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Several Old World and New World Mammarenavirus are responsible for hemorrhagic fever in humans. These enveloped viruses have a bi-segmented ambisense RNA genome that encodes four proteins. All Mammarenavirus identified to date share a common dependency on myristoylation: the addition of the C14 myristic acid on the N-terminal G2 residue on two of their proteins. The myristoylation of the Z matrix protein is required for viral particle budding, while the myristoylation of the signal peptide to the envelope glycoproteins is important for the entry mechanism. Using Mopeia virus as a model, we characterized the interaction of the Z matrix protein with the N-Myristoyltransferases (NMT) 1 and 2, the two enzymes responsible for myristoylation in mammals. While both enzymes were capable to interact with Z, we showed that only NMT1 was important for the production of viral progeny, the endogenous expression of NMT2 being insufficient to make up for NMT1 in its absence. Using the high affinity inhibitors of NMTs, IMP1088 and DDD85646, we demonstrated a strong, dose dependent and specific inhibition at the nanomolar range for all Mammarenavirus tested, including the highly pathogenic Lassa, Machupo, Junin and Lujo viruses. Mechanistically, IMP1088 and DDD85646 blocked the interaction between Z and both NMTs, preventing myristoylation and further viral particle formation, egress and spread. Unexpectedly, we found that the matrix protein devoid of myristate, despite being fully translated, did not accumulate as the other viral proteins in infected cells but was instead degraded in a proteasome- and autophagy-independent manner. These molecules represent a new broad-spectrum class of inhibitors against Mammarenavirus .

Despite several clinical trials implemented, no antiviral drug could demonstrate efficacy against Ebola virus. In non-human primates, early initiation of polymerase inhibitors favipiravir and remdesivir improves survival, but whether they could be effective in patients is unknown. Here we analyze the impact of antiviral therapy by using a mathematical model that integrates virological and immunological data of 44 cynomolgus macaques, left untreated or treated with favipiravir. We estimate that favipiravir has a ~50% efficacy in blocking viral production, which results in reducing virus growth and cytokine storm while IFNα reduces cell susceptibility to infection. Simulating the effect of delayed initiations of treatment, our model predicts survival rates of 60% for favipiravir and 100% for remdesivir when treatment is initiated within 3 and 4 days post infection, respectively. These results improve the understanding of Ebola immuno-pathogenesis and can help optimize antiviral evaluation in future outbreaks. Optimization of antiviral therapy can be crucial in the management of Ebola virus outbreaks. Here, Madelain et al. use an integrative mathematical model to correlate the dose and the time of treatment initiation with survival rate, enhanced immune response and viral clearance.

Lassa fever is a highly lethal hemorrhagic fever endemic to West Africa. In the absence of efficient prophylactic or therapeutic countermeasures, it poses a substantial threat to public health in this region. The pathophysiological mechanisms underlying the severity of the disease are poorly known because Lassa virus (LASV), its causative agent, has to be handled in BSL-4 laboratories and access to clinical samples is difficult. The control of Lassa fever is associated with a rapid and well-balanced immune response and viral clearance. However, severe disease is characterized by uncontrolled innate immune activation and symptoms reminiscent of sepsis and a cytokine storm. In a model of cynomolgus monkeys infected with two different strains of the virus, one causing moderate disease and the other a lethal outcome, we show that the control of LASV infection is characterized by the induction of a LASV-specific T-cell response, whereas severity is associated with the expansion of suppressive myeloid cells, alterations of the stromal network of secondary lymphoid organs, and the anergy of specific T cells. These results suggest that T cells are crucial for the control of LASV and that immunomodulatory therapeutics, such as checkpoint inhibitors, could contribute to new therapeutic strategies to treat Lassa fever. They also highlight how immunosuppressive mechanisms described in sepsis and cancer patients may play a role in the pathogenicity of Lassa fever, as well as in other similar hemorrhagic fevers.

Lassa virus (LASV) is responsible for a viral hemorrhagic fever in humans and the death of 3,000 to 5,000 people every year. The immune response to LASV is poorly understood, but type I interferon (IFN-I) and T-cell responses appear to be critical for the host. We studied the response of myeloid dendritic cells (mDC) to LASV, as mDCs are involved in both IFN-I production and T-cell activation. We compared the response of primary human mDCs to LASV and Mopeia virus (MOPV), which is similar to LASV, but non-pathogenic. We showed that mDCs produced substantial amounts of IFN-I in response to both LASV and MOPV. However, only MOPV-infected mDCs were able to activate T cells. More surprisingly, coculture with T cells completely inhibited the activation of LASV-infected mDCs. These differences between LASV and MOPV were mostly due to the LASV nucleoprotein, which has major immunosuppressive properties, but the glycoprotein was also involved. Overall, these results suggest that mDCs may be important for the global response to LASV and play a role in the outcome of Lassa fever.

The pathogenesis of Lassa fever has not yet been fully deciphered, particularly as concerns the mechanisms determining whether acute infection is controlled or leads to catastrophic illness and death. Using a cynomolgus monkey model of Lassa virus (LASV) infection reproducing the different outcomes of the disease, we performed histological and transcriptomic studies to investigate the dynamics of LASV infection and the immune mechanisms associated with survival or death. Lymphoid organs are an early major reservoir for replicating virus during Lassa fever, with LASV entering through the cortical sinus of draining lymph nodes regardless of disease outcome. However, subsequent viral tropism varies considerably with disease severity, with viral dissemination limited almost entirely to lymphoid organs and immune cells during nonfatal Lassa fever. By contrast, the systemic dissemination of LASV to all organs and diverse cell types, leading to infiltrations with macrophages and neutrophils and an excessive inflammatory response, is associated with a fatal outcome. These results provide new insight into early viral dynamics and the host response to LASV infection according to disease outcome.

Lassa fever hits West African countries annually in the absence of licensed vaccine to limit the burden of this viral hemorrhagic fever. We previously developed MeV-NP, a single-shot vaccine protecting cynomolgus monkeys against divergent strains one month or more than a year before Lassa virus infection. Given the limited dissemination area during outbreaks and the risk of nosocomial transmission, a vaccine inducing rapid protection could be useful to protect exposed people during outbreaks in the absence of preventive vaccination. Here, we test whether the time to protection can be reduced after immunization by challenging measles virus pre-immune male cynomolgus monkeys sixteen or eight days after a single shot of MeV-NP. None of the immunized monkeys develop disease and they rapidly control viral replication. Animals immunized eight days before the challenge are the best controllers, producing a strong CD8 T-cell response against the viral glycoprotein. A group of animals was also vaccinated one hour after the challenge, but was not protected and succumbed to the disease as the control animals. This study demonstrates that MeV-NP can induce a rapid protective immune response against Lassa fever in the presence of MeV pre-existing immunity but can likely not be used as therapeutic vaccine. Lassa virus vaccination is impeded by the limited capacity of vaccine candidates to induce rapid protection. In this study, the authors found that a single shot of a measles-based Lassa vaccine protected nonhuman primates 16 or 8 days after vaccination.

Ebola virus has been responsible for two major epidemics over the last several years and there has been a strong effort to find potential treatments that can improve the disease outcome. Antiviral favipiravir was thus tested on non-human primates infected with Ebola virus. Half of the treated animals survived the Ebola virus challenge, whereas the infection was fully lethal for the untreated ones. Moreover, the treated animals that did not survive died later than the controls. We evaluated the hematological, virological, biochemical, and immunological parameters of the animals and performed proteomic analysis at various timepoints of the disease. The viral load strongly correlated with dysregulation of the biological functions involved in pathogenesis, notably the inflammatory response, hemostatic functions, and response to stress. Thus, the management of viral replication in Ebola virus disease is of crucial importance in preventing the immunopathogenic disorders and septic-like shock syndrome generally observed in Ebola virus-infected patients.

Lassa virus (LASV) is endemic in West Africa and induces a viral hemorrhagic fever (VHF) with up to 30% lethality among clinical cases. The mechanisms involved in control of Lassa fever or, in contrast, the ensuing catastrophic illness and death are poorly understood. We used the cynomolgus monkey model to reproduce the human disease with asymptomatic to mild or fatal disease. After initial replication at the inoculation site, LASV reached the secondary lymphoid organs. LASV did not spread further in nonfatal disease and was rapidly controlled by balanced innate and T-cell responses. Systemic viral dissemination occurred during severe disease. Massive replication, a cytokine/chemokine storm, defective T-cell responses, and multiorgan failure were observed. Clinical, biological, immunological, and transcriptomic parameters resembled those observed during septic-shock syndrome, suggesting that similar pathogenesis is induced during Lassa fever. The outcome appears to be determined early, as differentially expressed genes in PBMCs were associated with fatal and non-fatal Lassa fever outcome very early after infection. These results provide a full characterization and important insights into Lassa fever pathogenesis and could help to develop early diagnostic tools.Baillet et al. use the cynomolgus monkey model to model Lassa virus and associated Lassa fever (LF). They provide a full characterisation of LF pathogenesis with the aim of assisting the development of early diagnostic tools.

Lassa virus (LASV) causes a viral haemorrhagic fever in humans and is a major public health concern in West Africa. An efficient immune response to LASV appears to rely on type I interferon (IFN-I) production and T-cell activation. We evaluated the response of plasmacytoid dendritic cells (pDC) to LASV, as they are an important and early source of IFN-I. We compared the response of primary human pDCs to LASV and Mopeia virus (MOPV), which is very closely related to LASV, but non-pathogenic. We showed that pDCs are not productively infected by either MOPV or LASV, but produce IFN-I. However, the activation of pDCs was more robust in response to MOPV than LASV. In vivo, pDC activation may support the control of viral replication through IFN-I production, but also improve the induction of a global immune response. Therefore, pDC activation could play a role in the control of LASV infection.

Lassa fever is a substantial health burden in west Africa. We evaluated the safety, tolerability, and immunogenicity of a recombinant, live-attenuated, measles-vectored Lassa fever vaccine candidate (MV-LASV). This first-in-human phase 1 trial—consisting of an open-label dose-escalation stage and an observer-blinded, randomised, placebo-controlled treatment stage—was conducted at a single site at the University of Antwerp, Antwerp, Belgium, and involved healthy adults aged 18–55 years. Participants in the dose-escalation stage were sequentially assigned to a low-dose group (two intramuscular doses of MV-LASV at 2 × 104 times the median tissue culture infectious dose) or a high-dose group (two doses at 1 × 105 times the median tissue culture infectious dose). Participants in the double-blinded treatment stage were randomly assigned in a 2:2:1 ratio to receive low dose, high dose, or placebo. The primary endpoint was the rate of solicited and unsolicited adverse events up to study day 56 and was assessed in all participants who received at least one dose of investigational product. The trial is registered with ClinicalTrials.gov, NCT04055454, and the European Union Drug Regulating Authorities Clinical Trials Database, 2018-003647-40, and is complete. Between Sept 26, 2019, and Jan 20, 2020, 60 participants were enrolled and assigned to receive placebo (n=12) or MV-LASV (n=48). All 60 participants received at least one study treatment. Most adverse events occurred during the treatment phase, and frequencies of total solicited or unsolicited adverse events were similar between treatment groups, with 96% of participants in the low-dose group, 100% of those in the high-dose group, and 92% of those in the placebo group having any solicited adverse event (p=0·6751) and 76% of those in the low-dose group, 70% of those in the high-dose group, and 100% of those in the placebo group having any unsolicited adverse event (p=0·1047). The only significant difference related to local solicited adverse events, with higher frequencies observed in groups receiving MV-LASV (24 [96%] of 25 participants in the low-dose group; all 23 [100%] participants in the high-dose group) than in the placebo group (6 [50%] of 12 participants; p=0·0001, Fisher-Freeman-Halton test). Adverse events were mostly of mild or moderate severity, and no serious adverse events were observed. MV-LASV also induced substantial concentrations of LASV-specific IgG (geometric mean titre 62·9 EU/ml in the low-dose group and 145·9 EU/ml in the high-dose group on day 42). MV-LASV showed an acceptable safety and tolerability profile, and immunogenicity seemed to be unaffected by pre-existing immunity against the vector. MV-LASV is therefore a promising candidate for further development. Coalition for Epidemic Preparedness Innovations.