Summary The 2013-2015 West African epidemic of Ebola virus disease (EVD) reminds us how little is known about biosafety level-4 viruses. Like Ebola virus, Lassa virus (LASV) can cause hemorrhagic fever with high case fatality rates. We generated a genomic catalog of almost 200 LASV sequences from clinical and rodent reservoir samples. We show that whereas the 2013-2015 EVD epidemic is fueled by human-to-human transmissions, LASV infections mainly result from reservoir-to-human infections. We elucidated the spread of LASV across West Africa and show that this migration was accompanied by changes in LASV genome abundance, fatality rates, codon adaptation, and translational efficiency. By investigating intrahost evolution, we found that mutations accumulate in epitopes of viral surface proteins, suggesting selection for immune escape. This catalog will serve as a foundation for the development of vaccines and diagnostics.

The arenavirus Lassa causes severe hemorrhagic fever and a significant disease burden in West Africa every year. The glycoprotein, GPC, is the sole antigen expressed on the viral surface and the critical target for antibody-mediated neutralization. Here we present the crystal structure of the trimeric, prefusion ectodomain of Lassa GP bound to a neutralizing antibody from a human survivor at 3.2-angstrom resolution. The antibody extensively anchors two monomers together at the base of the trimer, and biochemical analysis suggests that it neutralizes by inhibiting conformational changes required for entry. This work illuminates pH-driven conformational changes in both receptor-binding and fusion subunits of Lassa virus, illustrates the unique assembly of the arenavirus glycoprotein spike, and provides a much-needed template for vaccine design against these threats to global health.

Lassa fever is a severe multisystem disease that often has haemorrhagic manifestations. The epitopes of the Lassa virus (LASV) surface glycoproteins recognized by naturally infected human hosts have not been identified or characterized. Here we have cloned 113 human monoclonal antibodies (mAbs) specific for LASV glycoproteins from memory B cells of Lassa fever survivors from West Africa. One-half bind the GP2 fusion subunit, one-fourth recognize the GP1 receptor-binding subunit and the remaining fourth are specific for the assembled glycoprotein complex, requiring both GP1 and GP2 subunits for recognition. Notably, of the 16 mAbs that neutralize LASV, 13 require the assembled glycoprotein complex for binding, while the remaining 3 require GP1 only. Compared with non-neutralizing mAbs, neutralizing mAbs have higher binding affinities and greater divergence from germline progenitors. Some mAbs potently neutralize all four LASV lineages. These insights from LASV human mAb characterization will guide strategies for immunotherapeutic development and vaccine design.

Ebola virus (EBOV) remains one of the most lethal transmissible infections and is responsible for high fatality rates and substantial morbidity during sporadic outbreaks. With increasing human incursions into endemic regions and the reported possibility of airborne transmission, EBOV is a high-priority public health threat for which no preventive or therapeutic options are currently available. Recent studies have demonstrated that cocktails of monoclonal antibodies are effective at preventing morbidity and mortality in nonhuman primates (NHPs) when administered as a post-exposure prophylactic within 1 or 2 days of challenge. To test whether one of these cocktails (MB-003) demonstrates efficacy as a therapeutic (after the onset of symptoms), we challenged NHPs with EBOV and initiated treatment upon confirmation of infection according to a diagnostic protocol for U.S. Food and Drug Administration Emergency Use Authorization and observation of a documented fever. Of the treated animals, 43% survived challenge, whereas both the controls and all historical controls with the same challenge stock succumbed to infection. These results represent successful therapy of EBOV infection in NHPs. INTRODUCTIONSince its discovery and initial characterization in the mid-1970s, Ebola virus (EBOV; formerly known as Zaire ebolavirus; genus: Ebolavirus, family: Filoviridae) has remained one of the most virulent and deadly pathogens known. With mortality rates approaching 90%, the virus quickly overwhelms the host, inducing a severe hemorrhagic fever and often death during sporadic outbreaks (1, 2). There are currently no licensed vaccines or therapeutics to prevent or treat infection with EBOV or any filovirus. With the increasing ease and speed of global travel and the potential for viral spread via the aerosol route (3), EBOV is a potential public health threat (4). Classification by the Centers for Disease Control as a category A agent also designates EBOV as a bioterrorism threat, making this virus a biodefense research priority (5).Research has identified phosphorodiamidate morpholino oligomers (PMOs), small interfering RNAs (siRNAs), and a vesicular stomatitis virus (VSV)-based vaccine as potential candidates for post-exposure treatment (6-8). These candidates have shown promising efficacy in reducing mortality when administered to nonhuman primates (NHPs) up to 1 hour after exposure. More recently, antibodies were demonstrated to be highly effective in post-exposure prophylaxis of NHPs against EBOV. Passive transfer of macaque hyperimmune globulin was shown to protect rhesus macaques when dosing began 2 days after exposure (9). Similarly, a cocktail of three murine monoclonal antibodies (mAbs) provided 100 and 50% efficacy in cynomolgus macaques when dosing began 1 or 2 days after exposure, respectively (10). Finally, a cocktail of three mAbs with human constant regions (MB-003) manufactured in Nicotiana benthamiana (11) provided 100 or 67% protection in the rhesus macaque model when treatment began 1 hour or 2 days after expo...

There are no approved treatments for Lassa fever, which is endemic to the same regions of West Africa that were recently devastated by Ebola. Here we show that a combination of human monoclonal antibodies that cross-react with the glycoproteins of all four clades of Lassa virus is able to rescue 100% of cynomolgus macaques when treatment is initiated at advanced stages of disease, including up to 8 d after challenge.