CMV Infection in Transplant Recipients

M. Boeckh, A. Limaye

These research projects are focused on pathogenesis, diagnostic, and clinical approaches to prevention of infection with CMV. Studies are supported in part by the Adult Leukemia Research Center grant (NCI). The following projects are ongoing:

• CMV-specific immune reconstitution

Laboratory studies are on-going to define CMV-specific immune responses in various important clinical situations.  Techniques utilized include standard functional assays (CD4 lymphoproliferative assays, CD4 limiting dilution assays, chromium release assays), intracellular cytokine assays as well as tetramer assays.  Current studies include:

• An evaluation of the CMV-specific immunereconstitution following HCT recipients from unrelated donors receiving non-myeloablative conditioning regimens.  Studies are done in collaboration with Michael Maris, MD.
• The impact of long-term prophylaxis with valganciclovir on CMV-specific immunereconstitution is studied in participants of a large mulitcenter randomized trial (see below).
• A comparision of CMV specific T-cell immune reconstitution in D + 1R-liver transplant recipient comparison of prophylaxis with valganciclovir vs. preemptive therapy (collaboration with N. Singh, Pittsburgh).
• To characterize the immune responses following a novel CMV DNA vaccination (pp65 and gB) testing of CMV-specifi T cell responses is peformed as part of a phase I evaluation of the vaccine in healthy volunteers.

        

• Transmission of CMV

CMV infection occurs in appr. 15-20% of stem cell transplant recipients and 70% of liver transplant recipients who are CMV negative prior to transplant and receive an organ from a CMV positive donor will become infected after transplant.  Our studies are aimed at defining mechanisms of transmission of CMV via the transplanted organ using highly sensitive DNA PCR detection and strain typing techniques.  The central hypothesis is that CMV load in the transplant organ is the major determinant of virus transmission.  As an alternative hypothesis, host factors such as innate immunity and HLA mismatch will be examined. In liver transplant recipients, viral load in the transplanted organ will be examined as a variable for transmission as well.

• Innate Immunity

Studies are ongoing in collaboration with the Institute of Systems Biology, Seattle, WA (P-Y Bochud, A Aderem) to determine the role of immune response time in infection risk and outcome as well as with Dr. J. Chien (Pulmonology, FHCRC), Drs. John Hansen and Effie Petersdorf (Unrelated Donor Program, FHCRC) .

• Antiviral Resistance

Antiviral resistance is studied as part of the late CMV prevention trial in HCT using valganciclovir.  Studies in solid organ transplantation are ongoing in collaboration with Dr. Ajit Limaye, UW.  Molecular testing of resistance is performed at the molecular diagnostic lab (MeeiLi Huang, PhD, Linda Cook, PhD).  A sequence-based assay allows direct testing from DNA specimens.

• Prevention strategies (drug prevention, immunologic strategies)

A.  Late CMV disease.  A multicenter double-blind placebo controlled trial is conducted with FHCRC as the coordinating center using valganciclovir for prevention of late CMV infection and disease after stem cell transplantation.   Primary endpoint is CMV DNA load in plasma.  Since valganciclovir may delay CMV-specific T cell immunereconstitution and/or cause resistance, CMV-specific immune reconstitution and molecular marker of ganciclovir resistance are monitored throughout the trial [supported by NIH CA 18029].

B. Vaccination strategies.  In collaboration with Vical Inc., CA, a new CMV DNA vaccine is tested.  A phase I study will start early 2004 in normal volunteers.  The study will be performed at the UW Virology Research Clinic in collaboration with Anna Wald, MD. Testing of CMV-specific T  cell responses measured by standard functional assays as well as tetramer methodology will be performed at the Boeckh lab [ A Phase 1 Clinical Trial to Evaluate the Safety and Immunogenicity of the Intramuscular Vical CMV Immunotherapeutic Vaccine in Healthy Adult Subjects, Vical Inc. (PI: Michael Boeckh)

C.  Evaluation of novel antiviral compounds.

               •  A phase I/II study of maribavir (Viropharma Inc.) is presently ongoing. This is a randomized, double-blind, multicenter dose-ranging study to   

                  assess safety, tolerability, and prophylactic anti-CMV activity of maribavir in recipients of allogeneic stem cell transplantation.

 

CMV in Transplantation: Recent Publications

 

Limaye, A., Corey, L., Koelle, D., Davis, C., Boeckh, M.   Emergence of ganciclovir-resistant CMV disease among recipients of solid organ transplant.   Lancet 356 :645-49, 2000

Nichols, W.G., Corey,   L., Gooley,   T., Drew,   L., Miner, R., Huang, M.L., Davis, C., Boeckh, M.   Rising pp65 Antigenemia During Preemptive Anticytomegalovirus Therapy after Allogeneic Hematopoietic Stem Cell Transplantation:Risk Factors, Correlation with DNA Load, and Outcomes. Blood 97 :867-874, 2001.

Storek, J., Dawson, M.A., Storer, B., Stevens-Ayers, T., Maloney, D.G., Marr, K.A., Witherspoon, R.P., Bensinger, W., Flowers, M.E.D., Storb, R., Appelbaum, F.R., Boeckh, M. Immune reconstitution after allogeneic marrow transplantation compared with blood stem cell transplantation. Blood 97 :3380-33389, 2001.

Boeckh, M, Bowden, R.A., Storer, B., Chao, N.J., Spielberger, R., Tierney, D.K., Hawkins, G., Cunningham, T., Levitt, D., Zaia, J.A..   Randomized Placebo Controlled Double-Blind Study of a CMV Glycoprotein H-Specific Monoclonal Antibody (MSL-109) for Prevention of CMV Infection after Allogeneic Hematopoietic Stem Cell Transplant. Biol Blood Marrow Transplant   7 :343-351, 2001.

Limaye, A.P., Raghu, G., Koelle, D., Ferrenberg, J., Huang, M.L., Carter, R., Boeckh, M. High Incidence of Ganciclovir-Resistant Cytomegalovirus Among Lung Transplant Recipients Receiving Preemptive Therapy. J Infect Dis , 185:20-27, 2002 .

Nichols, W.G., Corey, L., Gooley, T., Davis, C., Boeckh, M. High Risk of Death due to Bacterial and Fungal Infection Among CMV Seronegative Recipients of Stem Cell Transplants from Seropositive Donors (D+/R-): Evidence for "Indirect" Effects of Primary CMV Infection. J. Infect. Dis 1;185:273-82, 2002 .

Boeckh, M ., Leisenring,W., Riddell, S.R., Bowden R.A., Huang, M., Myerson, D., Stevens-Ayers, T., Cunningham, T., Flowers, M., Corey, L. Late Cytomegalovirus Disease And Mortality In Allogeneic Marrow Transplant Recipients: Importance Of Viral Load And CMV-Specific T Cell Immunity. Blood 101 :407-414, 2003.

Nichols, W.G., Price, T.H., Gooley, T., Corey, L., Boeckh, M . Transfusion-transmitted cytomegalovirus infection after receipt of leukoreduced blood products. Blood , 101 :4195-4200, 2003 .

Hakki, M., Riddell, S.R., Storek, J., Carter, R.A., Stevens-Ayers, T., Sudour, P., White, K., Corey, L., Boeckh, M . Immune Reconstitution to Cytomegalovirus after Allogeneic Hematopoietic Stem Cell Transplantation: Impact of Host Factors, Drug Therapy, and Subclinical Reactivation. Blood 102 :3060-67, 2003 .

Maris, M., Boeckh, M. , Storer, B., Dawson, M., White, K., Keng, M., Sandmaier, B., Maloney, D., Storb, R., Storek, J. Immunologic Recovery after Hematopoietic Cell Transplantation with Nonmyeloablative Conditioning.   Exp. Hematol. 31 :941-52, 2003 .

Junghanss, C., Storb, R., Maris, M.B., Carter, R.A., Sandmaier, B.M., Malony, D.G., McSweeney, P.A., Corey,L., Boeckh, M . Impact of unrelated donor status on the incidence and outcome of CMV infection after non-myeloablative allogeneic stem cell transplantation. Brit J Haematol 123 :662-70, 2003 .

Boeckh, M., Huang, M.L., Ferrenberg, J., Stevens-Ayers, T., Stensland, L., Nichols, W.G., Corey L. Optimization of Quantitative Detection of Cytomegalovirus DNA in Plasma by Real-Time PCR. J Clin Microbiol 42 :1142-8, 2004.

Limaye, A.P., Ramaswamy,B., Kim,H.W., Kuhr, C.S., Halldorson, J.B., Healey, P.J., Levy , A.E.,   Boeckh, M. Late-Onset CMV Disease in Liver Transplant Recipients Despite Antiviral Prophylaxis. Transplantation 78:1390-96, 2004 .

Review Articles

Boeckh, M . , Ljungman, P. Cytomegalovirus Infection in Stem Cell Transplant Recipients.   In: Transplant Infections, 2nd Edition. Editors: R.A. Bowden, P. Ljungman, C.Paya.   Lippincott-Raven , pages 277-297, 2003.

Hakki, M., Boeckh, M.   Management of CMV infection in hematopoietic stem cell transplant recipients.   In: Management of Infection in Oncology Patients.   Isis Medical Media Ltd ., Oxford. Eds. Wingard, J.R. and Bowden, R.   pages 247-267, 2003 .

Boeckh, M ., Nichols, W.G. Immunosuppressive Effects of Beta-herpesviruses. Herpes , 10 :12-16, 2003 . [Peer-Reviewed]

Boeckh, M., Nichols, W.G., Papanicolaou, G., Rubin, R., Wingard, J.R., Zaia. J. Cytomegalovirus in Hematopoietic Stem Cell Transplant Recipients: Current Status, Known Challenges, and Future Strategies. Biol Blood Marrow Transplant 9 :543-58, 2003.

Boeckh, M., Nichols, W.G. Perspective: The Impact of Cytomegalovirus Serostatus of Donor and Recipient before Hematopoietic Stem Cell Transplantation in the Era of Antiviral Prophylaxis and Preemptive Therapy. Blood 103 :2003-2008, 2004 .

Boeckh, M., Fries, B., Nichols, W.G. Recent Advances in the Prevention of CMV Infection and Disease after Hematopoietic Stem Cell Transplantation. Pediatric Transplantation 8 (Suppl 5) :19-27, 2004.