key: cord-0713464-2w3spcwn authors: Tanguay, Mégane; Boutin, Marianne; Laumaea, Annemarie; Salaciak, Matthew; Mendoza, Alma; Cassis, Chantal; Ajjamada, Lissa; Assouline, Sarit; Patenaude, François; Clark, Michael Webster; Finzi, Andrés; Johnson, Nathalie A. title: B-cell cytopenia and time to last B-cell-depleting therapy predict response to SARS-COV-2 vaccines in patients with lymphoproliferative disorders date: 2022-01-24 journal: Vaccine DOI: 10.1016/j.vaccine.2022.01.040 sha: 7c10fd5d5c1dd453b9bbb2a3ea191fe2ac199067 doc_id: 713464 cord_uid: 2w3spcwn Patients with B-non-Hodgkin lymphoma (NHL) are at increased risk of morbidity and mortality from SARS-CoV-2. We investigated the relationship between B cell cytopenia and the SARS-CoV-2 vaccine response in B-NHL patients. We measured anti-RBD antibodies and the lymphocyte immunophenotype in 19 controls, 22 lymphoma patients on observation (cohort 1) and 55 lymphoma patients receiving their vaccines post B-cell depleting therapy (cohort 2). Half of the lymphoma patients in both cohorts achieved seropositivity compared to 100% of controls. In cohort 2, only 5% achieved an antibody response in the first year post B-cell depleting treatment, vs 88% treated >2 years prior. Also, 28% of patients with <50 B cells/µl achieved a serologic response vs 86% of patients with B-cell >50 B cells/µl. B-cell cytopenia is profound within the first year of exposure to B-cell depleting treatment, therefore an additional dose of vaccine within that timeframe is unlikely to raise antibody levels. 1 Introduction 2 Coronavirus disease 2019 caused by the severe acute respiratory syndrome 3 coronavirus 2 (SARS-CoV-2) infection created a pandemic that has killed more than 5 million 4 people (1). This RNA virus uses the receptor binding domain (RBD) of its Spike glycoprotein to 5 enter host cells, which is the target of neutralizing antibodies acquired from natural infection (2, 6 3) and vaccines (4, 5) . Vaccination against SARS-CoV-2 decreases COVID-19 related mortality 7 and hospitalizations. However, patients with B-non-Hodgkin lymphoma (NHL) experience 8 suboptimal antibody responses to COVID-19 vaccines, before and after B-cell-targeted therapies, 9 such as the anti-CD20 antibody rituximab (6-11). We investigated the relationship between B cell 10 cytopenia and vaccine response in B-NHL to identify the best time for "booster" doses in patients 11 receiving B cell-depleting therapies. We measured anti-RBD antibodies and the absolute number of B cells in the peripheral blood (PB) 14 of 77 patients with lymphoma and compared them to 19 healthy controls. This project was 15 approved by our research ethics board (REB#2022-3008, REB11-047,2012-95) . Participants 16 consented to PB collection prior to the first vaccine dose, two to five weeks after the first dose and 17 second doses. Cohort 1 comprised 22 lymphoma patients on observation or receiving their vaccine 18 at least 2 weeks prior to initiating treatment. Cohort 2 included 55 patients who received their 2 19 doses after exposure to B-cell depleting treatment (< 1 year (n=22), 1-2 year (n=16) and > 2 years 20 (n=17)). Baseline immune profile, available in 69 participants, was determined using the complete To evaluate the association between the timing of the last rituximab dose and antibody response, 33 we restricted to the cohort that received rituximab prior to the vaccine and estimated crude odds 34 ratios for antibody response for three categories of rituximab dose timing (up to 1 year before 35 vaccine receipt, 1-2 years before vaccine receipt, and 2 or more years before vaccine receipt as the 36 referent), as well as odds ratios for a ten year increase of age, a one week increase in time between 37 doses, and current disease status (active vs in remission). Multivariable logistic regression was 38 then used to determine if the association between the last dose of rituximab and the antibody 39 response changed when holding age, current disease status and time between vaccine doses were 40 constant. P values for the rituximab timing group were obtained from Type 3 tests. To assess 41 whether damage to B cells by recent rituximab therapy was a potential mechanism for this effect, 42 we also estimated the association between CD19 levels < 50 B cells/µl and antibody production 43 from a crude odds ratio and after multivariable regression adjusting for age and time between Table 1 ). Focusing on cohort 2, the timing vaccines, yet our results could potentially apply to other vaccines. In accordance with previous studies, our NHL patients generate poor antibody responses upon 99 COVID vaccine administration, with a more pronounced deficiency detected after exposure to 100 rituximab (18-22). Our data demonstrates that poor seroconversion rates occur concomitantly with 101 severe B-cell cytopenia, which is most severe within the first year post rituximab. We therefore 102 predict that additional vaccine doses won't be very effective at raising antibody levels within this 103 time frame or before B cell recovery, which occurs in the second-and third-year post treatment. Even in these later timeframes, the average antibody levels were lower than in controls (Figure 1 ). Poor antibody production in response to the COVID vaccines has been previously observed in B- While we focused on antibody levels, other aspects of immunity, including host characteristics 114 (e.g. co-morbidities, medications, germline polymorphisms and more specific immune profiling) 115 were not measured in this study and likely influence anti-COVID-19 immunity. We acknowledge 116 that the specific T-cell response to the vaccine was not measured in this study, but likely plays a 117 role in the development of . Our data confirms the importance of 118 appropriate counselling in these high-risk lymphoma patients that are vaccinated, but not COVID-19 Dashboard by the Center for Systems Science and Engineering Cryo-EM 154 structure of the 2019-nCoV spike in the prefusion conformation Antigenicity of the SARS-CoV-2 Spike Glycoprotein Efficacy and 160 Safety of the mRNA-1273 SARS-CoV-2 Vaccine. The New England journal of medicine Safety and 163 Efficacy of the BNT162b2 mRNA Covid-19 Vaccine. 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