Sex: M
Vaccine: COVID19
Symptoms: CD4 lymphocytes, CD8 lymphocytes, Drug ineffective, Immunoglobulins, Investigation
Clinical narrative: against the spike protein receptor binding domain was assessed five weeks after the second dose and was undetectable at <0.4/Immunogenicity of a heterologous COVID-19 vaccine after failed vaccination; against the spike protein receptor binding domain was assessed five weeks after the second dose and was undetectable at <0.4/Immunogenicity of a heterologous COVID-19 vaccine after failed vaccination; This is a literature report from a regulatory authority after failed vaccination in a lymphoma patient.  We read with great interest the recent publications in a regulatory authority. Both studies demonstrated that a lower proportion of patients with hematologic malignancies serocon verted. Additionally, these individuals had lower absolute antibody titers. Similar data have emerged from other studies, some showing even lower seroconversion rates of 50%-60% in patients with hema tologic malignancies. Seroconversion to other standard vaccinations is known to be relatively poor in this population, with rates of ~50% or lower in patients with chronic lymphocytic leukemia, for example, espe cially in those receiving agents such as Brutons tyrosine kinase inhibitors (BTKis) or anti-B cell antibody therapies. These observations are important given that individuals with hematologic malig nancies have a high incidence of morbidity and mortality from COVID-19, likely due to advanced age, comorbidities, and disease- and/or treatment-related immune dysfunction. Thus, as the authors emphasize, there is a critical need to determine better vacci nation 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, but to the authors knowl edge, there are no reports of these ap proaches 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 subse quently 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/Bio NTech) in February and March of 2021. An EUA-authorized semiquantitative total antibody assay against the spike protein receptor binding domain was assessed five weeks after the second dose and was undetectable at 0.79 AU/mL is considered pos itive, and 250 AU/mL is the undiluted up per 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 quali tative anti-nucleocapsid assay was also negative. The patient independently sought out and received a third vaccination with the JNJ-78436735 viral vector vaccine (John son & 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. Subse quent testing with the same assay 18 days later demonstrated seroconver sion based on an anti-spike protein total antibody titer of 215 AU/mL. Repeat testing 3 days later demonstrated a nega tive 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 neutraliza tion assay resulted in a 50% neutralization dose (ND50) of 242, corresponding to 51 international units (IU)/mL using the a regulatory authority for anti SARS-CoV-2 antibody. Laboratory results prior to and after vaccinations demonstrated less-than-normal/low-normal white blood cell counts, lymphocyte counts, and im munoglobulins (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 im munity in immunocompromised patients despite low B cell levels. Homologous booster doses may be similarly effica cious. However, this individual antibody titer after a third dose remained lower than typically observed with this assay in healthy individuals or those with solid tu mors, with most people generating titers >1,000 AU/mL. As of this writing, we are unaware of re ports 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, along with emerging data of impaired immunogenicity of primary SARS-CoV-2 vaccine series in immunocompromised patients, underscore the urgent need to perform trials assessing alternative vacci nation strategies in high-risk populations  Table S1. Immunologic markers and SARS-CoV-2 antibody response in a 59-year-old man with lymphoplasmacytic lymphoma receiving a Bruton's tyrosine kinase inhibitors (BTKi) Pre-vaccine 1              Pre-vaccine 2         Postvaccine 2  Post-vaccine 3                              (BNT162b2 mRNA)   (BNT162b2 mRNA)                            (JNJ-78436735,viral vector)   Anti-SARS-CoV-2 spike protein total  NA                              NA                              <0.4                   215 antibody titer (AU/mL)a   Anti-SARS-CoV-2  neutralilzing  antibody titer (ND50) NA                         NA                               NA                     242  WBC (103 cells/uL)b   3.68                  3.51                                                          4.48 ALC (103 cells/uL)      1.55                  1.41                                                          1.89 IgG (mg/dL                 587                     NA                                                           585 IgM (mg/dL)                 180                    NA                                                            189 IgA (mg/dL)                 94                      NA                                                            101 CD3+/CD4+ T cells    NA                     NA                                                            1039 (cells/uL) CD3+/CD8+ T cells    NA                     NA                                                            489 (cells/uL)d CD19+ B cells  (cells/uL)                    NA                    NA; Sender's Comments: Based on known drug safety profile, there is reasonable possibility of causal association between the events covid-19 and suspected covid-19 and the suspect drug BNT162B2.