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Protective mAbs and Cross-Reactive mAbs Raised by Immunization with Engineered Marburg Virus GPs.

Fusco ML, Hashiguchi T, Cassan R, Biggins JE, Murin CD, Warfield KL, Li S, Holtsberg FW, Shulenin S, Vu H, Olinger GG, Kim do H, Whaley KJ, Zeitlin L, Ward AB, Nykiforuk C, Aman MJ, Berry JD, Berry J, Saphire EO - PLoS Pathog. (2015)

Bottom Line: Antibodies against the filovirus surface glycoprotein (GP) have been shown to provide life-saving therapy in nonhuman primates, but such antibodies are generally virus-specific.Surprisingly, two of the mAbs raised against MARV GP also cross-react with the mucin-deleted GP cores of all tested ebolaviruses (Ebola, Sudan, Bundibugyo, Reston), but these epitopes are masked differently by the mucin-like domains themselves.The most efficacious mAbs in this panel were found to recognize a novel "wing" feature on the GP2 subunit that is unique to Marburg and does not exist in Ebola.

View Article: PubMed Central - PubMed

Affiliation: Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, California, United States of America.

ABSTRACT
The filoviruses, which include the marburg- and ebolaviruses, have caused multiple outbreaks among humans this decade. Antibodies against the filovirus surface glycoprotein (GP) have been shown to provide life-saving therapy in nonhuman primates, but such antibodies are generally virus-specific. Many monoclonal antibodies (mAbs) have been described against Ebola virus. In contrast, relatively few have been described against Marburg virus. Here we present ten mAbs elicited by immunization of mice using recombinant mucin-deleted GPs from different Marburg virus (MARV) strains. Surprisingly, two of the mAbs raised against MARV GP also cross-react with the mucin-deleted GP cores of all tested ebolaviruses (Ebola, Sudan, Bundibugyo, Reston), but these epitopes are masked differently by the mucin-like domains themselves. The most efficacious mAbs in this panel were found to recognize a novel "wing" feature on the GP2 subunit that is unique to Marburg and does not exist in Ebola. Two of these anti-wing antibodies confer 90 and 100% protection, respectively, one hour post-exposure in mice challenged with MARV.

No MeSH data available.


Related in: MedlinePlus

In vivo survival data.Groups of BALB/c mice at 10 animals per group were injected with individual mAbs one hour after challenge with mouse-adapted MARV Ravn virus. Two separate studies are represented; treatment groups are broken up into 3 or 4 mAbs to simplify survival and health score graphs. Studies continued for 28 days total, however no additional changes were observed beyond day 14. Asterisks represent P value summaries with non-significant curves labeled ns. (A) Study #1. PBS control survival is 10%. (B) Study #2. PBS control survival is 0%.
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ppat.1005016.g004: In vivo survival data.Groups of BALB/c mice at 10 animals per group were injected with individual mAbs one hour after challenge with mouse-adapted MARV Ravn virus. Two separate studies are represented; treatment groups are broken up into 3 or 4 mAbs to simplify survival and health score graphs. Studies continued for 28 days total, however no additional changes were observed beyond day 14. Asterisks represent P value summaries with non-significant curves labeled ns. (A) Study #1. PBS control survival is 10%. (B) Study #2. PBS control survival is 0%.

Mentions: All mAbs were evaluated for in vivo protection using BALB/c mice challenged with a lethal dose of MARV virus [45]. One hour after challenge with 1,000 pfu mouse-adapted MARV Ravn, mice were treated IP with 500 μg purified mAb. Two separate studies were performed, with half of the mAbs repeated in both studies. Control animals in study #1, treated with PBS, exhibited 1/10 survival (Fig 4A). Both control groups in study #2, treated with PBS or anti-HA mAb, exhibited 0/10 survival (Fig 4B). MARV mAb treatment groups varied widely in efficacy, ranging from 0–100% protection. All four mAbs against the GP2 wing were found to be moderately or highly protective: mAb 30G3 conferred 70% survival (14/20), mAb 30G4 60% survival (6/10), mAb 30G5 100% survival (20/20), and mAb 54G2 90% survival (18/20). Monoclonal antibody 9A11, against GP1, conferred 65% survival (13/20) (Fig 4A and 4B). Other mAbs against the GP1 core exhibited 0–40% survival; of these, only 40G1 offered strongly significant protection (P value 0.0029). The only mAb against a GP2 epitope other than the wing, mAb 54G1, exhibited zero protection (0/10) (Fig 4A). In both studies, mice in all treatment groups displayed an elevation of disease score by Day 4 (Fig 4A and 4B), and there were no significant differences in weight loss between treatment groups and control groups. In study #1, 30G5-treated mice faired only modestly better than the other groups, reaching a disease score maximum of 2 and fully recovering by Day 9 (Fig 4A).


Protective mAbs and Cross-Reactive mAbs Raised by Immunization with Engineered Marburg Virus GPs.

Fusco ML, Hashiguchi T, Cassan R, Biggins JE, Murin CD, Warfield KL, Li S, Holtsberg FW, Shulenin S, Vu H, Olinger GG, Kim do H, Whaley KJ, Zeitlin L, Ward AB, Nykiforuk C, Aman MJ, Berry JD, Berry J, Saphire EO - PLoS Pathog. (2015)

In vivo survival data.Groups of BALB/c mice at 10 animals per group were injected with individual mAbs one hour after challenge with mouse-adapted MARV Ravn virus. Two separate studies are represented; treatment groups are broken up into 3 or 4 mAbs to simplify survival and health score graphs. Studies continued for 28 days total, however no additional changes were observed beyond day 14. Asterisks represent P value summaries with non-significant curves labeled ns. (A) Study #1. PBS control survival is 10%. (B) Study #2. PBS control survival is 0%.
© Copyright Policy
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4482612&req=5

ppat.1005016.g004: In vivo survival data.Groups of BALB/c mice at 10 animals per group were injected with individual mAbs one hour after challenge with mouse-adapted MARV Ravn virus. Two separate studies are represented; treatment groups are broken up into 3 or 4 mAbs to simplify survival and health score graphs. Studies continued for 28 days total, however no additional changes were observed beyond day 14. Asterisks represent P value summaries with non-significant curves labeled ns. (A) Study #1. PBS control survival is 10%. (B) Study #2. PBS control survival is 0%.
Mentions: All mAbs were evaluated for in vivo protection using BALB/c mice challenged with a lethal dose of MARV virus [45]. One hour after challenge with 1,000 pfu mouse-adapted MARV Ravn, mice were treated IP with 500 μg purified mAb. Two separate studies were performed, with half of the mAbs repeated in both studies. Control animals in study #1, treated with PBS, exhibited 1/10 survival (Fig 4A). Both control groups in study #2, treated with PBS or anti-HA mAb, exhibited 0/10 survival (Fig 4B). MARV mAb treatment groups varied widely in efficacy, ranging from 0–100% protection. All four mAbs against the GP2 wing were found to be moderately or highly protective: mAb 30G3 conferred 70% survival (14/20), mAb 30G4 60% survival (6/10), mAb 30G5 100% survival (20/20), and mAb 54G2 90% survival (18/20). Monoclonal antibody 9A11, against GP1, conferred 65% survival (13/20) (Fig 4A and 4B). Other mAbs against the GP1 core exhibited 0–40% survival; of these, only 40G1 offered strongly significant protection (P value 0.0029). The only mAb against a GP2 epitope other than the wing, mAb 54G1, exhibited zero protection (0/10) (Fig 4A). In both studies, mice in all treatment groups displayed an elevation of disease score by Day 4 (Fig 4A and 4B), and there were no significant differences in weight loss between treatment groups and control groups. In study #1, 30G5-treated mice faired only modestly better than the other groups, reaching a disease score maximum of 2 and fully recovering by Day 9 (Fig 4A).

Bottom Line: Antibodies against the filovirus surface glycoprotein (GP) have been shown to provide life-saving therapy in nonhuman primates, but such antibodies are generally virus-specific.Surprisingly, two of the mAbs raised against MARV GP also cross-react with the mucin-deleted GP cores of all tested ebolaviruses (Ebola, Sudan, Bundibugyo, Reston), but these epitopes are masked differently by the mucin-like domains themselves.The most efficacious mAbs in this panel were found to recognize a novel "wing" feature on the GP2 subunit that is unique to Marburg and does not exist in Ebola.

View Article: PubMed Central - PubMed

Affiliation: Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, California, United States of America.

ABSTRACT
The filoviruses, which include the marburg- and ebolaviruses, have caused multiple outbreaks among humans this decade. Antibodies against the filovirus surface glycoprotein (GP) have been shown to provide life-saving therapy in nonhuman primates, but such antibodies are generally virus-specific. Many monoclonal antibodies (mAbs) have been described against Ebola virus. In contrast, relatively few have been described against Marburg virus. Here we present ten mAbs elicited by immunization of mice using recombinant mucin-deleted GPs from different Marburg virus (MARV) strains. Surprisingly, two of the mAbs raised against MARV GP also cross-react with the mucin-deleted GP cores of all tested ebolaviruses (Ebola, Sudan, Bundibugyo, Reston), but these epitopes are masked differently by the mucin-like domains themselves. The most efficacious mAbs in this panel were found to recognize a novel "wing" feature on the GP2 subunit that is unique to Marburg and does not exist in Ebola. Two of these anti-wing antibodies confer 90 and 100% protection, respectively, one hour post-exposure in mice challenged with MARV.

No MeSH data available.


Related in: MedlinePlus