Impaired Antibody-mediated Protection and Defective IgA B-Cell Memory in Experimental Infection of Adults with Respiratory Syncytial Virus

被引:233
作者
Habibi, Maximillian S. [1 ]
Jozwik, Agnieszka [1 ]
Makris, Spyridon [1 ]
Dunning, Jake [1 ]
Paras, Allan [1 ]
DeVincenzo, John P. [2 ]
de Haan, Cornelis A. M. [3 ]
Wrammert, Jens [4 ,5 ]
Openshaw, Peter J. M. [1 ]
Chiu, Christopher [1 ]
机构
[1] Univ London Imperial Coll Sci Technol & Med, Natl Heart & Lung Inst, London W2 1PG, England
[2] Univ Tennessee Hlth Sci Ctr, Dept Pediat, Memphis, TN USA
[3] Univ Utrecht, Fac Vet Med, Dept Infect Dis & Immunol, Virol Div, Utrecht, Netherlands
[4] Emory Univ Sch Med, Dept Pediat Infect Dis, Atlanta, GA USA
[5] Emory Univ Sch Med, Dept Hematol & Oncol, Atlanta, GA USA
基金
英国医学研究理事会; 英国惠康基金;
关键词
antibody-secreting cells; mucosal immunity; immunologic memory; respiratory syncytial virus vaccines; nontherapeutic human experimentation; AIRWAY EPITHELIAL-CELLS; SERUM ANTIBODY; HUMORAL IMMUNITY; RESPONSES; REINFECTION; INDUCTION; HUMANS; RISK; DIFFERENTIATION; MAINTENANCE;
D O I
10.1164/rccm.201412-2256OC
中图分类号
R4 [临床医学];
学科分类号
100218 [急诊医学];
摘要
Rationale: Despite relative antigenic stability, respiratory syncytial virus (RSV) reinfects throughout life. After more than 40 years of research, no effective human vaccine exists and correlates of protection remain poorly defined. Most current vaccine candidates seek to induce high levels of RSV-specific serum neutralizing antibodies, which are associated with reduced RSV-related hospitalization rates in observational studies but may not actually prevent infection. Objectives: To characterize correlates of protection from infection and the generation of RSV-specific humoral memory to promote effective vaccine development. Methods: We inoculated 61 healthy adults with live RSV and studied protection from infection by serum and mucosal antibody. We analyzed RSV-specific peripheral blood plasmablast and memory B-cell frequencies and antibody longevity. Measurements and Main Results: Despite moderately high levels of preexisting serum antibody, 34 (56%) became infected, Of whom 23 (68%) developed symptomatic colds. Prior RSV-specific nasal IgA correlated significantly more strongly with protection from polymerase chain reaction-confirmed infection than serum neutralizing antibody; Increases in-virus-specific antibody titers were variable and transient in infected subjects but correlated with plasmablasts that peaked around Day 10. During convalescence, only IgG (and no IgA) RSV-specific memory B cells were detectable in peripheral blood. This contrasted with natural influenza infection, in which virus-specific IgA memory B cells were readily recovered. Conclusions: This observed specific defect in IgA memory may partly explain the ability of RSV to cause recurrent symptomatic infections. If SO, vaccines able to induce durable RSV-specific IgA responses may be more protective than those generating systemic antibody alone.
引用
收藏
页码:1040 / 1049
页数:10
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