We found higher seroprotection rates pre-vaccination among CD19-directed CAR T-cell therapy recipients compared to those receiving BCMA-targeted therapy, in accordance with previous studies [15]. However, vaccine response rates did not differ significantly between CD19 and BCMA recipients. A substantial proportion of patients were seroprotected pre-vaccination, complicating the assessment of vaccine-induced responses. Most patients with pre-existing immunity retained their immunity following vaccination. Among those non-protected, humoral vaccines response rates varied considerably between different antigens, but for some antigens (tetanus, hepatitis A and B) the number of evaluable patients was relatively low. The particularly low response rate to conjugate pneumococcal vaccines (7/21 = 33%) is concerning, as pneumococcal vaccination is a key component of post-CAR T immunization strategies. While alternative approaches, such as penicillin prophylaxis and IVIG exist, they have distinct disadvantages, and their efficacy in this population remains unproven.
Among the immune markers assessed, IgA was the only parameter significantly associated with vaccine response status. Although absolute B-cell counts were numerically higher among global responders, this difference was not statistically significant. Notably, most clinicians defer vaccination until patients reach a CD4+ count above 200 cells/µL and IgG above 500 mg/dL, which may have led to a more selectively immunoreconstituted cohort at the time of vaccination, potentially impacting the observed associations.
The significant association with IgA may reflect its role as a marker of broader B-cell recovery and functional immune reconstitution. Unlike serum IgG, which can be influenced by passive immunoglobulin replacement, IgA is primarily produced by reconstituting plasma cells and may serve as a more dynamic indicator of vaccine readiness. Notably, expert recommendations have suggested using IgA levels to guide vaccination timing post-CAR T [21], as the presence of IgA implies successful class switching and B-cell maturation. Class switching from IgM to IgG and IgA is a key feature of humoral recovery, indicating not only B-cell presence but also functional differentiation, necessary for vaccine responsiveness.
No patient in the study was seroprotected against pneumococcus pre-vaccination, despite some patients (n = 20) having received a full vaccination schedule, including several pneumococcal conjugate vaccine doses, following prior autologous hematopoietic cell transplantation (auto-HCT). Since most of these patients had myeloma and had been vaccinated before CAR T therapy, it is conceivable that the lack of immunity may be specifically due to the depletion of plasma cells by BCMA CAR T-treatment. However, samples collected prior to CAR T-therapy, which were unfortunately not available, could have provided further clarification on this issue. Another potential explanation for this observation may be the immunoparesis observed in myeloma patients. Alternatively, the specific types of previous treatment lines may contribute to the disease-specific differences in seroprotection rates, as more myeloma patients had received CD38-targeting antibodies, autologous HCT, or BCMA/GPRC5D-directed bispecific antibodies.
As BCMA CAR T-recipients were less likely to be seroprotected against most antigens prior to vaccination, earlier or more intensive vaccination strategies may be justified in this population. This consideration is particularly relevant for patients with travel plans or in other settings with increased exposure risk, such as a local outbreak of vaccine-preventable disease.
Given the lack of data, practices for vaccination post-CAR T vary between centers, with some centers adapting the schedule from the stem cell population, some centers awaiting immunological milestones, some centers checking serology pre and post-vaccination and some centers not offering basic immunization [22]. Thus, different approaches to vaccination post-CAR T have been proposed. According to the recent ASTCT guidelines, it is recommended to assess serological responses both pre and post-vaccination to tailor immunization strategies [23], while Reynolds et al. propose an abbreviated vaccination schedule modeled on that used following hematopoietic stem cell transplantation [21]. Both approaches offer distinct advantages and disadvantages, with the former focusing on individualized monitoring and the latter prioritizing a simplified implementation. The retrospective nature of our study precludes us from providing definitive clinical recommendations. However, the particularly low seroprotection rates pre-vaccination in BCMA recipients, as well as in both groups for pneumococcus, warrant clinical attention.
The timing of vaccination post-CAR T-cell therapy remains a clinical challenge. On one hand, delaying vaccination until full immune reconstitution may optimize vaccine responsiveness. On the other hand, postponing immunization increases the period during which patients remain vulnerable to severe infections. The urgency of vaccination may also vary depending on the pathogen. For infections such as tetanus, diphtheria, polio and pertussis where the primary goal is long-term protection and herd immunity provides an additional layer of defense, a more cautious approach to vaccination timing may be justified. However, for pathogens like Streptococcus pneumoniae, Influenza, SARS-CoV-2, Respiratory syncytial virus (RSV) and Varicella-zoster, where the risk of severe infection is high [24,25,26] and protection relies primarily on individual immunity, it may be beneficial to vaccinate earlier, even if responses are suboptimal. Striking a balance between these factors is crucial, and identifying immune markers predictive of vaccine responsiveness, such as IgA levels and the extent of B-cell aplasia, could aid in determining the optimal timing of vaccination.
The current study has some limitations. T-cell-mediated immunity was not assessed, which may play an essential role in vaccine responses, particularly in B-cell-depleted patients. Given that humoral responses are often impaired following CAR T therapy, T-cell immunity could provide an alternative mechanism of protection. Previous studies have suggested that T-cell responses may compensate for diminished antibody production in immunocompromised individuals [9, 27]. However, evaluating T-cell responses remains challenging due to the high cost, labor-intensive nature, and lack of standardized assays for functional T-cell testing. Further limitations of the present study were its retrospective nature with relatively small patient numbers. The study cohort only consisted of patients who were considered eligible for vaccination by their treating clinician. Patients with ongoing severe infections, relapse, immunomodulating therapy, or those who had not achieved immunological milestones were often excluded from vaccination. Therefore, our data are most applicable to CAR T recipients who are clinically stable and progressing well.
Furthemore, the VZV serological testing was performed using commercially available IgG assays commonly used in clinical practice, which do not specifically measure glycoprotein E (gE)-directed antibodies. As a result, the reported seroprotection rates may reflect immunity from either prior infection or vaccination, as the assay does not distinguish between the two.
To our knowledge, this is the first study to evaluate vaccine responses post-CAR T beyond COVID-19 and influenza, providing novel insights into immunity against a broader range of pathogens. The availability of detailed immune reconstitution parameters allowed for a comprehensive analysis of factors influencing vaccine responses in this population.
