Moratti et al. exemplify how an effective management of IEI-related LPD demands close collaboration among immunologists, hematologists, and pathologists—integrating clinical presentation with serology, histology, immunohistochemistry, clonality assays, EBV status, and genetics. Reliance on histopathology alone risks misclassification, and atypical cases should prompt re-biopsy and multidisciplinary genetic reassessment to avoid overtreatment.

Individuals with inborn errors of immunity often mount suboptimal responses to vaccination, yet the molecular determinants underlying their variable responses to mRNA vaccines remain poorly defined. The present study aimed to identify baseline immune transcriptional signatures predictive of humoral responses to the BNT162b2 (Comirnaty) mRNA vaccine in individuals with inborn errors of immunity. Twenty-one SARS-CoV-2-naïve participants with diverse inborn errors of immunity were stratified as high or low responders to the BNT162b2 vaccine based on anti-SARS-CoV-2 spike IgG titers at day 28 post-vaccination. Although vaccine-induced T cell responses were broadly comparable, low responders had significantly lower frequencies of switched memory B cells (p = .014). Transcriptional profiling revealed 41 differentially expressed genes between groups at baseline. Activated memory B cells and peripheral T follicular helper cells from high responders exhibited greater induction of activation and memory-related genes, including NFKB1, CD69, TIGIT, CD40L, and BATF, indicating greater intrinsic readiness to support coordinated antibody production. These findings demonstrate that distinct pre-vaccination gene expression patterns within specific immune subsets are associated with differential humoral responses to mRNA vaccination in individuals with inborn errors of immunity. More broadly, the study highlights that baseline molecular immune features substantially influence vaccine efficacy and suggests that pre-vaccination transcriptional profiling may enable more personalized vaccination strategies for individuals with impaired immunity.

IntroductionChromosome 22q11.2 deletion syndrome (22q11DS) presents a wide variability of phenotypic features, including different grades of immune dysfunctions, leading to increased susceptibility to infections, autoimmune diseases and atopy. The most common autoimmune manifestation in 22q11DS patients is immune thrombocytopenia (ITP), which is often relapsing and refractory to standard therapy.MethodsWe present a cohort of four pediatric/adolescents 22q11DS patients presenting with refractory ITP, treated with low dosage Mycophenolate Mofetil (MMF) for more than 24 months. We performed complete deep longitudinal immunological investigations by multiparametric flow cytometry, and monitored blood counts as well as EBV viremia.ResultsAll four patients didn’t experience any relapse since the beginning of MMF therapy. Three out of four showed a complete remission with PLT > 100000/uL. All the patients presented immunological features reported to be associated with immunodysregulation: reduced naïve CD4+T cells and memory B cells, increased cTfh cells and reduced Treg cells frequency. During MMF treatment we detected a decrease in cTfh frequency and a reduction in PD-1 expression along with a moderate recovery of regulatory T cells.DiscussionMMF treatment was associated with sustained platelet stabilization in this cohort. Specific immunological biomarkers could help monitor treatment response, guide clinicians in selecting targeted therapies and may be used to monitor the response to therapy over time.

Inborn errors of immunity (IEI) are genetic disorders that not only heighten infection risk but also disrupt immune regulation, frequently leading to lymphoid tissue overgrowth known as lymphoid proliferations (LPD). We retrospectively reviewed 38 patients with genetically or clinically confirmed IEI and persistent LPD, comparing those with nonneoplastic/reactive hyperplasia to those who developed overt lymphoid neoplasm (lymphoma). Overall, 26% developed lymphoma—predominantly classical Hodgkin lymphoma or diffuse large B cell lymphoma—often after earlier IEI onset. Immunophenotyping and principal component analysis revealed that patients with common variable immunodeficiency developing Hodgkin lymphoma shared a distinctive T cell profile, differing from immunocompetent lymphoma cases. Centralized histologic re-evaluation reclassified several presumed lymphoma as nonneoplastic/reactive hyperplasia and identified Castleman-like and germinal center transformation patterns in nonneoplastic/reactive LPD. Notably, elevated blood IgM and circulating T follicular helper cells mirrored IgM deposits and PD-1+ T cells in lymph nodes. These findings highlight the importance of an integrated approach involving clinical, genetic, and pathological reviews to improve IEI diagnosis and avoid overtreatment.

Background: Whereas several studies have demonstrated the long-term immunogenicity of BNT162b2 vaccine in healthy adults, little evidence was provided in vulnerable populations (VPs) with generally low ability to respond to immunizations. We aimed to identify pre-vaccination immune phenotype and transcriptional signatures in B and T-cell subsets associated with immune response and long-term maintenance upon SARS-CoV-2 vaccination in VPs. Methods: A cohort of VPs (N = 169) including solid organ transplant recipients (SOT; N = 35), Inflammatory Bowel Disease (N = 31), Down Syndrome (N = 42), people living with HIV (N = 36), primary immune deficiencies (N = 25) and healthy controls (N = 37) were enrolled in the CONVERS Study. SARS-CoV-2 Vaccine responsiveness was evaluated by SARS-CoV-2-specific Ab and SARS-CoV-2-specific CD4+ T cells in VPs naive to infection or vaccination. Based on the humoral response at T28, individuals were classified as Protected (P: anti-spike antibody [anti-S] titer >= 0.8) and Not-Protected (NP: anti-S titer <0.8). Peripheral blood mononuclear cells, after SARS-CoV-2 Prot-S peptides stimulation were sort-purified in four cell subsets and analyzed by multiplexed RT-PCR (Fluidigm, Biomark). Results: SOT presented a significantly lower serological immunogenicity with 31 % of individuals being NP at T28 whereas only 1 out of the remaining 119 resulted Ab negative at T28. At T0, NP individuals showed a lower increase of Ag specific CD40L+ T cells and lower switched memory B cells compared to P patients. Gene-expression analysis revealed distinct signatures at baseline between P and NP individuals with 63 and 49 DEGs identified in two experimental conditions, respectively unstimulated and stimulated. Conclusions: Pre-vaccination B and T-cell characteristics at both phenotypic and gene- expression level correlate with short- and long- term memory maintenance in VPs with lower immunogenicity upon BNT162b2 vaccine. Such signatures need to be validated in larger cohorts and may provide a predictive score to inform personalized and more effective vaccine interventions.

Streptococcus pneumoniae contributes significantly to morbidity, mortality, and healthcare costs worldwide due to severe Invasive Pneumococcal Disease (IPD), particularly among young children and vulnerable populations. This review critically examines the current state of pneumococcal disease epidemiology, the evolution of vaccine strategies, and persistent challenges to achieve global control of the disease. The implementation of Pneumococcal Conjugate Vaccines (PCVs) has yielded substantial public health gains, establishing herd protection and sharply reducing vaccine-type IPD incidence. However, this success has been fundamentally challenged by serotype replacement, where non-vaccine serotypes have subsequently emerged to cause a significant proportion of the residual disease burden. This epidemiological shift has necessitated the development and deployment of higher-valency PCVs (PCV15, PCV20, and PCV21) to expand serotype coverage. Furthermore, optimal protection requires personalized strategies for high-risk cohorts where vaccine effectiveness can be compromised. In this context, the review details how pneumococcal vaccination—and particularly PPSV23—serves as an indispensable diagnostic tool to evaluate a broad spectrum of Inborn Errors of Immunity (IEI) and in particular humoral defects. Diagnostic challenges are strained by non-standardized assays and the limited panel of unique serotypes available for testing in the PCV era. The scientific priority is now the development of universal protein-based vaccines, to provide protection against all serotypes and non-encapsulated strains by targeting conserved virulence factors. This integrated approach, combining expanded PCV coverage with novel vaccine technology, is essential to mitigate the ongoing public health burden of pneumococcal disease.

The COVID-19 pandemic has significantly impacted immunocompromised patients, particularly those with inborn errors of immunity (IEI), transplant recipients, hematologic malignancies, and those undergoing treatment with immunosuppressive biologics and medications. These patients face an elevated risk of experiencing severe or even fatal consequences following SARS-CoV-2 infections. Vaccination is the primary defense against COVID-19; however, immune responses following immunization are often suboptimal in these patients, with variable specific humoral response rates. Despite the expedited regulatory approval and the widespread implementation of COVID-19 vaccines, the efficacy and safety for immunocompromised populations require thorough investigation. In future pandemics, including vulnerable populations (VPs) in vaccine and monoclonal antibody (mAb) trials is crucial to develop safe, effective immunization strategies, address gaps in vaccine efficacy and safety data, and create tailored guidelines for at-risk groups. This review provides a comprehensive examination of the efficacy of COVID-19 vaccines and mAbs in patients with primary and secondary immunodeficiency, with a specific focus on individuals with IEI, considering previous regulatory aspects and the necessity of including VPs in vaccine trials to enhance the quality of patient care and promote equitable health outcomes in future pandemics.

Maternal immunization is a key strategy for protecting pregnant individuals and newborns from infectious diseases. This review examines the mechanisms and benefits of maternal immunization, with a focus on transplacental IgG transfer and immune system interactions. We provide an overview of current recommendations and the safety and efficacy profiles of maternal vaccines, including influenza, tetanus–diphtheria–acellular pertussis (Tdap), respiratory syncytial virus (RSV), COVID-19, and hepatitis B. Additionally, we analyze the barriers to maternal immunization, such as misinformation, vaccine hesitancy, and disparities in healthcare access, while exploring potential strategies to overcome these challenges through targeted educational initiatives, improved provider communication, and policy-driven interventions aimed at increasing vaccine confidence and accessibility. Finally, this review highlights recent innovations and future directions in maternal immunization, including emerging vaccines for Group B Streptococcus and cytomegalovirus. Expanding immunization programs and advancing research on maternal–fetal immunity are essential to optimizing vaccination strategies, improving public health outcomes, and reducing the global burden of infectious diseases.

Children with hemato-oncological diseases represent a heterogeneous population at heightened risk for vaccine-preventable diseases. Their immunosuppressed state reduces vaccine efficacy and raises safety concerns regarding live attenuated vaccines due to the risk of viral reactivation. The immunological and clinical implications of the single conditions are significantly different; therefore, specific vaccination strategies are needed. Despite the availability of vaccine guidelines for immunocompromised patients, clinical practice remains highly variable. It is generally recommended to avoid vaccinations during chemotherapy, with some exceptions for influenza, pneumococcal, and, in some countries, hepatitis B vaccines. The timing of immune recovery after chemotherapy depends on the specific treatment and most guidelines recommend administering vaccines 3–6 months after treatment cessation. Concerning HSCT, the timing of immune recovery is affected by several factors such as the HSCT platform, graft-versus-host disease (GvHD), and infections. Inactivated vaccines are typically administered 3–6 months post-HSCT, while live attenuated vaccines are delayed for at least two years. In children with asplenia or hyposplenism, recommendations focus on immunization against encapsulated bacteria, with tailored schedules based on the patient’s age and underlying condition. This paper explores the biological factors influencing vaccination efficacy and safety in pediatric hematology and oncology patients. It also provides an updated overview of the available evidence and current vaccination guidelines. Finally, this paper highlights the main clinical and research areas for further improvement to provide tailored vaccination schedules for this vulnerable population.

To the Editor: Ataxia telangiectasia (AT) is a rare disorder caused by pathogenic variants in the ataxia telangiectasia-mutated (ATM) gene, characterized by progressive neurological involvement, oculocutaneous telangiectasia, variable degrees of immunodeficiency, radiosensitivity and increased susceptibility to tumors.1 The ATM kinase plays a role in detecting DNA lesions and in regulating the cell cycle progression, and its impairment is responsible for the instability of the genome and radiation sensitivity.2 Immunodeficiency may contribute to neoplasms development, particularly those associated with Epstein–Barr virus (EBV). EBV-associated smooth muscle tumor (EBV-SMT) is a rare mesenchymal tumor that generally occurs in immunocompromised individuals. To our knowledge, a single case report of EBV-SMT (laryngeal leiomyosarcoma) has been reported in the literature in a patient with AT.3 We present the case of a 9-year-old Romanian female from consanguineous parents frequently hospitalized for arthritis and pneumonia confirmed by serial chest radiographs. She was admitted to our hospital at the age of 7, for pneumonia and acute respiratory distress syndrome, displaying bulbar telangiectasias, ataxic gait, failure to thrive, and recurrent infections. Immunological evaluation revealed IgA deficiency, reduced naïve CD4 and CD8 T-cell counts, elevated alpha-fetoprotein, and sustained EBV replication (Table 1). Genetic testing identified a homozygous ATM gene deletion (c.8831_8832del).4-6 Both parents and her brother, diagnosed with acute myeloid leukemia, were heterozygous for this variant. Despite initial improvement with antibiotic prophylaxis and immunoglobulin replacement treatment, the patient continued to experience episodes of pneumonia. Clinical deterioration prompted bronchoalveolar lavage confirmed EBV pneumonia, with other microbiological tests negative. In light of persistent EBV replication, the patient received four weekly doses of rituximab. The radiosensitivity required a cautious approach to imaging. However, a computed tomography (CT) scan, considered essential due to the progressive decline in lung function, showed atelectasis in the lower left lobe and multiple bronchiectasis (Figure 1A). Her respiratory symptoms continued to worsen with frequent need for oxygen therapy despite antibiotic and asthma treatment. Lung ultrasound and magnetic resonance imaging (MRI) performed for follow-up showed fibrosis and dystelectasis in the left lower lobe (Figure 1B), leading to a recommendation for lobectomy. The histology of the removed lobe showed congestion and hepatization with extensive bronchial ectasias. Notably, a 1-cm nodular whitish mass was incidentally found (Figure 1D). Microscopic examination revealed a tumor composed of spindle cells with eosinophilic cytoplasm and oval nuclei, arranged in a fascicular pattern within a sparse stromal collagen matrix and accompanied by a lymphocytic infiltrate (Figure 1E). The surrounding lung parenchyma displayed pronounced congestion and severe inflammation, including bronchial abscesses filled with neutrophils, lymphocytic infiltration, and multiple foci of alveolar hemorrhage. The spindle cells were positive for α-smooth muscle actin (α-SMA) and negative for desmin, CD34, anaplastic lymphoma kinase (ALK, D5F3), and CD21. In situ hybridization for EBV-encoded RNA (EBER) was positive in the tumor cells, displaying nuclear localization (Figure 1F,G). These findings were diagnostic of EBV-SMT. Whole-body MRI showed no metastatic lesions or in situ macroscopic recurrence. Respiratory symptoms improved, although residual bronchiectasis persisted in the basal segments of the left lung (Figure 1C). EBV-SMT is a rare neoplasm associated with immunodeficiency, described in patients infected with human immunodeficiency virus (HIV),7 in the post-transplant setting,8 and in those with congenital immunodeficiency.9 It can manifest at any age, but rarely in pediatric patients with primary immunodeficiency. EBV-SMT typically manifests either as a single mass or multiple nodules often found in the liver, but can occur anywhere in the body.10 Although locally aggressive, metastasis are rarely reported.11 To the best of our knowledge, the literature has documented only a single case of EBV-SMT manifesting as laryngeal leiomyosarcoma in an AT patient.11 The case we present is notable for being an instance of pulmonary EBV-SMT. The differential diagnosis initially included inflammatory myofibroblastic tumor, but the presence of a monotypic T-lymphocyte infiltrate and EBER nuclear positivity suggested EBV-SMT. The pathogenesis of EBV-SMT remains a subject of scientific inquiry. The oncogenic role of EBV is well recognized, particularly in hematological malignancies.12, 13 Both EBV infection and immunodeficiency are critical factors in tumor development. In AT, thymic hypoplasia and restricted T-cell receptor repertoire led to T-cell lymphopenia mainly affecting naive T-cell impairing the control of EBV infection, allowing persistence in B cells. Additionally, the ATM protein is involved in the EBV lytic cycle, promoting its replication. However, the mechanism by which ATM mutation enhances EBV's oncogenic potential remains unclear.14 Finally, the intrinsic predisposition to cancer in AT may contribute to the pathogenesis of EBV-SMT.15 Therapeutic approach for EBV-SMT focuses on restoring T-cell function controlling EBV replication including antiretroviral therapy (ART) in HIV patients or reducing immunosuppression after transplant.9 Surgery is required for organ-compromising tumor masses. Despite the rarity of metastasis in EBV-SMT, strict follow-up is essential for timely intervention.16 Sirolimus, an mTOR-inhibitor, offers a potential therapeutic option, though its efficacy remains debated.17 In our AT patient, the coexistence of immunodeficiency (Table 1), EBV active replication, repeated chest x-rays for recurrent pneumonia, along with cancer predisposition and increased radiosensitivity may have collectively contributed to the cancer pathogenesis. In summary, EBV-SMT should be considered in the differential diagnosis of solid tumors, particularly in patients with primary immunodeficiency such as AT. Prompt diagnosis is crucial, as prognosis can be poor without appropriate treatment. We are grateful to patients and their parents, medical staff, and nurses. The authors declare that they have no conflicts of interest. Italian Ministry of Health with "Current Research funds"

Hypersensitivity reactions represent one of the most common causes of hesitancy for adherence to national vaccination programs. The majority of hypersensitivity reactions after vaccination are mild, and anaphylaxis is reported to be rare, although it remains challenging to estimate the frequency attributed to each single vaccine, either because of the lower number of administered doses of less common vaccines, or the administration of simultaneous vaccine in most of the vaccination programs. Although literature remains scattered, international consensus guides clinicians in identifying patients who might need the administration of vaccines in protected environments due to demonstrated hypersensitivity to vaccine components or adjuvants. Here we provide the current guidance on hypersensitivity reactions to vaccines and on vaccination of children with allergy disorders.

The emergence of vaccinomics and system vaccinology represents a transformative shift in immunization strategies, advocating for personalized vaccines tailored to individual genetic and immunological profiles. Integrating insights from genomics, transcriptomics, proteomics, and immunology, personalized vaccines offer the promise of enhanced efficacy and safety, revolutionizing the field of vaccinology. However, the development of personalized vaccines presents multifaceted challenges, including technical, ethical, economic, and regulatory considerations. Addressing these challenges is essential to ensure equitable access and safety of personalized vaccination strategies. Despite these hurdles, the potential of personalized vaccines to optimize responses and mitigate disease burden underscores the significance of ongoing research and collaboration in advancing precision medicine in immunization.

Children with perinatally acquired HIV (PHIV) have special vaccination needs, as they make suboptimal immune responses. Here, we evaluated safety and immunogenicity of 2 doses of 4 -component group B meningococcal vaccine in antiretroviral therapy-treated children with PHIV and healthy controls (HCs). Assessments included the standard human serum bactericidal antibody (hSBA) assay and measurement of IgG titers against capsular group B Neisseria meningitidis antigens (fHbp, NHBA, NadA). The B cell compartment and vaccine -induced antigen -specific (fHbp + ) B cells were investigated by flow cytometry, and gene expression was investigated by multiplexed real-time PCR. A good safety and immunogenicity profile was shown in both groups; however, PHIV demonstrated a reduced immunogenicity compared with HCs. Additionally, PHIV showed a reduced frequency of fHbp + and an altered B cell subset distribution, with higher fHbp + frequency in activated memory and tissue -like memory B cells. Gene expression analyses on these cells revealed distinct mechanisms between PHIV and HC seroconverters. Overall, these data suggest that PHIV presents a diverse immune signature following vaccination. The impact of such perturbation on long-term maintenance of vaccine -induced immunity should be further evaluated in vulnerable populations, such as people with PHIV.

BACKGROUND:Acute pericarditis/myocarditis is a rare complication of the mRNA-based vaccines and although mostly self-limiting, long-term sequelae remain unclear.METHODS:We enrolled all patients admitted to the emergency department between September 2021 and February 2022 meeting the CDC work case definition, with symptoms onset after mRNA-based COVID-19 vaccine. Alternative virologic causes were excluded. Clinical data, laboratory values, cardiologic evaluation, electrocardiogram (ECG), and echocardiogram (ECHO) were collected on admission, at discharge, and during follow-up in all patients. Cardiac Magnetic Resonance (CMR) was performed only in those with signs consistent with myocarditis.RESULTS:We observed 13 patients (11M and 2F), median age 15 years, affected by acute pericarditis/myocarditis after COVID-19 mRNA vaccination (11 after Comirnaty® and 2 after Spikevax®). Symptoms'onset occurred at a median of 5 days (range, 1 to 41 days) after receiving mRNA vaccine (13 Prizer 2 Moderna): 4 patients (31%) after the 1st dose, 6 (46%) after the 2nd, and 3 (23%) after 3rd dose. Increased levels of high-sensitive troponin T (hsTnT) (median 519,5 ng/mL) and N-terminal-pro hormone BNP (NT-proBNP) (median 268 pg/mL) and pathognomonic ECG and ECHO abnormalities were detected. On admission, 7 of 13 (54%) presented with myopericarditis, 3 (23%) with myocarditis, and 3 (23%) with pericarditis; CMR was performed in 5 patients upon pediatric cardiologist prescription and findings were consistent with myocarditis. At 12 weeks of follow-up, all but one patient (92%), still presenting mild pericardial effusion at ECHO, were asymptomatic with normal hsTnT and NT-proBNP levels and ECG. On CMR 6 of 9 patients showed persistent, although decreased, myocardial injury. Higher hsTnT levels on admission significantly correlated with persistent CMR lesions.CONCLUSION:Evidence of persistent CMR lesions highlights the need for a close and standardized follow-up for those patients who present high hsTnT levels on admission.

Whilst there has been significant public health benefits associated with global use of COVID-19 spike protein vaccines, potential serious adverse events following immunization have been reported. Acute myocarditis is a rare complication of COVID19 vaccines and often it is self-limiting. We describe two cases experiencing recurrent myocarditis following mRNA COVID-19 vaccine despite a prior episode with full clinical recovery. Between September 2021-September 2022 we observed two male adolescents with recurrent myocarditis related to mRNA-based-COVID19 vaccine. During the first episode both patients presented with fever and chest pain few days after their second dose of BNT162b2 mRNA Covid-19 Vaccine (Comirnaty®). The blood exams showed increased cardiac enzymes. In addition, complete viral panel was run, showing HHV7 positivity in a single case. The left ventricular ejection fraction (LVEF) was normal at echocardiogram but cardiac magnetic resonance scanning (CMR) was consistent with myocarditis. They were treated with supportive treatment with full recovery. The 6 months follow-up demonstrated good clinical conditions with normal cardiological findings. The CMR showed persistent lesions in left ventricle ‘s wall with LGE. After some months the patients presented at emergency department with fever and chest pain and increased cardiac enzymes. No decreased LVEF was observed. The CMR showed new focal areas of edema in the first case report and stable lesions in the second one. They reached full recovery with normalization of cardiac enzymes after few days. These case reports outline the need of strict follow-up in patients with CMR consistent with myocarditis after mRNA-based-COVID19 vaccine. More efforts are necessary to depict the underlying mechanisms of myocarditis after SARS-CoV2 vaccination to understand the risk of relapsing and the long-term sequelae.

Severe acute respiratory syndrome coronavirus 2 infection in children with autoimmune neutropenia may be a cause for concern. In this retrospective study, none of the 24 autoimmune neutropenia cases manifested severe coronavirus disease 2019. We found a significant improvement in neutrophils and a reduction in lymphocytes at post-infection follow-up compared with the median of previous values. We speculate that this paradoxical effect may be due to postinfection immunological phenomena.