Suppression of de novo antibody responses against SARS-CoV2 and the Omicron variant after mRNA vaccination and booster in patients with B cell malignancies undergoing active treatment, but maintenance of pre-existing antibody levels against endemic viruses
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Abstract
The impact of SARS-CoV2 vaccination in cancer patients remains incompletely understood given the heterogeneity of cancer and cancer therapies. We assessed vaccine-induced antibody response to the SARS-CoV2 Omicron (B.1.1.529) variant in 57 patients with B cell malignancies with and without active B cell-targeted therapy. Ancestral- and Omicron-reactive antibody levels were determined by ELISA and neutralization assays. In over one third of vaccinated patients at the pre-booster timepoint, there were no ELISA-detectable antibodies against either the ancestral strain or Omicron variant. The lack of vaccine-induced antibodies was predominantly in patients receiving active therapy such as anti-CD20 monoclonal antibody (mAb) or Bruton’s tyrosine kinase inhibitors (BTKi). While booster immunization was able to induce detectable antibodies in a small fraction of seronegative patients, the benefit was disproportionately evident in patients not on active therapy. Importantly, in patients with post-booster ELISA-detectable antibodies, there was a positive correlation of antibody levels against the ancestral strain and Omicron variant. Booster immunization increased overall antibody levels, including neutralizing antibody titers against the ancestral strain and Omicron variant; however, predominantly in patients without active therapy. Furthermore, ancestral strain neutralizing antibody titers were about 5-fold higher in comparison with those to Omicron, suggesting that even with booster administration, there may be reduced protection against the Omicron variant. Interestingly, in almost all patients regardless of active therapy, including those unable to generate detectable antibodies against SARS-CoV2 spike, we observed comparable levels of EBV, influenza, and common cold coronavirus reactive antibodies demonstrating that B cell-targeting therapies primarily impair de novo but not pre-existing antibody levels. These findings suggest that patients with B cell malignancies on active therapy may be at disproportionately higher risk to new versus endemic viral infection and suggest utility for vaccination prior to B cell-targeted therapy.
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SciScore for 10.1101/2022.03.17.22272389: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Ethics not detected. Sex as a biological variable not detected. Randomization not detected. Blinding not detected. Power Analysis not detected. Cell Line Authentication not detected. Table 2: Resources
Antibodies Sentences Resources Goat Anti-Human IgG/IgA/IgM Fc crossed-absorbed secondary antibody HRP, Invitrogen, used at 1:3000 dilution) antibody solution in 1% milk powder and PBS-T solution was added to each well and incubated in the dark at room temperature for 1 hour. Anti-Human IgG/IgA/IgMsuggested: (Sigma-Aldrich Cat# S4893, RRID:AB_10625701)Experimental Models: Cell Lines Sentences Resources Following 1hr incubation at 37°C, virus was used to infect HEK293T-ACE2 cells. HEK293T-ACE2suggested: NoneThe … SciScore for 10.1101/2022.03.17.22272389: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Ethics not detected. Sex as a biological variable not detected. Randomization not detected. Blinding not detected. Power Analysis not detected. Cell Line Authentication not detected. Table 2: Resources
Antibodies Sentences Resources Goat Anti-Human IgG/IgA/IgM Fc crossed-absorbed secondary antibody HRP, Invitrogen, used at 1:3000 dilution) antibody solution in 1% milk powder and PBS-T solution was added to each well and incubated in the dark at room temperature for 1 hour. Anti-Human IgG/IgA/IgMsuggested: (Sigma-Aldrich Cat# S4893, RRID:AB_10625701)Experimental Models: Cell Lines Sentences Resources Following 1hr incubation at 37°C, virus was used to infect HEK293T-ACE2 cells. HEK293T-ACE2suggested: NoneThe codon-optimized D614G and Omicron (B.1.1.529) SARS-CoV-2 S constructs were synthesized by GenScript (Piscataway, NJ) and subsequently cloned into a pcDNA3.1 vector by restriction enzyme cloning with Kpn I and BamH I. Cell Lines and Maintenance: HEK293T cells (ATCC CRL-11268, CVCL_1926) and HEK293T-ACE2 cells (BEI, NR-52511) were maintained in DMEM (Gibco, 11965-092) supplemented with 10% FBS (Sigma, F1051) and 1% penicillin/streptomycin (HyClone, SV30010). HEK293Tsuggested: ATCC Cat# CRL-11268, RRID:CVCL_1926)Recombinant DNA Sentences Resources Constructs: The construct used for the production of lentiviral pseudotypes was pNL4-3-ΔEnv-inGluc (49), which was originally obtained from David Derse’s lab at NIH (National Cancer Institute, Frederick, Maryland, USA) and Marc Johnson’s lab at the University of Missouri (Columbia, Missouri, USA). pNL4-3-ΔEnv-inGlucsuggested: NoneThis construct is based on a ΔEnv pNL4.3 HIV-1 vector and contains an anti-sense Gaussia luciferase (Gluc) gene with a sense intron. pNL4.3 HIV-1suggested: NoneThe codon-optimized D614G and Omicron (B.1.1.529) SARS-CoV-2 S constructs were synthesized by GenScript (Piscataway, NJ) and subsequently cloned into a pcDNA3.1 vector by restriction enzyme cloning with Kpn I and BamH I. Cell Lines and Maintenance: HEK293T cells (ATCC CRL-11268, CVCL_1926) and HEK293T-ACE2 cells (BEI, NR-52511) were maintained in DMEM (Gibco, 11965-092) supplemented with 10% FBS (Sigma, F1051) and 1% penicillin/streptomycin (HyClone, SV30010). pcDNA3.1suggested: RRID:Addgene_79663)Software and Algorithms Sentences Resources Neutralization curves were plotted in GraphPad Prism 5 using least-squares fit non-linear regression to determine neutralizing titers 50%. GraphPad Prismsuggested: (GraphPad Prism, RRID:SCR_002798)Statistical Analysis: GraphPad Prism 9 and R 4.1.1 were used for statistical analyses. GraphPadsuggested: (GraphPad Prism, RRID:SCR_002798)Results from OddPub: We did not detect open data. We also did not detect open code. Researchers are encouraged to share open data when possible (see Nature blog).
Results from LimitationRecognizer: We detected the following sentences addressing limitations in the study:Limitation of our study: An important limitation in our study is that while active therapy is associated with blunted antibody responses, we cannot formally determine whether reduced antibody responses are due to therapy or more advanced disease. Other limitations of our study include a relatively low patient number, the inherent heterogeneity in patients both in terms of disease and treatment, and the range in time between vaccination and blood draws. While we excluded patients with SARS-CoV2 therapeutic mAb treatment within 6 months of the post-booster blood draw, as our patient population is highly vulnerable, medical records may not have reflected mAb therapy performed at other sites. We also did not assess other immune correlates that may be impactful for protection including memory B cells, the presence of which may be more critical than antibody levels. Finally, while our data suggest that it may be important to vaccinate prior to initiating B cell targeted therapy, clinical studies will be necessary to further validate this possibility.
Results from TrialIdentifier: No clinical trial numbers were referenced.
Results from Barzooka: We did not find any issues relating to the usage of bar graphs.
Results from JetFighter: We did not find any issues relating to colormaps.
Results from rtransparent:- Thank you for including a conflict of interest statement. Authors are encouraged to include this statement when submitting to a journal.
- Thank you for including a funding statement. Authors are encouraged to include this statement when submitting to a journal.
- No protocol registration statement was detected.
Results from scite Reference Check: We found no unreliable references.
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