Identification of human neutralizing antibodies that bind to complex epitopes on dengue virions

Ruklanthi De Alwis, Scott A. Smith, Nicholas P. Olivarez, William Messer, Jeremy P. Huynh, Wahala M P B Wahala, Laura J. White, Michael S. Diamond, Ralph S. Baric, James E. Crowe, Aravinda M. De Silva

Research output: Contribution to journalArticle

243 Citations (Scopus)

Abstract

Dengue is a mosquito-borne flavivirus that is spreading at an unprecedented rate and has developed into a major health and economic burden in over 50 countries. Even though infected individuals develop potent and long-lasting serotype-specific neutralizing antibodies (Abs), the epitopes engaged by human neutralizing Abs have not been identified. Here, we demonstrate that the dengue virus (DENV)-specific serum Ab response in humans consists of a large fraction of cross-reactive, poorly neutralizing Abs and a small fraction of serotype-specific, potently inhibitory Abs. Although many mouse-generated, strongly neutralizing monoclonal antibodies (mAbs) recognize epitopes that are present on recombinant DENV envelope (E) proteins, unexpectedly, the majority of neutralizing Abs in human immune sera bound to intact virions but not to the ectodomain of purified soluble E proteins. These conclusions with polyclonal Abs were confirmed with newly generated human mAbs derived from DENV-immune individuals. Two of three strongly neutralizing human mAbs bound to E protein epitopes that were preserved on the virion but not on recombinant E (rE) protein.We propose that humans produce Abs that neutralize DENV infection by binding a complex, quaternary structure epitope that is expressed only when E proteins are assembled on a virus particle. Mapping studies indicate that this epitope has a footprint that spans adjacent E protein dimers and includes residues at the hinge between domains I and II of E protein. These results have significant implications for the DENV Ab and vaccine field.

Original languageEnglish (US)
Pages (from-to)7439-7444
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume109
Issue number19
DOIs
StatePublished - May 8 2012
Externally publishedYes

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Forensic Anthropology
Dengue
Dengue Virus
Neutralizing Antibodies
Virion
Epitopes
Monoclonal Antibodies
Proteins
Antibodies
Dengue Vaccines
Viral Envelope Proteins
Virus Attachment
Flavivirus
Virus Diseases
Culicidae
Recombinant Proteins
Immune Sera
Economics
Health
Serum

ASJC Scopus subject areas

  • General

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Identification of human neutralizing antibodies that bind to complex epitopes on dengue virions. / De Alwis, Ruklanthi; Smith, Scott A.; Olivarez, Nicholas P.; Messer, William; Huynh, Jeremy P.; Wahala, Wahala M P B; White, Laura J.; Diamond, Michael S.; Baric, Ralph S.; Crowe, James E.; De Silva, Aravinda M.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 109, No. 19, 08.05.2012, p. 7439-7444.

Research output: Contribution to journalArticle

De Alwis, R, Smith, SA, Olivarez, NP, Messer, W, Huynh, JP, Wahala, WMPB, White, LJ, Diamond, MS, Baric, RS, Crowe, JE & De Silva, AM 2012, 'Identification of human neutralizing antibodies that bind to complex epitopes on dengue virions', Proceedings of the National Academy of Sciences of the United States of America, vol. 109, no. 19, pp. 7439-7444. https://doi.org/10.1073/pnas.1200566109
De Alwis, Ruklanthi ; Smith, Scott A. ; Olivarez, Nicholas P. ; Messer, William ; Huynh, Jeremy P. ; Wahala, Wahala M P B ; White, Laura J. ; Diamond, Michael S. ; Baric, Ralph S. ; Crowe, James E. ; De Silva, Aravinda M. / Identification of human neutralizing antibodies that bind to complex epitopes on dengue virions. In: Proceedings of the National Academy of Sciences of the United States of America. 2012 ; Vol. 109, No. 19. pp. 7439-7444.
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