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Study of cross-reactive human antibodies against dengue virus envelope protein : implication for dengue vaccine

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Item Summary

Title: Study of cross-reactive human antibodies against dengue virus envelope protein : implication for dengue vaccine
Authors: Tsai, Wen-Yang
Keywords: infections
Issue Date: Aug 2014
Publisher: [Honolulu] : [University of Hawaii at Manoa], [August 2014]
Abstract: With an estimated 390 million infections and approximately 90 million apparent infections annually, the four serotypes of dengue virus (DENV) continue to be a global threat with no licensed vaccine available. A better understanding of correlates between protection and humoral immune responses is needed. First, we characterized cross-reactive human anti-E mAbs derived from patients after primary and secondary DENV infections. Group-reactive (GR) anti-E mAbs that recognized four DENV serotypes and another flavivirus, West Nile virus (WNV), were found as the predominant cross-reactive anti-E mAbs. The epitopes of 32 GR mAbs were found at residues in the fusion loop (FL) of E protein domain II and residues involving both FL and bc loop as a new epitope. The neutralizing potency and binding avidity of GR mAbs derived from secondary infection were stronger than those derived from primary infection.
Second, we investigated cross-reactive anti-E Abs in human polyclonal sera after secondary DENV infection. Stronger Ab responses to E protein, higher binding avidity and multitypic neutralizing pattern to both exposed and non-exposed serotypes were found in sera after secondary DENV infection, compared with those after primary infection. Depletion with WNV antigen resulted in a significant reduction of neutralizing activities against four DENV serotypes, suggesting that GR Abs contribute greatly to neutralizing activities after secondary infection.
Third, we investigated whether E protein ectodomain alone can preserve the conformation of E protein. We found that C-terminal α-helices domains of E protein were involved in prM-E interaction and maintenance of the stability of prM protein. E protein affected the recognition of prM protein by anti-prM mAbs; moreover, E protein ectodomain alone can be recognized well by all anti-E mAbs tested.
Taken together, our study of GR anti-E Abs at both monoclonal and polyclonal levels suggest the weakly neutralizing GR anti-E Abs generated from primary DENV infection become potent neutralizing against four serotypes after secondary infection. The observations that the dengue immune status of host affects the quality of cross-reactive Abs generated have implications for new strategies of DENV vaccines. Moreover, E protein ectodomain alone could be a promising subunit immunogen without inducing potentially harmful anti-prM response.
Description: Ph.D. University of Hawaii at Manoa 2014.
Includes bibliographical references.
Rights: All UHM dissertations and theses are protected by copyright. They may be viewed from this source for any purpose, but reproduction or distribution in any format is prohibited without written permission from the copyright owner.
Appears in Collections:Ph.D. - Biomedical Sciences (Tropical Medicine)

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