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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 vitro neutralization activity.Neutralization potency of mAbs against VSV pseudotyped with MARV Ravn GP (VSVΔG Ravn GP) in Vero cells. VSVΔG MARV Ravn GP was incubated with 50μg/ml of the indicated mAb for 1 hour before infection, and entry efficiency was calculated based on GFP expression. Positive control is human survivor mAb MR78.
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ppat.1005016.g003: In vitro neutralization activity.Neutralization potency of mAbs against VSV pseudotyped with MARV Ravn GP (VSVΔG Ravn GP) in Vero cells. VSVΔG MARV Ravn GP was incubated with 50μg/ml of the indicated mAb for 1 hour before infection, and entry efficiency was calculated based on GFP expression. Positive control is human survivor mAb MR78.

Mentions: Antibodies were screened for in vitro neutralization using a VSV-pseudovirus containing MARV Ravn GP on the surface. Six of the ten mAbs exhibit partial neutralization at the highest concentration tested (50ug/ml), reducing entry by 35–55%. The remaining four mAbs do not neutralize (Fig 3). Notably, all five GP2-directed mAbs produced in this study exhibit some neutralization, while only one GP1-directed mAb, 9A11, inhibits entry of Ravn GP pseudovirions. Polyclonal sera from mice that yielded the 30 series mAbs (30G3, 30G4 and 30G5) reduces entry by only about 60%, suggesting that mAbs 30G3, 30G4, and 30G5 represent the maximum potency of the polyclonal population (Fig 3). Human survivor mAb MR78 was used as a positive control and reduces pseudovirion entry by almost 95%.


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 vitro neutralization activity.Neutralization potency of mAbs against VSV pseudotyped with MARV Ravn GP (VSVΔG Ravn GP) in Vero cells. VSVΔG MARV Ravn GP was incubated with 50μg/ml of the indicated mAb for 1 hour before infection, and entry efficiency was calculated based on GFP expression. Positive control is human survivor mAb MR78.
© Copyright Policy
Related In: Results  -  Collection

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

ppat.1005016.g003: In vitro neutralization activity.Neutralization potency of mAbs against VSV pseudotyped with MARV Ravn GP (VSVΔG Ravn GP) in Vero cells. VSVΔG MARV Ravn GP was incubated with 50μg/ml of the indicated mAb for 1 hour before infection, and entry efficiency was calculated based on GFP expression. Positive control is human survivor mAb MR78.
Mentions: Antibodies were screened for in vitro neutralization using a VSV-pseudovirus containing MARV Ravn GP on the surface. Six of the ten mAbs exhibit partial neutralization at the highest concentration tested (50ug/ml), reducing entry by 35–55%. The remaining four mAbs do not neutralize (Fig 3). Notably, all five GP2-directed mAbs produced in this study exhibit some neutralization, while only one GP1-directed mAb, 9A11, inhibits entry of Ravn GP pseudovirions. Polyclonal sera from mice that yielded the 30 series mAbs (30G3, 30G4 and 30G5) reduces entry by only about 60%, suggesting that mAbs 30G3, 30G4, and 30G5 represent the maximum potency of the polyclonal population (Fig 3). Human survivor mAb MR78 was used as a positive control and reduces pseudovirion entry by almost 95%.

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