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      Fully Human Immunoglobulin G From Transchromosomic Bovines Treats Nonhuman Primates Infected With Ebola Virus Makona Isolate

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          Transchromosomic bovines (Tc-bovines) adaptively produce fully human polyclonal immunoglobulin (Ig)G antibodies after exposure to immunogenic antigen(s). The National Interagency Confederation for Biological Research and collaborators rapidly produced and then evaluated anti-Ebola virus IgG immunoglobulins (collectively termed SAB-139) purified from Tc-bovine plasma after sequential hyperimmunization with an Ebola virus Makona isolate glycoprotein nanoparticle vaccine. SAB-139 was characterized by several in vitro production, research, and clinical level assays using wild-type Makona-C05 or recombinant virus/antigens from different Ebola virus variants. SAB-139 potently activates natural killer cells, monocytes, and peripheral blood mononuclear cells and has high-binding avidity demonstrated by surface plasmon resonance. SAB-139 has similar concentrations of galactose-α-1,3-galactose carbohydrates compared with human-derived intravenous Ig, and the IgG1 subclass antibody is predominant. All rhesus macaques infected with Ebola virus/H.sapiens-tc/GIN/2014/Makona-C05 and treated with sufficient SAB-139 at 1 day (n = 6) or 3 days (n = 6) postinfection survived versus 0% of controls. This study demonstrates that Tc-bovines can produce pathogen-specific human Ig to prevent and/or treat patients when an emerging infectious disease either threatens to or becomes an epidemic.

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          Reversion of advanced Ebola virus disease in nonhuman primates with ZMapp™

          Without an approved vaccine or treatment, Ebola outbreak management has been limited to palliative care and barrier methods to prevent transmission. These approaches, however, have yet to end the 2014 outbreak of Ebola after its prolonged presence in West Africa. Here we show that a combination of monoclonal antibodies (ZMapp™), optimized from two previous antibody cocktails, is able to rescue 100% of rhesus macaques when treatment is initiated up to 5 days post-challenge. High fever, viremia, and abnormalities in blood count and chemistry were evident in many animals before ZMapp™ intervention. Advanced disease, as indicated by elevated liver enzymes, mucosal hemorrhages and generalized petechia could be reversed, leading to full recovery. ELISA and neutralizing antibody assays indicate that ZMapp™ is cross-reactive with the Guinean variant of Ebola. ZMapp™ currently exceeds all previous descriptions of efficacy with other therapeutics, and results warrant further development of this cocktail for clinical use.
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            The Effectiveness of Convalescent Plasma and Hyperimmune Immunoglobulin for the Treatment of Severe Acute Respiratory Infections of Viral Etiology: A Systematic Review and Exploratory Meta-analysis

            Background.  Administration of convalescent plasma, serum, or hyperimmune immunoglobulin may be of clinical benefit for treatment of severe acute respiratory infections (SARIs) of viral etiology. We conducted a systematic review and exploratory meta-analysis to assess the overall evidence. Methods.  Healthcare databases and sources of grey literature were searched in July 2013. All records were screened against the protocol eligibility criteria, using a 3-stage process. Data extraction and risk of bias assessments were undertaken. Results.  We identified 32 studies of SARS coronavirus infection and severe influenza. Narrative analyses revealed consistent evidence for a reduction in mortality, especially when convalescent plasma is administered early after symptom onset. Exploratory post hoc meta-analysis showed a statistically significant reduction in the pooled odds of mortality following treatment, compared with placebo or no therapy (odds ratio, 0.25; 95% confidence interval, .14–.45; I2 = 0%). Studies were commonly of low or very low quality, lacked control groups, and at moderate or high risk of bias. Sources of clinical and methodological heterogeneity were identified. Conclusions.  Convalescent plasma may reduce mortality and appears safe. This therapy should be studied within the context of a well-designed clinical trial or other formal evaluation, including for treatment of Middle East respiratory syndrome coronavirus CoV infection.
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              Meta-analysis: convalescent blood products for Spanish influenza pneumonia: a future H5N1 treatment?

              Studies from the Spanish influenza era reported that transfusion of influenza-convalescent human blood products reduced mortality in patients with influenza complicated by pneumonia. Treatments for H5N1 influenza are unsatisfactory, and convalescent human plasma containing H5N1 antibodies could be an effective therapy during outbreaks and pandemics. To determine whether transfusion with influenza-convalescent human blood products reduced the risk for death in patients with Spanish influenza pneumonia. Manual search of English-language journals from 1918 to 1925. Citations from retrieved studies were also searched. Published English-language studies that had at least 10 patients in the treatment group, used convalescent blood products to treat Spanish influenza pneumonia in a hospital setting, and reported on a control or comparison group. Two investigators independently extracted data on study characteristics, outcomes, adverse events, and quality. Eight relevant studies involving 1703 patients were found. Treated patients, who were often selected because of more severe illness, were compared with untreated controls with influenza pneumonia in the same hospital or ward. The overall crude case-fatality rate was 16% (54 of 336) among treated patients and 37% (452 of 1219) among controls. The range of absolute risk differences in mortality between the treatment and control groups was 8% to 26% (pooled risk difference, 21% [95% CI, 15% to 27%]). The overall crude case-fatality rate was 19% (28 of 148) among patients who received early treatment (after or =4 days of pneumonia complications). The range of absolute risk differences in mortality between the early treatment group and the late treatment group was 26% to 50% (pooled risk difference, 41% [CI, 29% to 54%]). Adverse effects included chill reactions and possible exacerbations of symptoms in a few patients. Studies were few and had many methodologic limitations. No study was a blinded, randomized, or placebo-controlled trial. Some pertinent studies may have been missed. Patients with Spanish influenza pneumonia who received influenza-convalescent human blood products may have experienced a clinically important reduction in the risk for death. Convalescent human H5N1 plasma could be an effective, timely, and widely available treatment that should be studied in clinical trials.

                Author and article information

                J Infect Dis
                J. Infect. Dis
                The Journal of Infectious Diseases
                Oxford University Press (US )
                15 December 2018
                16 July 2018
                16 July 2018
                : 218
                : Suppl 5 , Marburg and Ebola Viruses: Marking 50 Years Since Discovery
                : S636-S648
                [1 ]Viral and Rickettsial Diseases Department, Naval Medical Research Center, The Henry Jackson Foundation for the Advancement of Military Medicine, Silver Spring, Maryland
                [2 ]Integrated Research Facility at Fort Detrick, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Frederick, Maryland
                [3 ]Novavax, Inc., Gaithersburg, Maryland
                [4 ]Virology Division, United States Army Medical Research Institute of Infectious Diseases, Fort Detrick, Maryland
                [5 ]Biological Defense Research Directorate, Naval Medical Research Center, Ft. Detrick, Maryland
                [6 ]SAB Biotherapeutics Inc., Sioux Falls, South Dakota
                [7 ]Emerging Viral Pathogens Section, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Frederick, Maryland
                [8 ]Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology, and Harvard, Boston
                [9 ]Division of Viral Products, Center for Biologics Evaluation and Research, US Food and Drug Administration, Silver Spring, Maryland
                Author notes

                Present Affiliation: DSI, Minneapolis, Minnesota.

                Present Affiliation: MRIGlobal-Global Health Surveillance and Diagnostics, Gaithersburg, Maryland.

                Correspondence: E. Sullivan, PhD, 2301 E. 60th St N., Sioux Falls, SD 57104 ( esullivan@ ).
                © The Author(s) 2018. Published by Oxford University Press for the Infectious Diseases Society of America.

                This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs licence (, which permits non-commercial reproduction and distribution of the work, in any medium, provided the original work is not altered or transformed in any way, and that the work is properly cited. For commercial re-use, please contact

                Page count
                Pages: 13
                Funded by: Division of Intramural Research, National Institute of Allergy and Infectious Diseases 10.13039/100006492
                Funded by: Division of Clinical Research
                Funded by: Integrated Research Facility and Battelle Memorial Institute’s prime contract with NIAID
                Award ID: HHSN272200700016I
                Funded by: Naval Medical Research Center 10.13039/100007680
                Funded by: Viral and Rickettsial Diseases Department and Biologic Defense Research Directorate
                Award ID: N62645-14-C-4034
                Funded by: The Henry Jackson Foundation for the Advancement of Military Medicine
                Funded by: US Navy
                Award ID: Omnibus III DO-0005
                Funded by: SAB Biotherapeutics Inc
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