Vaccination after Allogenic Stem Cell Transplantation: Diminished Memory B Cell Response and High Number of Spontaneously IgG Secreting Plasmablasts
Authors: Tittlbach Hannes , Schneider Andrea , Buchstaller Corinna , Mayr Andreas , Vasova Ingrid , Roesler Wolf , Mackensen Andreas , Mach Michael , Winkler Thomas H , Winkler Julia 
Published: October 2019

Abstract
Infections are one of the major causes of morbidity and mortality in patients after allogeneic stem cell transplantation (allo-SCT). For the protection against infections Ag-specific plasmablasts (PBs) and long-living plasma cells provide long-lived humoral immunity. By the vaccination of transplanted patients the humoral memory function can be restored in the majority of cases. It is unclear, however, to what extend memory B cells contribute to the mobilization of antibody secreting cells and long term humoral memory.
Here we analyzed the mobilization of CD38high/CD27high PBs in the peripheral blood of 27 patients at day +180 after allo-SCT in response to vaccination against tetanus toxoid (TT), diphtheria toxoid (DT), pertussis toxoid (PT), haemophilus influenzae type b (HiB), and poliovirus on day 7 after immunization when the PBs peak in the peripheral blood. It has been described before (Odendahl et al., Blood, 2005) that such an early mobilization of PBs in the blood derives from memory B cell response. We observed a minor increase in the frequency of total PBs from 3.55% to 4.72% on day 7 after vaccination, whereas healthy donors (HD) revealed a strong PB mobilization from 1.04% to 11.35%. In contrast to the low mobilization of PBs on day 7 after vaccination a high number of PBs before vaccination was evident in patients after allo-SCT. This high frequency of PBs correlated with moderate/severe chronic GVHD (5.31%, range 0.19% to 31.7% in pts. with moderate/severe chronic GVHD versus 2.35%, range 0.1% to 13.4% in patients with no or mild chronic GvHD, p<0.05 ).
As measured by ELISPOT assays, HD responded with a profound increase in the frequencies of antigen-specific-IgG-secreting PBs against all vaccine-antigens tested on day 7 after vaccination. In contrast only 65% of patient showed a significant increase of IgG-secreting PBs on day 7 against TT, only 65% of patients against DT, 33% of patients against PT and 53% against poliovirus on day 7 after vaccination. Interestingly, all patients tested for HiB showed a significant increase of HiB-specific PBs. Whereas all HD tested revealed a strong increase in vaccine specific IgG in the serum already on day 7 after vaccination, none of the 27 patients after allo-SCT responded with an increase of serum antibodies.
We performed three repetitive vaccinations in the patient cohort as suggested by the EBMT guidelines. Four weeks after the first vaccination we found a significant increase of serum titers for the vaccine antigens in 72% of pts. against TT, in 39% against DT, in 55% against PT and in 56% against HiB. At the same time, an increase in the number of patients with protective titers from 88% to 100% for TT, from 42% to 72% for DT, from 8% to 44% for PT, and from 33% to 47% for HiB were detectable. After completion of vaccination on week 26 and 52 serum titers remained elevated for TT, DT, PT, HiB and poliovirus with 100% of patients showing protective titers for TT, 95% for DT, 95% for PT, 90% for HiB, and 78% for poliovirus. We found no correlations of the serological responses with clinical transplant parameters.
In summary, patients after allo-SCT showed a weak mobilization of antigen-specific PBs accompanied by an inadequate increase in antibody titers on day 7 after booster vaccination. Patients with moderate or severe chronic GVHD had a significantly higher percentage of IgG secreting PBs prior to vaccination. The antigen-specificity of these IgG-secreting PBs present in elevated frequency in the patients after allogeneic SCT is currently unknown.
Supported by Deutsche Forschungsgemeinschaft through SFB 643 and TRR 221.

Disclosures
Roesler: Pfizer: Consultancy; Merck: Consultancy; Biogen: Equity Ownership; Amgen: Equity Ownership; Immunomedics: Equity Ownership; Sanofi: Other: Travel, Accommodations, Expenses; Jazz Pharmaceuticals: Other: Travel, Accommodations, Expenses.