Evaluating patient immunocompetence through antibody response to pneumococcal polysaccharide vaccine using a newly developed 23 serotype multiplexed assay.

Assessing T-cell independent antibody response to polysaccharide vaccines is crucial for diagnosing humoral immune deficiencies. However, immunocompetence criteria based on S. pneumoniae vaccination remain unclear. We evaluated IgG antibody vaccine response in healthy individuals to establish interpretive criteria. Pre- and 4-week post-vaccination sera were collected from 79 adults. Antibody concentrations to PNEUMOVAX 23 serotypes were measured using a multiplexed platform. Immunocompetence was determined by fold increase in post-vaccination response, percentage of serotypes achieving 4- or 2-fold antibody ratio, and post-vaccination concentration ≥ 1.3 µg/mL. Immunogenicity varied widely across the 23 serotypes (26.6% to 94.9% for ≥4-fold increase, 51.9% to 98.7% for ≥2-fold increase). Immunocompetence based on historic criteria of ≥4-fold increase in antibody ratio to ≥70% of serotypes was low (72.2%), but increased to 98.7% with criteria of at least a 2-fold increase and/or post-vaccination concentration ≥ 1.3 µg/mL. Current criteria for assessing immunocompetence may be overly stringent and require updating.

Immunogenicity of COVID-19 adsorbed inactivated vaccine (CoronaVac) and additional doses of mRNA BNT162b2 vaccine in immunocompromised adults compared with immunocompetent persons.

Inactivated COVID-19 vaccines data in immunocompromised individuals are scarce. This trial assessed the immunogenicity of two CoronaVac doses and additional BNT162b2 mRNA vaccine doses in immunocompromised (IC) and immunocompetent (H) individuals. Adults with solid organ transplant (SOT), hematopoietic stem cell transplant, cancer, inborn immunity errors or rheumatic diseases were included in the IC group. Immunocompetent adults were used as control group for comparison. Participants received two CoronaVac doses within a 28-day interval. IC received two additional BNT162b2 doses and H received a third BNT162b2 dose (booster). Blood samples were collected at baseline, 28 days after each dose, pre-booster and at the trial end. We used three serological tests to detect antibodies to SARS-CoV-2 nucleocapsid (N), trimeric spike (S), and receptor binding domain (RBD). Outcomes included seroconversion rates (SCR), geometric mean titers (GMT) and GMT ratio (GMTR). A total of 241 IC and 100 H adults participated in the study. After two CoronaVac doses, IC had lower SCR than H: anti-N, 33.3% vs 79%; anti-S, 33.8% vs 86%, and anti-RBD, 48.5% vs 85%, respectively. IC also showed lower GMT than H: anti-N, 2.3 vs 15.1; anti-S, 58.8 vs 213.2 BAU/mL; and anti-RBD, 22.4 vs 168.0 U/mL, respectively. After the 3rd and 4th BNT162b2 doses, IC had significant anti-S and anti-RBD seroconversion, but still lower than H after the 3rd dose. After boosting, GMT increased in IC, but remained lower than in the H group. CoronaVac two-dose schedule immunogenicity was lower in IC than in H. BNT162b2 heterologous booster enhanced immune response in both groups.

Perturbations of the T-cell receptor repertoire in response to SARS-CoV-2 in immunocompetent and immunocompromised individuals.

BACKGROUND: Functional T-cell responses are essential for virus clearance and long-term protection after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, whereas certain clinical factors, such as older age and immunocompromise, are associated with worse outcome. OBJECTIVE: We sought to study the breadth and magnitude of T-cell responses in patients with coronavirus disease 2019 (COVID-19) and in individuals with inborn errors of immunity (IEIs) who had received COVID-19 mRNA vaccine. METHODS: Using high-throughput sequencing and bioinformatics tools to characterize the T-cell receptor ß repertoire signatures in 540 individuals after SARS-CoV-2 infection, 31 IEI recipients of COVID-19 mRNA vaccine, and healthy controls, we quantified HLA class I- and class II-restricted SARS-CoV-2-specific responses and also identified several HLA allele-clonotype motif associations in patients with COVID-19, including a subcohort of anti-type 1 interferon (IFN-1)-positive patients. RESULTS: Our analysis revealed that elderly patients with COVID-19 with critical disease manifested lower SARS-CoV-2 T-cell clonotype diversity as well as T-cell responses with reduced magnitude, whereas the SARS-CoV-2-specific clonotypes targeted a broad range of HLA class I- and class II-restricted epitopes across the viral proteome. The presence of anti-IFN-I antibodies was associated with certain HLA alleles. Finally, COVID-19 mRNA immunization induced an increase in the breadth of SARS-CoV-2-specific clonotypes in patients with IEIs, including those who had failed to seroconvert. CONCLUSIONS: Elderly individuals have impaired capacity to develop broad and sustained T-cell responses after SARS-CoV-2 infection. Genetic factors may play a role in the production of anti-IFN-1 antibodies. COVID-19 mRNA vaccines are effective in inducing T-cell responses in patients with IEIs.

Zika virus baculovirus-expressed envelope protein elicited humoral and cellular immunity in immunocompetent mice.

Zika virus (ZIKV) is a mosquito-borne virus that has a high risk of inducing Guillain-Barré syndrome and microcephaly in newborns. Because vaccination is considered the most effective strategy against ZIKV infection, we designed a recombinant vaccine utilizing the baculovirus expression system with two strains of ZIKV envelope protein (MR766, Env_M; ZBRX6, Env_Z). Animals inoculated with Env_M and Env_Z produced ZIKV-specific antibodies and secreted effector cytokines such as interferon-γ, tumor necrosis factor-α, and interleukin-12. Moreover, the progeny of immunized females had detectable maternal antibodies that protected them against two ZIKV strains (MR766 and PRVABC59) and a Dengue virus strain. We propose that the baculovirus expression system ZIKV envelope protein recombinant provides a safe and effective vaccine strategy.

Can early measles vaccination control both measles and respiratory syncytial virus infections?

Measles virus and respiratory syncytial virus (RSV) are two important global health pathogens causing substantial morbidity and mortality worldwide. The current measles vaccination schedule has the first dose given at 9-12 months of age and the second dose given at 15-18 months of age. Measles outbreaks have been associated with an increase in severe RSV infections in children younger than 6 months, probably as a result of measles-induced immunosuppression. A resurgence in measles cases was already occurring before the COVID-19 pandemic, which has affected global immunisation programmes, resulting in millions of children, mostly in low-income and middle-income countries (LMICs), missing out on their measles vaccine. This will leave many children living in the most vulnerable of circumstances highly susceptible to measles and RSV infections when current COVID-19 public health control measures are lifted. This Viewpoint discusses these issues and highlights the need for urgent action to address this looming crisis. The use of early measles vaccination at 4 months of age could be an effective strategy to prevent severe morbidity and death from both measles and RSV infections in many LMICs.

Tumour DDR1 promotes collagen fibre alignment to instigate immune exclusion.

Immune exclusion predicts poor patient outcomes in multiple malignancies, including triple-negative breast cancer (TNBC)1. The extracellular matrix (ECM) contributes to immune exclusion2. However, strategies to reduce ECM abundance are largely ineffective or generate undesired outcomes3,4. Here we show that discoidin domain receptor 1 (DDR1), a collagen receptor with tyrosine kinase activity5, instigates immune exclusion by promoting collagen fibre alignment. Ablation of Ddr1 in tumours promotes the intratumoral penetration of T cells and obliterates tumour growth in mouse models of TNBC. Supporting this finding, in human TNBC the expression of DDR1 negatively correlates with the intratumoral abundance of anti-tumour T cells. The DDR1 extracellular domain (DDR1-ECD), but not its intracellular kinase domain, is required for immune exclusion. Membrane-untethered DDR1-ECD is sufficient to rescue the growth of Ddr1-knockout tumours in immunocompetent hosts. Mechanistically, the binding of DDR1-ECD to collagen enforces aligned collagen fibres and obstructs immune infiltration. ECD-neutralizing antibodies disrupt collagen fibre alignment, mitigate immune exclusion and inhibit tumour growth in immunocompetent hosts. Together, our findings identify a mechanism for immune exclusion and suggest an immunotherapeutic target for increasing immune accessibility through reconfiguration of the tumour ECM.

Regnase-1 suppresses TCF-1+ precursor exhausted T-cell formation to limit CAR-T-cell responses against ALL.

Chimeric antigen receptor (CAR)-T-cell therapeutic efficacy is associated with long-term T-cell persistence and acquisition of memory. Memory-subset formation requires T-cell factor 1 (TCF-1), a master transcription factor for which few regulators have been identified. Here, we demonstrate using an immune-competent mouse model of B-cell acute lymphoblastic leukemia (ALL; B-ALL) that Regnase-1 deficiency promotes TCF-1 expression to enhance CAR-T-cell expansion and memory-like cell formation. This leads to improved CAR-T-mediated tumor clearance, sustained remissions, and protection against secondary tumor challenge. Phenotypic, transcriptional, and epigenetic profiling identified increased tumor-dependent programming of Regnase-1-deficient CAR-T cells into TCF-1+ precursor exhausted T cells (TPEX) characterized by upregulation of both memory and exhaustion markers. Regnase-1 directly targets Tcf7 messenger RNA (mRNA); its deficiency augments TCF-1 expression leading to the formation of TPEX that support long-term CAR-T-cell persistence and function. Regnase-1 deficiency also reduces exhaustion and enhances the activity of TCF-1- CAR-T cells. We further validate these findings in human CAR-T cells, where Regnase-1 deficiency mediates enhanced tumor clearance in a xenograft B-ALL model. This is associated with increased persistence and expansion of a TCF-1+ CAR-T-cell population. Our findings demonstrate the pivotal roles of TPEX, Regnase-1, and TCF-1 in mediating CAR-T-cell persistence and recall responses, and identify Regnase-1 as a modulator of human CAR-T-cell longevity and potency that may be manipulated for improved therapeutic efficacy.

Oligodeoxynucleotides containing unmethylated cytosine-guanine motifs are effective immunostimulants against pneumococcal meningitis in the immunocompetent and neutropenic host.

BACKGROUND: Bacterial meningitis is a fatal disease with a mortality up to 30% and neurological sequelae in one fourth of survivors. Available vaccines do not fully protect against this lethal disease. Here, we report the protective effect of synthetic oligodeoxynucleotides containing unmethylated cytosine-guanine motifs (CpG ODN) against the most frequent form of bacterial meningitis caused by Streptococcus pneumoniae. METHODS: Three days prior to the induction of meningitis by intracerebral injection of S. pneumoniae D39, wild-type and Toll-like receptor (TLR9)-/- mice received an intraperitoneal injection of 100 µg CpG ODN or vehicle. To render mice neutropenic, anti-Ly-6G monoclonal antibody was daily administrated starting 4 days before infection with a total of 7 injections. Kaplan-Meier survival analyses and bacteriological studies, in which mice were sacrificed 24 h and 36 h after infection, were performed. RESULTS: Pre-treatment with 100 µg CpG ODN prolonged survival of immunocompetent and neutropenic wild-type mice but not of TLR9-/- mice. There was a trend towards lower mortality in CpG ODN-treated immunocompetent and neutropenic wild-type mice. CpG ODN caused an increase of IL-12/IL-23p40 levels in the spleen and serum in uninfected animals. The effects of CpG ODN on bacterial concentrations and development of clinical symptoms were associated with an increased number of microglia in the CNS during the early phase of infection. Elevated concentrations of IL-12/IL-23p40 and MIP-1α correlated with lower bacterial concentrations in the blood and spleen during infection. CONCLUSIONS: Pre-conditioning with CpG ODN strengthened the resistance of neutropenic and immunocompetent mice against S. pneumoniae meningitis in the presence of TLR9. Administration of CpG ODN decreased bacterial burden in the cerebellum and reduced the degree of bacteremia. Systemic administration of CpG ODN may help to prevent or slow the progression to sepsis of bacterial CNS infections in healthy and immunocompromised individuals even after direct inoculation of bacteria into the intracranial compartments, which can occur after sinusitis, mastoiditis, open head trauma, and surgery, including placement of an external ventricular drain.

Doctor-Should I get the COVID-19 vaccine? Infection and immunization in individuals with neuromuscular disorders.

The clinical course of neuromuscular disorders (NMDs) can be affected by infections, both in immunocompetent individuals, and in those with reduced immunocompetence due to immunosuppressive/immunomodulating therapies. Infections and immunizations may also trigger NMDs. There is a potential for reduced efficacy of immunizations in patients with reduced immunocompetence. The recent vaccination program for coronavirus disease-2019 (COVID-19) raises several questions regarding the safety and efficacy of this vaccine in individuals with NMDs. In this Practice Topic article, we address the role of vaccine-preventable infections in NMDs and the safety and efficacy of immunization in individuals with NMDs, with emphasis on vaccination against COVID-19.

Of onions and men: Report of cavitary community acquired pneumonia due to Burkholderia cepacia complex in an immunocompetent patient and review of the literature.

Burkholderia cepacia complex consists of highly antibiotic resistant gram negative bacilli that are plant symbionts and also potential agents of human infection.  This bacterial family's claim to fame in clinical medicine is as the scourge of cystic fibrosis patients, in whom it is a notorious respiratory pathogen.  Outside of cystic fibrosis, it rarely comes to mind as an etiology of community acquired pneumonia with or without lung cavitation in immunocompetent hosts.  We describe a case of an otherwise healthy, community-dwelling man who presented with subacute cavitary lung disease, the causative organism of which turned out to be Burkholderia cepacia complex.  Our report is accompanied by a review of the literature, which identified an additional eleven cases in the same category.  We analyze all of the available cases for the emergence of any identifiable patterns or peculiarities.

Obesity and COVID-19: A Perspective from the European Association for the Study of Obesity on Immunological Perturbations, Therapeutic Challenges, and Opportunities in Obesity.

Accumulating evidence suggests that obesity is a major risk factor for the initiation, progression, and outcomes of coronavirus disease 2019 (COVID-19). The European Association for the Study of Obesity (EASO), as a scientific and medical society dedicated to the promotion of health and well-being, is greatly concerned about the concomitant obesity and COVID-19 pandemics and their impact on health and society at large. In this perspective, we will address the inherent immunological perturbations and alterations in the renin-angiotensin-aldosterone system in patients with obesity and COVID-19, and discuss how these impairments may underlie the increased susceptibility and more detrimental outcomes of COVID-19 in people with obesity. Clearly, this has important implications for preventive measures, vaccination, and future therapeutic strategies to combat COVID-19. Furthermore, we will highlight important knowledge gaps and provide suggestions for future research and recommendations for policy actions. Since many new reports on COVID-19 rapidly appear, the present perspective should be seen as a focus for discussion to drive forward further understanding, research initiatives, and clinical management of COVID-19.

MECHANISMS IN ENDOCRINOLOGY: Vitamin D and COVID-19.

The SARS-CoV-2 virus responsible for the COVID-19 pandemic has generated an explosion of interest both in the mechanisms of infection leading to dissemination and expression of this disease, and in potential risk factors that may have a mechanistic basis for disease propagation or control. Vitamin D has emerged as a factor that may be involved in these two areas. The focus of this article is to apply our current understanding of vitamin D as a facilitator of immunocompetence both with regard to innate and adaptive immunity and to consider how this may relate to COVID-19 disease. There are also intriguing potential links to vitamin D as a factor in the cytokine storm that portends some of the most serious consequences of SARS-CoV-2 infection, such as the acute respiratory distress syndrome. Moreover, cardiac and coagulopathic features of COVID-19 disease deserve attention as they may also be related to vitamin D. Finally, we review the current clinical data associating vitamin D with SARS-CoV-2 infection, a putative clinical link that at this time must still be considered hypothetical.

Varicella Vaccine Meningitis as a Complication of Herpes Zoster in Twice-Immunized Immunocompetent Adolescents.

Varicella-zoster virus vaccination is recommended for virtually all young children in the United States, Canada, and several other countries. Varicella vaccine is a live attenuated virus that retains some of its neurotropic properties. Herpes zoster caused by vaccine virus still occurs in immunized children, although the rate is much lower than in children who had wild-type varicella. It was commonly thought that 2 varicella vaccinations would protect children against the most serious complication of meningitis following herpes zoster; however, 2 meningitis cases have already been published. We now report a third case of varicella vaccine meningitis and define risk factors shared by all 3 immunized adolescents. The diagnosis in cerebrospinal fluid in this third case was verified by amplifying and sequencing portions of the viral genome, to document fixed alleles found only in the vaccine strain. Viral antibody was also detected in the cerebrospinal fluid by confocal microscopy. When compared with the other 2 cases, remarkably all 3 were 14 years old when meningitis occurred. All 3 were treated with intravenous acyclovir, with complete recovery. The adolescent in our case report also had recurrent asthma, which was treated with both prednisone tablets and beclomethasone inhaler before onset of meningitis. When the 3 cases were considered together, they suggested that immunity to varicella-zoster virus may be waning sufficiently in some twice-immunized adolescents to make them vulnerable to varicella vaccine virus reactivation and subsequent meningitis. This complication rarely happens in children after wild-type varicella.

Non-congenital viral infections of the central nervous system: from the immunocompetent to the immunocompromised child.

Non-congenital viral infections of the central nervous system in children can represent a severe clinical condition that needs a prompt diagnosis and management. However, the aetiological diagnosis can be challenging because symptoms are often nonspecific and cerebrospinal fluid analysis is not always diagnostic. In this context, neuroimaging represents a helpful tool, even though radiologic patterns sometimes overlap. The purpose of this pictorial essay is to suggest a schematic representation of different radiologic patterns of non-congenital viral encephalomyelitis based on the predominant viral tropism and vulnerability of specific regions: cortical grey matter, deep grey matter, white matter, brainstem, cerebellum and spine.

Zigomicosis y síndrome hemofagocítico en un paciente inmunocompetente: informe de caso / Zygomycosis and hemophagocytic lymphohistiocytosis in an immunocompetent patient: a case report

Introducción: la zigomicosis es una infección fúngica poco frecuente, con alta tasa de mortalidad y de mal pronóstico. Afecta principalmente a pacientes inmunocomprometidos. La asociación con el síndrome hemofagocítico es extremadamente inusual, más aún en pacientes inmunocompetentes, con pocos ejemplos registrados en la literatura. Caso clínico: se presenta el caso de un paciente masculino inmunocompetente de 40 años con diagnóstico de mucormicosis y síndrome hemofagocítico que evoluciona desfavorablemente, con fallo multiorgánico, a pesar de los esfuerzos médicos. Conclusión: la asociación de mucormicosis con síndrome hemofagocítico en un paciente inmunocompetente es extremadamente rara; existen pocos casos informados en Latinoamérica. Debemos tener presente esta asociación, ya que requiere un tratamiento agresivo y soporte vital avanzado. (AU)

Introduction: zygomycosis is a rare fungal infection that carries with high mortality rates. This poor prognosis, rapidly progressive infection mainly affects immunocompromised patients. The association with hemophagocytic lymphohistiocytosis is extremely unusual, even more in immunocompetent patients, with few cases reported. Case: we present the case of an immunocompetent male patient who was diagnosed with zygomycosis and hemophagocytic lymphohistiocytosis. Despite medical efforts he developed multiorganic failure. Conclusion: the association of mucormycosis with hemophagocytic lymphohistiocytosis in an immunocompetent patient is exceptional with few cases reported in Latin America. We must always suspect this association considering they require aggressive treatment and advanced life support. (AU)

Tuberculous splenic abscess in the immunocompetent host: a report and review of literature.

Tubercular splenic abscess is rare, particularly in immunocompetent patients. Diagnostic difficulties usually arise in patients with tubercular splenic abscess because of its non-specific presentation. We report an elderly male who presented with cough and fever and had pulmonary infiltrates suspicious of tuberculosis. Bronchoalveolar lavage microbiology including XpertMTB/Rif assay was non-contributory. Contrast enhanced computed tomography scan of abdomen revealed multiple non-enhancing lesions in the spleen. Ultrasound guided splenic aspirate revealed pus that was positive for Mycobacterium tuberculosis in XpertMTB/Rif assay confirming the diagnosis of tuberculosis.

Immune-competent in vitro co-culture models as an approach for skin sensitisation assessment.

There is a complex interplay between numerous cell types that act at different steps of the mechanism leading to allergic contact dermatitis. The validated in vitro methods for skin sensitisation assessment provide good statistical correspondence to local lymph node assay (LLNA) or to human data but, for the most part, poorly represent the actual in vivo situation as they generally involve single cell type culture in 2D. Significant progress has been made over the past decades to develop new technologies of data generation concurrently with novel approaches to improve the models especially by the use of co-culture. The importance of heterotypic cell-cell interactions in the in vitro assessment of skin sensitisation should not be overlooked. This review addresses the technical aspects to take into consideration when co-culturing depending on the desired objective and describes the different keratinocytes and dendritic cells co-cultures developed in 2D and 3D. To date, from a regulatory point of view, no alternative method to animal testing for skin sensitisation potential assessment using a keratinocytes and dendritic cells co-culture model is yet proposed. This review also presents several directions of further development.

[Pulmonary Aspergillosis in immunocompetent patient]. / Aspergillose pulmonaire chez le patient immunocompétent.

Aspergillus is a group of molds which is found everywhere worldwide, exposition of human being is common. Most of immunocompetent people do not develop disease caused by Aspergillus. However, diseases in different forms may occur in certain conditions in immunocompetent patient. These diseases include hypersensitivity reactions, like allergic broncho-pulmonary aspergillosis, or infectious process like chronic pulmonary aspergillosis or invasive pulmonary aspergillosis. This article reviewed the clinical features of these diseases and the current available diagnostic techniques.

Aspergillus englobe un groupe de champignons ubiquitaires auquels l'être humain est quotidiennement exposé. Il est rarement pathogène chez le patient immunocompétent, cependant il peut être responsable de différentes formes de maladies dans certaines conditions. Ces pathologies comprennent des réactions d'hypersensibilité, comme l'aspergillose bronchopulmonaire allergique, ou des processus infectieux comme l'aspergillose pulmonaire chronique et l'aspergillose pulmonaire invasive aiguë. Cet article aborde les situations cliniques lors desquelles ces pathologies doivent être suspectées, tout en décrivant les caractéristiques de ces dernières et les moyens diagnostiques à disposition.