Lack of Induction of RBD-Specific Neutralizing Antibodies despite Repeated Heterologous SARS-CoV-2 Vaccination Leading to Seroconversion and Establishment of T Cell-Specific Memory in a Patient in Remission of Multiple Myeloma

Abstract

Background: Prophylactic vaccination against infectious diseases may induce a state of long-term protection in the otherwise healthy host. However, the situation is less predictable in immunocompromised patients and may require adjustment of vaccination schedules and/or basic therapy. Methods: A patient in full remission of multiple myeloma since the last three years and on long-term maintenance therapy with pomalidomide, a drug inhibiting angiogenesis and myeloma cell growth, was vaccinated twice with Comirnaty followed by two vaccinations with Vaxzevria. Seroconversion and SARS-CoV-2-specific cellular responses were monitored. Results: No signs of seroconversion or T cellular memory were observed after the first “full immunization” with Comirnaty. Consequently, long-term-maintenance therapy with Pomalidomide was stopped and two additional shots of Vaxzevria were administered after which the patient seroconverted with Spike(S)-protein specific antibody levels reaching 49 BAU/mL, mild S-peptide pool-specific T cell proliferation, effector cytokine production (IL-2, IL-13), and T cellular activation with increased numbers of CD3+CD4+CD25+ T cells as compared to vaccinated and non-vaccinated control subjects. However, despite suspension of immunosuppression and administration of in total four consecutive heterologous SARS-CoV-2 vaccine shots, the patient did not develop neutralizing RBD-specific antibodies. Conclusions: Despite immunomonitoring-based adjustment of vaccination and/or therapy schedules vaccination success, with clear correlates of protection, the development of RBD-specific antibodies could not be achieved in the immunocompromised patient with current SARS-CoV-2 vaccines. Thus, our report emphasizes the need for improved active and passive immunization strategies for SARS-CoV-2 infections.

Combined assessment of S‐ and N‐specific IL‐2 and IL‐13 secretion and CD69 neo‐expression for discrimination of post–infection and post‐vaccination cellular SARS‐CoV‐2‐specific immune response

“…The vaccines currently authorized for use in Europe by the European Medical Association (EMA) are primarily mRNA‐ or vector‐based (Comirnaty, Spikevax, Vaxzevria, COVID‐19 Vaccine Janssen) and enable in vivo transfected or infected body cells, respectively, to exclusively express the SARS‐CoV‐2 S protein, but no other viral proteins. While in most cases, infection and vaccination induce humoral and cellular memory, 14 , 15 , 16 , 17 certain groups of individuals may have a considerable failure rate in doing so, 18 for example, those who suffer from (i) solid or hematologic malignancies and/or are in complete remission from such diseases, 19 , 20 or from (ii) primary 21 and secondary 22 , 23 immunodeficiency, have undergone (iii) solid 24 or bone marrow 25 transplantation, or are (iv) vaccine non‐responders. Apart from that, we have observed a considerable number (40%) of RBD non‐responders among COVID‐19 convalescent patients.…”

The frequency of differentiated CD3+CD27-CD28- T cells predicts response to CART cell therapy in diffuse large B-cell lymphoma

“…Five to seven days later, cells were used for in vitro assays. For proliferation assays, 1 x 10 5 CART cells were incubated with the indicated amounts of irradiated (120 Gray) CD19 + TM-LCL cells (ranging from 2 x 10 5 to 1 x 10 4 cells) in triplicates in 96-well round-bottom tissue culture plates (Sarstedt, Nümbrecht, Germany) in a total volume of 200 µl for 48 h. Cells were pulsed with [methyl- 3 H]-thymidine (1 µCi per well) for 18 hours and thymidine up-take was analyzed as previously described ( 44 ). For analysis of T cell activation and cytokine production, 1 x 10 5 CART cells were incubated with the indicated amounts of CD19 + TM-LCL cells (ranging from 2 x 10 5 to 1 x 10 4 cells) in triplicates in 96-well round-bottom plates in a total volume of 200 µl for 72 hours.…”

“…Subsequently, cell suspensions were transferred to 1.5 ml microcentrifuge tubes, centrifuged at 600 g for 5 minutes, supernatants were collected and subjected to cytokine analyses with a cytometric bead array (Luminex, Austin, TX) as described previously ( 45 ). Cells were stained as described ( 44 ), acquired on a Cytoflex flow cytometer (Beckmann Coulter) and data analyzed with the Flow Jo software package (Becton Dickinson).…”

Vaccine Response in the Immunocompromised Patient with Focus on Cellular Immunity

“…Additionally, another important aspect, the challenge of adapting immunization schedules and/or basic therapy for patients with haematological malignancies, is highlighted in a case report by Kratzer and colleagues [14]. A 58-year-old patient who suffered from multiple myeloma achieved complete remission after autologous stem cell transplantation and then received long-term maintenance treatment with the second-generation immunomodulatory agent pomalidomide for three years.…”

“…To improve the SARS-CoV-2 specific vaccine response, the attending physicians administered heterologous SARS-CoV-2 vaccination with two additional vaccinations with the vector-based vaccine ChAdOx1 and stopped the treatment with pomalidomide. Thereafter, the patient seroconverted with moderate spike-protein-specific antibody levels reaching 49 BAU/mL and achieved SARS-CoV-2-specific T-cell responses (T-cell proliferation, effector cytokine production (interleukin 2 and interleukin 13) and Tcell activation with increased numbers of CD3 + CD4 + CD25 + T cells) [14]. However, despite repeated heterologous SARS-CoV-2 vaccination, the patient did not develop neutralizing receptor-binding domain-specific antibodies.…”