Efficacy of Early Post-Transplant Vaccination Using a Prime and Boost Strategy Is Independent of a Prior History of GvHD: Results from BMT CTN 0201

Introduction: BMT CTN 0201 was a randomized trial of bone marrow (BM) vs G-CSF mobilized peripheral blood (G-PB) grafts in 550 patients with leukemia or MDS undergoing allogeneic hematopoietic stem cell transplantation from unrelated donors. Responses to the 23-valent-pneumococcal vaccine are poor in elderly and immune-compromised patients, including allo-transplant recipients. A secondary objective of BMT CTN 0201 compared responses to post-transplant vaccination using protein-based diphtheria-tetanus (dT) vaccine followed by two doses of a diphtheria-pneumococcal polysaccharide conjugate (PCV7) and the 23-valent pneumococcal polysaccharide vaccine (PPV23).

Methods: Vaccination started at 6 months post-transplant with dT followed by PCV7 at 7 and 9 months and PPV23 at 11 months post-transplant. Hepatitis B vaccination occurred at 6, 7 and 11 months. Serological responses in BMT CTN 0201 patients surviving to one year post-transplant were compared among those vaccinated per protocol (N=71), those that received partial vaccination (N=58) or no vaccines (N=39). Primary end-points were the fractions of vaccinated individuals with protective antibody titers to the 14 common pneumococcal bacterial serotypes, Hepatitis B, diphtheria and tetanus. Clinical history of acute or chronic GVHD, blood B-cells and T-cells, and serum immunoglobulin levels were studied as covariates of protective immunological responses.

Results: Overall survival at 3 years across the cohorts that received full, partial, or no vaccination was similar (81%, 87%, 84%). Lack of compliance with protocol vaccination did not vary according to whether subjects had a history of acute or chronic GVHD. The frequency of patients with prior history of grade 2-4 acute GVHD or chronic GVHD were similar across the three cohorts (82%, 90%, 82%), with comparable rates of severe grades 3-4 acute (10%, 12%, 13%) and extensive chronic GVHD (63%, 67%, 64%, respectively). Serological responses to vaccines did not differ between recipients of BM vs G-PB grafts, or whether patients had a history of grade 2-4 acute GVHD or chronic GVHD. Serological responses were highly associated with protocol-specified vaccination, with median (range) of titers (ug/mL) for fully vaccinated versus non-vaccinated individuals for HepB: 10.81 (0.05-110) versus 0.49 (0.05-63) p=0.01; tetanus, 2.80 (0.16-20) versus 0.40 (0.05-20) p<0.001; diphtheria: 1.62 (0.05-20) versus 0.08 (0.05-1.2) p<0.001; as well as protective antibody titers to each of the component pneumococcal epitopes shared between PCV7 and PPV23 (Table 1, N=71 fully vaccinated and N=48 with no pneumococcal vaccines). Among the fully-vaccinated cohort, a greater proportion had protective antibodies to individual pneumococcal serotypes present in the PCV7 "prime" vaccine (median 66%) versus those restricted to the PPV23 "boost" vaccine (median 41%). Serum levels of IgA, IgM, and IgG at 12 months post-transplant were correlated with the kinetics of B-cell recovery in the blood at 3, 6, and 12 months. Antibody titers to tetanus, diphtheria and 8/14 of the tested pneumococcal serotypes were correlated with total serum IgG levels at 12 months post-transplant. Titers to diphtheria, a T-cell dependent antigen, were correlated with day +100 blood levels of T-cells, myeloid dendritic cells and B-cells (p<0.05), while antibody levels to serotypes in PCV7 were correlated with day +100 levels of B-cells in the blood.

Conclusion: The efficacy of vaccination to specific pneumococcal serotypes among recipients of allogeneic transplants is enhanced by priming with dT and PCV7 prior to vaccination with the PPV23 vaccine. Vaccination is effective in patients with a history of acute or chronic GVHD. Strategies that enhance B-cell recovery post-transplant may improve responses to vaccines, especially those that are T-cell independent.

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