Strain-specific antibody therapy prevents cytomegalovirus reactivation after transplantation

Abstract

Cytomegalovirus infection is a frequent and life-threatening complication that significantly limits positive transplantation outcomes. We developed preclinical mouse models of cytomegalovirus reactivation after transplantation and found that humoral immunity is essential for preventing viral recrudescence. Preexisting antiviral antibodies decreased after transplant in the presence of graft-versus-host disease and were not replaced, owing to poor reconstitution of donor B cells and elimination of recipient plasma cells. Viral reactivation was prevented by the transfer of immune serum, without a need to identify and target specific antigenic determinants. Notably, serotherapy afforded complete protection, provided that the serum was matched to the infecting viral strain. Thus, we define the mechanisms for cytomegalovirus reactivation after transplantation and identify a readily translatable strategy of exceptional potency, which avoids the constraints of cellular therapies.

Comprehensive viromewide antibody responses by systematic epitope scanning after hematopoietic cell transplantation

“…Recent work in a murine model shows that strain-matched CMV antibodies are required to protect from reactivation. 11 Our work together with preclinical data supports the idea that the donor CMV repertoire may be less skilled at recognizing the recipient's endogenous virus in persons who reactivate CMV. We are also intrigued that Mean change in epitopes (95% CI) in D-R- across the cohort, in addition to the public epitopes, wide variability in CMV epitopes was detected, which could lead to continued work comparing viral strains with epitope responses.…”

“…[3][4][5][6] Much is known about how cytomegalovirus (CMV) impacts clinical outcomes, including death, following HCT, and recent data demonstrate the importance of humoral immunity and far-reaching immunologic effects of this virus. [7][8][9][10][11] Much less is known about the reconstitution of immunity toward other viruses, 12 the role of other viruses in post-HCT outcomes, or how other factors associated with altered B-cell responses, including graft-versus-host disease (GVHD) or CMV infection, might influence reconstitution of humoral antiviral immunity. 13,14 We longitudinally employed VirScan, 15 a novel serosurvey, to evaluate new metrics to define humoral antiviral immunity (the viral antibody repertoire).…”

Vaccine Vectors Harnessing the Power of Cytomegaloviruses

“…Reports on polyclonal IgG efficacy in congenital CMV infection [99,100] and in CMV prophylaxis in transplantation [101,102] showed very divergent outcomes. This apparent contradiction might be interpreted in light of a recent evidence showing that only strain-specific antibodies are effective in preventing MCMV reactivation in a model of post-transplant infection [103]. Evasion of CD8 T cells by virally-encoded MHC-I inhibitors further supports CMV replication and dissemination at superinfection [42].…”

Human Cytomegalovirus Congenital (cCMV) Infection Following Primary and Nonprimary Maternal Infection: Perspectives of Prevention through Vaccine Development

“…In Rhesus monkeys, following CD4 + T-cell depletion, administration of hyperimmune IgG to pregnant dams completely protected against fetal loss and placental transmission [104]. Recently, in a mouse model it was reported that strain-specific antibody therapy prevented HCMV reactivation after transplantation, provided that serotherapy was matched to the infecting HCMV strain [105]. On the other hand, the administration of commercial preparations of polyclonal human IgG did not significantly prevent cCMV in pregnant women with PI [2], while gB antibodies following gB vaccination of transplant recipients conferred some protection, independent of NAb activity [106].…”