Pentameric complex of viral glycoprotein H is the primary target for potent neutralization by a human cytomegalovirus vaccine

被引:113
作者
Freed, Daniel C. [1 ]
Tang, Qi [2 ]
Tang, Aimin [1 ]
Li, Fengsheng [1 ]
He, Xi [1 ]
Huang, Zhao [2 ]
Meng, Weixu [2 ]
Xia, Lin [2 ]
Finnefrock, Adam C. [1 ]
Durr, Eberhard [1 ]
Espeseth, Amy S. [1 ]
Casimiro, Danilo R. [1 ]
Zhang, Ningyan [2 ]
Shiver, John W. [1 ]
Wang, Dai [1 ]
An, Zhiqiang [2 ]
Fu, Tong-Ming [1 ]
机构
[1] Merck Res Labs, Dept Vaccines Res, West Point, PA 19486 USA
[2] Univ Texas Hlth Sci Ctr Houston, Brown Fdn, Inst Mol Med, Texas Therapeut Inst, Houston, TX 77030 USA
关键词
monoclonal antibody; antiviral antibody; ORGAN TRANSPLANT RECIPIENTS; LINKED-IMMUNOSORBENT-ASSAY; CMV-HYPERIMMUNE GLOBULIN; ENDOTHELIAL-CELLS; PRIMARY INFECTION; EPITHELIAL-CELLS; NATURAL INFECTION; ANTIBODY-RESPONSE; VIRUS-INFECTION; SMOOTH-MUSCLE;
D O I
10.1073/pnas.1316517110
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
Human cytomegalovirus (HCMV) can cause serious morbidity/ mortality in transplant patients, and congenital HCMV infection can lead to birth defects. Developing an effective HCMV vaccine is a high medical priority. One of the challenges to the efforts has been our limited understanding of the viral antigens important for protective antibodies. Receptor-mediated viral entry to endothelial/ epithelial cells requires a glycoprotein H (gH) complex comprising five viral proteins (gH, gL, UL128, UL130, and UL131). This gH complex is notably missing from HCMV laboratory strains as well as HCMV vaccines previously evaluated in the clinic. To support a unique vaccine concept based on the pentameric gH complex, we established a panel of 45 monoclonal antibodies (mAbs) from a rabbit immunized with an experimental vaccine virus in which the expression of the pentameric gH complex was restored. Over one-half (25 of 45) of the mAbs have neutralizing activity. Interestingly, affinity for an antibody to bind virions was not correlated with its ability to neutralize the virus. Genetic analysis of the 45 mAbs based on their heavy-and light-chain sequences identified at least 26 B-cell linage groups characterized by distinct binding or neutralizing properties. Moreover, neutralizing antibodies possessed longer complementarity-determining region 3 for both heavy and light chains than those with no neutralizing activity. Importantly, potent neutralizing mAbs reacted to the pentameric gH complex but not to gB. Thus, the pentameric gH complex is the primary target for antiviral antibodies by vaccination.
引用
收藏
页码:E4997 / E5005
页数:9
相关论文
共 79 条
  • [1] Safety and immunogenicity of the Towne strain cytomegalovirus vaccine
    Adler, SP
    Hempfling, SH
    Starr, SE
    Plotkin, SA
    Riddell, S
    [J]. PEDIATRIC INFECTIOUS DISEASE JOURNAL, 1998, 17 (03) : 200 - 206
  • [2] Human CMV vaccine trials: What if CMV caused a rash?
    Adler, Stuart P.
    [J]. JOURNAL OF CLINICAL VIROLOGY, 2008, 41 (03) : 231 - 236
  • [3] Effects of intrapulmonary viral tropism and cytokine expression on the histological patterns of cytomegalovirus pneumonia
    Arai, Yoshifumi
    Tsuchida, Takashi
    Kosugi, Isao
    Kawasaki, Hideya
    Meguro, Shiori
    Kinoshita, Mana
    Baba, Satoshi
    Maeda, Matsuyoshi
    Shinmura, Yuichiro
    Tsutsui, Yoshihiro
    Iwashita, Toshihide
    [J]. PATHOLOGY INTERNATIONAL, 2012, 62 (09) : 628 - 639
  • [4] Vaccine development to prevent cytomegalovirus disease: Report from the National Vaccine Advisory Committee
    Arvin, AM
    Fast, P
    Myers, M
    Plotkin, S
    Rabinovich, R
    [J]. CLINICAL INFECTIOUS DISEASES, 2004, 39 (02) : 233 - 239
  • [5] Human cytomegalovirus UL131A, UL130 and UL128 genes are highly conserved among field isolates
    Baldanti, F.
    Paolucci, S.
    Campanini, G.
    Sarasini, A.
    Percivalle, E.
    Revello, M. G.
    Gerna, G.
    [J]. ARCHIVES OF VIROLOGY, 2006, 151 (06) : 1225 - 1233
  • [6] Cytomegalovirus in Solid Organ Transplantation: Epidemiology, Prevention, and Treatment
    Beam, Elena
    Razonable, Raymund R.
    [J]. CURRENT INFECTIOUS DISEASE REPORTS, 2012, 14 (06) : 633 - 641
  • [7] How I treat cytomegalovirus in hematopoietic cell transplant recipients
    Boeckh, Michael
    Ljungman, Per
    [J]. BLOOD, 2009, 113 (23) : 5711 - 5719
  • [8] CMV-hyperimmune globulin for preventing cytomegalovirus infection and disease in solid organ transplant recipients: a meta-analysis
    Bonaros, Nikolaos
    Mayer, Bernd
    Schachner, Thomas
    Laufer, Guenther
    Kocher, Alfred
    [J]. CLINICAL TRANSPLANTATION, 2008, 22 (01) : 89 - 97
  • [9] Comparison of Antibody Repertoires Produced by HIV-1 Infection, Other Chronic and Acute Infections, and Systemic Autoimmune Disease
    Breden, Felix
    Lepik, Christa
    Longo, Nancy S.
    Montero, Marinieve
    Lipsky, Peter E.
    Scott, Jamie K.
    [J]. PLOS ONE, 2011, 6 (03):
  • [10] Britt W, 2007, HUMAN HERPESVIRUSES: BIOLOGY, THERAPY, AND IMMUNOPROPHYLAXIS, P737