Reduced Antibodies and Innate Cytokine Changes in SARS-CoV-2 BNT162b2 mRNA Vaccinated Transplant Patients With Hematological Malignancies

Abstract

Immunocompromised individuals including patients with hematological malignancies constitute a population at high risk of developing severe disease upon SARS-CoV-2 infection. Protection afforded by vaccination is frequently low and the biology leading to altered vaccine efficacy is not fully understood. A patient cohort who had received bone marrow transplantation or CAR-T cells was studied following a 2-dose BNT162b2 mRNA vaccination and compared to healthy vaccine recipients. Anti-Spike antibody and systemic innate responses were compared in the two vaccine cohorts. The patients had significantly lower SARS-CoV-2 Spike antibodies to the Wuhan strain, with proportional lower cross-recognition of Beta, Delta, and Omicron Spike-RBD proteins. Both cohorts neutralized the wildtype WA1 and Delta but not Omicron. Vaccination elicited an innate cytokine signature featuring IFN-γ, IL-15 and IP-10/CXCL10, but most patients showed a diminished systemic cytokine response. In patients who failed to develop antibodies, the innate systemic response was dominated by IL-8 and MIP-1α with significant attenuation in the IFN-γ, IL-15 and IP-10/CXCL10 signature response. Changes in IFN-γ and IP-10/CXCL10 at priming vaccination and IFN-γ, IL-15, IL-7 and IL-10 upon booster vaccination correlated with the Spike antibody magnitude and were predictive of successful antibody development. Overall, the patients showed heterogeneous adaptive and innate responses with lower humoral and reduced innate cytokine responses to vaccination compared to naïve vaccine recipients. The pattern of responses described offer novel prognostic approaches for potentiating the effectiveness of COVID-19 vaccination in transplant patients with hematological malignancies.

Low Spike Antibody Levels and Impaired BA.4/5 Neutralization in Patients with Multiple Myeloma or Waldenstrom’s Macroglobulinemia after BNT162b2 Booster Vaccination

“…However, the cohorts of WM on active therapy (G1) and of MM on anti-CD38 and anti-BCMA regimens (G3a and G3b) were severely affected in both vaccine-induced response rates and/or magnitude resulting in their severely reduced ability to bind to Spike-RBD. Since WA1 Spike-RBD endpoint titers of <3000 are predicted to lack neutralization ability in the pseudotype virus assay [ 12 , 27 ], 50–90% of patients (cohorts of WM on-therapy; MM on anti-CD38 or anti-BCMA regimens) were predicted to also have poor neutralization capabilities.…”

“…Responses at threshold (serum dilution 1:40; ID50 0.5 log) were considered negative. Applying a selection threshold, samples with Spike-RBD Ab titer >3000 were included ( Figure S1 ), because they were likely to show measurable neutralization in our functional assay [ 12 , 27 ]. In further support of this notion, we tested seven sera with Spike-RBD Ab levels below the selection cut-off (red symbols below the threshold line) which were indeed negative, along our prediction ( Figure 4 , red square symbol).…”

“…In-house ELISA assays using a panel of purified full-length trimeric Wuhan (WA1) Spike and Spike-RBD proteins and a panel of Variant of Concern (VOC) Spike and Spike-RBD proteins (Delta B.1.617.2, Omicron BA.1 (B.1.1.529) and BA.2) were detailed elsewhere [ 12 , 26 , 27 ]. Ab levels were measured using eight 4-fold serial serum dilutions starting at 1:50 and endpoint titers were determined using lastX feature using GraphPad prism area-under-the curve program.…”

“…Pseudotype neutralization was performed using a HIV NL DEnv-Nanoluc assay [ 30 , 31 ] carrying the 1254-AA WA1 (D616G), Delta, BA.1, BA.2 and BA.4/5 Spike proteins (AA 1-1254) as described [ 12 , 26 , 27 ]. BA.4/5 Spike, a gift from T. Hatziioannou (Rockefeller University, New York, NY, USA), also has the R683G substitution.…”

“…The majority of studies have evaluated neutralizing antibodies (NAb) against original Wuhan-HA-1 (referred to as WA1) SARS-CoV-2 virus or against initial mutants (Alpha to Delta) after primary and booster vaccination [ 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 ], but there is presently few data for the efficacy of vaccination against Omicron and its subvariants in patients with hematological malignancies [ 9 , 10 , 11 , 12 ]. Omicron variants, including the recently emerged variants BA.4 and BA.5, which are more infectious than the original WA1 strain, are spreading throughout the globe since late 2021 [ 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 ].…”