Macvittie T.J.,University of Maryland, Baltimore |
Gibbs A.,University of Maryland, Baltimore |
Farese A.M.,University of Maryland, Baltimore |
Barrow K.,SNBL United States Ltd. |
And 6 more authors.
Radiation Research | Year: 2017
Pneumonitis and fibrosis are potentially lethal, delayed effects of acute radiation exposure. In this study, male rhesus macaques received whole-thorax lung irradiation (WTLI) with a target dose of 10.74 Gy prescribed to midplane at a dose rate of 0.80 ± 0.05 Gy/min using 6 MV linear accelerator-derived photons. The study design was comprised of four animal cohorts: one control and three treated with AEOL 10150 (n = 20 animals per cohort). AEOL 10150, a metalloporphyrin antioxidant, superoxide dismutase mimetic was administered by daily subcutaneous injection at 5 mg/kg in each of three schedules, beginning 24 ± 2 h postirradiation: from day 1 to day 28, day 1 to day 60 or a divided regimen from day 1 to day 28 plus day 60 to day 88. Control animals received 0.9% saline injections from day 1 to day 28. All animals received medical management and were followed for 180 days. Computed tomography (CT) scan and baseline hematology values were assessed prior to WTLI. Postirradiation monthly CT scans were collected, and images were analyzed for evidence of lung injury (pneumonitis, fibrosis, pleural and pericardial effusion) based on differences in radiodensity characteristics of the normal versus damaged lung. The primary end point was survival to 180 days based on all-cause mortality. The latency, incidence and severity of lung injury were assessed through clinical, radiographic and histological parameters. A clear survival relationship was observed with the AEOL 10150 treatment schedule and time after lethal WTLI. The day 1-60 administration schedule increased survival from 25 to 50%, mean survival time of decedents and the latency to nonsedated respiratory rate to >60 or >80 breaths/min and diminished quantitative radiographic lung injury as determined by CT scans. It did not affect incidence or severity of pneumonitis/fibrosis as determined by histological evaluation, pleural effusion or pericardial effusion as determined by CT scans. Analysis of the Kaplan-Meier survival curves suggested that treatment efficacy could be increased by extending the treatment schedule to 90 days or longer after WTLI. No survival improvement was noted in the AEOL 10150 cohorts treated from day 1-28 or using the divided schedule of day 1-28 plus day 60-88. These results suggest that AEOL 10150 may be an effective medical countermeasure against severe and lethal radiation-induced lung injury. © 2017 by Radiation Research Society.
Tamminga C.,Naval Medical Research Center |
Sedegah M.,Naval Medical Research Center |
Regis D.,Naval Medical Research Center |
Chuang I.,Naval Medical Research Center |
And 63 more authors.
PLoS ONE | Year: 2011
Background: A protective malaria vaccine will likely need to elicit both cell-mediated and antibody responses. As adenovirus vaccine vectors induce both these responses in humans, a Phase 1/2a clinical trial was conducted to evaluate the efficacy of an adenovirus serotype 5-vectored malaria vaccine against sporozoite challenge. Methodology/Principal Findings: NMRC-MV-Ad-PfC is an adenovirus vector encoding the Plasmodium falciparum 3D7 circumsporozoite protein (CSP). It is one component of a two-component vaccine NMRC-M3V-Ad-PfCA consisting of one adenovector encoding CSP and one encoding apical membrane antigen-1 (AMA1) that was evaluated for safety and immunogenicity in an earlier study (see companion paper, Sedegah et al). Fourteen Ad5 seropositive or negative adults received two doses of NMRC-MV-Ad-PfC sixteen weeks apart, at 1 ×10̂10 particle units per dose. The vaccine was safe and well tolerated. All volunteers developed positive ELISpot responses by 28 days after the first immunization (geometric mean 272 spot forming cells/million[sfc/m]) that declined during the following 16 weeks and increased after the second dose to levels that in most cases were less than the initial peak (geometric mean 119 sfc/m). CD8+ predominated over CD4+ responses, as in the first clinical trial. Antibody responses were poor and like ELISpot responses increased after the second immunization but did not exceed the initial peak. Pre-existing neutralizing antibodies (NAb) to Ad5 did not affect the immunogenicity of the first dose, but the fold increase in NAb induced by the first dose was significantly associated with poorer antibody responses after the second dose, while ELISpot responses remained unaffected. When challenged by the bite of P. falciparum-infected mosquitoes, two of 11 volunteers showed a delay in the time to patency compared to infectivity controls, but no volunteers were sterilely protected. Significance: The NMRC-MV-Ad-PfC vaccine expressing CSP was safe and well tolerated given as two doses, but did not provide sterile protection. Trial Registration: ClinicalTrials.gov NCT00392015.
Mammen M.P.,U.S. Army |
Mammen M.P.,Vical Incorporated |
Lyons A.,U.S. Army |
Innis B.L.,U.S. Army |
And 16 more authors.
Vaccine | Year: 2014
Discordance between the measured levels of dengue virus neutralizing antibody and clinical outcomes in the first-ever efficacy study of a dengue tetravalent vaccine (Lancet, Nov 2012) suggests a need to re-evaluate the process of pre-screening dengue vaccine candidates to better predict clinical benefit prior to large-scale vaccine trials. In the absence of a reliable animal model and established correlates of protection for dengue, a human dengue virus challenge model may provide an approach to down-select vaccine candidates based on their ability to reduce risk of illness following dengue virus challenge. We report here the challenge of flavivirus-naïve adults with cell culture-passaged dengue viruses (DENV) in a controlled setting that resulted in uncomplicated dengue fever (DF). This sets the stage for proof-of-concept efficacy studies that allow the evaluation of dengue vaccine candidates in healthy adult volunteers using qualified DENV challenge strains well before they reach field efficacy trials involving children. Fifteen flavivirus-naïve adult volunteers received 1 of 7 DENV challenge strains (n= 12) or placebo (n= 3). Of the twelve volunteers who received challenge strains, five (two DENV-1 45AZ5 and three DENV-3 CH53489 cl24/28 recipients) developed DF, prospectively defined as ≥2 typical symptoms, ≥48. h of sustained fever (>100.4. °F) and concurrent viremia. Based on our study and historical data, we conclude that the DENV-1 and DENV-3 strains can be advanced as human challenge strains. Both of the DENV-2 strains and one DENV-4 strain failed to meet the protocol case definition of DF. The other two DENV-4 strains require additional testing as the illness approximated but did not satisfy the case definition of DF. Three volunteers exhibited effusions (1 pleural/ascites, 2 pericardial) and 1 volunteer exhibited features of dengue (rash, lymphadenopathy, neutropenia and thrombocytopenia), though in the absence of fever and symptoms. The occurrence of effusions in milder DENV infections counters the long-held belief that plasma leakage syndromes are restricted to dengue hemorrhagic fever/dengue shock syndromes (DHF/DSS). Hence, the human dengue challenge model may be useful not only for predicting the efficacy of vaccine and therapeutic candidates in small adult cohorts, but also for contributing to our further understanding of the mechanisms behind protection and virulence. © 2014.
Sedegah M.,Naval Medical Research Center |
Tamminga C.,Naval Medical Research Center |
McGrath S.,U.S. Army |
McGrath S.,Clinical Research Management |
And 47 more authors.
PLoS ONE | Year: 2011
Background: Models of immunity to malaria indicate the importance of CD8+ T cell responses for targeting intrahepatic stages and antibodies for targeting sporozoite and blood stages. We designed a multistage adenovirus 5 (Ad5)-vectored Plasmodium falciparum malaria vaccine, aiming to induce both types of responses in humans, that was tested for safety and immunogenicity in a Phase 1 dose escalation trial in Ad5-seronegative volunteers. Methodology/Principal Findings: The NMRC-M3V-Ad-PfCA vaccine combines two adenovectors encoding circumsporozoite protein (CSP) and apical membrane antigen-1 (AMA1). Group 1 (n = 6) healthy volunteers received one intramuscular injection of 2×10∧10 particle units (1×10∧10 each construct) and Group 2 (n = 6) a five-fold higher dose. Transient, mild to moderate adverse events were more pronounced with the higher dose. ELISpot responses to CSP and AMA1 peaked at 1 month, were higher in the low dose (geomean CSP = 422, AMA1 = 862 spot forming cells/million) than in the high dose (CSP = 154, p = 0.049, AMA1 = 423, p = 0.045) group and were still positive at 12 months in a number of volunteers. ELISpot depletion assays identified dependence on CD4+ or on both CD4+ and CD8+ T cells, with few responses dependent only on CD8+ T cells. Intracellular cytokine staining detected stronger CD8+ than CD4+ T cell IFN-γ responses (CSP p = 0.0001, AMA1 p = 0.003), but similar frequencies of multifunctional CD4+ and CD8+ T cells secreting two or more of IFN-γ, TNF-α or IL-2. Median fluorescence intensities were 7-10 fold higher in triple than single secreting cells. Antibody responses were low but trended higher in the high dose group and did not inhibit growth of cultured P. falciparum blood stage parasites. Significance: As found in other trials, adenovectored vaccines appeared safe and well-tolerated at doses up to 1×10∧11 particle units. This is the first demonstration in humans of a malaria vaccine eliciting strong CD8+ T cell IFN-γ responses. Trial Registration: ClinicalTrials.gov NCT00392015.
Yee S.B.,U.S. Army |
Hatkin J.M.,Pennsylvania Veterinary Diagnostic Laboratory |
Dyer D.N.,U.S. Army |
Orr S.A.,U.S. Army |
And 2 more authors.
Comparative Medicine | Year: 2010
The natural history for inhalational Bacillus anthracis (Ames strain) exposure in New Zealand white rabbits was investigated to better identify potential, early biomarkers of anthrax. Twelve SPF Bordetella-free rabbits were exposed to 150 LD50 aerosolized B. anthracis spores, and clinical signs, body temperature, complete blood count, bacteremia, and presence of protective antigen in the blood (that is, antigenemia) were examined. The development of antigenemia and bacteremia coincided and preceded both pyrexia and inversion of the heterophil:lymphocyte ratio, an indicator of infection. Antigenemia was determined within 1 h by electrochemiluminescence immunoassay, compared with the 24-h traditional culture needed for bacteremia determination. Rabbits appeared clinically normal until shortly before succumbing to anthrax approximately 47 h after challenge or approximately 22 h after antigenemia, which suggests a relatively narrow therapeutic window of opportunity. To evaluate the therapeutic rabbit model, B. anthracis-exposed rabbits were treated (after determination of antigenemia and later confirmed to be bacteremic) intravenously with the fluoroquinolone antibiotic levofloxacin for 5 d at a total daily dose of 25 or 12.5 mg/kg, resulting in nearly 90% and 70% survival, respectively, to the study end (28 d after challenge). The peak level for 12.5 mg/kg was equivalent to that observed for a 500-mg daily levofloxacin dose in humans. These results suggest that intravenous levofloxacin is an effective therapeutic against inhalational anthrax. Taken together, our findings indicate that antigenemia is a viable and early biomarker for B. anthracis infection that can be used as a treatment trigger to allow for timely intervention against this highly pathogenic disease. Copyright 2010 by the American Association for Laboratory Animal Science.
Ruiz S.I.,U.S. Army |
El-Gendy N.,University of Kansas |
Bowen L.E.,U.S. Army |
Bowen L.E.,Clinical Research Management |
And 2 more authors.
Journal of Pharmaceutical Sciences | Year: 2016
Melioidosis is an infectious disease caused by Burkholderia pseudomallei. The disease is responsible for a high proportion of human pneumonia and fatal bacteremia in the endemic areas of the world and is highly resistant to most commonly available antibiotics. Studies have shown that prophylactic antibiotic treatment, when administered 24 h following bacterial challenge, can prevent infection in a murine model. Prophylactic treatment against this disease using a pulmonary antibiotic formulation has not previously been examined, but may reduce the number of treatments required, allow for the delivery of higher doses, eliminate the need for intravenous administration, and help to minimize systemic side effects. Ceftazidime was formulated as a dry powder aerosol suitable for pulmonary delivery using previously developed NanoCluster dry powder technology. Pharmacokinetics of aerosolized ceftazidime was analyzed in a mouse model. This study demonstrates that ceftazidime can be formulated using NanoCluster technology as a dry powder aerosol suitable for pulmonary delivery to humans. We have also demonstrated the retention of nebulized ceftazidime in mouse lungs for up to 6 h after exposure. The results indicate that this treatment may be useful as a prophylactic treatment against melioidosis. Future work will examine the efficacy of this treatment against B. pseudomallei aerosol challenge. © 2016
Rosokha S.V.,Roosevelt University |
Korotchenko V.,University of Houston |
Korotchenko V.,Clinical Research Management |
Stern C.L.,Northwestern University |
And 2 more authors.
Journal of Organic Chemistry | Year: 2012
Addition of p-substituted styrenes, XSty (X = H, Me, MeO, or Cl) to the solutions of o-chloranil, oCA, in dichloromethane resulted in the transient formation of the charge-transfer complexes, [XSty, oCA], followed by the Diels-Alder reaction. At low temperatures, these reactions led to formation of essentially pure endocycloadducts. As expected for the inverse-electron-demand Diels-Alder reaction, the rate constants of the cycloaddition rose with the increase of the donor strength. However, while facile cycloaddition took place in the neat mixtures of the o-chloranil with p-methyl, p-chloro-, or unsubstituted styrenes at low temperatures, a similar system involving the strongest MeOSty donor was surprisingly persistent. X-ray structural measurements and quantum-mechanical computations indicated that this anomaly is related to the fact that the diene/dienophile orientation in the charge-transfer [MeOSty, oCA] complex is opposite to that in the endocycloadduct and in the lowest-energy transition state leading to this isomer. Thus, the proceeding of the cycloaddition requires dissociation of the (dead-end) complex. For the systems involving the oCA diene and either the HSty, ClSty, or MeSty dienophile, the donor/acceptor arrangements in the charge-transfer complexes apparently are consistent with that in the corresponding products, and the formation of these complexes does not hinder the Diels-Alder reaction. © 2012 American Chemical Society.
Aronson N.E.,Uniformed Services University of the Health Sciences |
Aronson N.E.,U.S. Army |
Wortmann G.W.,Uniformed Services University of the Health Sciences |
Wortmann G.W.,U.S. Army |
And 16 more authors.
PLoS Neglected Tropical Diseases | Year: 2010
Background: Cutaneous Leishmania major has affected many travelers including military personnel in Iraq and Afghanistan. Optimal treatment for this localized infection has not been defined, but interestingly the parasite is thermosensitive. Methodology/Principal Findings: Participants with parasitologically confirmed L. major infection were randomized to receive intravenous sodium stibogluconate (SSG) 20mg/kg/day for ten doses or localized ThermoMed (TM) device heat treatment (applied at 50°C for 30 seconds) in one session. Those with facial lesions, infection with other species of Leishmania, or more than 20 lesions were excluded. Primary outcome was complete re-epithelialization or visual healing at two months without relapse over 12 months. Fifty-four/56 enrolled participants received intervention, 27 SSG and 27 TM. In an intent to treat analysis the per subject efficacy at two months with 12 months follow-up was 54% SSG and 48% TM (p = 0.78), and the per lesion efficacy was 59% SSG and 73% TM (p = 0.053). Reversible abdominal pain/pancreatitis, arthralgias, myalgias, headache, fatigue, mild cytopenias, and elevated transaminases were more commonly present in the SSG treated participants, whereas blistering, oozing, and erythema were more common in the TM arm. Conclusions/Significance: Skin lesions due to L. major treated with heat delivered by the ThermoMed device healed at a similar rate and with less associated systemic toxicity than lesions treated with intravenous SSG. Clinical Trial Registration: ClinicalTrials.gov NCT 00884377.