key: cord-0981129-dlc6l3qm
authors: Hill, Joshua A.; Ujjani, Chaitra S.; Greninger, Alexander L.; Shadman, Mazyar; Gopal, Ajay K.
title: Immunogenicity of a heterologous COVID-19 vaccine after failed vaccination in a lymphoma patient
date: 2021-06-26
journal: Cancer Cell
DOI: 10.1016/j.ccell.2021.06.015
sha: fbe886fc5c27811189eec0f2cd56761f34136ff9
doc_id: 981129
cord_uid: dlc6l3qm

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These observations are important given that individuals with hematologic malignancies have a high incidence of morbidity and mortality from COVID-19 (Mato et al., 2020) , likely due to advanced age, comorbidities, and diseaseand/or treatment-related immune dysfunction. Thus, as the authors emphasize, there is a critical need to determine better vaccination strategies in immunocompromised individuals. There is clinical precedent for higher-, additional-, or heterologous-dose strategies for standard and SARS-CoV-2 vaccines in other contexts (Cardell et al., 2008; Hillus et al., 2021; Werbel et al., 2021) , but to the authors' knowledge, there are no reports of these approaches using SARS-CoV-2 vaccines in cancer patients.

Here, we describe a 59-year-old man with lymphoplasmacytic lymphoma who received four doses of rituximab (anti-CD20) in November 2016 and subsequently began daily ibrutinib (a BTKi) in November 2017, achieving a partial response. He switched to zanubrutinib (an alternative BTKi) in July 2020 due to intolerance with ibrutinib. He received the standard two doses of the BNT162b2 mRNA vaccine (Pfizer/BioNTech) in February and March of 2021. An EUA-authorized semiquantitative total antibody assay (Roche Elecsys Anti-SARS-CoV-2 S) against the spike protein receptor binding domain was assessed five weeks after the second dose and was undetectable at <0.4 arbitrary units (AU)/mL (>0.79 AU/mL is considered positive, and 250 AU/mL is the undiluted upper limit, which may be reported up to 2,500 AU/mL or 25,000 AU/ML for 10-fold or 100-fold diluted samples). A qualitative antinucleocapsid assay (Roche Elecsys Anti-SARS-CoV-2 N) was also negative.

The patient independently sought out and received a third vaccination with the JNJ-78436735 viral vector vaccine (Johnson & Johnson) 10 weeks after his second dose of the BNT162b2 mRNA vaccine. He reported mild malaise and headache starting 1 day post-vaccination, and that resolved by the following day. Subsequent testing with the same assay 18 days later demonstrated seroconversion based on an anti-spike protein total antibody titer of 215 AU/mL. Repeat testing 3 days later demonstrated a negative anti-nucleocapsid antibody and a positive anti-spike protein total antibody titer of 207 AU/mL on the same assays described above. A D614G SARS-CoV-2 spike pseudotyped lentivirus neutralization assay resulted in a 50% neutralization dose (ND 50 ) of 242, corresponding to 51 international units (IU)/mL using the WHO International Standard for anti-SARS-CoV-2 antibody (Table S1 ). Laboratory results prior to and after vaccinations demonstrated less-than-normal/low-normal white blood cell counts, lymphocyte counts, and immunoglobulins (Table S1 ). He did not receive immunoglobulin replacement therapy in the interim.

This case suggests that heterologous vaccination against SARS-CoV-2 may yield measurable antibody-mediated immunity in immunocompromised patients despite low B cell levels. Homologous booster doses may be similarly efficacious. However, this individual's antibody titer after a third dose remained lower than typically observed with this assay in healthy individuals or those with solid tumors, with most people generating titers >1,000 AU/mL (Addeo et al., 2021; Bradley et al., 2021; Herishanu et al., 2021) . As of this writing, we are unaware of reports of safety or immunogenicity of mixed COVID-19 vaccine regimens in cancer patients. Limitations of this report include that it is a single case, and we do not present data pertaining to cellular immunity. Nonetheless, these results,

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