CMV infection accelerates transplant vascular sclerosis (TVS) and chronic rejection (CR) in solid organ transplants. Recipients of latently HCMV infected donor grafts are at highest risk for developing CMV-disease, and consequently allograft rejection. The utility of the antiviral agents is often limited by toxicities and the emergence of resistance. An effective vaccine, while very appealing, has likewise proven an elusive goal. While a sterilizing vaccine, one that prevents infection may not be feasible due to the nature of the virus; a therapeutic vaccine that limits virus replication and prevents disease may be a more realistic alternative. Our objective is to determine the efficacy of a CMV vaccine in preventing virus-accelerated rat cardiac allograft rejection in the setting of CMV+ donor hearts transplanted into CMV naive recipients.

Methods: F344 donor rats were infected with RCMV 5 days prior to heterotopic cardiac transplantation into CMV-naive Lewis recipients-untreated or vaccinated with inactivated RCMV at 35 or 70 days prior to transplantation. The time to CR, degree of TVS, tissue CMV viral loads, and CMV-specific immune responses were assessed.

Results: Recipients of uninfected donor hearts rejected at POD 108, whereas recipients of RCMV-infected donor hearts rejected at POD 59. Similarly, recipients of infected donor hearts vaccinated at 35d pre-transplant developed CR at POD 61. However, recipients of infected donor hearts vaccinated at 70d exhibited a significantly prolonged time to rejection – POD 97. At transplantation, anti-RCMV IgG levels and virus neutralizing antibody capacity were similar for both 35 & 70d vaccinated groups but the immune responses were boosted in the 70-day group following transplantation. Although all of the donor hearts were infected, we observed that the recipients of the 70-day vaccine had both lower graft viral loads and PBMC at POD 7 compared to the 35-day vaccine and control groups, indicating that the vaccine lowers viral loads and dissemination. Similar findings in adoptive and passive transfer experiments will also be discussed.

Conclusions: A CMV vaccine prevents accelerated CR in recipients of infected donor hearts. The timing of the vaccine plays a critical role in mediating the anti-viral response and promoting graft survival and may effectively reduce the need for antiviral treatment.

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