Abstract
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.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 2323-2331 |
| Number of pages | 9 |
| Journal | Molecular Therapy |
| Volume | 25 |
| Issue number | 10 |
| DOIs | |
| State | Published - Oct 4 2017 |
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Keywords
- AAV
- dengue virus
- gene delivery
- monoclonal antibody
- neutralizing antibody
ASJC Scopus subject areas
- Molecular Medicine
- Molecular Biology
- Genetics
- Pharmacology
- Drug Discovery
Cite this
Dengue Virus Evades AAV-Mediated Neutralizing Antibody Prophylaxis in Rhesus Monkeys. / Magnani, Diogo M.; Ricciardi, Michael J.; Bailey, Varian K.; Gutman, Martin J.; Pedreño-Lopez, Núria; Silveira, Cassia G.T.; Maxwell, Helen S.; Domingues, Aline; Gonzalez-Nieto, Lucas; Su, Qin; Newman, Ruchi M.; Pack, Melissa; Martins, Mauricio; Martinez-Navio, José M.; Fuchs, Sebastian P.; Rakasz, Eva G.; Allen, Todd M.; Whitehead, Stephen S.; Burton, Dennis R.; Gao, Guangping; Desrosiers, Ronald Charles; Kallas, Esper G.; Watkins, David.
In: Molecular Therapy, Vol. 25, No. 10, 04.10.2017, p. 2323-2331.Research output: Contribution to journal › Article
}
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
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 Charles
AU - Kallas, Esper G.
AU - Watkins, David
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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U2 - 10.1016/j.ymthe.2017.06.020
DO - 10.1016/j.ymthe.2017.06.020
M3 - Article
VL - 25
SP - 2323
EP - 2331
JO - Molecular Therapy
JF - Molecular Therapy
SN - 1525-0016
IS - 10
ER -