RESUMEN
BACKGROUND: Recent outbreaks of Ebola virus disease (EVD) and Marburg virus disease (MVD) in sub-Saharan Africa illustrate the need to better understand animal reservoirs, burden of disease, and human transmission of filoviruses. This protocol outlines a systematic literature review to assess the prevalence of filoviruses that infect humans in sub-Saharan Africa. A secondary aim is to qualitatively describe and evaluate the assays used to assess prevalence. METHODS: The data sources for this systematic review include PubMed, Embase, and Web of Science. Titles, abstracts, and full texts will be reviewed for inclusion by a primary reviewer and then by a team of secondary reviewers, and data will be extracted using a pre-specified and piloted data extraction form. The review will include human cross-sectional studies, cohort studies, and randomized controlled trials conducted in sub-Saharan Africa up until March 13, 2024 that have been published in peer-reviewed scientific journals, with no language restrictions. Prevalence will be stratified by pathogen, population, assay, and sampling methodology and presented in forest plots with estimated prevalence and 95% confidence intervals. If there are enough studies within a stratum, I2 statistics will be calculated (using R statistical software), and data will be pooled if heterogeneity is low. In addition, assays used to detect infection will be evaluated. All studies included in the review will be assessed for quality and risk of bias using the JBI Prevalence Critical Appraisal Tool and for certainty using the GRADE certainty ratings. DISCUSSION: Accurately measuring the rate of exposure to filoviruses infecting humans in sub-Saharan Africa using prevalence provides an essential understanding of natural history, transmission, and the role of subclinical infection. This systematic review will identify research gaps and provide directions for future research seeking to improve our understanding of filovirus infections. Understanding the natural history, transmission, and the role of subclinical infection is critical for predicting the impact of an intervention on disease burden. SYSTEMATIC REVIEW REGISTRATION: In accordance with the guidelines outlined in the PRISMA-P methodology, this protocol was registered with PROSPERO on April 7, 2023 (ID: CRD42023415358).
Asunto(s)
Infecciones por Filoviridae , Revisiones Sistemáticas como Asunto , Humanos , África del Sur del Sahara/epidemiología , Prevalencia , Infecciones por Filoviridae/epidemiología , Metaanálisis como Asunto , Fiebre Hemorrágica Ebola/epidemiología , Animales , FiloviridaeRESUMEN
Anthrax is an acute infectious disease caused by the spore-forming bacterium Bacillus anthracis. Timely administration of antibiotics approved for the treatment of anthrax disease may prevent associated morbidity and mortality. However, any delay in initiating antimicrobial therapy may result in increased mortality, as inhalational anthrax progresses rapidly to the toxemic phase of disease. An anthrax antitoxin, AVP-21D9, also known as Thravixa (fully human anthrax monoclonal antibody), is being developed as a therapeutic agent against anthrax toxemia. The efficacy of AVP-21D9 in B. anthracis-infected New Zealand White rabbits and in cynomolgus macaques was evaluated, and its safety and pharmacokinetics were assessed in healthy human volunteers. The estimated mean elimination half-life values of AVP-21D9 in surviving anthrax-challenged rabbits and nonhuman primates (NHPs) ranged from approximately 2 to 4 days and 6 to 11 days, respectively. In healthy humans, the mean elimination half-life was in the range of 20 to 27 days. Dose proportionality was observed for the maximum serum concentration (Cmax) of AVP-21D9 and the area under the concentration-time curve (AUC). In therapeutic efficacy animal models, treatment with AVP-21D9 resulted in survival of up to 92% of the rabbits and up to 67% of the macaques. Single infusions of AVP-21D9 were well tolerated in healthy adult volunteers across all doses evaluated, and no serious adverse events were reported. (This study has been registered at ClinicalTrials.gov under registration no. NCT01202695.).
Asunto(s)
Carbunco/tratamiento farmacológico , Carbunco/inmunología , Antibacterianos/uso terapéutico , Anticuerpos Monoclonales/uso terapéutico , Anticuerpos Neutralizantes/uso terapéutico , Adolescente , Adulto , Animales , Antibacterianos/efectos adversos , Antibacterianos/farmacología , Anticuerpos Monoclonales/efectos adversos , Anticuerpos Monoclonales/farmacocinética , Anticuerpos Monoclonales/farmacología , Anticuerpos Monoclonales Humanizados , Anticuerpos Neutralizantes/efectos adversos , Anticuerpos Neutralizantes/farmacología , Antígenos Bacterianos/sangre , Bacteriemia/sangre , Bacteriemia/tratamiento farmacológico , Anticuerpos ampliamente neutralizantes , Células CHO , Cricetinae , Cricetulus , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Macaca fascicularis , Masculino , Persona de Mediana Edad , Conejos , Adulto JovenRESUMEN
Bacillus anthracis toxins can be neutralized by antibodies against protective antigen (PA), a component of anthrax toxins. Anthrivig (human anthrax immunoglobulin), also known as AIGIV, derived from plasma of humans immunized with BioThrax (anthrax vaccine adsorbed), is under development for the treatment of toxemia following exposure to anthrax spores. The pharmacokinetics (PK) of AIGIV was assessed in naive animals and healthy human volunteers, and the efficacy of AIGIV was assessed in animals exposed via inhalation to aerosolized B. anthracis spores. In the clinical study, safety, tolerability, and PK were evaluated in three dose cohorts (3.5, 7.1, and 14.2 mg/kg of body weight of anti-PA IgG) with 30 volunteers per cohort. The elimination half-life of AIGIV in rabbits, nonhuman primates (NHPs), and humans following intravenous infusion was estimated to be approximately 4, 12, and 24 days, respectively, and dose proportionality was observed. In a time-based treatment study, AIGIV protected 89 to 100% of animals when administered 12 h postexposure; however, a lower survival rate of 39% was observed when animals were treated 24 h postexposure, underscoring the need for early intervention. In a separate set of studies, animals were treated on an individual basis upon detection of a clinical sign or biomarker of disease, namely, a significant increase in body temperature (SIBT) in rabbits and presence of PA in the serum of NHPs. In these trigger-based intervention studies, AIGIV induced up to 75% survival in rabbits depending on the dose and severity of toxemia at the time of treatment. In NHPs, up to 33% survival was observed in AIGIV-treated animals. (The clinical study has been registered at ClinicalTrials.gov under registration no. NCT00845650.).
Asunto(s)
Vacunas contra el Carbunco/administración & dosificación , Carbunco/prevención & control , Anticuerpos Antibacterianos/administración & dosificación , Bacillus anthracis/efectos de los fármacos , Inmunoglobulinas Intravenosas/farmacocinética , Infecciones del Sistema Respiratorio/prevención & control , Esporas Bacterianas/efectos de los fármacos , Animales , Carbunco/inmunología , Carbunco/microbiología , Carbunco/mortalidad , Vacunas contra el Carbunco/inmunología , Anticuerpos Antibacterianos/inmunología , Anticuerpos Antibacterianos/aislamiento & purificación , Antígenos Bacterianos/sangre , Antígenos Bacterianos/inmunología , Bacillus anthracis/inmunología , Bacillus anthracis/patogenicidad , Toxinas Bacterianas/sangre , Toxinas Bacterianas/inmunología , Biomarcadores/análisis , Método Doble Ciego , Femenino , Semivida , Humanos , Inmunoglobulinas Intravenosas/inmunología , Inmunoglobulinas Intravenosas/aislamiento & purificación , Infusiones Intravenosas , Macaca fascicularis , Masculino , Conejos , Infecciones del Sistema Respiratorio/inmunología , Infecciones del Sistema Respiratorio/microbiología , Infecciones del Sistema Respiratorio/mortalidad , Esporas Bacterianas/inmunología , Esporas Bacterianas/patogenicidad , Análisis de Supervivencia , Factores de Tiempo , VacunaciónRESUMEN
Development of anthrax countermeasures that may be used concomitantly in a postexposure setting requires an understanding of the interaction between these products. Anthrax immune globulin intravenous (AIGIV) is a candidate immunotherapeutic that contains neutralizing antibodies against protective antigen (PA), a component of anthrax toxins. We evaluated the interaction between AIGIV and BioThrax (anthrax vaccine adsorbed) in rabbits. While pharmacokinetics of AIGIV were not altered by vaccination, the vaccine-induced immune response was abrogated in AIGIV-treated animals.
Asunto(s)
Vacunas contra el Carbunco/administración & dosificación , Anticuerpos Antibacterianos/administración & dosificación , Inmunoglobulinas Intravenosas/farmacocinética , Animales , Carbunco/inmunología , Carbunco/microbiología , Carbunco/prevención & control , Vacunas contra el Carbunco/inmunología , Anticuerpos Antibacterianos/sangre , Anticuerpos Antibacterianos/inmunología , Área Bajo la Curva , Bacillus anthracis/inmunología , Antagonismo de Drogas , Femenino , Semivida , Humanos , Inmunoglobulinas Intravenosas/sangre , Inmunoglobulinas Intravenosas/inmunología , Infusiones Intravenosas , Masculino , Conejos , Infecciones del Sistema Respiratorio/inmunología , Infecciones del Sistema Respiratorio/microbiología , Infecciones del Sistema Respiratorio/prevención & control , VacunaciónRESUMEN
INTRODUCTION: The use of hyperbaric oxygen (HBO) to expedite decompression from saturation has not been proven and may increase risk of toxicity to the pulmonary system. To evaluate any benefit of HBO during decompression, we used a 70-kg swine model of saturation and examined lung tissue by microarray analysis for evidence of RNA regulation. METHODS: Unrestrained, non-sedated swine were compressed to 132 fsw (5 ATA) for 22 h to achieve saturation. Animals then underwent decompression on air (AirD) or HBO (HBOD) starting at 45 fsw (2.36 ATA). Animals were evaluated for Type I and Type II decompression sickness (DCS) for 24 h. Control (SHAM) animals were placed in the chamber for the same duration, but were not compressed. Animals were sacrificed 24 h after exposure and total RNA was isolated from lung samples for microarray hybridizations on the Affymetrix platform. RESULTS: There was no evidence of Type I DCS or severe cardiopulmonary DCS in any of the animals; abnormal gaits were noted only in the HBOD group (4/9).Three genes (nidogen 2, calcitonin-like receptor, and pentaxin-related gene) were significantly up-regulated in both the AirD and HBOD groups compared to controls. Three other genes (TN3, platelet basic protein, and cytochrome P450) were significantly down-regulated in both groups. CONCLUSIONS: HBO during decompression from saturation did not reduce the incidence of DCS. Gene regulation was apparent and similar in both the AirD and HBOD groups, particularly in genes related to immune function and cell signaling.
Asunto(s)
Enfermedad de Descompresión/prevención & control , Regulación de la Expresión Génica , Oxigenoterapia Hiperbárica , Consumo de Oxígeno , ARN , Animales , Enfermedad de Descompresión/etiología , Enfermedad de Descompresión/genética , Pulmón/química , Masculino , Modelos Animales , Análisis de Secuencia por Matrices de Oligonucleótidos , ARN/química , ARN/aislamiento & purificación , PorcinosRESUMEN
Previously, combination DNA/nonreplicating adenovirus (Ad)- or poxvirus-vectored vaccines have strongly protected against SHIV(89.6P), DNAs expressing cytokines have modulated immunity elicited by DNA vaccines, and replication-competent Ad-recombinant priming and protein boosting has strongly protected against simian immunodeficiency virus (SIV) challenge. Here we evaluated a vaccine strategy composed of these promising components. Seven rhesus macaques per group were primed twice with multigenic SIV plasmid DNA with or without interleukin-12 (IL-12) DNA or IL-15 DNA. After a multigenic replicating Ad-SIV immunization, all groups received two booster immunizations with SIV gp140 and SIV Nef protein. Four control macaques received control DNA plasmids, empty Ad vector, and adjuvant. All vaccine components were immunogenic, but the cytokine DNAs had little effect. Macaques that received IL-15-DNA exhibited higher peak anti-Nef titers, a more rapid anti-Nef anamnestic response postchallenge, and expanded CD8(CM) T cells 2 weeks postchallenge compared to the DNA-only group. Other immune responses were indistinguishable between groups. Overall, no protection against intrarectal challenge with SIV(mac251) was observed, although immunized non-Mamu-A*01 macaques as a group exhibited a statistically significant 1-log decline in acute viremia compared to non-Mamu-A*01 controls. Possible factors contributing to the poor outcome include administration of cytokine DNAs to sites different from the Ad recombinants (intramuscular and intratracheal, respectively), too few DNA priming immunizations, a suboptimal DNA delivery method, failure to ensure delivery of SIV and cytokine plasmids to the same cell, and instability and short half-life of the IL-15 component. Future experiments should address these issues to determine if this combination approach is able to control a virulent SIV challenge.
Asunto(s)
Adyuvantes Inmunológicos/administración & dosificación , Citocinas/administración & dosificación , Vacunas contra el SIDAS/administración & dosificación , Vacunas contra el SIDAS/inmunología , Síndrome de Inmunodeficiencia Adquirida del Simio/prevención & control , Vacunas de ADN/administración & dosificación , Vacunas de ADN/inmunología , Adenoviridae/genética , Animales , Citocinas/inmunología , Inmunización Secundaria , Leucocitos Mononucleares/inmunología , Macaca mulatta , Plásmidos , Virus de la Inmunodeficiencia de los Simios/inmunología , Vacunas de Subunidad/administración & dosificación , Vacunas de Subunidad/inmunología , Carga Viral , Viremia/prevención & controlRESUMEN
BACKGROUND: Rapid resuscitation with oxygen-carrying fluids is critically important in hemorrhagic shock (HS) combat casualties in remote areas where blood is not available. Hemoglobin-based oxygen carrier-201 (HBOC-201) has been shown to increase survival and reduce immune activation following HS in animal models. Recombinant factor VIIa (rfVIIa), a systemic hemostatic agent, is Food and Drug Administration approved for use in acute hemorrhage in hemophilic patients. The combination of HBOC-201 and rfVIIa may form the basis of a prospective multifunctional blood substitute and provide benefits in the rapid restoration of hemostasis, decreased inflammation and improved survival of HS combat casualties. In the present study, we evaluated innate immune responses in a swine model of uncontrolled HS following resuscitation with HBOC-201 +/- rfVIIa. MATERIALS: Thirty-two pigs underwent uncontrolled hemorrhage/liver crush injury, followed by resuscitation with five doses of HBOC-201 or HBOC + rfVIIa (90 microg/kg, or 180 microg/kg, or 360 microg/kg) and simulated 4 hours hospital arrival. Immune parameters were evaluated by flow cytometry and enzyme-linked immunosorbent assay. RESULTS: Survival differences to 72 hours of animals resuscitated with HBOC, HBOC + rfVIIa (90), (180), and (360) were not statistically significant and resulted in survival of 25%, 63%, 63% and 50%, respectively. At the prehospital phase all groups exhibited minimal immunomodulation, characterized by stable CD4/CD8 ratio, marginal increase of apoptosis and insignificant fluctuations of adhesion markers; increase of plasma cytokines was comparable across all groups, except tumor necrosis factor-alpha, that was significantly elevated in the HBOC group. CONCLUSION: HBOC-201 + rfVIIa triggered minimum immune activation in an uncontrolled HS swine and there was a nonsignificant survival benefit.
Asunto(s)
Factor VIIa/administración & dosificación , Hemoglobinas/administración & dosificación , Resucitación/métodos , Choque Hemorrágico/tratamiento farmacológico , Choque Hemorrágico/inmunología , Animales , Sustitutos Sanguíneos/administración & dosificación , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Inmunidad Innata/efectos de los fármacos , Inmunidad Innata/inmunología , Estimación de Kaplan-Meier , Probabilidad , Distribución Aleatoria , Proteínas Recombinantes/administración & dosificación , Resucitación/mortalidad , Sensibilidad y Especificidad , Choque Hemorrágico/mortalidad , Tasa de Supervivencia , PorcinosRESUMEN
BACKGROUND: Some hemoglobin-based oxygen carriers (HBOCs) improve outcome in animal models of hemorrhagic shock (HS) in comparison with standard asanguinous resuscitation fluids. Nevertheless, concern about intrinsic vasoactivity, linked in part to low-molecular weight (MW) hemoglobin (Hb), has slowed HBOC development. We assessed the impact of decreasing the low-MW Hb component of bovine HBOC on vasoactivity in severe HS. METHODS: Anesthetized invasively monitored swine were hemorrhaged 55% blood volume and resuscitated with bovine HBOC containing 31% (31 TD [HBOC-301]), 2% (2 TD [HBOC-201]), or 0.4% (0.4 TD) low-MW Hb. Pigs received four 10 mL/kg infusions over 60 minutes, hospital arrival was simulated at 75 minutes, organ blood flow (BF) was evaluated by microsphere injection, and monitoring was continued for 4 hours followed by complete necrotic evaluation. RESULTS: There were few differences between 2 TD and 0.4 TD. Thirty-one TD pigs had higher systemic and pulmonary blood pressure (BP), systemic vascular resistance index, and pulmonary artery wedge pressure, compared with 2 TD or 0.4 TD (p < 0.01); however, pigs in all groups had at least mildly elevated BP. Transcutaneous tissue oxygenation, base excess, and mixed venous oxygen saturation were similar across groups; lactate and methemoglobin were highest with 0.4 TD (p < 0.03). There were no group differences in BF. Over time, myocardial BF increased and hepatic BF decreased in all groups (for 31 TD, p < 0.05); renal BF was unchanged in all groups. There were no group differences in heart, lung, or liver histopathology, and survival. CONCLUSIONS: Although purification from 31% to 2% low-MW Hb content significantly decreased vasoactive responses, further purification to 0.4% had no additional clinically measurable effects in severe HS. If further diminution in HBOC vasoactivity is desired for use in HS, additional technical approaches may be required.
Asunto(s)
Presión Sanguínea , Sustitutos Sanguíneos/uso terapéutico , Resucitación/métodos , Choque Hemorrágico/terapia , Animales , Modelos Animales de Enfermedad , Femenino , Peso Molecular , Flujo Sanguíneo Regional , PorcinosRESUMEN
Previously, replicating adenovirus type 5 host range (Ad5hr)-HIV/SIV recombinant priming in combination with SIV envelope boosting, resulted in significant, durable protection in 39% of rhesus macaques after SIVmac251 challenge. Both Env-specific antibody mediating ADCC, and cellular immunity correlated with protection. Here we evaluate the relative immunogenicities of novel HIV proteins and their contribution to protection in a SHIV89.6P model. All groups were primed with Ad-HIVenv89.6P, SIVgag239, and SIVnef239 recombinants. One group was not boosted, one received HIV89.6Pgp140DeltaCFI protein, and one a novel HIV-1 poly-peptide "peptomer". The HIV89.6Pgp140DeltaCFI protein in adjuvant strongly boosted Env-specific antibody and memory T cell responses in blood and tissue, resulting in significant reductions in acute and set point viremia. Macaques not boosted, showed a significant reduction in set point viremia, a full 32 weeks after the last Ad priming immunization. The HIV peptomer-boosted group showed a trend toward chronic viremia reduction, but was not protected.
Asunto(s)
Adenoviridae/fisiología , Vectores Genéticos , VIH-1/inmunología , Virus de la Inmunodeficiencia de los Simios/inmunología , Viremia/prevención & control , Productos del Gen env del Virus de la Inmunodeficiencia Humana/inmunología , Vacunas contra el SIDA/administración & dosificación , Vacunas contra el SIDA/inmunología , Adenoviridae/genética , Animales , Anticuerpos Anti-VIH/sangre , Infecciones por VIH/prevención & control , VIH-1/genética , VIH-1/patogenicidad , Antígenos de Histocompatibilidad Clase I/metabolismo , Humanos , Inmunización , Inmunización Secundaria , Macaca mulatta , Masculino , Recombinación Genética , Vacunas contra el SIDAS/administración & dosificación , Vacunas contra el SIDAS/inmunología , Síndrome de Inmunodeficiencia Adquirida del Simio/prevención & control , Virus de la Inmunodeficiencia de los Simios/genética , Virus de la Inmunodeficiencia de los Simios/patogenicidad , Virus de la Inmunodeficiencia de los Simios/efectos de la radiación , Linfocitos T/inmunología , Replicación Viral , Productos del Gen env del Virus de la Inmunodeficiencia Humana/administración & dosificaciónRESUMEN
Oral, replication-competent Ad-HIV vaccines are advancing to human trials. Previous evaluation of protective efficacy in non-human primates has primarily followed upper respiratory tract administrations. Here we compared sequential oral (O/O) versus intranasal/oral (I/O) priming of rhesus macaques with Ad5 host range mutant-SIV recombinants expressing SIV env/rev, gag, and nef genes followed by boosting with SIV gp120 protein. Cellular immune responses in PBMC were stronger and more frequent after I/O administration. Both groups developed mucosal immunity, including memory cells in bronchial alveolar lavage, and gut-homing receptors on PBMC. Following intrarectal SIV(mac251) challenge, both groups exhibited equivalent, significant protection and robust post-challenge cellular immunity. Our results illustrate the promise of oral replication-competent Ad-recombinant vaccines. Pre-challenge PBMC ELISPOT and proliferative responses did not predict protection in the O/O group, highlighting the need for simple, non-invasive methods to reliably assess mucosal immunity.
Asunto(s)
Adenoviridae/genética , Replicación del ADN/genética , Vacunas contra el SIDAS/inmunología , Síndrome de Inmunodeficiencia Adquirida del Simio/inmunología , Síndrome de Inmunodeficiencia Adquirida del Simio/prevención & control , Virus de la Inmunodeficiencia de los Simios/genética , Virus de la Inmunodeficiencia de los Simios/inmunología , Administración Intranasal , Administración Oral , Animales , Células Cultivadas , Heces/virología , Humanos , Memoria Inmunológica/inmunología , Integrinas/metabolismo , Interferón gamma/metabolismo , Leucocitos/citología , Leucocitos/inmunología , Leucocitos/metabolismo , Macaca mulatta , Masculino , Mutación/genética , Proteínas Recombinantes/genética , Proteínas Recombinantes/inmunología , Proteínas Recombinantes/metabolismo , Vacunas contra el SIDAS/administración & dosificación , Comprimidos , Vacunas SintéticasRESUMEN
OBJECTIVES: To test our hypothesis that the hemoglobin based oxygen carrier HBOC-201 would have similar or superior efficacy to 6% hetastarch (HEX) as a pre-hospital 'bridging' fluid for hemorrhagic shock when delay to definitive medical care is prolonged to 24h. METHODS: Twenty-four pigs were anesthetized, instrumented, given a soft tissue injury, and bled 55% estimated blood volume. Pigs were randomized to receive HBOC-201, HEX, or no resuscitation fluids (NON). At 4h post-injury, surgical sites were repaired and pigs were recovered from anesthesia. Animals were non-invasively monitored, administered blood for anemia or saline for hypotension at 24 and 48h, and monitored for 72h. RESULTS: Survival to 72h was 87.5% (7/8) in HBOC-201 and HEX pigs compared to 25% (2/8) in NON pigs (p=0.01). Increased mean arterial pressure was observed in the HBOC-201 group (p<0.0001). Cardiac index was highest in HEX pigs (overall p<0.001, HBOC-201 versus HEX p=0.002). Transcutaneous tissue oxygenation was higher with HBOC-201 (overall p=0.04, HBOC-201 versus HEX p<0.01). HBOC-201 and HEX pigs had comparable heart rates, pulmonary pressures, pre-hospital fluid requirements, venous O(2) saturation, base deficit, and lactic acid. Hemoglobin was decreased with HEX (overall p<0.0001, HBOC-201 versus HEX p<0.0002). At 24h, 14.3% (1/7) HBOC-201 pigs required blood transfusions versus 100% HEX (7/7) and NON (2/2) pigs (p>0.001). CONCLUSIONS: HBOC-201 restored hemodynamics, maintained tissue oxygenation, and decreased blood transfusions in comparison to HEX in severe controlled HS with 24h delay to simulated hospital care. These results support the potential use of HBOC-201 as a bridging resuscitation fluid for HS.