key: cord-0910025-hrjhszjd authors: Ujjani, Chaitra; Greninger, Alexander L.; Shadman, Mazyar; Hill, Joshua A.; Lynch, Ryan C.; Warren, Edus H.; Gopal, Ajay K. title: Heterologous SARS‐CoV‐2 vaccinations in patients with B‐cell lymphoid malignancies date: 2021-11-30 journal: Am J Hematol DOI: 10.1002/ajh.26418 sha: e17e18c38dc61f8f144a3a3115201955133dec93 doc_id: 910025 cord_uid: hrjhszjd nan To the Editor: The SARS-CoV-2 vaccines have been widely distributed based on remarkable efficacy in immunocompetent patients. Unfortunately, there is a growing body of literature indicating decreased efficacy in patients with lymphoma, particularly those receiving B-cell-directed therapy. 1 Given high rates of morbidity and mortality, improving vaccine strategies is a critical area of unmet need. Studies have shown improved immunogenicity in solid organ recipients with a third mRNA vaccine. 2 Here we present the first case series evaluating the use of a heterologous mRNA/vector/mRNA vaccination strategy in patients with lymphoma. By serology assessment alone, the use of a viral vector vaccine after the two-dose mRNA series was successful in inducing a response. Our results mirror a recent report from the LLS in which 9 of 17 seroconverted with J&J after mRNA vaccination; resulting antibody levels ranged from 2.3 to 157 AU/mL using the same Roche assay. 5 A more robust response was seen in three who were seropositive prior to J&J (> 2500 AU/mL). Interestingly, we also found that the addition of a fourth dose allowed for further augmentation of the serologic response. These findings are promising for vulnerable patients struggling to understand how to exist in their environment. Determining exactly who this strategy will benefit, however, is not possible from this small cohort. A number of variables such as type of B-cell directed therapy, length of and time from exposure, sequence of and duration between vaccinations, and underlying disease biology may have had an impact. There was a suggestion, though, that an absence of normal B-cells may be predictive of inability to mount an appropriate serologic response. Given the paucity of data we look to the transplant literature for insight into other vaccine-induced immunologic changes, recognizing the differences in mechanisms of immunosuppression, that is, calcineurin inhibitors and antimetabolites. In a German study of solid organ recipients, researchers found that the vector/mRNA vaccine schedule led to statistically significant increases in spike antibody levels, neutralization antibody activity, and SARS-CoV-2-reactive CD4 T-cells, as well as a trend toward increased numbers of CD8 T-cells. 6 Unfortunately, the scope of our analysis did not allow for assessment of cellular immune response. In light of our findings, we are challenged with new questions. What are the immunologic changes that allow for a viral vector/mRNA approach to be effective after failed response to homologous mRNA vaccination? Does the improvement in serologic response correlate with actual clinical benefit? For whom should a heterologous approach be considered before a homologous approach? Is one type of vaccine better utilized for priming and is that dependent on patient-specific F I G U R E 1 Serologic response with sequential vaccinations EW has no conflicts of interest. AG receives research funding from Merck Email: ujjani@uw Mazyar Shadman Antibody response to SARS-CoV-2 vaccines in patients with hematologic malignancies Antibody response after a third dose of the mRNA-1273 SARS-CoV-2 vaccine in kidney transplant recipients with minimal serologic response to 2 doses Heterologous ChAdOx1 nCoV-19 and mRNA-1273 vaccination Immunogenicity of a heterologous COVID-19 vaccine after failed vaccination in a lymphoma patient Anti-spike antibody response to SARS-CoV-2 booster vaccination in patients with B cellderived hematologic malignancies Cellular immunity predominates over humoral immunity after homologous and heterologous mRNA and vector-based COVID-19 vaccine regimens in solid organ transplant recipients Additional supporting information may be found in the online version of the article at the publisher's website. Received