Purpose: To compare the effect of calcineurin- versus costimulation-based immunosuppression on primary and secondary vaccine responses in non-human primate heart transplant recipients.

Background: Antibody response following immunization with bacterial and viral antigens reflects relative integrity of immune competence in transplant recipients treated with different immunosuppressive regimens.

Methods: Cynomolgus macaque recipients of heterotopic cardiac allografts were treated with a selective non-activating anti-CD28 reagent (αCD28, n=6), or with the calcineurin inhibitor cyclosporine (CsA) alone (n=5) or combined with αCD28 (n=6) or B-cell depletion (CsA+αCD20, n=4). These regimens are all associated with similar efficacy with respect to graft protection from alloimmune injury around the time of vaccination. Trivalent influenza, pneumococcus, and rubella (primary exposures) and tetanus, measles, and influenza (secondary challenge after prior vaccination at varying intervals before transplant) vaccines were given on day 14 after transplantation. A two-fold or greater increase in vaccine antigen-specific IgG levels (by ELISA) was defined as a “detectable” response; > 10-fold responses were considered “robust.”

Results: A 1⁰ response to T-helper-dependent antigens (influenza, and rubella) was detected during αCD28 monotherapy (to 20 of 21 antigens, with 10 robust), αCD28+CsA (12/18, 4 robust), but not with CsA+αCD20 (0/12). A 2⁰ response to tetanus, measles, or influenza was detected with αCD28 monotherapy (4/6, 2 robust), αCD28+CsA (4/12, 1 robust), and CsA alone (8/19, 3 robust), but not with CsA+αCD20 (2/4, 0 robust). Th-independent response to pneumococcus was detected in 3/6 with αCD28 monotherapy, 1/6 with αCD28+CsA, but not in any other treatment group.

Discussion: Compared to calcineurin inhibition, selective blockade of CD28 is associated with relatively preserved responses to primary and secondary challenge with T-dependent and T-independent vaccine antigens. These initial observations predict a favorable safety profile for this costimulation-based immunosuppressive agent with respect to host defense against infectious challenges, a hypothesis with potentially important clinical implications.

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