TY - JOUR
T1 - A humanized monoclonal antibody neutralizes yellow fever virus strain 17D-204 inA vitro but does not protect a mouse model from disease
AU - Calvert, Amanda E.
AU - Dixon, Kandice L.
AU - Piper, Joseph
AU - Bennett, Susan L.
AU - Thibodeaux, Brett A.
AU - Barrett, Alan D.T.
AU - Roehrig, John T.
AU - Blair, Carol D.
N1 - Funding Information:
This work was funded by NIH/NIAID grant U54AI-065357 to the Rocky Mountain Regional Center of Excellence in Biodefense and Emerging Infectious Disease Research. We thank Brad Biggerstaff, Rebecca Clark, and Barb Andre for help with statistical analyses.
Publisher Copyright:
© 2016 Elsevier B.V. All rights reserved.
PY - 2016/7
Y1 - 2016/7
N2 - The yellow fever virus (YFV) vaccine 17D-204 is considered safe and effective, yet rare severe adverse events (SAEs), some resulting in death, have been documented following vaccination. Individuals exhibiting post-vaccinal SAEs are ideal candidates for antiviral monoclonal antibody (MAb) therapy; the time until appearance of clinical signs post-exposure is usually short and patients are quickly hospitalized. We previously developed a murine-human chimeric monoclonal antibody (cMAb), 2C9-cIgG, reactive with both virulent YFV and 17D-204, and demonstrated its ability to prevent and treat YF disease in both AG129 mouse and hamster models of infection. To counteract possible selection of 17D-204 variants that escape neutralization by treatment with a single MAb (2C9-cIgG), we developed a second cMAb, 864-cIgG, for use in combination with 2C9-cIgG in post-vaccinal therapy. MAb 864-cIgG recognizes/neutralizes only YFV 17D-204 vaccine substrain and binds to domain III (DIII) of the viral envelope protein, which is different from the YFV type-specific binding site of 2C9-cIgG in DII. Although it neutralized 17D-204 inA vitro, administration of 864-cIgG had no protective capacity in the interferon receptor-deficient AG129 mouse model of 17D-204 infection. The data presented here show that although DIII-specific 864-cIgG neutralizes virus infectivity inA vitro, it does not have the ability to abrogate disease inA vivo. Therefore, combination of 864-cIgG with 2C9-cIgG for treatment of YF vaccination SAEs does not appear to provide an improvement on 2C9-cIgG therapy alone.
AB - The yellow fever virus (YFV) vaccine 17D-204 is considered safe and effective, yet rare severe adverse events (SAEs), some resulting in death, have been documented following vaccination. Individuals exhibiting post-vaccinal SAEs are ideal candidates for antiviral monoclonal antibody (MAb) therapy; the time until appearance of clinical signs post-exposure is usually short and patients are quickly hospitalized. We previously developed a murine-human chimeric monoclonal antibody (cMAb), 2C9-cIgG, reactive with both virulent YFV and 17D-204, and demonstrated its ability to prevent and treat YF disease in both AG129 mouse and hamster models of infection. To counteract possible selection of 17D-204 variants that escape neutralization by treatment with a single MAb (2C9-cIgG), we developed a second cMAb, 864-cIgG, for use in combination with 2C9-cIgG in post-vaccinal therapy. MAb 864-cIgG recognizes/neutralizes only YFV 17D-204 vaccine substrain and binds to domain III (DIII) of the viral envelope protein, which is different from the YFV type-specific binding site of 2C9-cIgG in DII. Although it neutralized 17D-204 inA vitro, administration of 864-cIgG had no protective capacity in the interferon receptor-deficient AG129 mouse model of 17D-204 infection. The data presented here show that although DIII-specific 864-cIgG neutralizes virus infectivity inA vitro, it does not have the ability to abrogate disease inA vivo. Therefore, combination of 864-cIgG with 2C9-cIgG for treatment of YF vaccination SAEs does not appear to provide an improvement on 2C9-cIgG therapy alone.
KW - Monoclonal antibody therapy
KW - Neutralizing antibody
KW - Post-vaccinal SAE
KW - YFV vaccine
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U2 - 10.1016/j.antiviral.2016.04.013
DO - 10.1016/j.antiviral.2016.04.013
M3 - Article
C2 - 27126613
AN - SCOPUS:84966350057
VL - 131
SP - 92
EP - 99
JO - Antiviral Research
JF - Antiviral Research
SN - 0166-3542
ER -