Search

IMPORTANCE: It has become common practice to offer immunocompromised patients with hematologic cancers a third COVID-19 vaccination dose, but data substantiating this are scarce. OBJECTIVE: To assess whether a third mRNA-1273 vaccination is associated with increased neutralizing antibody concentrations in immunocompromised patients with hematologic cancers comparable to levels obtained in healthy individuals after the standard 2-dose mRNA-1273 vaccination schedule. DESIGN, SETTING, AND PARTICIPANTS: This prospective observational cohort study was conducted at 4 university hospitals in the Netherlands and included 584 evaluable patients spanning the spectrum of hematologic cancers and 44 randomly selected age-matched adults without malignant or immunodeficient comorbidities. EXPOSURES: One additional mRNA-1273 vaccination 5 months after completion of the standard 2-dose mRNA-1273 vaccination schedule. MAIN OUTCOMES AND MEASURES: Serum immunoglobulin G (IgG) antibodies to spike subunit 1 (S1) antigens prior to and 4 weeks after a third mRNA-1273 vaccination, and antibody neutralization capacity of wild-type, Delta, and Omicron variants in a subgroup of patients. RESULTS: In this cohort of 584 immunocompromised patients with hematologic cancers (mean [SD] age, 60 [11.2] years; 216 [37.0%] women), a third mRNA-1273 vaccination was associated with median S1-IgG concentrations comparable to concentrations obtained by healthy individuals after the 2-dose mRNA-1273 schedule. The rise in S1-IgG concentration after the third vaccination was most pronounced in patients with a recovering immune system, but potent responses were also observed in patients with persistent immunodeficiencies. Specifically, patients with myeloid cancers or multiple myeloma and recipients of autologous or allogeneic hematopoietic cell transplantation (HCT) reached median S1-IgG concentrations similar to those obtained by healthy individuals after a 2-dose schedule. Patients receiving or shortly after completing anti-CD20 therapy, CD19-directed chimeric antigen receptor T-cell therapy recipients, and patients with chronic lymphocytic leukemia receiving ibrutinib were less responsive or unresponsive to the third vaccination. In the 27 patients who received cell therapy between the second and third vaccination, S1 antibodies were preserved, but a third mRNA-1273 vaccination was not associated with significantly enhanced S1-IgG concentrations except for patients with multiple myeloma receiving autologous HCT. A third vaccination was associated with significantly improved neutralization capacity per antibody. CONCLUSIONS AND RELEVANCE: Results of this cohort study support that the primary schedule for immunocompromised patients with hematologic cancers should be supplemented with a delayed third vaccination. Patients with B-cell lymphoma and allogeneic HCT recipients need to be revaccinated after treatment or transplantation. TRIAL REGISTRATION: EudraCT Identifier: 2021-001072-41

Vaccination guidelines for patients treated for hematological diseases are typically conservative. Given their high risk for severe COVID-19, it is important to identify those patients that benefit from vaccination. We prospectively quantified serum immunoglobulin G (IgG) antibodies to spike subunit 1 (S1) antigens during and after 2-dose mRNA-1273 (Spikevax/Moderna) vaccination in hematology patients. Obtaining S1 IgG ≥ 300 binding antibody units (BAUs)/mL was considered adequate as it represents the lower level of S1 IgG concentration obtained in healthy individuals, and it correlates with potent virus neutralization. Selected patients (n = 723) were severely immunocompromised owing to their disease or treatment thereof. Nevertheless, >50% of patients obtained S1 IgG ≥ 300 BAUs/mL after 2-dose mRNA-1273. All patients with sickle cell disease or chronic myeloid leukemia obtained adequate antibody concentrations. Around 70% of patients with chronic graft-versus-host disease (cGVHD), multiple myeloma, or untreated chronic lymphocytic leukemia (CLL) obtained S1 IgG ≥ 300 BAUs/mL. Ruxolitinib or hypomethylating therapy but not high-dose chemotherapy blunted responses in myeloid malignancies. Responses in patients with lymphoma, patients with CLL on ibrutinib, and chimeric antigen receptor T-cell recipients were low. The minimal time interval after autologous hematopoietic cell transplantation (HCT) to reach adequate concentrations was <2 months for multiple myeloma, 8 months for lymphoma, and 4 to 6 months after allogeneic HCT. Serum IgG4, absolute B- and natural killer–cell number, and number of immunosuppressants predicted S1 IgG ≥ 300 BAUs/mL. Hematology patients on chemotherapy, shortly after HCT, or with cGVHD should not be precluded from vaccination. This trial was registered at Netherlands Trial Register as #NL9553.

Interleukin-7 (IL-7) is essential to T-cell survival as well as homeostatic proliferation, and clinical trials that exploit the mitogenic effects of IL-7 have achieved success in treating human diseases. In mice, the in vivo potency of IL-7 improves dramatically when it is administered as a complex with the anti–IL-7 neutralizing monoclonal antibody clone M25. However, the mechanism whereby M25 augments IL-7 potency is unknown. We have analyzed the discrete contributions of the antibody constant (Fc) and IL-7-binding (Fab) domains to the mechanism. By engaging the neonatal Fc receptor the Fc domain extends the in vivo lifespan of IL-7/M25 complexes and accounts for the majority of their activity. Unexpectedly, the IL-7–neutralizing Fab domain provides an additional, albeit smaller, contribution, possibly by serving as a cytokine depot. This study is the first to demonstrate that the neutralizing aspect of the monoclonal antibody is directly involved in enhancing the potency of a cytokine with a single form of receptor. Lessons from the mechanism of IL-7/M25 complexes inform the design of next-generation cytokine therapeutics.

Caspase recruitment domain–containing protein 9 (CARD9) is an adaptor molecule in the cytosol of myeloid cells, required for induction of T-helper cells producing interleukin-17 (Th17 cells) and important in antifungal immunity. In a patient suffering from Candida dubliniensis meningoencephalitis, mutations in the CARD9 gene were found to result in the loss of protein expression. Apart from the reduced numbers of CD4+ Th17 lymphocytes, we identified a lack of monocyte-derived cytokines in response to Candida strains. Importantly, CARD9-deficient neutrophils showed a selective Candida albicans killing defect with abnormal ultrastructural phagolysosomes and outgrowth of hyphae. The neutrophil killing defect was independent of the generation of reactive oxygen species by the reduced NAD phosphate oxidase system. Taken together, this demonstrates that human CARD9 deficiency results in selective defect in the host defense against invasive fungal infection, caused by an impaired phagocyte killing.

It is believed that the size of the CD8+ T-cell pool is fixed and that with every new viral challenge, the size of the pre-existing memory-cell population shrinks to make way for the new virus-specific cells. CMV-seropositive individuals have high numbers of CMV-specific resting-effector type CD8+ T cells in their peripheral blood (PB). This prompted us to investigate whether CMV infection limits immunologic space at sites where immune reactions are initiated, such as in the lymph nodes (LNs). LN and paired PB samples were analyzed for CMV-, EBV-, and influenza-specific CD8+ T cells. In marked contrast to blood, LNs contained significantly lower numbers of CX3CR1-expressing effector-type CD8+ T cells, whereas the CMV-specific cells that were found in the LNs resembled polyfunctional memory-type cells. In contrast, EBV- and influenza-specific CD8+ T cells were highly similar between PB and LNs both in number and function. Therefore, it is unlikely that CMV-specific CD8+ T cells in the LNs restrain the immunologic space of other virus-specific cells.

A girl presented during childhood with a single course of extensive chickenpox and moderate albeit recurrent pneumonia in the presence of idiopathic CD4+ T lymphocytopenia (ICL). Her clinical condition remained stable over the past 10 years without infections, any granulomatous disease, or autoimmunity. Immunophenotyping demonstrated strongly reduced naive T and B cells with intact proliferative capacity. Antibody reactivity on in vivo immunizations was normal. T-cell receptor-Vβ repertoire was polyclonal with a very low content of T-cell receptor excision circles (TRECs). Kappa-deleting recombination excision circles (KRECs) were also abnormal in the B cells. Both reflect extensive in vivo proliferation. Patient-derived CD34+ hematopoietic stem cells could not repopulate RAG2−/−IL2Rγc−/− mice, indicating the lymphoid origin of the defect. We identified 2 novel missense mutations in RAG1 (p.Arg474Cys and p.Leu506Phe) resulting in reduced RAG activity. This report gives the first genetic clue for ICL and extends the clinical spectrum of RAG mutations from severe immune defects to an almost normal condition.

To obtain insight into human CD4+ T cell differentiation and selection in vivo, we longitudinally studied cytomegalovirus (CMV)–specific CD4+ T cells after primary infection. Early in infection, CMV-specific CD4+ T cells have the appearance of interferon γ (IFNγ)–producing T-helper 1 (TH1) type cells, whereas during latency a large population of CMV-specific CD4+CD28– T cells emerges with immediate cytotoxic capacity. We demonstrate that CD4+CD28– T cells could lyse CMV antigen–expressing target cells in a class II–dependent manner. To clarify the clonal relationship between early and late CMV-specific CD4+ T cells, we determined their Vβ usage and CDR3 sequences. The T-cell receptor β (TCRβ) diversity in the early CMV-specific CD4+ T-cell population was high in contrast to the use of a very restricted set of TCRβ sequences in latent infection. T-cell clones found in the late CMV-specific CD4+ T-cell population could not be retrieved from the early CD4+ T-cell population, or were present only at a low frequency. The observation that dominant CMV-specific CD4+ clones during latency were only poorly represented in the acute phase suggests that after the initial control of the virus strong selection and/or priming of novel clones takes place in persistent infections in humans.

Virus-specific CD8+ T cells emerge after infection with herpesviruses and maintain latency to these persistent pathogens. It has been demonstrated that murine memory CD8+ T-cell precursors specific for acute lymphocytic choriomeningitis virus express interleukin-7 receptor α (IL-7Rα), and IL-7 is involved in maintaining memory populations after the clearance of antigen. To investigate whether human CD8+ T cells reactive toward persistent viruses are maintained similarly, we analyzed IL-7Rα expression and function on these virus-specific cells. During primary infection, all cytomegalovirus (CMV)-specific CD8+ T cells and most Epstein-Barr virus (EBV)-specific CD8+ T cells lacked IL-7Rα expression. Only some virus-specific T cells expressed IL-7Rα late after viral replication became undetectable. CD8+ T cells specific for cleared viruses, influenza (FLU), and respiratory syncytial virus (RSV) all expressed IL-7Rα. Remarkably, the percentage of IL-7Rα- CMV-specific T cells correlated with the height of viral replication in the acute phase. Virus-specific IL-7Rα+ cells proliferated vigorously in response to IL-7, IL-15, or peptide, whereas IL-7Rα- cells required both peptide and helper-cell activation or IL-2 or IL-15 for optimal expansion. Our data suggest that although IL-7 is essential for the maintenance of memory cells in the absence of antigen, CD8+ T cells specific for latent viruses need T-cell receptor activation plus helper factors to persist. (Blood. 2005;106:2091-2098)

During latency circulating human cytomegalovirus (CMV)-specific CD8+ T cells do not express the chemokine receptor CCR7. We here show that antigen-specific stimulation in vitro with the specific CMV-peptide in combination with CMV-antigen, IL-2 or IL-21 induced re-expression of CCR7 on CMV-specific CD8+ T cells. Although IL-15 induced strong proliferation of peptide-pulsed CMV-specific CD8+ T cells, these cells did not re-express CCR7. CMV-specific cells that re-expressed CCR7 also expressed CD62L and were able to react to specific chemokine stimulation with changes in the cytoskeleton. In addition, activated CMV-specific cells specifically migrated towards a chemokine gradient in a transwell assay, with and without an endothelial cell monolayer. We conclude that antigenic stimulation induced functional re-expression of CCR7 which suggests that the migratory properties of virus-primed T cells are flexible and depend on the presence or absence of antigen and cytokines.

ABSTRACTAlthough serum amyloid P component (SAP) is known to bind many ligands, its biological function is not yet clear. Recently, it was demonstrated that SAP binds to lipopolysaccharide (LPS). In the present study, SAP was shown to bind to gram-negative bacteria expressing short types of LPS or lipo-oligosaccharide (LOS), such as Salmonella entericaserovar Copenhagen Re and Escherichia coliJ5, and also to clinical isolates of Haemophilus influenzae. It was hypothesized that SAP binds to the bacteria via the lipid A part of LPS or LOS, since the htrBmutant of the nontypeable H. influenzaestrain NTHi 2019-B29-3, which expresses a nonacetylated lipid A, did not bind SAP. This was in contrast to the parental strain NTHi 2019. The binding of SAP resulted in a clear inhibition of the deposition of complement component C3 on the bacteria. SAP inhibited only the activation of the classical complement pathway; the alternative route remained unaffected. In the classical route, SAP prevented the deposition of the first complement component, Clq, probably by interfering with the binding of Clq to LPS. Since antibody-mediated Clq activation was not inhibited by SAP, SAP seems to inhibit only the LPS-induced classical complement pathway activation. The SAP-induced inhibition of C3 deposition strongly diminished the complement-mediated lysis as well as the phagocytosis of the bacteria. The binding of SAP to gram-negative bacteria, therefore, might influence the pathophysiology of an infection with such bacteria.