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Concept: Ebola

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Ebola viruses (EBOV) cause often fatal hemorrhagic fever in several species of simian primates including human. While fruit bats are considered natural reservoir, involvement of other species in EBOV transmission is unclear. In 2009, Reston-EBOV was the first EBOV detected in swine with indicated transmission to humans. In-contact transmission of Zaire-EBOV (ZEBOV) between pigs was demonstrated experimentally. Here we show ZEBOV transmission from pigs to cynomolgus macaques without direct contact. Interestingly, transmission between macaques in similar housing conditions was never observed. Piglets inoculated oro-nasally with ZEBOV were transferred to the room housing macaques in an open inaccessible cage system. All macaques became infected. Infectious virus was detected in oro-nasal swabs of piglets, and in blood, swabs, and tissues of macaques. This is the first report of experimental interspecies virus transmission, with the macaques also used as a human surrogate. Our finding may influence prevention and control measures during EBOV outbreaks.

Concepts: Human, Influenza, Mammal, Primate, Ebola, Viral hemorrhagic fever, Simian, Crab-eating Macaque

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Background Ebola virus has been detected in the semen of men after their recovery from Ebola virus disease (EVD), but little information is available about its prevalence or the duration of its persistence. We report the initial findings of a pilot study involving survivors of EVD in Sierra Leone. Methods We enrolled a convenience sample of 100 male survivors of EVD in Sierra Leone, at different times after their recovery from EVD, and recorded self-reported information about sociodemographic characteristics, the EVD episode, and health status. Semen specimens obtained at baseline were tested by means of a quantitative reverse-transcriptase-polymerase-chain-reaction (RT-PCR) assay with the use of the target-gene sequences of NP and VP40. Results A total of 93 participants provided an initial semen specimen for analysis, of whom 46 (49%) had positive results on quantitative RT-PCR. Ebola virus RNA was detected in the semen of all 9 men who had a specimen obtained 2 to 3 months after the onset of EVD, in the semen of 26 of 40 (65%) who had a specimen obtained 4 to 6 months after onset, and in the semen of 11 of 43 (26%) who had a specimen obtained 7 to 9 months after onset; the results for 1 participant who had a specimen obtained at 10 months were indeterminate. The median cycle-threshold values (for which higher values indicate lower RNA levels) were 32.0 with the NP gene target and 31.1 with the VP40 gene target for specimens obtained at 2 to 3 months, 34.5 and 32.3, respectively, for specimens obtained at 4 to 6 months, and 37.0 and 35.6, respectively, for specimens obtained at 7 to 9 months. Conclusions These data showed the persistence of Ebola virus RNA in semen and declining persistence with increasing months since the onset of EVD. We do not yet have data on the extent to which positivity on RT-PCR is associated with virus infectivity. Although cases of suspected sexual transmission of Ebola have been reported, they are rare; hence the risk of sexual transmission of the Ebola virus is being investigated. (Funded by the World Health Organization and others.).

Concepts: DNA, Microbiology, Genome, RNA, Biological warfare, Ebola, Viral hemorrhagic fever, Sierra Leone

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A suspected case of sexual transmission from a male survivor of Ebola virus disease (EVD) to his female partner (the patient in this report) occurred in Liberia in March 2015. Ebola virus (EBOV) genomes assembled from blood samples from the patient and a semen sample from the survivor were consistent with direct transmission. The genomes shared three substitutions that were absent from all other Western African EBOV sequences and that were distinct from the last documented transmission chain in Liberia before this case. Combined with epidemiologic data, the genomic analysis provides evidence of sexual transmission of EBOV and evidence of the persistence of infective EBOV in semen for 179 days or more after the onset of EVD. (Funded by the Defense Threat Reduction Agency and others.).

Concepts: Gene, Epidemiology, Genome, Biological warfare, Ebola, Viral hemorrhagic fever, Incubation period

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Evidence for minimally symptomatic Ebola virus (EBOV) infection is limited. During the 2013-16 outbreak in West Africa, it was not considered epidemiologically relevant to published models or projections of intervention effects. In order to improve our understanding of the transmission dynamics of EBOV in humans, we investigated the occurrence of minimally symptomatic EBOV infection in quarantined contacts of reported Ebola virus disease cases in a recognized ‘hotspot.’

Concepts: Infectious disease, Biological warfare, Ebola, Viral hemorrhagic fever, Malaise, Incubation period

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In 1967, a woman became ill after exposure to a newly discovered pathogen that we now call Marburg virus, a member of the family Filoviridae (filoviruses), to which Ebola virus also belongs.(1) Testing of the semen of her husband, who had recovered from the disease 6 weeks previously, determined that her exposure was through sexual intercourse. This was the first confirmed case of sexual transmission of filovirus disease from a convalescent man. It was also the last…until recently. In March 2015, Ebola virus disease (EVD) developed in a Liberian woman after the country had been free from EVD for 30 . . .

Concepts: Microbiology, Ebola, Marburg virus, Mononegavirales, Viral hemorrhagic fever, Incubation period, Filoviridae, Hemorrhagic fevers

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Among the survivors of Ebola virus disease (EVD), complications that include uveitis can develop during convalescence, although the incidence and pathogenesis of EVD-associated uveitis are unknown. We describe a patient who recovered from EVD and was subsequently found to have severe unilateral uveitis during convalescence. Viable Zaire ebolavirus (EBOV) was detected in aqueous humor 14 weeks after the onset of EVD and 9 weeks after the clearance of viremia.

Concepts: Microbiology, Ebola, Viral hemorrhagic fever, Incubation period

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Background Malaria treatment is recommended for patients with suspected Ebola virus disease (EVD) in West Africa, whether systeomatically or based on confirmed malaria diagnosis. At the Ebola treatment center in Foya, Lofa County, Liberia, the supply of artemether-lumefantrine, a first-line antimalarial combination drug, ran out for a 12-day period in August 2014. During this time, patients received the combination drug artesunate-amodiaquine; amodiaquine is a compound with anti-Ebola virus activity in vitro. No other obvious change in the care of patients occurred during this period. Methods We fit unadjusted and adjusted regression models to standardized patient-level data to estimate the risk ratio for death among patients with confirmed EVD who were prescribed artesunate-amodiaquine (artesunate-amodiaquine group), as compared with those who were prescribed artemether-lumefantrine (artemether-lumefantrine group) and those who were not prescribed any antimalarial drug (no-antimalarial group). Results Between June 5 and October 24, 2014, a total of 382 patients with confirmed EVD were admitted to the Ebola treatment center in Foya. At admission, 194 patients were prescribed artemether-lumefantrine and 71 were prescribed artesunate-amodiaquine. The characteristics of the patients in the artesunate-amodiaquine group were similar to those in the artemether-lumefantrine group and those in the no-antimalarial group. A total of 125 of the 194 patients in the artemether-lumefantrine group (64.4%) died, as compared with 36 of the 71 patients in the artesunate-amodiaquine group (50.7%). In adjusted analyses, the artesunate-amodiaquine group had a 31% lower risk of death than the artemether-lumefantrine group (risk ratio, 0.69; 95% confidence interval, 0.54 to 0.89), with a stronger effect observed among patients without malaria. Conclusions Patients who were prescribed artesunate-amodiaquine had a lower risk of death from EVD than did patients who were prescribed artemether-lumefantrine. However, our analyses cannot exclude the possibility that artemether-lumefantrine is associated with an increased risk of death or that the use of artesunate-amodiaquine was associated with unmeasured patient characteristics that directly altered the risk of death.

Concepts: Death, Malaria, Biological warfare, Ebola, Viral hemorrhagic fever, Lofa County

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Background The unprecedented 2014 epidemic of Ebola virus disease (EVD) has prompted an international response to accelerate the availability of a preventive vaccine. A replication-defective recombinant chimpanzee adenovirus type 3-vectored ebolavirus vaccine (cAd3-EBO), encoding the glycoprotein from Zaire and Sudan species that offers protection in the nonhuman primate model, was rapidly advanced into phase 1 clinical evaluation. Methods We conducted a phase 1, dose-escalation, open-label trial of cAd3-EBO. Twenty healthy adults, in sequentially enrolled groups of 10 each, received vaccination intramuscularly in doses of 2×10(10) particle units or 2×10(11) particle units. Primary and secondary end points related to safety and immunogenicity were assessed throughout the first 4 weeks after vaccination. Results In this small study, no safety concerns were identified; however, transient fever developed within 1 day after vaccination in two participants who had received the 2×10(11) particle-unit dose. Glycoprotein-specific antibodies were induced in all 20 participants; the titers were of greater magnitude in the group that received the 2×10(11) particle-unit dose than in the group that received the 2×10(10) particle-unit dose (geometric mean titer against the Zaire antigen, 2037 vs. 331; P=0.001). Glycoprotein-specific T-cell responses were more frequent among those who received the 2x10(11) particle-unit dose than among those who received the 2×10(10) particle-unit dose, with a CD4 response in 10 of 10 participants versus 3 of 10 participants (P=0.004) and a CD8 response in 7 of 10 participants versus 2 of 10 participants (P=0.07). Conclusions Reactogenicity and immune responses to cAd3-EBO vaccine were dose-dependent. At the 2×10(11) particle-unit dose, glycoprotein Zaire-specific antibody responses were in the range reported to be associated with vaccine-induced protective immunity in challenge studies involving nonhuman primates. Clinical trials assessing cAd3-EBO are ongoing. (Funded by the Intramural Research Program of the National Institutes of Health; VRC 207 ClinicalTrials.gov number, NCT02231866 .).

Concepts: Immune system, Antibody, Vaccination, Immunology, T helper cell, Immunity, Ebola, Western Red Colobus

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Background In the wake of the recent outbreak of Ebola virus disease (EVD) in several African countries, the World Health Organization prioritized the evaluation of treatment with convalescent plasma derived from patients who have recovered from the disease. We evaluated the safety and efficacy of convalescent plasma for the treatment of EVD in Guinea. Methods In this nonrandomized, comparative study, 99 patients of various ages (including pregnant women) with confirmed EVD received two consecutive transfusions of 200 to 250 ml of ABO-compatible convalescent plasma, with each unit of plasma obtained from a separate convalescent donor. The transfusions were initiated on the day of diagnosis or up to 2 days later. The level of neutralizing antibodies against Ebola virus in the plasma was unknown at the time of administration. The control group was 418 patients who had been treated at the same center during the previous 5 months. The primary outcome was the risk of death during the period from 3 to 16 days after diagnosis with adjustments for age and the baseline cycle-threshold value on polymerase-chain-reaction assay; patients who had died before day 3 were excluded. The clinically important difference was defined as an absolute reduction in mortality of 20 percentage points in the convalescent-plasma group as compared with the control group. Results A total of 84 patients who were treated with plasma were included in the primary analysis. At baseline, the convalescent-plasma group had slightly higher cycle-threshold values and a shorter duration of symptoms than did the control group, along with a higher frequency of eye redness and difficulty in swallowing. From day 3 to day 16 after diagnosis, the risk of death was 31% in the convalescent-plasma group and 38% in the control group (risk difference, -7 percentage points; 95% confidence interval [CI], -18 to 4). The difference was reduced after adjustment for age and cycle-threshold value (adjusted risk difference, -3 percentage points; 95% CI, -13 to 8). No serious adverse reactions associated with the use of convalescent plasma were observed. Conclusions The transfusion of up to 500 ml of convalescent plasma with unknown levels of neutralizing antibodies in 84 patients with confirmed EVD was not associated with a significant improvement in survival. (Funded by the European Union’s Horizon 2020 Research and Innovation Program and others; ClinicalTrials.gov number, NCT02342171 .).

Concepts: AIDS, Antibody, Biological warfare, Blood transfusion, Ebola, Viral hemorrhagic fever, Incubation period, Crab-eating Macaque

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The 2013-15 Ebola outbreak was unprecedented due to sustained transmission within urban environments and thousands of survivors. In 2014 the World Health Organization stated that there was insufficient evidence to give definitive guidance about which body fluids are infectious and when they pose a risk to humans. We report a rapid systematic review of published evidence on the presence of filoviruses in body fluids of infected people and survivors.

Concepts: Infection, Pandemic, World Health Organization, Ebola, Marburg virus, Mononegavirales, Viral hemorrhagic fever, Filoviridae