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Ebolaviruses (family Filoviridae) comprise highly pathogenic RNA viruses with zoonotic potential. After sporadic introduction from an animal reservoir into the human population, the main route of transmission has been from [...]

Background The rVSV[DELTA]G-ZEBOV-GP vaccine prevented Ebola virus disease when used at 2 x 10.sup.7 plaque-forming units (PFU) in a trial in Guinea. This study provides further safety and immunogenicity data. Methods and findings A randomised, open-label phase I trial in Lambaréné, Gabon, studied 5 single intramuscular vaccine doses of 3 x 10.sup.3, 3 x 10.sup.4, 3 x 10.sup.5, 3 x 10.sup.6, or 2 x 10.sup.7 PFU in 115 adults and a dose of 2 x 10.sup.7 PFU in 20 adolescents and 20 children. The primary objective was safety and tolerability 28 days post-injection. Immunogenicity, viraemia, and shedding post-vaccination were evaluated as secondary objectives. In adults, mild-to-moderate adverse events were frequent, but there were no serious or severe adverse events related to vaccination. Before vaccination, Zaire Ebola virus (ZEBOV)-glycoprotein (GP)-specific and ZEBOV antibodies were detected in 11% and 27% of adults, respectively. In adults, 74%-100% of individuals who received a dose 3 x 10.sup.4, 3 x 10.sup.5, 3 x 10.sup.6, or 2 x 10.sup.7 PFU had a [greater than or equal to]4.0-fold increase in geometric mean titres (GMTs) of ZEBOV-GP-specific antibodies at day 28, reaching GMTs of 489 (95% CI: 264-908), 556 (95% CI: 280-1,101), 1,245 (95% CI: 899-1,724), and 1,503 (95% CI: 931-2,426), respectively. Twenty-two percent of adults had a [greater than or equal to]4-fold increase of ZEBOV antibodies, with GMTs at day 28 of 1,015 (647-1,591), 1,887 (1,154-3,085), 1,445 (1,013-2,062), and 3,958 (2,249-6,967) for the same doses, respectively. These antibodies persisted up to day 180 for doses [greater than or equal to]3 x 10.sup.5 PFU. Adults with antibodies before vaccination had higher GMTs throughout. Neutralising antibodies were detected in more than 50% of participants at doses [greater than or equal to]3 x 10.sup.5 PFU. As in adults, no serious or severe adverse events related to vaccine occurred in adolescents or children. At day 2, vaccine RNA titres were higher for adolescents and children than adults. At day 7, 78% of adolescents and 35% of children had recombinant vesicular stomatitis virus RNA detectable in saliva. The vaccine induced high GMTs of ZEBOV-GP-specific antibodies at day 28 in adolescents, 1,428 (95% CI: 1,025-1,989), and children, 1,620 (95% CI: 806-3,259), and in both groups antibody titres increased up to day 180. The absence of a control group, lack of stratification for baseline antibody status, and imbalances in male/female ratio are the main limitations of this study. Conclusions Our data confirm the acceptable safety and immunogenicity profile of the 2 x 10.sup.7 PFU dose in adults and support consideration of lower doses for paediatric populations and those who request boosting. Trial registration Pan African Clinical Trials Registry PACTR201411000919191, Author(s): Selidji T. Agnandji 1,2,3, José F. Fernandes 1,2, Emmanuel B. Bache 1, Régis M. Obiang Mba 1, Jessica S. Brosnahan 1,2,3, Lumeka Kabwende 1, Paul Pitzinger 1,2,4, Pieter Staarink [...]

Lassa virus (LASV) is the causative agent of human Lassa fever which in severe cases manifests as hemorrhagic fever leading to thousands of deaths annually. However, no approved vaccines or antiviral drugs are currently available. Recently, we screened approximately 2,500 compounds using a recombinant vesicular stomatitis virus (VSV) expressing LASV glycoprotein GP (VSV-LASVGP) and identified a P-glycoprotein inhibitor as a potential LASV entry inhibitor. Here, we show that another identified candidate, hexestrol (HES), an estrogen receptor agonist, is also a LASV entry inhibitor. HES inhibited VSV-LASVGP replication with a 50% inhibitory concentration (IC50) of 0.63 µM. Importantly, HES also inhibited authentic LASV replication with IC50 values of 0.31 µM–0.61 µM. Time-of-addition and cell-based membrane fusion assays suggested that HES inhibits the membrane fusion step during virus entry. Alternative estrogen receptor agonists did not inhibit VSV-LASVGP replication, suggesting that the estrogen receptor itself is unlikely to be involved in the antiviral activity of HES. Generation of a HES-resistant mutant revealed that the phenylalanine at amino acid position 446 (F446) of LASVGP, which is located in the transmembrane region, conferred resistance to HES. Although mutation of F446 enhanced the membrane fusion activity of LASVGP, it exhibited reduced VSV-LASVGP replication, most likely due to the instability of the pre-fusion state of LASVGP. Collectively, our results demonstrated that HES is a promising anti-LASV drug that acts by inhibiting the membrane fusion step of LASV entry. This study also highlights the importance of the LASVGP transmembrane region as a target for anti-LASV drugs. IMPORTANCE Lassa virus (LASV), the causative agent of Lassa fever, is the most devastating mammarenavirus with respect to its impact on public health in West Africa. However, no approved antiviral drugs or vaccines are currently available. Here, we identified hexestrol (HES), an estrogen receptor agonist, as the potential antiviral candidate drug. We showed that the estrogen receptor itself is not involved in the antiviral activity. HES directly bound to LASVGP and blocked membrane fusion, thereby inhibiting LASV infection. Through the generation of a HES-resistant virus, we found that phenylalanine at position 446 (F446) within the LASVGP transmembrane region plays a crucial role in the antiviral activity of HES. The mutation at F446 caused reduced virus replication, likely due to the instability of the pre-fusion state of LASVGP. These findings highlight the potential of HES as a promising candidate for the development of antiviral compounds targeting LASV. [ABSTRACT FROM AUTHOR]

Background In October 2015, 65 people came into direct contact with a healthcare worker presenting with a late reactivation of Ebola virus disease (EVD) in the United Kingdom. Vaccination was offered to 45 individuals with an initial assessment of high exposure risk. Methods Approval for rapid expanded access to the recombinant vesicular stomatitis virus–Zaire Ebola virus (rVSV-ZEBOV) vaccine as an unlicensed emergency medicine was obtained from the relevant authorities. An observational follow-up study was carried out for 1 year following vaccination. Results Twenty-six of 45 individuals elected to receive vaccination between 10 and 11 October 2015 following written informed consent. By day 14, 39% had seroconverted, increasing to 87% by day 28 and 100% by 3 months, although these responses were not always sustained. Neutralizing antibody responses were detectable in 36% by day 14 and 73% at 12 months. Common side effects included fatigue, myalgia, headache, arthralgia, and fever. These were positively associated with glycoprotein-specific T-cell but not immunoglobulin (Ig) M or IgG antibody responses. No severe vaccine-related adverse events were reported. No one exposed to the virus became infected. Conclusions This paper reports the use of the rVSV-ZEBOV vaccine given as an emergency intervention to individuals exposed to a patient presenting with a late reactivation of EVD. The vaccine was relatively well tolerated, but a high percentage developed a fever ≥37.5°C, necessitating urgent screening for Ebola virus, and a small number developed persistent arthralgia. [ABSTRACT FROM AUTHOR]

The small matrix protein Z of arenaviruses has been identified as the main driving force to promote viral particle production at the plasma membrane. Although multiple functions of Z in the arenaviral life cycle have been uncovered, the mechanism of intracellular transport of Z to the site of virus budding is poorly understood and cellular motor proteins that mediate Z trafficking remain to be identified. In the present study, we report that the Z protein of the Old World arenavirus Lassa virus ( LASV) interacts with the kinesin family member 13 A ( KIF13 A), a plus-end-directed microtubule-dependent motor protein. Plasmid-driven overexpression of KIF13 A results in relocalization of Z to the cell periphery, while functional blockage of endogenous KIF13 A by overexpression of a dominant-negative mutant or KIF13 A-specific siRNA causes a perinuclearaccumulation and decreased production of both Z-induced virus-like particles and infectious LASV. The interaction of KIF13 A with Z proteins from both Old and New World arenaviruses suggests a conserved intracellular transport mechanism. In contrast, the intracellular distribution of the matrix proteins of prototypic members of the paramyxo- and rhabdovirus family is independent of KIF13 A. In summary, our studies identify for the first time a molecular motor protein as a critical mediator for intracellular microtubule-dependent transport of arenavirus matrix proteins. [ABSTRACT FROM AUTHOR]

Arenaviruses are a family of enveloped negative-stranded RNA viruses that can cause severe human disease ranging from encephalitis symptoms to fulminant hemorrhagic fever. The bi-segmented RNA genome encodes four polypeptides: the nucleoprotein NP, the surface glycoprotein GP, the polymerase L, and the RING finger protein Z. Although it is the smallest arenavirus protein with a length of 90 to 99 amino acids and a molecular weight of approx. 11 kDa, the Z protein has multiple functions in the viral life cycle including (i) regulation of viral RNA synthesis, (ii) orchestration of viral assembly and budding, (iii) interaction with host cell proteins, and (iv) interferon antagonism. In this review, we summarize our current understanding of the structural and functional role of the Z protein in the arenavirus replication cycle [ABSTRACT FROM AUTHOR]