Safety and Immunogenicity of Accelerated Heterologous Two-dose Ebola Vaccine Regimens in Adults With and Without HIV in Africa.

BACKGROUND: Shorter prophylactic vaccine schedules may offer more rapid protection against Ebola in resource-limited settings. METHODS: This randomized, observer-blind, placebo-controlled, phase 2 trial conducted in five sub-Saharan African countries included people without HIV (PWOH, n = 249) and people living with HIV (PLWH, n = 250). Adult participants received one of two accelerated Ebola vaccine regimens (MVA-BN-Filo, Ad26.ZEBOV administered 14 days apart [n = 79] or Ad26.ZEBOV, MVA-BN-Filo administered 28 days apart [n = 322]) or saline/placebo (n = 98). The primary endpoints were safety (adverse events [AEs]) and immunogenicity (Ebola virus [EBOV] glycoprotein-specific binding antibody responses). Binding antibody responders were defined as participants with a > 2.5-fold increase from baseline or the lower limit of quantification if negative at baseline. RESULTS: The mean age was 33.4 years, 52% of participants were female, and among PLWH, the median (interquartile range) CD4+ cell count was 560.0 (418.0-752.0) cells/µL. AEs were generally mild/moderate with no vaccine-related serious AEs or remarkable safety profile differences by HIV status. At 21 days post-dose 2, EBOV glycoprotein-specific binding antibody response rates in vaccine recipients were 99% for the 14-day regimen (geometric mean concentrations [GMCs]: 5168 enzyme-linked immunosorbent assay units (EU)/mL in PWOH; 2509 EU/mL in PLWH), and 98% for the 28-day regimen (GMCs: 6037 EU/mL in PWOH; 2939 EU/mL in PLWH). At 12 months post-dose 2, GMCs in PWOH and PLWH were 635 and 514 EU/mL, respectively, for the 14-day regimen and 331 and 360 EU/mL, respectively, for the 28-day regimen. CONCLUSIONS: Accelerated 14- and 28-day Ebola vaccine regimens were safe and immunogenic in PWOH and PLWH in Africa. TRIAL REGISTRATION: NCT02598388.

Health care response to CCHF in US soldier and nosocomial transmission to health care providers, Germany, 2009.

In 2009, a lethal case of Crimean-Congo hemorrhagic fever (CCHF), acquired by a US soldier in Afghanistan, was treated at a medical center in Germany and resulted in nosocomial transmission to 2 health care providers (HCPs). After his arrival at the medical center (day 6 of illness) by aeromedical evacuation, the patient required repetitive bronchoscopies to control severe pulmonary hemorrhage and renal and hepatic dialysis for hepatorenal failure. After showing clinical improvement, the patient died suddenly on day 11 of illness from cerebellar tonsil herniation caused by cerebral/cerebellar edema. The 2 infected HCPs were among 16 HCPs who received ribavirin postexposure prophylaxis. The infected HCPs had mild or no CCHF symptoms. Transmission may have occurred during bag-valve-mask ventilation, breaches in personal protective equipment during resuscitations, or bronchoscopies generating infectious aerosols. This case highlights the critical care and infection control challenges presented by severe CCHF cases, including the need for experience with ribavirin treatment and postexposure prophylaxis.

Safety and Immunogenicity of an Accelerated Ebola Vaccination Schedule in People with and without Human Immunodeficiency Virus: A Randomized Clinical Trial.

The safety and immunogenicity of the two-dose Ebola vaccine regimen MVA-BN-Filo, Ad26.ZEBOV, 14 days apart, was evaluated in people without HIV (PWOH) and living with HIV (PLWH). In this observer-blind, placebo-controlled, phase 2 trial, healthy adults were randomized (4:1) to receive MVA-BN-Filo (dose 1) and Ad26.ZEBOV (dose 2), or two doses of saline/placebo, administered intramuscularly 14 days apart. The primary endpoints were safety (adverse events (AEs)) and immunogenicity (Ebola virus (EBOV) glycoprotein-specific binding antibody responses). Among 75 participants (n = 50 PWOH; n = 25 PLWH), 37% were female, the mean age was 44 years, and 56% were Black/African American. AEs were generally mild/moderate, with no vaccine-related serious AEs. At 21 days post-dose 2, EBOV glycoprotein-specific binding antibody responder rates were 100% among PWOH and 95% among PLWH; geometric mean antibody concentrations were 6286 EU/mL (n = 36) and 2005 EU/mL (n = 19), respectively. A total of 45 neutralizing and other functional antibody responses were frequently observed. Ebola-specific CD4+ and CD8+ T-cell responses were polyfunctional and durable to at least 12 months post-dose 2. The regimen was well tolerated and generated robust, durable immune responses in PWOH and PLWH. Findings support continued evaluation of accelerated vaccine schedules for rapid deployment in populations at immediate risk. Trial registration: NCT02598388 (submitted 14 November 2015).

Safety and immunogenicity of a highly attenuated rVSVN4CT1-EBOVGP1 Ebola virus vaccine: a randomised, double-blind, placebo-controlled, phase 1 clinical trial.

BACKGROUND: The safety and immunogenicity of a highly attenuated recombinant vesicular stomatitis virus (rVSV) expressing HIV-1 gag (rVSVN4CT1-HIV-1gag1) was shown in previous phase 1 clinical studies. An rVSV vector expressing Ebola virus glycoprotein (EBOV-GP) in place of HIV-1 gag (rVSVN4CT1-EBOVGP1) showed single-dose protection from lethal challenge with low passage Ebola virus in non-human primates. We aimed to evaluate the safety and immunogenicity of the rVSVN4CT1-EBOVGP1 vaccine in healthy adults. METHODS: We did a randomised double-blind, placebo-controlled, phase 1 dose-escalation study at a single clinical site (Optimal Research) in Melbourne, FL, USA. Eligible participants were healthy men and non-pregnant women aged 18-60 years, with a body-mass index (BMI) of less than 40 kg/m2, no history of filovirus infection, VSV infection, or receipt of rVSV in previous studies, and who had not visited regions where Ebola virus outbreaks have occurred. Three cohorts were enrolled to assess a low (2·5 × 104 plaque forming units [PFU]), intermediate (2 × 105 PFU), or high dose (1·8 × 106 PFU) of the vaccine. Participants within each cohort were randomly allocated (10:3) to receive vaccine or placebo by intramuscular injection in a homologous prime and boost regimen, with 4 weeks between doses. All syringes were masked with syringe sleeves; participants and study site staff were not blinded to dose level but were blinded to active vaccine and placebo. The primary outcomes were safety and tolerability; immunogenicity, assessed as GP-specific humoral immune response (at 2 weeks after each dose) and cellular immune response (at 1 and 2 weeks after each dose), was a secondary outcome. All randomised participants were included in primary and safety analyses. This trial is registered with ClinicalTrials.gov, NCT02718469. FINDINGS: Between Dec 22, 2015, and Sept 15, 2016, 39 individuals (18 [46%] men and 21 [54%] women, mean age 51 years [SD 10]) were enrolled, with ten participants receiving the vaccine and three participants receiving placebo in each of three cohorts. One participant in the intermediate dose cohort was withdrawn from the study because of a diagnosis of invasive ductal breast carcinoma 24 days after the first vaccination, which was considered unrelated to the vaccine. No severe adverse events were observed. Solicited local adverse events occurred in ten (26%) of 39 participants after the first dose and nine (24%) of 38 participants after the second dose; the events lasted 3 days or less, were predominantly injection site tenderness (17 events) and injection site pain (ten events), and were either mild (19 events) or moderate (ten events) in intensity. Systemic adverse events occurred in 13 (33%) of 39 participants after the first dose and eight (21%) of 38 participants after the second dose; the events were mild (45 events) or moderate (11 events) in severity, and the most common events were malaise or fatigue (13 events) and headache (12 events). Arthritis and maculopapular, vesicular, or purpuric rash distal to the vaccination site(s) were not reported. A GP-specific IgG response was detected in all vaccine recipients after two doses (and IgG response frequency was 100% after a single high dose), and an Ebola virus neutralising response was detected in 100% of participants in the high-dose cohort. INTERPRETATION: The rVSVN4CT1-EBOVGP1 vaccine was well tolerated at all dose levels tested and was immunogenic despite a high degree of attenuation. The combined safety and immunogenicity profile of the rVSVN4CT1-EBOVGP1 vaccine vector support phase 1-2 clinical evaluation. FUNDING: US Department of Defense Joint Program Executive Office for Chemical, Biological, Radiological and Nuclear Defense: Joint Project Manager for Chemical, Biological, Radiological and Nuclear Medical.

Botulinum neurotoxin vaccines: Past history and recent developments.

Botulinum toxin may cause a neuroparalytic illness that may result in respiratory failure and require prolonged mechanical ventilation. As medical resources needed for supportive care of botulism in a bioterrorist event may quickly overwhelm the local healthcare systems, biodefense research efforts have been directed towards the development of a vaccine to prevent botulism. While human botulism has been caused only by toxin serotypes A, B, and E (rarely serotype F), all seven known immunologically distinct toxin serotypes (A - G) may potentially cause intoxication in humans from a bioterrorist event. A pentavalent (ABCDE) botulinum toxoid (PBT) has been administered as an investigation new drug (IND) to at-risk individuals for nearly 50 years. Due to declining immunogenicity of the PBT, research efforts have been directed at development of both improved (less local reactogenicity) botulinum toxoids and recombinant vaccines as potential vaccine candidates to replace the PBT.

Development of a highly sensitive in vitro endothelial cell toxicity assay for evaluating ricin toxin A chain-based vaccines or therapeutics.

The ricin toxin A chain (RTA) is responsible for ricin intoxication due to inhibition of protein synthesis. RTA is also known to cause endothelial toxicity [via a 3 amino acid sequence (x)D(y) motif that acts as a natural disintegrin] resulting in vascular leak syndrome (VLS) in humans. An in vitro endothelial cell toxicity (ECT) assay was developed to evaluate if the ricin vaccine candidate (RVEc) exhibited endothelial toxicity, determined by altered transendothelial electrical resistance (TEER) across human umbilical vein endothelial cell (HUVEC) monolayers. Timepoints at 2 and 4 h were included to evaluate HUVEC monolayers before the effects of RTA ribotoxic activity are observed. Both the 3 µM and 6 µM RTA positive controls consistently demonstrated significantly reduced TEER values, compared to their corresponding vehicle control, in a time- and concentration-dependent manner at 2, 4, and 24 h. Fluorescent imaging of HUVECs exposed to 3 µM RTA showed cell rounding at 2 and 4 h and gap formation at 24 h. No changes in TEER or fluorescent imaging were observed after exposure to endothelial cell growth medium-2 (EGM-2) exchange (mock control). The negative controls, which included 2 mutant RTA vaccine derivatives [RVEc with an (x)D(y) VLS sequence modification to V76M or D75N] and bovine serum albumin (BSA), demonstrated no evidence of HUVEC toxicity at 3 µM and 6  µM concentrations. Overall, the performance of the ECT assay was consistent, allowing for the development of acceptance criteria that were related to time- and concentration-dependent decreases in TEER between 2 and 24 h.

Approach to Strain Selection and the Propagation of Viral Stocks for Venezuelan Equine Encephalitis Virus Vaccine Efficacy Testing under the Animal Rule.

Licensure of a vaccine to protect against aerosolized Venezuelan equine encephalitis virus (VEEV) requires use of the U.S. Food and Drug Administration (FDA) Animal Rule to assess vaccine efficacy as human studies are not feasible or ethical. An approach to selecting VEEV challenge strains for use under the Animal Rule was developed, taking into account Department of Defense (DOD) vaccine requirements, FDA Animal Rule guidelines, strain availability, and lessons learned from the generation of filovirus challenge agents within the Filovirus Animal Nonclinical Group (FANG). Initial down-selection to VEEV IAB and IC epizootic varieties was based on the DOD objective for vaccine protection in a bioterrorism event. The subsequent down-selection of VEEV IAB and IC isolates was based on isolate availability, origin, virulence, culture and animal passage history, known disease progression in animal models, relevancy to human disease, and ability to generate sufficient challenge material. Methods for the propagation of viral stocks (use of uncloned (wild-type), plaque-cloned, versus cDNA-cloned virus) to minimize variability in the potency of the resulting challenge materials were also reviewed. The presented processes for VEEV strain selection and the propagation of viral stocks may serve as a template for animal model development product testing under the Animal Rule to other viral vaccine programs. This manuscript is based on the culmination of work presented at the "Alphavirus Workshop" organized and hosted by the Joint Vaccine Acquisition Program (JVAP) on 15 December 2014 at Fort Detrick, Maryland, USA.

Managing potential laboratory exposure to ebola virus by using a patient biocontainment care unit.

In 2004, a scientist from the US Army Medical Research Institute of Infectious Diseases (USAMRIID) was potentially exposed to a mouse-adapted variant of the Zaire species of Ebola virus. The circumstances surrounding the case are presented, in addition to an update on historical admissions to the medical containment suite at USAMRIID. Research facilities contemplating work with pathogens requiring Biosafety Level 4 laboratory precautions should be mindful of the occupational health issues highlighted in this article.

Botulinum neurotoxin vaccines: past, present, and future.

In the early 1930s, a formalin-inactivated toxoid against botulinum neurotoxin was first tested in humans. In 1965, a pentavalent botulinum toxoid (PBT) received Investigational New Drug (IND) status under the Centers for Disease Control's IND 161 (for at-risk workers), and in 1991 under the United States Army's Office of the Surgeon General IND 3723 (for military deployment). This PBT vaccine has been shown to be safe, with over 20,000 injections given to date, and continues to be used in at-risk individuals. During the past decade, recombinant DNA technology has been employed to develop second-generation vaccines to prevent botulism. Recombinant subunit vaccines utilizing the receptor-binding domains of botulinum neurotoxin (BoNT) have been shown to be safe and efficacious in protecting animal models against BoNT serotypes A, B, C1, D, E, and F. In 2004, the first recombinant subunit vaccine [rBV A/B (Pichia pastoris) vaccine] was tested in humans during a phase I clinical trial. Results from that study demonstrated that the recombinant bivalent vaccine was safe and well tolerated at all dosage levels tested and stimulated serotype-specific neutralizing antibodies among the majority of vaccine recipients.

Comparison of Aerosol- and Percutaneous-acquired Venezuelan Equine Encephalitis in Humans and Nonhuman Primates for Suitability in Predicting Clinical Efficacy under the Animal Rule.

Licensure of medical countermeasure vaccines to protect against aerosolized Venezuelan equine encephalitis virus (VEEV) requires the use of the Animal Rule to assess vaccine efficacy, because human studies are not feasible or ethical. We therefore performed a retrospective study of VEE cases that occurred in at-risk laboratory workers and support personnel during the United States Biowarfare Program (1943-1969) to better define percutaneous- and aerosol-acquired VEE in humans and to compare these results with those described for the NHP model (in which high-dose aerosol VEEV challenge led to more severe encephalitis than parenteral challenge). Record review and analysis of 17 aerosol- and 23 percutaneous-acquired human cases of VEE included incubation period, symptoms, physical examination findings, and markers of infection. Human VEE disease by both exposure routes presented as acute febrile illness, typically with fever, chills, headache, back pain, malaise, myalgia, anorexia, and nausea. Aerosol exposure more commonly led to upper respiratory tract-associated findings of sore throat (59% compared with 26%), pharyngeal erythema (76% compared with 52%), neck pain (29% compared with 4%), and cervical lymphadenopathy (29% compared with 4%). Other disease manifestations, including encephalitis, were similar between the 2 exposure groups. The increase in upper respiratory tract findings in aerosol-acquired VEE in humans has not previously been reported but is supported by the mouse model, which showed nasal mucosal necrosis, necrotizing rhinitis, and an increase in upper respiratory tract viral burden associated with aerosol VEEV challenge. Fever, viremia, and lymphopenia were common markers of VEE disease in both humans and NHP, regardless of the exposure route. Taken collectively, our findings provide support for use of the nonlethal NHP model for advanced development of medical countermeasures against aerosol- or percutaneous-acquired VEE.

History of U.S. military contributions to the study of parasitic diseases.

U.S. military researchers have made major contributions to the discovery, diagnosis, treatment, and prevention of a number of parasitic diseases. We review the paramount U.S. military contributions to the understanding of leishmaniasis, filariasis, schistosomiasis, trypanosomiasis, gastrointestinal parasites, intestinal capillariasis, and angiostrongyliasis.

TCRBV CDR3 diversity of CD4+ and CD8+ T-lymphocytes in HIV-infected individuals.

TCRBV CDR3 repertoire diversity was analyzed in a cross-sectional study of HIV-infected individuals by CDR3 fingerprinting/spectratyping and single strand conformation polymorphism (SSCP). Most TCRBV families were detected in CD4+ cells of HIV-infected patients with CD4 counts ranging from 35 to 1103. In patients with CD4 counts >500, CD4+ TCRBV CDR3 fingerprinting profiles contained subtle variations with generally gaussian-distributed sizes. Lower CD4 counts coincided with more fragmented TCRBV CDR3 repertoires, containing dominant bands and bands missing from the CDR3 profiles. The CD8+ population of the same patients exhibited skewed CDR3 profiles of the majority of TCR BV families at CD4 counts >500. Irregularity of CD8+ CDR3 size distribution was most profound at low CD4 counts and suggested domination of the CD8+ TCRBV repertoire by a limited number of clones. Skewed patterns of CDR3 diversity probably reflect (oligo)clonal expansion of particular CD4+ and CD8+ cell populations during chronic infection with HIV. In addition, irregular CDR3 profiles of CD4+ and CD8+ at low CD4 counts suggest diminished TCR repertoire diversity, which may contribute to immunodeficiency.

Experience in the medical management of potential laboratory exposures to agents of bioterrorism on the basis of risk assessment at the United States Army Medical Research Institute of Infectious Diseases (USAMRIID).

Experience in managing laboratory exposures to potential agents of bioterrorism is limited. The United States Army Medical Research Institute of Infectious Diseases reviewed laboratory exposures involving these agents (1989 to 2002) to assess the effectiveness of medical management. The evaluation of 234 persons (78% vaccinated) for exposure to 289 infectious agents revealed 5 confirmed infections (glanders, Q fever, vaccinia, chikungunya, and Venezuelan equine encephalitis). Postexposure antibiotic prophylaxis was given for most moderate- or high-risk bacterial exposures (41/46; 89%); most unvaccinated minimal-risk (7/10; 70%), and subsets of vaccinated minimal-risk exposures (18/53; 34%) but generally not negligible-risk exposures (6/38; 16%). Vaccine "breakthroughs" were not unexpected (enzootic Venezuelan equine encephalitis, localized vaccinia) or presented with mild symptoms (Q fever). A multifaceted policy of personal protective measures, vaccination, early assessment, and postexposure antibiotic prophylaxis was effective in minimizing morbidity and mortality in at-risk laboratory workers.

Management guidelines for laboratory exposures to agents of bioterrorism.

Over the past several years, funding for biodefense research has increased dramatically, leading to the possibility of increased laboratory-acquired infections with potential bioterrorism agents. The Special Immunizations Program at United States Army Medical Research Institute of Infectious Diseases reviewed its policy and management of potential occupational exposures (1989-2002) to assess guidelines for determining the risk of exposure and disease and to determine criteria for initiating postexposure prophylaxis (PEP). Initiating antibiotic PEP was based primarily on exposure risk but was also influenced by vaccination status and agent virulence. PEP was given to nearly all moderate- and high-risk bacterial exposures, regardless of vaccination status, to most unvaccinated and subsets of vaccinated minimal-risk exposures, but generally not to negligible-risk exposures. Algorithms for evaluating and managing potential exposures are presented to provide guidance to other agencies as they begin to work with these agents.

Risk of occupationally acquired illnesses from biological threat agents in unvaccinated laboratory workers.

Many vaccines for bioterrorism agents are investigational and therefore not available (outside of research protocol use) to all at-risk laboratory workers who have begun working with these agents as a result of increased interest in biodefense research. Illness surveillance data archived from the U.S. offensive biological warfare program (from 1943 to 1969) were reviewed to assess the impact of safety measures on disease prevention (including biosafety cabinets [BSCs]) before and after vaccine availability. Most laboratory-acquired infections from agents with higher infective doses (e.g., anthrax, glanders, and plague) were prevented with personal protective measures and safety training alone. Safety measures (including BSCs) without vaccination failed to sufficiently prevent illness from agents with lower infective doses in this high-risk research setting. Infections continued with tularemia (average 15/year), Venezuelan equine encephalitis (1.9/year), and Q fever (3.4/year) but decreased dramatically once vaccinations became available (average of 1, 0.6, and 0 infections per year, respectively). While laboratory-acquired infections are not expected to occur frequently in the current lower-risk biodefense research setting because of further improvements in biosafety equipment and changes in biosafety policies, the data help to define the inherent risks of working with the specific agents of bioterrorism. The data support the idea that research with these agents should be restricted to laboratories with experience in handling highly hazardous agents and where appropriate safety training and precautions can be implemented.

A Phase 1 clinical trial of Hantaan virus and Puumala virus M-segment DNA vaccines for hemorrhagic fever with renal syndrome.

Candidate DNA vaccines for hemorrhagic fever with renal syndrome expressing the envelope glycoprotein genes of Hantaan (HTNV) or Puumala (PUUV) viruses were evaluated in an open-label, single-center Phase 1 study consisting of three vaccination groups of nine volunteers. The volunteers were vaccinated by particle-mediated epidermal delivery (PMED) three times at four-week intervals with the HTNV DNA vaccine, the PUUV DNA vaccine or both vaccines. At each dosing, the volunteers received 8 µg DNA/4 mg gold. There were no study-related serious adverse events, and all injection site pain was graded as mild. The most commonly reported systemic adverse events were fatigue, headache, malaise, myalgia, and lymphadenopathy. Blood samples were collected on days 0, 28, 56, 84, 140, and 180, and assayed for the presence of neutralizing antibodies. In the single vaccine groups, neutralizing antibodies to HTNV or PUUV were detected in 30% or 44% of individuals, respectively. In the combined vaccine group, 56% of the volunteers developed neutralizing antibodies to one or both viruses. These results demonstrate that the HTNV and PUUV DNA vaccines are safe and can be immunogenic in humans when delivered by PMED.

Immunogenicity and safety of an inactivated Rift Valley fever vaccine in a 19-year study.

An investigational, formalin-inactivated Rift Valley fever (RVF) vaccine, known as The Salk Institute-Government Services Division (TSI-GSD) 200 vaccine, was administered to 1860 at-risk subjects (5954 doses) between 1986 and 2004 as a three-dose primary series (days 0, 7, and 28) followed by booster doses as needed for declining titers. An initial positive serological response (PRNT(80)≥1:40) to the primary series was observed in 90% of subjects. Estimate of the PRNT(80) response half-life in initial responders to the primary series by Kaplan-Meier plot was 315 days after the primary series dose 3. Differences in a serological response were observed at 2 weeks after dose 3 of the primary series between vaccine lots and for gender (women>men); a trend was observed for age (<40 years). When response to the primary series was measured by PRNT(50) titer ≥1:40, nearly all subjects (99.1%) responded. In individuals not initially responding to the primary series (PRNT(80)<1:40), a response was observed in most subjects after receiving only one booster dose. Immune response (all subjects) to subsequent booster doses for a declining titer (PRNT(80)<1:40) was 98.4%. The vaccine was well-tolerated; vaccine-related adverse reactions were generally mild and self-limited. Differences in adverse events were observed with vaccine lot and sex. The data support the safety and immunogenicity of the inactivated RVF vaccine, and may serve as a standard of comparison for immunogenicity and safety for future RVF vaccines.

Experience with intravenous ribavirin in the treatment of hemorrhagic fever with renal syndrome in Korea.

Results of a clinical study using intravenous (IV) ribavirin for treating Department of Defense personnel with hemorrhagic fever with renal syndrome (HFRS) acquired in Korea from 1987 to 2005 were reviewed to determine the clinical course of HFRS treated with IV ribavirin. A total of 38 individuals enrolled in the study had subsequent serological confirmation of HFRS. Four of the 38 individuals received three or fewer doses of ribavirin and were excluded from treatment analysis. Of the remaining 34 individuals, oliguria was present in one individual at treatment initiation; none of the remaining 33 subjects developed oliguria or required dialysis. The mean peak serum creatinine was 3.46 mg/dl and occurred on day 2 of ribavirin therapy. Both the peak serum creatinine and the onset of polyuria occurred on mean day 6.8 of illness. Reversible hemolytic anemia was the main adverse event of ribavirin, with a >or=25% decrease in hematocrit observed in 26/34 (76.5%) individuals. While inability to adjust for all baseline variables prevents comparison to historical cohorts in Korea where oliguria has been reported in 39-69% cases and dialysis required in approximately 40% HFRS cases caused by Hantaan virus, the occurrence of 3% oliguria and 0% dialysis requirement in the treatment cohort is supportive of a previous placebo-controlled HFRS trial in China where IV ribavirin given early resulted in decreased occurrence of oliguria and decreased severity of renal insufficiency.

Botulism: cause, effects, diagnosis, clinical and laboratory identification, and treatment modalities.

Botulism is a neuroparalytic disease caused by neurotoxins produced by the bacteria Clostridium botulinum. Botulinum neurotoxins (BoNTs) are among the most potent naturally occurring toxins and are a category A biological threat agent. The 7 toxin serotypes of BoNTs (serotypes A-G) have different toxicities, act through 3 different intracellular protein targets, and exhibit different durations of effect. Botulism may follow ingestion of food contaminated with BoNT, from toxin production of C botulinum present in the intestine or wounds, or from inhalation of aerosolized toxin. Intoxication classically presents as an acute, symmetrical, descending flaccid paralysis. Early diagnosis is important because antitoxin therapy is most effective when administered early. Confirmatory testing of botulism with BoNT assays or C botulinum cultures is time-consuming, and may be insensitive in the diagnosis of inhalational botulism and in as many as 32% of food-borne botulism cases. Therefore, the decision to initiate botulinum antitoxin therapy is primarily based on symptoms and physical examination findings that are consistent with botulism, with support of epidemiological history and electrophysiological testing. Modern clinical practice and antitoxin treatment has reduced botulism mortality rates from approximately 60% to < or =10%. The pentavalent botulinum toxoid is an investigational product and has been used for more than 45 years in at-risk laboratory workers to protect against toxin serotypes A to E. Due to declining immunogenicity and potency of the pentavalent botulinum toxoid, novel vaccine candidates are being developed.