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.

Respiratory syncytial virus (RSV) can cause devastating lower respiratory tract infections in preterm infants or when other serious health problems are present. Immunoprophylaxis with palivizumab (Synagis), a humanized IgG1 mAb, is the current standard of care for preventing RSV infection in at-risk neonates. We have explored the contribution of effector function to palivizumab efficacy using a plant-based expression system to produce palivizumab N-glycan structure variants with high homogeneity on different antibody isotypes. We compared these isotype and N-glycoform variants with commercially available palivizumab with respect to both in vitro receptor and C1q binding and in vivo efficacy. Whereas the affinity for antigen and neutralization activity of each variant were indistinguishable from those of palivizumab, their Fcγ receptor binding profiles were very different, which was reflected in either a reduced or enhanced ability to influence the RSV lung titer in challenged cotton rats. Enhanced Fcγ receptor binding was associated with reduced viral lung titers compared with palivizumab, whereas abrogation of receptor binding led to a drastic reduction in efficacy. The results support the hypotheses that classic antibody neutralization is a minor component of efficacy by palivizumab in the cotton rat and that antibody-dependent cell-mediated cytotoxicity activity can significantly enhance the efficacy of this antiviral mAb.

Middle East Respiratory Syndrome Coronavirus (MERS-CoV) was identified in 2012 as the causative agent of a severe, lethal respiratory disease occurring across several countries in the Middle East. To date there have been over 1,600 laboratory confirmed cases of MERS-CoV in 26 countries with a case fatality rate of 36%. Given the endemic region, it is possible that MERS-CoV could spread during the annual Hajj pilgrimage, necessitating countermeasure development. In this report, we describe the clinical and radiographic changes of rhesus monkeys following infection with 5×106 PFU MERS-CoV Jordan-n3/2012. Two groups of NHPs were treated with either a human anti-MERS monoclonal antibody 3B11-N or E410-N, an anti-HIV antibody. MERS-CoV Jordan-n3/2012 infection resulted in quantifiable changes by computed tomography, but limited other clinical signs of disease. 3B11-N treated subjects developed significantly reduced lung pathology when compared to infected, untreated subjects, indicating that this antibody may be a suitable MERS-CoV treatment.

As observed during the 2013–2016 Ebola virus disease epidemic, containment of filovirus outbreaks is challenging and made more difficult by the lack of approved vaccine or therapeutic options. Marburg and Ravn viruses are highly virulent and cause severe and frequently lethal disease in humans. Monoclonal antibodies (mAbs) are a platform technology in wide use for autoimmune and oncology indications. Previously, we described human mAbs that can protect mice from lethal challenge with Marburg virus. We demonstrate that one of these mAbs, MR191-N, can confer a survival benefit of up to 100% to Marburg or Ravn virus–infected rhesus macaques when treatment is initiated up to 5 days post-inoculation. These findings extend the small but growing body of evidence that mAbs can impart therapeutic benefit during advanced stages of disease with highly virulent viruses and could be useful in epidemic settings.

e Recent incidents in the United States and abroad have heightened concerns about the use of ricin toxin as a bioterrorism agent. In this study, we produced, using a robust plant-based platform, four chimeric toxin-neutralizing monoclonal antibodies that were then evaluated for the ability to passively protect mice from a lethal-dose ricin challenge. The most effective antibody, c-PB10, was further evaluated in mice as a therapeutic following ricin exposure by injection and inhalation. Ricin toxin is a member of the medically important A-B family of plant and bacterial ribosome-inactivating proteins (RIPs) (1). In its mature form, ricin is a 65-kDa heterodimeric glycoprotein that is a natural constituent of the seeds of the castor plant (Ricinus communis). The 267-amino-acid A subunit (RTA) of ricin is an RNA N-glycosidase that depurinates a conserved adenosine residue within the so-called sarcin-ricin loop (SRL) of eukaryotic 28S rRNA, which is required for activation of the elongation factor EF-Tu (2, 3). RTA is linked via a single disulfide bond to ricin's B subunit (RTB), a 262-amino-acid lectin that is specific for glycoproteins and glycolipids terminating in galactose and Nacetylgalactosamine (Gal/GalNAc). In addition to its role in attachment, RTB also mediates the retrograde transport of ricin to the trans-Golgi network (TGN) and endoplasmic reticulum (ER), where RTA is ultimately delivered across the ER membrane and into the cytoplasm (4, 5). The extraordinary capacity of RTA to inactivate ribosomes (k cat , 1,500/min) makes ricin one of the most potent known RIPs (6, 7). For example, in rodents and nonhuman primates, the 50% lethal dose (LD 50 ) of ricin by injection is approximately 5 g/kg, while the LD 50 of ricin by inhalation is estimated to be as low as 3 g/kg (8). The respiratory mucosa is especially sensitive to ricin, as even trace amounts of toxin are known to elicit widespread necrosis in the airways and alveoli, peribronchovascular edema, mixed inflammatory cell infiltrates, and massive pulmonary alveolar flooding (9-15).The U.S. Departments of Defense (DOD) and Health and Human Services (HHS) have ongoing initiatives to develop antibody-based products capable of providing passive protection against systemic and mucosal ricin exposure (16,17). In addition to protective efficacy, issues related to platform technology, scalability, and speed of manufacturing will ultimately dictate which product(s) will be pursued for advanced development and are consistent with the unique needs for biodefense. In this regard, the Nicotiana benthamiana-based rapid antibody-manufacturing platform (RAMP) provides the potential for extremely fast and high-yield monoclonal antibody (MAb) production that has already proven to be applicable to biodefense (18-21). The technology entails mass infiltration of mature Nicotiana plants with an Agrobacterium tumefaciens suspension carrying T-DNA encoding viral replicons and results in high MAb recovery from original DNA constructs within days (22). The Nicotiana-based RAMP...