Redundancy and plasticity of neutralizing antibody responses are cornerstone attributes of the human immune response to the smallpox vaccine

被引:89
作者
Benhnia, Mohammed Rafii-El-Idrissi [1 ]
McCausland, Megan M. [1 ]
Su, Hua-Poo [2 ]
Singh, Kavita [2 ]
Hoffmann, Julia [3 ]
Davies, D. Huw [4 ]
Felgner, Philip L. [4 ]
Head, Steven [3 ]
Sette, Alessandro [1 ]
Garboczi, David N. [2 ]
Crotty, Shane [1 ]
机构
[1] La Jolla Inst Allergy & Immunol, Div Vaccine Discovery, La Jolla, CA 92037 USA
[2] NIAID, Immunogenet Lab, Struct Biol Sect, Rockville, MD 20852 USA
[3] Scripps Res Inst, DNA Array Core Facil & Consortium Funct Glycom, La Jolla, CA 92037 USA
[4] Univ Calif Irvine, Dept Med, Div Infect Dis, Irvine, CA 92697 USA
关键词
D O I
10.1128/JVI.02244-07
中图分类号
Q93 [微生物学];
学科分类号
071005 ; 100705 ;
摘要
The smallpox vaccine is widely considered the gold standard for human vaccines, yet the key antibody targets in humans remain unclear. We endeavored to identify a stereotypic, dominant, mature virion (MV) neutralizing antibody target in humans which could be used as a diagnostic serological marker of protective Immoral immunity induced by the smallpox vaccine (vaccinia virus [VACV]). We have instead found that diversity is a defining characteristic of the human antibody response to the smallpox vaccine. We show that H3 is the most immunodominant VACV neutralizing antibody target, as determined by correlation analysis of immunoglobulin G (IgG) specificities to MV neutralizing antibody titers. It was determined that purified human anti-H3 IgG is sufficient for neutralization of VACV; however, depletion or blockade of anti-H3 antibodies revealed no significant reduction in neutralization activity, showing anti-H3 IgG is not required in vaccinated humans (or mice) for neutralization of MV. Comparable results were obtained for human (and mouse) anti-L1 IgG and even for anti-H3 and anti-L1 IgG in combination. In addition to H3 and L1, human antibody responses to D8, A27, D13, and A14 exhibited statistically significant correlations with virus neutralization. Altogether, these data indicate the smallpox vaccine succeeds in generating strong neutralizing antibody responses not by eliciting a stereotypic response to a single key antigen but instead by driving development of neutralizing antibodies to multiple viral proteins, resulting in a "safety net" of highly redundant neutralizing antibody responses, the specificities of which can vary from individual to individual. We propose that this is a fundamental attribute of the smallpox vaccine.
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收藏
页码:3751 / 3768
页数:18
相关论文
共 61 条
[1]   Physical and immunological characterization of a recombinant secreted form of the membrane protein encoded by the vaccinia virus L1R gene [J].
Aldaz-Carroll, L ;
Whitbeck, JC ;
de Leon, MP ;
Lou, H ;
Pannell, LK ;
Lebowitz, J ;
Fogg, C ;
White, CL ;
Moss, B ;
Cohen, GH ;
Eisenberg, RJ .
VIROLOGY, 2005, 341 (01) :59-71
[2]   Epitope-mapping studies define two major neutralization sites on the vaccinia virus extracellular enveloped virus glycoprotein B5R [J].
Aldaz-Carroll, L ;
Whitbeck, JC ;
de Leon, MP ;
Lou, H ;
Hirao, L ;
Isaacs, SN ;
Moss, B ;
Eisenberg, RJ ;
Cohen, GH .
JOURNAL OF VIROLOGY, 2005, 79 (10) :6260-6271
[3]  
ALIBEK K, 1998, NY TIMES 0327, pA19
[4]  
Alibek K., 1999, BIOHAZARD
[5]   Immunity and immunological memory following smallpox vaccination [J].
Amanna, Ian J. ;
Slifka, Mark K. ;
Crotty, Shane .
IMMUNOLOGICAL REVIEWS, 2006, 211 :320-337
[6]   Shared modes of protection against poxvirus infection by attenuated and conventional smallpox vaccine viruses [J].
Belyakov, IM ;
Earl, P ;
Dzutsev, A ;
Kuznetsov, VA ;
Lemon, M ;
Wyatt, LS ;
Snyder, JT ;
Ahlers, JD ;
Franchini, G ;
Moss, B ;
Berzofsky, JA .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2003, 100 (16) :9458-9463
[7]  
Chertov OYu, 1991, Biomed Sci, V2, P151
[8]   Vaccinia virus 4c (A26L) protein on intracellular mature virus binds to the extracellular cellular matrix laminin [J].
Chiu, Wen-Ling ;
Lin, Chi-Long ;
Yang, Min-Hsiang ;
Tzou, Der-Lii M. ;
Chang, Wen .
JOURNAL OF VIROLOGY, 2007, 81 (05) :2149-2157
[9]   Vaccinia virus proteome: Identification of proteins in vaccinia virus intracellular mature virion particles [J].
Chung, CS ;
Chen, CH ;
Ho, MY ;
Huang, CY ;
Liao, CL ;
Chang, W .
JOURNAL OF VIROLOGY, 2006, 80 (05) :2127-2140
[10]   In a nutshell: Structure and assembly of the vaccinia virion [J].
Condit, Richard C. ;
Moussatche, Nissin ;
Traktman, Paula .
ADVANCES IN VIRUS RESEARCH, VOL 66, 2006, 66 :31-+