Complexity of neutralizing antibodies against multiple dengue virus serotypes after heterotypic immunization and secondary infection revealed by in-depth analysis of cross-reactive antibodies

Wen Yang Tsai, Anna P Durbin, Jih Jin Tsai, Szu Chia Hsieh, Stephen Whitehead, Wei Kung Wang

Research output: Contribution to journalArticle

Abstract

The four serotypes of dengue virus (DENV) cause the most important and rapidly emerging arboviral diseases in humans. The recent phase 2b and 3 studies of a tetravalent dengue vaccine reported a moderate efficacy despite the presence of neutralizing antibodies, highlighting the need for a better understanding of neutralizing antibodies in polyclonal human sera. Certain type-specific (TS) antibodies were recently discovered to account for the monotypic neutralizing activity and protection after primary DENV infection. The nature of neutralizing antibodies after secondary DENV infection remains largely unknown. In this study, we examined sera from 10 vaccinees with well-documented exposure to first and second DENV serotypes through heterotypic immunization with live-attenuated vaccines. Higher serum IgG avidities to both exposed and nonexposed serotypes were found after secondary immunization than after primary immunization. Using a two-step depletion protocol to remove different anti-envelope antibodies, including group-reactive (GR) and complex-reactive (CR) antibodies separately, we found GR and CR antibodies together contributed to more than 50% of neutralizing activities against multiple serotypes after secondary immunization. Similar findings were demonstrated in patients after secondary infection. Anti-envelope antibodies recognizing previously exposed serotypes consisted of a large proportion of GR antibodies, CR antibodies, and a small proportion of TS antibodies, whereas those recognizing nonexposed serotypes consisted ofGRand CR antibodies. These findings have implications for sequential heterotypic immunization or primary immunization of DENV-primed individuals as alternative strategies for DENV vaccination. The complexity of neutralizing antibodies after secondary infection provides new insights into the difficulty of their application as surrogates of protection.

Original languageEnglish (US)
Pages (from-to)7348-7362
Number of pages15
JournalJournal of Virology
Volume89
Issue number14
DOIs
StatePublished - 2015

Fingerprint

Dengue virus
Dengue Virus
Neutralizing Antibodies
Coinfection
neutralizing antibodies
Immunization
immunization
serotypes
antibodies
Antibodies
Secondary Immunization
Virus Diseases
Anti-Idiotypic Antibodies
live vaccines
Dengue Vaccines
Serum
neutralization
Attenuated Vaccines
Serogroup
secondary infection

ASJC Scopus subject areas

  • Immunology
  • Virology

Cite this

Complexity of neutralizing antibodies against multiple dengue virus serotypes after heterotypic immunization and secondary infection revealed by in-depth analysis of cross-reactive antibodies. / Tsai, Wen Yang; Durbin, Anna P; Tsai, Jih Jin; Hsieh, Szu Chia; Whitehead, Stephen; Wang, Wei Kung.

In: Journal of Virology, Vol. 89, No. 14, 2015, p. 7348-7362.

Research output: Contribution to journalArticle

@article{89a6d78541014dcd9f246f884ce5c2ac,
title = "Complexity of neutralizing antibodies against multiple dengue virus serotypes after heterotypic immunization and secondary infection revealed by in-depth analysis of cross-reactive antibodies",
abstract = "The four serotypes of dengue virus (DENV) cause the most important and rapidly emerging arboviral diseases in humans. The recent phase 2b and 3 studies of a tetravalent dengue vaccine reported a moderate efficacy despite the presence of neutralizing antibodies, highlighting the need for a better understanding of neutralizing antibodies in polyclonal human sera. Certain type-specific (TS) antibodies were recently discovered to account for the monotypic neutralizing activity and protection after primary DENV infection. The nature of neutralizing antibodies after secondary DENV infection remains largely unknown. In this study, we examined sera from 10 vaccinees with well-documented exposure to first and second DENV serotypes through heterotypic immunization with live-attenuated vaccines. Higher serum IgG avidities to both exposed and nonexposed serotypes were found after secondary immunization than after primary immunization. Using a two-step depletion protocol to remove different anti-envelope antibodies, including group-reactive (GR) and complex-reactive (CR) antibodies separately, we found GR and CR antibodies together contributed to more than 50{\%} of neutralizing activities against multiple serotypes after secondary immunization. Similar findings were demonstrated in patients after secondary infection. Anti-envelope antibodies recognizing previously exposed serotypes consisted of a large proportion of GR antibodies, CR antibodies, and a small proportion of TS antibodies, whereas those recognizing nonexposed serotypes consisted ofGRand CR antibodies. These findings have implications for sequential heterotypic immunization or primary immunization of DENV-primed individuals as alternative strategies for DENV vaccination. The complexity of neutralizing antibodies after secondary infection provides new insights into the difficulty of their application as surrogates of protection.",
author = "Tsai, {Wen Yang} and Durbin, {Anna P} and Tsai, {Jih Jin} and Hsieh, {Szu Chia} and Stephen Whitehead and Wang, {Wei Kung}",
year = "2015",
doi = "10.1128/JVI.00273-15",
language = "English (US)",
volume = "89",
pages = "7348--7362",
journal = "Journal of Virology",
issn = "0022-538X",
publisher = "American Society for Microbiology",
number = "14",

}

TY - JOUR

T1 - Complexity of neutralizing antibodies against multiple dengue virus serotypes after heterotypic immunization and secondary infection revealed by in-depth analysis of cross-reactive antibodies

AU - Tsai, Wen Yang

AU - Durbin, Anna P

AU - Tsai, Jih Jin

AU - Hsieh, Szu Chia

AU - Whitehead, Stephen

AU - Wang, Wei Kung

PY - 2015

Y1 - 2015

N2 - The four serotypes of dengue virus (DENV) cause the most important and rapidly emerging arboviral diseases in humans. The recent phase 2b and 3 studies of a tetravalent dengue vaccine reported a moderate efficacy despite the presence of neutralizing antibodies, highlighting the need for a better understanding of neutralizing antibodies in polyclonal human sera. Certain type-specific (TS) antibodies were recently discovered to account for the monotypic neutralizing activity and protection after primary DENV infection. The nature of neutralizing antibodies after secondary DENV infection remains largely unknown. In this study, we examined sera from 10 vaccinees with well-documented exposure to first and second DENV serotypes through heterotypic immunization with live-attenuated vaccines. Higher serum IgG avidities to both exposed and nonexposed serotypes were found after secondary immunization than after primary immunization. Using a two-step depletion protocol to remove different anti-envelope antibodies, including group-reactive (GR) and complex-reactive (CR) antibodies separately, we found GR and CR antibodies together contributed to more than 50% of neutralizing activities against multiple serotypes after secondary immunization. Similar findings were demonstrated in patients after secondary infection. Anti-envelope antibodies recognizing previously exposed serotypes consisted of a large proportion of GR antibodies, CR antibodies, and a small proportion of TS antibodies, whereas those recognizing nonexposed serotypes consisted ofGRand CR antibodies. These findings have implications for sequential heterotypic immunization or primary immunization of DENV-primed individuals as alternative strategies for DENV vaccination. The complexity of neutralizing antibodies after secondary infection provides new insights into the difficulty of their application as surrogates of protection.

AB - The four serotypes of dengue virus (DENV) cause the most important and rapidly emerging arboviral diseases in humans. The recent phase 2b and 3 studies of a tetravalent dengue vaccine reported a moderate efficacy despite the presence of neutralizing antibodies, highlighting the need for a better understanding of neutralizing antibodies in polyclonal human sera. Certain type-specific (TS) antibodies were recently discovered to account for the monotypic neutralizing activity and protection after primary DENV infection. The nature of neutralizing antibodies after secondary DENV infection remains largely unknown. In this study, we examined sera from 10 vaccinees with well-documented exposure to first and second DENV serotypes through heterotypic immunization with live-attenuated vaccines. Higher serum IgG avidities to both exposed and nonexposed serotypes were found after secondary immunization than after primary immunization. Using a two-step depletion protocol to remove different anti-envelope antibodies, including group-reactive (GR) and complex-reactive (CR) antibodies separately, we found GR and CR antibodies together contributed to more than 50% of neutralizing activities against multiple serotypes after secondary immunization. Similar findings were demonstrated in patients after secondary infection. Anti-envelope antibodies recognizing previously exposed serotypes consisted of a large proportion of GR antibodies, CR antibodies, and a small proportion of TS antibodies, whereas those recognizing nonexposed serotypes consisted ofGRand CR antibodies. These findings have implications for sequential heterotypic immunization or primary immunization of DENV-primed individuals as alternative strategies for DENV vaccination. The complexity of neutralizing antibodies after secondary infection provides new insights into the difficulty of their application as surrogates of protection.

UR - http://www.scopus.com/inward/record.url?scp=84931081889&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84931081889&partnerID=8YFLogxK

U2 - 10.1128/JVI.00273-15

DO - 10.1128/JVI.00273-15

M3 - Article

C2 - 25972550

AN - SCOPUS:84931081889

VL - 89

SP - 7348

EP - 7362

JO - Journal of Virology

JF - Journal of Virology

SN - 0022-538X

IS - 14

ER -