duration 14.5 days and 21 days in the PIO and control groups, respectively; p=0.0444). At least 10% of control subjects continued to shed VACV at day 28, and 3.4% continued to shed the virus at day 42. PIO reduced the proportion of subjects shedding virus from the vaccination site from day 8 until days 21-23 compared with control subjects. Groups did not differ significantly in the proportion of subjects mounting an immune response, as measured by neutralizing antibodies, IgM, IgG, and interferon-gamma enzyme-linked immunospot assay. When applied to the vaccination site starting on day 7, PIO reduced viral shedding without altering the immune response. The use of PIO in addition to a semipermeable dressing may reduce the rates of autoinoculation and contact transmission originating from the vaccination site in smallpox-vaccinated individuals.
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Personal Militar , Povidona Yodada/administración & dosificación , Vacuna contra Viruela/administración & dosificación , Vacuna contra Viruela/inmunología , Virus Vaccinia/fisiología , Vaccinia/prevención & control , Esparcimiento de Virus , Adulto , Antiinfecciosos Locales/administración & dosificación , Anticuerpos Neutralizantes/sangre , Anticuerpos Neutralizantes/inmunología , Anticuerpos Antivirales/sangre , Anticuerpos Antivirales/inmunología , Ensayo de Immunospot Ligado a Enzimas , Femenino , Humanos , Inmunidad Celular , Interferón gamma/sangre , Interferón gamma/inmunología , Masculino , Piel/virología , Viruela/inmunología , Viruela/prevención & control , Estados Unidos , Vacunación , Vaccinia/transmisión , Virus Vaccinia/inmunología , Adulto JovenRESUMEN
Henipaviruses are implicated in severe and frequently fatal pneumonia and encephalitis in humans. There are no approved vaccines or treatments available for human use, and testing of candidates requires the use of well-characterized animal models that mimic human disease. We performed a comprehensive and statistically-powered evaluation of the African green monkey model to define parameters critical to disease progression and the extent to which they correlate with human disease. African green monkeys were inoculated by the intratracheal route with 2.5 × 10(4) plaque forming units of the Malaysia strain of Nipah virus. Physiological data captured using telemetry implants and assessed in conjunction with clinical pathology were consistent with shock, and histopathology confirmed widespread tissue involvement associated with systemic vasculitis in animals that succumbed to acute disease. In addition, relapse encephalitis was identified in 100% of animals that survived beyond the acute disease phase. Our data suggest that disease progression in the African green monkey is comparable to the variable outcome of Nipah virus infection in humans.
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Chlorocebus aethiops/virología , Infecciones por Henipavirus/patología , Infecciones por Henipavirus/virología , Virus Nipah/patogenicidad , Animales , Enfermedades Transmisibles/patología , Enfermedades Transmisibles/virología , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Encefalitis/patología , Encefalitis/virología , MalasiaRESUMEN
BACKGROUND: Human monkeypox is a zoonotic disease endemic to parts of Africa. Similar to other orthopoxviruses, virus and host have considerable interactions through immunomodulation. These interactions likely drive the establishment of a productive infection and disease progression, resulting in the range of disease presentations and case fatality rates observed for members of the Orthopoxvirus genus. OBJECTIVES: Much of our understanding about the immune response to orthopoxvirus infection comes from either in vitro or in vivo studies performed in small animals or non-human primates. Here, we conducted a detailed assessment of cytokine responses to monkeypox virus using serum from acutely ill humans collected during monkeypox active disease surveillance (2005-2007) in the Democratic Republic of the Congo. STUDY DESIGN: Nineteen serum samples that were from patients with confirmed monkeypox virus infections were selected for cytokine profiling. Cytokine profiling was performed on the Bio-Rad Bioplex 100 system using a 30-plex human cytokine panel. RESULTS: Cytokine profiling revealed elevated cytokine concentrations in all samples. Overproduction of certain cytokines (interleukin [IL]-2R, IL-10, and granulocyte macrophage-colony stimulating factor were observed in patients with serious disease (defined as >250 lesions based on the World Health Organization scoring system). CONCLUSIONS: The data suggest that cytokine modulation affects monkeypox disease severity in humans.
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Citocinas/sangre , Monkeypox virus/inmunología , Mpox/inmunología , Mpox/patología , Índice de Severidad de la Enfermedad , Adolescente , Adulto , Animales , Niño , Preescolar , República Democrática del Congo , Femenino , Humanos , Lactante , Masculino , Adulto JovenRESUMEN
Monkeypox virus is a zoonotic virus endemic to Central Africa. Although active disease surveillance has assessed monkeypox disease prevalence and geographic range, information about virus diversity is lacking. We therefore assessed genome diversity of viruses in 60 samples obtained from humans with primary and secondary cases of infection from 2005 through 2007. We detected 4 distinct lineages and a deletion that resulted in gene loss in 10 (16.7%) samples and that seemed to correlate with human-to-human transmission (p = 0.0544). The data suggest a high frequency of spillover events from the pool of viruses in nonhuman animals, active selection through genomic destabilization and gene loss, and increased disease transmissibility and severity. The potential for accelerated adaptation to humans should be monitored through improved surveillance.