Following hematopoietic stem cell transplantation (HSCT) influenza infections can be potentially life threatening. Prior studies demonstrate that following HSCT, the influenza vaccine is relatively ineffective at inducing influenza specific immunity—especially early after transplant. Additionally, the effectiveness of the annual vaccine depends on recipient age, immune competence and antigenic potential of the three strains included. We hypothesized that a second vaccine dose, as is standard of care in vaccine naïve pediatric patients, might improve vaccine specific immune responses in patients following allogeneic HSCT. During the 2010 influenza season, we conducted a clinical trial where patients who were >60 days post HSCT were stratified by age and steroid use, and randomized to receive either 1 (n=33) or 2 (n=32) influenza vaccinations separated by one month. Blood samples were obtained pre-vaccination, 4 weeks and 8 weeks after the first vaccine. Vaccine specific B and T cell responses were assessed using hemagglutination inhibition (HAI) and IFN-g ELISPOT, respectively. Of the 65 patients, 73% (n=48) were >18 yrs old, 40% (n=26) received non-myeloablative conditioning and 35% (n=23) were umbilical cord blood (UCB) transplant recipients. HAI responses to the 2010/2011 vaccine components (H3N2, H1N1 and B/Victoria) were significantly greater for patients vaccinated >1 year post transplant (p<=0.005 for all 3 strains) compared to those vaccinated at earlier time points. Testing of T cell specific responses (IFN-g ELISPOT at week 8) showed 29/65 (45%) patients had IFN-g vaccine specific responses (defined as >5x increase in the number of spots over baseline). Recipients of 2 vaccines did not show a significant improvement in either HAI or in IFN-g ELISPOT responses. The HAI results were similar to the T cell specific responses in that patients >1 year after HSCT were more likely to develop positive responses compared to those vaccinated <1 yr (p=0.03). UCB recipients were less likely to have an influenza specific T cell response (p=<0.001). Flow cytometry was performed to determine whether the numbers of pre-vaccination naïve, effector memory or central memory T and or similar B cell populations were associated with responses. There was a positive correlation between the total number of CD19+ cells prior to vaccination and seroconversion (p=0.01) and an inverse correlation for IFN-g responses (p=0.05). No correlation with CD4+ subsets were found for either seroconversion or IFN-g positivity. In multivariate analysis for HAI responses, time from transplant to vaccination, and greater numbers of prevaccination CD19+ cells were significantly associated with responses (p<0.001 and p=0.01 respectively). Multivariate analysis for vaccine specific ELISPOT responses demonstrated significance for stem cell source (PB/BM > UCB, p=0.005) and CD19+ unswitched memory cells (p=0.008). Our study illustrates that time from transplantation was the strongest predictor of vaccine associated responses, and that vaccine specific T cell responses can be elicited prior to antibody responses. Furthermore, UCB recipients had significantly fewer IFN-g vaccine specific responses. Surprisingly steroid use did not negatively impact vaccine responses. In summary an additional influenza vaccine dose, separated by 1 month, did not increase vaccine responses.
Blazar:Tarix Pharmaceuticals: Research Funding; Boehringer Ingelheim: Research Funding; Acetylon Pharmaceuticals, Inc.: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; University of Minnesota/University of Pennsylvania: Licensing Agreement, Licensing Agreement Other; Athelos-NeoStem, Inc.: Consultancy.
Asterisk with author names denotes non-ASH members.