Divergent Immune Responses to SARS-CoV-2 Vaccines in Immunocompromised Patients.

To The Editor:

Understanding the composition and duration of immune responses to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination is critical for prevention of infection. The most critical elements of immunity to SARS-CoV-2 are neutralizing antibody and T-cell immunity. Current assessments of immunity and risk for infections largely depended on detection of antibodies to SARS-CoV-2. However, taken alone, this represents an often-unreliable tool due to the evanescent nature of spike immunoglobulin G (IgG) responses.[1-3] Here, an important and more durable response involves cytotoxic T-cells that can eliminate virally infected cells and T helper cells, which are critical to coordinating adaptive immunity toward the virus and generating long-lasting immunologic memory. However, T-cell responses are more difficult to assess. These issues become more prescient in determining immunity to SARS-CoV-2 in immunocompromised individuals where a majority show no IgG responses to vaccines and the recent emergence of the Delta variant with reports of >74% vaccine breakthrough cases.[4,5]

Here, we report on patients demonstrating divergent immune responses to SARS-CoV-2 vaccination. Institutional Review Board approval and informed consent was obtained before performance of assays (Appendix 1, SDC, http://links.lww.com/TP/C290). Seven patients were identified from a cohort of 70 immunocompromised patients, with all demonstrating spike-specific IgG unresponsiveness 2–4 mo postvaccination. All had received treatment with B-cell modifying agents. We subsequently examined CD4+/CD8+ T-cell–spike-specific immune responses in all patients and repeat examination after revaccination in 2 patients (see Appendix 1, SDC, http://links.lww.com/TP/C290, for Methods and Data). CD4+/CD8+ T-cell responses are shown in Figure 1 and demonstrate robust CD4+T-cell (0.94 ± 1.2%, Normal > 0.05%) and CD8+ T-cell (0.89 ± 1.2%, Normal > 0.05%) immune responses to spike peptides. Two patients receiving Johnson & Johnson booster vaccines demonstrated increased T-cell responses but remained spike IgG negative. This suggests that T-cell immune responses to SARS-CoV-2 vaccines are primal and retentive and that B-cell depletion before vaccine exposure prevents the cascade of progression of B-cell activation necessary for SARS-CoV-2 spike IgG production.

FIGURE 1.

A, Detectable CD4+/CD8+ T-cell immune responses in vaccinated patients against SARS-CoV-2 spike peptides. Flow cytometry diagrams from 7 patients (P1–P7) assessed after 2 doses of Pfizer or Moderna vaccines. Cells were stimulated by SARS-CoV-2 spike peptides pool (PepMix SARS-CoV-2 [spike glycoprotein, JPT) for 9 h in vitro in the presence of Brefeldin A and anti-CD28/CD49d (BD Bioscience, San Jose, CA). Cells were stained for T-cell surface markers followed by fixation, permeabilization, and intracellular staining of cytokines (BD Bioscience, San Jose, CA). Activated CD4+ T cells (IL-2+TNFα+) and CD8+ T cells (IFNγ+TNFα+) are shown in the upper right-hand corner of each flow box. B, This figure shows immune responses to SARS-CoV-2 spike peptides in 2 patients who obtained external revaccination with the Johnson & Johnson vaccine. As in (A), percentages of activated CD4+ T cells (IL-2+TNFα+) and CD8+ T cells (IFNγ+TNFα+) in blood are shown after first vaccination (2 doses) and after third vaccination (booster). Activated CD4+ T cells (IL-2+TNFα+) and CD8+ T cells (IFNγ+TNFα+) are shown in the upper right-hand corner of each flow box. IFNγ, interferon γ; IL, interleukin; P, patient; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2; TNFα, tumor necrosis factor α.

Absence of IgG responses to SARS-CoV-2 suggests patients be considered “unvaccinated.” However, we show that patients treated with B-cell–modifying agents develop robust T-cell immune responses to SARS-CoV-2 without generating IgG responses. These observations should be considered in light of data presented by Peng et al showing robust CD4+/CD8+ T-cell responses to SARS-CoV-2 after infection. A critical observation was the diversity of T-cell responses that likely extend beyond the persistence of spike antibody. IgG is necessary for sterilizing immunity and T-cells cannot prevent infection as antigen presentation is required, but T-cell immunity can be at the ready for viral elimination. This may provide an inside track for rapid deployment of SARS-CoV-2 immunity, and although not preventing infection, could alter the severity and duration of SARS-CoV-2 disease.[6] This is supported by data from Oberhardt et al[7] who recently showed that vaccine-induced CD8+ T cells were the main mediators of protection after vaccination since they emerged before detection of neutralizing antibody and expanded after booster vaccination. Thus, detection of T-cell immune responses in patients failing to generate spike-specific IgG may aid in a more comprehensive assessment of immunity to SARS-CoV-2, identifying patients who would no longer be considered “unvaccinated” based on negative spike-specific IgG. This likely has relevance to patients receiving B-cell directed therapies for autoimmune and hematologic diseases.

ACKNOWLEDGMENTS

The authors would like to express our gratitude to the members of the Transplant Immunotherapy Program and the Transplant Immunology Laboratory at Cedars-Sinai Medical Center for their dedication to improving patient outcomes and safety during the coronavirus disease 2019 pandemic. We would also like to thank the patients who participated in this study by donating their blood for analysis of SARS-CoV-2 reactive T-cells.