TY - JOUR
T1 - Dengue Virus Evades AAV-Mediated Neutralizing Antibody Prophylaxis in Rhesus Monkeys
AU - Magnani, Diogo M.
AU - Ricciardi, Michael J.
AU - Bailey, Varian K.
AU - Gutman, Martin J.
AU - Pedreño-Lopez, Núria
AU - Silveira, Cassia G.T.
AU - Maxwell, Helen S.
AU - Domingues, Aline
AU - Gonzalez-Nieto, Lucas
AU - Su, Qin
AU - Newman, Ruchi M.
AU - Pack, Melissa
AU - Martins, Mauricio A.
AU - Martinez-Navio, José M.
AU - Fuchs, Sebastian P.
AU - Rakasz, Eva G.
AU - Allen, Todd M.
AU - Whitehead, Stephen S.
AU - Burton, Dennis R.
AU - Gao, Guangping
AU - Desrosiers, Ronald C.
AU - Kallas, Esper G.
AU - Watkins, David I.
N1 - Funding Information:
This work was supported by NIH grant 4P01AI094420-05 , the Wallace H. Coulter Center for Translational Research at the University of Miami , and the Miami Clinical and Translational Science Institute (CTSI). This work was in part supported by NIH grant P51OD011106 to the WNPRC at the University of Wisconsin-Madison. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. We would like to thank Kim Weisgrau, Jessica Furlott, Nicholas Pomplun, and Logan Vosler for technical support and Eric Peterson, Kristin Crosno, and Wendy Newton for providing care of the rhesus macaques used in this experiment. We also thank the veterinary and animal care staff for their contribution to this study.
Funding Information:
This work was supported by NIH grant 4P01AI094420-05, the Wallace H. Coulter Center for Translational Research at the University of Miami, and the Miami Clinical and Translational Science Institute (CTSI). This work was in part supported by NIH grant P51OD011106 to the WNPRC at the University of Wisconsin-Madison. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. We would like to thank Kim Weisgrau, Jessica Furlott, Nicholas Pomplun, and Logan Vosler for technical support and Eric Peterson, Kristin Crosno, and Wendy Newton for providing care of the rhesus macaques used in this experiment. We also thank the veterinary and animal care staff for their contribution to this study.
Publisher Copyright:
© 2017 The American Society of Gene and Cell Therapy
PY - 2017/10/4
Y1 - 2017/10/4
N2 - Development of vaccines against mosquito-borne Flaviviruses is complicated by the occurrence of antibody-dependent enhancement (ADE), which can increase disease severity. Long-term delivery of neutralizing antibodies (nAbs) has the potential to effectively block infection and represents an alternative to vaccination. The risk of ADE may be avoided by using prophylactic nAbs harboring amino acid mutations L234A and L235A (LALA) in the immunoglobulin G (IgG) constant region. Here, we used recombinant adeno-associated viruses (rAAVs) to deliver the anti-dengue virus 3 (DENV3) nAb P3D05. While the administration of rAAV-P3D05-rhesus immunoglobulin G1 (rhIgG1)-LALA to rhesus macaques engendered DENV3-neutralizing activity in serum, it did not prevent infection. The emergence of viremia following DENV3 challenge was delayed by 3–6 days in the rAAV-treated group, and replicating virus contained the envelope mutation K64R. This neutralization-resistant variant was also confirmed by virus outgrowth experiments in vitro. By delivering P3D05 with unmutated Fc sequences, we further demonstrated that DENV3 also evaded wild-type nAb prophylaxis, and serum viral loads appeared to be higher in the presence of low levels of unmutated P3D05-rhIgG1. Our study shows that a vectored approach for long-term delivery of nAbs with the LALA mutations is promising, but prophylaxis using a single nAb is likely insufficient at preventing DENV infection and replication. Vectored-delivery of virus-neutralizing antibodies could represent an alternative approach to vaccines in controlling viral replication. Magnani and colleagues show that despite sustained antibody transgene expression, dengue virus can evade single serotype-specific antibody gene-based prophylaxis by the emergence of a viral variant that is not sensitive to neutralization.
AB - Development of vaccines against mosquito-borne Flaviviruses is complicated by the occurrence of antibody-dependent enhancement (ADE), which can increase disease severity. Long-term delivery of neutralizing antibodies (nAbs) has the potential to effectively block infection and represents an alternative to vaccination. The risk of ADE may be avoided by using prophylactic nAbs harboring amino acid mutations L234A and L235A (LALA) in the immunoglobulin G (IgG) constant region. Here, we used recombinant adeno-associated viruses (rAAVs) to deliver the anti-dengue virus 3 (DENV3) nAb P3D05. While the administration of rAAV-P3D05-rhesus immunoglobulin G1 (rhIgG1)-LALA to rhesus macaques engendered DENV3-neutralizing activity in serum, it did not prevent infection. The emergence of viremia following DENV3 challenge was delayed by 3–6 days in the rAAV-treated group, and replicating virus contained the envelope mutation K64R. This neutralization-resistant variant was also confirmed by virus outgrowth experiments in vitro. By delivering P3D05 with unmutated Fc sequences, we further demonstrated that DENV3 also evaded wild-type nAb prophylaxis, and serum viral loads appeared to be higher in the presence of low levels of unmutated P3D05-rhIgG1. Our study shows that a vectored approach for long-term delivery of nAbs with the LALA mutations is promising, but prophylaxis using a single nAb is likely insufficient at preventing DENV infection and replication. Vectored-delivery of virus-neutralizing antibodies could represent an alternative approach to vaccines in controlling viral replication. Magnani and colleagues show that despite sustained antibody transgene expression, dengue virus can evade single serotype-specific antibody gene-based prophylaxis by the emergence of a viral variant that is not sensitive to neutralization.
KW - AAV
KW - dengue virus
KW - gene delivery
KW - monoclonal antibody
KW - neutralizing antibody
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UR - http://www.scopus.com/inward/citedby.url?scp=85025429297&partnerID=8YFLogxK
U2 - 10.1016/j.ymthe.2017.06.020
DO - 10.1016/j.ymthe.2017.06.020
M3 - Article
C2 - 28750738
AN - SCOPUS:85025429297
VL - 25
SP - 2323
EP - 2331
JO - Molecular Therapy
JF - Molecular Therapy
SN - 1525-0016
IS - 10
ER -