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

Abstract

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.

Comparative Transcriptomics in Ebola Makona-Infected Ferrets, Nonhuman Primates, and Humans

“…Gross inspection at necropsy revealed hallmark features of EHF in ferrets as previously reported [ 11–13 ] (histopathology data not shown). All NHPs analyzed developed progressive disease consistent with a lethal dose of EBOV as previously described with a time to euthanasia ranging from day 6 to 9 PI ( Figure 1C ) (histopathology data not shown) [ 19–21 ].…”

“…In brief, 3 healthy female ferrets and 12 rhesus macaques ( Macaca mulatta ) were challenged with 1000 plaque-forming units (PFUs) of EBOV (Makona C07 variant) intranasally or intramuscularly, respectively. Of the 12 NHPs used for analysis, a subset of samples was not included in this work because they were part of a postexposure treatment study, beginning on day 5; thus, only sampling time points before treatment (days 0, 3, 5) and samples from untreated control animals were used in this analysis [ 19 ].…”

Enrichment post-library preparation enhances the sensitivity of high-throughput sequencing-based detection and characterization of viruses from complex samples

“…3g and h). The total nucleic acid samples were processed without a DNase step to allow for potential detection of both the DNA viral genome as Previously used in [9][10][11] well as viral transcripts. In the case of both HAdV-4 (species E) and HAdV-51 (species D, not targeted specifically by probes), the vast majority of the resulting sequencing reads were virus-specific and the reads were well-distributed along the length of the genome in coding regions, and in the case of the total nucleic acid samples, noncoding regions as well (Fig.…”

“…A composite panel of 80-mer DNA probes was assembled using a previously described panel for respiratory viruses [13,14,20], a previously described panel for Filoviruses [9][10][11], plus an additional panel of newly designed probes for 41 viruses of biosurveillance and biodefense concern, for a total of 19,077 probes. The methods employed for capture oligo design were…”

“…Ebola virus (EBOV) is one specific example of a pathogen for which false-negative PCR results can have devastating consequences and for which available PCR-based assay effectiveness has been shown to be affected by drift [8]. Therefore, a panel of 80-mer oligonucleotide probes designed against eight Filovirus genomes was recently used for post-sequencing library enrichment in a HTSbased study of a recent EBOV outbreak in West Africa and in an investigation of potential genetic variation of EBOV in experimentally infected nonhuman primates [9][10][11]. In this protocol, viral enrichment is coupled with the RNA Access kit, developed by Illumina, Inc.…”