Systems vaccinology study of responses to BNT162b2 vaccine in allogeneic hematopoietic stem cell transplant recipients

We previously reported that following two doses of BNT162b2 administration (n=40), 86% of the COVID-19 naive patients achieved detectable anti-RBD antibodies (Ab) while 49% of them had detectable neutralizing Ab against the wild type SARS-CoV-2 virus (Canti et al., J Hem&Oncol 2021). We then reported that administration of a third dose of the vaccine (booster) approximately 150 days after first vaccination significantly increased Ab responses and allowed the generation of detectable neutralizing Ab against the wild type and omicron variants of the virus in 87% and 60.5% of the patients, respectively (Canti et al., Cancer Cell 2022). The aim of the current study was to determine the transcriptomic signature of the vaccine as well as to identify baseline signatures associated with the serological response to the vaccine. We first compared gene expression on day 1 versus 0 of the first and third vaccine, using paired methods. We observed 171 and 451 genes significantly upregulated after the 1st dose and the 3rd dose of the vaccine, respectively. GSEA analyses demonstrated that the first dose of the vaccine upregulated 7 blood transcriptional modules (BTMs, 2 related to interferon signaling and 7 related to the innate immune response) while the third dose of the vaccine upregulated 20 BTMs (5 related to interferon signaling, 13 related to the innate immune response and 2 related to B-cells). In contrast, BTMs related to T-cell activation were downregulated and particularly after the third dose of the vaccine. Further, importantly, patients who achieved a good serological response to the vaccine had higher frequencies of BTMs associated with B-cell enrichment at baseline. We observed that BNT162b2 vaccine induced a higher innate immune response after the 3rd than after the 1st dose of the vaccine. Further, a B-cell signature at baseline predicted serological response to the vaccine.