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

Allogeneic hematopoietic stem cell transplantation (allo-HCT) is the best treatment option for many patients affected by hematological diseases with an unfavorable prognosis. This therapeutic procedure induces severe immunosuppression that persists months or even years after transplantation. As a result, infections caused by SARS-Cov2 can lead to severe complications and even death in allo-HCT patients, especially if they are close to transplantation and/or suffer from chronic graft-versus-host disease (GVHD). Establishing lasting protection in transplant patients is challenging, however, as their immune system is heavily affected by the transplant itself and by the possible occurrence of chronic GVHD. In this project, we conducted a systems biology/vaccinology analysis of response to the BNT162b2 messenger RNA vaccine against the SARS-Cov2 in 45 allo-HCT recipients. These patients received three doses of BNT162b2 vaccine: day 0 (1st dose), day 21 (2nd dose) and day 150 (3rd dose). Various blood samples were taken following vaccination. We performed bulk RNA-seq at days 0 and 1 of the 1st and 3rd doses, corresponding to day 0/day 1 and day 150/day 151 respectively. We then compared gene expression on day 1 versus 0 and day 151 versus 150 using paired methods. We observed 146 and 4005 genes significantly upregulated after the 1st dose and the 3rd dose of the vaccine, respectively. Grouping genes upregulated into signaling pathways using the Tmod package (https://rdrr.io/cran/tmod/), we observed upregulation of four modules after the 1st dose (3 modules related to interferon (IFN) signature and one module related to activated dendritic cells). The same 4 modules and 9 additional ones were upregulated after the 3rd dose. Interestingly, IFN upregulation did not correlate with antibody (Ab) responses to the vaccine. We next investigated whether gene expression at baseline (day 0) predicted Ab response to the vaccine after the 1st and the 3rd dose. Significantly enriched Gene Ontology (GO) terms about B cell population (differentiation, proliferation, activation) were upregulated in responders in comparison to non-responders. Finally, by TCR/BCR repertoire analysis, we observed that responders to the vaccine at higher numbers of B clonotypes at baseline than non-responders. In conclusion, we observed that the vaccine induced a IFN response that was higher after the third than after the first dose of the vaccine. In contrast to what was observed in healthy adults, this IFN response did not correlate with serological response to the vaccine. In contrast, importantly, a B-cell signature at baseline predicted better serological response.