Donor-Specific Alloantibody Upregulation After Influenza Vaccination in Transplant Recipients

To the Editor: We read with interest the article by Katerinis et al. They evaluated influenza vaccination and HLA alloantibody upregulation and report that 17.3 and 11.9% of kidney transplant recipients in two cohorts had a rise in HLA alloantibody levels after receiving two doses of influenza vaccine (1Katerinis I Hadaya K Duquesnoy R et al.De novo anti-HLA antibody after pandemic H1N1 and seasonal influenza immunization in kidney transplant recipients.Am J Transplant. 2011; 11: 1727-1733Abstract Full Text Full Text PDF PubMed Scopus (116) Google Scholar). We believe that there are two major limitations with this study: (i) It was performed during an influenza pandemic where high rates of natural infection were observed in the community. Therefore, it is possible (and in fact likely) that many of these patients were exposed to and/or had infection with natural (pandemic H1N1) influenza. This may be a major confounder and was not adequately addressed in the study. (ii) The vaccine utilized in this study contained an adjuvant (ASO3) that may partially explain why such significant alloupregulation was observed. In North America, marketed seasonal influenza vaccines do not typically contain adjuvants. Adjuvanted vaccines in general have not been well evaluated in transplant patients. We have studied influenza vaccination in the lung transplant population in a setting that avoids these two potential confounders and present data below that differs from the report by Katerinis et al. In the 2006–2007 influenza season (a nonpandemic year), we conducted a study in a cohort of 60 lung transplant recipients where patients received two doses of influenza vaccine 4 weeks apart. The complete details of this study are available in Manuel et al., AJT, 2007 (2Manuel O Humar A Chen MH et al.Immunogenicity and safety of an intradermal boosting strategy for vaccination against influenza in lung transplant recipients.Am J Transplant. 2007; 7: 2567-2572Crossref PubMed Scopus (57) Google Scholar). The dose was an intramuscular dose that contained 15 μg of nonadjuvanted antigen followed 4 weeks later by a 3 μg intradermal dose of the same vaccine (2Manuel O Humar A Chen MH et al.Immunogenicity and safety of an intradermal boosting strategy for vaccination against influenza in lung transplant recipients.Am J Transplant. 2007; 7: 2567-2572Crossref PubMed Scopus (57) Google Scholar). Serum was collected prevaccination, 4 weeks after the first vaccine and 4 weeks after the booster dose. In response to Katerinis et al., we analyzed stored serum from these patients after the first and second vaccinations for the presence of HLA alloantibodies using FlowPRA™ (One Lambda Inc., Canoga Park, CA, USA) for screening. Flow high-definition single antigen beads were used for specificity testing in positive samples. Of the 60 patients, 21 (35%) had a positive screening test on a postvaccination serum. In this subset, antibody was present after the initial vaccination and no new antibody appeared after the booster dose. To determine the clinical significance, these patients’ pre- and postvaccination sera underwent specificity testing. De novo alloantibody was present in only one patient and this was not donor specific. In this patient, DQ7 reactivity was stronger postvaccination and new specificities for DQ8 and DQ9 were detected. Of the remaining 20 patients, specificities did not significantly change from pre- to postvaccination. No patient had donor-specific antibody. Our findings are similar to one other previous study that has looked at upregulation of HLA alloantibodies following kidney transplantation (3Candon S Thervet E Lebon P et al.Humoral and cellular immune responses after influenza vaccination in kidney transplant recipients.Am J Transplant. 2009; 9: 2346-2354Abstract Full Text Full Text PDF PubMed Scopus (97) Google Scholar). Therefore, we suggest that the findings of Katerinis et al. may be due to the adjuvant contained in the vaccine or from widespread influenza infection itself, which may also be a trigger for an alloimmune response, and are therefore not generalizable. We believe that when a choice is available for influenza vaccine preparation, a nonadjuvanted vaccine should be preferentially used in the organ transplant population. Adjuvants, in general, have not been well explored in this population and should not be used until their safety in this population is determined. The authors of this manuscript have conflicts of interest to disclose as described by the American Journal of Transplantation. D.K. has received research support paid to the institution from Hoffmann-LaRoche and Sanofi-Pasteur. A.H. has received research support paid to the institution from Hoffmann-LaRoche and speaker honoraria from Hoffmann-LaRoche. P.C. has no relevant disclosures.

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