Effect of i.p. favipiravir treatment on day 14 viral loads in JUNV-challenged guinea pigs.

<p>Animals were infected and treated as described in <a href="http://www.plosntds.org/article/info:doi/10.1371/journal.pntd.0002614#pntd-0002614-g003" target="_blank">Figure 3</a>. Three pre-designated animals in each treatment group were sacrificed on day 14 post-infection for analysis of A) serum, B) brain, C) heart, D) kidney, E) liver, F) lung and G) spleen virus titers. Two serum samples and 1 liver sample collected from 2 moribund animals from the placebo group euthanized on days 12 and 14 were also included in the analysis. Unique symbols in each treatment group represent values for the same animal across all parameters and hashed lines indicate the assay limits of detection in tissue samples. **<i>P</i><0.01, ***<i>P</i><0.001 compared to placebo.</p

Survival outcome following oral treatment of JUNV-infected guinea pigs with favipiravir.

<p>Guinea pigs (n = 10/group) were challenged i.p. with 1300 PFU of JUNV. They were dosed by instillation of favipiravir, ribavirin, or carrot baby food vehicle (placebo) into the back of the oral cavity. Treatments (Tx) with the indicated concentrations of drugs were initiated 24 h post-infection (p.i.) and administered twice daily for 14 days (capped hashed line). A) survival, B) mean body weight (relative to initial starting weight), and C) temperature were monitored for 40 days. ***<i>P</i><0.001 compared to placebo-treated animals by the log-rank test.</p

Survival outcome following i.p. treatment of JUNV-infected guinea pigs with favipiravir.

<p>Guinea pigs (n = 12/experimental group) were challenged i.p. with 750 PFU of JUNV and dosed i.p. with favipiravir (300 mg/kg/d), ribavirin (50 mg/kg/d), or 2.9% sodium bicarbonate vehicle (placebo) beginning 48 h post-infection (p.i.). Treatments (Tx) were administered twice daily for 14 days (capped hashed line). A) survival (n = 9/group), and B) mean body weight (relative to initial starting weight) and C) temperature were monitored in all surviving animals for 42 days. **<i>P</i><0.01, ***<i>P</i><0.001 compared to placebo-treated animals by the log-rank test.</p

PK analysis of favipiravir in male Hartley guinea pigs dosed by oral instillation or intraperitoneal (i.p.) injection.

<p>Favipiravir (100 mg/kg) was administered orally in carrot baby food vehicle or by i.p. injection in 2.9% sodium bicarbonate. Longitudinal plasma favipiravir levels are shown from 3 animals per treatment group at 15 and 30 minutes, and 1, 2, and 4 h after treatment. Data points represent the mean and standard error of the mean.</p

Immunogenicity of heterologous (Ad26-Ad35) tetravalent and homologous (Ad26) trivalent vaccine regimens and protection from MARV Angola challenge.

<p>(A-D) Cynomolgus macaques were immunized with heterologous Ad26 prime at week 0 and Ad35 boost at week 4 with a tetravalent vaccine, or a monovalent Ad26 MARV GP vaccine, or empty Ad vectors, at the doses indicated. (E-H) Cynomolgus macaques were immunized with homologous trivalent Ad26 prime at week 0 and Ad26 boost at week 4, or a monovalent Ad5 MARV GP vaccine (prime only at week 4), or empty Ad vectors, at the doses indicated. A challenge with 1000 pfu MARV Angola was given at week 8. (A+E) Kaplan-Meier representation of survival. (B+F) Clinical scoring of individual animals after lethal challenge. (C+G) Humoral immune response over time measured by MARV GP-specific ELISA. Horizontal dotted line represents the lower limit of detection. Solid lines indicate the group mean. (D+H) Cellular immune response to MARV GP peptide pool by IFNγ ELISpot. Vertical dotted lines indicate the time of boost immunization. Solid lines indicate the group mean.</p

Comparison of EBOV GP-specific cellular and antibody responses 1 week prior to EBOV challenge in challenge survivors and non-survivors.

<p>Summary of data from lethal challenge experiments with EBOV Kikwit shown in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0192312#pone.0192312.g004" target="_blank">Fig 4</a> and <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0192312#pone.0192312.g005" target="_blank">Fig 5</a>. Animals receiving vectors with EBOV GP in mono- or multivalent regimens are shown. Dots: 100 pfu challenge, squares: 1000 pfu challenge; blue: 0–4 week regimen, red: 0–8 week regimen. (A) Cellular immune response to EBOV GP peptides measured by IFNγ ELISpot. (B) Humoral immune response measured by EBOV GP-specific ELISA. p-values were calculated with the exact Wilcoxon rank sum test, and adjusted for multiplicity for each of the 2 pairs of tests (ELISpot and ELISA) using the Bonferroni adjustment.</p

Immunogenicity of heterologous (Ad26-Ad35) and homologous (Ad26-Ad26) trivalent vaccine regimen and protection from SUDV Gulu challenge.

<p>Cynomolgus macaques were immunized with heterologous (Ad26-Ad35) or homologous (Ad26-Ad26) prime at week 0 and boost at week 4 with a trivalent vaccine, or a monovalent Ad5 SUDV GP vaccine (prime only at week 4), or Ad empty vectors at the doses indicated. A challenge with 1000 pfu SUDV Gulu was given at week 8. (A) Kaplan-Meier representation of survival. (B) Clinical scoring of individual animals after lethal challenge. (C) Humoral immune response over time measured by SUDV GP-specific ELISA. Solid lines indicate the group mean. (D) Cellular immune response to SUDV GP peptide pool measured by IFNγ ELISpot. Vertical dotted lines indicate the time of boost immunization. Solid lines indicate the group mean.</p

Immunogenicity of tetravalent, trivalent, and monovalent vaccines and protection from EBOV Kikwit challenge.

<p>(A-D) Cynomolgus macaques were immunized with heterologous Ad26-prime at week 0 and Ad35 boost at week 4 with a trivalent vaccine, or a monovalent vaccine (Ad.ZEBOV), or empty Ad vectors, at the doses indicated. A challenge with 100 pfu EBOV Kikwit was given at week 8. (E-H) Cynomolgus macaques were immunized with a heterologous (Ad26-Ad35) or homologous (Ad26-Ad26) prime at week 0 and boost at week 4 with a trivalent vaccine, or tetravalent vaccine, or empty Ad vectors, or a bivalent Ad5 EBOV GP + SUDV GP vaccine (prime only at week 4), at the doses indicated. A lethal challenge with 1000 pfu EBOV Kikwit was given at week 8. (A+E) Kaplan-Meier representation of survival. (B+F) Clinical scoring of individual animals after lethal challenge. Clinical score criteria for euthanasia was 15 in (B) and 9 in (F). (C+G) Humoral immune response over time measured by EBOV GP-specific ELISA. Horizontal dotted line represents the lower limit of detection. Solid lines indicate the group mean (D+H) Cellular immune response to EBOV GP peptide pool by IFNγ ELISpot. Vertical dotted lines indicate the time of boost immunization. Solid lines indicate the group mean.</p

Immunogenicity of heterologous (Ad26-Ad35, Ad26-MVA-BN-Filo or MVA-BN-Filo-Ad26) trivalent, and Ad26-Ad35 monovalent vaccines and protection from EBOV Kikwit challenge.

<p>Heterologous (Ad26-Ad35, Ad26-MVA or MVA-Ad26) prime at week 0 and boost at week 8 with a trivalent vaccine, or empty Ad26-Ad35 vectors, at the doses indicated. One group received a heterologous Ad26-Ad35 prime at week 4 and boost at week 8 of monovalent vaccine (Ad.ZEBOV). A challenge with 100 pfu EBOV Kikwit was given at week 12. (A) Kaplan-Meier representation of survival. (B) Clinical scoring of individual animals after lethal challenge. (C) Cellular immune response to EBOV GP peptide pool by IFNγ ELISpot. (D) Humoral immune response over time measured by EBOV GP-specific ELISA. Horizontal dotted line represents the lower limit of detection. (E) Neutralizing antibody response over time measured by pseudovirion neutralization assay. (C-E) Solid lines indicate the group mean. (F) Correlation of pre-boost (black symbols) and post-boost (blue symbols) ELISA titers with virus neutralization antibody titers. Vertical dotted lines indicate the time of boost immunization.</p