Dengue Virus Evades AAV-Mediated Neutralizing Antibody Prophylaxis in Rhesus Monkeys

Diogo M. Magnani, Michael J. Ricciardi, Varian K. Bailey, Martin J. Gutman, Núria Pedreño-Lopez, Cassia G.T. Silveira, Helen S. Maxwell, Aline Domingues, Lucas Gonzalez-Nieto, Qin Su, Ruchi M. Newman, Melissa Pack, Mauricio Martins, José M. Martinez-Navio, Sebastian P. Fuchs, Eva G. Rakasz, Todd M. Allen, Stephen S. Whitehead, Dennis R. Burton, Guangping Gao & 3 others Ronald Charles Desrosiers, Esper G. Kallas, David Watkins

Research output: Contribution to journalArticle

2 Citations (Scopus)

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 languageEnglish (US)
Pages (from-to)2323-2331
Number of pages9
JournalMolecular Therapy
Volume25
Issue number10
DOIs
StatePublished - Oct 4 2017

Fingerprint

Dengue Virus
Neutralizing Antibodies
Macaca mulatta
Dependovirus
Antibody-Dependent Enhancement
Viruses
Mutation
Immunoglobulins
Immunoglobulin Constant Regions
Vaccines
Infection
Flavivirus
Antibodies
Viremia
Culicidae
Viral Load
Serum
Transgenes
Vaccination
Immunoglobulin G

Keywords

  • AAV
  • dengue virus
  • gene delivery
  • monoclonal antibody
  • neutralizing antibody

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Genetics
  • Pharmacology
  • Drug Discovery

Cite this

Magnani, D. M., Ricciardi, M. J., Bailey, V. K., Gutman, M. J., Pedreño-Lopez, N., Silveira, C. G. T., ... Watkins, D. (2017). Dengue Virus Evades AAV-Mediated Neutralizing Antibody Prophylaxis in Rhesus Monkeys. Molecular Therapy, 25(10), 2323-2331. https://doi.org/10.1016/j.ymthe.2017.06.020

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 journalArticle

Magnani, DM, Ricciardi, MJ, Bailey, VK, Gutman, MJ, Pedreño-Lopez, N, Silveira, CGT, Maxwell, HS, Domingues, A, Gonzalez-Nieto, L, Su, Q, Newman, RM, Pack, M, Martins, M, Martinez-Navio, JM, Fuchs, SP, Rakasz, EG, Allen, TM, Whitehead, SS, Burton, DR, Gao, G, Desrosiers, RC, Kallas, EG & Watkins, D 2017, 'Dengue Virus Evades AAV-Mediated Neutralizing Antibody Prophylaxis in Rhesus Monkeys', Molecular Therapy, vol. 25, no. 10, pp. 2323-2331. https://doi.org/10.1016/j.ymthe.2017.06.020
Magnani DM, Ricciardi MJ, Bailey VK, Gutman MJ, Pedreño-Lopez N, Silveira CGT et al. Dengue Virus Evades AAV-Mediated Neutralizing Antibody Prophylaxis in Rhesus Monkeys. Molecular Therapy. 2017 Oct 4;25(10):2323-2331. https://doi.org/10.1016/j.ymthe.2017.06.020
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. / Dengue Virus Evades AAV-Mediated Neutralizing Antibody Prophylaxis in Rhesus Monkeys. In: Molecular Therapy. 2017 ; Vol. 25, No. 10. pp. 2323-2331.
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