Zoonotic risk factors associated with seroprevalence of Ebola virus GP antibodies in the absence of diagnosed Ebola virus disease in the Democratic Republic of Congo

BackgroundEbola virus (EBOV) is a zoonotic filovirus spread through exposure to infected bodily fluids of a human or animal. Though EBOV is capable of causing severe disease, referred to as Ebola Virus Disease (EVD), individuals who have never been diagnosed with confirmed, probable or suspected EVD can have detectable EBOV antigen-specific antibodies in their blood. This study aims to identify risk factors associated with detectable antibody levels in the absence of an EVD diagnosis.MethodologyData was collected from September 2015 to August 2017 from 1,366 consenting individuals across four study sites in the DRC (Boende, Kabondo-Dianda, Kikwit, and Yambuku). Seroreactivity was determined to EBOV GP IgG using Zaire Ebola Virus Glycoprotein (EBOV GP antigen) ELISA kits (Alpha Diagnostic International, Inc.) in Kinshasa, DRC; any result above 4.7 units/mL was considered seroreactive. Among the respondents, 113 (8.3%) were considered seroreactive. Several zoonotic exposures were associated with EBOV seroreactivity after controlling for age, sex, healthcare worker status, location, and history of contact with an EVD case, namely: ever having contact with bats, ever having contact with rodents, and ever eating non-human primate meat. Contact with monkeys or non-human primates was not associated with seroreactivity.ConclusionsThis analysis suggests that some zoonotic exposures that have been linked to EVD outbreaks can also be associated with EBOV GP seroreactivity in the absence of diagnosed EVD. Future investigations should seek to clarify the relationships between zoonotic exposures, seroreactivity, asymptomatic infection, and EVD.     

A New Approach for Monitoring Ebolavirus in Wild Great Apes

Background

Central Africa is a “hotspot” for emerging infectious diseases (EIDs) of global and local importance, and a current outbreak of ebolavirus is affecting multiple countries simultaneously. Ebolavirus is suspected to have caused recent declines in resident great apes. While ebolavirus vaccines have been proposed as an intervention to protect apes, their effectiveness would be improved if we could diagnostically confirm Ebola virus disease (EVD) as the cause of die-offs, establish ebolavirus geographical distribution, identify immunologically naïve populations, and determine whether apes survive virus exposure.

Methodology/Principal findings

Here we report the first successful noninvasive detection of antibodies against Ebola virus (EBOV) from wild ape feces. Using this method, we have been able to identify gorillas with antibodies to EBOV with an overall prevalence rate reaching 10% on average, demonstrating that EBOV exposure or infection is not uniformly lethal in this species. Furthermore, evidence of antibodies was identified in gorillas thought previously to be unexposed to EBOV (protected from exposure by rivers as topological barriers of transmission).

Conclusions/Significance

Our new approach will contribute to a strategy to protect apes from future EBOV infections by early detection of increased incidence of exposure, by identifying immunologically naïve at-risk populations as potential targets for vaccination, and by providing a means to track vaccine efficacy if such intervention is deemed appropriate. Finally, since human EVD is linked to contact with infected wildlife carcasses, efforts aimed at identifying great ape outbreaks could have a profound impact on public health in local communities, where EBOV causes case-fatality rates of up to 88%.     

埃博拉病毒小分子抑制剂的研究进展

目前尚没有可靠的埃博拉病毒(Ebola virus,EBOV)疫苗和特异性治疗药物.2014年埃博拉病毒病在西非的爆发和肆虐警醒人类,需要加快对该病的防控研究.近几年,在EBOV小分子抑制剂的研究方面取得了较好的进展,有的已进入临床试验阶段.小分子化合物通常是针对病毒致病作用的某种机制而设计,是一个很有发展前途的研究领域.本文从抑制EBOV和其他病毒在生活周期中的穿入细胞、复制和出芽等方面综述EBOV小分子抑制剂的研究进展.     

Ebolavirus Evolution: Past and Present

The past year has marked the most devastating Ebola outbreak the world has ever witnessed, with over 28,000 cases and over 11,000 deaths. Ebola virus (EBOV) has now been around for almost 50 years. In this review, we discuss past and present outbreaks of EBOV and how those variants evolved over time. We explore and discuss selective pressures that drive the evolution of different Ebola variants, and how they may modify the efficacy of therapeutic treatments and vaccines currently being developed. Finally, given the unprecedented size and spread of the outbreak, as well as the extended period of replication in human hosts, specific attention is given to the 2014–2015 West African outbreak variant (Makona).     

埃博拉病毒疫苗研究进展

埃博拉病毒是一种可引起人和非人灵长类动物出血热传染病的最为致命的烈性病毒,致死率可达90%。2014年在西非爆发的埃博拉疫情引起了全世界的关注。疫苗接种是预防和控制传染病最为常规和有效的方法,尽管目前还没有正式获得批准上市的埃博拉病毒疫苗,但是已有多个尚处于研究阶段的疫苗在非人灵长类动物上取得了很好的保护效果,并有几个已进入临床Ⅰ期试验阶段,有望尽快用于本次埃博拉疫情的防控。本文对目前处于研究阶段的多个类型的埃博拉病毒疫苗进行了综述,为相关研究人员提供参考。     

Human activities link fruit bat presence to Ebola virus disease outbreaks

1. A significant link between forest loss and fragmentation and outbreaks of Ebola virus disease (EVD) in humans has been documented. Deforestation may alter the natural circulation of viruses and change the composition, abundance, behaviour and possibly viral exposure of reservoir species. This in turn might increase contact between infected animals and humans.
2. Fruit bats of the family Pteropodidae have been suspected as reservoirs of the Ebola virus. At present, the only evidence associating fruit bats with EVD is the presence of seropositive individuals in eight species and polymerase chain reaction-positive individuals in three of these.
3. Our study investigates whether human activities can increase African fruit bat geographical ranges and whether this influence overlaps geographically with EVD outbreaks that, in turn, are favoured by deforestation.
4. We use species observation records for the 20 fruit bat species found in favourable areas for the Ebola virus to determine factors affecting the bats' range inside the predicted Ebola virus area. We do this by employing a hypothetico-deductive approach based on favourability modelling.
5. We show that the range of some fruit bat species is linked to human activities within the favourable areas for the Ebola virus. More specifically, the areas where human activities favour the presence of five fruit bat species overlap with the areas where EVD outbreaks in humans were themselves favoured by deforestation. These five species are as follows: Eidolon helvum, Epomops franqueti, Megaloglossus woermanni, Micropteropus pusillus and Rousettus aegyptiacus. Of these five, all but Megaloglossus woermanni have recorded seropositive individuals. For the remaining 15 bat species, we found no biogeographical support for the hypothesis that positive human influence on fruit bats could be associated with EVD outbreaks in deforested areas within the tropical forest biome in West and Central Africa.
6. Our work is a useful first step allowing further investigation of the networks and pathways that may lead to an EVD outbreak. The modelling framework we employ here can be used for other emerging infectious diseases.

     

埃博拉病毒,何去何从

埃博拉病毒(Ebola Virus,EBOV)是丝状病毒科的单股负链RNA病毒,其形态呈丝状,共有5个型别,其中扎伊尔型致死率高,曾在非洲大陆引起多次暴发。EBOV自然宿主尚不明确,猪、非人灵长类及蝙蝠都可能与病毒的传播有关,其中果蝠的关系最为密切。由于EBOV的毒力强和传播性强,加之目前尚无特效药物和疫苗,被列为生物危害四级,同时也被视为生物恐怖主义的工具之一。最近该病毒在西非肆虐人类,引起了广泛关注,因而就此做一综述,供广大同行参考。     

Assessment of Environmental Contamination and Environmental Decontamination Practices within an Ebola Holding Unit,Freetown, Sierra Leone

Evidence to inform decontamination practices at Ebola holding units (EHUs) and treatment centres is lacking. We conducted an audit of decontamination procedures inside Connaught Hospital EHU in Freetown, Sierra Leone, by assessing environmental swab specimens for evidence of contamination with Ebola virus by RT-PCR. Swabs were collected following discharge of Ebola Virus Disease (EVD) patients before and after routine decontamination. Prior to decontamination, Ebola virus RNA was detected within a limited area at all bedside sites tested, but not at any sites distant to the bedside. Following decontamination, few areas contained detectable Ebola virus RNA. In areas beneath the bed there was evidence of transfer of Ebola virus material during cleaning. Retraining of cleaning staff reduced evidence of environmental contamination after decontamination. Current decontamination procedures appear to be effective in eradicating persistence of viral RNA. This study supports the use of viral swabs to assess Ebola viral contamination within the clinical setting. We recommend that regular refresher training of cleaning staff and audit of environmental contamination become standard practice at all Ebola care facilities during EVD outbreaks.     

Diagnostics in Ebola Virus Disease in Resource-Rich and Resource-Limited Settings

The Ebola virus disease (EVD) outbreak in West Africa was unprecedented in scale and location. Limited access to both diagnostic and supportive pathology assays in both resource-rich and resource-limited settings had a detrimental effect on the identification and isolation of cases as well as individual patient management. Limited access to such assays in resource-rich settings resulted in delays in differentiating EVD from other illnesses in returning travellers, in turn utilising valuable resources until a diagnosis could be made. This had a much greater impact in West Africa, where it contributed to the initial failure to contain the outbreak. This review explores diagnostic assays of use in EVD in both resource-rich and resource-limited settings, including their respective limitations, and some novel assays and approaches that may be of use in future outbreaks.     

Rapid establishment of a frontline field laboratory in response to an imported outbreak of Ebola virus disease in western Uganda,June 2019

The Democratic Republic of the Congo (DRC) declared an Ebola virus disease (EVD) outbreak in North Kivu in August 2018. By June 2019, the outbreak had spread to 26 health zones in northeastern DRC, causing >2,000 reported cases and >1,000 deaths. On June 10, 2019, three members of a Congolese family with EVD-like symptoms traveled to western Uganda’s Kasese District to seek medical care. Shortly thereafter, the Viral Hemorrhagic Fever Surveillance and Laboratory Program (VHF program) at the Uganda Virus Research Institute (UVRI) confirmed that all three patients had EVD. The Ugandan Ministry of Health declared an outbreak of EVD in Uganda’s Kasese District, notified the World Health Organization, and initiated a rapid response to contain the outbreak. As part of this response, UVRI and the United States Centers for Disease Control and Prevention, with the support of Uganda’s Public Health Emergency Operations Center, the Kasese District Health Team, the Superintendent of Bwera General Hospital, the United States Department of Defense’s Makerere University Walter Reed Project, and the United States Mission to Kampala’s Global Health Security Technical Working Group, jointly established an Ebola Field Laboratory in Kasese District at Bwera General Hospital, proximal to an Ebola Treatment Unit (ETU). The laboratory consisted of a rapid containment kit for viral inactivation of patient specimens and a GeneXpert Instrument for performing Xpert Ebola assays. Laboratory staff tested 76 specimens from alert and suspect cases of EVD; the majority were admitted to the ETU (89.3%) and reported recent travel to the DRC (58.9%). Although no EVD cases were detected by the field laboratory, it played an important role in patient management and epidemiological surveillance by providing diagnostic results in <3 hours. The integration of the field laboratory into Uganda’s National VHF Program also enabled patient specimens to be referred to Entebbe for confirmatory EBOV testing and testing for other hemorrhagic fever viruses that circulate in Uganda.     

Elucidating variations in the nucleotide sequence of Ebola virus associated with increasing pathogenicity

Background

Ebolaviruses cause a severe and often fatal haemorrhagic fever in humans, with some species such as Ebola virus having case fatality rates approaching 90%. Currently, the worst Ebola virus outbreak since the disease was discovered is occurring in West Africa. Although thought to be a zoonotic infection, a concern is that with increasing numbers of humans being infected, Ebola virus variants could be selected which are better adapted for human-to-human transmission.

Results

To investigate whether genetic changes in Ebola virus become established in response to adaptation in a different host, a guinea pig model of infection was used. In this experimental system, guinea pigs were infected with Ebola virus (EBOV), which initially did not cause disease. To simulate transmission to uninfected individuals, the virus was serially passaged five times in naïve animals. As the virus was passaged, virulence increased and clinical effects were observed in the guinea pig. An RNAseq and consensus mapping approach was then used to evaluate potential nucleotide changes in the Ebola virus genome at each passage.

Conclusions

Upon passage in the guinea pig model, EBOV become more virulent, RNA editing and also coding changes in key proteins become established. The data suggest that the initial evolutionary trajectory of EBOV in a new host can lead to a gain in virulence. Given the circumstances of the sustained transmission of EBOV in the current outbreak in West Africa, increases in virulence may be associated with prolonged and uncontrolled epidemics of EBOV.     

Ebola Outbreak in West Africa; Is Selenium Involved?

One of the current international public health emergencies is the outbreak of Ebola virus disease (EVD), requiring extraordinary response. The current outbreak in West Africa is the most dangerous since Ebola was first discovered on 26 August 1976. Till January 6th 2015, It resulted in 13,387 laboratory confirmed human cases and 8274 deaths. Ebola virus has 5 strains, 4 are pathogenic in humans while the 5th strain Ebola reston strain is not. The current outbreak is caused by Ebola most pathogenic strain, Ebola Zaire strain whose genome differs from that of Reston Ebola virus strain, by the existence of several open reading frames containing large numbers of UGA codons. These codons act as stop codons and in addition they may encode for Selenocysteine, the 21st aminoacid, which is essential for the formation of Selenoproteins. Selenoproteins are integral to the metabolism and have been linked to the progression of certain viral diseases. In this review, we discuss the relation between Selenium and the progression of the current EVD in Africa supported by geographical distribution of Se and genetic evidence.     

Ebola in great apes – current knowledge,possibilities for vaccination,and implications for conservation and human health

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埃博拉病毒检测与防治技术在中国的专利申请状况分析

近年来,埃博拉病毒(EBOV)因其在非洲造成的严峻疫情而引起了广泛关注。本文对涉及埃博拉病毒检测与防治技术方面的在中国申请的国内外专利申请数量、年代分布、技术发展状况等信息进行分析,对国内埃博拉病毒检测、免疫、治疗相关专利技术进行简要总结,并对目前热点关注药物(jk-05,ZMapp,VSV-EBOV)专利申请信息进行比较概括,结果表明,我国申请人在提出的相关专利申请数量以及技术多样性上与国外申请人存在差距,为国内科研人员提供了相关技术领域参考。     

Analytical Performance Characteristics of the Cepheid GeneXpert Ebola Assay for the Detection of Ebola Virus

BackgroundThe recently developed Xpert® Ebola Assay is a novel nucleic acid amplification test for simplified detection of Ebola virus (EBOV) in whole blood and buccal swab samples. The assay targets sequences in two EBOV genes, lowering the risk for new variants to escape detection in the test. The objective of this report is to present analytical characteristics of the Xpert® Ebola Assay on whole blood samples.ConclusionIn summary, we found the Xpert® Ebola Assay to have high analytical sensitivity and specificity for the detection of EBOV in whole blood. It offers ease of use, fast turnaround time, and remote monitoring. The test has an efficient viral inactivation protocol, fulfills inclusivity and exclusivity criteria, and has specimen stability characteristics consistent with the need for decentralized testing. The simplicity of the assay should enable testing in a wide variety of laboratory settings, including remote laboratories that are not capable of performing highly complex nucleic acid amplification tests, and during outbreaks where time to detection is critical.     

Ebola virus: unravelling pathogenesis to combat a deadly disease

Ebola virus (EBOV) causes severe haemorrhagic fever leading to up to 90% lethality. Increasingly frequent outbreaks and the placement of EBOV in the category A list of potential biothreat agents have boosted interest in this virus. Furthermore, development of new technologies (e.g. reverse genetics systems) and extensive studies on Ebola haemorrhagic fever (EHF) in animal models have substantially expanded the knowledge on the pathogenic mechanisms that underlie this disease. Two major factors in EBOV pathogenesis are the impairment of the immune response and vascular dysfunction. Here, we attempt to summarize the current knowledge on EBOV pathogenesis focusing on these two factors and on recent progress in the development of vaccines and potential therapeutics.     

First laboratory confirmation and sequencing of Zaire ebolavirus in Uganda following two independent introductions of cases from the 10th Ebola Outbreak in the Democratic Republic of the Congo,June 2019

Uganda established a domestic Viral Hemorrhagic Fever (VHF) testing capacity in 2010 in response to the increasing occurrence of filovirus outbreaks. In July 2018, the neighboring Democratic Republic of Congo (DRC) experienced its 10^th Ebola Virus Disease (EVD) outbreak and for the duration of the outbreak, the Ugandan Ministry of Health (MOH) initiated a national EVD preparedness stance. Almost one year later, on 10^th June 2019, three family members who had contracted EVD in the DRC crossed into Uganda to seek medical treatment.Samples were collected from all the suspected cases using internationally established biosafety protocols and submitted for VHF diagnostic testing at Uganda Virus Research Institute. All samples were initially tested by RT-PCR for ebolaviruses, marburgviruses, Rift Valley fever (RVF) virus and Crimean-Congo hemorrhagic fever (CCHF) virus. Four people were identified as being positive for Zaire ebolavirus, marking the first report of Zaire ebolavirus in Uganda. In-country Next Generation Sequencing (NGS) and phylogenetic analysis was performed for the first time in Uganda, confirming the outbreak as imported from DRC at two different time point from different clades. This rapid response by the MoH, UVRI and partners led to the control of the outbreak and prevention of secondary virus transmission.     

Development of a cAdVax-based bivalent ebola virus vaccine that induces immune responses against both the Sudan and Zaire species of Ebola virus

Ebola virus (EBOV) causes a severe hemorrhagic fever for which there are currently no vaccines or effective treatments. While lethal human outbreaks have so far been restricted to sub-Saharan Africa, the potential exploitation of EBOV as a biological weapon cannot be ignored. Two species of EBOV, Sudan ebolavirus (SEBOV) and Zaire ebolavirus (ZEBOV), have been responsible for all of the deadly human outbreaks resulting from this virus. Therefore, it is important to develop a vaccine that can prevent infection by both lethal species. Here, we describe the bivalent cAdVaxE(GPs/z) vaccine, which includes the SEBOV glycoprotein (GP) and ZEBOV GP genes together in a single complex adenovirus-based vaccine (cAdVax) vector. Vaccination of mice with the bivalent cAdVaxE(GPs/z) vaccine led to efficient induction of EBOV-specific antibody and cell-mediated immune responses to both species of EBOV. In addition, the cAdVax technology demonstrated induction of a 100% protective immune response in mice, as all vaccinated C57BL/6 and BALB/c mice survived challenge with a lethal dose of ZEBOV (30,000 times the 50% lethal dose). This study demonstrates the potential efficacy of a bivalent EBOV vaccine based on a cAdVax vaccine vector design.