Pan-ebolavirus and Pan-filovirus Mouse Monoclonal Antibodies: Protection against Ebola and Sudan Viruses.

UNLABELLED: The unprecedented 2014-2015 Ebola virus disease (EVD) outbreak in West Africa has highlighted the need for effective therapeutics against filoviruses. Monoclonal antibody (MAb) cocktails have shown great potential as EVD therapeutics; however, the existing protective MAbs are virus species specific. Here we report the development of pan-ebolavirus and pan-filovirus antibodies generated by repeated immunization of mice with filovirus glycoproteins engineered to drive the B cell responses toward conserved epitopes. Multiple pan-ebolavirus antibodies were identified that react to the Ebola, Sudan, Bundibugyo, and Reston viruses. A pan-filovirus antibody that was reactive to the receptor binding regions of all filovirus glycoproteins was also identified. Significant postexposure efficacy of several MAbs, including a novel antibody cocktail, was demonstrated. For the first time, we report cross-neutralization and in vivo protection against two highly divergent filovirus species, i.e., Ebola virus and Sudan virus, with a single antibody. Competition studies indicate that this antibody targets a previously unrecognized conserved neutralizing epitope that involves the glycan cap. Mechanistic studies indicated that, besides neutralization, innate immune cell effector functions may play a role in the antiviral activity of the antibodies. Our findings further suggest critical novel epitopes that can be utilized to design effective cocktails for broad protection against multiple filovirus species. IMPORTANCE: Filoviruses represent a major public health threat in Africa and an emerging global concern. Largely driven by the U.S. biodefense funding programs and reinforced by the 2014 outbreaks, current immunotherapeutics are primarily focused on a single filovirus species called Ebola virus (EBOV) (formerly Zaire Ebola virus). However, other filoviruses including Sudan, Bundibugyo, and Marburg viruses have caused human outbreaks with mortality rates as high as 90%. Thus, cross-protective immunotherapeutics are urgently needed. Here, we describe monoclonal antibodies with cross-reactivity to several filoviruses, including the first report of a cross-neutralizing antibody that exhibits protection against Ebola virus and Sudan virus in mice. Our results further describe a novel combination of antibodies with enhanced protective efficacy. These results form a basis for further development of effective immunotherapeutics against filoviruses for human use. Understanding the cross-protective epitopes are also important for rational design of pan-ebolavirus and pan-filovirus vaccines.

Comparison of neural correlates of risk decision making between genders: an exploratory fNIRS study of the Balloon Analogue Risk Task (BART).

Functional magnetic resonance imaging (fMRI) research rarely reports gender differences in the neural correlates of risk decision making due to small sample sizes. In this functional near-infrared spectroscopy (fNIRS)-based imaging study of active and passive risk decision making, gender differences in oxygenated hemoglobin (HbO) concentration changes were investigated in the prefrontal cortex (PFC) of healthy adults. Forty adult participants (25-44 years; males=23) completed two sets of 15 balloon trials in active and passive decision making modes of the Balloon Analogue Risk Task (BART). In active mode, participants chose the number of balloon inflations, decided when to collect money, or risked accrued money if balloons exploded. BART is psychometrically well established and has predictive validity to real-world risk taking. The blocked experimental design and modification of BART for fNIRS were guided by a previous fMRI study that examined the neural correlates of risk decision making in young adults [Rao, H., Korczykowski, M., Pluta, J., Hoang, A., Detre, J.A., 2008. Neural correlates of voluntary and involuntary risk taking in the human brain: An fMRI study of the Balloon Analog Risk Task (BART). NeuroImage 42, 902-910]. Our findings were consistent with the previous fMRI study: no or little PFC activation during passive mode but strong PFC activation during active wins and losses among total sample. Active losses in females were associated with more significant bilateral activation in dorsal lateral prefrontal cortex (DLPFC) than males; no significant gender differences were found in DLPFC activation during active wins. Gender differences existed in direction and strength of correlations between BART behavioral and hemodynamic data. This study shows that use of fNIRS is a feasible, accessible, and less costly way to achieve adequate study power and investigate gender differences in neural correlates of risk decision making.