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Arenaviruses are a global threat, causing thousands of deaths each year in several countries around the world. Despite strong efforts in the development of vaccine candidates, vaccines against Lassa fever or Bolivian and Venezuelan hemorrhagic fevers are yet to be licensed for a use in humans. In this synthesis, we present the arenaviruses causing fatal diseases in humans and the main vaccine candidates that have been developed over the past decades with an emphasis on the measles-Lassa vaccine, the first Lassa vaccine ever tested in humans, and on the MOPEVAC platform that can potentially be used as a pan-arenavirus vaccine platform., (© 2023 médecine/sciences – Inserm.)

Background: Viral haemorrhagic fevers (VHF) cause significant economic and public health impact in Sub-Saharan Africa. Community knowledge, awareness and practices regarding such outbreaks play a pivotal role in their management and prevention. This study was carried out to assess community knowledge, attitude and practices regarding VHF in five geo-ecological zones in Tanzania., Methods: A cross-sectional study was conducted in Buhigwe, Kalambo, Kyela, Kinondoni, Kilindi, Mvomero, Kondoa and Ukerewe districts representing five geo-ecological zones in Tanzania. Study participants were selected by multistage cluster sampling design. A semi-structured questionnaire was used to collect socio-demographic and information related to knowledge, attitude and practices regarding VHFs. Descriptive statistics and logistic regression were used for the analysis., Results: A total of 2,965 individuals were involved in the study. Their mean age was 35 (SD ± 18.9) years. Females accounted for 58.2% while males 41.8%. Most of the respondents (70.6%; n = 2093) had never heard of VHF, and those who heard, over three quarters (79%) mentioned the radio as their primary source of information. Slightly over a quarter (29.4%) of the respondents were knowledgeable, 25% had a positive attitude, and 17.9% had unfavourable practice habits. The level of knowledge varied between occupation and education levels (P < 0.005). Most participants were likely to interact with a VHF survivor or take care of a person suffering from VHF (75%) or visit areas with known VHF (73%). There were increased odds of having poor practice among participants aged 36-45 years (AOR: 3.566, 95% CI: 1.593-7.821) and those living in Western, North-Eastern and Lake Victoria zones (AOR: 2.529, 95% CI: 1.071-6.657; AOR: 2.639, 95% CI: 1.130-7.580 AOR: 2.248, 95% CI: 1.073-3.844, respectively)., Conclusion: Overall, the knowledge on VHF among communities is low, while a large proportion of individuals in the community are involved in activities that expose them to the disease pathogens in Tanzania. These findings highlight the need for strengthening health educational and promotion efforts on VHF targeting specific populations., (© 2023. The Author(s).)

Mankind has developed strategies to mitigate calamitous pandemics, by using vaccines. Eradication of some diseases was successful through usage of vaccines. Lassa, Yellow, Crimean-Congo, Marburg and Ebola viruses need special attention. Lassa fever, that now has a candidate vaccine, was discovered in 1969 when two missionary nurses died in Nigeria, while Yellow fever has a vaccine from its 17D attenuated strain. Crimean-Congo haemorrhagic fever is a widespread tick-borne viral disease, and the nucleoprotein and glycoproteins are identified for inclusion in a vaccine. Marburg virus is highly pathogenic with mortality rate of 90%. Ebola virus outbreak in West Africa in 2013-2016 necessitated an early introduction of a vaccine. The classical vaccine platforms are commonly used for human vaccines, and next-generation platforms, are being developed. Development of a novel multivalent vaccine against viral haemorrhagic fevers will eliminate the difficulties of single vaccines and may lead to the eradication of these diseases., Competing Interests: The Authors declare that no competing interest exists, (Copyright © 2023 by West African Journal of Medicine.)

Background: Adequate preparation and support for healthcare workers (HCWs) managing high-consequence infectious diseases (HCIDs) is critical to the overall clinical management of HCIDs. Qualitative studies examining how well prepared and supported HCWs feel are lacking despite their key role. This study investigated how prepared and supported front-line HCWs at an Australian tertiary hospital felt about managing HCIDs such as viral haemorrhagic fever (VHF)., Methods: A qualitative research approach was used to undertake interviews with 45 Royal Melbourne Hospital medical and nursing staff from emergency, intensive care and infectious diseases. Interview questions captured data on HCWs' role, familiarity with using protocols, psychological attributes and training for scenarios related to VHF patient management. Interviews were recorded and transcribed. Categorical responses were analysed quantitatively and open-ended responses were analysed thematically., Results: Ninety-eight percent of participants indicated feeling capable of undertaking their role in managing VHF patients; 77% felt supported through personnel/resources. However, 69% indicated barriers to managing these patients effectively; and 68% felt anxious at the prospect of managing VHF patients. Themes emerging from participants' observations included concerns about training frequency, miscommunication, difficulty with uncertainty, feeling underprepared, and fear of transmitting infection to others., Conclusion: Although the majority of HCWs feel confident about their ability to care for VHF patients, they also have a moderately-high degree of anxiety. Perceptions of interviewed staff have fed into recommendations to increase HCW preparedness and reduce anxiety, which include investigating support services, and exploring training options that create multi-departmental groups of highly specialised medical officers and nurses., (Crown Copyright © 2020. Published by Elsevier B.V. All rights reserved.)

A variety of viral hemorrhagic fevers such as Ebola virus disease exist in Africa and impose a great threat in public health due to their high fatality. It is considered to be difficult to eradicate the etiological agents of viral hemorrhagic fever because they have non-human natural hosts. Therefore, the importance of public health measures remains high in addition to the urgent need for the development of medicines for treatment and prevention. Furthermore, public health measures directly lead to the accumulation of epidemiological knowledge about the diseases. As an infectious disease consultant for the World Health Organization, I have been involved with public health activities including the development of clinical guidelines, the establishment of laboratory diagnostic systems, the training for infection, prevention and control, the planning of budget for outbreak response, and the analysis of epidemiological data. On the last point, I reported the situation of Ebola virus disease outbreak in Liberia, 2014-2015 and Lassa fever outbreak in Nigeria, 2018-2019 describing the risk factors, morbidity, and mortality of the diseases.

Argentine hemorrhagic fever is a potentially lethal disease that is caused by Junin virus (JUNV). There are currently around 5 million individuals at risk of infection within regions of endemicity in Argentina. The live attenuated vaccine strain Candid #1 (Can) is approved for use in regions of endemicity and has substantially decreased the number of annual Argentine hemorrhagic fever (AHF) cases. The glycoprotein (GPC) gene is primarily responsible for attenuation of the Can strain, and we have shown that the absence of an N -linked glycosylation motif in the subunit G1 of the glycoprotein complex of Can, which is otherwise present in the wild-type pathogenic JUNV, causes GPC retention in the endoplasmic reticulum (ER). Here, we show that Can GPC aggregates in the ER of infected cells, forming incorrect cross-chain disulfide bonds, which results in impaired GPC processing into G1 and G2. The GPC fails to cleave into its G1 and G2 subunits and is targeted for degradation within lysosomes. Cells infected with the wild-type Romero (Rom) strain do not produce aggregates that are observed in Can infection, and the stress on the ER remains minimal. While the mutation of the N -linked glycosylation motif (T168A) is primarily responsible for the formation of aggregates, other mutations within G1 that occurred earlier in the passage history of the Can strain also contribute to aggregation of the GPC within the ER. IMPORTANCE The development of vaccines and therapeutics to combat viral hemorrhagic fevers remains a top priority within the Implementation Plan of the U.S. Department of Health and Human Services Public Health Emergency Medical Countermeasures Enterprise. The Can strain, derived from the pathogenic XJ strain of JUNV, has been demonstrated to be both safe and protective against AHF. While the vaccine strain is approved for use in regions of endemicity within Argentina, the mechanisms of Can attenuation have not been elucidated. A better understanding of the viral genetic determinants of attenuation will improve our understanding of the mechanisms contributing to disease pathogenesis and provide critical information for the rational design of live attenuated vaccine candidates for other viral hemorrhagic fevers., (Copyright © 2020 American Society for Microbiology.)

Background: The 2013-2016 Ebola epidemic in West Africa began in Guinea's Forest region, a region now considered to be at high risk for future epidemics of viral haemorrhagic fevers (VHF). Good knowledge, attitudes and practices towards VHF amongst healthcare workers in such regions are a central pillar of infection prevention and control (IPC). To inform future training in IPC, this study assesses the knowledge, attitudes and practices (KAP) towards VHF amongst healthcare workers in public healthcare facilities in the most populated prefecture in Forest Guinea, and compares results from urban and rural areas., Methods: In June and July 2019, we interviewed 102 healthcare workers in the main urban and rural public healthcare facilities in the N'zérékoré prefecture in Forest Guinea. We used an interviewer-administered questionnaire adapted from validated KAP surveys., Results: The great majority of respondents demonstrated good knowledge and favourable attitudes towards VHF. However, respondents reported some gaps in preventive practices such as VHF suspect case detection. They also reported a shortage of protective medical equipment used in everyday clinical work in both urban and rural healthcare facilities and a lack of training in IPC, especially in rural healthcare facilities. However, whether or not healthcare workers had been trained in IPC did not seem to influence their level of KAP towards VHF., Conclusions: Three years after the end of the Ebola epidemic, our findings suggest that public healthcare facilities in the N'zérékoré prefecture in Forest Guinea still lack essential protective equipment and some practical training in VHF suspect case detection. To minimize the risk of future VHF epidemics and improve management of outbreaks of infectious diseases in the region, current efforts to strengthen the public healthcare system in Guinea should encompass questions of supply and IPC training.

The West Africa Ebola virus disease outbreak of 2014-2016 demonstrated that responses to viral hemorrhagic fever epidemics must go beyond emergency stopgap measures and should incorporate high-quality medical care and clinical research. Optimal patient management is essential to improving outcomes, and it must be implemented regardless of geographical location or patient socioeconomic status. Coupling clinical research with improved care has a significant added benefit: Improved data quality and management can guide the development of more effective supportive care algorithms and can support regulatory approvals of investigational medical countermeasures (MCMs), which can alter the cycle of emergency response to reemerging pathogens. However, executing clinical research during outbreaks of high-consequence pathogens is complicated and comes with ethical and research regulatory challenges. Aggressive care and excellent quality control must be balanced by the requirements of an appropriate infection prevention and control posture for healthcare workers and by overcoming the resource limitations inherent in many outbreak settings. The Joint Mobile Emerging Disease Intervention Clinical Capability was established in 2015 to develop a high-quality clinical trial capability in Uganda to support rigorous evaluation of MCMs targeting high-consequence pathogens like Ebola virus. This capability assembles clinicians, laboratorians, clinical researchers, logisticians, and regulatory professionals trained in infection prevention and control and in good clinical and good clinical laboratory practices. The resulting team is prepared to provide high-quality medical care and clinical research during high-consequence outbreaks.

For more than 20 years, researchers have used laboratory mice lacking type I or both type I and II interferon (IFN) responses to study high-containment viruses that cause hemorrhagic fevers (HF) in humans. With the exception of Rift Valley fever virus, agents that cause viral HF in humans, such as Ebola and Lassa virus, do not cause disease in mature immunocompetent mice. In contrast, IFN-deficient mice typically develop severe or fatal disease when inoculated with these agents. The sensitivity of IFN-deficient mice to disease has led to their widespread use in biocontainment laboratories to assess the efficacy of novel vaccines against HF viruses, often without considering whether adaptive immune responses in IFN-deficient mice accurately mirror those in immunocompetent humans. Failure to recognize these questions may lead to inappropriate expectations of the predictive value of mouse experiments. In two invited articles, we investigate these questions. The present article reviews the use of IFN-deficient mice for assessing novel vaccines against HF viruses, including Ebola, Lassa, Crimean-Congo hemorrhagic fever and Rift Valley fever viruses. A companion paper examines the general question of how the lack of IFN signaling may affect adaptive immune responses and the outcome of vaccine studies in mice., (Published by Elsevier B.V.)

For more than 20 years, researchers have used laboratory mice lacking type I or both type I and type II interferon (IFN) responses to study viruses that cause hemorrhagic fever (HF) in humans. Whereas immunocompetent mice do not become ill when infected with Ebola, Lassa, dengue and other HF viruses, IFN-deficient mice typically develop severe or fatal disease when inoculated with these pathogens. The ease of employment of these "mouse models" has led to their extensive use in biocontainment laboratories to assess the efficacy of novel vaccines, often without consideration of whether adaptive immune responses in IFN-deficient mice accurately mirror those in humans. Failure to consider these questions may lead to inappropriate expectations of the predictive value of mouse experiments. In two invited articles, we investigate this question. This paper examines how the lack of type I or both type I and type II IFN signaling may affect the development of adaptive immune responses in mice and the outcome of vaccine studies. A second article reviews the published literature on the use of IFN-deficient mice for the assessment of novel vaccines against HF viruses., (Copyright © 2019. Published by Elsevier B.V.)

Purpose of Review: Viral hemorrhagic fevers (VHF) encompass many organisms that have caused sporadic outbreaks with high case fatality rates. This article reviews VHF with reported human-to-human transmission and describes updates about personal protective equipment (PPE) for healthcare personnel (HCP) and others. We summarize existing information about appropriate PPE use, training, and compliance for care of VHF patients in endemic and nonendemic countries, as well as addresses the challenges HCP experience when using PPE., Recent Findings: PPE is essential in protecting HCP from exposure to disease-causing pathogens. Recent evidence shows that anyone involved in care, management, and transport of certain VHF patients must use elements of PPE as part of appropriate infection prevention and control (IPC) practices. Strict adherence to standard precautions has effectively interrupted human-to-human transmission of a number of VHF. However, unclear protocols, inconsistent training, climate challenges, and cultural sensitivities impede proper PPE use. Appropriate PPE use can drastically reduce the risk of HCP exposure to VHF., Summary: Infections caused by certain VHFs can be highly pathogenic and associated with significant morbidity and mortality. Though it is well documented that use of PPE and good IPC practices are critical to reducing transmission, little conclusive evidence exists about the ideal PPE ensemble or components. Concerns with comfort, compliance, training, and usability may impede proper PPE use. Basic PPE elements, used appropriately as part of stringent IPC, must always form the foundation of care for HCP-treating patients with VHF. More research is required to identify the ideal PPE ensemble for caring for VHF patients in various settings.

Infection caused by the severe fever and thrombocytopenia syndrome virus (SFTSV) causes a hemorrhagic illness with a mortality between 20% and 40%. Initially recognized in 2009 in China, cases have additionally been documented in Japan and Korea although retrospective studies have documented seroprevalence since 1996. Although case rates have increased due to increased awareness and more widely available diagnostics, SFTSV infection remains rare with the highest rates documented in Korea for Jeju Province (3.5 cases per 100,000 population) and the Inje-gun region (66.2 cases per 100,000). Because of the very low incidence of infection, a placebo-controlled study with 1:1 randomization to evaluate an SFTSV vaccine would require a sample size that is 25% greater than the region of study. We discuss alternatives to licensure. Vaccine effectiveness may be assessed through a registry, comparing rates of infection over time between vaccine recipients versus regional populations. Modeled data can be updated based on actual case rates and population changes over the years of follow-up. Using one model, statistically significant differences are seen after 10 years in Inje-gun and 15 years of follow-up in Jeju. This approach may be applicable to other uncommon infectious diseases for which a standard study design is difficult.

Viral hemorrhagic fever (VHF) refers to a group of diseases characterized by an acute febrile syndrome with hemorrhagic manifestations and high mortality rates caused by several families of viruses that affect humans and animals. These diseases are typically endemic in certain geographical regions and sometimes cause major outbreaks. The history of hemorrhagic fever in the Arabian Peninsula refers to the 19th century and most outbreaks were reported in the Tihamah region-the Red Sea coastal plain of the Arabian Peninsula in the west and southwest of Saudi Arabia and Yemen. Herein, we describe the agents that cause VHFs and their epidemiology in Tihamah, the history of the diseases, transmission, species affected, and clinical signs. Finally, we address challenges in the diagnosis and control of VHFs in this region.

The concept of containment care for patients with highly hazardous infectious diseases originated in conjunction with the development of sophisticated biosafety level 4 laboratories at the US Army Medical Research Institute of Infectious Diseases in the late 1960s. Over time, the original containment facility served as a model for the development of other facilities in the United States at government and academic centers. The Ebola outbreak of 2014-2015 brought the issue of containment care into the mainstream and led to the development of such capabilities at strategic points around the country. We describe the original concepts behind development of such facilities, how the concept and acceptance has evolved over time, and how the guidelines for managing patients infected with viral hemorrhagic fevers have evolved as new information has been learned about protecting medical care providers from highly hazardous infectious pathogens., (Published by Oxford University Press for the Infectious Diseases Society of America 2016. This work is written by (a) US Government employee(s) and is in the public domain in the US.)

Introduction: Several arenaviruses, chiefly Lassa virus (LASV), cause hemorrhagic fever (HF) disease in humans and pose significant public health problems in their endemic regions. Moreover, HF arenaviruses represent credible biodefense threats. There are not FDA-approved arenavirus vaccines and current anti-arenaviral therapy is limited to an off-label use of ribavirin that is only partially effective., Areas Covered: Live-attenuated vaccines (LAV) represent the most feasible approach to control HF arenaviruses within their endemic regions. Different platforms, including recombinant viral vectors expressing LASV antigens, and the use of attenuated reassortant arenaviruses, have been used to develop LAV candidates against LASV with promising results in animal models of LASV infection, but none of them has entered a clinical trial. These vaccine efforts have been the subject of recent reviews and will not be examined in this review, which is focused on new avenues for the development of safe and effective LAV to combat HF arenaviruses. Expert commentary: The development of arenavirus reverse genetics has provided investigators with a novel powerful approach to manipulate the genomes of HF arenaviruses, which has opened new avenues for the rapid development of safe and effective LAV to combat these human pathogens., Competing Interests: Declaration of Interests The authors were supported by NIH grants RO1 AI047140 (Juan C. de la Torre), RO1 AI077719 (Juan C. de la Torre and Luis Martinez-Sobrido), RO1 AI079665 (Luis Martinez-Sobrido) and R03AI099681-01A1 (Luis Martinez-Sobrido). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Internists should expect to be the first contact for patients with rare, but highly contagious, life-threatening illnesses. Although certainly not encountered often, it is associated with significant consequences. Thus, physicians should be familiar with viral hemorrhagic fevers: filoviruses cause Ebola and Marburg fever, arenaviruses cause Lassa fever and South American hemorrhagic fevers, and the bunyaviruses cause among others Crimean-Congo hemorrhagic fever. Furthermore, physicians should be familiar with highly contagious respiratory infections, such as hantavirus pulmonary syndrome, pneumonic plague, and Middle East respiratory syndrome (MERS).

Viral haemorrhagic fevers (VHFs) include a diverse array of diseases caused by a broad range of viruses transmitted from various animal hosts and originating from almost all the continents in the world. These are potentially fatal and highly transmissible diseases without specific treatments or prophylactic vaccines. As has been demonstrated during the Ebola virus disease outbreak in West Africa, the consequences of VHFs are not limited to specific countries - they may become epidemic, and may have considerable economic impact and disrupt local public health and social service structures. Intensive public health intervention is necessary to contain these diseases. Here we provide a concise overview of the VHFs that are of current public health importance to South Africa.

The status of the various recombinant DNA and RNA-derived candidate vaccines, as well as the Venezuelan equine encephalomyelitis virus (VEEV) replicon vaccine system against extremely hazardous viral hemorrhagic fevers, were reviewed. The VEEV-based replication-incompetent vectors offer attractive features in terms of safety, high expression levels of the heterologous viral antigen, tropism to dendritic cells, robust immune responses, protection efficacy, low potential for pre-existing anti-vector immunity and possibility of engineering multivalent vaccines were tested. These features of the VEEV replicon system hold much promise for the development of new generation vaccine candidates against viral hemorrhagic fevers.

The term "viral hemorrhagic fever" (VHF) designates a syndrome of acute febrile illness, increased vascular permeability and coagulation defects which often progresses to bleeding and shock and may be fatal in a significant percentage of cases. The causative agents are some 20 different RNA viruses in the families Arenaviridae, Bunyaviridae, Filoviridae and Flaviviridae, which are maintained in a variety of animal species and are transferred to humans through direct or indirect contact or by an arthropod vector. Except for dengue, which is transmitted among humans by mosquitoes, the geographic distribution of each type of VHF is determined by the range of its animal reservoir. Treatments are available for Argentine HF and Lassa fever, but no approved countermeasures have been developed against other types of VHF. The development of effective interventions is hindered by the sporadic nature of most infections and their occurrence in geographic regions with limited medical resources. Laboratory animal models that faithfully reproduce human disease are therefore essential for the evaluation of potential vaccines and therapeutics. The goal of this review is to highlight the current status of animal models that can be used to study the pathogenesis of VHF and test new countermeasures., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Although several biological agents have been recognized as presenting a significant threat to public health if used in a bioterrorist attack, those that are of greatest importance are known as the Category A agents: Bacillus anthracis (anthrax); variola major (smallpox); Yersinia pestis (plague); Francisella tularensis (tularemia); ribonucleic acid viruses (hemorrhagic fevers); and Clostridium botulinum (botulism toxin). In the previous issue, Part I of this review focused on the clinical presentation and treatment of anthrax, plague, and tularemia. In this second part of this 2-part review of these agents, the focus is on the clinical presentation and treatment of smallpox, viral hemorrhagic fevers, and botulism toxin. The utilization of mass prophylaxis to limit the morbidity and mortality associated with all these agents is also discussed along with the role emergency care personnel play in its implementation.

The viral haemorrhagic fevers (VHF) are a growing public health threat in the Eastern Mediterranean Region. Nearly all of them are of zoonotic origin. VHF often cause outbreaks with high fatalities and, except for yellow fever, currently there are no specific treatment or vaccination options available. In response to this growing threat, the Regional Office for the Eastern Mediterranean of the World Health Organization convened a technical consultation in Tehran on 27-30 November 2011 to review the current gaps in prevention and control of VHF outbreaks in the Region. The meeting recommended a number of strategic public health approaches for prevention and control of VHF outbreaks through synergizing effective collaboration between the human and animal health sectors on areas that involve better preparedness, early detection and rapid response. Implementation of these approaches would require working together with vision, commitment and a sense of purpose involving partnerships and cooperation from all relevant sectors.

Many pathogens that can cause major public health, economic, and social damage are relatively easily accessible and could be used as biological weapons. Wildlife is a natural reservoir for many potential bioterrorism agents, and, as history has shown, eliminating a pathogen that has dispersed among wild fauna can be extremely challenging. Since a number of wild rodent species live close to humans, rodents constitute a vector for pathogens to circulate among wildlife, domestic animals, and humans. This article reviews the possible consequences of a deliberate spread of rodentborne pathogens. It is relatively easy to infect wild rodents with certain pathogens or to release infected rodents, and the action would be difficult to trace. Rodents can also function as reservoirs for diseases that have been spread during a bioterrorism attack and cause recurring disease outbreaks. As rats and mice are common in both urban and rural settlements, deliberately released rodentborne infections have the capacity to spread very rapidly. The majority of pathogens that are listed as potential agents of bioterrorism by the Centers for Disease Control and Prevention and the National Institute of Allergy and Infectious Diseases exploit rodents as vectors or reservoirs. In addition to zoonotic diseases, deliberately released rodentborne epizootics can have serious economic consequences for society, for example, in the area of international trade restrictions. The ability to rapidly detect introduced diseases and effectively communicate with the public in crisis situations enables a quick response and is essential for successful and cost-effective disease control.

Introduction: Bioterrorism is a terrorist action involving the intentional release or dissemination of a biological warfare agent (BWA), which includes some bacteria, viruses, rickettsiae, fungi or biological toxins. BWA is a naturally occurring or human-modified form that may kill or incapacitate humans, animals or plants as an act of war or terrorism. BWA is a weapon of choice for mass destruction and terrorism, because of the incubation period, less effective amount than chemical warfare agents, easily distribution, odorless, colorless, difficult to detect, no need of specialized equipment for production and naturally distribution which can easily be obtained. BWA may be disseminating as an aerosol, spray, explosive device, and by food or water., Classification: Based on the risk for human health, BWAs have been prioritized into three categories of A, B and C. Category A includes microorganisms or toxins that easily spread, leading to intoxication with high death rates such as Anthrax, Botulism, Plague, Smallpox, Tularemia and Viral hemorrhagic fevers. Category B has lower toxicity with wider range, including Staphylococcal Entrotoxin type B (SEB), Epsilon toxin of Clostridium perfringens, Ricin, Saxotoxins, Abrin and Trichothecene mycotoxins. The C category includes emerging pathogens that could also be engineered for mass spread such as Hanta viruses, multidrug-resistant tuberculosis, Nipah virus, the tick-borne encephalitis viruses, hemorrhagic fever viruses and yellow fever. CLINICAL MANIFESTATIONS OF BIOTOXINS IN HUMAN: Clinical features and severity of intoxication depend on the agent and exposed dose, route of entry, individual variation and environmental factors. Onset of symptoms varies from 2-24 h in Ricin to 24-96 h in Botulism. Clinical manifestations also vary from irritation of the eyes, skin and mucus membranes in T2 toxin to an acute flaccid paralysis of bilateral cranial nerve impairment of descending manner in botulism. Most of the pyrogenic toxins such as SEB produce the same signs and symptoms as toxic shock syndrome including a rapid drop in blood pressure, elevated temperature, and multiple organ failure., Management: There is no specific antidote or effective treatment for most of the biotoxins. The clinical management is thus more supportive and symptomatic. Fortunately vaccines are now available for most of BWA. Therefore, immunization of personnel at risk of exposure is recommended., Conclusion: Biotoxins are very wide and bioterrorism is a heath and security threat that may induce national and international problems. Therefore, the security authorities, health professional and even public should be aware of bioterrorism., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

The Defense Threat Reduction Agency's Joint Science and Technology Office manages the Chemical and Biological Defense Program's Science and Technology portfolio. The Joint Science and Technology Office's mission is to invest in transformational ideas, innovative people and actionable technology development for Chemical and Biological Defense solutions, with the primary goal to deliver Science and Technology products and capabilities to the warfighter and civilian population that outpace the threat. This commentary focuses on one thrust area within this mission: the Vaccine program of the Joint Science and Technology Office's Translational Medical Division. Here, we will describe candidate vaccines currently in the S&T pipeline, enabling technologies that should facilitate advanced development of these candidates into FDA licensed vaccines, and how the ever-changing biological threat landscape impacts the future of biodefense vaccines.

With a few exceptions, vaccines for viruses that cause hemorrhagic fever remain unavailable or lack well-documented efficacy. In the past decade this has not been due to a lack of the ability to develop vaccine platforms against highly pathogenic viruses, but rather the lack of will/interest to invest in platforms that have the potential to become successful vaccines. The two exceptions to this are vaccines against Dengue virus (DENV) and Rift Valley fever virus (RVFV), which recently have seen significant progress in putting forward new and improved vaccines, respectively. Experimental vaccines for filoviruses and Lassa virus (LASV) do exist but are hindered by a lack of financial interest and only partially or ill-defined correlates/mechanisms of protection that could be assessed in clinical trials., (Published by Elsevier B.V.)

Viral haemorrhagic fevers (VHFs) typically manifest as rapidly progressing acute febrile syndromes with profound haemorrhagic manifestations and very high fatality rates. VHFs that have the potential for human-to-human transmission and onset of large nosocomial outbreaks include Crimean-Congo haemorrhagic fever, Ebola haemorrhagic fever, Marburg haemorrhagic fever and Lassa fever. Nosocomial outbreaks of VHFs are increasingly reported nowadays, which likely reflects the dynamics of emergence of VHFs. Such outbreaks are associated with an enormous impact in terms of human lives and costs for the management of cases, contact tracing and containment. Surveillance, diagnostic capacity, infection control and the overall preparedness level for management of a hospital-based VHF event are very limited in most endemic countries. Diagnostic capacities for VHFs should increase in the field and become affordable. Availability of appropriate protective equipment and education of healthcare workers about safe clinical practices and infection control is the mainstay for the prevention of nosocomial spread of VHFs., (Copyright © 2012 The Healthcare Infection Society. Published by Elsevier Ltd. All rights reserved.)

Vaccination is one of the most valuable weapons against infectious diseases and has led to a significant reduction in mortality and morbidity. However, for most viral hemorrhagic fevers caused by arenaviruses, no prophylactic vaccine is available. This is particularly problematic as these diseases are notoriously difficult to diagnose and treat. Lassa fever is globally the most important of the fevers caused by arenaviruses, potentially affecting millions of people living in endemic areas, particularly in Nigeria. Annually, an estimated 300,000 humans are infected and several thousands succumb to the disease. The successful development of the vaccine "Candid#1" against Junin virus, the causative agent of Argentine hemorrhagic fever, proved that an effective arenavirus vaccine can be developed. Although several promising studies toward the development of a Lassa fever vaccine have been published, no vaccine candidate has been tested in human volunteers or patients. This review summarizes the immunology and other aspects of existing experimental arenavirus vaccine studies, discusses the reasons for the lack of a vaccine, and proposes a plan for overcoming the final hurdles toward clinical trials.

Viral hemorrhagic fevers are severe zoonotic diseases caused by RNA-viruses classified into 4 families: Arenaviridae, Bunyaviridae, Filoviridae, and Flaviviridae. They are present on all continents except Antarctica, their person-to-person spread is easy, and there is a high risk of them being used as weapon by bioterrorists. So far, efforts to develop effective drugs against these viruses have failed, and typical therapy usually relies on symptomatic treatment. Search for substances that could effectively inhibit this type of infections is now a priority. The presented paper gives an overview of different approaches used in combating the viral hemorrhagic fevers. Researchers look for safe antiviral agents with appropriate properties among natural sources, such as various types of herbs plants, algae, or essential oils obtained from trees, as well as investigate the use of various synthetic substances. The aim is to broaden the pool of available antiviral drugs that could replace hitherto applied medicines such as ribavirin, which is not always sufficiently effective and may have side-effects. The scientists focus not only on combating the diseases, but also on their prevention. For this purpose, recombinant vaccines or various types of immunomodulators may serve as a useful tools. Results of the latest studies are promising and encourage further work which may eventually lead to the solution of the urgent problem of hemorrhagic fevers.

Ebola virus (EBOV) and Marburg virus (MARV) are among the deadliest human pathogens, with no vaccines or therapeutics available. Multiple vaccine platforms have been tested for efficacy as prophylactic pretreatments or therapeutics for prevention of filovirus hemorrhagic fever. Most successful vaccines are based on a virus-vectored approach expressing the protective glycoprotein (GP); protein-based subunit and DNA vaccines have been tested with moderate success. Virus-like particle (VLP) vaccines have realized promising results when tested in both rodents and nonhuman primates. VLPs rely on the natural properties of the viral matrix protein (VP) 40 to drive budding of filamentous particles that can also incorporate ≥ 1 other filovirus protein, including GP, VP24, and nucleoprotein (NP). Filovirus VLP vaccines have used particles containing 2 or 3 (GP and VP40, with or without NP) viral proteins generated in either mammalian or insect cells. Early studies successfully demonstrated efficacy of bivalent VLP vaccines in rodents; more recent studies have shown the ability of the VLP vaccines containing GP, NP, and VP40 to confer complete homologous protection against Ebola virus and Marburg virus in a prophylactic setting against in macaques. This review will discuss published work to date regarding development of the VLP vaccines for prevention of lethal filovirus hemorrhagic fever.

Background: Viral haemorrhagic fevers (VHFs) are severe infections capable of causing haemorrhagic disease and fatal multi-organ failure. Crimean-Congo, Marburg, Ebola and Lassa viruses cause both sporadic cases and large epidemics over wide endemic areas., Sources of Data: Original articles and reviews identified by PubMed search and personal reading; European and United States national guidance and legislation. World Health Organization information, documents and reports. VHFs cause significant morbidity and mortality in their endemic areas; they can cause healthcare-related infections, and their broad diversity and range are increasingly recognized., Areas of Controversy: There is uncertainty about the risks presented by VHFs in non-endemic countries, particularly in healthcare environments. Consensus on the best modes of care and infection control are only slowly emerging., Growing Points: With increasing commerce in rural and low-income areas, VHF outbreaks increasingly expand, causing social and economic damage., Areas Timely for Developing Research: New ecologies, viral strains and clinical syndromes are being discovered. There is a great need for rapid diagnostic tests and effective antiviral treatments. Vaccine development programmes are challenged by multiple viral strains and the need for trials in rural communities.

Arenaviruses are the causative pathogens of severe hemorrhagic fever and aseptic meningitis in humans, for which no licensed vaccines are currently available. Pathogen heterogeneity within the Arenaviridae family poses a significant challenge for vaccine development. The main hypothesis we tested in the present study was whether it is possible to design a universal vaccine strategy capable of inducing simultaneous HLA-restricted CD8+ T cell responses against 7 pathogenic arenaviruses (including the lymphocytic choriomeningitis, Lassa, Guanarito, Junin, Machupo, Sabia, and Whitewater Arroyo viruses), either through the identification of widely conserved epitopes, or by the identification of a collection of epitopes derived from multiple arenavirus species. By inoculating HLA transgenic mice with a panel of recombinant vaccinia viruses (rVACVs) expressing the different arenavirus proteins, we identified 10 HLA-A02 and 10 HLA-A03-restricted epitopes that are naturally processed in human antigen-presenting cells. For some of these epitopes we were able to demonstrate cross-reactive CD8+ T cell responses, further increasing the coverage afforded by the epitope set against each different arenavirus species. Importantly, we showed that immunization of HLA transgenic mice with an epitope cocktail generated simultaneous CD8+ T cell responses against all 7 arenaviruses, and protected mice against challenge with rVACVs expressing either Old or New World arenavirus glycoproteins. In conclusion, the set of identified epitopes allows broad, non-ethnically biased coverage of all 7 viral species targeted by our studies.

This article explores the use of isolation precautions to prevent the spread of infection. The standard infection control precautions, which should be undertaken routinely with all patients, and the additional measures which should be adopted when a patient has a specific infection, are discussed. The use of single room accommodation for patients with infections is debated.

In the 40 years since the recognition of filoviruses as agents of lethal human disease, there have been no specific advances in antiviral therapies or vaccines and few clinical studies on the efficacy of supportive care. On 20 September 2006, experts from 14 countries representing 68 institutions integrally involved in the response to outbreaks of filovirus hemorrhagic fever gathered at the National Microbiology Laboratory of the Public Health Agency of Canada in Winnipeg to discuss possible remedies for this grim situation, in a unique workshop entitled "Marburg and Ebola Hemorrhagic Fever: Feasibility of Prophylaxis and Therapy." A summary of the opportunities for and challenges to improving treatment of filovirus hemorrhagic fevers is presented here.

The emergence and re-emergence of infectious diseases involves many interrelated factors. Global interconnectedness continues to increase with international travel and trade; economic, political, and cultural interactions; and human-to-human and animal-to-human interactions. These interactions include the accidental and deliberate sharing of microbial agents and antimicrobial resistance and allow the emergence of new and unrecognized microbial disease agents. As the 21st century begins, already new agents have been identified, and new outbreaks have occurred. Solutions to limiting the spread of emerging infectious diseases will require cooperative efforts among many disciplines and entities worldwide. This article defines emerging infectious diseases, summarizes historical background, and discusses factors that contribute to emergence. Seven agents that have made a significant appearance, particularly in the 21st century, are reviewed, including: Ebola and Marburg hemorrhagic fevers, human monkeypox, bovine spongiform encephalopathy, severe acute respiratory syndrome (SARS), West Nile virus, and avian influenza. The article provides for each agent a brief historical background, case descriptions, and health care implications.

Two Institute of Medicine reports since 1992 have emphasized the dangerous and continuing threat to the world from emerging infectious diseases. Working with viral hemorrhagic fevers provides a number of lessons related to the processes that control emergence, the pattern of disease after emergence, and how to cope with these incidents. This short paper uses two arenavirus hemorrhagic fevers to illustrate some of these principles. Argentine and Bolivian hemorrhagic fevers first came to medical attention in the 1950's. The forces that underlie the emergence of disease in Argentina are not understood, but the Bolivian episode has a reasonably understandable train of events behind it. The Argentine disease had serious impact on the large agricultural economy, and the ecology of the rodent reservoir did not lend itself to control; a vaccine was developed by Argentina and the U.S. with the latter motivated largely by biodefense. The Bolivian disease was controlled in large part by eliminating rodents that invaded towns, and the impact was subsequently below the level needed to trigger drug or vaccine development. These two viruses were important in the recognition of a new family of viruses (Arenaviridae), and this finding of new taxons during the investigation of emerging infectious diseases continues.

The outbreak of Marburg haemorrhagic fever in Angola in 2004-2005 shows once again the devastating and rapid spread of viral haemorrhagic fevers in medical settings where hygiene practices are poorly applied or ignored. The legacy of years of war and poverty in Angola has resulted in very poor medical education and services. The initial high rate of infection among infants in Angola may have been related to poor hospital practices, possibly administration of vaccines. Though the outbreak in Angola was in a part of Africa not previously known to have filovirus infection, prior ecological modelling had predicted this location and many others. Prevention of future outbreaks will not be easy. The urgent need is dissemination of knowledge and the training, discipline and resources for good clinical practice. Educating the public to demand higher standards could be a powerful tool. Good practices are difficult to establish and maintain on the scale needed.

Viral hemorrhagic fever (VHF) is defined as virus infections that usually cause pyrexia and hemorrhagic symptoms with multiple organ failure. VHF includes following viral infections: Ebola hemorrhagic fever (EHF), Marburg hemorrhagic fever (MHF), Crimean-Congo hemorrhagic fever (CCHF) and Lassa fever. In particular, the causative agents of EHF, MHF, CCHF, and Lassa fever are Ebola, Marburg, CCHF, Lassa viruses, respectively, and regarded as biosafety level-4 pathogens because of their high virulence to humans. Recently, relatively large outbreaks of EHF and MHF have occurred in Africa, and areas of EHF- and MHF-outbreaks seem to be expanding. Although outbreaks of VHF have not been reported in Japan, there is a possibility that the deadly hemorrhagic fever viruses would be introduced to Japan in future. Therefore, preparedness for possible future outbreaks of VHF is necessary in areas without VHF outbreaks.

Human have struggled against many infectious diseases such as cholera, plague, dysentery and yellow fever for a long time. And we have spent a lot of energy to control these infectious diseases and developed various tool for them. One of these efforts was Quarantine system that was established in 14th century in Europe. But during recent days, we are suffering from newly emerged diseases. These new infectious diseases are zoonosis and most of them are serious and highly infectious. Viral hemorrhagic fever such as Ebola hemorrhagic fever, Marburg hemorrhagic fever and Lassa fever are typical these emerging serious diseases, and these outbreak always have occurred in Africa and neighboring countries. Fortunately we have never experienced any case, but as these diseases are so serious, we are so nervous diseases entering in Japan. Against these serious diseases, in Japan, Quarantine Station are doing screening examination at airport and port by questionnaire and measuring body temperature, because these viral hemorrhagic fever patients show high fever. If people were suspected viral hemorrhagic fever at Quarantine Station at the border, they will be leaded to hospital for further examination and treatment as soon as possible.

Infection control faces radical changes at the beginning of the third millennium. The first part of this review focuses on problems not yet solved, such as 1) surveillance systems, which should be active and extremely flexible; 2) infection outbreaks in hospitals and strategies to avoid them; 3) hand washing and alternatives such as rapid hand antisepsis; 4) water and food in the hospital as potential reservoirs of nosocomial pathogens; 5) upgrading of infection control programs to turn them into systems to improve the quality of care; 6) fatal Gram-negative bacteremias in hospitals from developing countries, which can be avoided with better standards of care; 7) the elemental role of the microbiology laboratory in the prevention and control of infections; 8) the unprecedented crisis due to the emergence of specific multi-resistant pathogens; 9) the risks for healthcare workers, such as tuberculosis, hepatitis, HIV, SARS, and hemorrhagic fevers; and 10) the need for the consistent application of guidelines. The second part of this review focuses on new challenges for infection control, such as 1) the ever-growing number of immunocompromised patients and basic control measures to avoid opportunistic infections; 2) the concerns about the capacity of the public health systems to deal with terrorist acts; 3) the practice of high-risk procedures in facilities lacking trained personnel, efficient laboratories, and protective items; and 4) gene therapy and its potential infectious complications. Consideration is given to the asymmetric development of infection control globally.

Biological terrorism is intentionally to use infectious substances for developing diseases or death in animals or humans, leading to disaster and panic in our community. Bioterrorism-associated diseases are mostly rare or eradicated infectious diseases, and recently, we do not have experience to make a clinical and laboratory diagnosis. In particular, these infectious diseases have incubation periods from infection to development of the disease. The staff working at public health institutions, including legal medicine, must be involved in as a first responder when bioterrorism would happen. The preparedness in general against bioterrorism and the bioterrorism-related diseases, such as anthrax, smallpox, viral hemorrhagic fever, tularemia, and botulinum toxin, important for us are described. Both medical knowledge of bioterrorism and the preparedness with training under simulation should be required in advance.

The majority of haemorrhagic fever viruses are responsible for various clinical manifestations, the mutual characteristics of which are fever and haemorrhage in 5 to 70% of cases. All degrees of severity can be observed, ranging from isolated fever to multi-organ failure and death. These viruses belong to one of the following families: filoviridae, arenaviridae, bunyaviridae, and flaviviridae. They must be considered as dangerous biological weapons that could potentially be used. Most of the viruses responsible for haemorrhagic fever can be transmitted to humans through the air in spray form, except the dengue virus and the agents of haemorrhagic fever from the Congo Crimea and the haemorrhagic fever with renal syndrome that are difficult to handle in cell culture. In the event of a bioterrorist act, the management of persons infected or suspected of being so will be made by the referent departments of infectious diseases, defined by the French Biotox plan. Management includes isolation, confirmation or invalidation of the diagnosis and rapid initiation of treatment with ribavirin. Ribavirin is recommended for the treatment and prophylaxis of arenavirus and bunyavirus infections; it is not effective for the other families of virus. Except for yellow fever, there is no vaccination for the other forms of viral haemorrhagic fever.

USED FOR WARFARE: Bioterrorism is a perfectly foreseeable eventuality. It is defined by the international use, or menace of use, of living organisms whatever their nature, or of substances derived from these organisms, aimed at provoking a disease or the death of human beings, animals or plants. UPDATED COUNTERACTING STRATEGIES: More than 180 infectious agents could be used for terrorist ends. The recent events in the dawn of this twenty-first century have reactivated and notably updated the strategies to counteract such an event. Clinical and therapeutic guidelines have been circulated in many countries. INFECTIONS THAT REQUIRE RECOGNITION: The role of practitioners in the rapid recognition of bioterrorism-related infections is crucial. Hence, updated knowledge on these potentially emerging or reemerging infections is required.