Antiviral Immune Response After Live Yellow Fever Vaccination of a Kidney Transplant Recipient Treated With IVIG (2013)

Despite the serious risk that live yellow fever virus (YFV) vaccination poses for immunocompromised individuals, inadvertent immunization does occur (1–3). We present a case study in which we measured the antiviral immune response of a kidney transplant (KTX) recipient who received intravenous immunoglobulin (IVIG) as a precautionary step to reduce the risk of vaccine-associated viscerotropic disease after YFV vaccination. CLINICAL HISTORY In 2007, a 55-year-old Caucasian male KTX patient received live attenuated YFV-17D vaccine (Sanofi-Pasteur, Lyon, France) in addition to concurrent immunization with an inactivated hepatitis A vaccine in preparation for a trip to South America. At the time of vaccination, the subject was 19 years post-deceased-donor KTX and receiving maintenance immune suppression with cyclosporine (100 mg twice daily) and mycophenolic acid (360 mg twice daily). Shortly after immunization, the patient reviewed the vaccine contraindications and, realizing the risks associated with his vaccination, he contacted his nephrologist, who then contacted Oregon Health & Science University Transplant Infectious Disease for further consultation. Because viremia could not be monitored in real-time, liver enzymes were followed as a marker for yellow fever–associated viscerotropic disease (YEL-AVD), a potentially life-threatening condition that results in virus dissemination and multiorgan failure (4). Prior to vaccination, the subject had average aspartate aminotransferase (AST) values of 28 units/mL (range, 19–38) and alanine aminotransferase (ALT) levels of 27 units/mL (range, 16–27; Fig. 1A). At 11 days postvaccination, the patient did not report having a fever, but AST and ALT levels had increased to 60 and 53 units/mL, respectively. IVIG was administered on days 20, 21, and 22 postimmunization, with a daily dose of 500 mg/kg. AST and ALT levels had returned to normal by day 18 postvaccination, but total bilirubin was elevated (2.4 units/mL) at day 25 postvaccination. On day 26 (i.e., 4 days after final IVIG administration), the patient reported what may have been an urticarial or eczematous response on his face that resolved within 5 days. Total bilirubin, AST, and ALT levels were within normal range when examined at day 47 postvaccination. Follow-up with the patient at approximately 8 months postvaccination indicated no long-term adverse events.FIGURE 1: Analysis of liver enzymes and immune responses after yellow fever vaccination of a KTX patient. The KTX patient was immunized with YFV-17D in preparation for international travel despite contraindications due to ongoing immunosuppressive therapy. A, blood chemistries are shown in relation to the time of vaccination and IVIG administration. B, YFV-specific neutralizing antibody titers and T-cell frequencies were determined for the KTX patient as well as eight healthy controls (median age, 28 years; range, 26–36 years; 63% female). Neutralizing titers were determined using a standard PRNT50 measurement (6). Virus-specific CD4+ and CD8+ T-cell frequencies are based on T cells capable of producing both interferon-γ and tumor necrosis factor-α after direct ex vivo stimulation with live purified YFV using previously described flow cytometry and intracellular cytokine staining methods (7).Retrospective testing was performed on patient blood samples and on the IVIG lot administered to the KTX patient. The IVIG lot yielded a YFV-specific 50% plaque reduction neutralizing test (PRNT50) value of 320, demonstrating the presence of YFV-specific neutralizing antibodies similar to 10 other lots of IVIG sampled across four vendors (geometric mean PRNT50, 226; range, 80–320). Blood samples were drawn from the patient at 20, 47, and 246 days after vaccination and analyzed for YFV-specific neutralizing antibody as well as CD4+ and CD8+ T-cell responses (Fig. 1B). For comparison, the immune responses of eight healthy adults at 30 days after YFV-17D vaccination were examined. The patient seroconverted by 20 days postvaccination with antibody titers within the lower range of the controls. In contrast to neutralizing antibody levels, the patient’s virus-specific CD4+ and CD8+ T-cell responses remained below detection (i.e., equivalent to naïve controls) at all time points examined. DISCUSSION YFV-17D is formally contraindicated for immunosuppressed patients due to an increased risk of serious adverse events (4). In this report, we found that although the KTX subject had depressed cellular immunity, he was able to mount a YFV-specific neutralizing antibody response after vaccination. Time to onset of YEL-AVD symptoms typically range from 4 to 8 days postvaccination (4) and a prior report described a YEL-AVD case who had presented with fever and AST of 111 units/mL and ALT of 72 units/mL before rapid development of multiple organ failure ending in death on hospital day 4 (5). There is no approved therapy for YEL-AVD; however, IVIG is often administered to KTX patients after high-risk exposure to other viruses, such as measles or varicella zoster virus, and because IVIG was expected to contain YFV-specific neutralizing antibodies (4), the clinical team considered it prudent to treat the patient with IVIG before the onset of severe viscerotropic disease because the therapeutic effect would be greatest if administered at the earliest stages of disease. Although it is unknown if IVIG prevented viral dissemination or viscerotropic disease, it did not appear to inhibit successful YFV vaccination as judged by seroconversion. These results suggest that IVIG could be administered as a precaution against potential YFV-AVD or other YFV vaccine-associated adverse events. Mark K. Slifka 1 Erika Hammarlund1 Matthew W. Lewis1 Elizabeth A. Poore2 Jon M. Hanifin3 Kieren A. Marr4 Douglas Hecox5 Ian J. Amanna2 1 Oregon National Primate Research Center Oregon Health & Science University Beaverton, OR 2 Najít Technologies, Inc Beaverton, OR 3 Department of Dermatology Oregon Health & Science University Portland, OR 4 Department of Medicine Johns Hopkins University School of Medicine Baltimore, MD 5 Renal Care Consultants Medford, OR ACKNOWLEDGMENTS The authors thank D.J. Norman, L. Strassfeld, M.R. Arnesen, and A. Mittalhenkle for insightful discussion.