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Abstract: The promising results obtained with immunotherapeutic approaches for multiple myeloma (MM) call for a better stratification of patients based on immune components. The most pressing being cytotoxic lymphocytes such as natural killer (NK) cells that are mandatory for MM surveillance and therapy. Here, we performed a single-cell RNA sequencing analysis of NK cells from 10 patients with MM and 10 age/sex-matched healthy donors that revealed important transcriptomic changes in the NK cell landscape affecting both the bone marrow (BM) and peripheral blood compartment. The frequency of mature cytotoxic CD56dim NK cell subsets was reduced in patients with MM at the advantage of late-stage NK cell subsets expressing NF-κB and interferon-I inflammatory signatures. These NK cell subsets accumulating in patients with MM were characterized by low CD16 and CD226 expression and poor cytotoxic functions. MM CD16/CD226Lo NK cells also had adhesion defects with reduced lymphocyte function-associated antigen 1 (LFA-1) integrin activation and actin polymerization that may account for their limited effector functions in vitro. Finally, analysis of BM-infiltrating NK cells in a retrospective cohort of 177 patients with MM from the Intergroupe Francophone du Myélome (IFM) 2009 trial demonstrated that a high frequency of NK cells and their low CD16 and CD226 expression were associated with a shorter overall survival. Thus, CD16/CD226Lo NK cells with reduced effector functions accumulate along MM development and negatively affect patients' clinical outcomes. Given the growing interest in harnessing NK cells to treat myeloma, this improved knowledge around MM-associated NK cell dysfunction will stimulate the development of more efficient immunotherapeutic drugs against MM., (© 2024 American Society of Hematology. Published by Elsevier Inc. All rights are reserved, including those for text and data mining, AI training, and similar technologies.)

An exome sequencing strategy employed to identify pathogenic variants in patients with pediatric-onset systemic lupus or Evans syndrome resulted in the discovery of six novel monoallelic mutations in PTPN2. PTPN2 is a phosphatase that acts as an essential negative regulator of the JAK/STAT pathways. All mutations led to a loss of PTPN2 regulatory function as evidenced by in vitro assays and by hyperproliferation of patients' T cells. Furthermore, patients exhibited high serum levels of inflammatory cytokines, mimicking the profile observed in individuals with gain-of-function mutations in STAT factors. Flow cytometry analysis of patients' blood cells revealed typical alterations associated with autoimmunity and all patients presented with autoantibodies. These findings further supported the notion that a loss of function in negative regulators of cytokine pathways can lead to a broad spectrum of autoimmune manifestations and that PTPN2 along with SOCS1 haploinsufficiency constitute a new group of monogenic autoimmune diseases that can benefit from targeted therapy., (© 2024 Jeanpierre et al.)

Natural killer (NK) cells often become dysfunctional during tumor progression, but the molecular mechanisms underlying this phenotype remain unclear. To explore this phenomenon, we set up mouse lymphoma models activating or not activating NK cells. Both tumor types elicited type I interferon production, leading to the expression of a T cell exhaustion-like signature in NK cells, which included immune checkpoint proteins (ICPs). However, NK cell dysfunction occurred exclusively in the tumor model that triggered NK cell activation. Moreover, ICP-positive NK cells demonstrated heightened reactivity compared to negative ones. Furthermore, the onset of NK cell dysfunction was swift and temporally dissociated from ICPs induction, which occurred as a later event during tumor growth. Last, NK cell responsiveness was restored when stimulation was discontinued, and interleukin-15 had a positive impact on this reversion. Therefore, our data demonstrate that the reactivity of NK cells is dynamically controlled and that NK cell dysfunction is a reversible process uncoupled from the expression of ICPs.

Background: DNA-dependent protein kinase catalytic subunit (DNA-PKcs) has an essential role in the non-homologous end-joining pathway that repairs DNA double-strand breaks in V(D)J recombination involved in the expression of T- and B-cell receptors. Whereas homozygous mutations in PRKDC define the scid mouse, a model that has been widely used in biology, human mutations in PRKDC are extremely rare and the disease spectrum has not been described so far., Objective: To provide an update on the genetics, clinical spectrum, immunological profile, and therapy of DNA-PKcs deficiency in human., Methods: The clinical, biological, and treatment data from the 6 cases published to date and from 1 new patient were obtained and analyzed. Rubella PCR was performed on available granuloma material., Results: We report on 7 patients; Six patients displayed the autosomal recessive p.L3062R mutation in PRKDC gene encoding DNA-PKcs. Atypical severe combined immunodeficiency with inflammatory lesions, granulomas, and autoimmunity was the predominant clinical manifestation (n=5/7). Rubella viral strain was detected in the granuloma of 1 patient over the 2 tested. T-cell counts, including naïve CD4 + CD45RA + T cells and T-cell function were low at diagnosis for 6 patients. For most patients with available values naïve CD4 + CD45RA + T cells decreased over time (n=5/6). Hematopoietic stem cell transplantation (HSCT) was performed in 5 patients, of whom 4 are still alive without transplant-related morbidity. Sustained T- and B-cell reconstitution was respectively observed for 4 and 3 patients, after a median follow-up of 8 years (range 3-16 y)., Conclusion: DNA-PKcs deficiency mainly manifests as an inflammatory disease with granuloma and autoimmune features, along with severe infections., (Copyright © 2024. Published by Elsevier Inc.)

Objectives: In the post-SARS-CoV-2 pandemic era, "breakthrough infections" are still documented, due to variants of concerns (VoCs) emergence and waning humoral immunity. Despite widespread utilization, the definition of the anti-Spike (S) immunoglobulin-G (IgG) threshold to define protection has unveiled several limitations. Here, we explore the advantages of incorporating T-cell response assessment to enhance the definition of immune memory profile., Methods: SARS-CoV-2 interferon-gamma release assay test (IGRA) was performed on samples collected longitudinally from immunocompetent healthcare workers throughout their immunization by infection and/or vaccination, anti-receptor-binding domain IgG levels were assessed in parallel. The risk of symptomatic infection according to cellular/humoral immune capacities during Omicron BA.1 wave was then estimated., Results: Close to 40% of our samples were exclusively IGRA-positive, largely due to time elapsed since their last immunization. This suggests that individuals have sustained long-lasting cellular immunity, while they would have been classified as lacking protective immunity based solely on IgG threshold. Moreover, the Cox regression model highlighted that Omicron BA.1 circulation raises the risk of symptomatic infection while increased anti-receptor-binding domain IgG and IGRA levels tended to reduce it., Conclusion: The discrepancy between humoral and cellular responses highlights the significance of assessing the overall adaptive immune response. This integrated approach allows the identification of vulnerable subjects and can be of interest to guide antiviral prophylaxis at an individual level., (© 2024 The Authors. European Journal of Immunology published by Wiley‐VCH GmbH.)

Hexokinases (HKs) control the first step of glucose catabolism. A switch of expression from liver HK (glucokinase, GCK) to the tumor isoenzyme HK2 is observed in hepatocellular carcinoma progression. Our prior work revealed that HK isoenzyme switch in hepatocytes not only regulates hepatic metabolic functions but also modulates innate immunity and sensitivity to Natural Killer (NK) cell cytotoxicity. This study investigates the impact of HK2 expression and its mitochondrial binding on the resistance of human liver cancer cells to NK-cell-induced cytolysis. We have shown that HK2 expression induces resistance to NK cell cytotoxicity in a process requiring mitochondrial binding of HK2. Neither HK2 nor GCK expression affects target cells' ability to activate NK cells. In contrast, mitochondrial binding of HK2 reduces effector caspase 3/7 activity both at baseline and upon NK-cell activation. Furthermore, HK2 tethering to mitochondria enhances their resistance to cytochrome c release triggered by tBID. These findings indicate that HK2 mitochondrial binding in liver cancer cells is an intrinsic resistance factor to cytolysis and an escape mechanism from immune surveillance., (© 2024 The Author(s). European Journal of Immunology published by Wiley‐VCH GmbH.)

The mechanisms whereby Eomes controls tissue accumulation of T cells and strengthens inflammation remain ill-defined. Here, we show that Eomes deletion in antigen-specific CD4+ T cells is sufficient to protect against central nervous system (CNS) inflammation. While Eomes is dispensable for the initial priming of CD4+ T cells, it is required for long-term maintenance of CNS-infiltrating CD4+ T cells. We reveal that the impact of Eomes on effector CD4+ T cell longevity is associated with sustained expression of multiple genes involved in mitochondrial organization and functions. Accordingly, epigenetic studies demonstrate that Eomes supports mitochondrial function by direct binding to either metabolism-associated genes or mitochondrial transcriptional modulators. Besides, the significance of these findings was confirmed in CD4+ T cells from healthy donors and multiple sclerosis patients. Together, our data reveal a new mechanism by which Eomes promotes severity and chronicity of inflammation via the enhancement of CD4+ T cell mitochondrial functions and resistance to stress-induced cell death., (© 2024 Joulia et al.)

T cell receptor (TCR) Vγ4-expressing γδ T cells comprise interferon γ (IFNγ)- and interleukin-17 (IL-17)-producing effector subsets, with a preference for IL-17 effector fate decisions during early ontogeny. The existence of adult-thymus-derived IL-17 + T cells (γδ17) remains controversial. Here, we use a mouse model in which T cells are generated exclusively in the adult thymus and employ single-cell chromatin state analysis to study their development. We identify adult-thymus-derived Vγ4 T cells that have all the molecular programs to become IL-17 producers. However, they have reduced IL-17 production capabilities and rarely reach the periphery. Moreover, this study provides high-resolution profiles of Vγ4 T cells in the adult thymus and lymph nodes and identifies Zeb1 as a potential γδ17 cell regulator. Together, this study provides valuable insights into the developmental traits of Vγ4 T cells during adulthood and supports the idea of age-specific signals required for thymic export and/or peripheral maturation of γδ17 cells., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

CD8+ T cells and Natural Killer (NK) cells are cytotoxic lymphocytes important in the response to intracellular pathogens and cancer. Their activity depends on the integration of a large set of intracellular and environmental cues, including antigenic signals, cytokine stimulation and nutrient availability. This integration is achieved by signaling hubs, such as the mechanistic target of rapamycin (mTOR). mTOR is a conserved protein kinase that controls cellular growth and metabolism in eukaryotic cells and, therefore, is essential for lymphocyte development and maturation. However, our current understanding of mTOR signaling comes mostly from studies performed in transformed cell lines, which constitute a poor model for comprehending metabolic pathway regulation. Therefore, it is only quite recently that the regulation of mTOR in primary cells has been assessed. Here, we review the signaling pathways leading to mTOR activation in CD8+ T and NK cells, focusing on activation by cytokines. We also discuss how this knowledge can contribute to immunotherapy development, particularly for cancer treatment.

An European Alliance of Associations for Rheumatology task force recently recommended specific points to consider for exploring type I interferon pathway in patients, highlighting the lack of analytical assays validated for clinical routine. We report here the French experience on a type I interferon pathway assay that has been set up and used routinely since 2018 in Lyon, France., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Autosomal recessive PRKCD deficiency has previously been associated with the development of systemic lupus erythematosus in human patients, but the mechanisms underlying autoimmunity remain poorly understood. We introduced the Prkcd G510S mutation that we previously associated to a Mendelian cause of systemic lupus erythematosus in the mouse genome, using CRISPR-Cas9 gene editing. PrkcdG510S/G510S mice recapitulated the human phenotype and had reduced lifespan. We demonstrate that this phenotype is linked to a B cell-autonomous role of Prkcd. A detailed analysis of B cell activation in PrkcdG510S/G510S mice shows an upregulation of the PI3K/mTOR pathway after the engagement of the BCR in these cells, leading to lymphoproliferation. Treatment of mice with rapamycin, an mTORC1 inhibitor, significantly improves autoimmune symptoms, demonstrating in vivo the deleterious effect of mTOR pathway activation in PrkcdG510S/G510S mice. Additional defects in PrkcdG510S/G510S mice include a decrease in peripheral mature NK cells that might contribute to the known susceptibility to viral infections of patients with PRKCD mutations., (Copyright © 2023 by The American Association of Immunologists, Inc.)

BackgroundTo cope with the persistence of the COVID-19 epidemic and the decrease in antibody levels following vaccination, a third dose of vaccine has been recommended in the general population. However, several vaccine regimens had been used initially for the primary vaccination course, and the heterologous Vaxzevria/Comirnaty regimen had shown better efficacy and immunogenicity than the homologous Comirnaty/Comirnaty regimen.AimWe wanted to determine if this benefit was retained after a third dose of an mRNA vaccine.MethodsWe combined an observational epidemiological study of SARS-CoV-2 infections among vaccinated healthcare workers at the University Hospital of Lyon, France, with a prospective cohort study to analyse immunological parameters before and after the third mRNA vaccine dose.ResultsFollowing the second vaccine dose, heterologous vaccination regimens were more protective against infection than homologous regimens (adjusted hazard ratio (HR) = 1.88; 95% confidence interval (CI): 1.18-3.00; p = 0.008), but this was no longer the case after the third dose (adjusted HR = 0.86; 95% CI: 0.72-1.02; p = 0.082). Receptor-binding domain-specific IgG levels and serum neutralisation capacity against different SARS-CoV-2 variants were higher after the third dose than after the second dose in the homologous regimen group, but not in the heterologous group.ConclusionThe advantage conferred by heterologous vaccination was lost after the third dose in terms of both protection and immunogenicity. Immunological measurements 1 month after vaccination suggest that heterologous vaccination induces maximal immunity after the second dose, whereas the third dose is required to reach the same level in individuals with a homologous regimen.

The diversity of vaccination modalities and infection history are both variables that have an impact on the immune memory of individuals vaccinated against SARS-CoV-2. To gain more accurate knowledge of how these parameters imprint on immune memory, we conducted a long-term follow-up of SARS-CoV-2 spike protein-specific immune memory in unvaccinated and vaccinated COVID-19 convalescent individuals as well as in infection-naïve vaccinated individuals. Here, we report that individuals from the convalescent vaccinated (hybrid immunity) group have the highest concentrations of spike protein-specific antibodies at 6 months after vaccination. As compared with infection-naïve vaccinated individuals, they also display increased frequencies of an atypical mucosa-targeted memory B cell subset. These individuals also exhibited enhanced T H 1 polarization of their SARS-CoV-2 spike protein-specific follicular T helper cell pool. Together, our data suggest that prior SARS-CoV-2 infection increases the titers of SARS-CoV-2 spike protein-specific antibody responses elicited by subsequent vaccination and induces modifications in the composition of the spike protein-specific memory B cell pool that are compatible with enhanced functional protection at mucosal sites.

Type I and III interferons (IFN-I/λ) are important antiviral mediators against SARS-CoV-2 infection. Here, we demonstrate that plasmacytoid dendritic cells (pDC) are the predominant IFN-I/λ source following their sensing of SARS-CoV-2-infected cells. Mechanistically, this short-range sensing by pDCs requires sustained integrin-mediated cell adhesion with infected cells. In turn, pDCs restrict viral spread by an IFN-I/λ response directed toward SARS-CoV-2-infected cells. This specialized function enables pDCs to efficiently turn-off viral replication, likely via a local response at the contact site with infected cells. By exploring the pDC response in SARS-CoV-2 patients, we further demonstrate that pDC responsiveness inversely correlates with the severity of the disease. The pDC response is particularly impaired in severe COVID-19 patients. Overall, we propose that pDC activation is essential to control SARS-CoV-2-infection. Failure to develop this response could be important to understand severe cases of COVID-19., (© 2023. The Author(s).)

Background: Deoxyribonuclease 1 like 3 (DNASE1L3) is a secreted enzyme that has been shown to digest the extracellular chromatin derived from apoptotic bodies, and DNASE1L3 pathogenic variants have been associated with a lupus phenotype. It is unclear whether interferon signaling is sustained in DNASE1L3 deficiency in humans., Objectives: To explore interferon signaling in DNASE1L3 deficient patients. To depict the characteristic features of DNASE1L3 deficiencies in human., Methods: We identified, characterized, and analyzed five new patients carrying biallelic DNASE1L3 variations. Whole or targeted exome and/or Sanger sequencing was performed to detect pathogenic variations in five juvenile systemic erythematosus lupus (jSLE) patients. We measured interferon-stimulated gene (ISG) expression in all patients. We performed a systematic review of all published cases available from its first description in 2011 to March 24 th 2022., Results: We identified five new patients carrying biallelic DNASE1L3 pathogenic variations, including three previously unreported mutations. Contrary to canonical type I interferonopathies, we noticed a transient increase of ISGs in blood, which returned to normal with disease remission. Disease in one patient was characterized by lupus nephritis and skin lesions, while four others exhibited hypocomplementemic urticarial vasculitis syndrome. The fourth patient presented also with early-onset inflammatory bowel disease. Reviewing previous reports, we identified 35 additional patients with DNASE1L3 deficiency which was associated with a significant risk of lupus nephritis and a poor outcome together with the presence of anti-neutrophil cytoplasmic antibodies (ANCA). Lung lesions were reported in 6/35 patients., Conclusions: DNASE1L3 deficiencies are associated with a broad phenotype including frequently lupus nephritis and hypocomplementemic urticarial vasculitis with positive ANCA and rarely, alveolar hemorrhages and inflammatory bowel disease. This report shows that interferon production is transient contrary to anomalies of intracellular DNA sensing and signaling observed in Aicardi-Goutières syndrome or STING-associated vasculitis in infancy (SAVI)., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Introduction: Patients with metastatic non-small cell lung cancer (mNSCLC) suffer from numerous symptoms linked to disease and treatment which may further impair the patient's overall condition. In addition to its benefits on quality of life and fatigue, physical exercise may improve treatment response, notably due to its known effects on the immune system. The ERICA study is designed to assess the feasibility of a supervised acute physical exercise therapy realised immediately prior immune-chemotherapy infusion in patients with mNSCLC. Secondary objectives will examine the effects of acute exercise combined with an unsupervised home-walking programme on clinical, physical, psychosocial and biological parameters., Methods and Analysis: ERICA is a prospective, monocentric, randomised controlled, open-label feasibility study conducted at the Centre Léon Bérard Comprehensive Cancer Center (France). Thirty patients newly diagnosed with mNSCLC will be randomised (2:1 ratio) to the 'exercise' or the 'control' group. At baseline and during the last treatment cycle, participants in both groups will receive Physical Activity recommendations, and two nutritional assessments. In the exercise group, participants will receive a 3-month programme consisting of a supervised acute physical exercise session prior to immune-chemotherapy infusion, and an unsupervised home-based walking programme with an activity tracker. The acute exercise consists of 35 min interval training at submaximal intensity scheduled to terminate 15 min prior to infusion. Clinical, physical, biological and psychosocial parameters will be assessed at baseline, 3 and 6 months after inclusion. Biological measures will include immune, inflammatory, metabolic, oxidative stress biomarkers and molecular profiling., Ethics and Dissemination: The study protocol was approved by the French ethics committee (Comité de protection des personnes Ile de France II, N°ID-RCB 20.09.04.65226, 8 December 2020). The study is registered on ClinicalTrials.gov (NCT number:NCT04676009) and is at the pre-results stage. All participants will sign an informed consent form. The findings will be disseminated in peer-reviewed journals and academic conferences., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

NK cell receptors allow NK cells to recognize targets such as tumor cells. Many of them are expressed on a subset of NK cells, independently of each other, which creates a vast diversity of receptor combinations. Whether these combinations influence NK cell antitumor responses is not well understood. We addressed this question in the C57BL/6 mouse model and analyzed the individual effector response of 444 mouse NK cell subsets, defined by combinations of 12 receptors, against tumor cell lines originating from different tissues and mouse strains. We found a wide range of reactivity among NK subsets, but the same hierarchy of responses was observed for the different tumor types, showing that the repertoire of NK cell receptors does not encode for different tumor specificities but for different intrinsic reactivities. The coexpression of CD27, NKG2A, and DNAM-1 identified subsets with relative cytotoxic specialization, whereas reciprocally, CD11b and KLRG1 defined the best IFN-γ producers. The expression of educating receptors Ly49C, Ly49I, and NKG2A was also strongly correlated with IFN-γ production, but this effect was suppressed by unengaged receptors Ly49A, Ly49F, and Ly49G2. Finally, IL-15 coordinated NK cell effector functions, but education and unbound inhibitory receptors retained some influence on their response. Collectively, these data refine our understanding of the mechanisms governing NK cell reactivity, which could help design new NK cell therapy protocols., (Copyright © 2022 by The American Association of Immunologists, Inc.)

T-bet and Eomes are two related transcription factors (TFs) that regulate the differentiation of cytotoxic lymphocytes such as Natural Killer (NK) cells and CD8 T cells. Recent genome-wide analyses suggest they have complementary roles in instructing the transcriptional program of NK cells, although their DNA binding sites appear to be very similar. In this essay, we discuss the mechanisms that could specify their action, addressing their expression profile, the cofactors they interact with, as well as their roles in the epigenetic regulation of chromatin accessibility. Based on the recent literature on these TFs, we propose different models to describe how they regulate gene expression in NK cells at steady state, or in the context of activation or exhaustion. We also discuss recent findings in the field of CD8 T cell differentiation and residency, where Eomes and T-bet appear to be major regulators, and the parallels that can be drawn between mechanisms of NK and CD8 T cell differentiation and trafficking., (© 2022 Wiley Periodicals LLC.)

Natural Killer (NK) cells are potent anti-leukemic immune effectors. However, they display multiple defects in acute myeloid leukemia (AML) patients leading to reduced anti-tumor potential. Our limited understanding of the mechanisms underlying these defects hampers the development of strategies to restore NK cell potential. Here, we have used a mouse model of AML to gain insight into these mechanisms. We found that leukemia progression resulted in NK cell maturation defects and functional alterations. Next, we assessed NK cell cytokine signaling governing their behavior. We showed that NK cells from leukemic mice exhibit constitutive IL-15/mTOR signaling and type I IFN signaling. However, these cells failed to respond to IL-15 stimulation in vitro as illustrated by reduced activation of the mTOR pathway. Moreover, our data suggest that mTOR-mediated metabolic responses were reduced in NK cells from AML-bearing mice. Noteworthy, the reduction of mTOR-mediated activation of NK cells during AML development partially rescued NK cell metabolic and functional defects. Altogether, our data strongly suggest that NK cells from leukemic mice are metabolically and functionally exhausted as a result of a chronic cytokine activation, at least partially IL-15/mTOR signaling. NK cells from AML patients also displayed reduced IL-2/15Rβ expression and showed cues of reduced metabolic response to IL-15 stimulation in vitro , suggesting that a similar mechanism might occur in AML patients. Our study pinpoints the dysregulation of cytokine stimulation pathways as a new mechanism leading to NK cell defects in AML., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Bou-Tayeh, Laletin, Salem, Just-Landi, Fares, Leblanc, Balzano, Kerdiles, Bidaut, Hérault, Olive, Aurrand-Lions, Walzer, Nunès and Fauriat.)

Following severe adverse reactions to the AstraZeneca ChAdOx1-S-nCoV-19 vaccine 1,2 , European health authorities recommended that patients under the age of 55 years who received one dose of ChAdOx1-S-nCoV-19 receive a second dose of the Pfizer BNT162b2 vaccine as a booster. However, the effectiveness and the immunogenicity of this vaccination regimen have not been formally tested. Here we show that the heterologous ChAdOx1-S-nCoV-19 and BNT162b2 combination confers better protection against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection than the homologous BNT162b2 and BNT162b2 combination in a real-world observational study of healthcare workers (n = 13,121). To understand the underlying mechanism, we conducted a longitudinal survey of the anti-spike immunity conferred by each vaccine combination. Both combinations induced strong anti-spike antibody responses, but sera from heterologous vaccinated individuals displayed a stronger neutralizing activity regardless of the SARS-CoV-2 variant. This enhanced neutralizing potential correlated with increased frequencies of switched and activated memory B cells that recognize the SARS-CoV-2 receptor binding domain. The ChAdOx1-S-nCoV-19 vaccine induced a weaker IgG response but a stronger T cell response than the BNT162b2 vaccine after the priming dose, which could explain the complementarity of both vaccines when used in combination. The heterologous vaccination regimen could therefore be particularly suitable for immunocompromised individuals., (© 2021. The Author(s), under exclusive licence to Springer Nature Limited.)