Vaccine-Derived Neutralizing Antibodies to the Human Cytomegalovirus gH/gL Pentamer Potently Block Primary Cytotrophoblast Infection

被引:73
作者
Chiuppesi, Flavia [1 ]
Wussow, Felix [1 ]
Johnson, Erica [2 ]
Bian, Chao [1 ]
Zhuo, Meng [1 ]
Rajakumar, Augustine [3 ]
Barry, Peter A. [4 ]
Britt, William J. [5 ,6 ,7 ]
Chakraborty, Rana [2 ]
Diamond, Don J. [1 ]
机构
[1] Beckman Res Inst City Hope, Dept Expt Therapeut, Duarte, CA 91010 USA
[2] Emory Univ, Sch Med, Dept Pediat, Atlanta, GA USA
[3] Emory Univ, Sch Med, Dept Gynecol & Obstet, Atlanta, GA USA
[4] Univ Calif Davis, Dept Pathol & Lab Med, Davis, CA 95616 USA
[5] Univ Alabama Birmingham, Sch Med, Childrens Hosp Alabama, Dept Pediat, Birmingham, AL USA
[6] Univ Alabama Birmingham, Sch Med, Dept Microbiol, Childrens Hosp Alabama, Birmingham, AL 35294 USA
[7] Univ Alabama Birmingham, Sch Med, Dept Neurobiol, Childrens Hosp Alabama, Birmingham, AL 35294 USA
基金
美国国家卫生研究院;
关键词
VILLOUS TROPHOBLAST CELLS; CONGENITAL CYTOMEGALOVIRUS; INTRAUTERINE TRANSMISSION; ENDOTHELIAL-CELLS; EPITHELIAL-CELLS; GLYCOPROTEIN-B; HYPERIMMUNE GLOBULIN; VIRION ENVELOPE; FLOW-CYTOMETRY; HOFBAUER CELLS;
D O I
10.1128/JVI.01701-15
中图分类号
Q93 [微生物学];
学科分类号
071005 ; 100705 ;
摘要
Human cytomegalovirus (HCMV) elicits neutralizing antibodies (NAb) of various potencies and cell type specificities to prevent HCMV entry into fibroblasts (FB) and epithelial/endothelial cells (EpC/EnC). NAb targeting the major essential envelope glycoprotein complexes gB and gH/gL inhibit both FB and EpC/EnC entry. In contrast to FB infection, HCMV entry into EpC/EnC is additionally blocked by extremely potent NAb to conformational epitopes of the gH/gL/UL128/130/131A pentamer complex (PC). We recently developed a vaccine concept based on coexpression of all five PC subunits by a single modified vaccinia virus Ankara (MVA) vector, termed MVA-PC. Vaccination of mice and rhesus macaques with MVA-PC resulted in a high titer and sustained NAb that blocked EpC/EnC infection and lower-titer NAb that inhibited FB entry. However, antibody function responsible for the neutralizing activity induced by the MVA-PC vaccine is uncharacterized. Here, we demonstrate that MVA-PC elicits NAb with cell type-specific neutralization potency and antigen recognition pattern similar to human NAb targeting conformational and linear epitopes of the UL128/130/131A subunits or gH. In addition, we show that the vaccine-derived PC-specific NAb are significantly more potent than the anti-gH NAb to prevent HCMV spread in EpC and infection of human placental cytotrophoblasts, cell types thought to be of critical importance for HCMV transmission to the fetus. These findings further validate MVA-PC as a clinical vaccine candidate to elicit NAb that resembles those induced during HCMV infection and provide valuable insights into the potency of PC-specific NAb to interfere with HCMV cell-associated spread and infection of key placental cells. IMPORTANCE As a consequence of the leading role of human cytomegalovirus (HCMV) in causing permanent birth defects, developing a vaccine against HCMV has been assigned a major public health priority. We have recently introduced a vaccine strategy based on a widely used, safe, and well-characterized poxvirus vector platform to elicit potent and durable neutralizing antibody (NAb) responses targeting the HCMV envelope pentamer complex (PC), which has been suggested as a critical component for a vaccine to prevent congenital HCMV infection. With this work, we confirm that the NAb elicited by the vaccine vector have properties that are similar to those of human NAb isolated from individuals chronically infected with HCMV. In addition, we show that PC-specific NAb have potent ability to prevent infection of key placental cells that HCMV utilizes to cross the fetal-maternal interface, suggesting that NAb targeting the PC may be essential to prevent HCMV vertical transmission.
引用
收藏
页码:11884 / 11898
页数:15
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